Last updated on October 30th, 2024 at 02:15 am
Title 21—Food and Drugs–Volume 6
CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED)
SUBCHAPTER E—ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS
PART 500—GENERAL
Subpart A [Reserved]
Subpart B—Specific Administrative Rulings and Decisions
§ 500.23 Thermally processed low-acid foods packaged in hermetically sealed containers.
Except as provided in § 507.5(b) of this chapter, the provisions of parts 507 and 113 of this chapter apply to the manufacturing, processing, or packing of low-acid foods in hermetically sealed containers, and intended for use as food for animals.
§ 500.24 Emergency permit control.
The provisions of part 108 of this chapter shall apply to the issuance of emergency control permits for the manufacturer or packer of thermally processed low-acid foods packaged in hermetically sealed containers, and intended for use as food for animals.
§ 500.25 Anthelmintic drugs for use in animals.
(a) The Commissioner of Food and Drugs has determined that, in order to assure that anthelmintic drugs, including animal feeds bearing or containing such drugs, which do not carry the prescription statement are labeled to provide adequate directions for their effective use, labeling of these anthelmintic drugs shall bear, in addition to other required information, a statement that a veterinarian should be consulted for assistance in the diagnosis, treatment, and control of parasitism.
(b) The label and any labeling furnishing or purporting to furnish directions for use, shall bear conspicuously the following statement: “Consult your veterinarian for assistance in the diagnosis, treatment, and control of parasitism.”
(c) For drugs covered by approved new animal drug applications, the labeling revisions required for compliance with this section may be placed into effect without prior approval, as provided for in § 514.8(c)(3) of this chapter. For drugs listed in the index, the labeling revisions required for compliance with this section may be placed into effect without prior granting of a request for a modification, as provided for in § 516.161(b)(1) of this chapter.
(d) Labeling revisions required for compliance with this section shall be placed into effect by February 25, 1975, following which, any such drugs that are introduced into interstate commerce and not in compliance with this section will be subject to regulatory proceedings.
§ 500.26 Timed-release dosage form drugs.
(a) Drugs are being offered in dosage forms that are designed to release the active ingredients over a prolonged period of time. There is a possibility of unsafe overdosage or ineffective dosage if such products are improperly made and the active ingredients are released at one time, over too short or too long a period of time, or not released at all. Drugs marketed in this form, which are referred to by such terms as timed-release, controlled-release, prolonged-release, sustained-release, or delayed-release drugs, are regarded as new animal drugs within the meaning of section 201(v) of the Federal Food, Drug, and Cosmetic Act.
(b) Timed-release dosage form animal drugs that are introduced into interstate commerce are deemed to be adulterated within the meaning of section 501(a)(5) of the act and subject to regulatory action, unless such animal drug is the subject of an approved new animal drug application, or listed in the index, as required by paragraph (a) of this section.
(c) The fact that the labeling of this kind of drug may claim delayed, prolonged, controlled, or sustained-release of all or only some of the active ingredients does not affect the new animal drug status of such articles. A new animal drug application or index listing is required in any such case.
(d) New animal drug applications for timed-release dosage form animal drugs must contain, among other things, data to demonstrate safety and effectiveness by establishing that the article is manufactured using procedures and controls to ensure release of the total dosage at a safe and effective rate. Data submitted in the new animal drug application must demonstrate that the formulation of the drug and the procedures used in its manufacture will ensure release of the active ingredient(s) of the drug at a safe and effective rate and that these release characteristics will be maintained until the expiration date of the drug. When the drug is intended for use in food-producing animals, data submitted must also demonstrate that, with respect to possible residues of the drug, food derived from treated animals is safe for consumption.
§ 500.27 Methylene blue-containing drugs for use in animals.
(a) New information requires a re- evaluation of the status of drugs containing methylene blue (tetramethylthionine chloride) for oral use in cats or dogs.
(1)(i) It has been demonstrated that two orally administered urinary antiseptic-antispasmodic preparations that contained methylene blue cause Heinz body hemolytic anemia in cats when used according to label directions. The specific cause of the reaction was determined to be the methylene blue contained in the preparations. The reaction can be severe enough to cause death of treated animals.
(ii) The Heinz body hemolytic anemia reaction to methylene blue has also been demonstrated in dogs under laboratory conditions. The precise mechanism by which methylene blue produces the characteristic erythrocytic inclusion bodies (Heinz bodies) and associated hemolytic anemia is unclear.
(2) The effectiveness of orally administered methylene blue as a urinary antiseptic is open to question. It appears that following oral administration, methylene blue is poorly and erratically absorbed and also slowly and erratically excreted in the urine. Studies in the dog indicate it is excreted in the urine essentially as leukomethylene blue stabilized in some manner. Methylene blue itself is stepwise demethylated in alkaline solutions (alkaline urine being a frequent consequence of urinary infection) to Azure B, Azure A, and Azure C. The antiseptic efficacy of all of these excretion products is unsubstantiated.
(3) In view of the foregoing, the Commissioner has concluded that animal drugs containing methylene blue for oral use in cats or dogs are neither safe nor generally recognized as effective within the meaning of section 201(v) of the act and are therefore considered new animal drugs. Accordingly, all prior formal and informal opinions expressed by the Food and Drug Administration that such drugs are “not new drugs” or “no longer new drugs” are hereby revoked.
(b) Animal drugs that contain methylene blue for oral use in cats or dogs and not the subject of an approved new animal drug application (NADA) are deemed to be adulterated under the provisions of section 501(a) (5) and/or (6) and/or misbranded under section 502(a) of the act and subject to regulatory action as of April 10, 1978.
(c) Sponsors of animal drugs that contain methylene blue for oral use in cats or dogs and not the subject of an approved new animal drug application (NADA) may submit an application in conformity with § 514.1 of this chapter. Such applications will be processed in accordance with section 512 of the act. Submission of an NADA will not constitute grounds for continued marketing of this drug substance until such application is approved.
(d) New animal drug applications required by this regulation pursuant to section 512 of the act shall be submitted to the Food and Drug Administration. Center for Veterinary Medicine, Office of New Animal Drug Evaluation (HFV-100), 7500 Standish Pl., Rockville, MD 20855.
§ 500.29 Gentian violet for use in animal feed.
The Food and Drug Administration has determined that gentian violet is not generally recognized as safe for use in animal feed and is a food additive subject to section 409 of the Federal Food, Drug, and Cosmetic Act (the act), unless it is intended for use as a new animal drug, in which case it is subject to section 512 of the act. The Food and Drug Administration has determined that gentian violet is not prior sanctioned for any use in animal feed.
§ 500.30 Gentian violet for animal drug use.
The Food and Drug Administration (FDA) has determined that gentian violet is not generally recognized as safe and effective for any veterinary drug use in food animals and is a new animal drug subject to section 512 of the Federal Food, Drug, and Cosmetic Act. FDA has determined that gentian violet is not exempted from new animal drug status under the “grandfather” provisions of the Drug Amendments of 1962 (21 U.S.C. 342).
§ 500.45 Use of polychlorinated biphenyls (PCB’s) in the production, handling, and storage of animal feed.
(a) Polychlorinated biphenyls (PCB’s) represent a class of toxic industrial chemicals manufactured and sold under a variety of trade names, including: Aroclor (United States); Phenoclor (France); Colphen (Germany); and Kanaclor (Japan). PCB’s are highly stable, heat resistant, and nonflammable chemicals. Industrial uses of PCB’s include, or did include in the past, their use as electrical transformer and capacitor fluids, heat transfer fluids, hydraulic fluids, plasticizers, and in formulations of lubricants, coatings, and inks. Their unique physical and chemical properties and widespread, uncontrolled industrial applications have caused PCB’s to be a persistent and ubiquitous contaminant in the environment, causing the contamination of certain foods. In addition, incidents have occurred in which PCB’s have directly contaminated animal feeds as a result of industrial accidents (leakage or spillage of PCB fluids from plant equipment). These accidents in turn cause the contamination of food intended for human consumption (meat, milk, and eggs). Investigations by the Food and Drug Administration have revealed that heat exchange fluids for certain pasteurization equipment used in processing animal feed contain PCB’s. Although heat exchange fluids in such equipment are considered to be in closed systems, leakage has occurred that resulted in direct contamination of animal feed with PCB’s and subsequently resulted in the transfer of PCB’s to human food produced by animals consuming the contaminated feed. The use of PCB-containing coatings on the inner walls of silos has resulted in the contamination of silage which has in turn caused PCB residues in the milk of dairy cows consuming the contaminated silage. Since PCB’s are toxic chemicals, the PCB contamination of food as a result of these and other incidents represent a hazard to public health. It is therefore necessary to place certain restrictions on the industrial uses of PCB’s in the production, handling, and storage of animal feed.
(b) The following special provisions are necessary to preclude accidental PCB contamination of animal feed:
(1) Coatings or paints for use on the contact surfaces of feed storage areas may not contain PCB’s or any other harmful or deleterious substances likely to contaminate feed.
(2) New equipment or machinery for handling or processing feed in or around an establishment producing animal feed shall not contain PCB’s.
(3) On or before Sept. 4, 1973, the management of establishments producing animal feed shall:
(i) Have the heat exchange fluid used in existing equipment or machinery for handling and processing feed sampled and tested to determine whether it contains PCB’s, or verify the absence of PCB’s in such formulations by other appropriate means. On or before Sept. 4, 1973, any such fluid formulated with PCB’s must to the fullest extent possible commensurate with current good manufacturing practices, be replaced with a heat exchange fluid that does not contain PCB’s.
(ii) Eliminate to the fullest extent possible commensurate with current good manufacturing practices from the animal feed producing establishment any PCB-containing lubricants for equipment or machinery used for handling or processing animal feed.
(iii) Eliminate to the fullest extent possible commensurate with current good manufacturing practices from the animal feed producing establishment any other PCB-containing materials, whenever there is a reasonable expectation that such materials could cause animal feed to become contaminated with PCB’s either as a result of normal use or as a result of accident, breakage, or other mishap.
(iv) The toxicity and other characteristics of fluids selected as PCB replacements must be adequately determined so that the least potentially hazardous replacement should be used. In making this determination with respect to a given fluid, consideration should be given to (a) its toxicity; (b) the maximum quantity that could be spilled onto a given quantity of food before it would be noticed, taking into account its color and odor; (c) possible signaling devices in the equipment to indicate a loss of fluid, etc.; (d) and its environmental stability and tendency to survive and be concentrated through the food chain. The judgment as to whether a replacement fluid is sufficiently non-hazardous is to be made on an individual installation and operation basis.
(c) For the purpose of this section, the provisions do not apply to electrical transformers and condensers containing PCB’s in sealed containers.
(d) For the purpose of this section, the term animal feed includes all articles used for food or drink for animals other than man.
§ 500.46 Hexachlorophene in animal drugs.
(a) The Commissioner of Food and Drugs has determined that there are no adequate data to establish that animal drugs containing hexachlorophene are safe and effective for any animal use other than in topical products for use on non-food-producing animals as part of a product preservative system at a level not to exceed 0.1 percent; that there is no information on the potential risk to humans from exposure to hexachlorophene by persons who apply animal products containing the drug at levels higher than 0.1 percent; and that there is likewise no information on human exposure to animals on which these animal drugs have been used and no information on possible residues of hexachlorophene in edible products of food-producing animals treated with new animal drugs that contain any quantity of hexachlorophene.
(b) Animal drugs containing hexachlorophene for other than preservative use on non-food-producing animals at levels not exceeding 0.1 percent are considered new animal drugs and shall be the subject of new animal drug applications (NADA’s).
(c) Any person currently marketing animal drugs that contain hexachlorophene other than as part of a product preservative system for products used on non-food-producing animals at a level not exceeding 0.1 percent shall submit a new animal drug application, supplement an existing application, or reformulate the product by September 29, 1977. Each application or supplemental application shall include adequate data to establish that the animal drug is safe and effective. If the animal drug is currently subject to an approved new animal drug application, each reformulation shall require an approved supplemental application. The interim marketing of these animal drugs may continue until the application has been approved, until it has been determined that the application is not approvable under the provisions of § 514.111 of this chapter, or until an existing approved application has been withdrawn.
(d) After September 29, 1977, animal drugs that contain hexachlorophene other than for preservative use on non-food-producing animals at a level not exceeding 0.1 percent that are introduced into interstate commerce shall be deemed to be adulterated within the meaning of section 501(a)(5) of the act (21 U.S.C. 351(a)(5)) unless such animal drug is the subject of a new animal drug application submitted pursuant to paragraph (c) of this section. Action to withdraw approval of new animal drug applications will be initiated if supplemental new animal drug applications have not been submitted in accordance with this section.
(e) New animal drug applications submitted for animal drugs containing hexachlorophene for use in or on food-producing animals shall include adequate data to assure that edible products from treated animals are safe for human consumption under the labeled conditions of use.
§ 500.50 Propylene glycol in or on cat food.
The Food and Drug Administration has determined that propylene glycol in or on cat food is not generally recognized as safe and is a food additive subject to section 409 of the Federal Food, Drug, and Cosmetic Act (the act). The Food and Drug Administration also has determined that this use of propylene glycol is not prior sanctioned.
Subpart C—Animal Drug Labeling Requirements
§ 500.51 Labeling of animal drugs; misbranding.
(a) Among the representations on the label or labeling of an animal drug which will render the drug misbranded are any broad statements suggesting or implying that the drug is not safe and effective for use when used in accordance with labeling direction, or suggesting or implying that the labeling does not contain adequate warnings or adequate directions for use. Such statements include, but are not limited to:
(1) Any statement that disclaims liability when the drug is used in accordance with directions for use contained on the label or labeling.
(2) Any statement that disclaims liability when the drug is used under “abnormal” or “unforeseeable” conditions.
(3) Any statement limiting the warranty for the products to a warranty that the drug in the package contains the ingredients listed on the label.
(b) This regulation is not intended to prohibit any liability disclaimer that purports to limit the amount of damages or that sets forth the legal theory under which damages are to be recovered.
(c) Any person wishing to obtain an evaluation of an animal drug liability disclaimer under this regulation may submit it to Division of Compliance, (HFV-230), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. A supplemental NADA providing appropriately revised labeling shall be submitted for any approved new animal drug the labeling of which is not in compliance with this regulation.
§ 500.52 Use of terms such as “tonic”, “tone”, “toner”, or “conditioner” in the labeling of preparations intended for use in or on animals.
(a) The use of terms such as tonic, tone, toner, and similar terms in the labeling of a product intended for use in or on animals implies that such product is capable of a therapeutic effect(s) and causes such a product to be a drug within the meaning of section 201(g) of the Federal Food, Drug, and Cosmetic Act. The unqualified use of such terms in a product’s labeling fails to provide adequate directions and indications for use of such product and causes it to be misbranded within the meaning of section 502(a) and (f)(1) of the act. The terms tonic, tone, toner, and similar terms may be used in labeling only when appropriately qualified so as to fully inform the user regarding the intended use(s) of the product.
(b) The unqualified use of the term conditioner and similar terms in the labeling of a product intended for use in or on animals implies that such product is capable of a therapeutic effect(s) and causes such a product to be a drug within the meaning of section 201(g) of the act. The unqualified use of such terms in a product’s labeling fails to provide adequate directions and indications for use of such product and causes it to be misbranded within the meaning of section 502(a) and (f)(1) of the act. The term conditioner and similar terms may be used in labeling only when appropriately qualified so as to fully inform the user regarding the intended use(s) of the product. A product labeled as a “conditioner” or with a similar term can be either a food or drug depending upon the manner in which the term is qualified in the labeling to reflect the product’s intended use.
(c) An article so qualified as to be represented as a drug must be the subject of an approved new animal drug application unless the use of the article under the conditions set forth in its labeling is generally recognized as safe and effective among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs.
§ 500.55 Exemption from certain drug-labeling requirements.
(a) Section 201.105(c) of this chapter provides that in the case of certain drugs for which directions, hazards, warnings, and use information are commonly known to practitioners licensed by law, such information may be omitted from the dispensing package. Under this proviso, the Commissioner of Food and Drugs will offer an opinion, upon written request, stating reasonable grounds therefore on a proposal to omit such information from the dispensing package.
(b) The Commissioner of Food and Drugs has considered submitted material covering a number of drug products and has offered the opinion that the following drugs when intended for those veterinary uses for which they are now generally employed by the veterinary medical profession, should be exempt from the requirements of § 201.105(c) of this chapter, provided that they meet the conditions prescribed in this paragraph. Preparations that are not in dosage unit form (for example, solutions) will be regarded as meeting the conditions with respect to the maximum quantity of drug per dosage unit if they are prepared in a manner that enables accurate and ready administration of a quantity of drug not in excess of the stated maximum per dosage unit:
Subpart D—Requirements for Specific Animal Drugs
§ 500.65 Epinephrine injection 1:1,000 in 10-milliliter containers for emergency treatment of anaphylactoid shock in cattle, horses, sheep, and swine.
(a) Anaphylactoid reactions in cattle, horses, sheep, and swine occur occasionally from the injection of antibiotics, bacterins, and vaccines. Adequate directions for use of these antibiotics, bacterins, and vaccines can generally be written for use by the laity and thus are available to livestock producers. Epinephrine injection is effective for the treatment of anaphylactoid reactions in animals and would be of value in saving lives of animals if it were readily available at the time of administration of the causative agents. In connection with this problem the Food and Drug Administration has obtained the views of the Advisory Committee on Veterinary Medicine, and other experts, and has concluded that adequate directions for over-the-counter sale of epinephrine injection 1:1,000 can be prepared.
(b) In view of the above, the Commissioner of Food and Drugs has concluded that it is in the public interest to make epinephrine injection 1:1,000 available for sale without a prescription provided that it is packaged in vials not exceeding 10 milliliters and its label bears, in addition to other required information, the following statements in a prominent and conspicuous manner: “For emergency use only in treating anaphylactoid shock. Usual Dosage: Cattle, horses, sheep, and swine—1 cubic centimeter per 100 pounds of body weight. Inject subcutaneously”.
(c) The labeling must also bear a description of the symptoms of anaphylactoid shock including glassy eyes, increased salivation, grinding of the teeth, rapid breathing, muscular tremors, staggering gait, and collapse with death following. These symptoms may appear shortly after injection of a bacterin, vaccine, or antibiotic.
Subpart E—Regulation of Carcinogenic Compounds Used in Food-Producing Animals
§ 500.80 Scope of this subpart.
(a) The Federal Food, Drug, and Cosmetic Act requires that sponsored compounds intended for use in food-producing animals be shown to be safe and that food produced from animals exposed to these compounds be shown to be safe for consumption by people. The statute prohibits the use in food-producing animals of any compound found to induce cancer when ingested by people or animals unless it can be determined by methods of examination prescribed or approved by the Secretary (a function delegated to the Commissioner of Food and Drugs) that no residue of that compound will be found in the food produced from those animals under conditions of use reasonably certain to be followed in practice. This subpart identifies the steps a sponsor of a compound shall follow to secure the approval of the compound. The requirements of this subpart shall also apply to a request for an import tolerance under § 510.205 of this chapter. FDA guidance documents contain the procedures and protocols FDA recommends for the implementation of this subpart. These guidance documents are available from the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Requests for these guidance documents should be identified with Docket No. 1983D-0288.
(b) If FDA concludes on the basis of the threshold assessment that a sponsor shall conduct carcinogenicity testing on the sponsored compound, FDA will also determine whether and to what extent the sponsor shall conduct carcinogenicity testing on metabolites of the sponsored compound. The bioassays that a sponsor conducts must be designed to assess carcinogenicity and to determine the quantitative aspects of any carcinogenic response.
(c) If FDA concludes on the basis of the threshold assessment or at a later time during the approval process or during the review of a request for an import tolerance that the data show that the sponsored compound and its metabolites should not be subject to this subpart, FDA will continue to consider the compound for approval under the general safety provisions of the Federal Food, Drug, and Cosmetic Act for risks other than cancer or continue its review of the import tolerance request under the provisions of §§ 510.201 through 510.213 of this chapter (Subpart C—Import Tolerances for Residues of Unapproved New Animal Drugs in Food).
(d) This subpart does not apply to essential nutrients.
§ 500.82 Definitions.
(a) The definitions and interpretations contained in section 201 of the act apply to those terms when used in this subpart.
(b) The following definitions apply to this subpart:
Act means the Federal Food, Drug, and Cosmetic Act (sections 201-901, 52 Stat. 1040 et seq. as amended (21 U.S.C. 301-392)).
Essential nutrients means compounds that are found in the tissues of untreated, healthy target animals and not produced in sufficient quantity to support the animal’s growth, development, function, or reproduction, e.g., vitamins, essential minerals, essential amino acids, and essential fatty acids. These compounds must be supplied from external sources.
FDA means the Food and Drug Administration.
Limit of detection (LOD) means the lowest concentration of analyte that can be confirmed by the approved regulatory method.
Marker residue means the residue selected for assay whose concentration is in a known relationship to the concentration of the residue of carcinogenic concern in the last tissue to deplete to its S
No residue means the marker residue is below the limit of detection using the approved regulatory method. The “no residue” designation applies only to compounds of carcinogenic concern.
Preslaughter withdrawal period or milk discard time means the time after cessation of administration of the sponsored compound at which no residue is detectable in the edible product using the approved regulatory method (i.e., the marker residue is below the LOD).
Regulatory method means the aggregate of all experimental procedures for measuring and confirming the presence of the marker residue of the sponsored compound in the target tissue of the target animal.
R
Residue means any compound present in edible tissues of the target animal which results from the use of the sponsored compound, including the sponsored compound, its metabolites, and any other substances formed in or on food because of the sponsored compound’s use.
Residue of carcinogenic concern means all compounds in the total residue of a demonstrated carcinogen excluding any compounds judged by FDA not to present a carcinogenic risk.
S
S
Sponsor means the person or organization proposing or holding an approval by FDA for the use of a sponsored compound or the person initiating a request for an import tolerance under § 510.205 of this chapter.
Sponsored compound means any drug or food additive or color additive proposed for use, or used, in food-producing animals or in their feed.
Target animals means the production class of animals in which a sponsored compound is proposed or intended for use.
Target tissue means the edible tissue selected to monitor for residues in the target animals, including, where appropriate, milk or eggs.
Test animals means the species selected for use in the toxicity tests.
Threshold assessment means FDA’s review of data and information about a sponsored compound to determine whether chronic bioassays in test animals are necessary to resolve questions concerning the carcinogenicity of the compound.
§ 500.84 Conditions for approval of the sponsored compound.
(a) On the basis of the results of the chronic bioassays and other information, FDA will determine whether any of the substances tested are carcinogenic.
(b) If FDA concludes that the results of the bioassays do not establish carcinogenicity, then FDA will not subject the sponsored compound to the remainder of the requirements of this subpart.
(c) For each sponsored compound that FDA decides should be regulated as a carcinogen, FDA will either analyze the data from the bioassays using a statistical extrapolation procedure as outlined in paragraph (c)(1) of this section or evaluate an alternate procedure proposed by the sponsor as provided in § 500.90. In either case, paragraphs (c)(2) and (3) of this section apply.
(1) For each substance tested in separate bioassays, FDA will calculate the concentration of the residue of carcinogenic concern that corresponds to a maximum lifetime risk to the test animal of 1 in 1 million. FDA will designate the lowest value obtained as S
(2) From the appropriate residue chemistry data FDA will calculate the R
(3) FDA will conclude that the provisions of this subpart are satisfied when no residue of the compound is detectable (that is, the marker residue is below the LOD) using the approved regulatory method under the conditions of use of the sponsored compound, including any required preslaughter withdrawal period or milk discard time.
§ 500.86 Marker residue and target tissue.
(a) For each edible tissue, the sponsor shall measure the depletion of the residue of carcinogenic concern until its concentration is at or below S
(b) In one or more edible tissues, the sponsor shall also measure the depletion of one or more potential marker residues until the concentration of the residue of carcinogenic concern is at or below S
(c) From these data, FDA will select a target tissue and a marker residue and designate the concentration of marker residue (R
(d) When a compound is to be used in milk- or egg-producing animals, milk or eggs must be the target tissue in addition to the tissue selected to monitor for residues in the edible carcass.
§ 500.88 Regulatory method.
(a) The sponsor shall submit for evaluation and validation a regulatory method developed to monitor compliance with FDA’s operational definition of no residue.
(b) The regulatory method must be able to confirm the identity of the marker residue in the target tissue at a minimum concentration corresponding to the R
(c) FDA will publish in the
(d) If the sponsor initially submitted a request for an import tolerance under § 510.205 of this chapter, FDA will make the complete regulatory method for ascertaining the marker residue in the target tissue publicly available pursuant to § 510.207(b) of this chapter.
§ 500.90 Waiver of requirements.
In response to a petition or on the Commissioner’s own initiative, the Commissioner may waive, in whole or in part, the requirements of this subpart except those provided under § 500.88. A petition for this waiver may be filed by any person who would be adversely affected by the application of the requirements to a particular compound. The petition shall explain and document why the requirements from which a waiver is requested are not reasonably applicable to the compound, and set forth clearly the reasons why the alternative procedures will provide the basis for concluding that approval of the compound satisfies the requirements of the anticancer provisions of the act. If the Commissioner determines that waiver of any of the requirements of this subpart is appropriate, the Commissioner will state the basis for that determination in the regulation approving marketing of the sponsored compound.
§ 500.92 Implementation.
(a) This subpart E applies to all new animal drug applications, food additive petitions, color additive petitions, and requests for import tolerances concerning any compound intended for use in food-producing animals (including supplemental applications and amendments to petitions).
(b) This subpart E also applies in the following manner to compounds already approved:
(1) For those compounds that FDA determines may induce cancer when ingested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply.
(2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or animals, §§ 500.82 through 500.90 apply.
Subpart F—Methods for Detection of Residues of Carcinogenic Compounds Used in Food-Producing Animals
§ 500.1410 N-methyl-2-pyrrolidone.
(a) Standard for residues. No residues of n-methyl-2-pyrrolidone may be found in the uncooked edible tissues of cattle and swine as determined by methods in paragraph (b) of this section.
(b) Incorporation by reference. The standards required in this section are incorporated by reference into this section with the approval of the Director of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. All approved material is available for inspection at the Food and Drug Administration’s Dockets Management Staff (HFA-305), 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500, between 9 a.m. and 4 p.m., Monday through Friday. It may be obtained from the sources indicated elsewhere in paragraph (b) of this section and at: https://www.fda.gov/about-fda/center-veterinary-medicine/cvm-foia-electronic-reading-room. It is also available for inspection at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, email [email protected], or go to: www.archives.gov/federal-register/cfr/ibr-locations.html.
(1) Food and Drug Administration, Center for Veterinary Medicine, 7500 Standish Pl., Rockville, MD 20855, 240-402-7002.
(i) “Method of Analysis: N-methyl-2-pyrrolidone,” September 26, 2011; the method of analysis for uncooked edible tissues of cattle.
(ii) [Reserved]
(2) Merck Animal Health, 29160 Intervet Lane, Millsboro, DE 19966, 1-800-211-3573.
(i) “Determinative and Confirmatory Procedures for the Analysis of N-Methyl-2-pyrrolidone (NMP) in Swine Liver Tissue using LC-MS/MS,” July 20, 2017; the method of analysis for uncooked edible tissues of swine.
(ii) [Reserved]
(c) Related conditions of use. See §§ 522.814, 522.955, and 522.1660a of this chapter.
PART 501—ANIMAL FOOD LABELING
Subpart A—General Provisions
§ 501.1 Principal display panel of package form animal food.
The term principal display panel as it applies to food in package form and as used in this part, means the part of a label that is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accommodate all the mandatory label information required to be placed thereon by this part with clarity and conspicuousness and without obscuring design, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents for all packages of substantially the same size, the term area of the principal display panel means the area of the side or surface that bears the principal display panel, which area shall be:
(a) In the case of a rectangular package where one entire side properly can be considered to be the principal display panel side, the product of the height times the width of that side;
(b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the container times the circumference;
(c) In the case of any otherwise shaped container, 40 percent of the total surface of the container: Provided, however, That where such container presents an obvious principal display panel such as the top of a triangular or circular package, the area shall consist of the entire top surface. In determining the area of the principal display panel, exclude tops, bottoms, flanges at tops and bottoms of cans, and shoulders and necks of bottles or jars. In the case of cylindrical or nearly cylindrical containers, information required by this part to appear on the principal display panel shall appear within that 40 percent of the circumference which is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale.
§ 501.2 Information panel of package for animal food.
(a) The term information panel as it applies to packaged food means that part of the label immediately contiguous and to the right of the principal display panel as observed by an individual facing the principal display panel with the following exceptions:
(1) If the part of the label immediately contiguous and to the right of the principal display panel is too small to accommodate the necessary information or is otherwise unusable label space, e.g., folded flaps or can ends, the panel immediately contiguous and to the right of this part of the label may be used.
(2) If the package has one or more alternate principal display panels, the information panel is immediately contiguous and to the right of any principal display panel.
(3) If the top of the container is the principal display panel and the package has no alternate principal display panel, the information panel is any panel adjacent to the principal display panel.
(b) All information required to appear on the label of any package of food pursuant to §§ 501.4, 501.5, 501.8 and 501.17 shall appear either on the principal display panel or on the information panel, unless otherwise specified by regulations in this chapter.
(c) All information appearing on the principal display panel or the information panel pursuant to this section shall appear prominently and conspicuously, but in no case may the letters and/or numbers be less than
(1) Packaged foods are exempt from the type size requirements of this paragraph: Provided, That:
(i) The package is designed such that it has a surface area that can bear an information panel and/or an alternate principal display panel.
(ii) The area of surface available for labeling on the principal display panel of the package as this term is defined in § 501.1 is less than 10 square inches.
(iii) The label information includes a full list of ingredients in accordance with regulations in this part.
(iv) The information required by paragraph (b) of this section appears on the principal display panel or information panel label in accordance with the provisions of this paragraph (c) except that the type size is not less than
(2) Packaged foods are exempt from the type size requirements of this paragraph: Provided, That:
(i) The package is designed such that it has a single obvious principal display panel as this term is defined in § 501.1 and has no other available surface area for an information panel or alternate principal display panel.
(ii) The area of surface available for labeling on the principal display panel of the package as this term is defined in § 501.1 is less than 12 square inches and bears all labeling appearing on the package.
(iii) The label information includes a full list of ingredients in accordance with regulations in this part.
(iv) The information required by paragraph (b) of this section appears on the single, obvious principal display panel in accordance with the provisions of this paragraph (c) except that the type size is not less than
(3) Packaged foods are exempt from the type size requirements of this paragraph: Provided, That:
(i) The package is designed such that it has a total surface area available to bear labeling of less than 12 square inches.
(ii) The label information includes a full list of ingredients in accordance with regulations in this part.
(iii) The information required by paragraph (b) of this section appears on the principal display panel or information panel label in accordance with the provisions of this paragraph (c) except that the type size is not less than
(d) All information required to appear on the principal display panel or on the information panel pursuant to this section shall appear on the same panel unless there is insufficient space. In determining the sufficiency of the available space, any vignettes, design, and other nonmandatory label information shall not be considered. If there is insufficient space for all of this information to appear on a single panel, it may be divided between these two panels except that the information required pursuant to any given section or part shall all appear on the same panel. A food whose label is required to bear the ingredient statement on the principal display panel may bear all other information specified in paragraph (b) of this section on the information panel.
(e) All information appearing on the information panel pursuant to this section shall appear in one place without other intervening material.
(f) If the label of any package of food is too small to accommodate all of the information required by §§ 501.4, 501.5, 501.8, and 501.17, the Commissioner may establish by regulation an acceptable alternative method of disseminating such information to the public, e.g., a type size smaller than one-sixteenth inch in height, or labeling attached to or inserted in the package or available at the point of purchase. A petition requesting such a regulation, as an amendment to this paragraph shall be submitted pursuant to part 10 of this chapter.
§ 501.3 Identity labeling of animal food in package form.
(a) The principal display panel of a food in package form shall bear as one of its principal features a statement of the identity of the commodity.
(b) Such statement of identity shall be in terms of:
(1) The name now or hereafter specified in or required by any applicable Federal law or regulation; or, in the absence thereof,
(2) The common or usual name of the food; or, in the absence thereof,
(3) An appropriately descriptive term, or when the nature of the food is obvious, a fanciful name commonly used by the public for such food.
(c) Where a food is marketed in various optional forms (whole, slices, diced, etc.), the particular form shall be considered to be a necessary part of the statement of identity and shall be declared in letters of a type size bearing a reasonable relation to the size of the letters forming the other components of the statement of identity; except that if the optional form is visible through the container or is depicted by an appropriate vignette, the particular form need not be included in the statement. This specification does not affect the required declarations of identity under definitions and standards for foods promulgated pursuant to section 401 of the act.
(d) This statement of identity shall be presented in bold type on the principal display panel, shall be in a size reasonably related to the most prominent printed matter on such panel, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.
(e) Under the provisions of section 403(c) of the Federal Food, Drug, and Cosmetic Act, a food shall be deemed to be misbranded if it is an imitation of another food unless its label bears, in type of uniform size and prominence, the word imitation and, immediately thereafter, the name of the food imitated.
(1) A food shall be deemed to be an imitation and thus subject to the requirements of section 403(c) of the act if it is a substitute for and resembles another food but is nutritionally inferior to that food.
(2) A food that is a substitute for and resembles another food shall not be deemed to be an imitation provided it meets each of the following requirements:
(i) It is not nutritionally inferior to the food for which it substitutes and which it resembles.
(ii) Its label bears a common or usual name that complies with the provisions of § 502.5 of this chapter and that is not false or misleading, or in the absence of an existing common or usual name, an appropriately descriptive term that is not false or misleading. The label may, in addition, bear a fanciful name which is not false or misleading.
(3) A food for which a common or usual name is established by regulation (e.g., in a standard of identity pursuant to section 401 of the act, in a common or usual name regulation and may, in addition, bear a fanciful name which is not false or misleading, and established pursuant to part 502 of this chapter), and which complies with all of the applicable requirements of such regulation(s), shall not be deemed to be an imitation.
(4) Nutritional inferiority includes:
(i) Any reduction in the content of an essential nutrient that is present in a measurable amount.
(ii) If the Commissioner concludes that a food is a substitute for and resembles another food but is inferior to the food imitated for reasons other than those set forth in this paragraph, he may propose appropriate revisions to this regulation or he may propose a separate regulation governing the particular food.
(f) A label may be required to bear the percentage(s) of a characterizing ingredient(s) or information concerning the presence or absence of an ingredient(s) or the need to add an ingredient(s) as part of the common or usual name of the food pursuant to part 502 of this chapter.
§ 501.4 Animal food; designation of ingredients.
(a) Ingredients required to be declared on the label of a food, including foods that comply with standards of identity that require labeling in compliance with this part 501, except those exempted by § 501.100, shall be listed by common or usual name in descending order of predominance by weight on either the principal display panel or the information panel in accordance with the provisions of § 501.2.
(b) The name of an ingredient shall be a specific name and not a collective (generic) name, except that:
(1) Spices, flavorings, colorings and chemical preservatives shall be declared according to the provisions of § 501.22.
(2) An ingredient which itself contains two or more ingredients and which has an established common or usual name, conforms to a standard established pursuant to the Meat Inspection or Poultry Products Inspection Acts by the U.S. Department of Agriculture, or conforms to a definition and standard of identity established pursuant to section 401 of the Federal Food, Drug, and Cosmetic Act, shall be designated in the statement of ingredients on the label of such food by either of the following alternatives:
(i) By declaring the established common or usual name of the ingredient followed by a parenthetical listing of all ingredients contained therein in descending order of predominance except that, if the ingredient is a food subject to a definition and standard of identity established in this subchapter E, only the ingredients required to be declared by the definition and standard of identity need be listed; or
(ii) By incorporating into the statement of ingredients in descending order of predominance in the finished food, the common or usual name of every component of the ingredient without listing the ingredient itself.
(3) Skim milk, concentrated skim milk, reconstituted skim milk, and nonfat dry milk may be declared as skim milk or nonfat milk.
(4) Milk, concentrated milk, reconstituted milk, and dry whole milk may be declared as milk.
(5) Bacterial cultures may be declared by the word cultured followed by the name of the substrate, e.g., made from cultured skim milk or cultured buttermilk.
(6) Sweetcream buttermilk, concentrated sweetcream buttermilk, reconstituted sweetcream buttermilk, and dried sweetcream buttermilk may be declared as buttermilk.
(7) Whey, concentrated whey, reconstituted whey, and dried whey may be declared as whey.
(8) Cream, reconstituted cream, dried cream, and plastic cream (sometimes known as concentrated milkfat) may be declared as cream.
(9) Butteroil and anhydrous butterfat may be declared as butterfat.
(10) Dried whole eggs, frozen whole eggs, and liquid whole eggs may be declared as eggs.
(11) Dried egg whites, frozen egg whites, and liquid egg whites may be declared as egg whites.
(12) Dried egg yolks, frozen egg yolks, and liquid egg yolks may be declared as egg yolks.
(13) A livestock or poultry feed may be declared by a collective name listed in § 501.110 if it is an animal feed within the meaning of section 201(w) of the act and meets the requirements for the use of a collective name as prescribed in § 501.110 for certain feed ingredients.
(14) [Reserved]
(15) When all the ingredients of a wheat flour are declared in an ingredient statement, the principal ingredient of the flour shall be declared by the name(s) specified in §§ 137.105, 137.200, 137.220, 137.225 of this chapter, i.e., the first ingredient designated in the ingredient list of flour, or bromated flour, or enriched flour, or self-rising flour is flour, white flour, wheat flour, or plain flour; the first ingredient designated in the ingredient list of durum flour is durum flour; the first ingredient designated in the ingredient list of whole wheat flour, or bromated whole wheat flour is whole wheat flour, graham flour, or entire wheat flour; and the first ingredient designated in the ingredient list of whole durum wheat flour is whole durum wheat flour.
(c) When water is added to reconstitute, completely or partially, an ingredient permitted by paragraph (b) of this section to be declared by a class name, the position of the ingredient class name in the ingredient statement shall be determined by the weight of the unreconstituted ingredient plus the weight of the quantity of water added to reconstitute that ingredient, up to the amount of water needed to reconstitute the ingredient to single strength. Any water added in excess of the amount of water needed to reconstitute the ingredient to single strength shall be declared as water in the ingredient statement.
§ 501.5 Animal food; name and place of business of manufacturer, packer, or distributor.
(a) The label of a food in packaged form shall specify conspicuously the name and place of business of the manufacturer, packer, or distributor.
(b) The requirement for declaration of the name of the manufacturer, packer, or distributor shall be deemed to be satisfied, in the case of a corporation, only by the actual corporate name, which may be preceded or followed by the name of the particular division of the corporation. In the case of an individual, partnership, or association, the name under which the business is conducted shall be used.
(c) Where the food is not manufactured by the person whose name appears on the label, the name shall be qualified by a phrase that reveals the connection such person has with such food; such as “Manufactured for ______,” “Distributed by ______,” or any other wording that expresses the facts.
(d) The statement of the place of business shall include the street address, city, state, and ZIP Code; however, the street address may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclusion of the ZIP Code shall apply only to consumer commodity labels developed or revised after the effective date of this section. In the case of nonconsumer packages, the ZIP Code shall appear either on the label or the labeling (including invoice).
(e) If a person manufactures, packs, or distributes a food at a place other than his principal place of business, the label may state the principal place of business in lieu of the actual place where such food was manufactured or packed or is to be distributed, unless such statement would be misleading.
§ 501.8 Labeling of animal food with number of servings.
(a) The label of any package of a food which bears a representation as to the number of servings contained in such package shall bear in immediate conjunction with such statement, and in the same size type as is used for such statement, a statement of the net quantity (in terms of weight, measure, or numerical count) of each such serving; however, such statement may be expressed in terms that differ from the terms used in the required statement of net quantity of contents (for example, cupfuls, tablespoonfuls, etc.) when such differing term is common to cookery and describes a constant quantity. Such statement may not be misleading in any particular. A statement of the number of units in a package is not in itself a statement of the number of servings.
(b) If there exists a voluntary product standard promulgated pursuant to the procedures found in 15 CFR part 10 by the Department of Commerce, quantitatively defining the meaning of the term serving with respect to a particular food, then any label representation as to the number of servings in such packaged food shall correspond with such quantitative definition. (Copies of published standards are available upon request from the National Bureau of Standards, Department of Commerce, Washington, DC 20234.)
§ 501.15 Animal food; prominence of required statements.
(a) A word, statement, or other information required by or under authority of the act to appear on the label may lack that prominence and conspicuousness required by section 403(f) of the act by reason (among other reasons) of:
(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;
(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;
(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;
(4) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;
(5) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device; or
(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.
(b) No exemption depending on insufficiency of label space, as prescribed in regulations promulgated under section 403(e) or (i) of the act, shall apply if such insufficiency is caused by:
(1) The use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;
(2) The use of label space to give greater conspicuousness to any word, statement, or other information that is required by section 403(f) of the act; or
(3) The use of label space for any representation in a foreign language.
(c)(1) All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a territory where the predominant language is one other than English, the predominant language may be substituted for English.
(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.
(3) If any article of labeling (other than a label) contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear on such article of labeling.
§ 501.17 Animal food labeling warning statements.
(a) Self-pressurized containers. (1) The label of a food packaged in a self-pressurized container and intended to be expelled from the package under pressure shall bear the following warning:
Warning Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperature above 120 °F. Keep out of reach of children.
(2) In the case of products intended for use by children, the phrase “except under adult supervision” may be added at the end of the last sentence in the warning required by paragraph (a)(1) of this section.
(3) In the case of products packaged in glass containers, the word “break” may be substituted for the word “puncture” in the warning required by paragraph (a)(1) of this section.
(4) The words “Avoid spraying in eyes” may be deleted from the warning required by paragraph (a)(1) of this section in the case of a product not expelled as a spray.
(b) Self-pressurized containers with halocarbon or hydrocarbon propellants. (1) In addition to the warning required by paragraph (a) of this section, the label of a food packaged in a self-pressurized container in which the propellant consists in whole or in part of a halocarbon or a hydrocarbon shall bear the following warning:
Warning Use only as directed. Intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal.
(2) The warning required by paragraph (b)(1) of this section is not required for the following products:
(i) Products expelled in the form of a foam or cream, which contain less than 10 percent propellant in the container.
(ii) Products in a container with a physical barrier that prevents escape of the propellant at the time of use.
(iii) Products of a net quantity of contents of less than 2 ozs that are designed to release a measured amount of product with each valve actuation.
(iv) Products of a net quantity of contents of less than
(c) Animal food containing or manufactured with a chlorofluorocarbon or other ozone-depleting substance. Labeling requirements for animal foods that contain or are manufactured with a chlorofluorocarbon or other ozone-depleting substance designated by the Environmental Protection Agency (EPA) are set forth in 40 CFR part 82.
§ 501.18 Misbranding of animal food.
(a) Among representations in the labeling of a food which render such food misbranded is a false or misleading representation with respect to another food or a drug, device, or cosmetic.
(b) The labeling of a food which contains two or more ingredients may be misleading by reason (among other reasons) of the designation of such food in such labeling by a name which includes or suggests the name of one or more but not all such ingredients, even though the names of all such ingredients are stated elsewhere in the labeling.
(c) Among representations in the labeling of a food which render such food misbranded is any representation that expresses or implies a geographical origin of the food or any ingredient of the food except when such representation is either:
(1) A truthful representation of geographical origin.
(2) A trademark or trade name provided that as applied to the article in question its use is not deceptively misdescriptive. A trademark or trade name comprised in whole or in part of geographical words shall not be considered deceptively misdescriptive if it:
(i) Has been so long and exclusively used by a manufacturer or distributor that it is generally understood by the consumer to mean the product of a particular manufacturer or distributor; or
(ii) Is so arbitrary or fanciful that it is not generally understood by the consumer to suggest geographic origin.
(3) A part of the name required by applicable Federal law or regulation.
(4) A name whose market significance is generally understood by the consumer to connote a particular class, kind, type, or style of food rather than to indicate geographical origin.
Subpart B—Specific Animal Food Labeling Requirements
§ 501.22 Animal foods; labeling of spices, flavorings, colorings, and chemical preservatives.
(a)(1) The term artificial flavor or artificial flavoring means any substance, the function of which is to impart flavor, which is not derived from a spice, fruit or fruit juice, vegetable or vegetable juice, edible yeast, herb, bark, bud, root, leaf or similar plant material, meat, fish, poultry, eggs, dairy products, or fermentation products thereof. Artificial flavor includes the substances listed in §§ 172.515(b) and 582.60 of this chapter except where these are derived from natural sources.
(2) The term spice means any aromatic vegetable substance in the whole, broken, or ground form, except for those substances which have been traditionally regarded as foods, such as onions, garlic and celery; whose significant function in food is seasoning rather than nutritional; that is true to name; and from which no portion of any volatile oil or other flavoring principle has been removed. Spices include the spices listed in subpart A of part 582 of this chapter, such as the following:
(3) The term natural flavor or natural flavoring means the essential oil, oleoresin, essence or extractive, protein hydrolysate, distillate, or any product of roasting, heating or enzymolysis, which contains the flavoring constituents derived from a spice, fruit or fruit juice, vegetable or vegetable juice, edible yeast, herb, bark, bud, root, leaf or similar plant material, meat, seafood, poultry, eggs, dairy products, or fermentation products thereof, whose significant function in food is flavoring rather than nutritional. Natural flavors, include the natural essence or extractives obtained from plants listed in subpart A of part 582 of this chapter, and the substances listed in § 172.510 of this chapter.
(4) The term artificial color or artificial coloring means any color additive as defined in § 70.3(f) of this chapter.
(5) The term chemical preservative means any chemical that, when added to food, tends to prevent or retard deterioration thereof, but does not include common salt, sugars, vinegars, spices, or oils extracted from spices, substances added to food by direct exposure thereof to wood smoke, or chemicals applied for their insecticidal or herbicidal properties.
(b) A food which is subject to the requirements of section 403(k) of the act shall bear labeling, even though such food is not in package form.
(c) A statement of artificial flavoring, artificial coloring, or chemical preservative shall be placed on the food, or on its container or wrapper, or on any two or all of these, as may be necessary to render such statement likely to be read by the ordinary individual under customary conditions of purchase and use of such food.
(d) A food shall be exempt from compliance with the requirements of section 403(k) of the act if it is not in package form and the units thereof are so small that a statement of artificial flavoring, artificial coloring, or chemical preservative, as the case may be, cannot be placed on such units with such conspicuousness as to render it likely to be read by the ordinary individual under customary conditions of purchase and use.
(e) A food shall be exempt while held for sale from the requirements of section 403(k) of the act (requiring label statement of any artificial flavoring, artificial coloring, or chemical preservatives) if said food, having been received in bulk containers at a retail establishment, is displayed to the purchaser with either (1) the labeling of the bulk container plainly in view or (2) a counter card, sign, or other appropriate device bearing prominently and conspicuously the information required to be stated on the label pursuant to section 403(k) of the act.
(f) A fruit or vegetable shall be exempt from compliance with the requirements of section 403(k) of the act with respect to a chemical preservative applied to the fruit or vegetable as a pesticide chemical prior to harvest.
(g) A flavor shall be labeled in the following way when shipped to a food manufacturer or processor (but not a consumer) for use in the manufacture of a fabricated food, unless it is a flavor for which a standard of identity has been promulgated, in which case it shall be labeled as provided in the standard:
(1) If the flavor consists of one ingredient, it shall be declared by its common or usual name.
(2) If the flavor consists of two or more ingredients, the label either may declare each ingredient by its common or usual name or may state “All flavor ingredients contained in this product are approved for use in a regulation of the Food and Drug Administration.” Any flavor ingredient not contained in one of these regulations, and any nonflavor ingredient, shall be separately listed on the label.
(3) In cases where the flavor contains a solely natural flavor(s), the flavor shall be so labeled, e.g., strawberry flavor, banana flavor, or natural strawberry flavor. In cases where the flavor contains both a natural flavor and an artificial flavor, the flavor shall be so labeled, e.g., natural and artificial strawberry flavor. In cases where the flavor contains a solely artificial flavor(s), the flavor shall be so labeled, e.g., artificial strawberry flavor.
(h) The label of a food to which flavor is added shall declare the flavor in the statement of ingredients in the following way:
(1) Spice, natural flavor, and artificial flavor may be declared as spice, natural flavor, or artificial flavor, or any combination thereof, as the case may be.
(2) An incidental additive in a food, originating in a spice or flavor used in the manufacture of the food, need not be declared in the statement of ingredients if it meets the requirements of § 501.100(a)(3).
(3) Substances obtained by cutting, grinding, drying, pulping, or similar processing of tissues derived from fruit, vegetable, meat, fish, or poultry, e.g., powdered or granulated onions, garlic powder, and celery powder, are commonly understood by consumers to be food rather than flavor and shall be declared by their common or usual name.
(4) Any salt (sodium chloride) used as an ingredient in food shall be declared by its common or usual name salt.
(5) Any monosodium glutamate used as an ingredient in food shall be declared by its common or usual name monosodium glutamate.
(6) Any pyroligneous acid or other artificial smoke flavors used as an ingredient in a food may be declared as artificial flavor or artificial smoke flavor. No representation may be made, either directly or implied, that a food flavored with pyroligneous acid or other artificial smoke flavor has been smoked or has a true smoked flavor, or that a seasoning sauce or similar product containing pyroligneous acid or other artificial smoke flavor and used to season or flavor other foods will result in a smoked product or one having a true smoked flavor.
(i) If the label, labeling, or advertising of a food makes any direct or indirect representations with respect to the primary recognizable flavor(s), by word, vignette, e.g., depiction of a fruit, or other means, or if for any other reason the manufacturer or distributor of a food wishes to designate the type of flavor in the food other than through the statement of ingredients, such flavor shall be considered the characterizing flavor and shall be declared in the following way:
(1) If the food contains no artificial flavor which simulates, resembles or reinforces the characterizing flavor, the name of the food on the principal display panel or panels of the label shall be accompanied by the common or usual name of the characterizing flavor in letters not less than one-half the height of the letters used in the name of the food, except that:
(i) If the food is one that is commonly expected to contain a characterizing food ingredient, and the food contains natural flavor derived from such ingredient and an amount of characterizing ingredient insufficient to independently characterize the food, or the food contains no such ingredient, the name of the characterizing flavor may be immediately preceded by the word natural and shall be immediately followed by the word flavored in letters not less than one-half the height of the letters in the name of the characterizing flavor.
(ii) If none of the natural flavor used in the food is derived from the product whose flavor is simulated, the food in which the flavor is used shall be labeled either with the flavor of the product from which the flavor is derived or as artificially flavored.
(iii) If the food contains both a characterizing flavor from the product whose flavor is simulated and other natural flavor which simulates, resembles or reinforces the characterizing flavor, the food shall be labeled in accordance with the introductory text and paragraph (i)(1)(i) of this section and the name of the food shall be immediately followed by the words with other natural flavor in letters not less than one-half the height of the letters used in the name of the characterizing flavor.
(2) If the food contains any artificial flavor which simulates, resembles or reinforces the characterizing flavor, the name of the food on the principal display panel or panels of the label shall be accompanied by the common or usual name(s) of the characterizing flavor, in letters not less than one-half the height of the letters used in the name of the food and the name of the characterizing flavor shall be accompanied by the word(s) artificial or artificially flavored, in letters not less than one-half the height of the letters in the name of the characterizing flavor.
(3) Wherever the name of the characterizing flavor appears on the label (other than in the statement of ingredients) so conspicuously as to be easily seen under customary conditions of purchase, the words prescribed by this paragraph shall immediately and conspicuously precede or follow such name, without any intervening written, printed, or graphic matter, except:
(i) Where the characterizing flavor and a trademark or brand are presented together, other written, printed, or graphic matter that is a part of or is associated with the trademark or brand may intervene if the required words are in such relationship with the trademark or brand as to be clearly related to the characterizing flavor; and
(ii) If the finished product contains more than one flavor subject to the requirements of this paragraph, the statements required by this paragraph need appear only once in each statement of characterizing flavors present in such food.
(iii) If the finished product contains three or more distinguishable characterizing flavors, or a blend of flavors with no primary recognizable flavor, the flavor may be declared by an appropriately descriptive generic term in lieu of naming each flavor.
(4) A flavor supplier shall certify, in writing, that any flavor he supplies which is designated as containing no artificial flavor does not, to the best of his knowledge and belief, contain any artificial flavor, and that he has added no artificial flavor to it. The requirement for such certification may be satisfied by a guarantee under section 303(c)(2) of the act which contains such a specific statement. A flavor used shall be required to make such a written certification only where he adds to or combines another flavor with a flavor which has been certified by a flavor supplier as containing no artificial flavor, but otherwise such user may rely upon the supplier’s certification and need make no separate certification. All such certifications shall be retained by the certifying party throughout the period in which the flavor is supplied and for a minimum of 3 years thereafter, and shall be subject to the following conditions:
(i) The certifying party shall make such certifications available upon request at all reasonable hours to any duly authorized officer, or employee of the Food and Drug Administration or any other employee acting on behalf of the Secretary of Health and Human Services. Such certifications are regarded by the Food and Drug Administration as reports to the government and as guarantees or other undertakings within the meaning of section 301(h) of the act and subject the certifying party to the penalties for making any false report to the government under 18 U.S.C. 1001 and any false guarantee or undertaking under section 303(a) of the act. The defenses provided under section 303(c)(2) of the act shall be applicable to the certifications provided for in this section.
(ii) Wherever possible, the Food and Drug Administration shall verify the accuracy of a reasonable number of certifications made pursuant to this section, constituting a representative sample of such certifications, and shall not request all such certifications.
(iii) Where no person authorized to provide such information is reasonably available at the time of inspection, the certifying party shall arrange to have such person and the relevant materials and records ready for verification as soon as practicable; provided that, whenever the Food and Drug Administration has reason to believe that the supplier or user may utilize this period to alter inventories or records, such additional time shall not be permitted. Where such additional time is provided, the Food and Drug Administration may require the certifying party to certify that relevant inventories have not been materially disturbed and relevant records have not been altered or concealed during such period.
(iv) The certifying party shall provide, to an officer or representative duly designated by the Secretary, such qualitative statement of the composition of the flavor or product covered by the certification as may be reasonably expected to enable the Secretary’s representatives to determine which relevant raw and finished materials and flavor ingredient records are reasonably necessary to verify the certifications. The examination conducted by the Secretary’s representative shall be limited to inspection and review of inventories and ingredient records for those certifications which are to be verified.
(v) Review of flavor ingredient records shall be limited to the qualitative formula and shall not include the quantitative formula. The person verifying the certifications may make only such notes as are necessary to enable him to verify such certification. Only such notes or such flavor ingredient records as are necessary to verify such certification or to show a potential or actual violation may be removed or transmitted from the certifying party’s place of business: Provided, That, where such removal or transmittal is necessary for such purposes the relevant records and notes shall be retained as separate documents in Food and Drug Administration files, shall not be copied in other reports, and shall not be disclosed publicly other than in a judicial proceeding brought pursuant to the act or 18 U.S.C. 1001.
(j) A food to which a chemical preservative(s) is added shall, except when exempt pursuant to § 501.100, bear a label declaration stating both the common or usual name of the ingredient(s) and a separate description of its function, e.g., preservative, to retard spoilage, a mold inhibitor, to help protect flavor or to promote color retention.
(k) The label of an animal food to which any coloring has been added shall declare the coloring in the statement of ingredients in the manner specified in paragraphs (k)(1) and (k)(2) of this section.
(1) A color additive or the lake of a color additive subject to certification under section 721(c) of the act shall be declared by the name of the color additive listed in the applicable regulation in part 74 or part 82 of this chapter, except that it is not necessary to include the “FD&C” prefix or the term “No.” in the declaration, but the term “Lake” shall be included in the declaration of the lake of the certified color additive (e.g., Blue 1 Lake). Manufacturers may parenthetically declare an appropriate alternative name of the certified color additive following its common or usual name as specified in part 74 or part 82 of this chapter.
(2) Color additives not subject to certification may be declared as “Artificial Color,” “Artificial Color Added,” or “Color Added” (or by an equally informative term that makes clear that a color additive has been used in the food). Alternatively, such color additives may be declared as “Colored with ____” or “____ color,” the blank to be filled with the name of the color additive listed in the applicable regulation in part 73 of this chapter.
Subparts C-E [Reserved]
Subpart F—Exemptions From Animal Food Labeling Requirements
§ 501.100 Animal food; exemptions from labeling.
(a) The following foods are exempt from compliance with the requirements of section 403(i)(2) of the act (requiring a declaration on the label of the common or usual name of each ingredient when the food is fabricated from two or more ingredients).
(1) An assortment of different items of food, when variations in the items that make up different packages packed from such assortment normally occur in good packing practice and when such variations result in variations in the ingredients in different packages, with respect to any ingredient that is not common to all packages. Such exemption, however, shall be on the condition that the label shall bear, in conjunction with the names of such ingredients as are common to all packages, a statement (in terms that are as informative as practicable and that are not misleading) indicating by name other ingredients which may be present.
(2) A food having been received in bulk containers at a retail establishment, if displayed to the purchaser with either (i) the labeling of the bulk container plainly in view or (ii) a counter card, sign, or other appropriate device bearing prominently and conspicuously the information required to be stated on the label pursuant to section 403(i)(2) of the act.
(3) Incidental additives that are present in a food at insignificant levels and do not have any technical or functional effect in that food. For the purposes of this paragraph (a)(3), incidental additives are:
(i) Substances that have no technical or functional effect but are present in a food by reason of having been incorporated into the food as an ingredient of another food, in which the substance did have a functional or technical effect.
(ii) Processing aids, which are as follows:
(a) Substances that are added to a food during the processing of such food but are removed in some manner from the food before it is packaged in its finished form.
(b) Substances that are added to a food during processing, are converted into constituents normally present in the food, and do not significantly increase the amount of the constituents naturally found in the food.
(c) Substances that are added to a food for their technical or functional effect in the processing but are present in the finished food at insignificant levels and do not have any technical or functional effect in that food.
(iii) Substances migrating to food from equipment or packaging or otherwise affecting food that are not food additives as defined in section 201(s) of the act; or if they are food additives as so defined, they are used in conformity with regulations established pursuant to section 409 of the act.
(b) A food repackaged in a retail establishment is exempt from the following provisions of the act if the conditions specified are met.
(1) Section 403(e)(1) of the act (requiring a statement on the label of the name and place of business of the manufacturer, packer, or distributor).
(2) Section 403(g)(2) of the act (requiring the label of a food which purports to be or is represented as one for which a definition and standard of identity has been prescribed to bear the name of the food specified in the definition and standard and, insofar as may be required by the regulation establishing the standard the common names of the optional ingredients present in the food), if the food is displayed to the purchaser with its interstate labeling clearly in view, or with a counter card, sign, or other appropriate device bearing prominently and conspicuously the information required by these provisions.
(3) Section 403(i)(1) of the act (requiring the label to bear the common or usual name of the food), if the food is displayed to the purchaser with its interstate labeling clearly in view, or with a counter card, sign, or other appropriate device bearing prominently and conspicuously the common or usual name of the food, or if the common or usual name of the food is clearly revealed by its appearance.
(c) [Reserved]
(d) Except as provided by paragraphs (e) and (f) of this section, a shipment or other delivery of a food which is, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling requirements of section 403 (c), (e), (g), (h), (i), (j) and (k) of the act if:
(1) The person who introduced such shipment or delivery into interstate commerce is the operator of the establishment where such food is to be processed, labeled, or repacked; or
(2) In case such person is not such operator, such shipment or delivery is made to such establishment under a written agreement, signed by and containing the post office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such food in such establishment as will ensure, if such specifications are followed, that such food will not be adulterated or misbranded within the meaning of the act upon completion of such processing, labeling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such food from such establishment, and shall make such copies available for inspection at any reasonable hour to any officer or employee of the Department who requests them.
(e) Conditions affecting expiration of exemptions.
(1) An exemption of a shipment or other delivery of a food under paragraph (d)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment become void ab initio if the food comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed.
(2) An exemption of a shipment or other delivery of a food under paragraph (d)(2) of this section shall become void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by paragraph (d)(2) of this section.
(3) An exemption of a shipment or other delivery of a food under paragraph (d)(2) of this section shall expire:
(i) At the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment if the food comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or
(ii) Upon refusal by the operator of the establishment where such food is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement as required by such paragraph.
(f) [Reserved]
(g) The label declaration of a harmless marker used to identify a particular manufacturer’s product may result in unfair competition through revealing a trade secret. Exemption from the label declaration of such a marker is granted, therefore, provided that the following conditions are met:
(1) The person desiring to use the marker without label declaration of its presence has submitted to the Commissioner of Food and Drugs full information concerning the proposed usage and the reasons why he believes label declaration of the marker should be subject to this exemption; and
(2) The person requesting the exemption has received from the Commissioner of Food and Drugs a finding that the marker is harmless and that the exemption has been granted.
§ 501.103 Petitions requesting exemptions from or special requirements for label declaration of ingredients.
The Commissioner of Food and Drugs, either on his own initiative or on behalf of any interested person who has submitted a petition pursuant to part 10 of this chapter may issue a proposal to amend § 501.4 to specify the manner in which an ingredient(s) shall be declared, i.e., by specific or class name, or § 501.100 to exempt an ingredient(s) from the requirements for label declaration.
§ 501.105 Declaration of net quantity of contents when exempt.
(a) The principal display panel of a food in package form shall bear a declaration of the net quantity of contents. This shall be expressed in the terms of weight, measure, numerical count, or a combination of numerical count and weight or measure. The statement shall be in terms of fluid measure if the food is liquid, or in terms of weight if the food is solid, semisolid, or viscous, or a mixture of solid and liquid; except that such statement may be in terms of dry measure if the food is a fresh fruit, fresh vegetable, or other dry commodity that is customarily sold by dry measure. If there is a firmly established general consumer usage and trade custom of declaring the contents of a liquid by weight, or a solid, semisolid, or viscous product by fluid measure, it may be used. Whenever the Commissioner determines that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a combination in the case of a specific packaged food does not facilitate value comparisons by consumers and offers opportunity for consumer confusion, he will by regulation designate the appropriate term or terms to be used for such commodity.
(b)(1) Statements of weight shall be in terms of avoirdupois pound and ounce.
(2) Statements of fluid measure shall be in terms of the U.S. gallon of 231 cubic inches and quart, pint, and fluid ounce subdivisions thereof, and shall:
(i) In the case of frozen food that is sold and consumed in a frozen state, express the volume at the frozen temperature.
(ii) In the case of refrigerated food that is sold in the refrigerated state, express the volume at 40 °F (4 °C).
(iii) In the case of other foods, express the volume at 68 °F (20 °C).
(3) Statements of dry measure shall be in terms of the U.S. bushel of 2,150.42 cubic inches and peck, dry quart, and dry pint subdivisions thereof.
(c) When the declaration of quantity of contents by numerical count does not give adequate information as to the quantity of food in the package, it shall be combined with such statement of weight, measure, or size of the individual units of the foods as will provide such information.
(d) The declaration may contain common or decimal fractions. A common fraction shall be in terms of halves, quarters, eighths, sixteenths, or thirty-seconds; except that if there exists a firmly established general consumer usage and trade custom of employing different common fractions in the net quantity declaration of a particular commodity, they may be employed. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than two places. A statement that includes small fractions of an ounce shall be deemed to permit smaller variations than one which does not include such fractions.
(e) The declaration shall be located on the principal display panel of the label, and with respect to packages bearing alternate principal panels it shall be duplicated on each principal display panel.
(f) The declaration shall appear as a distinct item on the principal display panel, shall be separated (by at least a space equal to the height of the lettering used in the declaration) from other printed label information appearing above or below the declaration and (by at least a space equal to twice the width of the letter “N” of the style of type used in the quantity of contents statement) from other printed label information appearing to the left or right of the declaration. It shall not include any term qualifying a unit of weight, measure, or count (such as jumbo quart and full gallon) that tends to exaggerate the amount of the food in the container. It shall be placed on the principal display panel within the bottom 30 percent of the area of the label panel in lines generally parallel to the base on which the package rests as it is designed to be displayed: Provided, That on packages having a principal display panel of 5 square inches or less, the requirement for placement within the bottom 30 percent of the area of the label panel shall not apply when the declaration of net quantity of contents meets the other requirements of this part.
(g) The declaration shall accurately reveal the quantity of food in the package exclusive of wrappers and other material packed therewith; provided that in the case of foods packed in containers designed to deliver the food under pressure, the declaration shall state the net quantity of the contents that will be expelled when the instructions for use as shown on the container are followed. The propellant is included in the net quantity declaration.
(h) The declaration shall appear in conspicuous and easily legible boldface print or type in distinct contrast (by typography, layout, color, embossing, or molding) to other matter on the package; except that a declaration of net quantity blown, embossed, or molded on a glass or plastic surface is permissible when all label information is so formed on the surface. Requirements of conspicuousness and legibility shall include the specifications that:
(1) The ratio of height to width (of the letter) shall not exceed a differential of 3 units to 1 unit (no more than 3 times as high as it is wide).
(2) Letter heights pertain to upper case or capital letters. When upper and lower case or all lower case letters are used, it is the lower case letter “o” or its equivalent that shall meet the minimum standards.
(3) When fractions are used, each component numeral shall meet one-half the minimum height standards.
(i) The declaration shall be in letters and numerals in a type size established in relationship to the area of the principal display panel of the package and shall be uniform for all packages of substantially the same size by complying with the following type specifications:
(1) Not less than
(2) Not less than
(3) Not less than
(4) Not less than
(j) On packages containing less than 4 pounds or 1 gallon and labeled in terms of weight or fluid measure:
(1) The declaration shall be expressed both in ounces, with identification by weight or by liquid measure and, if applicable (1 pound or 1 pint or more) followed in parentheses by a declaration in pounds for weight units, with any remainder in terms of ounces or common or decimal fractions of the pound (see examples set forth in paragraphs (m) (1) and (2) of this section), or in the case of liquid measure, in the largest whole units (quarts, quarts and pints, or pints, as appropriate) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (see examples in paragraphs (m) (3) and (4) of this section).
(2) If the net quantity of contents declaration appears on a random package, that is a package which is one of a lot, shipment, or delivery of packages of the same consumer commodity with varying weights and with no fixed weight pattern, it may, when the net weight exceeds 1 pound, be expressed in terms of pounds and decimal fractions of the pound carried out to not more than two decimal places. When the net weight does not exceed 1 pound, the declaration on the random package may be in decimal fractions of the pound in lieu of ounces (see example in paragraph (m)(5) of this section).
(3) The declaration may appear in more than one line. The term net weight shall be used when stating the net quantity of contents in terms of weight. Use of the terms net or net contents in terms of fluid measure or numerical count is optional. It is sufficient to distinguish avoirdupois ounce from fluid ounce through association of terms; for example, Net wt. 6 oz. or 6 oz. net wt. and 6 fl. oz. or net contents 6 fl. oz.
(k) On packages containing 4 pounds or 1 gallon or more and labeled in terms of weight or fluid measure, the declaration shall be expressed in pounds for weight units with any remainder in terms of ounces or common or decimal fraction of the pound, or in the case of fluid measure, it shall be expressed in the largest whole unit (gallons followed by common or decimal fraction of a gallon or by the next smaller whole unit or units (quarts, or quarts and pints)) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (see paragraph (m)(6) of this section).
(l) [Reserved]
(m) Examples: (1) A declaration of 1
(2) A declaration of
(3) A declaration of 1 quart liquid measure shall be expressed as Net 32 fl. oz. (1 qt.).
(4) A declaration of 1
(5) On a random package, declaration of
(6) A declaration of 2
(n) For quantities, the following abbreviations and none other may be employed (periods and plural forms are optional):
(o) Nothing in this section shall prohibit supplemental statements at locations other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents; provided, that such supplemental statements of net quantity of contents shall not include any term qualifying a unit of weight, measure, or count that tends to exaggerate the amount of the food contained in the package; for example, jumbo quart and full gallon. Dual or combination declarations of net quantity of contents as provided for in paragraphs (a), (c), and (j) of this section (for example, a combination of net weight plus numerical count, net contents plus dilution directions of a concentrate, etc.) are not regarded as supplemental net quantity statements and may be located on the principal display panel.
(p) A separate statement of the net quantity of contents in terms of the metric system is not regarded as a supplemental statement and an accurate statement of the net quantity of contents in terms of the metric system of weight or measure may also appear on the principal display panel or on other panels.
(q) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large.
(r) [Reserved]
(s) On a multiunit retail package, a statement of the quantity of contents shall appear on the outside of the package and shall include the number of individual units, the quantity of each individual unit, and, in parentheses, the total quantity of contents of the multiunit package in terms of avoirdupois or fluid ounces, except that such declaration of total quantity need not be followed by an additional parenthetical declaration in terms of the largest whole units and subdivisions thereof, as required by paragraph (j)(1) of this section. A multiunit retail package may thus be properly labeled: 6-16 oz. bottles—(96 fl. oz.) or 3-16 oz. cans—(net wt. 48 oz). For the purposes of this section, multiunit retail package means a package containing two or more individually packaged units of the identical commodity and in the same quantity, intended to be sold as part of the multiunit retail package but capable of being individually sold in full compliance with all requirements of the regulations in this part. Open multiunit retail packages that do not obscure the number of units nor prevent examination of the labeling on each of the individual units are not subject to this paragraph if the labeling of each individual unit complies with the requirements of paragraphs (f) and (i) of this section.
(t) Where the declaration of net quantity of contents is in terms of net weight and/or drained weight or volume and does not accurately reflect the actual quantity of the contents or the product falls below the applicable standard of fill of container because of equipment malfunction or otherwise unintentional product variation, and the label conforms in all other respects to the requirements of this chapter, the mislabeled food product may be sold by the manufacturer or processor directly to institutions operated by Federal, State or local governments: Provided, That:
(1) The purchaser shall sign a statement at the time of sale stating that he is aware that the product is mislabeled to include acknowledgement of the nature and extent of the mislabeling, e.g., “Actual net weight may be as low as __% below labeled quantity” and that any subsequent distribution by him of said product except for his own institutional use is unlawful. This statement shall be kept on file at the principal place of business of the manufacturer or processor for 2 years subsequent to the date of shipment of the product and shall be available to the Food and Drug Administration upon request.
(2) The product shall be labeled on the outside of its shipping container with the statement(s):
(i) When the variation concerns net weight and/or drained weight of volume—“Product Mislabeled. Actual net weight (drained weight or volume where appropriate) may be as low as __% below labeled quantity. This Product Not for Retail Distribution,” the blank to be filled in with the maximum percentage variance between the labeled and actual weight or volume of contents of the individual packages in the shipping container, and
(ii) When the variation is in regard to a fill of container standard—“Product Mislabeled. Actual fill may be as low as __% below standard of fill. This Product Not for Retail Distribution.”
(3) The statements required by paragraphs (t)(2) (i) and (ii) of this section, which may be consolidated where appropriate, shall appear prominently and conspicuously as compared to other printed matter on the shipping container and in boldface print or type on a clear, contrasting background in order to render them likely to be read and understood by the purchaser under ordinary conditions of purchase.
§ 501.110 Animal feed labeling; collective names for feed ingredients.
(a) An animal feed shall be exempt from the requirements of section 403(i)(2) of the act with respect to its label bearing the common or usual names of the animal feed ingredients listed in paragraph (b) of this section under the following prescribed conditions:
(1) The animal feed is intended solely for livestock and poultry.
(2) The label of the animal feed bears the collective name(s) prescribed in paragraph (b) of this section in lieu of the corresponding common or usual names of the individual feed ingredients contained therein.
(3) The label of the animal feed otherwise conforms to the requirements of section 403(i)(2) of the act.
(4) The ingredients of any feed listed in paragraph (b) of this section neither contain nor are food additives as defined in section 201(s) of the act unless provided for by and in conformity with applicable regulations established pursuant to section 409 of the act.
(b) Each collective name referred to in this paragraph may be used for the purpose of labeling where one or more of the ingredients listed for that collective name are present. The animal feed ingredients listed under each of the collective names are the products defined by the Association of American Feed Control Officials. The collective names are as follows:
(1) Animal protein products include one or more of the following: Animal products, marine products, and milk products.
(2) Forage products include one or more of the following: Alfalfa meals, entire plant meals, hays, and stem meals.
(3) Grain products include one or more of the following: Barley, grain sorghums, maize (corn), oats, rice, rye, and wheat.
(4) Plant protein products include one or more of the following: Algae meals, coconut meals (copra), cottonseed meals, guar meal, linseed meals, peanut meals, safflower meals, soybean meals, sunflower meals, and yeasts.
(5) Processed grain byproducts include one or more of the following: Brans, brewers dried grains, distillers grains, distillers solubles, flours, germ meals, gluten feeds, gluten meals, grits, groats, hominy feeds, malt sprouts, middlings, pearled, polishings, shorts, and wheat mill run.
(6) Roughage products include one or more of the following: Cobs, hulls, husks, pulps, and straws.
PART 502—COMMON OR USUAL NAMES FOR NONSTANDARDIZED ANIMAL FOODS
§ 502.5 General principles.
(a) The common or usual name of a food, which may be a coined term, shall accurately identify or describe, in as simple and direct terms as possible, the basic nature of the food or its characterizing properties or ingredients. The name shall be uniform among all identical or similar products and may not be confusingly similar to the name of any other food that is not reasonably encompassed within the same name. Each class or subclass of food shall be given its own common or usual name that states, in clear terms, what it is in a way that distinguishes it from different foods.
(b) The common or usual name of a food shall include the percentage(s) of any characterizing ingredient(s) or component(s) when the proportion of such ingredient(s) or component(s) in the food has a material bearing on price or consumer acceptance or when the labeling or the appearance of the food may otherwise create an erroneous impression that such ingredient(s) or component(s) is present in an amount greater than is actually the case. The following requirements shall apply unless modified by a specific regulation in this part.
(1) The percentage of a characterizing ingredient or component shall be declared on the basis of its quantity in the finished product (i.e., weight/weight in the case of solids, or volume/volume in the case of liquids).
(2) The percentage of a characterizing ingredient or component shall be declared by the words “containing (or contains) __ percent (or %) __” or “__ percent (or %) __” with the first blank filled in with the percentage expressed as a whole number not greater than the actual percentage of the ingredient or component named and the second blank filled in with the common or usual name of the ingredient or component. The word “containing” (or “contains”), when used, shall appear on a line immediately below the part of the common or usual name of the food required by paragraph (a) of this section. For each characterizing ingredient or component, the words “__ percent (or %) __”shall appear following or directly below the word “containing” (or “contains”), or directly below the part of the common or usual name of the food required by paragraph (a) of this section when the word “containing” (or “contains”) is not used, in easily legible boldface print or type in distinct contrast to other printed or graphic matter, and in a height not less than the larger of the following alternatives:
(i) Not less than one-sixteenth inch in height on packages having a principal display panel with an area of 5 square inches or less and not less than one-eighth inch in height if the area of the principal display panel is greater than 5 square inches; or
(ii) Not less than one-half the height of the largest type appearing in the part of the common or usual name of the food required by paragraph (a) of this section.
(c) The common or usual name of a food shall include a statement of the presence or absence of any characterizing ingredient(s) or component(s) and/or the need for the user to add any characterizing ingredient(s) or component(s) when the presence or absence of such ingredient(s) or component(s) in the food has a material bearing on price or consumer acceptance or when the labeling or the appearance of the food may otherwise create an erroneous impression that such ingredient(s) or component(s) is present when it is not, and consumers may otherwise be misled about the presence or absence of the ingredient(s) or component(s) in the food. The following requirements shall apply unless modified by a specific regulation in this part.
(1) The presence or absence of a characterizing ingredient or component shall be declared by the words “containing (or contains) ____” or “containing (or contains) _____” or “no _____” or “does not contain _____”, with the blank being filled in with the common or usual name of the ingredient or component.
(2) The need for the user of a food to add any characterizing ingredient(s) or component(s) shall be declared by an appropriate informative statement.
(3) The statement(s) required under paragraph (c) (1) and/or (2) of this section shall appear following or directly below the part of the common or usual name of the food required by paragraphs (a) and (b) of this section, in easily legible boldface print or type in distinct contrast to other printed or graphic matter, and in a height not less than the larger of the alternatives established under paragraph (b)(2) (i) and (ii) of this section.
(d) A common or usual name of a food may be established by common usage or by establishment of a regulation in this part, in a standard of identity, or in other regulations in this chapter.
§ 502.19 Petitions.
(a) The Commissioner of Food and Drugs, either on his own initiative or on behalf of any interested person who has submitted a petition, may publish a proposal to issue, amend, or revoke, under this part, a regulation prescribing a common or usual name for a food, pursuant to part 10 of this chapter.
(b) If the principal display panel of a food for which a common or usual name regulation is established is too small to accommodate all mandatory requirements, the Commissioner may establish by regulation an acceptable alternative, e.g., a smaller type size. A petition requesting such a regulation, which would amend the applicable regulation, shall be submitted pursuant to part 10 of this chapter.
PART 507—CURRENT GOOD MANUFACTURING PRACTICE, HAZARD ANALYSIS, AND RISK-BASED PREVENTIVE CONTROLS FOR FOOD FOR ANIMALS
Subpart A—General Provisions
§ 507.1 Applicability and status.
(a) The criteria and definitions in this part apply in determining whether an animal food is:
(1) Adulterated within the meaning of:
(i) Section 402(a)(3) of the Federal Food, Drug, and Cosmetic Act in that the food has been manufactured under such conditions that it is unfit for food; or
(ii) Section 402(a)(4) of the Federal Food, Drug, and Cosmetic Act in that the food has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health; and
(2) In violation of section 361 of the Public Health Service Act (42 U.S.C. 264).
(b) The operation of a facility that manufactures, processes, packs, or holds animal food for sale in the United States if the owner, operator, or agent in charge of such facility is required to comply with, and is not in compliance with, section 418 of the Federal Food, Drug, and Cosmetic Act or subparts C, D, E, or F of this part and § 507.7 is a prohibited act under section 301(uu) of the Federal Food, Drug, and Cosmetic Act.
(c) Animal food covered by specific current good manufacturing practice regulations also is subject to the requirements of those regulations.
(d) Except as provided by § 507.12, if a facility is required to comply with subpart B of part 507 and is also required to comply with subpart B of part 117 of this chapter because the facility manufactures, processes, packs, or holds human food and animal food, then the facility may choose to comply with the requirements in subpart B of part 117, instead of subpart B of part 507, as to the manufacturing, processing, packing, and holding of animal food at that facility. If a facility is required to comply with subpart C of part 507 and is also required to comply with subpart C of part 117 of this chapter, then the facility may choose to comply with the requirements in subpart C of part 117 as to the manufacturing, processing, packing, and holding of animal food at the facility, instead of subpart C of part 507, provided the food safety plan also addresses hazards for the animal food, if applicable, that require a preventive control. When applying the requirements of part 117 of this chapter to animal food, the term “food” in part 117 includes animal food.
§ 507.3 Definitions.
The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act apply to such terms when used in this part. The following definitions also apply:
Adequate means that which is needed to accomplish the intended purpose in keeping with good public (human and animal) health practice.
Affiliate means any facility that controls, is controlled by, or is under common control with another facility.
Animal food means food for animals other than man and includes pet food, animal feed, and raw materials and ingredients.
Audit means the systematic, independent, and documented examination (through observation, investigation, records review, discussions with employees of the audited entity, and, as appropriate, sampling and laboratory analysis) to assess an audited entity’s food safety processes and procedures.
Calendar day means every day shown on the calendar.
Correction means an action to identify and correct a problem that occurred during the production of animal food, without other actions associated with a corrective action procedure (such as actions to reduce the likelihood that the problem will recur, evaluate all affected animal food for safety, and prevent affected animal food from entering commerce).
Critical control point means a point, step, or procedure in a food process at which control can be applied and is essential to prevent or eliminate a food safety hazard or reduce such hazard to an acceptable level.
Environmental pathogen means a pathogen capable of surviving and persisting within the manufacturing, processing, packing, or holding environment such that food for animals may be contaminated and may result in foodborne illness if that animal food is not treated to significantly minimize or prevent the environmental pathogen. Examples of environmental pathogens for the purposes of this part include Listeria monocytogenes and Salmonella spp. but do not include the spores of pathogenic sporeforming bacteria.
Facility means a domestic facility or a foreign facility that is required to register under section 415 of the Federal Food, Drug, and Cosmetic Act, in accordance with the requirements of part 1, subpart H of this chapter.
Farm means farm as defined in § 1.227 of this chapter.
FDA means the Food and Drug Administration.
Food means food as defined in section 201(f) of the Federal Food, Drug, and Cosmetic Act and includes raw materials and ingredients.
Food-contact surfaces are those surfaces that contact animal food and those surfaces from which drainage, or other transfer, onto the animal food or onto surfaces that contact the animal food ordinarily occurs during the normal course of operations. “Food-contact surfaces” includes utensils and animal food-contact surfaces of equipment.
Full-time equivalent employee is a term used to represent the number of employees of a business entity for the purpose of determining whether the business qualifies for the small business exemption. The number of full-time equivalent employees is determined by dividing the total number of hours of salary or wages paid directly to employees of the business entity and of all of its affiliates and subsidiaries by the number of hours of work in 1 year, 2,080 hours (i.e., 40 hours × 52 weeks). If the result is not a whole number, round down to the next lowest whole number.
Harvesting applies to farms and farm mixed-type facilities and means activities that are traditionally performed on farms for the purpose of removing raw agricultural commodities from the place they were grown or raised and preparing them for use as animal food. Harvesting is limited to activities performed on raw agricultural commodities, or on processed foods created by drying/dehydrating a raw agricultural commodity without additional manufacturing/processing, on a farm. Harvesting does not include activities that transform a raw agricultural commodity into a processed food as defined in section 201(gg) of the Federal Food, Drug, and Cosmetic Act. Examples of harvesting include cutting (or otherwise separating) the edible portion of the raw agricultural commodity from the crop plant and removing or trimming part of the raw agricultural commodity (e.g., foliage, husks, roots, or stems). Examples of harvesting also include cooling, field coring, filtering, gathering, hulling, shelling, sifting, threshing, trimming of outer leaves of, and washing raw agricultural commodities grown on a farm.
Hazard means any biological, chemical (including radiological), or physical agent that has the potential to cause illness or injury in humans or animals.
Hazard requiring a preventive control means a known or reasonably foreseeable hazard for which a person knowledgeable about the safe manufacturing, processing, packing, or holding of animal food would, based on the outcome of a hazard analysis (which includes an assessment of the severity of the illness or injury to humans or animals if the hazard were to occur and the probability that the hazard will occur in the absence of preventive controls), establish one or more preventive controls to significantly minimize or prevent the hazard in an animal food and components to manage those controls (such as monitoring, corrections or corrective actions, verification, and records) as appropriate to the animal food, the facility, and the nature of the preventive control and its role in the facility’s food safety system.
Holding means storage of animal food and also includes activities performed incidental to storage of an animal food (e.g., activities performed for the safe or effective storage of that animal food, such as fumigating animal food during storage, and drying/dehydrating raw agricultural commodities when the drying/dehydrating does not create a distinct commodity (such as drying/dehydrating hay or alfalfa)). Holding also includes activities performed as a practical necessity for the distribution of that animal food (such as blending of the same raw agricultural commodity and breaking down pallets), but does not include activities that transform a raw agricultural commodity into a processed food as defined in section 201(gg) of the Federal Food, Drug, and Cosmetic Act. Holding facilities could include warehouses, cold storage facilities, storage silos, grain elevators, and liquid-storage tanks.
Known or reasonably foreseeable hazard means a biological, chemical (including radiological), or physical hazard that is known to be, or has the potential to be, associated with the facility or the animal food.
Lot means the animal food produced during a period of time and identified by an establishment’s specific code.
Manufacturing/processing means making animal food from one or more ingredients, or synthesizing, preparing, treating, modifying, or manipulating animal food, including food crops or ingredients. Examples of manufacturing/processing activities include: Baking, boiling, bottling, canning, cooking, cooling, cutting, distilling, drying/dehydrating raw agricultural commodities to create a distinct commodity (such as drying/dehydrating grapes to produce raisins), evaporating, eviscerating, extracting juice, extruding, formulating, freezing, grinding, homogenizing, irradiating, labeling, milling, mixing, packaging (including modified atmosphere packaging), pasteurizing, peeling, pelleting, rendering, treating to manipulate ripening, trimming, washing, or waxing. For farms and farm mixed-type facilities, manufacturing/processing does not include activities that are part of harvesting, packing, or holding.
Microorganisms means yeasts, molds, bacteria, viruses, protozoa, and microscopic parasites and includes species that are pathogens. The term “undesirable microorganisms” includes those microorganisms that are pathogens, that subject animal food to decomposition, that indicate that animal food is contaminated with filth, or that otherwise may cause animal food to be adulterated.
Mixed-type facility means an establishment that engages in both activities that are exempt from registration under section 415 of the Federal Food, Drug, and Cosmetic Act and activities that require the establishment to be registered. An example of such a facility is a “farm mixed-type facility,” which is an establishment that is a farm, but also conducts activities outside the farm definition that require the establishment to be registered.
Monitor means to conduct a planned sequence of observations or measurements to assess whether control measures are operating as intended.
Packing means placing animal food into a container other than packaging the animal food and also includes repacking and activities performed incidental to packing or repacking an animal food (e.g., activities performed for the safe or effective packing or repacking of that animal food (such as sorting, culling, grading, and weighing or conveying incidental to packing or repacking)), but does not include activities that transform a raw agricultural commodity into a processed food as defined in section 201(gg) of the Federal Food, Drug, and Cosmetic Act.
Pathogen means a microorganism of public (human or animal) health significance.
Pest refers to any objectionable animals or insects including birds, rodents, flies, and larvae.
Plant means the building or structure, or parts thereof, used for or in connection with the manufacturing, processing, packing, or holding of animal food.
Preventive controls means those risk-based, reasonably appropriate procedures, practices, and processes that a person knowledgeable about the safe manufacturing, processing, packing, or holding of animal food would employ to significantly minimize or prevent the hazards identified under the hazard analysis that are consistent with the current scientific understanding of safe food manufacturing, processing, packing, or holding at the time of the analysis.
Preventive controls qualified individual means a qualified individual who has successfully completed training in the development and application of risk-based preventive controls at least equivalent to that received under a standardized curriculum recognized as adequate by FDA, or is otherwise qualified through job experience to develop and apply a food safety system.
Qualified auditor means a person who is a qualified individual as defined in this part and has technical expertise obtained through education, training, or experience (or the combination thereof) necessary to perform the auditing function. Examples of potential qualified auditors include:
(1) A government employee, including a foreign government employee; and
(2) An audit agent of a certification body that is accredited in accordance with regulations in part 1, subpart M of this chapter.
Qualified end-user, with respect to food, means the consumer of the food (where the term consumer does not include a business); or a restaurant or retail food establishment (as those terms are defined in § 1.227 of this chapter) that:
(1) Is located:
(i) In the same State or the same Indian reservation as the qualified facility that sold the food to such restaurant or retail food establishment; or
(ii) Not more than 275 miles from such facility; and
(2) Is purchasing the food for sale directly to consumers at such restaurant or retail food establishment.
Qualified facility means (when including the sales by any subsidiary; affiliate; or subsidiaries or affiliates, collectively, of any entity of which the facility is a subsidiary or affiliate) a facility that is a very small business as defined in this part, or a facility to which both of the following apply:
(1) During the 3-year period preceding the applicable calendar year, the average annual monetary value of the food manufactured, processed, packed, or held at such facility that is sold directly to qualified end-users (as defined in this part) during such period exceeded the average annual monetary value of the food sold by such facility to all other purchasers; and
(2) The average annual monetary value of all food sold during the 3-year period preceding the applicable calendar year was less than $500,000, adjusted for inflation.
Qualified facility exemption means an exemption applicable to a qualified facility under § 507.5(d).
Qualified individual means a person who has the education, training, or experience (or a combination thereof) necessary to manufacture, process, pack, or hold safe animal food as appropriate to the individual’s assigned duties. A qualified individual may be, but is not required to be, an employee of the establishment.
Raw agricultural commodity has the meaning given in section 201(r) of the Federal Food, Drug, and Cosmetic Act.
Receiving facility means a facility that is subject to subparts C and E of this part and that manufactures/processes a raw material or other ingredient that it receives from a supplier.
Rework means clean, unadulterated animal food that has been removed from processing for reasons other than insanitary conditions or that has been successfully reconditioned by reprocessing and that is suitable for use as animal food.
Sanitize means to adequately treat cleaned surfaces by a process that is effective in destroying vegetative cells of pathogens, and in substantially reducing numbers of other undesirable microorganisms, but without adversely affecting the product or its safety for animals or humans.
Significantly minimize means to reduce to an acceptable level, including to eliminate.
Small business means, for purposes of this part, a business (including any subsidiaries and affiliates) employing fewer than 500 full-time equivalent employees.
Subsidiary means any company which is owned or controlled directly or indirectly by another company.
Supplier means the establishment that manufactures/processes the animal food, raises the animal, or grows the food that is provided to a receiving facility without further manufacturing/processing by another establishment, except for further manufacturing/processing that consists solely of the addition of labeling or similar activity of a de minimis nature.
Supply-chain-applied control means a preventive control for a hazard in a raw material or other ingredient when the hazard in the raw material or other ingredient is controlled before its receipt.
Unexposed packaged animal food means packaged animal food that is not exposed to the environment.
Validation means obtaining and evaluating scientific and technical evidence that a control measure, combination of control measures, or the food safety plan as a whole, when properly implemented, is capable of effectively controlling the identified hazards.
Verification means the application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine whether a control measure or combination of control measures is or has been operating as intended and to establish the validity of the food safety plan.
Very small business means, for purposes of this part, a business (including any subsidiaries and affiliates) averaging less than $2,500,000, adjusted for inflation, per year, during the 3-year period preceding the applicable calendar year in sales of animal food plus the market value of animal food manufactured, processed, packed, or held without sale (e.g., held for a fee or supplied to a farm without sale).
Water activity (a
Written procedures for receiving raw materials and other ingredients means written procedures to ensure that raw materials and other ingredients are received only from suppliers approved by the receiving facility (or, when necessary and appropriate, on a temporary basis from unapproved suppliers whose raw materials or other ingredients are subjected to adequate verification activities before acceptance for use).
You means, for purposes of this part, the owner, operator, or agent in charge of a facility.
§ 507.4 Qualifications of individuals who manufacture, process, pack, or hold animal food.
(a)(1) The management of an establishment must ensure that all individuals who manufacture, process, pack, or hold animal food subject to subparts B and F of this part are qualified to perform their assigned duties; and
(2) The owner, operator, or agent in charge of a facility must ensure that all individuals who manufacture, process, pack, or hold animal food subject to subparts C, D, E, or F of this part are qualified to perform their assigned duties.
(b) Each individual engaged in manufacturing, processing, packing, or holding animal food (including temporary and seasonal personnel) or in the supervision thereof must:
(1) Be a qualified individual as that term is defined in § 507.3, i.e., have the education, training, or experience (or a combination thereof) necessary to manufacture, process, pack, or hold safe animal food as appropriate to the individual’s assigned duties; and
(2) Receive training in the principles of animal food hygiene and animal food safety, including the importance of employee health and personal hygiene, as appropriate to the animal food, the facility and the individual’s assigned duties.
(c) Responsibility for ensuring compliance by individuals with the requirements of this part must be clearly assigned to supervisory personnel who have the education, training, or experience (or a combination thereof) necessary to supervise the production of safe animal food.
(d) Records that document training required by paragraph (b)(2) of this section must be established and maintained and are subject to the recordkeeping requirements in subpart F of this part.
§ 507.5 Exemptions.
(a) This part does not apply to establishments, including “farms” (as defined in § 1.227 of this chapter), that are not required to register under section 415 of the Federal Food, Drug, and Cosmetic Act.
(b)(1) Subparts C and E of this part do not apply with respect to activities that are subject to § 500.23 and part 113 of this chapter (Thermally Processed Low-Acid Foods Packaged in Hermetically Sealed Containers) at an animal food facility if you are required to comply with, and are in compliance with, part 113 of this chapter with respect to those activities.
(2) The exemption in paragraph (b)(1) of this section is applicable only with respect to those microbiological hazards regulated under part 113 of this chapter.
(c) Subparts C and E of this part do not apply to activities of a facility that are subject to section 419 of the Federal Food, Drug, and Cosmetic Act (Standards for Produce Safety).
(d) Except as provided in subpart D of this part, subparts C and E of this part do not apply to a qualified facility. Qualified facilities are subject to the requirements in § 507.7.
(e) For a farm mixed-type facility that is a small or very small business, subparts C and E of this part do not apply to on-farm packing or holding of processed animal food, and § 507.7 does not apply to on-farm packing or holding of processed animal food by a very small business, if the only packing or holding activities subject to section 418 of the Federal Food, Drug, and Cosmetic Act that the business conducts are the following low-risk packing or holding activity/animal food combinations—i.e., packing (or repacking) (including weighing or conveying incidental to packing or repacking); sorting, culling, or grading incidental to packing or storing; and storing (ambient, cold and controlled atmosphere) of:
(1) Roughage products (e.g., alfalfa meal, entire plant meal, stem meal, pomace, and pulp);
(2) Plant protein meals (e.g., algae, coconut (copra), guar, and peanut);
(3) Grain by-products and processed grain products (e.g., bran, flour, germ meal, grits, groats, hominy feed, malt sprouts, middlings, pearled grain, polished grain, brewers grain, distillers grain, and gluten meal);
(4) Oilseed products (e.g., oil and meal of safflower, soybean, or sunflower);
(5) Molasses (e.g., processed sugar cane, sugar beets, and citrus);
(6) Animal protein meals (e.g., blood, feather, meat, meat and bone, and marine (e.g., crab, fish, shrimp));
(7) Milk products (e.g., casein, cheese rind, and lactalbumin);
(8) Animal tissue-derived products (e.g., fat);
(9) Vitamins, minerals, and concentrates;
(10) Processing aids (e.g., enzymes, preservatives, and stabilizers); and
(11) Any other processed animal food that does not require time/temperature control for safety.
(f) For a farm mixed-type facility that is a small or very small business, subparts C and E of this part do not apply to on-farm manufacturing/processing activities conducted by a small or very small business for distribution into commerce, and § 507.7 does not apply to on-farm manufacturing/processing activities conducted by a very small business for distribution into commerce, if the only manufacturing/processing activities subject to section 418 of the Federal Food, Drug, and Cosmetic Act that the business conducts consists of the following low-risk manufacturing/processing activity/animal food combinations:
(1) Chopping or shredding hay;
(2) Cracking, crimping, flaking, pearling, peeling, shelling, or wafering—grain (e.g., barley, sorghum, corn, oats, rice, rye, and wheat) or oilseed (e.g., beans, canola, cottonseed, linseed, soybeans, and sunflowers);
(3) Crushing, dry rolling, grinding, milling, pulverizing—grain, oilseed, grain by-products and processed grain products, oilseed products, hay, ensiled material, culled fruits and vegetables, roughage (e.g., cobs, hulls, husks, and straws), or roughage products;
(4) Ensiling (including chopping, shredding, mixing, storing, or fermenting), that is, making silage or haylage from forage (e.g., sorghum (milo), corn (maize), alfalfa, and grass), grain, culled fruits and vegetables, or roughage;
(5) Extracting (mechanical) or wet rolling grain, oilseed, brewers grain by-products, or distillers grain by-products;
(6) Labeling roughage products, plant protein meals, grain by-products and processed grain products, oilseed products, molasses, animal protein meals, milk products, animal tissue-derived products, vitamins, minerals, concentrates, processing aids, finished animal food, including animal food ready for consumption, or any other processed animal food that does not require time/temperature control for safety; and
(7) Packaging roughage products, plant protein meals, grain by-products and processed grain products, oilseed products, molasses, animal protein meals, milk products, animal tissue-derived products, vitamins, minerals, concentrates, processing aids, finished animal food, including animal food ready for consumption, or any other processed animal food that does not require time/temperature control for safety.
(g) Subparts C and E of this part do not apply to facilities that are solely engaged in the storage of raw agricultural commodities (other than fruits and vegetables) intended for further distribution or processing.
(h) Subpart B of this part does not apply to any of the following:
(1) Establishments solely engaged in the holding and/or transportation of one or more raw agricultural commodities;
(2) Establishments solely engaged in hulling, shelling, drying, packing, and/or holding nuts and hulls (without manufacturing/processing, such as grinding shells or roasting nuts); and
(3) Establishments solely engaged in ginning of cotton (without manufacturing/processing, such as extracting oil from cottonseed).
§ 507.7 Requirements that apply to a qualified facility.
(a) A qualified facility must submit the following attestations to FDA:
(1) An attestation that the facility is a qualified facility as defined in § 507.3. For the purpose of determining whether a facility satisfies the definition of qualified facility, the baseline year for calculating the adjustment for inflation is 2011; and
(2)(i) An attestation that you have identified the potential hazards associated with the animal food being produced, are implementing preventive controls to address the hazards, and are monitoring the performance of the preventive controls to ensure that such controls are effective; or
(ii) An attestation that the facility is in compliance with State, local, county, tribal, or other applicable non-Federal food safety law, including relevant laws and regulations of foreign countries, including an attestation based on licenses, inspection reports, certificates, permits, credentials, certification by an appropriate agency (such as a State department of agriculture), or other evidence of oversight.
(b) The attestations required by paragraph (a) of this section must be submitted to FDA by any one of the following means:
(1) Electronic submission. To submit electronically, go to http://www.fda.gov/furls and follow the instructions. This Web site is available from wherever the Internet is accessible, including libraries, copy centers, schools, and Internet cafes. FDA encourages electronic submission.
(2) Submission by mail. (i) You must use Form FDA 3942b. You may obtain a copy of this form by any of the following mechanisms:
(A) Download it from http://www.fda.gov/pcafrule;
(B) Write to the U.S. Food and Drug Administration (HFS-681), 5001 Campus Dr., College Park, MD 20740; or
(C) Request a copy of this form by phone at 1-800-216-7331 or 301-575-0156.
(ii) Send a paper Form FDA 3942b to the U.S. Food and Drug Administration (HFS-681), 5001 Campus Dr., College Park, MD 20740. We recommend that you submit a paper copy only if your facility does not have reasonable access to the Internet.
(c)(1) A facility must determine and document its status as a qualified facility on an annual basis no later than July 1 of each calendar year.
(2) The attestations required by paragraph (a) of this section must be:
(i) Submitted to FDA initially:
(A) By December 16, 2019 for a facility that begins manufacturing, processing, packing, or holding animal food before September 17, 2019;
(B) Before beginning operations, for a facility that begins manufacturing, processing, packing, or holding animal food after September 17, 2019; or
(C) By July 31 of the applicable calendar year, when the status of a facility changes from “not a qualified facility” to “qualified facility” based on the annual determination required by paragraph (c)(1) of this section; and
(ii) Beginning in 2020, submitted to FDA every 2 years during the period beginning on October 1 and ending on December 31.
(3) When the status of a facility changes from “qualified facility” to “not a qualified facility” based on the annual determination required by paragraph (c)(1) of this section, the facility must notify FDA of that change in status using Form FDA 3942b by July 31 of the applicable calendar year.
(d) When the status of a facility changes from “qualified facility” to “not a qualified facility,” the facility must comply with subparts C and E of this part no later than December 31 of the applicable calendar year unless otherwise agreed to by FDA and the facility.
(e) A qualified facility that does not submit attestations under paragraph (a)(2)(i) of this section must provide notification to consumers as to the name and complete business address of the facility where the animal food was manufactured or processed (including the street address or P.O. Box, city, state, and zip code for domestic facilities, and comparable full address information for foreign facilities) as follows:
(1) If an animal food packaging label is required, the notification required by paragraph (e) of this section must appear prominently and conspicuously on the label of the animal food.
(2) If an animal food packaging label is not required, the notification required by paragraph (e) of this section must appear prominently and conspicuously, at the point of purchase, on a label, poster, sign, placard, or documents delivered contemporaneously with the animal food in the normal course of business, or in an electronic notice, in the case of Internet sales.
(f)(1) A qualified facility must maintain those records relied upon to support the attestations that are required by paragraph (a) of this section.
(2) The records that a qualified facility must maintain are subject to the requirements of subpart F of this part.
§ 507.10 Applicability of subparts C and E of this part to a facility solely engaged in the storage of unexposed packaged animal food.
(a) Subparts C and E of this part do not apply to a facility solely engaged in the storage of unexposed packaged animal food that does not require time/temperature control to significantly minimize or prevent the growth of, or toxin production by, pathogens.
(b) A facility solely engaged in the storage of unexposed packaged animal food, including unexposed packaged animal food that requires time/temperature control to significantly minimize or prevent the growth of, or toxin production by, pathogens is subject to the modified requirements in § 507.51 for any unexposed packaged animal food that requires time/temperature control to significantly minimize or prevent the growth of, or toxin production by, pathogens.
§ 507.12 Applicability of this part to the holding and distribution of human food by-products for use as animal food.
(a) Except as provided by paragraph (b) of this section, the requirements of this part do not apply to by-products of human food production, or the off-farm packing and holding of raw agricultural commodities, that are packed or held by that human food facility for distribution as animal food if:
(1)(i) The human food facility is subject to and in compliance with subpart B of part 117 of this chapter and in compliance with all applicable human food safety requirements of the Federal Food, Drug, and Cosmetic Act and implementing regulations; or
(ii) For the off-farm packing and holding of produce (as defined in part 112 of this chapter), the human food facility is subject to and in compliance with § 117.8 of this chapter and in compliance with all applicable human food safety requirements of the Federal Food, Drug, and Cosmetic Act and implementing regulations; and
(2) The human food facility does not further manufacture or process the by-products intended for use as animal food.
(b) The human food by-products for use as animal food identified in paragraph (a) of this section must be held and distributed by that facility in accordance with §§ 507.28 and 117.95 of this chapter.
Subpart B—Current Good Manufacturing Practice
§ 507.14 Personnel.
(a) The management of the establishment must take reasonable measures and precautions to ensure that all persons working in direct contact with animal food, animal food-contact surfaces, and animal food-packaging materials conform to hygienic practices to the extent necessary to protect against the contamination of animal food.
(b) The methods for conforming to hygienic practices and maintaining cleanliness include:
(1) Maintaining adequate personal cleanliness;
(2) Washing hands thoroughly in an adequate hand-washing facility as necessary and appropriate to protect against contamination;
(3) Removing or securing jewelry and other objects that might fall into animal food, equipment, or containers;
(4) Storing clothing or other personal belongings in areas other than where animal food is exposed or where equipment or utensils are cleaned; and
(5) Taking any other necessary precautions to protect against the contamination of animal food, animal food-contact surfaces, or animal food-packaging materials.
§ 507.17 Plant and grounds.
(a) The grounds around an animal food plant under the control of the management of the establishment must be kept in a condition that will protect against the contamination of animal food. Maintenance of grounds must include:
(1) Properly storing equipment, removing litter and waste, and cutting weeds or grass within the immediate vicinity of the plant that may constitute an attractant, breeding place, or harborage for pests;
(2) Maintaining driveways, yards, and parking areas so that they do not constitute a source of contamination in areas where animal food is exposed;
(3) Adequately draining areas that may contribute to contamination of animal food; and
(4) Treating and disposing of waste so that it does not constitute a source of contamination in areas where animal food is exposed.
(b) The plant must be suitable in size, construction, and design to facilitate cleaning, maintenance, and pest control to reduce the potential for contamination of animal food, animal food-contact surfaces, and animal food-packaging materials, including that the plant must:
(1) Provide adequate space between equipment, walls, and stored materials to permit employees to perform their duties and to allow cleaning and maintenance of equipment;
(2) Be constructed in a manner such that drip or condensate from fixtures, ducts, and pipes does not serve as a source of contamination;
(3) Provide adequate ventilation (mechanical or natural) where necessary and appropriate to minimize vapors (e.g., steam) and fumes in areas where they may contaminate animal food and in a manner that minimizes the potential for contaminating animal food;
(4) Provide adequate lighting in hand-washing areas, toilet rooms, areas where animal food is received, manufactured, processed, packed, or held, and areas where equipment or utensils are cleaned; and
(5) Provide shatter-resistant light bulbs, fixtures, and skylights, or other glass items suspended over exposed animal food in any step of preparation, to protect against the contamination of animal food in case of glass breakage.
(c) The plant must protect animal food stored outdoors in bulk from contamination by any effective means, including:
(1) Using protective coverings where necessary and appropriate;
(2) Controlling areas over and around the bulk animal food to eliminate harborages for pests; and
(3) Checking on a regular basis for pests, pest infestation, and product condition related to safety of the animal food.
§ 507.19 Sanitation.
(a) Buildings, structures, fixtures, and other physical facilities of the plant must be kept clean and in good repair to prevent animal food from becoming adulterated.
(b) Animal food-contact and non-contact surfaces of utensils and equipment must be cleaned and maintained and utensils and equipment stored as necessary to protect against the contamination of animal food, animal food-contact surfaces, or animal food-packaging materials. When necessary, equipment must be disassembled for thorough cleaning. In addition:
(1) When animal food-contact surfaces used for manufacturing, processing, packing, or holding animal food are wet-cleaned, the surfaces must, when necessary, be thoroughly dried before subsequent use; and
(2) In wet processing of animal food, when cleaning and sanitizing are necessary to protect against the introduction of undesirable microorganisms into animal food, all animal food-contact surfaces must be cleaned and sanitized before use and after any interruption during which the animal food-contact surfaces may have become contaminated.
(c) Cleaning compounds and sanitizing agents must be safe and adequate under the conditions of use.
(d) The following applies to toxic materials:
(1) Only the following toxic materials may be used or stored in the plant area where animal food is manufactured, processed, or exposed:
(i) Those required to maintain clean and sanitary conditions;
(ii) Those necessary for use in laboratory testing procedures;
(iii) Those necessary for plant and equipment maintenance and operation; and
(iv) Those necessary for use in the plant’s operations.
(2) Toxic materials described in paragraph (d)(1) of this section (e.g., cleaning compounds, sanitizing agents, and pesticide chemicals) must be identified, used, and stored in a manner that protects against the contamination of animal food, animal food-contact surfaces, or animal food-packaging materials; and
(3) Other toxic materials (such as fertilizers and pesticides not included in paragraph (d)(1) of this section) must be stored in an area of the plant where animal food is not manufactured, processed, or exposed.
(e) Effective measures must be taken to exclude pests from the manufacturing, processing, packing, and holding areas and to protect against the contamination of animal food by pests. The use of pesticides in the plant is permitted only under precautions and restrictions that will protect against the contamination of animal food, animal food-contact surfaces, and animal food-packaging materials.
(f) Trash must be conveyed, stored, and disposed of in a way that protects against the contamination of animal food, animal food-contact surfaces, animal food-packaging materials, water supplies, and ground surfaces, and minimizes the potential for the trash to become an attractant and harborage or breeding place for pests.
§ 507.20 Water supply and plumbing.
(a) The following apply to the water supply:
(1) Water must be adequate for the operations and must be derived from an adequate source;
(2) Running water at a suitable temperature, and under suitable pressure as needed, must be provided in all areas where required for the manufacturing, processing, packing, or holding of animal food, for the cleaning of equipment, utensils, and animal food-packaging materials, or for employee hand-washing facilities;
(3) Water that contacts animal food, animal food-contact surfaces, or animal food-packaging materials must be safe for its intended use; and
(4) Water may be reused for washing, rinsing, or conveying animal food if it does not increase the level of contamination of the animal food.
(b) Plumbing must be designed, installed, and maintained to:
(1) Carry adequate quantities of water to required locations throughout the plant;
(2) Properly convey sewage and liquid disposable waste from the plant;
(3) Avoid being a source of contamination to animal food, water supplies, equipment, or utensils, or creating an unsanitary condition;
(4) Provide adequate floor drainage in all areas where floors are subject to flooding-type cleaning or where normal operations release or discharge water or other liquid waste on the floor; and
(5) Ensure that there is no backflow from, or cross-connection between, piping systems that discharge waste water or sewage and piping systems that carry water for animal food or animal food manufacturing.
(c) Sewage and liquid disposal waste must be disposed of through an adequate sewerage system or through other adequate means.
(d) Each plant must provide employees with adequate, readily accessible toilet facilities. Toilet facilities must be kept clean and must not be a potential source of contamination of animal food, animal food-contact surfaces, or animal food-packaging materials.
(e) Each plant must provide hand-washing facilities designed to ensure that an employee’s hands are not a potential source of contamination of animal food, animal food-contact surfaces, or animal food-packaging materials.
§ 507.22 Equipment and utensils.
(a) The following apply to plant equipment and utensils used in manufacturing, processing, packing, and holding animal food:
(1) All plant equipment and utensils, including equipment and utensils that do not come in contact with animal food, must be designed and constructed of such material and workmanship to be adequately cleanable, and must be properly maintained;
(2) Equipment and utensils must be designed, constructed, and used appropriately to avoid the adulteration of animal food with non-food grade lubricants, fuel, metal fragments, contaminated water, or any other contaminants;
(3) Equipment must be installed so as to facilitate the cleaning and maintenance of the equipment and adjacent spaces;
(4) Animal food-contact surfaces must be:
(i) Made of materials that withstand the environment of their use and the action of animal food, and, if applicable, the action of cleaning compounds, cleaning procedures, and sanitizing agents;
(ii) Made of nontoxic materials; and
(iii) Maintained to protect animal food from being contaminated.
(b) Holding, conveying, manufacturing, and processing systems, including gravimetric, pneumatic, closed, and automated systems, must be designed, constructed, and maintained in a way to protect against the contamination of animal food.
(c) Each freezer and cold storage compartment used to hold animal food must be fitted with an accurate temperature-measuring device.
(d) Instruments and controls used for measuring, regulating, or recording temperatures, pH, a
(e) Compressed air or other gases mechanically introduced into animal food or used to clean animal food-contact surfaces or equipment must be used in such a way to protect against the contamination of animal food.
§ 507.25 Plant operations.
(a) Management of the establishment must ensure that:
(1) All operations in the manufacturing, processing, packing, and holding of animal food (including operations directed to receiving, inspecting, transporting, and segregating) are conducted in accordance with the current good manufacturing practice requirements of this subpart;
(2) Animal food, including raw materials, other ingredients, or rework is accurately identified;
(3) Animal food-packaging materials are safe and suitable;
(4) The overall cleanliness of the plant is under the supervision of one or more competent individuals assigned responsibility for this function;
(5) Adequate precautions are taken so that plant operations do not contribute to contamination of animal food, animal food-contact surfaces, and animal food-packaging materials;
(6) Chemical, microbial, or extraneous-material testing procedures are used where necessary to identify sanitation failures or possible animal food contamination;
(7) Animal food that has become adulterated is rejected, disposed of, or if appropriate, treated or processed to eliminate the adulteration. If disposed of, it must be done in a manner that protects against the contamination of other animal food; and
(8) All animal food manufacturing, processing, packing, and holding is conducted under such conditions and controls as are necessary to minimize the potential for the growth of undesirable microorganisms to protect against the contamination of animal food.
(b) Raw materials and other ingredients:
(1) Must be examined to ensure that they are suitable for manufacturing and processing into animal food and must be handled under conditions that will protect against contamination and minimize deterioration. In addition:
(i) Shipping containers (e.g., totes, drums, and tubs) and bulk vehicles holding raw materials and other ingredients must be examined upon receipt to determine whether contamination or deterioration of animal food has occurred;
(ii) Raw materials must be cleaned as necessary to minimize contamination; and
(iii) Raw materials and other ingredients, including rework, must be stored in containers designed and constructed in a way that protects against contamination and deterioration, and held under conditions, e.g., appropriate temperature and relative humidity, that will minimize the potential for growth of undesirable microorganisms and prevent the animal food from becoming adulterated;
(2) Susceptible to contamination with mycotoxins or other natural toxins must be evaluated and used in a manner that does not result in animal food that can cause injury or illness to animals or humans; and
(3) If frozen, must be kept frozen. If thawing is required prior to use, it must be done in a manner that minimizes the potential for the growth of undesirable microorganisms.
(c) For the purposes of manufacturing, processing, packing, and holding operations, the following apply:
(1) Animal food must be maintained under conditions, e.g., appropriate temperature and relative humidity, that will minimize the potential for growth of undesirable microorganisms and prevent the animal food from becoming adulterated during manufacturing, processing, packing, and holding;
(2) Measures taken during manufacturing, processing, packing, and holding of animal food to significantly minimize or prevent the growth of undesirable microorganisms (e.g., heat treating, freezing, refrigerating, irradiating, controlling pH, or controlling a
(3) Work-in-process and rework must be handled in such a way that it is protected against contamination and the growth of undesirable microorganisms;
(4) Steps such as cutting, drying, defatting, grinding, mixing, extruding, pelleting, and cooling, must be performed in a way that protects against the contamination of animal food;
(5) Filling, assembling, packaging, and other operations must be performed in such a way that protects against the contamination of animal food and the growth of undesirable microorganisms;
(6) Animal food that relies principally on the control of water activity (a
(7) Animal food that relies principally on the control of pH for preventing the growth of undesirable microorganisms must be monitored and maintained at the appropriate pH; and
(8) When ice is used in contact with animal food, it must be made from water that is safe and must be used only if it has been manufactured in accordance with current good manufacturing practice as outlined in this subpart.
§ 507.27 Holding and distribution.
(a) Animal food held for distribution must be held under conditions that will protect against contamination and minimize deterioration, including the following:
(1) Containers used to hold animal food before distribution must be designed, constructed of appropriate material, cleaned as necessary, and maintained to protect against the contamination of animal food; and
(2) Animal food held for distribution must be held in a way that protects against contamination from sources such as trash.
(b) The labeling for the animal food ready for distribution must contain, when applicable, information and instructions for safely using the animal food for the intended animal species.
(c) Shipping containers (e.g., totes, drums, and tubs) and bulk vehicles used to distribute animal food must be examined prior to use to protect against the contamination of animal food from the container or vehicle when the facility is responsible for transporting the animal food itself or arranges with a third party to transport the animal food.
(d) Animal food returned from distribution must be assessed for animal food safety to determine the appropriate disposition. Returned animal food must be identified as such and segregated until assessed.
(e) Unpackaged or bulk animal food must be held in a manner that does not result in unsafe cross contamination with other animal food.
§ 507.28 Holding and distribution of human food by-products for use as animal food.
(a) Human food by-products held for distribution as animal food must be held under conditions that will protect against contamination, including the following:
(1) Containers and equipment used to convey or hold human food by-products for use as animal food before distribution must be designed, constructed of appropriate material, cleaned as necessary, and maintained to protect against the contamination of human food by-products for use as animal food;
(2) Human food by-products for use as animal food held for distribution must be held in a way to protect against contamination from sources such as trash; and
(3) During holding, human food by-products for use as animal food must be accurately identified.
(b) Labeling that identifies the product by the common or usual name must be affixed to or accompany the human food by-products for use as animal food when distributed.
(c) Shipping containers (e.g., totes, drums, and tubs) and bulk vehicles used to distribute human food by-products for use as animal food must be examined prior to use to protect against the contamination of animal food from the container or vehicle when the facility is responsible for transporting the human food by-products for use as animal food itself or arranges with a third party to transport the human food by-products for use as animal food.
Subpart C—Hazard Analysis and Risk-Based Preventive Controls
§ 507.31 Food safety plan.
(a) You must prepare, or have prepared, and implement a written food safety plan.
(b) One or more preventive controls qualified individuals must prepare, or oversee the preparation of, the food safety plan.
(c) The written food safety plan must include:
(1) The written hazard analysis as required by § 507.33(a)(2);
(2) The written preventive controls as required by § 507.34(b);
(3) The written supply-chain program as required by subpart E of this part;
(4) The written recall plan as required by § 507.38(a)(1);
(5) The written procedures for monitoring the implementation of the preventive controls as required by § 507.40(a);
(6) The written corrective action procedures as required by § 507.42(a)(1); and
(7) The written verification procedures as required by § 507.49(b).
(d) The food safety plan required by this section is a record that is subject to the requirements of subpart F of this part.
§ 507.33 Hazard analysis.
(a)(1) You must conduct a hazard analysis to identify and evaluate, based on experience, illness data, scientific reports, and other information, known or reasonably foreseeable hazards for each type of animal food manufactured, processed, packed, or held at your facility to determine whether there are any hazards requiring a preventive control; and
(2) The hazard analysis must be written regardless of its outcome.
(b) The hazard identification must consider:
(1) Known or reasonably foreseeable hazards that include:
(i) Biological hazards, including microbiological hazards such as parasites, environmental pathogens, and other pathogens;
(ii) Chemical hazards, including radiological hazards, substances such as pesticide and drug residues, natural toxins, decomposition, unapproved food or color additives, and nutrient deficiencies or toxicities (such as inadequate thiamine in cat food, excessive vitamin D in dog food, and excessive copper in food for sheep); and
(iii) Physical hazards (such as stones, glass, and metal fragments); and
(2) Known or reasonably foreseeable hazards that may be present in the animal food for any of the following reasons:
(i) The hazard occurs naturally;
(ii) The hazard may be unintentionally introduced; or
(iii) The hazard may be intentionally introduced for purposes of economic gain.
(c)(1) The hazard analysis must include an evaluation of the hazards identified in paragraph (b) of this section to assess the severity of the illness or injury to humans or animals if the hazard were to occur and the probability that the hazard will occur in the absence of preventive controls.
(2) The hazard evaluation required by paragraph (c)(1) of this section must include an evaluation of environmental pathogens whenever an animal food is exposed to the environment prior to packaging and the packaged animal food does not receive a treatment or otherwise include a control measure (such as a formulation lethal to the pathogen) that would significantly minimize the pathogen.
(d) The hazard evaluation must consider the effect of the following on the safety of the finished animal food for the intended animal:
(1) The formulation of the animal food;
(2) The condition, function, and design of the facility and equipment;
(3) Raw materials and other ingredients;
(4) Transportation practices;
(5) Manufacturing/processing procedures;
(6) Packaging activities and labeling activities;
(7) Storage and distribution;
(8) Intended or reasonably foreseeable use;
(9) Sanitation, including employee hygiene; and
(10) Any other relevant factors such as the temporal (e.g., weather-related) nature of some hazards (e.g., levels of some natural toxins).
§ 507.34 Preventive controls.
(a)(1) You must identify and implement preventive controls to provide assurances that any hazards requiring a preventive control will be significantly minimized or prevented and the animal food manufactured, processed, packed, or held by your facility will not be adulterated under section 402 of the Federal Food, Drug, and Cosmetic Act; and
(2) Preventive controls required by paragraph (a)(1) of this section include:
(i) Controls at critical control points (CCPs), if there are any CCPs; and
(ii) Controls, other than those at CCPs, that are also appropriate for animal food safety.
(b) Preventive controls must be written.
(c) Preventive controls include, as appropriate to the facility and animal food:
(1) Process controls. Process controls include procedures, practices, and processes to ensure the control of parameters during operations such as heat processing, irradiating, and refrigerating animal food. Process controls must include, as appropriate to the nature of the applicable control and its role in the facility’s food safety system:
(i) Parameters associated with the control of the hazard; and
(ii) The maximum or minimum value, or combination of values, to which any biological, chemical, or physical parameter must be controlled to significantly minimize or prevent a hazard requiring a process control.
(2) Sanitation controls. Sanitation controls include procedures, practices, and processes to ensure that the facility is maintained in a sanitary condition adequate to significantly minimize or prevent hazards such as environmental pathogens and biological hazards due to employee handling. Sanitation controls must include, as appropriate to the facility and the animal food, procedures, practices, and processes for the:
(i) Cleanliness of animal food-contact surfaces, including animal food-contact surfaces of utensils and equipment; and
(ii) Prevention of cross-contamination from insanitary objects and from personnel to animal food, animal food-packaging material, and other animal food-contact surfaces and from raw product to processed product.
(3) Supply-chain controls. Supply-chain controls include the supply-chain program as required by subpart E of this part;
(4) A recall plan as required by § 507.38; and
(5) Other preventive controls. These include any other procedures, practices, and processes necessary to satisfy the requirements of paragraph (a) of this section. Examples of other controls include hygiene training and other current good manufacturing practices.
§ 507.36 Circumstances in which the owner, operator, or agent in charge of a manufacturing/processing facility is not required to implement a preventive control.
(a) If you are a manufacturer/processor, you are not required to implement a preventive control when you identify a hazard requiring a preventive control (identified hazard) and any of the following circumstances apply:
(1) You determine and document that the type of animal food could not be consumed without application of an appropriate control;
(2) You rely on your customer who is subject to the requirements for hazard analysis and risk-based preventive controls in this subpart to ensure that the identified hazard will be significantly minimized or prevented; and you:
(i) Disclose in documents accompanying the animal food, in accordance with the practice of the trade, that the animal food is “not processed to control [identified hazard]”; and
(ii) Annually obtain from your customer written assurance, subject to the requirements of § 507.37, that the customer has established and is following procedures (identified in the written assurance) that will significantly minimize or prevent the identified hazard (except as provided in paragraph (c) of this section);
(3) You rely on your customer who is not subject to the requirements for hazard analysis and risk-based preventive controls in this subpart to provide assurance it is manufacturing, processing, or preparing the animal food in accordance with applicable animal food safety requirements and you:
(i) Disclose in documents accompanying the animal food, in accordance with the practice of the trade, that the animal food is “not processed to control [identified hazard]”; and
(ii) Annually obtain from your customer written assurance that it is manufacturing, processing, or preparing the animal food in accordance with applicable animal food safety requirements;
(4) You rely on your customer to provide assurance that the animal food will be processed to control the identified hazard by an entity in the distribution chain subsequent to the customer and you:
(i) Disclose in documents accompanying the animal food, in accordance with the practice of the trade, that the animal food is “not processed to control [identified hazard]”; and
(ii) Annually obtain from your customer written assurance, subject to the requirements of § 507.37, that your customer:
(A) Will disclose in documents accompanying the animal food, in accordance with the practice of the trade, that the animal food is “not processed to control [identified hazard]”; and
(B) Will only sell to another entity that agrees, in writing, it will:
(1) Follow procedures (identified in a written assurance) that will significantly minimize or prevent the identified hazard (if the entity is subject to the requirements for hazard analysis and risk-based preventive controls in subpart C of this part), except as provided in paragraph (d) of this section, or manufacture, process, or prepare the animal food in accordance with applicable animal food safety requirements (if the entity is not subject to the requirements for hazard analysis and risk-based preventive controls in subpart C of this part); or
(2) Obtain a similar written assurance from the entity’s customer, subject to the requirements of § 507.37, as in paragraphs (a)(4)(ii)(A) and (B) of this section, as appropriate; or
(5) You have established, documented, and implemented a system that ensures control, at a subsequent distribution step, of the hazards in the animal food you distribute and you document the implementation of that system.
(b) You must document any circumstance specified in paragraph (a) of this section that applies to you, including:
(1) A determination in accordance with paragraph (a) of this section that the type of animal food could not be consumed without application of an appropriate control;
(2) The annual written assurance from your customer in accordance with paragraph (a)(2) of this section;
(3) The annual written assurance from your customer in accordance with paragraph (a)(3) of this section;
(4) The annual written assurance from your customer in accordance with paragraph (a)(4) of this section; and
(5) Your system, in accordance with paragraph (a)(5) of this section, that ensures control, at a subsequent distribution step, of the hazards in the animal food you distribute.
(c) For the written assurance required by paragraph (a)(2)(ii) of this section, if your customer has determined that the identified hazard in paragraph (a) of this section is not a hazard in the animal food intended for use for a specific animal species, your customer’s written assurance may provide this determination (including animal species and why the identified hazard is not a hazard) instead of providing assurance of procedures established and followed that will significantly minimize or prevent the identified hazard.
(d) For the written assurance required by paragraph (a)(4)(ii)(B) of this section, if the entity in the distribution chain subsequent to your customer is subject to subpart C of this part and has determined that the identified hazard in paragraph (a) of this section is not a hazard in the animal food intended for use for a specific animal species, that entity’s written assurance may provide this determination (including animal species and why the identified hazard is not a hazard) instead of providing assurance that the identified hazard will be significantly minimized or prevented.
§ 507.37 Provision of assurances required under § 507.36(a)(2), (3), and (4).
A facility that provides a written assurance under § 507.36(a)(2), (3), or (4) must act consistently with the assurance and document its actions taken to satisfy the written assurance.
§ 507.38 Recall plan.
(a) For animal food with a hazard requiring a preventive control you must:
(1) Establish a written recall plan for the animal food; and
(2) Assign responsibility for performing all procedures in the recall plan.
(b) The written recall plan must include procedures that describe the steps to perform the following actions as appropriate to the facility:
(1) Directly notify direct consignees about the animal food being recalled, including how to return or dispose of the affected animal food;
(2) Notify the public about any hazard presented by the animal food when appropriate to protect human and animal health;
(3) Conduct effectiveness checks to verify the recall has been carried out; and
(4) Appropriately dispose of recalled animal food, e.g., through reprocessing, reworking, diverting to another use that would not present a safety concern, or destroying the animal food.
§ 507.39 Preventive control management components.
(a) Except as provided by paragraphs (b) and (c) of this section, the preventive controls required under § 507.34 are subject to the following preventive control management components as appropriate to ensure the effectiveness of the preventive controls, taking into account the nature of the preventive control and its role in the facility’s food safety system:
(1) Monitoring in accordance with § 507.40;
(2) Corrective actions and corrections in accordance with § 507.42; and
(3) Verification in accordance with § 507.45.
(b) The supply-chain program established in subpart E of this part is subject to the following preventive control management components as appropriate to ensure the effectiveness of the supply-chain program, taking into account the nature of the hazard controlled before receipt of the raw material or other ingredient:
(1) Corrective actions and corrections in accordance with § 507.42, taking into account the nature of any supplier non-conformance;
(2) Review of records in accordance with § 507.49(a)(4)(ii); and
(3) Reanalysis in accordance with § 507.50.
(c) The recall plan established in § 507.38 is not subject to the requirements of paragraph (a) of this section.
§ 507.40 Monitoring.
As appropriate to the nature of the preventive control and its role in the facility’s food safety system you must:
(a) Establish and implement written procedures, including the frequency with which they are to be performed, for monitoring the preventive controls; and
(b) Monitor the preventive controls with adequate frequency to provide assurance that they are consistently performed.
(c)(1) You must document the monitoring of preventive controls in accordance with this section in records that are subject to verification in accordance with § 507.45(a)(2) and records review in accordance with § 507.49(a)(4)(i);
(2)(i) Records of refrigeration temperature during storage of animal food that requires time/temperature control to significantly minimize or prevent the growth of, or toxin production by, pathogens may be affirmative records demonstrating temperature is controlled or exception records demonstrating loss of temperature control; and
(ii) Exception records may be adequate in circumstances other than monitoring of refrigeration temperature.
§ 507.42 Corrective actions and corrections.
(a) As appropriate to the nature of the hazard and the nature of the preventive control, except as provided by paragraph (c) of this section:
(1) You must establish and implement written corrective action procedures that must be taken if preventive controls are not properly implemented, including procedures to address, as appropriate:
(i) The presence of a pathogen or appropriate indicator organism in animal food detected as a result of product testing conducted in accordance with § 507.49(a)(2); and
(ii) The presence of an environmental pathogen or appropriate indicator organism detected through the environmental monitoring conducted in accordance with § 507.49(a)(3).
(2) The corrective action procedures must describe the steps to be taken to ensure that:
(i) Appropriate action is taken to identify and correct a problem that has occurred with implementation of a preventive control;
(ii) Appropriate action is taken when necessary, to reduce the likelihood that the problem will recur;
(iii) All affected animal food is evaluated for safety; and
(iv) All affected animal food is prevented from entering into commerce if you cannot ensure the affected animal food is not adulterated under section 402 of the Federal Food, Drug, and Cosmetic Act.
(b)(1) Except as provided by paragraph (c) of this section, you are subject to the requirements of paragraph (b)(2) of this section if any of the following circumstances apply:
(i) A preventive control is not properly implemented and a corrective action procedure has not been established;
(ii) A preventive control, combination of preventive controls, or the food safety plan as a whole is found to be ineffective; or
(iii) A review of records in accordance with § 507.49(a)(4) finds that the records are not complete, the activities conducted did not occur in accordance with the food safety plan, or appropriate decisions were not made about corrective actions.
(2) If any of the circumstances listed in paragraph (b)(1) of this section apply, you must:
(i) Take corrective action to identify and correct the problem;
(ii) Reduce the likelihood that the problem will recur;
(iii) Evaluate all affected animal food for safety;
(iv) As necessary, prevent affected animal food from entering commerce as would be done following the corrective action procedure under paragraph (a)(2) of this section; and
(v) When appropriate, reanalyze the food safety plan in accordance with § 507.50 to determine whether modification of the food safety plan is required.
(c) You do not need to comply with the requirements of paragraphs (a) and (b) of this section if:
(1) You take action, in a timely manner, to identify and correct conditions and practices that are not consistent with the sanitation controls in § 507.34(c)(2)(i) or (ii); or
(2) You take action, in a timely manner, to identify and correct a minor and isolated problem that does not directly impact product safety.
(d) All corrective actions (and, when appropriate, corrections) taken in accordance with this section must be documented in records. These records are subject to verification in accordance with § 507.45(a)(3) and records review in accordance with § 507.49(a)(4)(i).
§ 507.45 Verification.
(a) Verification activities must include, as appropriate to the nature of the preventive control and its role in the facility’s food safety system:
(1) Validation in accordance with § 507.47;
(2) Verification that monitoring is being conducted as required by § 507.39 (and in accordance with § 507.40);
(3) Verification that appropriate decisions about corrective actions are being made as required by § 507.39 (and in accordance with § 507.42);
(4) Verification of implementation and effectiveness in accordance with § 507.49; and
(5) Reanalysis in accordance with § 507.50.
(b) All verification activities conducted in accordance with this section must be documented in records.
§ 507.47 Validation.
(a) You must validate that the preventive controls identified and implemented in accordance with § 507.34 are adequate to control the hazard as appropriate to the nature of the preventive control and its role in the facility’s food safety system.
(b) The validation of the preventive controls:
(1) Must be performed (or overseen) by a preventive controls qualified individual:
(i)(A) Prior to implementation of the food safety plan; or
(B) When necessary to demonstrate the control measures can be implemented as designed:
(1) Within 90 calendar days after production of the applicable animal food first begins; or
(2) Within a reasonable timeframe, provided that the preventive controls qualified individual prepares (or oversees the preparation of) a written justification for a timeframe that exceeds 90 calendar days after production of the applicable animal food first begins;
(ii) Whenever a change to a control measure or combination of control measures could impact whether the control measure or combination of control measures, when properly implemented, will effectively control the hazards; and
(iii) Whenever a reanalysis of the food safety plan reveals the need to do so.
(2) Must include obtaining and evaluating scientific and technical evidence (or, when such evidence is not available or is inadequate, conducting studies) to determine whether the preventive controls, when properly implemented, will effectively control the hazards.
(c) You do not need to validate:
(1) The sanitation controls in § 507.34(c)(2);
(2) The recall plan in § 507.38;
(3) The supply-chain program in subpart E of this part; and
(4) Other preventive controls, if the preventive controls qualified individual prepares (or oversees the preparation of) a written justification that validation is not applicable based on factors such as the nature of the hazard, and the nature of the preventive control and its role in the facility’s food safety system.
§ 507.49 Verification of implementation and effectiveness.
(a) You must verify that the preventive controls are consistently implemented and are effectively and significantly minimizing or preventing the hazards. To do so, you must conduct activities that include the following, as appropriate to the facility, the animal food, and the nature of the preventive control and its role in the facility’s food safety system:
(1) Calibration of process monitoring and verification instruments (or checking them for accuracy);
(2) Product testing for a pathogen (or appropriate indicator organism) or other hazard;
(3) Environmental monitoring, for an environmental pathogen or for an appropriate indicator organism, if contamination of an animal food with an environmental pathogen is a hazard requiring a preventive control, by collecting and testing environmental samples; and
(4) Review of the following records within the specified timeframes, by (or under the oversight of) a preventive controls qualified individual, to ensure the records are complete, the activities reflected in the records occurred in accordance with the food safety plan, the preventive controls are effective, and appropriate decisions were made about corrective actions:
(i) Monitoring and corrective action records within 7-working days after the records are created or within a reasonable timeframe, provided that the preventive controls qualified individual prepares (or oversees the preparation of) a written justification for a timeframe that exceeds 7-working days; and
(ii) Records of calibration, testing (e.g., product testing, environmental monitoring), and supplier and supply-chain verification activities, and other verification activities within a reasonable time after the records are created; and
(5) Other activities appropriate for verification of implementation and effectiveness.
(b) As appropriate to the facility, the food, the nature of the preventive control, and the role of the preventive control in the facility’s food safety system, you must establish and implement written procedures for the following activities:
(1) The method and frequency of calibrating process monitoring instruments and verification instruments (or checking them for accuracy) as required by paragraph (a)(1) of this section;
(2) Product testing as required by paragraph (a)(2) of this section. Procedures for product testing must:
(i) Be scientifically valid;
(ii) Identify the test microorganism(s) or other analyte(s);
(iii) Specify the procedures for identifying samples, including their relationship to specific lots of product;
(iv) Include the procedures for sampling, including the number of samples and the sampling frequency;
(v) Identify the test(s) conducted, including the analytical method(s) used;
(vi) Identify the laboratory conducting the testing; and
(vii) Include the corrective action procedures required by § 507.42(a)(1).
(3) Environmental monitoring as required by paragraph (a)(3) of this section. Procedures for environmental monitoring must:
(i) Be scientifically valid;
(ii) Identify the test microorganism(s);
(iii) Identify the locations from which samples will be collected and the number of sites to be tested during routine environmental monitoring. The number and location of sampling sites must be adequate to determine whether preventive controls are effective;
(iv) Identify the timing and frequency for collecting and testing samples. The timing and frequency for collecting and testing samples must be adequate to determine whether preventive controls are effective;
(v) Identify the test(s) conducted, including the analytical method(s) used;
(vi) Identify the laboratory conducting the testing; and
(vii) Include the corrective action procedures required by § 507.42(a)(1)(ii).
§ 507.50 Reanalysis.
(a) You must conduct a reanalysis of the food safety plan as a whole at least once every 3 years.
(b) You must conduct a reanalysis of the food safety plan as a whole, or the applicable portion of the food safety plan:
(1) Whenever a significant change in the activities conducted at your facility creates a reasonable potential for a new hazard or creates a significant increase in a previously identified hazard;
(2) Whenever you become aware of new information about potential hazards associated with the animal food;
(3) Whenever appropriate after an unanticipated animal food safety problem in accordance with § 507.42(b); and
(4) Whenever you find that a preventive control, combination of preventive controls, or the food safety plan as a whole is ineffective.
(c) You must complete the reanalysis required by paragraphs (a) and (b) of this section and validate, as appropriate to the nature of the preventive control and its role in the facility’s food safety system, any additional preventive controls needed to address the hazard identified:
(1) Before any change in activities (including any change in preventive control) at the facility is operative; or
(2) When necessary to demonstrate the control measures can be implemented as designed:
(i) Within 90 calendar days after production of the applicable animal food first begins; or
(ii) Within a reasonable timeframe, provided that the preventive controls qualified individual prepares (or oversees the preparation of) a written justification for a timeframe that exceeds 90 calendar days after production of the applicable animal food first begins.
(d) You must revise the written food safety plan if a significant change in the activities conducted at your facility creates a reasonable potential for a new hazard or a significant increase in a previously identified hazard, or document the basis for the conclusion that no revisions are needed.
(e) A preventive controls qualified individual must perform (or oversee) the reanalysis.
(f) You must conduct a reanalysis of the food safety plan when FDA determines it is necessary to respond to new hazards and developments in scientific understanding.
§ 507.51 Modified requirements that apply to a facility solely engaged in the storage of unexposed packaged animal food.
(a) If a facility that is solely engaged in the storage of unexposed packaged animal food stores any such refrigerated packaged animal food that requires time/temperature control to significantly minimize or prevent the growth of, or toxin formation by pathogens, the facility must conduct the following activities as appropriate to ensure the effectiveness of the temperature controls:
(1) Establish and implement temperature controls adequate to significantly minimize or prevent the growth of, or toxin formation by, pathogens;
(2) Monitor the temperature controls with adequate frequency to provide assurance that the temperature controls are consistently performed;
(3) If there is a loss of temperature control that may impact the safety of such refrigerated packaged animal food, take appropriate corrective actions to:
(i) Correct the problem and reduce the likelihood that the problem will recur;
(ii) Evaluate all affected animal food for safety; and
(iii) Prevent the animal food from entering commerce, if you cannot ensure the affected animal food is not adulterated under section 402 of the Federal Food, Drug, and Cosmetic Act;
(4) Verify that temperature controls are consistently implemented by:
(i) Calibrating temperature monitoring and recording devices (or checking them for accuracy);
(ii) Reviewing records of calibration within a reasonable time after the records are created; and
(iii) Reviewing records of monitoring and corrective actions taken to correct a problem with the control of temperature within 7-working days after the records are created or within a reasonable timeframe, provided that the preventive controls qualified individual prepares (or oversees the preparation of) a written justification for a timeframe that exceeds 7-working days; and
(5) Establish and maintain the following records:
(i) Records (whether affirmative records demonstrating temperature is controlled or exception records demonstrating loss of temperature control) documenting the monitoring of temperature controls for any such refrigerated packaged animal food;
(ii) Records of corrective actions taken when there is a loss of temperature control that may impact the safety of any such refrigerated packaged animal food; and
(iii) Records documenting the verification activities.
(b) The records that a facility must establish and maintain under paragraph (a)(5) of this section are subject to the requirements of subpart F of this part.
§ 507.53 Requirements applicable to a preventive controls qualified individual and a qualified auditor.
(a) One or more preventive controls qualified individuals must do or oversee the following:
(1) Preparation of the food safety plan (§ 507.31(b));
(2) Validation of the preventive controls (§ 507.47(b)(1));
(3) Written justification for validation to be performed in a timeframe that exceeds the first 90 calendar days of production of the applicable animal food;
(4) Determination that validation is not required (§ 507.47(c)(4));
(5) Review of records (§ 507.49(a)(4));
(6) Written justification for review of records of monitoring and corrective actions within a timeframe that exceeds 7-working days;
(7) Reanalysis of the food safety plan (§ 507.50(d)); and
(8) Determination that reanalysis can be completed, and additional preventive controls validated, as appropriate to the nature of the preventive control and its role in the facility’s food safety system, in a timeframe that exceeds the first 90 calendar days of production of the applicable animal food.
(b) A qualified auditor must conduct an onsite audit (§ 507.135(a)).
(c)(1) To be a preventive controls qualified individual, the individual must have successfully completed training in the development and application of risk-based preventive controls at least equivalent to that received under a standardized curriculum recognized as adequate by FDA or be otherwise qualified through job experience to develop and apply a food safety system. Job experience may qualify an individual to perform these functions if such experience has provided an individual with knowledge at least equivalent to that provided through the standardized curriculum. This individual may be, but is not required to be, an employee of the facility; and
(2) To be a qualified auditor, a qualified individual must have technical expertise obtained through education, training, or experience (or a combination thereof) necessary to perform the auditing function.
(d) All applicable training in the development and application of risk-based preventive controls must be documented in records, including the date of the training, the type of training, and the person(s) trained.
§ 507.55 Implementation records required for this subpart.
(a) You must establish and maintain the following records documenting implementation of the food safety plan:
(1) Documentation, as required by § 507.36(b), of the basis for not establishing a preventive control in accordance with § 507.36(a);
(2) Records that document the monitoring of preventive controls;
(3) Records that document corrective actions;
(4) Records that document verification, including, as applicable, those related to:
(i) Validation;
(ii) Verification of monitoring;
(iii) Verification of corrective actions;
(iv) Calibration of process monitoring and verification instruments;
(v) Product testing;
(vi) Environmental monitoring;
(vii) Records review; and
(viii) Reanalysis;
(5) Records that document the supply-chain program; and
(6) Records that document applicable training for the preventive controls qualified individual and the qualified auditor.
(b) The records that you must establish and maintain are subject to the requirements of subpart F of this part.
Subpart D—Withdrawal of a Qualified Facility Exemption
§ 507.60 Circumstances that may lead FDA to withdraw a qualified facility exemption.
(a) FDA may withdraw a qualified facility exemption under § 507.5(d):
(1) In the event of an active investigation of a foodborne illness outbreak that is directly linked to the qualified facility; or
(2) If FDA determines that it is necessary to protect the public (human or animal) health and prevent or mitigate a foodborne illness outbreak based on conditions or conduct associated with the qualified facility that are material to the safety of the animal food manufactured, processed, packed, or held at such facility.
(b) Before FDA issues an order to withdraw a qualified facility exemption, FDA:
(1) May consider one or more other actions to protect the public (human or animal) health or mitigate a foodborne illness outbreak, including, a warning letter, recall, administrative detention, suspension of registration, refusal of animal food offered for import, seizure, and injunction;
(2) Must notify the owner, operator, or agent in charge of the facility, in writing of circumstances that may lead FDA to withdraw the exemption, and provide an opportunity for the owner, operator, or agent in charge of the facility to respond in writing, within 15 calendar days of the date of receipt of the notification, to FDA’s notification; and
(3) Must consider the actions taken by the facility to address the circumstances that may lead FDA to withdraw the exemption.
§ 507.62 Issuance of an order to withdraw a qualified facility exemption.
(a) An FDA Division Director in whose division the qualified facility is located (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine), or an FDA official senior to either such Director, must approve an order to withdraw the exemption before the order is issued.
(b) Any officer or qualified employee of FDA may issue an order to withdraw the exemption after it has been approved in accordance with paragraph (a) of this section.
(c) FDA must issue an order to withdraw the exemption to the owner, operator, or agent in charge of the facility.
(d) FDA must issue an order to withdraw the exemption in writing, signed and dated by the officer or qualified employee of FDA who is issuing the order.
§ 507.65 Contents of an order to withdraw a qualified facility exemption.
An order to withdraw a qualified facility exemption under § 507.5(d) must include the following information:
(a) The date of the order;
(b) The name, address, and location of the qualified facility;
(c) A brief, general statement of the reasons for the order, including information relevant to one or both of the following circumstances that leads FDA to issue the order:
(1) An active investigation of a foodborne illness outbreak that is directly linked to the facility; or
(2) Conditions or conduct associated with a qualified facility that are material to the safety of the animal food manufactured, processed, packed, or held at such facility.
(d) A statement that the facility must either:
(1) Comply with subparts C and E of this part on the date that is 120 calendar days after the date of receipt of the order or within a reasonable timeframe, agreed to by FDA, based on a written justification, submitted to FDA, for a timeframe that exceeds 120 calendar days from the date of receipt of the order; or
(2) Appeal the order within 15 calendar days of the date of receipt of the order in accordance with the requirements of § 507.69.
(e) A statement that a facility may request that FDA reinstate an exemption that was withdrawn by following the procedures in § 507.85;
(f) The text of section 418(l) of the Federal Food, Drug, and Cosmetic Act and of this subpart;
(g) A statement that any informal hearing on an appeal of the order must be conducted as a regulatory hearing under part 16 of this chapter, with certain exceptions described in § 507.73;
(h) The mailing address, telephone number, email address, fax number, and name of the FDA Division Director in whose division the facility is located (or, in the case of a foreign facility, the same information for the Director of the Division of Compliance in the Center for Veterinary Medicine); and
(i) The name and the title of the FDA representative who approved the order.
§ 507.67 Compliance with, or appeal of, an order to withdraw a qualified facility exemption.
(a) If you receive an order under § 507.65 to withdraw a qualified facility exemption, you must either:
(1) Comply with applicable requirements of this part within 120 calendar days of the date of receipt of the order, or within a reasonable timeframe, agreed to by FDA, based on a written justification, submitted to FDA, for a timeframe that exceeds 120 calendar days from the date of receipt of the order; or
(2) Appeal the order within 15 calendar days of the date of receipt of the order in accordance with the requirements of § 507.69.
(b) Submission of an appeal, including submission of a request for an informal hearing, will not operate to delay or stay any administrative action, including enforcement action by FDA, unless the Commissioner of Food and Drugs, as a matter of discretion, determines that delay or a stay is in the public interest.
(c) If you appeal the order, and FDA confirms the order:
(1) You must comply with applicable requirements of this part within 120 calendar days of the date of receipt of the order, or within a reasonable timeframe, agreed to by FDA, based on a written justification, submitted to FDA, for a timeframe that exceeds 120 calendar days from the date of receipt of the order; and
(2) You are no longer subject to the requirements in § 507.7.
§ 507.69 Procedure for submitting an appeal.
(a) To appeal an order to withdraw a qualified facility exemption, you must:
(1) Submit the appeal in writing to the FDA Division Director in whose division the facility is located (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine), at the mailing address, email address, or fax number identified in the order within 15 calendar days of the date of receipt of confirmation of the order; and
(2) Respond with particularity to the facts and issues contained in the order, including any supporting documentation upon which you rely.
(b) In a written appeal of the order withdrawing an exemption provided under § 507.5(d), you may include a written request for an informal hearing as provided in § 507.71.
§ 507.71 Procedure for requesting an informal hearing.
(a) If you appeal the order, you:
(1) May request an informal hearing; and
(2) Must submit any request for an informal hearing together with your written appeal submitted in accordance with § 507.69 within 15 calendar days of the date of receipt of the order.
(b) A request for an informal hearing may be denied, in whole or in part, if the presiding officer determines that no genuine and substantial issue of material fact has been raised by the material submitted. If the presiding officer determines that a hearing is not justified, written notice of the determination will be given to you explaining the reason for the denial.
§ 507.73 Requirements applicable to an informal hearing.
If you request an informal hearing, and FDA grants the request:
(a) The hearing will be held within 15 calendar days after the date the appeal is filed or, if applicable, within a timeframe agreed upon in writing by you and FDA.
(b) The presiding officer may require that a hearing conducted under this subpart be completed within 1 calendar day, as appropriate.
(c) FDA must conduct the hearing in accordance with part 16 of this chapter, except that:
(1) The order withdrawing an exemption under §§ 507.62 and 507.65, rather than the notice under § 16.22(a) of this chapter, provides notice of opportunity for a hearing under this section and is part of the administrative record of the regulatory hearing under § 16.80(a) of this chapter.
(2) A request for a hearing under this subpart must be addressed to the FDA Division Director (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine) as provided in the order withdrawing an exemption.
(3) Section 507.75, rather than § 16.42(a) of this chapter, describes the FDA employees who preside at hearings under this subpart.
(4) Section 16.60(e) and (f) of this chapter does not apply to a hearing under this subpart. The presiding officer must prepare a written report of the hearing. All written material presented at the hearing will be attached to the report. The presiding officer must include as part of the report of the hearing a finding on the credibility of witnesses (other than expert witnesses) whenever credibility is a material issue, and must include a proposed decision, with a statement of reasons. The hearing participant may review and comment on the presiding officer’s report within 2 calendar days of issuance of the report. The presiding officer will then issue the final decision.
(5) Section 16.80(a)(4) of this chapter does not apply to a regulatory hearing under this subpart. The presiding officer’s report of the hearing and any comments on the report by the hearing participant under paragraph (c)(4) of this section are part of the administrative record.
(6) No party shall have the right, under § 16.119 of this chapter to petition the Commissioner of Food and Drugs for reconsideration or a stay of the presiding officer’s final decision.
(7) If FDA grants a request for an informal hearing on an appeal of an order withdrawing an exemption, the hearing must be conducted as a regulatory hearing under a regulation in accordance with part 16 of this chapter, except that § 16.95(b) does not apply to a hearing under this subpart. With respect to a regulatory hearing under this subpart, the administrative record of the hearing specified in §§ 16.80(a)(1) through (3), and (a)(5), of this chapter, and 507.73(c)(5) constitutes the exclusive record for the presiding officer’s final decision. For purposes of judicial review under § 10.45 of this chapter, the record of the administrative proceeding consists of the record of the hearing and the presiding officer’s final decision.
§ 507.75 Presiding officer for an appeal and for an informal hearing.
The presiding officer for an appeal, and for an informal hearing, must be an Office of Regulatory Affairs Program Director or another FDA official senior to an FDA Division Director.
§ 507.77 Timeframe for issuing a decision on an appeal.
(a) If you appeal the order without requesting a hearing, the presiding officer must issue a written report that includes a final decision confirming or revoking the withdrawal by the 10th calendar day after the appeal is filed.
(b) If you appeal the order and request an informal hearing:
(1) If FDA grants the request for a hearing and the hearing is held, the presiding officer must provide a 2 calendar day opportunity for the hearing participants to review and submit comments on the report of the hearing under § 507.73(c)(4), and must issue a final decision within 10 calendar days after the hearing is held; or
(2) If FDA denies the request for a hearing, the presiding officer must issue a final decision on the appeal confirming or revoking the withdrawal within 10 calendar days after the date the appeal is filed.
§ 507.80 Revocation of an order to withdraw a qualified facility exemption.
An order to withdraw a qualified facility exemption is revoked if:
(a) You appeal the order and request an informal hearing, FDA grants the request for an informal hearing, and the presiding officer does not confirm the order within the 10 calendar days after the hearing, or issues a decision revoking the order within that time; or
(b) You appeal the order and request an informal hearing, FDA denies the request for an informal hearing, and FDA does not confirm the order within the 10 calendar days after the appeal is filed, or issues a decision revoking the order within that time; or
(c) You appeal the order without requesting an informal hearing, and FDA does not confirm the order within the 10 calendar days after the appeal is filed, or issues a decision revoking the order within that time.
§ 507.83 Final agency action.
Confirmation of a withdrawal order by the presiding officer is considered a final agency action for purposes of 5 U.S.C. 702.
§ 507.85 Reinstatement of a qualified facility exemption that was withdrawn.
(a) If the FDA Division Director in whose division your facility is located (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine) determines that a facility has adequately resolved any problems with the conditions and conduct that are material to the safety of the animal food manufactured, processed, packed, or held at the facility and that continued withdrawal of the exemption is not necessary to protect public (human and animal) health and prevent or mitigate a foodborne illness outbreak, the FDA Division Director in whose division your facility is located (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine) will, on his or her own initiative or on the request of a facility, reinstate the exemption.
(b) You may ask FDA to reinstate an exemption that has been withdrawn under the procedures of this subpart as follows:
(1) Submit a request, in writing, to the FDA Division Director in whose division your facility is located (or, in the case of a foreign facility, the Director of the Division of Compliance in the Center for Veterinary Medicine); and
(2) Present data and information to demonstrate that you have adequately resolved any problems with the conditions and conduct that are material to the safety of the animal food manufactured, processed, packed, or held at your facility, such that continued withdrawal of the exemption is not necessary to protect public (human and animal) health and prevent or mitigate a foodborne illness outbreak.
(c) If your exemption was withdrawn under § 507.60(a)(1) and FDA later determines, after finishing the active investigation of a foodborne illness outbreak, that the outbreak is not directly linked to your facility, FDA will reinstate your exemption under § 507.5(d), and FDA will notify you in writing that your exempt status has been reinstated.
(d) If your exemption was withdrawn under both § 507.60(a)(1) and (2) and FDA later determines, after finishing the active investigation of a foodborne illness outbreak, that the outbreak is not directly linked to your facility, FDA will inform you of this finding and you may ask FDA to reinstate your exemption under § 507.5(d) in accordance with the requirements of paragraph (b) of this section.
Subpart E—Supply-Chain Program
§ 507.105 Requirement to establish and implement a supply-chain program.
(a)(1) Except as provided by paragraphs (a)(2) and (3) of this section, the receiving facility must establish and implement a risk-based supply-chain program for those raw materials and other ingredients for which the receiving facility has identified a hazard requiring a supply-chain-applied control.
(2) A receiving facility that is an importer, is in compliance with the foreign supplier verification requirements under part 1, subpart L of this chapter, and has documentation of verification activities conducted under § 1.506(e) of this chapter (which provides assurance that the hazards requiring a supply-chain-applied control for the raw material or other ingredient have been significantly minimized or prevented) need not conduct supplier verification activities for that raw material or other ingredient.
(3) The requirements in this subpart do not apply to animal food that is supplied for research or evaluation use, provided that such animal food:
(i) Is not intended for retail sale and is not sold or distributed to the public;
(ii) Is labeled with the statement “Animal food for research or evaluation use”;
(iii) Is supplied in a small quantity that is consistent with a research, analysis, or quality assurance purpose, the animal food is used only for this purpose, and any unused quantity is properly disposed of; and
(iv) Is accompanied with documents, in accordance with the practice of the trade, stating that the animal food will be used for research or evaluation purposes and cannot be sold or distributed to the public.
(b) The supply-chain program must be written.
(c) When a supply-chain-applied control is applied by an entity other than the receiving facility’s supplier (e.g., when a non-supplier applies controls to certain produce (i.e., produce covered by part 112 of this chapter), because growing, harvesting, and packing activities are under different management), the receiving facility must:
(1) Verify the supply-chain-applied control; or
(2) Obtain documentation of an appropriate verification activity from another entity, review and assess the entity’s applicable documentation, and document that review and assessment.
§ 507.110 General requirements applicable to a supply-chain program.
(a) The supply-chain program must include:
(1) Using approved suppliers as required by § 507.120;
(2) Determining appropriate supplier verification activities (including determining the frequency of conducting the activity) as required by § 507.125;
(3) Conducting supplier verification activities as required by §§ 507.130 and 507.135;
(4) Documenting supplier verification activities as required by § 507.175; and
(5) When applicable, verifying a supply-chain-applied control applied by an entity other than the receiving facility’s supplier and documenting that verification as required by § 507.175, or obtaining documentation of an appropriate verification activity from another entity, reviewing and assessing that documentation, and documenting the review and assessment as required by § 507.175.
(b) The following are appropriate supplier verification activities for raw materials and other ingredients:
(1) Onsite audits;
(2) Sampling and testing of the raw material or other ingredient;
(3) Review of the supplier’s relevant food safety records; and
(4) Other appropriate supplier verification activities based on supplier performance and the risk associated with the raw material or other ingredient.
(c) The supply-chain program must provide assurance that a hazard requiring a supply-chain-applied control has been significantly minimized or prevented.
(d)(1) Except as provided by paragraph (d)(2) of this section, in approving suppliers and determining the appropriate supplier verification activities and the frequency with which they are conducted, the following must be considered:
(i) The hazard analysis of the animal food, including the nature of the hazard controlled before receipt of the raw material or other ingredient, applicable to the raw material and other ingredients;
(ii) The entity or entities that will be applying controls for the hazards requiring a supply-chain-applied control;
(iii) Supplier performance, including:
(A) The supplier’s procedures, processes, and practices related to the safety of the raw material and other ingredients;
(B) Applicable FDA food safety regulations and information relevant to the supplier’s compliance with those regulations, including an FDA warning letter or import alert relating to the safety of animal food and other FDA compliance actions related to animal food safety (or, when applicable, relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States, and information relevant to the supplier’s compliance with those laws and regulations); and
(C) The supplier’s food safety history relevant to the raw materials or other ingredients that the receiving facility receives from the supplier, including available information about results from testing raw materials or other ingredients for hazards, audit results relating to the safety of the animal food, and responsiveness of the supplier in correcting problems; and
(iv) Any other factors as appropriate and necessary, such as storage and transportation practices.
(2) Considering supplier performance can be limited to the supplier’s compliance history as required by paragraph (d)(1)(iii)(B) of this section, if the supplier is:
(i) A qualified facility as defined by § 507.3;
(ii) A farm that grows produce and is not a covered farm under part 112 of this chapter in accordance with § 112.4(a), or in accordance with §§ 112.4(b) and 112.5; or
(iii) A shell egg producer that is not subject to the requirements of part 118 of this chapter because it has less than 3,000 laying hens.
(e) If the owner, operator, or agent in charge of a receiving facility determines through auditing, verification testing, document review, relevant consumer, customer, or other complaints, or otherwise that the supplier is not controlling hazards that the receiving facility has identified as requiring a supply-chain-applied control, the receiving facility must take and document prompt action in accordance with § 507.42 to ensure that raw materials or other ingredients from the supplier do not cause animal food that is manufactured or processed by the receiving facility to be adulterated under section 402 of the Federal Food, Drug, and Cosmetic Act.
§ 507.115 Responsibilities of the receiving facility.
(a)(1) The receiving facility must approve suppliers.
(2) Except as provided by paragraphs (a)(3) and (4) of this section, the receiving facility must determine and conduct appropriate supplier verification activities, and satisfy all documentation requirements of this subpart.
(3) An entity other than the receiving facility may do any of the following, provided that the receiving facility reviews and assesses the entity’s applicable documentation, and documents that review and assessment:
(i) Establish written procedures for receiving raw materials and other ingredients by the entity;
(ii) Document that written procedures for receiving raw materials and other ingredients are being followed by the entity; and
(iii) Determine, conduct, or both determine and conduct, the appropriate supplier verification activities, with appropriate documentation.
(4) The supplier may conduct and document sampling and testing of raw materials and other ingredients, for the hazard controlled by the supplier, as a supplier verification activity for a particular lot of product and provide such documentation to the receiving facility, provided that the receiving facility reviews and assesses that documentation, and documents that review and assessment.
(b) For the purposes of this subpart, a receiving facility may not accept any of the following as a supplier verification activity:
(1) A determination by its supplier of the appropriate supplier verification activities for that supplier;
(2) An audit conducted by its supplier;
(3) A review by its supplier of that supplier’s own relevant food safety records; or
(4) The conduct by its supplier of other appropriate supplier verification activities for that supplier within the meaning of § 507.110(b)(4).
(c) The requirements of this section do not prohibit a receiving facility from relying on an audit provided by its supplier when the audit of the supplier was conducted by a third-party qualified auditor in accordance with §§ 507.130(f) and 507.135.
§ 507.120 Using approved suppliers.
(a) The receiving facility must approve suppliers in accordance with the requirements of § 507.110(d), and document that approval, before receiving raw materials and other ingredients received from those suppliers;
(b)(1) Written procedures for receiving raw materials and other ingredients must be established and followed;
(2) The written procedures for receiving raw materials and other ingredients must ensure that raw materials and other ingredients are received only from approved suppliers (or, when necessary and appropriate, on a temporary basis from unapproved suppliers whose raw materials or other ingredients are subjected to adequate verification activities before acceptance for use); and
(3) Use of the written procedures for receiving raw materials and other ingredients must be documented.
§ 507.125 Determining appropriate supplier verification activities (including determining the frequency of conducting the activity).
Appropriate supplier verification activities (including the frequency of conducting the activity) must be determined in accordance with the requirements of § 507.110(d).
§ 507.130 Conducting supplier verification activities for raw materials and other ingredients.
(a) Except as provided by paragraphs (c), (d), or (e) of this section, one or more of the supplier verification activities specified in § 507.110(b), as determined under § 507.110(d), must be conducted for each supplier before using the raw material or other ingredient from that supplier and periodically thereafter.
(b)(1) Except as provided by paragraph (b)(2) of this section, when a hazard in a raw material or other ingredient will be controlled by the supplier and is one for which there is a reasonable probability that exposure to the hazard will result in serious adverse health consequences or death to humans or animals:
(i) The appropriate supplier verification activity is an onsite audit of the supplier; and
(ii) The audit must be conducted before using the raw material or other ingredient from the supplier and at least annually thereafter.
(2) The requirements of paragraph (b)(1) of this section do not apply if there is a written determination that other verification activities and/or less frequent onsite auditing of the supplier provide adequate assurance that the hazards are controlled.
(c) If a supplier is a qualified facility as defined by § 507.3, the receiving facility does not need to comply with paragraphs (a) and (b) of this section if the receiving facility:
(1) Obtains written assurance that the supplier is a qualified facility as defined by § 507.3:
(i) Before first approving the supplier for an applicable calendar year; and
(ii) On an annual basis thereafter, by December 31 of each calendar year, for the following calendar year; and
(2) Obtains written assurance, at least every 2 years, that the supplier is producing the raw material or other ingredient in compliance with applicable FDA food safety regulations (or, when applicable, relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States). The written assurance must include either:
(i) A brief description of the preventive controls that the supplier is implementing to control the applicable hazard in the animal food; or
(ii) A statement that the facility is in compliance with State, local, county, tribal, or other applicable non-Federal food safety laws, including relevant laws and regulations of foreign countries.
(d) If a supplier is a farm that grows produce and is not a covered farm under part 112 of this chapter in accordance with § 112.4(a), or in accordance with §§ 112.4(b) and 112.5, the receiving facility does not need to comply with paragraphs (a) and (b) of this section for produce that the receiving facility receives from the farm as a raw material or other ingredient if the receiving facility:
(1) Obtains written assurance that the raw material or other ingredient provided by the supplier is not subject to part 112 of this chapter in accordance with § 112.4(a), or in accordance with §§ 112.4(b) and 112.5:
(i) Before first approving the supplier for an applicable calendar year; and
(ii) On an annual basis thereafter, by December 31 of each calendar year, for the following calendar year; and
(2) Obtains written assurance, at least every 2 years, that the farm acknowledges that its food is subject to section 402 of the Federal Food, Drug, and Cosmetic Act (or, when applicable, that its food is subject to relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States).
(e) If a supplier is a shell egg producer that is not subject to the requirements of part 118 of this chapter because it has less than 3,000 laying hens, the receiving facility does not need to comply with paragraphs (a) and (b) of this section if the receiving facility:
(1) Obtains written assurance that the shell eggs produced by the supplier are not subject to part 118 because the shell egg producer has less than 3,000 laying hens:
(i) Before first approving the supplier for an applicable calendar year; and
(ii) On an annual basis thereafter, by December 31 of each calendar year, for the following calendar year; and
(2) Obtains written assurance, at least every 2 years, that the shell egg producer acknowledges that its food is subject to section 402 of the Federal Food, Drug, and Cosmetic Act (or, when applicable, that its food is subject to relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States).
(f) There must not be any financial conflicts of interest that influence the results of the verification activities listed in § 507.110(b) and payment must not be related to the results of the activity.
§ 507.135 Onsite audit.
(a) An onsite audit of a supplier must be performed by a qualified auditor.
(b) If the raw material or other ingredient at the supplier is subject to one or more FDA food safety regulations, an onsite audit must consider such regulations and include a review of the supplier’s written plan (e.g., Hazard Analysis and Critical Control Point (HACCP) plan or other food safety plan), if any, and its implementation, for the hazard being controlled (or, when applicable, an onsite audit may consider relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States).
(c)(1) The following may be substituted for an onsite audit, provided that the inspection was conducted within 1 year of the date that the onsite audit would have been required to be conducted:
(i) The written results of an appropriate inspection of the supplier for compliance with applicable FDA food safety regulations by FDA, by representatives of other Federal Agencies (such as the United States Department of Agriculture), or by representatives of State, local, tribal, or territorial agencies; or
(ii) For a foreign supplier, the written results of an inspection by FDA or the food safety authority of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States.
(2) For inspections conducted by the food safety authority of a country whose food safety system FDA has officially recognized as comparable or determined to be equivalent, the animal food that is the subject of the onsite audit must be within the scope of the official recognition or equivalence determination, and the foreign supplier must be in, and under the regulatory oversight of, such country.
(d) If the onsite audit is solely conducted to meet the requirements of this subpart by an audit agent of a certification body that is accredited in accordance with regulations in part 1, subpart M of this chapter, the audit is not subject to the requirements in those regulations.
§ 507.175 Records documenting the supply-chain program.
(a) The records documenting the supply-chain program are subject to the requirements of subpart F of this part.
(b) The receiving facility must review the records listed in paragraph (c) of this section in accordance with § 507.49(a)(4).
(c) The receiving facility must document the following in records as applicable to its supply-chain program:
(1) The written supply-chain program;
(2) Documentation that a receiving facility that is an importer is in compliance with the foreign supplier verification program requirements under part 1, subpart L of this chapter, including documentation of verification activities conducted under § 1.506(e) of this chapter;
(3) Documentation of the approval of a supplier;
(4) Written procedures for receiving raw materials and other ingredients;
(5) Documentation demonstrating use of the written procedures for receiving raw materials and other ingredients;
(6) Documentation of the determination of the appropriate supplier verification activities for raw materials and other ingredients;
(7) Documentation of the conduct of an onsite audit. This documentation must include:
(i) The name of the supplier subject to the onsite audit;
(ii) Documentation of audit procedures;
(iii) The dates the audit was conducted;
(iv) The conclusions of the audit;
(v) Corrective actions taken in response to significant deficiencies identified during the audit; and
(vi) Documentation that the audit was conducted by a qualified auditor;
(8) Documentation of sampling and testing conducted as a supplier verification activity. This documentation must include:
(i) Identification of the raw material or other ingredient tested (including lot number, as appropriate) and the number of samples tested;
(ii) Identification of the test(s) conducted, including the analytical method(s) used;
(iii) The date(s) on which the test(s) were conducted and the date of the report;
(iv) The results of the testing;
(v) Corrective actions taken in response to detection of hazards; and
(vi) Information identifying the laboratory conducting the testing;
(9) Documentation of the review of the supplier’s relevant food safety records. This documentation must include:
(i) The name of the supplier whose records were reviewed;
(ii) The date(s) of review;
(iii) The general nature of the records reviewed;
(iv) The conclusions of the review; and
(v) Corrective actions taken in response to significant deficiencies identified during the review;
(10) Documentation of other appropriate supplier verification activities based on the supplier performance and the risk associated with the raw material or other ingredient;
(11) Documentation of any determination that verification activities other than an onsite audit, and/or less frequent onsite auditing of a supplier, provide adequate assurance that the hazards are controlled when a hazard in a raw material or other ingredient will be controlled by the supplier and is one for which there is a reasonable probability that exposure to the hazard will result in serious adverse health consequences or death to humans or animals;
(12) The following documentation of an alternative verification activity for a supplier that is a qualified facility:
(i) The written assurance that the supplier is a qualified facility as defined by § 507.3; and
(ii) The written assurance that the supplier is producing the raw material or other ingredient in compliance with applicable FDA food safety regulations (or, when applicable, relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States);
(13) The following documentation of an alternative verification activity for a supplier that is a farm that supplies a raw material or other ingredient and is not a covered farm under part 112 of this chapter:
(i) The written assurance that supplier is not a covered farm under part 112 of this chapter in accordance with § 112.4(a), or in accordance with §§ 112.4(b) and 112.5; and
(ii) The written assurance that the farm acknowledges that its food is subject to section 402 of the Federal Food, Drug, and Cosmetic Act (or, when applicable, that its food is subject to relevant laws and regulations of a country whose food safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States);
(14) The following documentation of an alternative verification activity for a supplier that is a shell egg producer that is not subject to the requirements established in part 118 of this chapter because it has less than 3,000 laying hens:
(i) The written assurance that the shell eggs provided by the supplier are not subject to part 118 of this chapter because the supplier has less than 3,000 laying hens; and
(ii) The written assurance that the shell egg producer acknowledges that its food is subject to section 402 of the Federal Food, Drug, and Cosmetic Act (or, when applicable, that its food is subject to relevant laws and regulations of a country whose safety system FDA has officially recognized as comparable or has determined to be equivalent to that of the United States);
(15) The written results of an appropriate inspection of the supplier for compliance with applicable FDA food safety regulations by FDA, by representatives of other Federal Agencies (such as the United States Department of Agriculture), or by representatives from State, local, tribal, or territorial agencies, or the food safety authority of another country when the results of such an inspection is substituted for an onsite audit;
(16) Documentation of actions taken with respect to supplier non-conformance;
(17) Documentation of verification of a supply-chain-applied control applied by an entity other than the receiving facility’s supplier; and
(18) When applicable, documentation of the receiving facility’s review and assessment of:
(i) Applicable documentation from an entity other than the receiving facility that written procedures for receiving raw materials and other ingredients are being followed;
(ii) Applicable documentation, from an entity other than the receiving facility, of the determination of the appropriate supplier verification activities for raw materials and other ingredients;
(iii) Applicable documentation, from an entity other than the receiving facility, of conducting the appropriate supplier verification activities for raw materials and other ingredients;
(iv) Applicable documentation, from its supplier, of:
(A) The results of sampling and testing conducted by the supplier; or
(B) The results of an audit conducted by a third-party qualified auditor in accordance with §§ 507.130(f) and 507.135; and
(v) Applicable documentation, from an entity other than the receiving facility, of verification activities when a supply-chain-applied control is applied by an entity other than the receiving facility’s supplier.
Subpart F—Requirements Applying to Records That Must Be Established and Maintained
§ 507.200 Records subject to the requirements of this subpart.
(a) Except as provided by paragraphs (d) and (e) of this section, all records required by this part are subject to all requirements of this subpart.
(b) Records obtained by FDA in accordance with this part are subject to the disclosure requirements under part 20 of this chapter.
(c) All records required by this part must be made promptly available to a duly authorized representative of the Secretary of Health and Human Services for official review and copying upon oral or written request.
(d) The requirements of § 507.206 apply only to the written food safety plan.
(e) The requirements of § 507.202(a)(2), (4), and (5) and (b) do not apply to the records required by § 507.7.
§ 507.202 General requirements applying to records.
(a) Records must:
(1) Be kept as original records, true copies (such as photocopies, pictures, scanned copies, microfilm, microfiche, or other accurate reproductions of the original records), or electronic records;
(2) Contain the actual values and observations obtained during monitoring and as appropriate, during verification activities;
(3) Be accurate, indelible, and legible;
(4) Be created concurrently with performance of the activity documented; and
(5) Be as detailed as necessary to provide history of work performed.
(b) All records must include:
(1) Information adequate to identify the plant or facility (e.g., the name, and when necessary, the location of the plant or facility);
(2) The date and, when appropriate, the time of the activity documented;
(3) The signature or initials of the person performing the activity; and
(4) Where appropriate, the identity of the product and the lot code, if any.
(c) Records that are established or maintained to satisfy the requirements of this part and that meet the definition of electronic records in § 11.3(b)(6) of this chapter are exempt from the requirements of part 11 of this chapter. Records that satisfy the requirements of this part, but that also are required under other applicable statutory provisions or regulations, remain subject to part 11 of this chapter.
§ 507.206 Additional requirements applying to the food safety plan.
The owner, operator, or agent in charge of the facility must sign and date the food safety plan upon initial completion and upon any modification.
§ 507.208 Requirements for record retention.
(a)(1) All records required by this part must be retained at the plant or facility for at least 2 years after the date they were prepared.
(2) Records that a facility relies on during the 3-year period preceding the applicable calendar year to support its status as a qualified facility must be retained at the facility as long as necessary to support the status of a facility as a qualified facility during the applicable calendar year.
(b) Records that relate to the general adequacy of the equipment or processes being used by a facility, including the results of scientific studies and evaluations, must be retained by the facility for at least 2 years after their use is discontinued (e.g., because the facility has updated the written food safety plan (§ 507.31) or records that document validation of the written food safety plan (§ 507.45(b))).
(c) Except for the food safety plan, offsite storage of records is permitted if such records can be retrieved and provided onsite within 24 hours of request for official review. The food safety plan must remain onsite. Electronic records are considered to be onsite if they are accessible from an onsite location.
(d) If the plant or facility is closed for a prolonged period, the food safety plan may be transferred to some other reasonably accessible location but must be returned to the plant or facility within 24 hours for official review upon request.
§ 507.212 Use of existing records.
(a) Existing records (e.g., records that are kept to comply with other Federal, State, or local regulations, or for any other reason) do not need to be duplicated if they contain all of the required information and satisfy the requirements of this subpart. Existing records may be supplemented as necessary to include all of the required information and satisfy the requirements of this subpart.
(b) The information required by this part does not need to be kept in one set of records. If existing records contain some of the required information, any new information required by this part may be kept either separately or combined with the existing records.
§ 507.215 Special requirements applicable to a written assurance.
(a) Any written assurance required by this part must contain the following elements:
(1) Effective date;
(2) Printed names and signatures of authorized officials;
(3) The applicable assurance under:
(i) § 507.36(a)(2);
(ii) § 507.36(a)(3);
(iii) § 507.36(a)(4);
(iv) § 507.130(c)(2);
(v) § 507.130(d)(2); or
(vi) § 507.130(e)(2).
(b) A written assurance required under § 507.36(a)(2), (3) or (4) must include:
(1) Acknowledgement that the facility that provides the written assurance assumes legal responsibility to act consistently with the assurance and document its actions taken to satisfy the written assurance; and
(2) Provision that if the assurance is terminated in writing by either entity, responsibility for compliance with the applicable provisions of this part reverts to the manufacturer/processor as of the date of termination.
PART 509—UNAVOIDABLE CONTAMINANTS IN ANIMAL FOOD AND FOOD-PACKAGING MATERIAL
Subpart A—General Provisions
§ 509.3 Definitions and interpretations.
(a) Act means the Federal Food, Drug, and Cosmetic Act.
(b) The definitions of terms contained in section 201 of the act are applicable to such terms when used in this part unless modified in this section.
(c) A naturally occurring poisonous or deleterious substance is a poisonous or deleterious substance that is an inherent natural constituent of a food and is not the result of environmental, agricultural, industrial, or other contamination.
(d) An added poisonous or deleterious substance is a poisonous or deleterious substance that is not a naturally occurring poisonous or deleterious substance. When a naturally occurring poisonous or deleterious substance is increased to abnormal levels through mishandling or other intervening acts, it is an added poisonous or deleterious substance to the extent of such increase.
(e) Food includes pet food, animal feed, and substances migrating to food from food-contact articles.
§ 509.4 Establishment of tolerances, regulatory limits, and action levels.
(a) When appropriate under the criteria of § 509.6, a tolerance for an added poisonous or deleterious substance, which may be a food additive, may be established by regulation in subpart B of this part under the provisions of section 406 of the act. A tolerance may prohibit any detectable amount of the substance in food.
(b) When appropriate under the criteria of § 509.6, and under section 402(a)(1) of the act, a regulatory limit for an added poisonous or deleterious substance, which may be a food additive, may be established by regulation in subpart C of this part under the provisions of sections 402(a)(1) and 701(a) of the act. A regulatory limit may prohibit any detectable amount of the substance in food. The regulatory limit established represents the level at which food is adulterated within the meaning of section 402(a)(1) of the act.
(c)(1) When appropriate under the criteria of § 509.6, an action level for an added poisonous or deleterious substance, which may be a food additive, may be established to define a level of contamination at which a food may be regarded as adulterated.
(2) Whenever an action level is established or changed, a notice shall be published in the
(d) A regulation may be established in subpart D of this part to identify a food containing a naturally occurring poisonous or deleterious substance which will be deemed to be adulterated under section 402(a)(1) of the act. These regulations do not constitute a complete list of such foods.
§ 509.5 Petitions.
The Commissioner of Food and Drugs, either on his own initiative or on behalf of any interested person who has submitted a petition, may issue a proposal to establish, revoke, or amend a regulation under this part. Any such petition shall include an adequate factual basis to support the petition, shall be in the form set forth in § 10.30 of this chapter, and will be published in the
§ 509.6 Added poisonous or deleterious substances.
(a) Use of an added poisonous or deleterious substance, other than a pesticide chemical, that is also a food additive will be controlled by a regulation issued under section 409 of the act when possible. When such a use cannot be approved under the criteria of section 409 of the act, or when the added poisonous or deleterious substance is not a food additive, a tolerance, regulatory limit, or action level may be established pursuant to the criteria in paragraphs (b), (c), or (d) of this section. Residues resulting from the use of an added poisonous or deleterious substance that is also a pesticide chemical will ordinarily be controlled by a tolerance established in a regulation issued under sections 406, 408, or 409 of the act by the U.S. Environmental Protection Agency (EPA). When such a regulation has not been issued, an action level for an added poisonous or deleterious substance that is also a pesticide chemical may be established by the Food and Drug Administration. The Food and Drug Administration will request EPA to recommend such an action level pursuant to the criteria established in paragraph (d) of this section.
(b) A tolerance for an added poisonous or deleterious substance in any food may be established when the following criteria are met:
(1) The substance cannot be avoided by good manufacturing practice.
(2) The tolerance established is sufficient for the protection of the public health, taking into account the extent of which the presence of the substance cannot be avoided and the other ways in which the consumer may be affected by the same or related poisonous or deleterious substances.
(3) No technological or other changes are foreseeable in the near future that might affect the appropriateness of the tolerance established. Examples of changes that might affect the appropriateness of the tolerance include anticipated improvements in good manufacturing practice that would change the extent to which use of the substance is unavoidable and anticipated studies expected to provide significant new toxicological or use data.
(c) A regulatory limit for an added poisonous or deleterious substance in any food may be established when each of the following criteria is met:
(1) The substance cannot be avoided by current good manufacturing practices.
(2) There is no tolerance established for the substance in the particular food under sections 406, 408, or 409 of the act.
(3) There is insufficient information by which a tolerance may be established for the substance under section 406 of the act or technological changes appear reasonably possible that may affect the appropriateness of a tolerance. The regulatory limit established represents the level at which food is adulterated within the meaning of section 402(a)(1) of the act.
(d) An action level for an added poisonous or deleterious substance in any food may be established when the criteria in paragraph (b) of this section are met, except that technological or other changes that might affect the appropriateness of the tolerance are foreseeable in the near future. An action level for an added poisonous or deleterious substance in any food may be established at a level at which the Food and Drug Administration may regard the food as adulterated within the meaning of section 402(a)(1) of the act, without regard to the criteria in paragraph (b) of this section or in section 406 of the act. An action level will be withdrawn when a tolerance or regulatory limit for the same substance and use has been established.
(e) Tolerances will be established under authority appropriate for action levels (sections 306, 402(a), and 701(a) of the act, together with section 408 or 409 of the act, if appropriate) as well as under authority appropriate for tolerances (sections 406 and 701 of the act). In the event the effectiveness of a tolerance is stayed pursuant to section 701(e)(2) of the act by the filing of an objection, the order establishing the tolerance shall be deemed to be an order establishing an action level until final action is taken upon such objection.
(a) Tolerances and action levels in this part are established at levels based on the unavoidability of the poisonous or deleterious substance concerned and do not establish a permissible level of contamination where it is avoidable.
(b) Compliance with tolerances, regulatory limits, and action levels does not excuse failure to observe either the requirement in section 402(a)(4) of the act that food may not be prepared, packed, or held under insanitary conditions or the other requirements in this chapter that food manufacturers must observe current good manufacturing practices. Evidence obtained through factory inspection or otherwise indicating such a violation renders the food unlawful, even though the amounts of poisonous or deleterious substances are lower than the currently established tolerances, regulatory limits, or action levels. The manufacturer of food must at all times utilize quality control procedures which will reduce contamination to the lowest level currently feasible.
§ 509.15 Use of polychlorinated biphenyls (PCB’s) in establishments manufacturing food-packaging materials.
(a) Polychlorinated biphenyls (PCB’s) represent a class of toxic industrial chemicals manufactured and sold under a variety of trade names, including: Aroclor (United States); Phenoclor (France); Colphen (Germany); and Kanaclor (Japan). PCB’s are highly stable, heat resistant, and nonflammable chemicals. Industrial uses of PCB’s include, or did include in the past, their use as electrical transformer and capacitor fluids, heat transfer fluids, hydraulic fluids, and plasticizers, and in formulations of lubricants, coatings, and inks. Their unique physical and chemical properties and widespread, uncontrolled industrial applications have caused PCB’s to be a persistent and ubiquitous contaminant in the environment, causing the contamination of certain foods. In addition, incidents have occurred in which PCB’s have directly contaminated animal feeds as a result of industrial accidents (leakage or spillage of PCB fluids from plant equipment). These accidents in turn caused the contamination of food products intended for human consumption (meat, milk and eggs). Investigations by the Food and Drug Administration have revealed that a significant percentage of paper food-packaging material contains PCB’s which can migrate to the packaged food. The origin of PCB’s in such material is not fully understood. Reclaimed fibers containing carbonless copy paper (contains 3 to 5 percent PCB’s) have been identified as a primary source of PCB’s in paper products. Some virgin paper products have also been found to contain PCB’s, the source of which is generally attributed to direct contamination from industrial accidents from the use of PCB-containing equipment and machinery in food-packaging manufacturing establishments. Since PCB’s are toxic chemicals, the PCB contamination of food-packaging materials as a result of industrial accidents, which can cause the PCB contamination of food, represents a hazard to public health. It is therefore necessary to place certain restrictions on the industrial uses of PCB’s in establishments manufacturing food-packaging materials.
(b) The following special provisions are necessary to preclude the accidental PCB contamination of food-packaging materials:
(1) New equipment or machinery for manufacturing food-packaging materials shall not contain or use PCB’s.
(2) On or before September 4, 1973, the management of establishments manufacturing food-packaging materials shall:
(i) Have the heat exchange fluid used in existing equipment for manufacturing food-packaging materials sampled and tested to determine whether it contains PCB’s or verify the absence of PCB’s in such formulations by other appropriate means. On or before Sept. 4, 1973, any such fluid formulated with PCB’s must to the fullest extent possible commensurate with current good manufacturing practices be replaced with a heat exchange fluid that does not contain PCB’s.
(ii) Eliminate to the fullest extent possible commensurate with current good manufacturing practices from the establishment any other PCB-containing equipment, machinery and materials wherever there is a reasonable expectation that such articles could cause food-packaging materials to become contaminated with PCB’s either as a result of normal use or as a result of accident, breakage, or other mishap.
(iii) The toxicity and other characteristics of fluids selected as PCB replacements must be adequately determined so that the least potentially hazardous replacement is used. In making this determination with respect to a given fluid, consideration should be given to (a) its toxicity; (b) the maximum quantity that could be spilled onto a given quantity of food before it would be noticed, taking into account its color and odor; (c) possible signaling devices in the equipment to indicate a loss of fluid, etc.; and (d) its environmental stability and tendency to survive and be concentrated through the food chain. The judgment as to whether a replacement fluid is sufficiently non-hazardous is to be made on an individual installation and operation basis.
(c) The provisions of this section do not apply to electrical transformers and condensers containing PCB’s in sealed containers.
§ 509.30 Temporary tolerances for polychlorinated biphenyls (PCB’s).
(a) Polychlorinated biphenyls (PCB’s) are toxic, industrial chemicals. Because of their widespread, uncontrolled industrial applications, PCB’s have become a persistent and ubiquitous contaminant in the environment. As a result, certain foods and animal feeds, principally those of animal and marine origin, contain PCB’s as unavoidable, environmental contaminants. PCB’s are transmitted to the food portion (meat, milk, and eggs) of food producing animals ingesting PCB contaminated animal feed. In addition, a significant percentage of paper food-packaging materials contain PCB’s which may migrate to the packaged food. The source of PCB’s in paper food-packaging materials is primarily of certain types of carbonless copy paper (containing 3 to 5 percent PCB’s) in waste paper stocks used for manufacturing recycled paper. Therefore, temporary tolerances for residues of PCB’s as unavoidable environmental or industrial contaminants are established for a sufficient period of time following the effective date of this paragraph to permit the elimination of such contaminants at the earliest practicable time. For the purposes of this paragraph, the term polychlorinated biphenyls (PCB’s) is applicable to mixtures of chlorinated biphenyl compounds, irrespective of which mixture of PCB’s is present as the residue. The temporary tolerances for residues of PCB’s are as follows:
(1) 0.2 part per million in finished animal feed for food-producing animals (except the following finished animal feeds: feed concentrates, feed supplements, and feed premixes).
(2) 2 parts per million in animal feed components of animal origin, including fishmeal and other by-products of marine origin and in finished animal feed concentrates, supplements, and premixes intended for food-producing animals.
(3) 10 parts per million in paper food-packaging material intended for or used with finished animal feed and any components intended for animal feeds. The tolerance shall not apply to paper food-packaging material separated from the food therein by a functional barrier which is impermeable to migration of PCB’s.
(b) A compilation entitled “Analytical Methodology for Polychlorinated Biphenyls, February 1973” for determining compliance with the tolerances established in this section is available from the Dockets Management Staff, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Subpart C—Regulatory Limits for Added Poisonous or Deleterious Substances [Reserved]
Subpart D—Naturally Occurring Poisonous or Deleterious Substances [Reserved]
PART 510—NEW ANIMAL DRUGS
Subpart A—General Provisions
§ 510.3 Definitions and interpretations.
As used in this part:
(a) The term act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
(b) Department means the Department of Health and Human Services.
(c) Secretary means the Secretary of Health and Human Services.
(d) Commissioner means the Commissioner of Food and Drugs.
(e) Person means individuals, partnerships, corporations, and associations.
(f) The definitions and interpretations of terms contained in section 201 of the act shall be applicable to such terms when used in the regulations in this part.
(g) The term new animal drug means any drug intended for use for animals other than man, including any drug intended for use in animal feed but not including such animal feed:
(1) The composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof; except that such a drug not so recognized shall not be deemed to be a new animal drug if at any time prior to June 25, 1938, it was subject to the Food and Drug Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or
(2) The composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.
(h) The term animal feed means an article which is intended for use for food for animals other than man and which is intended for use as a substantial source of nutrients in the diet of the animal, and is not limited to a mixture intended to be the sole ration of the animal.
(i) The newness of an animal drug, including a new animal drug intended for use in or on animal feed, may arise by reason of: (1) The newness for its intended drug use of any substance of which the drug is comprised, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component; (2) the newness for its intended drug use of a combination of two or more substances, none of which is itself a new animal drug; (3) the newness for its intended drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new animal drug; (4) the newness for its intended drug use in a different species of animal; (5) the newness of its intended drug use in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the animal body, even though such drug is not a new animal drug when used in another disease or to affect another structure or function of the body; or (6) the newness of a dosage, or method or duration of administration or application, or any other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug or animal feed containing such drug when used in another dosage, or another method or duration of administration or application, or different condition, is not a new animal drug.
(j) Animals used only for laboratory research and laboratory research animals mean individual animals or groups of animals intended for use and used solely for laboratory research purposes, regardless of species, and does not include animals intended to be used for any food purposes or animals intended to be kept as livestock.
(k) Sponsor means the person requesting designation for a minor-use or minor-species drug as defined in part 516 of this chapter, who must be the real party in interest of the development and the intended or actual production and sales of such drug (in this context, the sponsor may be an individual, partnership, organization, or association). Sponsor also means the person responsible for an investigation of a new animal drug. In this context, the sponsor may be an individual, partnership, corporation, or Government agency or may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new animal drugs. Sponsor also means the person submitting or receiving approval for a new animal drug application (in this context, the sponsor may be an individual, partnership, organization, or association). In all contexts, the sponsor is responsible for compliance with applicable provisions of the act and regulations.
§ 510.4 Biologics; products subject to license control.
An animal drug produced and distributed in full conformance with the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq. ) and any regulations issued thereunder shall not be deemed to be subject to section 512 of the Federal Food, Drug, and Cosmetic Act.
§ 510.7 Consignees of new animal drugs for use in the manufacture of animal feed.
(a) A new animal drug intended for use in the manufacture of animal feed shall be deemed to be unsafe unless at the time of its removal from the establishment of a manufacturer, packer, or distributor of such drug, such manufacturer, packer, or distributor has an unrevoked written statement from the consignee of such drug, or a notice from the Secretary, to the effect that with respect to the use of such drug in animal feed the consignee:
(1) Holds a license issued under § 515.20 of this chapter; or
(2) Will, if the consignee is not the user of the drug, ship such drug only to a holder of an approved application under § 515.10 of this chapter.
(b) The requirements of paragraph (a) of this section do not apply:
(1) Where such drugs are intended for export and/or
(2) When the use of such drug in the manufacture of a finished feed has been exempted from the requirements of section 512(m) of the act under the conditions specified by regulations published in part 558 of this chapter.
§ 510.95 [Reserved]
Subpart B—Specific Administrative Rulings and Decisions
§ 510.105 Labeling of drugs for use in milk-producing animals.
(a) Part 526 of this chapter provides for new animal drugs intended for intramammary use in animals and includes conditions of use intended to prevent the contamination of milk from the use of such drugs.
(b) Preparations containing antibiotics and other potent drugs labeled with directions for use in milk-producing animals will be misbranded under section 502(f)(2) of the act unless their labeling bears appropriate warnings and directions for use to avoid adulteration of milk under section 402(a)(2)(c)(ii) of the act.
(c) It is the position of the Food and Drug Administration that the labeling for such preparations should bear a clear warning that either:
(1) The article should not be administered to animals producing milk, since to do so would result in contamination of the milk; or
(2) The label should bear the following statement: “Warning: Milk that has been taken from animals during treatment and for __ hours after the latest treatment must not be used for food”, the blank being filled in with the figure that the manufacturer has determined by appropriate investigation is needed to insure that the milk will not carry violative residues resulting from use of the preparation. If the use of the preparation as recommended does not result in contamination of the milk, neither of the above warning statements is required.
§ 510.106 Labeling of antibiotic and antibiotic-containing drugs intended for use in milk-producing animals.
Whenever the labeling of an antibiotic drug included in the regulations in this chapter suggests or recommends its use in milk-producing animals, the label of such drugs shall bear either the statement “Warning: Not for use in animals producing milk, since this use will result in contamination of the milk” or the statement “Warning: Milk that has been taken from animals during treatment and for __hours after the latest treatment must not be used for food”, the blank being filled in with the figure that the Commissioner has authorized the manufacturer of the drug to use. The Commissioner shall determine what such figures shall be from information submitted by the manufacturer and which the Commissioner considers is adequate to prove that period of time after the latest treatment that the milk from treated animals will contain no violative residues from use of the preparation. If the Commissioner determines from the information submitted that the use of the antibiotic drug as recommended does not result in its appearance in the milk, the Commissioner may exempt the drug from bearing either of the above warning statements.
§ 510.110 Antibiotics used in food-producing animals.
(a) The Food and Drug Administration in the interest of fulfilling its responsibilities with regard to protection of the public health has requested an evaluation of the public health aspects of the use of antibiotics in veterinary medical and nonmedical uses. There is particular concern with regard to the potential hazards associated with the extensive use of antibiotics administered to food-producing animals. Accordingly, an ad hoc committee on the Veterinary Medical and Nonmedical Uses of Antibiotics was established by the Food and Drug Administration to study and advise the Commissioner of Food and Drugs on the uses of antibiotics in veterinary medicine and for various nonmedical purposes as such uses may affect the enforcement of the Federal Food, Drug, and Cosmetic Act with respect to their safety and effectiveness.
(b) Based upon an evaluation of the conclusions of said Committee and other relevant material, § 510.112 was published in the
(c) An evaluation of the data now available shows that use of many antibiotic preparations cause residues in edible products of treated animals for varying and, in some cases, for long periods of time following the last administration. Because of the accumulation of new information with regard to the development of resistance of bacteria to antibiotics, the ability of bacteria to transfer this resistance, and the development of sensitivity to antibiotics in humans, unauthorized and unsafe residues of antibiotics cannot be permitted in food obtained from treated animals.
(d) Based on evaluation of information available, including the conclusions of the aforementioned ad hoc Committee, the Commissioner concludes that antibiotic preparations intended for use in food-producing animals, other than topical and ophthalmic preparations, are not generally recognized among qualified experts as having been shown to be safe for their intended use(s) within the meaning of section 201(s) of the Federal Food, Drug, and Cosmetic Act.
(e) Therefore, all exemptions from the provisions of section 409 of the act for use of antibiotics in food-producing animals based on sanctions or approvals granted prior to enactment of the Food Additives Amendment of 1958 (Pub. L. 85-929; 72 Stat. 1784) will be revoked and the uses which are concluded to be safe will be covered by food additive regulations. On those products for which there are inadequate residue data, actions will be initiated to withdraw approval of new-drug applications under the provisions of section 505 of the act. Antibiotic preparations, other than those for topical and ophthalmic application in food-producing animals, which are not covered by food additive regulations will be subject to regulatory action within 180 days after publication of the forthcoming revocation order.
(f) Because of the variation in the period of time that antibiotic residues may remain in edible products from treated animals, all injectable, intramammary infusion, intrauterine, and oral preparations, including medicated premixes intended for use in food-producing animals, are deemed to be new drugs as well as food additives.
§ 510.112 Antibiotics used in veterinary medicine and for nonmedical purposes; required data.
(a) An ad hoc committee, Committee on the Veterinary Medical and Nonmedical Uses of Antibiotics, was formed by the Food and Drug Administration to study, and advise the Commissioner on, the use of antibiotics in veterinary medicine and for various nonmedical purposes as such uses may affect the enforcement of the Federal Food, Drug, and Cosmetic Act with respect to the safety and effectiveness of such substances. A copy of the report may be obtained from the Food and Drug Administration, Office of Public Affairs, Room 15-05, Parklawn Building, 5600 Fishers Lane, Rockville, MD 20857.
(b) On the basis of the report of the Committee and other information, sponsors of drugs containing any antibiotic intended for use in food-producing animals shall submit data for determining whether or not such antibiotics and their metabolites are present as residues in edible tissues, milk, and eggs from treated animals; however, in the case of a drug for which such data have already been submitted and for which a regulation has been promulgated under section 409 of the act, only such data as has been accumulated since the issuance of the regulation need be submitted.
(c) The required data shall be submitted within 180 days of the date of publication of this section in the
(d) Regulatory proceedings including revocation of prior sanctions, or actions to suspend or amend new drug or antibiotic approvals granted prior to passage of the Food Additives Amendment of 1958 (72 Stat. 1784), may be initiated with regard to the continued marketing of any antibiotic preparation on which the required information is not submitted within the period of time prescribed by paragraph (c) of this section.
(e) Questions relating to the acceptability of proposed research protocols and assay methods for determining the amount of antibiotic residues in food should be directed to the Director, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.
Subpart C—Import Tolerances for Residues of Unapproved New Animal Drugs in Food
§ 510.201 Scope.
This subpart applies to tolerances for residues of new animal drugs not approved or conditionally approved for use in the United States, but lawfully used in another country and present in imported, animal-derived food and food products.
§ 510.202 Definitions.
The following definitions of terms apply when used in this subpart:
CNADA means an application for conditional approval of a new animal drug submitted under section 571 of the Federal Food, Drug, and Cosmetic Act, and includes all amendments and permissible supplements.
Import tolerance means a tolerance for a residue of a new animal drug not approved or conditionally approved for use in the United States, but present in any imported edible portion of any animal.
NADA means a new animal drug application submitted under section 512 of the Federal Food, Drug, and Cosmetic Act, including all amendments and permissible supplements, for approval of a new animal drug.
Request means a request to establish or amend an import tolerance.
§ 510.203 Initiation of a proceeding to establish or amend an import tolerance.
(a) Any interested person may request that the Commissioner establish or amend an import tolerance. Such a request must be in the form specified in § 510.205 of this chapter.
(b) The Commissioner may initiate a proceeding to establish or amend an import tolerance on his or her own initiative pursuant to § 10.25(b) of this chapter.
§ 510.205 Content and administration of a request.
(a) Pertinent information previously submitted to and currently retained in the files of the Food and Drug Administration (FDA) may be incorporated in, and will be considered as part of, a request on the basis of specific reference to such information. If the requester refers to any nonpublic information other than its own, the requester shall obtain a written right of reference to that nonpublic information and submit the right of reference with the request. Any reference to published information offered in support of a request should be accompanied by reprints or copies of such references.
(b) Requests shall be submitted and addressed to the Document Control Unit (HFV-199), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. Requests may be submitted in an electronic format as authorized by FDA. See FDA′s Electronic Submissions Gateway website: https://www.fda.gov/industry/electronic-submissions-gateway.
(c) Any material submitted in a foreign language shall be accompanied by a complete and accurate English translation. Translations of literature printed in a language other than English shall be accompanied by copies of the original publication.
(d) The request must be dated and must be signed by the requester or by his or her authorized attorney, agent, or official and shall state the requester’s correspondence address. If the requester or such authorized representative does not reside or have a place of business within the United States, the requester must also furnish the name and post office address of, and the request must be countersigned by, an authorized attorney, agent, or official residing or maintaining a place of business within the United States.
(e) The request must include the following information:
(1) The established name and all pertinent information concerning the new animal drug, including chemical identity and composition of the new animal drug, and its physical, chemical, and biological properties;
(2) The conditions of use for the new animal drug, including the route of administration and dosage, together with all labeling, directions, and recommendations regarding the uses in countries in which the new animal drug is lawfully used;
(3) The proposed import tolerance(s) for residues of the new animal drug;
(4) Human food safety information to support the proposed import tolerance(s) in either of the following forms:
(i) If a permanent maximum residue limit (MRL) has been established by the Codex Alimentarius Committee (Codex MRL), the requester shall provide the permanent Codex MRL and monographs and reports from the Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO) of the United Nations and/or monographs and reports from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) that support the development of the permanent Codex MRL. FDA may request additional information as needed.
(ii) If no permanent Codex MRL has been established, or upon notification by FDA, the requester must provide full reports of investigations made with respect to the human food safety of the new animal drug. A request may be regarded as incomplete unless it includes full reports of adequate tests by all methods reasonably applicable to show whether or not any imported edible portion of any animal receiving the new animal drug will be safe for human consumption. The reports must include detailed data derived from appropriate animal and other biological experiments in which the methods used and the results obtained are clearly set forth, including data submitted to the appropriate regulatory authority in any country where the new animal drug is lawfully used. The request must also include a statement that all such reports have been submitted or contain an explanation of why such reports were not submitted. With respect to each nonclinical laboratory study contained in the request, the requestor must submit either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance, and how this may have impacted the study;
(5) Other human food safety information as deemed necessary by the Commissioner;
(6) A description of practicable methods for determining the quantity, if any, of the new animal drug in or on food, and any substance formed in or on food because of its use;
(7) An environmental assessment under § 25.40 of this chapter; and
(8) Any information required under §§ 500.80 through 500.92 of this chapter (Subpart E, Regulation of Carcinogenic Compounds Used in Food-Producing Animals), where applicable.
(f) A request to amend an established import tolerance must contain information to support each proposed change. The request may omit statements made in the original request for which no change is proposed.
(g) The requester may withdraw the request at any time before the notification provided for in § 510.207(a) of this chapter has been made publicly available.
§ 510.206 Review of information supporting actions to establish or amend an import tolerance.
In establishing or amending an import tolerance, the Commissioner shall rely on data sufficient to demonstrate that a proposed tolerance is safe based on similar food safety criteria used by the Commissioner to establish tolerances for applications for new animal drugs filed under section 512(b)(1) of the Federal Food, Drug, and Cosmetic Act. In establishing or amending an import tolerance, the Commissioner will give appropriate consideration to the anticipated residue concentrations and conditions of use of the new animal drug specified.
§ 510.207 Disclosure of information submitted in a request.
(a) When a request is determined to be complete for FDA’s consideration, the Commissioner will provide public notification of the request containing the name of the requester and a brief description of the request in general terms. A copy of the notification will be sent to the requester at the time the information is made available to the public.
(b) Any notification establishing, amending, or revoking an import tolerance will be made publicly available. A summary of the basis for the decision will be publicly released in accordance with the provisions of part 20 of this chapter. If FDA determines that the new animal drug referred to in the request is a new animal drug that induces cancer when ingested by people or animals, and the requester complies with the requirements of §§ 500.80 through 500.92 of this chapter (Subpart E, Regulation of Carcinogenic Compounds Used in Food-Producing Animals), the regulatory method for ascertaining the marker residue in the target tissue will be made publicly available. All information and safety data submitted with the request, or previously submitted information incorporated in, and considered as part of, a request on the basis of specific reference to such information, shall be available for public disclosure, also in accordance with the provisions of part 20 of this chapter. Trade secrets and confidential commercial or financial information are exempted from release under § 20.61 of this chapter.
§ 510.209 Establishment, denial, or amendment of an import tolerance.
(a) If an import tolerance is established or amended, the Commissioner will provide public notification of the action, which will be effective from the date of public notification. A copy of the notification will be sent to any requestor at the time the information is made available to the public.
(b) If a request to establish or amend an import tolerance is denied, a notification of the denial will be made publicly available, and a copy of the denial letter, including the reasons for such action, will be sent to the requester.
(c) A tolerance established in an approved NADA or conditionally approved CNADA will supersede an existing import tolerance. In the event the conditionally approved CNADA is not renewed or is withdrawn, or such drug does not achieve approval under section 512 of the Federal Food, Drug, and Cosmetic Act within 5 years following the date of the conditional approval, the Agency will reinstate the import tolerance unless § 510.210(a)(1) or (a)(2) is applicable at that time.
§ 510.210 Revocation of an import tolerance.
(a) The Commissioner, on his or her own initiative or on the petition of an interested person, under § 10.25 of this chapter, may revoke an import tolerance if:
(1) Scientific evidence shows an import tolerance to be unsafe; or
(2) Information demonstrates that the use of a new animal drug under actual use conditions results in food being imported into the United States with residues exceeding the import tolerance.
(b) The Commissioner will provide public notification under § 510.207(b) that will specify the basis for the decision and will be effective at the time the information is made available to the public.
(c) A petition for revocation must be submitted in the form specified in § 10.30 of this chapter.
§ 510.212 Administrative reconsideration of action.
(a) The Commissioner may at any time, on his or her own initiative or on the petition of an interested person under part 10 of this chapter, reconsider part or all of a decision to establish, not establish, amend, or revoke an import tolerance.
(b) A petition for reconsideration must be submitted in accordance with § 10.20 of this chapter and in the form specified in § 10.33 of this chapter no later than 30 days after the date of public notification of the decision involved. The Commissioner may, for good cause, permit a petition to be filed more than 30 days after public notification of the decision. The petition for reconsideration must demonstrate that relevant information contained in the administrative record was not previously or not adequately considered by the Commissioner. No new information may be included in a petition for reconsideration.
(c) An interested person who wishes to rely on information not included in the administrative record shall submit either a petition to amend an import tolerance under § 510.205 or to revoke an import tolerance under § 510.210 and § 10.25 of this chapter.
§ 510.213 Administrative stay of action.
(a) The Commissioner may at any time, on his or her own initiative or on the request of an interested person under part 10 of this chapter, stay or extend the effective date of a decision to establish, not establish, amend, or revoke an import tolerance.
(b) A request for stay must be submitted in accordance with § 10.20 of this chapter and in the form specified in § 10.35 of this chapter no later than 30 days after public notification of the decision involved. The Commissioner may, for good cause, permit a petition to be filed more than 30 days after public notification of the decision.
Subpart D—Records and Reports
§ 510.301 Records and reports concerning experience with animal feeds bearing or containing new animal drugs for which an approved medicated feed mill license application is in effect.
Records and reports of clinical and other experience with the new animal drug will be maintained and reported, appropriately identified with the new animal drug application(s) or index listing(s) to which they relate, to the Center for Veterinary Medicine in duplicate in accordance with the following:
(a) Immediately upon receipt by the applicant, complete records or reports covering information of the following kinds:
(1) Information concerning any mixup in the new animal drug or its labeling with another article.
(2) Information concerning any bacteriological or any significant chemical, physical, or other change or deterioration in the drug, or any failure of one or more distributed batches of the drug to meet the specifications established for it in the new animal drug application or request for determination of eligibility for indexing.
(b) As soon as possible, and in any event within 15 working days of its receipt by the applicant, complete records or reports concerning any information of the following kinds:
(1) Information concerning any unexpected side effect, injury, toxicity, or sensitivity reaction or any unexpected incidence or severity thereof associated with clinical uses, studies, investigations, or tests, whether or not determined to be attributable to the new animal drug, except that this requirement shall not apply to the submission of information described in a written communication to the applicant from the Food and Drug Administration as types of information that may be submitted at other designated intervals. Unexpected as used in this paragraph refers to conditions or developments not previously submitted as part of the new animal drug application or in support of the index listing or not encountered during clinical trials of the drug, or conditions or developments occurring at a rate higher than shown by information previously submitted as part of the new animal drug application or in support of the index listing or at a rate higher than encountered during such clinical trials.
(2) Information concerning any unusual failure of the new animal drug to exhibit its expected pharmacological activity.
§ 510.305 Maintenance of copies of approved medicated feed mill licenses to manufacture animal feed bearing or containing new animal drugs.
Each applicant shall maintain in a single accessible location:
(a) A copy of the approved medicated feed mill license (Form FDA 3448) on the premises of the manufacturing establishment; and
(b) Approved or index listed labeling for each Type B and/or Type C feed being manufactured on the premises of the manufacturing establishment or the facility where the feed labels are generated.
Subpart E—Requirements for Specific New Animal Drugs
§ 510.410 Corticosteroids for oral, injectable, and ophthalmic use in animals; warnings and labeling requirements.
(a) The Food and Drug Administration has received reports of side effects associated with the oral, injectable, and ophthalmic use of corticosteroid animal drugs. The use of these drugs administered orally or by injection has resulted in premature parturition when administered during the last trimester of pregnancy. Premature parturition may be followed by dystocia, fetal death, retained placenta, and metritis. Additionally, corticosteroids used in dogs, rabbits, and rodents during pregnancy have produced cleft palate in offspring. Use in dogs has resulted in other congenital anomalies, including deformed forelegs, phocomelia, and anasarca. Drugs subject to this section are required to carry the veterinary prescription legend and are subject to the labeling requirements of § 201.105 of this chapter.
(b) In view of these potentially serious side effects, the Food and Drug Administration has concluded that the labeling on or within packaged corticosteroid-containing preparations intended for animal use shall bear conspicuously the following warning statement:
Warning: Clinical and experimental data have demonstrated that corticosteroids administered orally or by injection to animals may induce the first stage of parturition if used during the last trimester of pregnancy and may precipitate premature parturition followed by dystocia, fetal death, retained placenta, and metritis.
Additionally, corticosteroids administered to dogs, rabbits, and rodents during pregnancy have resulted in cleft palate in offspring. Corticosteroids administered to dogs during pregnancy have also resulted in other congenital anomalies, including deformed forelegs, phocomelia, and anasarca.
§ 510.440 Injectable iron preparations.
There has been an increasing interest in the use of injectable iron compounds for the prevention or treatment of iron-deficiency anemia in animals. Although some such preparations have been shown to be safe, such articles are regarded as new animal drugs within the meaning of the Federal Food, Drug, and Cosmetic Act. Accordingly, an approved new animal drug application is required prior to the marketing of such preparations within the jurisdiction of the act. In addition to the need for demonstrating the safety of such articles, the labeling of such preparations should not only recommend appropriate dosages of iron but also declare the amount (in milligrams) of available iron (Fe) per milliliter of the subject product.
§ 510.455 Requirements for free-choice medicated feeds.
(a) What is free-choice medicated feed? For the purpose of this part, free-choice medicated feed is medicated feed that is placed in feeding or grazing areas and is not intended to be consumed fully at a single feeding or to constitute the entire diet of the animal. Free-choice feeds include, but are not limited to, medicated blocks (agglomerated feed compressed or rendered into a solid mass and cohesive enough to hold its form), mineral mixes, and liquid feed tank supplements (“lick tank” supplements) containing one or more new animal drugs. The manufacture of medicated free-choice feeds is subject to the current good manufacturing practice regulations in part 225 of this chapter for medicated feeds.
(b) What is required for new animal drugs intended for use in free-choice feed? Any new animal drug intended for use in free-choice feed must be approved for such use under section 512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360(b)) or listed in the index under section 572 of the act (21 U.S.C. 360ccc-1). Such approvals under section 512 of the act must be:
(1) An original new animal drug application (NADA),
(2) A supplemental NADA, or
(3) An abbreviated NADA.
(c) What are the approval requirements under section 512 of the act for new animal drugs intended for use in free-choice feed? An approval under section 512 of the act for a Type A medicated article intended for use in free-choice feed must contain the following information:
(1) Data, or reference to data in a master file (MF), showing that the target animal consumes the new animal drug in the Type C free-choice feed in an amount that is safe and effective (consumption/effectiveness data); and
(2) Data, or reference to data in an MF, showing the relevant ranges of conditions under which the drug will be chemically and physically stable in the Type C free-choice feed under field conditions.
(d) How are consumption/effectiveness and/or stability data to be submitted? The data must be submitted as follows:
(1) Directly in the NADA, by a sponsor; and/or
(2) To an MF that a sponsor may then reference in its NADA with written consent of the MF holder.
(e) What will be stated in the published approval for a new animal drug intended for use in free-choice feed? The approval of a new animal drug intended for use in free-choice feed, as published in this subchapter, will include:
(1) The formula and/or specifications of the free-choice medicated feed, where the owner of this information requests such publication, or
(2) A statement that the approval has been granted for a proprietary formula and/or specifications.
(f) When is a medicated feed mill license required for the manufacture of a free-choice medicated feed? An approved medicated feed mill license is required for the manufacture of the following types of feeds:
(1) All free-choice medicated feeds that contain a Category II drug, and
(2) Free-choice medicated feeds that contain a Category I drug and use a proprietary formula and/or specifications.
Subpart F [Reserved]
Subpart G—Sponsors of Approved Applications
§ 510.600 Names, addresses, and drug labeler codes of sponsors of approved applications.
(a) Section 512(i) of the act requires publication of names and addresses of sponsors of approved applications for new animal drugs.
(b) In this section each name and address is identified by a numerical drug labeler code. The labeler codes identify the sponsors of the new animal drug applications associated with the regulations published pursuant to section 512(i) of the act. The codes appear in the appropriate regulations and serve as a reference to the names and addresses listed in this section. The drug labeler code is established pursuant to section 510 of the act.
(c) The names, addresses, and drug labeler codes of sponsors of approved new animal drug applications are as follows:
(1) Alphabetical Listing of Sponsors
| Firm name and address | Drug labeler code |
|---|---|
| A & G Pharmaceuticals, Inc., 1030 West Commodore Blvd., Jackson, NJ 08527 | 057699 |
| Accord Healthcare, Inc., 126 E Lincoln Ave., Rahway, NJ 07065 | 016729 |
| ADM Animal Nutrition, Inc., 1000 North 30th St., Quincy, IL 62305-3115 | 012286 |
| Agri Laboratories, Ltd., P.O. Box 3103, St. Joseph, MO 64503 | 057561 |
| Agri-Tech, Inc., 4722 Broadway, Kansas City, MO 64112 | 017762 |
| Aiping Pharmaceutical, Inc., 350W Wireless Blvd., Hauppauge, NY 11788 | 011788 |
| Akorn Operating Co. LLC, 5605 Centerpoint Ct., Suite A, Gurnee, IL 60031 | 059399 |
| Alexion Pharmaceuticals, Inc., 121 Seaport Blvd., Boston, MA 02210 | 069334 |
| American Regent, Inc., Animal Health Division, Shirley, NY 11967 | 010797 |
| Anika Therapeutics Inc., 236 West Cummings Park, Woburn, MA 01801 | 060865 |
| Anivive Lifesciences, Inc., 3777 Worsham Ave., Long Beach, CA 90808 | 086121 |
| Anzac Animal Health, LLC, 218 Millwell Dr., Suite B, Maryland Heights, MO 63043 | 086073 |
| AquaBounty Technologies, Inc., 2 Mill and Main Pl., Suite 395, Maynard, MA 01754 | 086053 |
| Aurora Pharmaceutical, Inc., 1196 Highway 3 South, Northfield, MN 55057-3009 | 051072 |
| Axcentive SARL, Chemin de Champouse, Quartier Violesi, 13320 Bouc Bel Air, France | 086009 |
| B.L. Mitchell, Inc., 103 Hwy. 82 E., Leland, MS 38756 | 067188 |
| Bausch Health US, LLC, 400 Somerset Corporate Blvd., Bridgewater, NJ 08807 | 099207 |
| Belcher Pharmaceuticals, LLC, 6911 Bryan Dairy Rd., Largo, FL 33777 | 062250 |
| Bimeda Animal Health Ltd., 1B The Herbert Building, The Park, Carrickmines, Dublin 18, Ireland | 061133 |
| Boehringer Ingelheim Animal Health USA, Inc., 3239 Satellite Blvd., Duluth, GA 30096 | 000010 |
| Cephazone Pharma, LLC, 250 East Bonita Ave., Pomona, CA 91767 | 068330 |
| Ceva Sante Animale, 10 Avenue de la Ballastière, 33500 Libourne, France | 013744 |
| Chanelle Pharmaceuticals Manufacturing Ltd., Loughrea, County Galway, Ireland | 061651 |
| Cronus Pharma Specialities India Private Ltd., Plot No.9(B), Survey No. 99/1, GMR Hyderabad Aviation SEZ Ltd., Mamidipalle Village, Balapur Mandal, Shamshabad, Rangareddy, Hyderabad, Telangana, 500108, India | 069043 |
| Dechra, Ltd., Snaygill Industrial Estate, Keighley Rd., Skipton, North Yorkshire, BD23 2RW, United Kingdom | 043264 |
| Dechra Veterinary Products LLC, 7015 College Blvd., Suite 525, Overland Park, KS 66211 | 017033 |
| Diamond Animal Health, Inc., 2538 SE 43rd St., Des Moines, IA 50327 | 053701 |
| Domes Pharma S.A., ZAC de Champ Lamet, 3 rue Andre Citroen, Pont-du-Chateau, Auvergne-Rhône-Alpes, 63430, FRANCE | 086189 |
| ECO LLC, 11224 Aurora Ave., Urbandale, IA 50322 | 066916 |
| Elanco US Inc., 2500 Innovation Way, Greenfield, IN 46140 | 058198 |
| Farnam Companies, Inc., 301 West Osborn, Phoenix, AZ 85013-3928 | 017135 |
| Felix Pharmaceuticals Pvt. Ltd., 25-28 North Wall Quay, Dublin 1, Ireland | 086101 |
| First Priority, Inc., 1590 Todd Farm Dr., Elgin, IL 60123 | 058829 |
| Fougera Pharmaceuticals, Inc., P.O. Box 2006, 60 Baylis Rd., Melville, NY 11747 | 025463 |
| Genus Lifesciences Inc., 700 N Fenwick St., Allentown, PA 18109 | 064950 |
| GTC Biotherapeutics, Inc., 175 Crossing Blvd., Framingham, MA 01702 | 042976 |
| Happy Jack, Inc., Snow Hill, NC 28580 | 023851 |
| Hemoglobin Oxygen Therapeutics, LLC, 674 Souder Rd., Souderton, PA 18964 | 063075 |
| HQ Specialty Pharma Corp., 120 Rte. 17 North, suite 130, Paramus, NJ 07652 | 042791 |
| Huvepharma EOOD, 5th Floor, 3A Nikolay Haytov Str., 1113 Sofia, Bulgaria | 016592 |
| IMPAX Laboratories, Inc., 30831 Huntwood Ave., Hayward, CA 94544 | 000115 |
| Intervet, Inc., 126 E Lincoln Ave., Rahway, NJ 07065 | 000061 |
| Ishihara Sangyo Kaisha, Ltd., 3-15, Edobori 1-chome, Nishi-ku, Osaka 550-0002, Japan | 064642 |
| Ivaoes Animal Health, 2101 W Atlantic Blvd., Suite 108, Pompano Beach, FL 33069 | 086064 |
| Jaguar Animal Health, 200 Pine St., Suite 600, San Francisco, CA 94104 | 086149 |
| Kinetic Technologies, LLC, 961 Beasley St., suite 270, Lexington, KY 40509 | 051031 |
| Lloyd, Inc., 604 W. Thomas Ave., Shenandoah, IA 51601 | 061690 |
| Med-Pharmex, Inc., 2727 Thompson Creek Rd., Pomona, CA 91767-1861 | 054925 |
| Mizner Bioscience LLC, 225 NE Mizner Blvd., Suite 760, Boca Raton, FL 33432 | 086039 |
| Modern Veterinary Therapeutics, LLC, 14343 SW 119th Ave., Miami, FL 33186 | 015914 |
| Mylan Institutional, Inc., 12720 Dairy Ashford Rd., Sugar Land, TX 77478 | 051079 |
| Mylan Institutional LLC, a Viatris Company, 3711 Collins Ferry Rd., Morgantown, WV 26505 | 063286 |
| Natchez Animal Supply Co., 201 John R. Junkin Dr., Natchez, MS 39120 | 049968 |
| Neogen Corp., 944 Nandino Blvd., Lexington, KY 40511 | 059051 |
| Noble Pharma, LLC, 4602 Domain Dr., Menomonie, WI 54751 | 086119 |
| Norbrook Laboratories Ltd., Carnbane Industrial Estate, Newry, County Down, BT35 6QQ, United Kingdom | 055529 |
| Orion Corp., Orionintie 1, 02200 Espoo, Finland | 052483 |
| Parnell Technologies Pty. Ltd., unit 4, 476 Gardeners Rd., Alexandria, New South Wales 2015, Australia | 068504 |
| Pegasus Laboratories, Inc., 8809 Ely Rd., Pensacola, FL 32514 | 055246 |
| Pharmaceutical Ventures, Ltd., P.O. Box D1400, Pomona, NY 10970 | 050057 |
| Pharmacosmos, Inc., 776 Mountain Blvd., Watchung, NJ 07069 | 042552 |
| Pharmaq AS, Skogmo Industriomrade, N-7863 Overhalla, Norway | 015331 |
| Pharmgate Inc., 1800 Sir Tyler Dr., Wilmington, NC 28405 | 069254 |
| Phibro Animal Health Corp., GlenPointe Centre East, 3d floor, 300 Frank W. Burr Blvd., suite 21, Teaneck, NJ 07666 | 066104 |
| Piramal Pharma Ltd., Ground Floor, Piramal Ananta, Agastya Corporate Park, Mumbai, Maharashtra, 400070, India | 065085 |
| Planalquimica Industrial Ltda., Rua das Magnolias nr. 2405, Jardim das Bandeiras, CEP 13053-120, Campinas, Sao Paulo, Brazil | 060728 |
| Provetica LLC, 8735 Rosehill Rd., Suite 300, Lenexa, KS 66215 | 086097 |
| Purina Animal Nutrition LLC, 4001 Lexington Ave., North Arden Hills, MN 55126-2910 | 017800 |
| QBiotics Group Ltd., Suite 3A, Level 1, 165 Moggill Rd., Taringa, Queensland 4068, Australia | 086132 |
| Quo Vademus, LLC, 277 Faison McGowan Rd., Kenansville, NC 28349 | 076475 |
| Revivicor, Inc., a wholly owned subsidiary of United Therapeutics Corp., 1700 Kraft Dr., Suite 2400, Blacksburg, VA 24060 | 086134 |
| Ridley USA, Inc., 111 W Cherry St., Suite 500, Mankato, MN 56001 | 067949 |
| Sergeant’s Pet Care Products, Inc., 10077 S. 134th St., Omaha, NE 68138 | 021091 |
| Sparhawk Laboratories, Inc., 12340 Santa Fe Trail Dr., Lenexa, KS 66215 | 058005 |
| Squire Laboratories, Inc., 100 Mill St., Revere, MA 02151 | 017153 |
| Summit Hill Laboratories, P.O. Box 535, Navesink, NJ 07752 | 037990 |
| Superior Equine Pharmaceuticals, Inc., Pleasant Grove, UT 84062 | 027053 |
| Syndel USA, 1441 W. Smith Rd., Ferndale, WA 98248 | 050378 |
| Taro Pharmaceuticals U.S.A., Inc., 3 Skyline Dr., Hawthorne, NY 10532 | 051672 |
| Therio, Inc., 8801 Anderson Ave., Manhattan, KS 66503 | 052923 |
| Union Agener, Inc., 1788 Lovers Ln., Augusta, GA 30901 | 086106 |
| United-AH II LLC, 322 S Main St., Sheridan, IN 46069 | 051233 |
| VetDC, Inc., 320 E. Vine Dr., suite 218, Fort Collins, CO 80524 | 086072 |
| Vétoquinol N.-A., Inc., 2000 chemin Georges, Lavaltrie (PQ), Canada, J5T 3S5 | 059320 |
| Vetoquinol USA, Inc., 4250 N Sylvania Ave., Fort Worth, TX 76137 | 017030 |
| Virbac AH, Inc., PO Box 162059, Fort Worth, TX 76161 | 051311 |
| Warburton Technology Ltd., 36 Fitzwilliam Square, Dublin 2, Dublin, D02HX82, Ireland | 066679 |
| Wildcat Feeds, 215 NE Strait Ave., Topeka, KS 66616 | 086113 |
| Wildlife Laboratories, Inc., 1230 W. Ash St., suite D, Windsor, CO 80550 | 053923 |
| Zoetis Inc., 333 Portage St., Kalamazoo, MI 49007 | 054771 |
| ZyVet Animal Health, Inc., 73 Route 31N, Pennington, NJ 08534 | 086117 |
(2) Numerical Listing of Sponsors
| Drug labeler code | Firm name and address |
|---|---|
| 000010 | Boehringer Ingelheim Animal Health USA, Inc., 3239 Satellite Blvd., Duluth, GA 30096. |
| 000061 | Intervet, Inc., 126 E Lincoln Ave., Rahway, NJ 07065 |
| 000115 | IMPAX Laboratories, Inc., 30831 Huntwood Ave., Hayward, CA 94544. |
| 010797 | American Regent, Inc., Animal Health Division, Shirley, NY 11967. |
| 011788 | Aiping Pharmaceutical, Inc., 350W Wireless Blvd., Hauppauge, NY 11788. |
| 012286 | ADM Animal Nutrition, Inc., 1000 North 30th St., Quincy, IL 62305-3115. |
| 012578 | Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. |
| 013744 | Ceva Sante Animale, 10 Avenue de la Ballastière, 33500 Libourne, France. |
| 015331 | Pharmaq AS, Skogmo Industriomrade, N-7863 Overhalla, Norway. |
| 015914 | Modern Veterinary Therapeutics, LLC, 14343 SW 119th Ave., Miami, FL 33186. |
| 016592 | Huvepharma EOOD, 5th Floor, 3A Nikolay Haytov Str., 1113 Sofia, Bulgaria. |
| 016729 | Accord Healthcare, Inc., 126 E Lincoln Ave., Rahway, NJ 07065. |
| 017030 | Vetoquinol USA, Inc., 4250 N. Sylvania Ave., Fort Worth, TX 76137. |
| 017033 | Dechra Veterinary Products LLC, 7015 College Blvd., Suite 525, Overland Park, KS 66211. |
| 017135 | Farnam Companies, Inc., 301 West Osborn, Phoenix, AZ 85013-3928. |
| 017153 | Squire Laboratories, Inc., 100 Mill St., Revere, MA 02151. |
| 017762 | Agri-Tech, Inc., 4722 Broadway, Kansas City, MO 64112. |
| 017800 | Purina Animal Nutrition LLC, 4001 Lexington Ave., North Arden Hills, MN 55126-2910. |
| 021091 | Sergeant’s Pet Care Products, Inc., 10077 S. 134th St., Omaha, NE 68138. |
| 023851 | Happy Jack, Inc., Snow Hill, NC 28580. |
| 025463 | Fougera Pharmaceuticals, Inc., P.O. Box 2006, 60 Baylis Rd., Melville, NY 11747. |
| 027053 | Superior Equine Pharmaceuticals, Inc., Pleasant Grove, UT 84062. |
| 037990 | Summit Hill Laboratories, P.O. Box 535, Navesink, NJ 07752. |
| 042552 | Pharmacosmos, Inc., 776 Mountain Blvd., Watchung, NJ 07069. |
| 042791 | HQ Specialty Pharma Corp., 120 Rte. 17 North, suite 130, Paramus, NJ 07652. |
| 042976 | GTC Biotherapeutics, Inc., 175 Crossing Blvd., Framingham, MA 01702. |
| 043264 | Dechra, Ltd., Snaygill Industrial Estate, Keighley Rd., Skipton, North Yorkshire, BD23 2RW, United Kingdom. |
| 049968 | Natchez Animal Supply Co., 201 John R. Junkin Dr., Natchez, MS 39120. |
| 050057 | Pharmaceutical Ventures, Ltd., P.O. Box D1400, Pomona, NY 10970. |
| 050378 | Syndel USA, 1441 W. Smith Rd., Ferndale, WA 98248. |
| 051031 | Kinetic Technologies, LLC, 961 Beasley St., suite 270, Lexington, KY 40509. |
| 051072 | Aurora Pharmaceutical, Inc., 1196 Highway 3 South, Northfield, MN 55057-3009. |
| 051079 | Mylan Institutional, Inc., 12720 Dairy Ashford Rd., Sugar Land, TX 77478. |
| 051233 | United-AH II LLC, 322 S Main St., Sheridan, IN 46069. |
| 051311 | Virbac AH, Inc., PO Box 162059, Fort Worth, TX 76161. |
| 051672 | Taro Pharmaceuticals U.S.A., Inc., 3 Skyline Dr., Hawthorne, NY 10532. |
| 052483 | Orion Corp., Orionintie 1, 02200 Espoo, Finland. |
| 052923 | Therio, Inc., 8801 Anderson Ave., Manhattan, KS 66503. |
| 053701 | Diamond Animal Health, Inc., 2538 SE 43rd St., Des Moines, IA 50327. |
| 053923 | Wildlife Laboratories, Inc., 1230 W. Ash St., suite D, Windsor, CO 80550. |
| 054771 | Zoetis Inc., 333 Portage St., Kalamazoo, MI 49007. |
| 054925 | Med-Pharmex, Inc., 2727 Thompson Creek Rd., Pomona, CA 91767-1861. |
| 055246 | Pegasus Laboratories, Inc., 8809 Ely Rd., Pensacola, FL 32514. |
| 055529 | Norbrook Laboratories Ltd., Carnbane Industrial Estate, Newry, County Down, BT35 6QQ, United Kingdom. |
| 057561 | Agri Laboratories, Ltd., P.O. Box 3103, St. Joseph, MO 64503. |
| 057699 | A & G Pharmaceuticals, Inc., 1030 West Commodore Blvd., Jackson, NJ 08527. |
| 058005 | Sparhawk Laboratories, Inc., 12340 Santa Fe Trail Dr., Lenexa, KS 66215. |
| 058198 | Elanco US Inc., 2500 Innovation Way, Greenfield, IN 46140. |
| 058829 | First Priority, Inc., 1590 Todd Farm Dr., Elgin, IL 60123. |
| 059051 | Neogen Corp., 944 Nandino Blvd., Lexington, KY 40511. |
| 059320 | Vétoquinol N.-A., Inc., 2000 chemin Georges, Lavaltrie (PQ), Canada, J5T 3S5. |
| 059399 | Akorn Operating Co. LLC, 5605 Centerpoint Ct., Suite A, Gurnee, IL 60031. |
| 060728 | Planalquimica Industrial Ltda., Rua das Magnolias nr. Jardim das Bandeiras, CEP 13053-120, Campinas, Sao Alto, Brazil. |
| 060865 | Anika Therapeutics Inc., 236 West Cummings Park, Woburn, MA 01801. |
| 061133 | Bimeda Animal Health Ltd., 1B The Herbert Building, The Park, Carrickmines, Dublin 18, Ireland. |
| 061651 | Chanelle Pharmaceuticals Manufacturing Ltd., Loughrea, County Galway, Ireland. |
| 061690 | Lloyd, Inc., 604 W. Thomas Ave., Shenandoah, IA 51601. |
| 062250 | Belcher Pharmaceuticals, LLC, 6911 Bryan Dairy Rd., Largo, FL 33777. |
| 062794 | Mylan Bertek Pharmaceuticals, Inc., 12720 Dairy Ashford, Sugar Land, TX 77478. |
| 063075 | Hemoglobin Oxygen Therapeutics, LLC, 674 Souder Rd., Souderton, PA 18964. |
| 063286 | Mylan Institutional LLC, a Viatris Company, 3711 Collins Ferry Rd., Morgantown, WV 26505. |
| 064642 | Ishihara Sangyo Kaisha, Ltd., 3-15, Edobori 1-chome, Nishi-ku, Osaka 550-0002, Japan. |
| 064950 | Genus Lifesciences Inc., 700 N Fenwick St., Allentown, PA 18109. |
| 065085 | Piramal Pharma Ltd., Ground Floor, Piramal Ananta, Agastya Corporate Park, Mumbai, Maharashtra, 400070, India. |
| 066104 | Phibro Animal Health Corp., GlenPointe Centre East, 3d floor, 300 Frank W. Burr Blvd., suite 21, Teaneck, NJ 07666. |
| 066679 | Warburton Technology Ltd., 36 Fitzwilliam Square, Dublin 2, Dublin, D02HX82, Ireland. |
| 066916 | ECO LLC, 11224 Aurora Ave., Urbandale, IA 50322. |
| 067188 | B.L. Mitchell, Inc., 103 Hwy. 82 E., Leland, MS 38756. |
| 067949 | Ridley USA, Inc., 111 W Cherry St., Suite 500, Mankato, MN 56001. |
| 068330 | Cephazone Pharma, LLC, 250 East Bonita Ave., Pomona, CA 91767. |
| 068504 | Parnell Technologies Pty. Ltd., unit 4, 476 Gardeners Rd., Alexandria, New South Wales 2015, Australia. |
| 069043 | Cronus Pharma Specialities India Private Ltd., Plot No.9(B), Survey No. 99/1, GMR Hyderabad Aviation SEZ Ltd., Mamidipalle Village, Balapur Mandal, Shamshabad, Rangareddy, Hyderabad, Telangana, 500108, India. |
| 069254 | Pharmgate Inc., 1800 Sir Tyler Dr., Wilmington, NC 28405. |
| 069334 | Alexion Pharmaceuticals, Inc., 121 Seaport Blvd., Boston, MA 02210. |
| 076475 | Quo Vademus, LLC, 277 Faison McGowan Rd., Kenansville, NC 28349. |
| 086009 | Axcentive SARL, Chemin de Champouse, Quartier Violesi, 13320 Bouc Bel Air, France. |
| 086039 | Mizner Bioscience LLC, 225 NE Mizner Blvd., Suite 760, Boca Raton, FL 33432. |
| 086053 | AquaBounty Technologies, Inc., 2 Mill and Main Pl., Suite 395, Maynard, MA 01754. |
| 086064 | Ivaoes Animal Health, 2101 W Atlantic Blvd., Suite 108, Pompano Beach, FL 33069. |
| 086072 | VetDC, Inc., 320 E Vine Dr., suite 218, Fort Collins, CO 80524. |
| 086073 | Anzac Animal Health, LLC, 218 Millwell Dr., Suite B, Maryland Heights, MO 63043. |
| 086097 | Provetica LLC, 8735 Rosehill Rd., Suite 300, Lenexa, KS 66215. |
| 086101 | Felix Pharmaceuticals Pvt. Ltd., 25-28 North Wall Quay, Dublin 1, Ireland. |
| 086106 | Union Agener, Inc., 1788 Lovers Ln., Augusta, GA 30901. |
| 086113 | Wildcat Feeds, 215 NE Strait Ave., Topeka, KS 66616. |
| 086117 | ZyVet Animal Health, Inc., 73 Route 31N, Pennington, NJ 08534. |
| 086119 | Noble Pharma, LLC, 4602 Domain Dr., Menomonie, WI 54751. |
| 086121 | Anivive Lifesciences, Inc., 3777 Worsham Ave., Long Beach, CA 90808. |
| 086132 | QBiotics Group Ltd., Suite 3A, Level 1, 165 Moggill Rd., Taringa, Queensland 4068, Australia. |
| 086134 | Revivicor, Inc., a wholly owned subsidiary of United Therapeutics Corp., 1700 Kraft Dr., Suite 2400, Blacksburg, VA 24060. |
| 086149 | Jaguar Animal Health, 200 Pine St., Suite 600, San Francisco, CA 94104. |
| 086189 | Domes Pharma S.A., ZAC de Champ Lamet, 3 rue Andre Citroen, Pont-du-Chateau, Auvergne-Rhône-Alpes, 63430, FRANCE. |
| 099207 | Bausch Health US, LLC, 400 Somerset Corporate Blvd., Bridgewater, NJ 08807. |
PART 511—NEW ANIMAL DRUGS FOR INVESTIGATIONAL USE
§ 511.1 New animal drugs for investigational use exempt from section 512(a) of the Federal Food, Drug, and Cosmetic Act.
(a) New animal drugs for tests in vitro and in laboratory research animals. (1) A shipment or other delivery of a new animal drug or animal feed bearing or containing a new animal drug intended solely for tests in vitro or in animals used only for laboratory research purposes shall be exempt from section 512 (a) and (m) of the act if it is labeled as follows:
Caution. Contains a new animal drug for investigational use only in laboratory research animals or for tests in vitro. Not for use in humans.
(2) The person distributing or causing the distribution of new animal drugs for tests in vitro or in animals used only for laboratory research purposes under this exemption shall use due diligence to assure that the consignee is regularly engaged in conducting such tests and that the shipment of the new animal drug will actually be used for tests in vitro or in animals used only for laboratory research.
(3) The person who introduced such shipment or who delivered the new animal drug for introduction into interstate commerce shall maintain adequate records showing the name and post office address of the expert or expert organization to whom the new animal drug is shipped and the date, quantity, and batch or code mark of each shipment and delivery for a period of 2 years after such shipment and delivery. Upon the request of a properly authorized employee of the Department at reasonable times, he shall make such records available for inspection and copying.
(4) The exemption allowed in this paragraph shall not apply to any new animal drug intended for in vitro use in the regular course of diagnosing or treating disease, including antibacterial sensitivity discs impregnated with any new animal drug or drugs, which discs are intended for use in determining susceptibility of microorganisms to the new animal drug or drugs.
(b) New animal drugs for clinical investigation in animals. A shipment or other delivery of a new animal drug or an animal feed containing a new animal drug intended for clinical investigational use in animals shall be exempt from section 512(a) and (m) of the act if all the following conditions are met:
(1) The label shall bear the statements:
Caution. Contains a new animal drug for use only in investigational animals in clinical trials. Not for use in humans. Edible products of investigational animals are not to be used for food unless authorization has been granted by the U.S. Food and Drug Administration or by the U.S. Department of Agriculture.
In the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear the caution statements required by paragraph (a) or (b) of this section, the statements may be included on the carton label and other labeling on or within the package from which the new animal drug is to be dispensed.
(2) The person or firm distributing or causing the distribution of the new animal drug or animal feed containing a new animal drug shall use due diligence to assure that the new animal drug or animal feed containing a new animal drug will actually be used for tests in animals and is not used in humans.
(3) The person who introduced such shipment or who delivered the new animal drug or animal feed containing a new animal drug for introduction into interstate commerce shall maintain adequate records showing the name and post office address of the investigator to whom the new animal drug or animal feed containing a new animal drug is shipped and the date, quantity, and batch or code mark of each shipment and delivery for a period of 2 years after such shipment and delivery. Upon the request of a properly authorized employee of the Department at reasonable times, such records shall be made available for inspection and copying.
(4) Prior to shipment of the new animal drug for clinical tests in animals, the sponsor of the investigation shall submit in triplicate to FDA a “Notice of Claimed Investigational Exemption for a New Animal Drug” including a signed statement containing the following information:
(i) The identity of the new animal drug.
(ii) All labeling and other pertinent information to be supplied to the investigators. When such pertinent information includes nonclinical laboratory studies, the information shall include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.
(iii) The name and address of each clinical investigator.
(iv) The approximate number of animals to be treated (or if not available, the amount of new animal drug to be shipped).
(v) If the new animal drug is given to food-producing animals, the statement shall contain the following additional information:
(a) A commitment that the edible products from such animals shall not be used for food without prior authorization in accordance with the provisions prescribed in this section.
(b) Approximate dates of the beginning and end of the experiment or series of experiments.
(c) The maximum daily dose(s) to be administered to a given species, the size of animal, maximum duration of administration, method(s) of administration, and proposed withdrawal time, if any.
(vi) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted.
(5) Authorization for use of edible products derived from a treated food-producing animal may be granted under the provisions of this section and when the following specified conditions are met, except that in the case of an animal administered any unlicensed experimental veterinary biological product regulated under the viruses, serums, toxins statute (21 U.S.C., chapter V, sec. 151 et seq. ) the product shall be exempt from the requirements of this section when U.S. Department of Agriculture approval has been obtained as provided in 9 CFR 103.2. Conditional authorization may be granted in advance of identification of the name(s) and address(es) of the clinical investigator(s) as required by paragraph (b)(4)(iii) of this section. Information required for authorization shall include, in addition to all other requirements of this section, the following:
(i) Data to show that consumption of food derived from animals treated at the maximum levels with the minimum withdrawal periods, if any, specified in accordance with paragraph (b)(4)(v)(c) of this section, will not be inconsistent with the public health; or
(ii) Data to show that food derived from animals treated at the maximum levels and with the minimum withdrawal periods, if any, specified in accordance with paragraph (b)(4)(v)(c) of this section, does not contain drug residues or metabolites.
(iii) The name and location of the packing plant where the animals will be processed, except that this requirement may be waived, on request, by the terms of the authorization.
(6) On written request of FDA, the sponsor shall submit any additional information reported to or otherwise received by him with respect to the investigation deemed necessary to facilitate a determination whether there are grounds in the interest of public health for terminating the exemption.
(7) The sponsor shall assure himself that the new animal drug is shipped only to investigators who:
(i) Are qualified by scientific training and/experience to evaluate the safety and/or effectiveness of the new animal drug.
(ii) Shall maintain complete records of the investigations, including complete records of the receipt and disposition of each shipment or delivery of the new animal drug under investigation. Copies of all records of the investigation shall be retained by the investigator for 2 years after the termination of the investigation or approval of a new animal drug application.
(iii) Shall furnish adequate and timely reports of the investigation to the sponsor.
(8) The sponsor:
(i) Shall retain all reports received from investigators for 2 years after the termination of the investigation or approval of a new animal drug application and make such reports available to a duly authorized employee of the Department for inspection at all reasonable times.
(ii) Shall provide for current monitoring of the investigation by a person qualified by scientific training and experience to evaluate information obtained from the investigation, and shall promptly investigate and report to FDA and to all investigators any findings associated with use of the new animal drug that may suggest significant hazards pertinent to the safety of the new animal drug.
(iii) Shall not unduly prolong distribution of the new animal drug for investigational use.
(iv) Shall not, nor shall any person acting for or on behalf of the sponsor, represent that the new animal drug is safe or effective for the purposes for which it is under investigation. This requirement is not intended to restrict the full exchange of scientific information.
(v) Shall not commercially distribute nor test-market the new animal drug until a new animal drug application is approved pursuant to section 512(c) of the act.
(9) If the shipment or other delivery of the new animal drug is imported or offered for importation into the United States for clinical investigational use in animals, it shall also meet the following conditions:
(i) The importer of all such shipments or deliveries is an agent of the foreign exporter residing in the United States or the ultimate consignee, which person has, prior to such shipments and deliveries, informed FDA of his intention to import the new animal drug as sponsor in compliance with the conditions prescribed in this subdivision; or
(ii) The new animal drug is shipped directly to a scientific institution with adequate facilities and qualified personnel to conduct laboratory or clinical investigations and is intended solely for use in such institutions and which institution has submitted a statement as sponsor of the investigation.
(10) The sponsor shall submit either a claim for categorical exclusion under § 25.30 or § 25.33 of this chapter or an environmental assessment under § 25.40 of this chapter.
(c) Disqualification of a clinical investigator. (1) If FDA has information indicating that an investigator (including a sponsor-investigator) has repeatedly or deliberately failed to comply with the conditions of these exempting regulations or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Center for Veterinary Medicine will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered and accepted by the Center for Veterinary Medicine, the Center will discontinue the disqualification proceeding. If an explanation is offered but not accepted by the Center for Veterinary Medicine, the investigator will be given an opportunity for a regulatory hearing under part 16 of this chapter on the question of whether the investigator is eligible to receive test articles under this part and eligible to conduct:
(i) Any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA; and
(ii) Any nonclinical laboratory study intended to support an application for a research or marketing permit for a new animal drug.
(2) After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the conditions of the exempting regulations in this subchapter, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not eligible to receive test articles under this part. The notification to the investigator and sponsor will provide a statement of the basis for such determination. The notification also will explain that an investigator determined to be ineligible to receive test articles under this part will be ineligible to conduct:
(i) Any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, including drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products; and
(ii) Any nonclinical laboratory study intended to support an application for a research or marketing permit for a new animal drug.
(3) Each application or submission to FDA under the provisions of this chapter containing data reported by an investigator who has been determined to be ineligible to receive FDA-regulated test articles is subject to examination to determine whether the investigator has submitted unreliable data that are essential to the continuation of an investigation or essential to the approval of a marketing application, or essential to the continued marketing of an FDA-regulated product.
(4) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor, who shall have an opportunity for a regulatory hearing under part 16 of this chapter. If a danger to the public health exists, however, the Commissioner shall terminate the exemption immediately and notify the sponsor of the termination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the exemption should be reinstated. The determination that an investigation may not be considered in support of a research or marketing application or a notification or petition submission does not, however, relieve the sponsor of any obligation under any other applicable regulation to submit to FDA the results of the investigation.
(5) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued approval of the product for which the data were submitted cannot be justified, the Commissioner will proceed to withdraw approval of the product in accordance with the applicable provisions of the relevant statutes.
(6) An investigator who has been determined to be ineligible under paragraph (c)(2) of this section may be reinstated as eligible when the Commissioner determines that the investigator has presented adequate assurances that the investigator will employ all test articles, and will conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA and any nonclinical laboratory study intended to support an application for a research or marketing permit for a new animal drug, solely in compliance with the applicable provisions of this chapter.
(d) Termination of exemption. If the Commissioner finds that:
(1) The sponsor of the investigation has failed to comply with any of the conditions for the exemption established under this section, or
(2) The continuance of the investigation is unsafe or otherwise contrary to the public interest or the drug is being or has been used for purposes other than bona fide scientific investigation, he shall first notify the sponsor and invite his immediate correction. If the conditions of the exemption are not immediately met, the sponsor shall have an opportunity for a regulatory hearing before FDA pursuant of part 16 of this chapter on whether the exemption should be terminated. If the exemption is terminated the sponsor shall recall or have destroyed the unused supplies of the new animal drug.
(e) Statements and requests. “Notice(s) of Claimed Investigational Exemption for a New Animal Drug” and requests for authorization to use investigational animals and their products for food should be addressed to the Department of Health and Human Services, Food and Drug Administration, Center for Veterinary Medicine, 7500 Standish Pl., Rockville, MD 20855.
(f) Contract research organizations. (1) For purposes of this part and part 514, contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to FDA.
(2) A sponsor may transfer responsibility for any or all of the obligations set forth in this part to a contract research organization. Any such transfer shall be in writing and, if not all obligations are transferred, shall describe each of the obligations being assumed by the contract research organization. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.
(3) A contract research organization that assumes any obligation of a sponsor shall comply with the specific regulations in this chapter applicable to this obligation and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations. Thus, all references to sponsor in this part apply to a contract research organization to the extent that it assumes one or more obligations of the sponsor.
(g) Index of legally marketed unapproved new animal drugs for minor species. All provisions of part 511 apply to new animal drugs for investigational use in support of indexing, as described in section 572 of the act, subject to the provisions of § 516.125 of this chapter.
§ 511.3 Definitions.
As used in this part:
Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration.
Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Subinvestigator” includes any other individual member of that team.
Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.
Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.
PART 514—NEW ANIMAL DRUG APPLICATIONS
Subpart A—General Provisions
§ 514.1 Applications.
(a) Applications to be filed under section 512(b) of the act shall be submitted in the form and contain the information described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part. Translations of literature printed in a foreign language shall be accompanied by copies of the original publication. The application must be signed by the applicant or by an authorized attorney, agent, or official. If the applicant or such authorized representative does not reside or have a place of business within the United States, the application must also furnish the name and post office address of, and must be countersigned by, an authorized attorney, agent, or official residing or maintaining a place of business within the United States. Pertinent information may be incorporated in, and will be considered as part of, an application on the basis of specific reference to such information, including information submitted under the provisions of § 511.1 of this chapter, in the files of the Food and Drug Administration; however, the reference must be specific in identifying the information. Any reference to information furnished by a person other than the applicant may not be considered unless its use is authorized in a written statement signed by the person who submitted it.
(b) Applications for new animal drugs shall be submitted in triplicate and assembled in the manner prescribed by paragraph (b)(15) of this section, and shall include the following information, as appropriate to support the particular submission:
(1) Identification. Whether the submission is an original or supplemental application; the name and the address of the applicant; the date of the application; the trade name(s) (if one has been proposed) and chemical name(s) of the new animal drug. Upon receipt, the application will be assigned a number NADA __, which shall be used for all correspondence with respect to the application.
(2) Table of contents and summary. The application shall be organized in a cohesive fashion, shall contain a table of contents which identifies the data and other material submitted, and shall contain a well-organized summary and evaluation of the data in the following form:
(i) Chemistry:
(a) Chemical structural formula or description for any new animal drug substance.
(b) Relationship to other chemically or pharmacologically related drugs.
(c) Description of dosage form and quantitative composition.
(ii) Scientific rationale and purpose the new animal drug is to serve:
(a) Clinical purpose.
(b) Highlights of laboratory studies: The reasons why certain types of studies were done or omitted as related to the proposed conditions of use and to information already known about this class of compounds. Emphasize any unusual or particularly significant pharmacological effects or toxicological findings.
(c) Highlights of clinical studies: The rationale of the clinical study plan showing why types of studies were done, amended, or omitted as related to laboratory studies and prior clinical experience.
(d) Conclusions: A short statement of conclusions combining the major points of effectiveness and safety as they relate to the use of the new animal drug.
(3) Labeling. Three copies of each piece of all labeling to be used for the article (total of 9).
(i) All labeling should be identified to show its position on, or the manner in which it is to accompany the market package.
(ii) Labeling for nonprescription new animal drugs should include adequate directions for use by the layman under all conditions of use for which the new animal drug is intended, recommended, or suggested in any of the labeling or advertising sponsored by the applicant.
(iii) Labeling for prescription veterinary drugs should bear adequate information for use under which veterinarians can use the new animal drug safely and for the purposes for which it is intended, including those purposes for which it is to be advertised or represented, in accord with § 201.105 of this chapter.
(iv) All labeling for prescription or nonprescription new animal drugs shall be submitted with any necessary use restrictions prominently and conspicuously displayed.
(v) Labeling for new animal drugs intended for use in the manufacture of medicated feeds shall include:
(a) Specimens of labeling to be used for such new animal drug with adequate directions for the manufacture and use of finished feeds for all conditions for which the new animal drug is intended, recommended, or suggested in any of the labeling, including advertising, sponsored by the applicant. Ingredient labeling may utilize collective names as provided in § 501.110 of this chapter.
(b) Representative labeling proposed to be used for Type B and Type C medicated feeds containing the new animal drug.
(vi) Draft labeling may be submitted for preliminary consideration of an application. Final printed labeling will ordinarily be required prior to approval of an application. Proposed advertising for veterinary prescription drugs may be submitted for comment or approval.
(4) Components and composition. A complete list of all articles used for production of the new animal drug including a full list of the composition of each article:
(i) A full list of the articles used as components of the new animal drug. This list should include all substances used in the synthesis, extraction, or other method of preparation of any new animal drug and in the preparation of the finished dosage form, regardless of whether they undergo chemical change or are removed in the process. Each component should be identified by its established name, if any, or complete chemical name, using structural formulas when necessary for specific identification. If any proprietary name is used, it should be followed by a complete quantitative statement of composition. Reasonable alternatives for any listed component may be specified.
(ii) A full statement of the composition of the new animal drug. The statement shall set forth the name and amount of each ingredient, whether active or not, contained in a stated quantity of the new animal drug in the form in which it is to be distributed (for example, amount per tablet or milliliter) and a batch formula representative of that to be employed for the manufacture of the finished dosage form. All components should be included in the batch formula regardless of whether they appear in the finished product. Any calculated excess of an ingredient over the label declaration should be designated as such and percent excess shown. Reasonable variation may be specified.
(iii) If it is a new animal drug produced by fermentation:
(a) Source and type of microorganism used to produce the new animal drug.
(b) Composition of media used to produce the new animal drug.
(c) Type of precursor used, if any, to guide or enhance production of the antibiotic during fermentation.
(d) Name and composition of preservative, if any, used in the broth.
(e) A complete description of the extraction and purification processes including the names and compositions of the solvents, precipitants, ion exchange resins, emulsifiers, and all other agents used.
(f) If the new animal drug is produced by a catalytic hydrogenation process (such as tetracycline from chlortetracycline), a complete description of each chemical reaction with graphic formulas used to produce the new animal drug, including the names of the catalyst used, how it is removed, and how the new animal drug is extracted and purified.
(5) Manufacturing methods, facilities, and controls. A full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of the new animal drug. This description should include full information with respect to any new animal drug in sufficient detail to permit evaluation of the adequacy of the described methods of manufacture, processing, and packing, and the described facilities and controls to determine and preserve the identity, strength, quality, and purity of the new animal drug, and the following:
(i) If the applicant does not himself perform all the manufacturing, processing, packaging, labeling, and control operations for any new animal drug, he shall: Identify each person who will perform any part of such operations and designate the part; and provide a signed statement from each such person fully describing, directly or by reference, the methods, facilities, and controls he will use in his part of the operation. The statement shall include a commitment that no changes will be made without prior approval by the Food and Drug Administration, unless permitted under § 514.8.
(ii) A description of the qualifications, including educational background and experience, of the technical and professional personnel who are responsible for assuring that the new animal drug has the identity, strength, quality, and purity it purports or is represented to possess, and a statement of their responsibilities.
(iii) A description of the physical facilities including building and equipment used in manufacturing, processing, packaging, labeling, storage, and control operations.
(iv) The methods used in the synthesis, extraction, isolation, or purification of any new animal drug. When the specifications and controls applied to such new animal drugs are inadequate in themselves to determine its identity, strength, quality, and purity, the methods should be described in sufficient detail, including quantities used, times, temperature, pH, solvents, etc., to determine these characteristics. Alternative methods or variations in methods within reasonable limits that do not affect such characteristics of the new animal drug may be specified. A flow sheet and indicated equations should be submitted when needed to explain the process.
(v) Precautions to insure proper identity, strength, quality, and purity of the raw materials, whether active or not, including:
(a) The specifications for acceptance and methods of testing for each lot of raw material.
(b) A statement as to whether or not each lot of raw materials is given a serial number to identify it, and the use made of such numbers in subsequent plant operations.
(vi) The instructions used in the manufacturing, processing, packaging, and labeling of each dosage form of the new animal drug, including:
(a) The method of preparation of the master formula records and individual batch records and the manner in which these records are used.
(b) The number of individuals checking weight or volume of each individual ingredient entering into each batch of the new animal drug.
(c) A statement as to whether or not the total weight or volume of each batch is determined at any stage of the manufacturing process subsequent to making up a batch according to the formula card and, if so, at what stage and by whom it is done.
(d) The precautions used in checking the actual package yield produced from a batch of the new animal drug with the theoretical yield. This should include a description of the accounting for such items as discards, breakage, etc., and the criteria used in accepting or rejecting batches of drugs in the event of an unexplained discrepancy.
(e) The precautions used to assure that each lot of the new animal drug is packaged with the proper label and labeling, including provisions for labeling storage and inventory control.
(f) Any special precautions used in the operations.
(vii) The analytical controls used during the various stages of the manufacturing, processing, packaging, and labeling of the new animal drug, including a detailed description of the collection of samples and the analytical procedures to which they are subjected. The analytical procedures should be capable of determining the active components within a reasonable degree of accuracy and of assuring the identity of such components.
(a) A description of practicable methods of analysis of adequate sensitivity to determine the amount of the new animal drug in the final dosage form should be included. The dosage form may be a finished pharmaceutical product, a Type A medicated article, a Type B or a Type C medicated feed, or a product for use in animal drinking water. Where two or more active ingredients are included, methods should be quantitative and specific for each active ingredient.
(b) If the article is one that is represented to be sterile, the same information with regard to the manufacturing, processing, packaging, and the collection of samples of the drug should be given for sterility controls. Include the standards used for acceptance of each lot of the finished drug.
(viii) An explanation of the exact significance of any batch control numbers used in the manufacturing, processing, packaging, and labeling of the new animal drug, including such control numbers that may appear on the label of the finished article. State whether these numbers enable determination of the complete manufacturing history of the product. Describe any methods used to permit determination of the distribution of any batch if its recall is required.
(ix) Adequate information with respect to the characteristics of and the test methods employed for the container, closure, or other component parts of the drug package to assure their suitability for the intended use.
(x) A complete description of, and data derived from, studies of the stability of the new animal drug in the final dosage form, including information showing the suitability of the analytical methods used. A description of any additional stability studies underway or planned. Stability data for the finished dosage form of the new animal drug in the container in which it is to be marketed, including any proposed multiple dose container, and, if it is to be put into solution at the time of dispensing, for the solution prepared as directed. If the new animal drug is intended for use in the manufacture of Type C medicated feed as defined in § 558.3 of this chapter, stability data derived from studies in which representative formulations of the medicated feed articles are used. Similar data may be required for Type B medicated feeds as determined by the Food and Drug Administration on a case-by-case basis. Expiration dates shall be proposed for finished pharmaceutical dosage forms and Type A medicated articles. If the data indicate that an expiration date is needed for Type B or Type C medicated feeds, the applicant shall propose such expiration date. If no expiration date is proposed for Type B or Type C medicated feeds, the applicant shall justify its absence with data.
(xi) Additional procedures employed which are designed to prevent contamination and otherwise assure proper control of the product. An application may be refused unless it includes adequate information showing that the methods used in, and the facilities and controls used for, the manufacturing, processing, and packaging of the new animal drug are adequate to preserve its identity, strength, quality, and purity in conformity with good manufacturing practice and identifies each establishment, showing the location of the plant conducting these operations.
(6) Samples. Samples of the new animal drug and articles used as components and information concerning them may be requested by the Center for Veterinary Medicine as follows:
(i) Each sample shall consist of four identical, separately packaged subdivisions, each containing at least three times the amount required to perform the laboratory test procedures described in the application to determine compliance with its control specifications for identity and assays. Each of the samples submitted shall be appropriately packaged and labeled to preserve its characteristics, to identify the material and the quantity in each subdivision of the sample, and to identify each subdivision with the name of the applicant and the new animal drug application to which it relates. Included are:
(a) A sample or samples of any reference standard and blank used in the procedures described in the application for assaying each new animal drug and other assayed components of the finished new animal drug.
(b) A representative sample or samples of each strength of the finished dosage form proposed in the application and employed in the clinical investigations and a representative sample or samples of each new animal drug from the batch(es) employed in the production of such dosage form.
(c) A representative sample or samples of finished market packages of each strength of the dosage form of the new animal drug prepared for initial marketing and, if any such sample is not from a representative commercial-scale production batch, such a sample from a representative commercial-scale production batch, and a representative sample or samples of each new animal drug from the batch(es) employed in the production of such dosage form, provided that in the case of new animal drugs marketed in large packages the sample should contain only three times a sufficient quantity of the new animal drug to allow for performing the control tests for drug identity and assays.
(ii) The following information shall be included for the samples when requested:
(a) For each sample submitted, full information regarding its identity and the origin of any new animal drug contained therein (including a statement whether it was produced on a laboratory, pilot-plant, or full-production scale) and detailed results of all laboratory tests made to determine the identity, strength, quality, and purity of the batch represented by the sample, including assays.
(b) For any reference standard submitted, a complete description of its preparation and the results of all laboratory tests on it. If the test methods used differed from those described in the application, full details of the methods employed in obtaining the reporting results.
(7) Analytical methods for residues. Applications shall include a description of practicable methods for determining the quantity, if any, of the new animal drug in or on food, and any substance formed in or on food because of its use, and the proposed tolerance or withdrawal period or other use restrictions to ensure that the proposed use of this drug will be safe. When data or other adequate information establish that it is not reasonable to expect the new animal drug to become a component of food at concentrations considered unsafe, a regulatory method is not required.
(i) The kind of information required by this subdivision may include: Complete experimental protocols for determining drug residue levels in the edible products, and the length of time required for residues to be eliminated from such products following the drug’s use; residue studies conducted under appropriate (consistent with the proposed usage) conditions of dosage, time, and route of administration to show levels, if any, of the drug and/or its metabolites in test animals during and upon cessation of treatment and at intervals thereafter in order to establish a disappearance curve; if the drug is to be used in combination with other drugs, possible effects of interaction demonstrated by the appropriate disappearance curve or depletion patterns after drug withdrawal under appropriate (consistent with the proposed usage) conditions of dosage, time, and route of administration; if the drug is given in the feed or water, appropriate consumption records of the medicated feed or water and appropriate performance data in the treated animal; if the drug is to be used in more than one species, drug residue studies or appropriate metabolic studies conducted for each species that is food-producing. To provide these data, a sufficient number of birds or animals should be used at each sample interval. Appropriate use of labeled compounds (e.g. radioactive tracers), may be utilized to establish metabolism and depletion curves. Drug residue levels ordinarily should be determined in muscle, liver, kidney, and fat and where applicable, in skin, milk, and eggs (yolk and egg white). As a part of the metabolic studies, levels of the drug or metabolite should be determined in blood where feasible. Samples may be combined where necessary. Where residues are suspected or known to be present in litter from treated animals, it may be necessary to include data with respect to such residues becoming components of other agricultural commodities because of use of litter from treated animals.
(ii) A new animal drug that has the potential to contaminate human food with residues whose consumption could present a risk of cancer to people must satisfy the requirements of subpart E of part 500 of this chapter.
(8) Evidence to establish safety and effectiveness. (i) An application may be refused unless it contains full reports of adequate tests by all methods reasonably applicable to show whether or not the new animal drug is safe and effective for use as suggested in the proposed labeling.
(ii) An application may be refused unless it includes substantial evidence of the effectiveness of the new animal drug as defined in § 514.4.
(iii) An application may be refused unless it contains detailed reports of the investigations, including studies made on laboratory animals, in which the purpose, methods, and results obtained are clearly set forth of acute, subacute, and chronic toxicity, and unless it contains appropriate clinical laboratory results related to safety and efficacy. Such information should include identification of the person who conducted each investigation, a statement of where the investigations were conducted, and where the raw data are available in the application.
(iv) All information pertinent to an evaluation of the safety and effectiveness of the new animal drug received or otherwise obtained by the applicant from any source, including information derived from other investigations or commercial marketing (for example, outside the United States), or reports in the scientific literature, both favorable and unfavorable, involving the new animal drug that is the subject of the application and related new animal drugs shall be submitted. An adequate summary may be acceptable in lieu of a reprint of a published report that only supports other data submitted. Include any evaluation of the safety or effectiveness of the new animal drug that has been made by the applicant’s veterinary or medical department, expert committee, or consultants.
(v) If the new animal drug is a combination of active ingredients or animal drugs, an application may be refused unless it includes substantial evidence of the effectiveness of the combination new animal drug as required in § 514.4.
(vi) An application shall include a complete list of the names and post office addresses of all investigators who received the new animal drug. This may be incorporated in whole or in part by reference to information submitted under the provisions of § 511.1 of this chapter.
(vii) Explain any omission of reports from any investigator to whom the investigational new animal drug has been made available. The unexplained omission of any reports of investigations made with the new animal drug by the applicant or submitted to him by an investigator or the unexplained omission of any pertinent reports of investigations or clinical experience received or otherwise obtained by the applicant from published literature or other sources that would bias an evaluation of the safety of the new animal drug or its effectiveness in use, constitutes grounds for the refusal or withdrawal of the approval of an application.
(viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, the application is required to include a statement containing the name and address of the contract research organization, identifying the clinical study, and listing the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted.
(ix) If original subject records were audited or reviewed by the sponsor in the course of monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical study so audited or reviewed.
(9) Veterinary feed directive. Three copies of a veterinary feed directive (VFD) must be submitted in a form that accounts for the information described under § 558.6(b)(3) and 558.6(b)(4) of this chapter.
(10) Supplemental applications. If it is a supplemental application, full information shall be submitted on each proposed change concerning any statement made in the approved application.
(11) Applicant’s commitment. It is understood that the labeling and advertising for the new animal drug will prescribe, recommend, or suggest its use only under the conditions stated in the labeling which is part of this application and if the article is a prescription new animal drug, it is understood that any labeling which furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for use of the new animal drug will also contain, in the same language and emphasis, information for its use including indications, effects, dosages, routes, methods, and frequency and duration of administration, any relevant hazards, contraindications, side effects, and precautions contained in the labeling which is part of this application. It is understood that all representations in this application apply to the drug produced until changes are made in conformity with § 514.8.
(12) Additional commitments. (i) New animal drugs as defined in § 510.3 of this chapter, intended for use in the manufacture of animal feeds in any State will be shipped only to persons who may receive such drugs in accordance with § 510.7 of this chapter.
(ii) The methods, facilities, and controls described under item 5 of this application conform to the current good manufacturing practice regulations in subchapter C of this chapter.
(iii) With respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.
(13) [Reserved]
(14) Environmental assessment. The applicant is required to submit either a claim for categorical exclusion under § 25.30 or § 25.33 of this chapter or an environmental assessment under § 25.40 of this chapter.
(15) Assembling and binding the application. Assemble and bind an original and two copies of the application as follows:
(i) Bind the original or ribbon copy of the application as copy No. 1.
(ii) Bind two identical copies as copy No. 2 and copy No. 3.
(iii) Identify each front cover with the name of the applicant, new animal drug, and the copy number.
(iv) Number each page of the application sequentially in the upper right hand corner or in another location so that the page numbers remain legible after the application has been bound, and organize the application consistent with paragraphs (b) (1) through (14) of this section. Each copy should bear the same page numbering, whether sequential in each volume or continuous and sequential throughout the application.
(v) Include complete labeling in each of the copies. It is suggested that labeling be identified by date of printing or date of preparation.
(vi) Submit separate applications for each different dosage form of the drug proposed. Repeating basic information pertinent to all dosage forms in each application is unnecessary if reference is made to the application containing such information. Include in each application information applicable to the specific dosage form, such as labeling, composition, stability data, and method of manufacture.
(vii) Submit in folders amendments, supplements, and other correspondence sent after submission of an original application. The front cover of these submissions should be identified with the name of the applicant, new animal drug, copy number, and the new animal drug application number, if known.
(c) When a new animal drug application is submitted for a new animal drug which has a stimulant, depressant, or hallucinogenic effect on the central nervous system, if it appears that the drug has a potential for abuse, the Commissioner shall forward that information to the Attorney General of the United States.
§ 514.3 Definitions.
The definition and interpretation of terms contained in this section apply to those terms as used throughout subchapter E.
Adverse drug experience is any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in accordance with the approved labeling (i.e., used according to label directions or used in an extralabel manner, including but not limited to different route of administration, different species, different indications, or other than labeled dosage). Adverse drug experience includes, but is not limited to:
(1) An adverse event occurring in animals in the course of the use of an animal drug product by a veterinarian or by a livestock producer or other animal owner or caretaker.
(2) Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected effectiveness).
(3) An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug.
ANADA is an abbreviated new animal drug application including all amendments and supplements.
Applicant is a person or entity who owns or holds on behalf of the owner the approval for an NADA or an ANADA, and is responsible for compliance with applicable provisions of the act and regulations.
Increased frequency of adverse drug experience is an increased rate of occurrence of a particular serious adverse drug event, expected or unexpected, after appropriate adjustment for drug exposure.
NADA is a new animal drug application including all amendments and supplements.
Nonapplicant is any person other than the applicant whose name appears on the label and who is engaged in manufacturing, packing, distribution, or labeling of the product.
Potential applicant means any person:
(1) Intending to investigate a new animal drug under section 512(j) of the Federal Food, Drug, and Cosmetic Act (the act),
(2) Investigating a new animal drug under section 512(j) of the act,
(3) Intending to file a new animal drug application (NADA) or supplemental NADA under section 512(b)(1) of the act, or
(4) Intending to file an abbreviated new animal drug application (ANADA) under section 512(b)(2) of the act.
Presubmission conference means one or more conferences between a potential applicant and FDA to reach a binding agreement establishing a submission or investigational requirement.
Presubmission conference agreement means that section of the memorandum of conference headed “Presubmission Conference Agreement” that records any agreement on the submission or investigational requirement reached by a potential applicant and FDA during the presubmission conference.
Product defect/manufacturing defect is the deviation of a distributed product from the standards specified in the approved application, or any significant chemical, physical, or other change, or deterioration in the distributed drug product, including any microbial or chemical contamination. A manufacturing defect is a product defect caused or aggravated by a manufacturing or related process. A manufacturing defect may occur from a single event or from deficiencies inherent to the manufacturing process. These defects are generally associated with product contamination, product deterioration, manufacturing error, defective packaging, damage from disaster, or labeling error. For example, a labeling error may include any incident that causes a distributed product to be mistaken for, or its labeling applied to, another product.
Serious adverse drug experience is an adverse event that is fatal, or life-threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability, or disfigurement.
Unexpected adverse drug experience is an adverse event that is not listed in the current labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an event listed on the labeling, but differs from the event because of greater severity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling referred only to elevated hepatic enzymes or hepatitis.
§ 514.4 Substantial evidence.
(a) Definition of substantial evidence. Substantial evidence means evidence consisting of one or more adequate and well-controlled studies, such as a study in a target species, study in laboratory animals, field study, bioequivalence study, or an in vitro study, on the basis of which it could fairly and reasonably be concluded by experts qualified by scientific training and experience to evaluate the effectiveness of the new animal drug involved that the new animal drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. Substantial evidence shall include such adequate and well-controlled studies that are, as a matter of sound scientific judgment, necessary to establish that a new animal drug will have its intended effect.
(b) Characteristics of substantial evidence—(1) Qualifications of experts. Any study that is intended to be part of substantial evidence of the effectiveness of a new animal drug shall be conducted by experts qualified by scientific training and experience.
(2) Intended uses and conditions of use. Substantial evidence of effectiveness of a new animal drug shall demonstrate that the new animal drug is effective for each intended use and associated conditions of use for and under which approval is sought.
(i) Dose range labeling. Sponsors should, to the extent possible, provide for a dose range because it increases the utility of the new animal drug by providing the user flexibility in the selection of a safe and effective dose. In general, substantial evidence to support dose range labeling for a new animal drug intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at the lowest dose of the dose range suggested in the proposed labeling for that intended use. Substantial evidence to support dose range labeling for a new animal drug intended to affect the structure or function of the body of an animal generally must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at all doses within the range suggested in the proposed labeling for the intended use.
(ii) [Reserved]
(3) Studies—(i) Number. Substantial evidence of the effectiveness of a new animal drug for each intended use and associated conditions of use shall consist of a sufficient number of current adequate and well-controlled studies of sufficient quality and persuasiveness to permit qualified experts:
(A) To determine that the parameters selected for measurement and the measured responses reliably reflect the effectiveness of the new animal drug;
(B) To determine that the results obtained are likely to be repeatable, and that valid inferences can be drawn to the target animal population; and
(C) To conclude that the new animal drug is effective for the intended use at the dose or dose range and associated conditions of use prescribed, recommended, or suggested in the proposed labeling.
(ii) Types. Adequate and well-controlled studies that are intended to provide substantial evidence of the effectiveness of a new animal drug may include, but are not limited to, published studies, foreign studies, studies using models, and studies conducted by or on behalf of the sponsor. Studies using models shall be validated to establish an adequate relationship of parameters measured and effects observed in the model with one or more significant effects of treatment.
(c) Substantial evidence for combination new animal drugs—(1) Definitions. The following definitions of terms apply to this section:
(i) Combination new animal drug means a new animal drug that contains more than one active ingredient or animal drug that is applied or administered simultaneously in a single dosage form or simultaneously in or on animal feed or drinking water.
(ii) Dosage form combination new animal drug means a combination new animal drug intended for use other than in animal feed or drinking water.
(iii) Antibacterial with respect to a particular target animal species means an active ingredient or animal drug: That is approved in that species for the diagnosis, cure, mitigation, treatment, or prevention of bacterial disease; or that is approved for use in that species for any other use that is attributable to its antibacterial properties. But, antibacterial does not include ionophores or arsenicals intended for use in combination in animal feed or drinking water.
(iv) Appropriate concurrent use exists when there is credible evidence that the conditions for which the combination new animal drug is intended can occur simultaneously.
(2) Combination new animal drugs that contain only active ingredients or animal drugs that have previously been separately approved. (i) For dosage form combination new animal drugs, except for those that contain a nontopical antibacterial, that contain only active ingredients or animal drugs that have previously been separately approved for the particular uses and conditions of use for which they are intended in combination, a sponsor shall demonstrate:
(A) By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug;
(B) That each active ingredient or animal drug intended for at least one use that is different from all the other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and
(C) That the active ingredients or animal drugs are physically compatible and do not have disparate dosing regimens if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible or have disparate dosing regimens.
(ii) For combination new animal drugs intended for use in animal feed or drinking water that contain only active ingredients or animal drugs that have previously been separately approved for the particular uses and conditions of use for which they are intended in combination, the sponsor shall demonstrate:
(A) By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug;
(B) For such combination new animal drugs that contain more than one antibacterial ingredient or animal drug, by substantial evidence, as defined in this section, that each antibacterial makes a contribution to labeled effectiveness;
(C) That each active ingredient or animal drug intended for at least one use that is different from all other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and
(D) That the active ingredients or animal drugs intended for use in drinking water are physically compatible if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible.
(3) Other combination new animal drugs. For all other combination new animal drugs, the sponsor shall demonstrate by substantial evidence, as defined in this section, that the combination new animal drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling and that each active ingredient or animal drug contributes to the effectiveness of the combination new animal drug.
§ 514.5 Presubmission conferences.
(a) General principle underlying the conduct of a presubmission conference. The general principle underlying the conduct of any presubmission conference is that there should be candid, full, and open communication.
(b) Requesting a presubmission conference. A potential applicant is entitled to one or more conferences prior to the submission of an NADA, supplemental NADA, or an ANADA to reach an agreement establishing part or all of a submission or investigational requirement. A potential applicant’s request for a presubmission conference must be submitted to FDA in a signed letter. The letter must include a proposed agenda that clearly outlines the scope, purpose, and objectives of the presubmission conference and must list the names and positions of the representatives who are expected to attend the presubmission conference on behalf of the applicant.
(c) Timing. A potential applicant may request one or more presubmission conferences at any time prior to the filing of a NADA, supplemental NADA, or an ANADA. A request for a presubmission conference must be received by FDA at least 30 calendar days in advance of the requested conference date. FDA will schedule the presubmission conference at a time agreeable to both FDA and the potential applicant.
(d) Advance information. The potential applicant must provide to FDA, at least 30 calendar days before a scheduled presubmission conference, a detailed agenda, a copy of any materials to be presented at the conference, a list of proposed indications and, if available, a copy of the proposed labeling for the product under consideration, and copies of materials evaluated or referenced relative to issues listed in the agenda for the conference. If the materials are not provided or are not sufficient to provide the basis for meaningful discussion, FDA may elect to postpone part or all of the meeting until sufficient materials are provided to FDA.
(e) Conduct of a presubmission conference. The potential applicant and FDA may each bring consultants to the presubmission conference. The presubmission conference(s) will be directed primarily at establishing agreement between FDA and the potential applicant regarding a submission or investigational requirement. The submission or investigational requirement may include, among other things, the number, types, and general design of studies that are necessary to demonstrate the safety and effectiveness of a new animal drug for the intended uses and conditions of use prescribed, recommended, or suggested in the proposed labeling for the new animal drug.
(f) Documentation of a presubmission conference—(1) Memorandum of conference—(i) Preparation. FDA will prepare a memorandum for each presubmission conference that will include, among other things, any background pertinent to the request for meeting; a summary of the key points of discussion; agreements; and action items and assignments of responsibility. That portion of the memorandum of conference that documents any agreements reached regarding all or part of a submission or investigational requirement will be included under the heading “Presubmission Conference Agreement.” If the presubmission conference agreement section of the memorandum is silent on an issue, including one that was discussed in the conference or addressed by materials provided for the conference, such silence does not constitute agreement between FDA and the potential applicant on the issue.
(ii) Sending a copy to the potential applicant. FDA will send a copy of the memorandum to the potential applicant for review no later than 45 calendar days after the date of the conference
(iii) Requests for changes or clarification. If a potential applicant requests changes to, or clarification of, the substance of the memorandum, the request must be sent to FDA within 30 calendar days from the date a copy of the memorandum is sent to the applicant. If the potential applicant requests changes or clarification, FDA will send the potential applicant a response to their request no later than 45 calendar days after the date of receipt of the request.
(iv) Administrative record. A copy of FDA’s original memorandum of conference and, as appropriate, a copy of an amended memorandum to correct or clarify the content of the original memorandum will be made part of the administrative file.
(2) Field studies. If FDA requires more than one field study to establish by substantial evidence that the new animal drug is effective for its intended uses under the conditions of use prescribed, recommended, or suggested in the proposed labeling, FDA will provide written scientific justification for requiring more than one field study. Such justification must be provided no later than 25 calendar days after the date of the conference at which the requirement for more than one field study is established. If FDA does not believe more than one field study is required but the potential applicant voluntarily proposes to conduct more than one field study, FDA will not provide such written justification. If FDA requires one field study to be conducted at multiple locations, FDA will provide justification for requiring multiple locations verbally during the presubmission conference and in writing as part of the memorandum of conference.
(g) Modification of presubmission conference agreements. An agreement made under a presubmission conference requested under section 512(b)(3) of the act and documented in a memorandum of conference is binding on the potential applicant and FDA and may only be modified if:
(1) FDA and the potential applicant mutually agree to modify, in part or in whole, the agreement and such modification is documented and provided to the potential applicant as described in paragraph (f)(1) of this section; or
(2) FDA by written order determines that a substantiated scientific requirement essential to the determination of safety or effectiveness of the new animal drug appeared after the conference.
(h) When the terms of a presubmission conference agreement are not valid. (1) A presubmission conference agreement will no longer be valid if:
(i) The potential applicant makes to FDA, before, during, or after the presubmission conference, any untrue statement of material fact; or
(ii) The potential applicant fails to follow any material term of the agreement; and
(2) A presubmission conference may no longer be valid if the potential applicant submits false or misleading data relating to a new animal drug to FDA.
(i) Dispute resolution. FDA is committed to resolving differences between a potential applicant and FDA reviewing divisions with respect to requirements for the investigation of new animal drugs and for NADAs, supplemental NADAs, and ANADAs as quickly and amicably as possible through a cooperative exchange of information and views. When administrative or procedural disputes arise, a potential applicant should first attempt to resolve the matter within the appropriate review division beginning with the individual(s) most directly assigned to the review of the application or investigational exemption. If the dispute cannot be resolved after such attempts, the dispute shall be evaluated and administered in accordance with applicable regulations (21 CFR 10.75). Dispute resolution procedures may be further explained by guidance available from the Center for Veterinary Medicine.
§ 514.6 Amended applications.
The applicant may submit an amendment to an application that is pending, including changes that may alter the conditions of use, the labeling, safety, effectiveness, identity, strength, quality, or purity of the drug or the adequacy of the manufacturing methods, facilities, and controls to preserve them, in which case the unamended application may be considered as withdrawn and the amended application may be considered resubmitted on the date on which the amendment is received by the Food and Drug Administration. The applicant will be notified of such date.
§ 514.7 Withdrawal of applications without prejudice.
The sponsor may withdraw his pending application from consideration as a new animal drug application upon written notification to the Food and Drug Administration. Such withdrawal may be made without prejudice to a future filing. Upon resubmission, the time limitation will begin to run from the date the resubmission is received by the Food and Drug Administration. The original application will be retained by the Food and Drug Administration although it is considered withdrawn. The applicant shall be furnished a copy at cost on request.
§ 514.8 Supplements and other changes to an approved application.
(a) Definitions. (1) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) apply to those terms when used in this part.
(2) The following definitions of terms apply to this part:
(i) Assess the effects of the change means to evaluate the effects of a manufacturing change on the identity, strength, quality, purity, and potency of a drug as these factors may relate to the safety or effectiveness of the drug.
(ii) Drug substance means an active ingredient as defined under § 210.3(b)(7) of this chapter.
(iii) Minor changes and stability report (MCSR) means an annual report that is submitted to the application once each year within 60 days before or after the anniversary date of the application’s original approval or on a mutually agreed upon date. The report must include minor manufacturing and control changes made according to § 514.8(b)(4) or state that no changes were made; and stability data generated on commercial or production batches according to an approved stability protocol or commitment.
(iv) Specification means the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of drugs including, for example, drug substances, Type A medicated articles, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug. For the purpose of this definition, the term “acceptance criteria” means numerical limits, ranges, or other criteria for the tests described.
(b) Manufacturing changes to an approved application—(1) General provisions. (i) The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about it in a supplement under paragraph (b)(2) or (b)(3) of this section or by inclusion of the information in the annual report to the application under paragraph (b)(4) of this section.
(ii) The holder of an approved application under section 512 of the act must assess the effects of the change before distributing a drug made with a manufacturing change.
(iii) Notwithstanding the requirements of paragraphs (b)(2) and (b)(3) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the drug, or by notification in the next annual report described in paragraph (b)(4) of this section).
(iv) In each supplement and amendment to a supplement providing for a change under paragraph (b)(2) or (b)(3) of this section, the applicant must include a statement certifying that a field copy has been provided to the appropriate FDA district office. No field copy is required for a supplement providing for a change made to a drug manufactured outside of the United States.
(v) A supplement or annual report described in paragraph (b)(4) of this section must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the cover letter.
(2) Changes requiring submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (i) A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.
(ii) These changes include, but are not limited to:
(A) Except those described in paragraphs (b)(3) and (b)(4) of this section, changes in the qualitative or quantitative formulation of the drug, including inactive ingredients, or in the specifications provided in the approved application;
(B) Changes requiring completion of appropriate clinical studies to demonstrate the equivalence of the drug to the drug as manufactured without the change;
(C) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation;
(D) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance;
(E) Changes in a drug product container closure system that controls the drug delivered to the animal or changes in the type or composition of a packaging component that may affect the impurity profile of the drug product;
(F) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following:
(1) Changes in the virus or adventitious agent removal or inactivation method(s),
(2) Changes in the source material or cell line, and
(3) Establishment of a new master cell bank or seed;
(G) Changes to a drug under an application that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that application.
(iii) The applicant must obtain approval of a supplement from FDA prior to distribution of a drug made using a change under paragraph (b)(2) of this section. The supplement must be labeled “Prior Approval Supplement.” Except for submissions under paragraph (b)(2)(v) of this section, the following information must be contained in the supplement:
(A) A completed Form FDA 356V;
(B) A detailed description of the proposed change;
(C) The drug(s) involved;
(D) The manufacturing site(s) or area(s) affected;
(E) A description of the methods used and studies performed to assess the effects of the change;
(F) The data derived from such studies;
(G) Appropriate documentation (for example, updated master batch records, specification sheets) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;
(H) For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section;
(I) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section; and
(J) Any other information as directed by FDA.
(iv) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover must be plainly marked: “Prior Approval Supplement-Expedited Review Requested.”
(v) Comparability Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug as these factors may relate to the safety or effectiveness of the drug. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of the drug produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect. A comparability protocol supplement must be labeled “Prior Approval Supplement—Comparability Protocol.”
(3) Changes requiring submission of a supplement at least 30 days prior to distribution of the drug made using the change (moderate changes). (i) A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.
(ii) These changes include, but are not limited to:
(A) A change in the container closure system that does not affect the quality of the drug except as otherwise described in paragraphs (b)(2) and (b)(4) of this section;
(B) Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including:
(1) An increase or decrease in production scale during finishing steps that involves different equipment, and
(2) Replacement of equipment with that of a different design that does not affect the process methodology or process operating parameters.
(C) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.
(iii) A supplement submitted under paragraph (b)(3)(i) or (b)(3)(vi) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is made. The supplement submitted under paragraph (b)(3)(i) must be labeled “Supplement-Changes Being Effected in 30 Days.”
(iv) Pending approval of the supplement by FDA and except as provided in paragraph (b)(3)(vi) of this section, distribution of the drug made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement.
(v) The applicant must not distribute the drug made using the change if within 30 days following FDA’s receipt of the supplement, FDA informs the applicant that either:
(A) The change requires approval prior to distribution of the drug in accordance with paragraph (b)(2) of this section; or
(B) Any of the information required under paragraph (b)(3)(iv) of this section is missing. In this case, the applicant must not distribute the drug made using the change until the supplement has been amended to provide the missing information.
(vi) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved application may commence distribution of the drug involved upon receipt by the agency of a supplement for the change. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement. The supplement must be labeled “Supplement-Changes Being Effected.” These changes include, but are not limited to:
(A) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess; and
(B) A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another.
(vii) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug(s) made with the manufacturing change.
(4) Changes and updated stability data to be described and submitted in an annual report (minor changes). (i) Changes in the drug, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug must be documented by the applicant in an annual report to the application as described under paragraph (a)(2)(iii) of this section. The report must be labeled “Minor Changes and Stability Report.”
(ii) These changes include but are not limited to:
(A) Any change made to comply with a change to an official compendium, except a change in paragraph (b)(3)(ii)(C) of this section, that is consistent with FDA statutory and regulatory requirements;
(B) The deletion or reduction of an ingredient intended to affect only the color of the drug product;
(C) Replacement of equipment with that of the same design and operating principles except for those equipment changes described in paragraph (b)(3)(ii)(B)(2) of this section;
(D) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another;
(E) A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;
(F) An extension of an expiration dating period based upon full shelf-life data on production batches obtained from a protocol approved in the application;
(G) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the drug being tested as the analytical procedure described in the approved application, or deletion of an alternative analytical procedure; and
(H) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.
(iii) For changes under this category, the applicant is required to submit in the annual report:
(A) A completed Form FDA 356V;
(B) A statement by the holder of the approved application that the effects of the change have been assessed;
(C) A detailed description of the change(s);
(D) The manufacturing site(s) or area(s) involved;
(E) The date each change was implemented;
(F) Data from studies and tests performed to assess the effects of the change;
(G) For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, relevant validation protocols and/or standard operating procedures;
(H) Appropriate documentation (for example, updated master batch records, specification sheets, etc.) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;
(I) Updated stability data generated on commercial or production batches according to an approved stability protocol or commitment; and
(J) Any other information as directed by FDA.
(c) Labeling and other changes to an approved application—(1) General provisions. The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully.
(2) Labeling changes requiring the submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (i) Addition of intended uses and changes to package labeling require a supplement. These changes include, but are not limited to:
(A) Revision in labeling, such as updating information pertaining to effects, dosages, adverse reactions, contraindications, which includes information headed “adverse reactions,” “warnings,” “precautions,” and “contraindications,” except ones described in (c)(3) of this section;
(B) Addition of an intended use;
(C) If it is a prescription drug, any mailing or promotional piece used after the drug is placed on the market is labeling requiring a supplemental application, unless:
(1) The parts of the labeling furnishing directions, warnings, and information for use of the drug are the same in language and emphasis as labeling approved or permitted; and
(2) Any other parts of the labeling are consistent with and not contrary to such approved or permitted labeling.
(3) Prescription drug labeling not requiring an approved supplemental application is submitted in accordance with § 514.80(b)(5)(ii).
(D) Any other changes in labeling, except ones described in paragraph (c)(3) of this section.
(ii) The applicant must obtain approval of the supplement from FDA prior to distribution of the drug. The supplement must contain the following:
(A) A completed Form FDA 356V;
(B) A detailed description of the proposed change;
(C) The drug(s) involved;
(D) The data derived from studies in support of the change; and
(E) Any other information as directed by FDA.
(3) Labeling changes to be placed into effect prior to receipt of a written notice of approval of a supplemental application. (i) Labeling changes of the following kinds that increase the assurance of drug safety proposed in supplemental applications must be placed into effect immediately:
(A) The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, adverse reaction, and precaution information;
(B) The deletion from package labeling, promotional labeling, or drug advertising of false, misleading, or unsupported intended uses or claims for effectiveness; and
(C) Any other changes as directed by FDA.
(ii) Labeling changes (for example, design and style) that do not decrease safety of drug use proposed in supplemental applications may be placed into effect prior to written notice of approval from FDA of a supplemental application.
(iii) A supplement submitted under paragraph (c)(3) of this section must include the following information:
(A) A full explanation of the basis for the changes, the date on which such changes are being effected, and plainly marked on the mailing cover and on the supplement, “Supplement—Labeling Changes Being Effected”;
(B) Two sets of printed copies of any revised labeling to be placed in use, identified with the new animal drug application number; and
(C) A statement by the applicant that all promotional labeling and all drug advertising will promptly be revised consistent with the changes made in the labeling on or within the new animal drug package no later than upon approval of the supplemental application.
(iv) If the supplemental application is not approved and the drug is being distributed with the proposed labeling, FDA may initiate an enforcement action because the drug is misbranded under section 502 of the act and/or adulterated under section 501 of the act. In addition, under section 512(e) of the act, FDA may, after due notice and opportunity for a hearing, issue an order withdrawing approval of the application.
(4) Changes providing for additional distributors to be reported under Records and reports concerning experience with approved new animal drugs (§ 514.80). Supplemental applications as described under paragraph (c)(2) of this section will not be required for an additional distributor to distribute a drug that is the subject of an approved new animal drug application or abbreviated new animal drug application if the conditions described under § 514.80(b)(5)(iii) are met.
(d) Patent information. The applicant must comply with the patent information requirements under section 512(c)(3) of the act.
(e) Claimed exclusivity. If an applicant claims exclusivity under section 512(c)(2)(F) of the act upon approval of a supplemental application for a change in its previously approved drug, the applicant must include such a statement.
(f) Good laboratory practice for nonclinical laboratory studies. A supplemental application that contains nonclinical laboratory studies must include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.
§ 514.11 Confidentiality of data and information in a new animal drug application file.
(a) For purposes of this section the NADA file includes all data and information submitted with or incorporated by reference in the NADA, INAD’s incorporated into the NADA, supplemental NADA’s, reports under §§ 514.80 and 510.301 of this chapter, master files, and other related submissions. The availability for public disclosure of any record in the NADA file shall be handled in accordance with the provisions of this section.
(b) The existence of an NADA file will not be disclosed by the Food and Drug Administration before the application has been approved, unless it has been previously disclosed or acknowledged.
(c) If the existence of an NADA file has not been publicly disclosed or acknowledged, no data or information in the NADA file is available for public disclosure.
(d) If the existence of an NADA file has been publicly disclosed or acknowledged before the application has been approved, no data or information contained in the file is available for public disclosure, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, i.e., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.
(e) After an application has been approved, the following data and information in the NADA file are immediately available for public disclosure unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information previously disclosed to the public, as defined in § 20.81 of this chapter.
(2) A summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the NADA file. Such summaries do not constitute the full reports of investigations under section 512(b)(1) of the act (21 U.S.C. 360b(b)(1)) on which the safety or effectiveness of the drug may be approved. Such summaries shall consist of the following:
(i) For an NADA approved prior to July 1, 1975, internal agency records that describe such data and information, e.g., a summary of basis for approval or internal reviews of the data and information, after deletion of:
(a) Names and any information that would identify the investigators.
(b) Any inappropriate gratuitous comments unnecessary to an objective analysis of the data and information.
(ii) For an NADA approved after July 1, 1975, a summary of such data and information prepared in one of the following two alternative ways shall be publicly released when the application is approved.
(a) The Center for Veterinary Medicine may at an appropriate time prior to approval of the NADA require the applicant to prepare a summary of such data and information, which will be reviewed and, where appropriate, revised by the Center.
(b) The Center for Veterinary Medicine may prepare its own summary of such data and information.
(3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61 of this chapter.
(4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using the product.
(ii) Names and any information that would identify any third party involved with the report, such as a physician, hospital, or other institution.
(5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as defined in § 20.81 of this chapter.
(6) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established in § 20.61 of this chapter.
(7) All correspondence and written summaries of oral discussions relating to the NADA, in accordance with the provisions of part 20 of this chapter.
(f) All safety and effectiveness data and information not previously disclosed to the public are available for public disclosure at the time any one of the following events occurs unless extraordinary circumstances are known:
(1) The NADA has been abandoned and no further work is being undertaken with respect to it.
(2) A final determination is made that the NADA is not approvable, and all legal appeals have been exhausted.
(3) Approval of the NADA is withdrawn, and all legal appeals have been exhausted.
(4) A final determination has been made that the animal drug is not a new animal drug.
(5) A final determination has been made that the animal drug may be marketed without submission of such safety and/or effectiveness data and information.
(g) The following data and information in an NADA file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control procedures.
(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(h) For purposes of this regulation, safety and effectiveness data include all studies and tests of an animal drug on animals and all studies and tests on the animal drug for identity, stability, purity, potency, and bioavailability.
§ 514.12 Confidentiality of data and information in an investigational new animal drug notice.
(a) The existence of an INAD notice will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and information in an INAD file shall be handled in accordance with provisions established in § 514.11.
§ 514.15 Untrue statements in applications.
Among the reasons why an application for a new animal drug or animal feed bearing or containing a new animal drug may contain an untrue statement of a material fact are:
(a) Differences in:
(1) Conditions of use prescribed, recommended, or suggested by the applicant for the product from the conditions of such use stated in the application;
(2) Articles used as components of the product from those listed in the application;
(3) Composition of the product from that stated in the application;
(4) Methods used in or the facilities and controls used for the manufacture, processing, or packing of the product from such methods, facilities, and controls described in the application;
(5) Labeling from the specimens contained in the application; or
(b) The unexplained omission in whole or in part from an application or from an amendment or supplement to an application or from any record or report required under the provisions of section 512 of the act and § 514.80 or § 510.301 of this chapter of any information obtained from:
(1) Investigations as to the safety, effectiveness, identity, strength, quality, or purity of the drug, made by the applicant on the drug, or
(2) Investigations or experience with the product that is the subject of the application, or any related product, available to the applicant from any source if such information is pertinent to an evaluation of the safety, effectiveness, identity, strength, quality, or purity of the drug, when such omission would bias an evaluation of the safety or effectiveness of the product.
(c) Any nonclinical laboratory study contained in the application was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter, and the application fails to include a brief statement of the reason for the noncompliance.
Subpart B—Administrative Actions on Applications
§ 514.80 Records and reports concerning experience with approved new animal drugs.
The following table outlines the purpose for each paragraph of this section:
| Purpose | 21 CFR Paragraph and Title |
|---|---|
| What information must be reported concerning approved NADAs or ANADAs? | 514.80(a) Applicability. |
| What authority does FDA have for requesting records and reports? Who is required to establish, maintain, and report required information relating to experiences with a new animal drug? Is information from foreign sources required? | 514.80(a)(1). |
| What records must be established and maintained and what reports filed with FDA? | 514.80(a)(2). |
| What is FDA’s purpose for requiring reports? | 514.80(a)(3). |
| Do applicants of Type A medicated articles have to establish, maintain, and report information required under § 514.80? | 514.80(a)(4). |
| How do the requirements under § 514.80 relate to current good manufacturing practices? | 514.80(a)(5). |
| 514.80(b) Reporting requirements. | |
| What are the requirements for reporting product/manufacturing defects? | 514.80(b)(1) Three-day NADA/ANADA field alert report. |
| 514.80(b)(2) Fifteen-day NADA/ANADA alert report. | |
| What are the requirements for reporting serious and unexpected adverse drug experiences? | 514.80(b)(2)(i) Initial report. |
| What are the requirements for followup reporting of serious and unexpected adverse drug experiences? | 514.80(b)(2)(ii) Followup report. |
| What are the requirements for nonapplicants for reporting adverse drug experiences? | 514.80(b)(3) Nonapplicant report. |
| What are the general requirements for submission of periodic drug experience reports, How do I petition to change the date of submission or frequency of submissions? | 514.80(b)(4) Periodic drug experience report. |
| What must be submitted in the periodic drug experience reports? | 514.80(b)(4)(i) through (b)(4)(iv). |
| What distribution data must be submitted? How should the distribution data be submitted? | 514.80(b)(4)(i) Distribution data. |
| What labeling materials should be submitted? How do I report changes to the labeling materials since the last report? | 514.80(b)(4)(ii) Labeling. |
| 514.80(b)(4)(iii) Nonclinical laboratory studies and clinical data not previously reported. | |
| What are the requirements for submission of nonclinical laboratory studies? | 514.80(b)(4)(iii)(A). |
| What are the requirements for submission of clinical laboratory data? | 514.80(b)(4)(iii)(B). |
| When must results of clinical trials conducted by or for the applicant be reported? | 514.80(b)(4)(iii)(C). |
| 514.80(b)(4)(iv) Adverse drug experiences. | |
| How do I report product/manufacturing defects and adverse drug experiences not previously reported to FDA? | 514.80(b)(4)(iv)(A). |
| What are the requirements for submitting adverse drug experiences cited in literature? | 514.80(b)(4)(iv)(B). |
| What are the requirements for submitting adverse drug experiences in postapproval studies and clinical trials? | 514.80(b)(4)(iv)(C). |
| What are the requirements for reporting increases in the frequency of serious, expected, and unexpected adverse drug experiences? | 514.80(b)(4)(v) Summary report of increased frequency of adverse drug experience. |
| 514.80(b)(5) Other reporting. | |
| Can FDA request that an applicant submit information at different times than stated specifically in this regulation? | 514.80(b)(5)(i) Special drug experience report. |
| What are the requirements for submission of advertisement and promotional labeling to FDA? | 514.80(b)(5)(ii) Advertisements and promotional labeling. |
| What are the requirements for adding a new distributor to the approved application? | 514.80(b)(5)(iii) Distributor’s statement. |
| What labels and how many labels need to be submitted for review? | 514.80(b)(5)(iii)(A). |
| What changes are required and allowed to distributor labeling? | 514.80(b)(5)(iii)(A)( |
| What are the requirements for making other changes to the distributor labeling? | 514.80(b)(5)(iii)(A)( |
| What information should be included in each new distributor’s signed statement? | 514.80(b)(5)(iii)(B)( |
| What are the conditions for submitting information that is common to more than one application? (i.e., can I submit common information to one application?) | 514.80(c) Multiple applications. |
| What information has to be submitted to the common application and related application? | 514.80(c)(1) through (c)(4). |
| What reports must be submitted to FDA electronically? How can I apply for a waiver from the electronic reporting requirements? How do I obtain Form FDA 1932 and Form FDA 2301? | 514.80(d) Format for Submissions. |
| How long must I maintain records and reports required by this section? | 514.80(e) Records to be maintained. |
| What are the requirements for allowing access to these records and reports, and copying by authorized FDA officer or employee? | 514.80(f) Access to records and reports. |
| Where do I mail reports that are not required to be submitted electronically? | 514.80(g) Mailing addresses. |
| What happens if the applicant fails to establish, maintain, or make the required reports? What happens if the applicant refuses to allow FDA access to, and/or copying and/or verify records and reports? | 514.80(h) Withdrawal of approval. |
| Does an adverse drug experience reflect a conclusion that the report or information constitutes an admission that the drug caused an adverse effect? | 514.80(i) Disclaimer. |
(a) Applicability. (1) Each applicant must establish and maintain indexed and complete files containing full records of all information pertinent to safety or effectiveness of a new animal drug that has not been previously submitted as part of the NADA or ANADA. Such records must include information from domestic as well as foreign sources. Each nonapplicant must establish and maintain indexed and complete files containing full records of all information pertinent to safety or effectiveness of a new animal drug that is received or otherwise obtained by the nonapplicant. Such records must include information from domestic as well as foreign sources.
(2) Each applicant must submit reports of data, studies, and other information concerning experience with new animal drugs to the Food and Drug Administration (FDA) for each approved NADA and ANADA, as required in this section. A nonapplicant must submit data, studies, and other information concerning experience with new animal drugs to the appropriate applicant, as required in this section. The applicant, in turn, must report the nonapplicant’s data, studies, and other information to FDA. Applicants and nonapplicants must submit data, studies, and other information described in this section from domestic, as well as foreign sources.
(3) FDA reviews the records and reports required in this section to facilitate a determination under section 512(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(e)) as to whether there may be grounds for suspending or withdrawing approval of the NADA or ANADA.
(4) The requirements of this section also apply to any approved Type A medicated article. In addition, the requirements contained in § 514.80(b)(1), (b)(2), (b)(4)(iv), and (b)(4)(v) apply to any approved Type A medicated article incorporated in animal feeds.
(5) The records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations in parts 211, 225, and 226 of this chapter.
(b) Reporting requirements—(1) Three-day NADA/ANADA field alert report. This report provides information pertaining to product and manufacturing defects that may result in serious adverse drug events. The applicant (or nonapplicant through the applicant) must submit the report to the appropriate FDA District Office or local FDA resident post within 3 working days of first becoming aware that a defect may exist. The information initially may be provided by telephone or other telecommunication means, with prompt written followup using Form FDA 1932 “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report.” The mailing cover for these reports must be plainly marked “3-Day NADA/ANADA Field Alert Report.” If the applicant elects to also report directly to the FDA’s Center for Veterinary Medicine (CVM), the applicant must submit the report to CVM in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format.
(2) Fifteen-day NADA/ANADA alert report—(i) Initial report. This report provides information on each serious, unexpected adverse drug event, regardless of the source of the information. The applicant (or nonapplicant through the applicant) must submit the report to FDA within 15 working days of first receiving the information. The report must be submitted to FDA in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format.
(ii) Followup report. The applicant must promptly investigate all adverse drug events that are the subject of 15-day NADA/ANADA alert reports. If this investigation reveals significant new information, a followup report must be submitted within 15 working days of receiving such information. A followup report must be submitted to FDA in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format. The followup report must state the date of the initial report and provide the additional information. If additional information is sought but not obtained within 3 months of the initial report, a followup report is required describing the steps taken and why additional information was not obtained.
(3) Nonapplicant report. Nonapplicants must forward reports of adverse drug experiences to the applicant within 3 working days of first receiving the information. The applicant must then submit the report(s) to FDA as required in this section. The nonapplicant must maintain records of all nonapplicant reports, including the date the nonapplicant received the information concerning adverse drug experiences, the name and address of the applicant, and a copy of the adverse drug experience report including the date such report was submitted to the applicant. If the nonapplicant elects to also report directly to FDA, the nonapplicant must submit the report to FDA in electronic format as described in paragraph (d)(1) of this section, unless the nonapplicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format.
(4) Periodic drug experience report. This report must be accompanied by a completed Form FDA 2301 “Transmittal of Periodic Reports and Promotional Materials for New Animal Drugs.” It must be submitted every 6 months for the first 2 years following approval of an NADA or ANADA and yearly thereafter. Reports required by this section must contain data and information for the full reporting period. The 6-month periodic drug experience reports must be submitted within 30 days following the end of the 6-month reporting period. The yearly periodic drug experience reports must be submitted within 90 days of the anniversary date of the approval of the NADA or ANADA. Any previously submitted information contained in the report must be identified as such. For yearly (annual) periodic drug experience reports, the applicant may petition FDA to change the date of submission or frequency of reporting, and after approval of such petition, file such reports on the new filing date or at the new reporting frequency. Also, FDA may require a report at different times or more frequently. The periodic drug experience report must contain the following:
(i) Distribution data. (A) Information about the distribution of each new animal drug product, including information on any distributor-labeled product. This information must include the total number of distributed units of each size, strength, or potency (e.g., 100,000 bottles of 100 5-milligram tablets; 50,000 10-milliliter vials of 5-percent solution). This information must be presented in two categories: Quantities distributed domestically and quantities exported.
(B) Applicants submitting annual sales and distribution reports for antimicrobial new animal drug products under § 514.87 have the option not to report distribution data under paragraph (b)(4)(i)(A) of this section for the approved applications that include these same products, but only provided each of the following conditions are met:
(1) Applicants must have submitted complete periodic drug experience reports under this section for such applications for at least 2 full years after the date of their initial approval.
(2) Applicants must ensure that the beginning of the reporting period for the annual periodic drug experience reports for such applications is January 1. For applications that currently have a reporting period that begins on a date other than January 1, applicants must request a change in reporting submission date such that the reporting period begins on January 1 and ends on December 31, as described in paragraph (b)(4) of this section.
(3) Applicants that change their reporting submission date must also submit a special drug experience report, as described in paragraph (b)(5)(i) of this section, that addresses any gaps in distribution data caused by the change in date of submission.
(4) Applicants who choose not to report under paragraph (b)(4)(i)(A) of this section must ensure that full sales and distribution data for each product approved under such applications are alternatively reported under § 514.87, including products that are labeled for use only in nonfood-producing animals.
(ii) Labeling. Applicant and distributor current package labeling, including package inserts (if any). For large-size package labeling or large shipping cartons, a representative copy must be submitted (e.g., a photocopy of pertinent areas of large feed bags). A summary of any changes in labeling made since the last report (listed by date of implementation) must be included with the labeling or if there have been no changes, a statement of such fact must be included with the labeling.
(iii) Nonclinical laboratory studies and clinical data not previously reported.
(A) Copies of in vitro studies (e.g., mutagenicity) and other nonclinical laboratory studies conducted by or otherwise obtained by the applicant.
(B) Copies of published clinical trials of the new animal drug (or abstracts of them) including clinical trials on safety and effectiveness, clinical trials on new uses, and reports of clinical experience pertinent to safety conducted by or otherwise obtained by the applicant. Review articles, papers, and abstracts in which the drug is used as a research tool, promotional articles, press clippings, and papers that do not contain tabulations or summaries of original data are not required to be reported.
(C) Descriptions of completed clinical trials conducted by or for the applicant must be submitted no later than 1 year after completion of research. Supporting information is not to be reported.
(iv) Adverse drug experiences. (A) Product/manufacturing defects and adverse drug experiences not previously reported under paragraphs (b)(1) and (2) of this section must be reported individually to FDA in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format.
(B) Reports of adverse drug experiences in the literature must be noted in the periodic drug experience report. A bibliography of pertinent references must be included with the report. Upon FDA’s request, the applicant must provide a full text copy of these publications.
(C) Reports of previously not reported adverse drug experiences that occur in postapproval studies must be reported individually to FDA in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format.
(v) Summary report of increased frequency of adverse drug experience. The applicant must periodically review the incidence of reports of adverse drug experiences to determine if there has been an increased frequency of serious (expected and unexpected) adverse drug events. The applicant must evaluate the increased frequency of serious (expected or unexpected) adverse drug events at least as often as reporting of periodic drug experience reports. The applicant must report the increased frequency of serious (expected and unexpected) adverse drug events in the periodic drug experience report. Summaries of reports of increased frequency of adverse drug events must be submitted in narrative form. The summaries must state the time period on which the increased frequency is based, time period comparisons in determining increased frequency, references to any reports previously submitted under paragraphs (b)(1), (2), and (3) and (b)(4)(iv)(A) and (C) of this section, the method of analysis, and the interpretation of the results. The summaries must be submitted in a separate section within the periodic drug experience report.
(5) Other reporting—(i) Special drug experience report. Upon written request, FDA may require that the applicant submit a report required under § 514.80 at different times or more frequently than the timeframes stated in § 514.80.
(ii) Advertisements and promotional labeling. The applicant must submit at the time of initial dissemination one set of specimens of mailing pieces and other labeling for prescription and over-the-counter new animal drugs. For prescription new animal drugs, the applicant must also submit one set of specimens of any advertisement at the time of initial publication or broadcast. Mailing pieces and labeling designed to contain product samples must be complete except that product samples may be omitted. Each submission of promotional labeling or advertisements must be accompanied by a completed Form FDA 2301.
(iii) Distributor’s statement. At the time of initial distribution of a new animal drug product by a distributor, the applicant must submit a special drug experience report accompanied by a completed Form FDA 2301 containing the following:
(A) The distributor’s current product labeling.
(1) The distributor’s labeling must be identical to that in the approved NADA/ANADA except for a different and suitable proprietary name (if used) and the name and address of the distributor. The name and address of the distributor must be preceded by an appropriate qualifying phrase as permitted by the regulations such as “manufactured for” or “distributed by.”
(2) Other labeling changes must be the subject of a supplemental NADA or ANADA as described under § 514.8.
(B) A signed statement by the distributor stating:
(1) The category of the distributor’s operations (e.g., wholesale or retail),
(2) That the distributor will distribute the new animal drug only under the approved labeling,
(3) That the distributor will promote the product only for use under the conditions stated in the approved labeling,
(4) That the distributor will adhere to the records and reports requirements of this section, and
(5) That the distributor is regularly and lawfully engaged in the distribution or dispensing of prescription products if the product is a prescription new animal drug.
(c) Multiple applications. Whenever an applicant is required to submit a periodic drug experience report under the provisions of § 514.80(b)(4) with respect to more than one approved NADA or ANADA for preparations containing the same new animal drug so that the same information is required to be reported for more than one application, the applicant may elect to submit as a part of the report for one such application (the primary application) all the information common to such applications in lieu of reporting separately and repetitively on each. If the applicant elects to do this, the applicant must do the following:
(1) State when a report applies to multiple applications and identify all related applications for which the report is submitted by NADA or ANADA number.
(2) Ensure that the primary application contains a list of the NADA or ANADA numbers of all related applications.
(3) Submit a completed Form FDA 2301 to the primary application and each related application with reference to the primary application by NADA/ANADA number and submission date for the complete report of the common information.
(4) All other information specific to a particular NADA/ANADA must be included in the report for that particular NADA/ANADA.
(d) Format for submissions—(1) Electronic submissions. Except as provided in paragraph (d)(2) of this section, reports submitted to FDA under paragraphs (b)(2)(i) and (ii), (b)(3), and (b)(4)(iv)(A) and (C) of this section and reports submitted to CVM under paragraph (b)(1) of this section must be submitted in an electronic format that FDA can process, review, and archive. Data provided in electronic submissions must be in conformance with the data elements in Form FDA 1932 and FDA technical documents describing transmission. As necessary, FDA will issue updated technical documents on how to provide the electronic submission (e.g., method of transmission and processing, media, file formats, preparation, and organization of files). Unless requested by FDA, paper copies of reports submitted electronically should not be submitted to FDA.
(2) Waivers. An applicant or nonapplicant may request, in writing, a temporary waiver of the electronic submission requirements in paragraph (d)(1) of this section. The initial request may be by telephone or email to CVM’s Division of Veterinary Product Safety, with prompt written followup submitted as a letter to the application(s). FDA will grant waivers on a limited basis for good cause shown. If FDA grants a waiver, the applicant or nonapplicant must comply with the conditions for reporting specified by FDA upon granting the waiver.
(3) Paper forms. If approved by FDA before use, a computer-generated equivalent of Form FDA 1932 may be used for reports submitted to the appropriate FDA District Office or local FDA resident post under paragraph (b)(1) of this section and to FDA under paragraph (d)(2) of this section, and a computer-generated equivalent of Form FDA 2301 may be used for reports submitted to FDA under paragraph (b)(4) of this section. Form FDA 1932 may be obtained on the FDA website, by telephoning CVM’s Division of Veterinary Product Safety, or by submitting a written request to the following address: Food and Drug Administration, Center for Veterinary Medicine, Division of Veterinary Product Safety (HFV-240), 7500 Standish Pl., Rockville, MD 20855-2764. Form FDA 2301 may be obtained on the FDA website, by telephoning CVM’s Division of Surveillance (HFV-210), or by submitting a written request to the following address: Food and Drug Administration, Center for Veterinary Medicine, Division of Surveillance (HFV-210), 7500 Standish Pl., Rockville, MD 20855-2764.
(e) Records to be maintained. The applicants and nonapplicants must maintain records and reports of all information required by this section for a period of 5 years after the date of submission.
(f) Access to records and reports. The applicant and nonapplicant must, upon request from any authorized FDA officer or employee, at all reasonable times, permit such officer or employee to have access to copy and to verify all such required records and reports.
(g) Mailing addresses. Three-day alert reports must be submitted to the appropriate FDA District Office or local FDA resident post. Addresses for District Offices and resident posts may be obtained on the FDA website. Other reports not required to be submitted to FDA in electronic format must be submitted to the following address: Food and Drug Administration, Center for Veterinary Medicine, Document Control Unit (HFV-199), 7500 Standish Pl., Rockville, MD 20855-2764.
(h) Withdrawal of approval. If FDA finds that the applicant has failed to establish the required records, or has failed to maintain those records, or failed to make the required reports, or has refused access to an authorized FDA officer or employee to copy or to verify such records or reports, FDA may withdraw approval of the application to which such records or reports relate. If FDA determines that withdrawal of the approval is necessary, the agency shall give the applicant notice and opportunity for hearing, as provided in § 514.200, on the question of whether to withdraw approval of the application.
(i) Disclaimer. Any report or information submitted under this section and any release of that report or information by FDA will be without prejudice and does not necessarily reflect a conclusion that the report or information constitutes an admission that the drug caused or contributed to an adverse event. A person need not admit, and may deny, that the report or information constitutes an admission that a drug caused or contributed to an adverse event.
§ 514.87 Annual reports for antimicrobial animal drug sales and distribution.
(a) The applicant for each new animal drug product approved under section 512 of the Federal Food, Drug, and Cosmetic Act, or conditionally approved under section 571 of the Federal Food, Drug, and Cosmetic Act, and containing an antimicrobial active ingredient, must submit an annual report to FDA on the amount of each such antimicrobial active ingredient in the drug that is sold or distributed in the reporting year for use in food-producing animal species, including information on any distributor-labeled product.
(b) This report must identify the approved or conditionally approved application and must include the following information for each new animal drug product described in paragraph (a) of this section:
(1) A listing of each antimicrobial active ingredient contained in the product;
(2) A description of each product sold or distributed by unit, including the container size, strength, and dosage form of such product units;
(3) For each such product, a listing of the target animal species, indications, and production classes that are specified on the approved label;
(4) For each such product, the number of units sold or distributed in the United States (i.e., domestic sales) for each month of the reporting year; and
(5) For each such product, the number of units sold or distributed outside the United States (i.e., quantities exported) for each month of the reporting year.
(c) Each report must also provide a species-specific estimate of the percentage of each product described in paragraph (b)(2) of this section that was sold or distributed domestically in the reporting year for use in any of the following animal species categories, but only for such species that appear on the approved label: Cattle, swine, chickens, turkeys. The total of the species-specific percentages reported for each product must account for 100 percent of its sales and distribution; therefore, a fifth category of “other species/unknown” must also be reported.
(d) Each report must:
(1) Be submitted not later than March 31 each year;
(2) Cover the period of the preceding calendar year; and
(3) Be submitted using Form FDA 3744, “Antimicrobial Animal Drug Distribution Report.”
(e) Sales and distribution data and information reported under this section will be considered to fall within the exemption for confidential commercial information established in § 20.61 of this chapter and will not be publicly disclosed, except that summary reports of such information aggregated in such a way that does not reveal information that is not available for public disclosure under this provision will be prepared by FDA and made available to the public as provided in paragraph (f) of this section.
(f) FDA will publish an annual summary report of the data and information it receives under this section for each calendar year by December 31 of the following year. Such annual reports must include a summary of sales and distribution data and information by antimicrobial drug class and may include additional summary data and information as determined by FDA. In order to protect confidential commercial information, each individual datum appearing in the summary report must:
(1) Reflect combined product sales and distribution data and information obtained from three or more distinct sponsors of approved products that were actively sold or distributed that reporting year, and
(2) Be reported in a manner consistent with protecting both national security and confidential commercial information.
§ 514.100 Evaluation and comment on applications.
(a) After the filed application has been evaluated, the applicant will be furnished written comment on any apparent deficiencies in the application.
(b) When the description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such new animal drug appears adequate on its face, but it is not feasible to reach a conclusion as to the safety and effectiveness of the new animal drug solely from consideration of this description, the applicant may be notified that an establishment inspection is required to verify their adequacy.
(c) A request for samples of a new animal drug or any edible tissues and byproducts of animals treated with such a drug, shall specify the quantity deemed adequate to permit tests of analytical methods to determine their adequacy for regulatory purposes. The request should be made as early in the 180-day period as possible to assure timely completion. The date used for computing the 180-day limit for the purposes of section 512(c) of the act shall be moved forward 1 day for each day after the mailing date of the request until all of the requested samples are received. If the samples are not received within 90 days after the request, the application will be considered withdrawn without prejudice.
(d) The information contained in an application may be insufficient to determine whether a new animal drug is safe or effective in use if it fails to include (among other things) a statement showing whether such drug is to be limited to prescription sale and exempt under section 502(f) of the act from the requirement that its labeling bear adequate directions for lay use. If such drug is to be exempt, the information may also be insufficient if:
(1) The specimen labeling proposed fails to bear adequate information for professional use including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer such drug can use the drug for the purposes for which it is intended, including all purposes for which it is to be advertised, or represented, in accordance with § 201.105 of this chapter, and information concerning hazards, contraindications, side effects, and precautions relevant with respect to any uses for which such drug is to be prescribed.
(2) The application fails to show that the labeling and advertising of such drug will offer the drug for use only under those conditions for which it is offered in the labeling that is part of the application.
(3) The application fails to show that all labeling that furnishes or purports to furnish information for professional use of such drug will contain, in the same language and emphasis, the information for use including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant warnings, hazards, contraindications, side effects, and precautions, which is contained in the labeling that is part of the application in accordance with § 201.105 of this chapter.
(e) The information contained in an application will be considered insufficient to determine whether a new animal drug is safe and effective for use when there is a refusal or failure upon written notice to furnish inspectors authorized by the Food and Drug Administration an adequate opportunity to inspect the facilities, controls, and records pertinent to the application.
(f) On the basis of preliminary consideration of an application or supplemental application containing typewritten or other draft labeling in lieu of final printed labeling, an applicant may be informed that such application is approvable when satisfactory final printed labeling identical in content to such draft copy is submitted.
(g) When an application has been found incomplete on the basis of a need for the kind of information described in § 514.6, such application shall be considered withdrawn without prejudice to future filing on the date of issuance of the letter citing the inadequacies contained in the application, unless within 30 days the sponsor chooses to avail himself of the opportunity for hearing as prescribed by § 514.111.
§ 514.105 Approval of applications.
(a) The Commissioner shall forward for publication in the
(b) He shall notify the applicant by sending him a copy of the proposed publication as described in paragraph (a)(1) of this section.
§ 514.106 Approval of supplemental applications.
(a) Within 180 days after a supplement to an approved application is filed pursuant to § 514.8, the Commissioner shall approve the supplemental application in accordance with procedures set forth in § 514.105(a)(1) and (2) if he/she determines that the application satisfies the requirements of applicable statutory provisions and regulations.
(b) The Commissioner will assign a supplemental application to its proper category to ensure processing of the application.
(1) Category I. Supplements that ordinarily do not require a reevaluation of any of the safety or effectiveness data in the parent application. Category I supplements include the following:
(i) A corporate change that alters the identity or address of the sponsor of the new animal drug application (NADA).
(ii) The sale, purchase, or construction of manufacturing facilities.
(iii) The sale or purchase of an NADA.
(iv) A change in container, container style, shape, size, or components.
(v) A change in approved labeling (color, style, format, addition, deletion, or revision of certain statements, e.g., trade name, storage, expiration dates, etc).
(vi) A change in promotional material for a prescription new animal drug not exempted by § 514.8(c)(2)(i)(C)(1) through (c)(2)(i)(C)(3).
(vii) Changes in manufacturing processes that do not alter the method of manufacture or change the final dosage form.
(viii) A change in bulk drug shipments.
(ix) A change in an analytical method or control procedures that do not alter the approved standards.
(x) A change in an expiration date.
(xi) Addition of an alternate manufacturer, repackager, or relabeler of the drug product.
(xii) Addition of an alternate supplier of the new drug substance.
(xiii) A change permitted in advance of approval as described under § 514.8(b)(3).
(2) Category II. Supplements that may require a reevaluation of certain safety or effectiveness data in the parent application. Category II supplements include the following:
(i) A change in the active ingredient concentration or composition of the final product.
(ii) A change in quality, purity, strength, and identity specifications of the active or inactive ingredients.
(iii) A change in dose (amount of drug administered per dose).
(iv) A change in the treatment regimen (schedule of dosing).
(v) Addition of a new therapeutic claim to the approved uses of the product.
(vi) Addition of a new or revised animal production claim.
(vii) Addition of a new species.
(viii) A change in the prescription or over-the-counter status of a drug product.
(ix) A change in statements regarding side effects, warnings, precautions, and contraindications, except the addition of approved statements to container, package, and promotional labeling, and prescription drug advertising.
(x) A change in the drug withdrawal period prior to slaughter or in the milk discard time.
(xi) A change in the tolerance for drug residues.
(xii) A change in analytical methods for drug residues.
(xiii) A revised method of synthesis or fermentation of the new drug substance.
(xiv) Updating or changes in the manufacturing process of the new drug substance and/or final dosage form (other than a change in equipment that does not alter the method of manufacture of a new animal drug, or a change from one commercial batch size to another without any change in manufacturing procedure), or changes in the methods, facilities, or controls used for the manufacture, processing, packaging, or holding of the new animal drug (other than use of an establishment not covered by the approval that is in effect) that give increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess.
§ 514.110 Reasons for refusing to file applications.
(a) The date of receipt of an application for a new animal drug shall be the date on which the application shall be deemed to be filed.
(b) An application for a new animal drug shall not be considered acceptable for filing for any of the following reasons:
(1) It does not contain complete and accurate English translations of any pertinent part in a foreign language.
(2) Fewer than three copies are submitted.
(3) It is incomplete on its face in that it is not properly organized and indexed.
(4) On its face the information concerning required matter is so inadequate that the application is clearly not approvable.
(5) The new animal drug is to be manufactured, prepared, propagated, compounded, or processed in whole or in part in any State in an establishment that has not been registered or exempted from registration under the provisions of section 510 of the act.
(6) The sponsor does not reside or maintain a place of business within the United States and the application has not been countersigned by an attorney, agent, or other representative of the applicant, which representative resides in the United States and has been duly authorized to act on behalf of the applicant and to receive communications on all matters pertaining to the application.
(7) The new animal drug is a drug subject to licensing under the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq. ). Such applications will be referred to the U.S. Department of Agriculture for action.
(8) It fails to include, with respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reasons for the noncompliance.
(9) [Reserved]
(10) The applicant fails to submit a complete environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.33 of this chapter.
(c) If an application is determined not to be acceptable for filing, the applicant shall be notified within 30 days of receipt of the application and shall be given the reasons therefore.
(d) If the applicant disputes the findings that his application is not acceptable for filing, he may make written request that the application be filed over protest, in which case it will be filed as of the day originally received.
§ 514.111 Refusal to approve an application.
(a) The Commissioner shall, within 180 days after the filing of the application, inform the applicant in writing of his intention to issue a notice of opportunity for a hearing on a proposal to refuse to approve the application, if the Commissioner determines upon the basis of the application, or upon the basis of other information before him with respect to a new animal drug, that:
(1) The reports of investigations required to be submitted pursuant to section 512(b) of the act do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; or
(2) The results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; or
(3) The methods used in and the facilities and controls used for the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; or
(4) Upon the basis of the information submitted to the Food and Drug Administration as part of the application, or upon the basis of any other information before it with respect to such drug, it has insufficient information to determine whether such drug is safe for use under such conditions. In making this determination the Commissioner shall consider, among other relevant factors:
(i) The probable consumption of such drug and of any substance formed in or on food because of the use of such drug;
(ii) The cumulative effect on man or animal of such drug, taking into account any chemically or pharmacologically related substances;
(iii) Safety factors which, in the opinion of experts qualified by scientific training and experience to evaluate the safety of such drugs, are appropriate for the use of animal experimentation data; and
(iv) Whether the conditions of use prescribed, recommended, or suggested in the proposed labeling are reasonably certain to be followed in practice; or
(5) Evaluated on the basis of information submitted as part of the application and any other information before the Food and Drug Administration with respect to such drug, there is lack of substantial evidence as defined in § 514.4.
(6) Failure to include an appropriate proposed tolerance for residues in edible products derived from animals or a withdrawal period or other restrictions for use of such drug if any tolerance or withdrawal period or other restrictions for use are required in order to assure that the edible products derived from animals treated with such drug will be safe.
(7) Based on a fair evaluation of all material facts, the labeling is false or misleading in any particular; or
(8) Such drug induces cancer when ingested by man or animal or, after appropriate tests for evaluation of the safety of such drug, induces cancer in man or animal, except that this subparagraph shall not apply with respect to such drug if the Commissioner finds that, under the conditions of use specified in proposed labeling and reasonably certain to be followed in practice:
(i) Such drug will not adversely affect the animal for which it is intended; and
(ii) No residue of such drug will be found (by methods of examination prescribed or approved by the Commissioner by regulations) in any edible portion of such animal after slaughter or in any food yielded by, or derived from the living animals.
(9) The applicant fails to submit an adequate environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.33 of this chapter.
(10) The drug fails to satisfy the requirements of subpart E of part 500 of this chapter.
(11) Any nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.
(12) The drug will be produced in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the Federal Food, Drug, and Cosmetic Act and part 207 of this chapter.
(b) The Commissioner, as provided in § 514.200 of this chapter, shall expeditiously notify the applicant of an opportunity for a hearing on the question of whether such application is approvable, unless by the 30th day following the date of issuance of the letter informing the applicant of the intention to issue a notice of opportunity for a hearing the applicant:
(1) Withdraws the application; or
(2) Waives the opportunity for a hearing; or
(3) Agrees with the Commissioner on an additional period to precede issuance of such notice of hearing.
§ 514.115 Withdrawal of approval of applications.
(a) The Secretary may suspend approval of an application approved pursuant to section 512(c) of the act and give the applicant prompt notice of his action and afford the applicant the opportunity for an expedited hearing on a finding that there is an imminent hazard to the health of man or of the animals for which such new animal drug or animal feed is intended.
(b) The Commissioner shall notify in writing the person holding an application approved pursuant to section 512(c) of the act and afford an opportunity for a hearing on a proposal to withdraw approval of such application if he finds:
(1) That the application contains any untrue statement of a material fact; or
(2) That the applicant has made any changes from the standpoint of safety or effectiveness beyond the variations provided for in the application unless he has supplemented the application by filing with the Secretary adequate information respecting all such changes and unless there is in effect an approval of the supplemental application, or such changes are those for which written authorization or approval is not required as provided for in § 514.8. The supplemental application shall be treated in the same manner as the original application.
(3) That in the case of an application for use of a new animal drug approved or deemed approved pursuant to section 512(c) of the act:
(i) Experience or scientific data show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; or
(ii) New evidence not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved or that section 512 (d)(1)(H) of the act applies to such drug; or
(iii) On the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, there is a lack of substantial evidence that such drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof.
(4) That any nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.
(c) The Commissioner may notify in writing the person holding an application approved pursuant to section 512(c) of the act and afford an opportunity for a hearing on a proposal to withdraw approval of such application if he finds:
(1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain such records or to make required reports in accordance with a regulation or order under section 512(l)(1) of the act, or the applicant has refused to permit access to, or copying, or verification of, such records as required by section 512(l)(2) of the act; or
(2) That on the basis of new information before him evaluated together with the evidence before him when the application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of such drug or animal feed are inadequate to assure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of; or
(3) That on the basis of new information before him, evaluated together with the evidence before him when the application was approved, the labeling of such drug, based on a fair evaluation of all material facts, is false or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of.
(d) Approval of an application pursuant to section 512(c) of the act will be withdrawn on the basis of a request for its withdrawal submitted in writing by a person holding an approved new animal drug application on the grounds that the drug subject to such application is no longer being marketed and information is included in support of this finding, provided none of the conditions cited in paragraphs (a), (b), and (c) of this section pertain to the subject drug. A written request for such withdrawal shall be construed as a waiver of the opportunity for a hearing as otherwise provided for in this section. Withdrawal of approval of an application under the provisions of this paragraph shall be without prejudice.
(e) On the basis of the withdrawal of approval of an application for a new animal drug approved pursuant to section 512(c) of the act, the regulation published pursuant to section 512(i) of the act covering the conditions of use of such drug as provided for in the application shall be revoked.
§ 514.116 Notice of withdrawal of approval of application.
When an approval of an application submitted pursuant to section 512 of the act is withdrawn by the Commissioner, he will give appropriate public notice of such action by publication in the
§ 514.117 Adequate and well-controlled studies.
(a) Purpose. The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and well-controlled studies are required to establish, by substantial evidence, that a new animal drug is effective. The characteristics described in paragraph (b) of this section have been developed over a period of years and are generally recognized as the essentials of an adequate and well-controlled study. Well controlled, as used in the phrase adequate and well controlled, emphasizes an important aspect of adequacy. The Food and Drug Administration (FDA) considers these characteristics in determining whether a study is adequate and well controlled for purposes of section 512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). Adequate and well-controlled studies, in addition to providing a basis for determining whether a new animal drug is effective, may also be relied upon to support target animal safety. The report of an adequate and well-controlled study should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.
(b) Characteristics. An adequate and well-controlled study has the following characteristics:
(1) The protocol for the study (protocol) and the report of the study results (study report) must include a clear statement of the study objective(s).
(2) The study is conducted in accordance with an appropriate standard of conduct that addresses, among other issues, study conduct, study personnel, study facilities, and study documentation. The protocol contains a statement acknowledging the applicability of, and intention to follow, a standard of conduct acceptable to FDA. The study report contains a statement describing adherence to the standard.
(3) The study is conducted with a new animal drug that is produced in accordance with appropriate manufacturing practices, which include, but are not necessarily limited to, the manufacture, processing, packaging, holding, and labeling of the new animal drug such that the critical characteristics of identity, strength, quality, purity, and physical form of the new animal drug are known, recorded, and reproducible, to permit meaningful evaluations of and comparisons with other studies conducted with the new animal drug. The physical form of a new animal drug includes the formulation and physical characterization (including delivery systems thereof, if any) of the new animal drug as presented to the animal. The protocol and study report must include an identification number which can be correlated with the specific formulation and production process used to manufacture the new animal drug used in the study.
(4) The study uses a design that permits a valid comparison with one or more controls to provide a quantitative evaluation of drug effects. The protocol and the study report must describe the precise nature of the study design, e.g., duration of treatment periods, whether treatments are parallel, sequential, or crossover, and the determination of sample size. Within the broad range of studies conducted to support a determination of the effectiveness of a new animal drug, certain of the controls listed below would be appropriate and preferred depending on the study conducted:
(i) Placebo concurrent control. The new animal drug is compared with an inactive preparation designed to resemble the new animal drug as far as possible.
(ii) Untreated concurrent control. The new animal drug is compared with the absence of any treatment. The use of this control may be appropriate when objective measurements of effectiveness, not subject to observer bias, are available.
(iii) Active treatment concurrent control. The new animal drug is compared with known effective therapy. The use of this control is appropriate when the use of a placebo control or of an untreated concurrent control would unreasonably compromise the welfare of the animals. Similarity of the new animal drug and the active control drug can mean either that both drugs were effective or that neither was effective. The study report should assess the ability of the study to have detected a difference between treatments. The evaluation of the study should explain why the new animal drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control.
(iv) Historical control. The results of treatment with the new animal drug are quantitatively compared with experience historically derived from the adequately documented natural history of the disease or condition, or with a regimen (therapeutic, diagnostic, prophylactic) whose effectiveness is established, in comparable animals. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies in which the effect of the new animal drug is self-evident or studies of diseases with high and predictable mortality, or signs and symptoms of predictable duration or severity, or, in the case of prophylaxis, predictable morbidity.
(5) The study uses a method of selecting animals that provides adequate assurances that the animals are suitable for the purposes of the study. For example, the animals can reasonably be expected to have animal production characteristics typical of the class(es) of animals for which the new animal drug is intended, there is adequate assurance that the animals have the disease or condition being studied, or, in the case of prophylactic agents, evidence of susceptibility and exposure to the condition against which prophylaxis is desired has been provided. The protocol and the study report describe the method of selecting animals for the study.
(6) The study uses a method to assign a treatment or a control to each experimental unit of animals that is random and minimizes bias. Experimental units of animals are groups of animals that are comparable with respect to pertinent variables such as age, sex, class of animal, severity of disease, duration of disease, dietary regimen, level of animal production, and use of drugs or therapy other than the new animal drug. The protocol and the study report describe the method of assignment of animals to an experimental unit to account for pertinent variables and method of assignment of a treatment or a control to the experimental units. When the effect of such variables is accounted for by an appropriate design, and when, within the same animal, effects due to the test drug can be obtained free of the effects of such variables, the same animal may be used for both the test drug and the control using the controls set forth in paragraph (b)(4) of this section.
(7) The study uses methods to minimize bias on the part of observers and analysts of the data that are adequate to prevent undue influences on the results and interpretation of the study data. The protocol and study report explain the methods of observation and recording of the animal response variables and document the methods, such as “blinding” or “masking,” used in the study for excluding or minimizing bias in the observations.
(8) The study uses methods to assess animal response that are well defined and reliable. The protocol and study report describe the methods for conducting the study, including any appropriate analytical and statistical methods, used to collect and analyze the data resulting from the conduct of the study, describe the criteria used to assess response, and, when appropriate, justify the selection of the methods to assess animal response.
(9) There is an analysis and evaluation of the results of the study in accord with the protocol adequate to assess the effects of the new animal drug. The study report evaluates the methods used to conduct, and presents and evaluates the results of, the study as to their adequacy to assess the effects of the new animal drug. This evaluation of the results of the study assesses, among other items, the comparability of treatment and control groups with respect to pertinent variables and the effects of any interim analyses performed.
(c) Field studies. (1) Field conditions as used in this section refers to conditions which closely approximate the conditions under which the new animal drug, if approved, is intended to be applied or administered.
(2) Studies of a new animal drug conducted under field conditions shall, consistent with generally recognized scientific principles and procedures, use an appropriate control that permits comparison, employ procedures to minimize bias, and have the characteristics generally described in paragraph (b) of this section. However, because field studies are conducted under field conditions, it is recognized that the level of control over some study conditions need not or should not be the same as the level of control in laboratory studies. While not all conditions relating to a field study need to be or should be controlled, observations of the conditions under which the new animal drug is tested shall be recorded in sufficient detail to permit evaluation of the study. Adequate and well-controlled field studies shall balance the need to control study conditions with the need to observe the true effect of the new animal drug under closely approximated actual use conditions.
(d) Waiver. The Director of the Center for Veterinary Medicine (the Director) may, on the Director’s own initiative or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph (b) of this section with respect to a specific study. A petition for a waiver is required to set forth clearly and concisely the specific criteria from which waiver is sought, why the criteria are not reasonably applicable to the particular study, what alternative procedures, if any, are to be, or have been employed, and what results have been obtained. The petition is also required to state why the studies so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.
(e) Uncontrolled studies. Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness or target animal safety. Such studies, carefully conducted and documented, may provide corroborative support of adequate and well-controlled studies regarding effectiveness and may yield valuable data regarding safety of the new animal drug. Such studies will be considered on their merits in light of the characteristics listed here. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.
§ 514.120 Revocation of order refusing to approve an application or suspending or withdrawing approval of an application.
The Commissioner, upon his own initiative or upon request of an applicant stating reasonable grounds therefor and if he finds that the facts so require, may issue an order approving an application that previously has had its approval refused, suspended, or withdrawn.
§ 514.121 Service of notices and orders.
All notices and orders under this subchapter E and section 512 of the act pertaining to new animal drug applications shall be served:
(a) In person by any officer or employee of the Department designated by the Commissioner; or
(b) By mailing the order by certified mail addressed to the applicant or respondent at his last known address in the records of the Food and Drug Administration.
Subpart C—Hearing Procedures
§ 514.200 Notice of opportunity for hearing; notice of participation and requests for hearing; grant or denial of hearing.
(a) The notice to the applicant of opportunity for a hearing on a proposal by the Commissioner to refuse to approve an application or to withdraw the approval of an application will be published in the
(b) If the applicant fails to request a hearing within the 30-day timeframe, the Commissioner, without further notice, will publish a final order denying or withdrawing approval of the application.
(c) If the applicant desires to request a hearing:
(1) Within 30 days after publication of the notice of opportunity for hearing, the applicant must submit to the Dockets Management Staff written objections and a request for a hearing in accordance with §§ 12.20 and 12.22. This request for a hearing must include each specific objection to the proposal on which a hearing is requested, together with a detailed description and analysis of the factual information (including all relevant clinical and other investigational data) the applicant will present in support of that objection. A request for a hearing may not rest upon mere allegations or denials or general descriptions of positions or contentions, but must set forth specific reliable evidence showing there is a genuine and substantial issue of fact that requires a hearing.
(2) If the Commissioner determines upon review of the data and information submitted in the objections and request for a hearing that a hearing is not justified because no genuine and substantial issue of fact precludes the refusal to approve the application or the withdrawal of approval of the application (for example, the applicant has not identified any adequate and well-controlled clinical investigations to support the claims of effectiveness), the Commissioner will enter an order denying the hearing and stating the final findings and conclusions.
(3) If the Commissioner determines upon review of the data and information submitted in the objections and request for a hearing that a hearing is justified, the Commissioner will publish a notice setting forth the following:
(i) The regulation or order that is the subject of the hearing;
(ii) A statement specifying any part of the regulation or order that has been stayed by operation of law or in the Commissioner’s discretion;
(iii) The parties to the hearing;
(iv) The specific issues of fact for resolution at the hearing;
(v) The presiding officer, or a statement that the presiding officer will be designated in a later notice; and
(vi) The date, time, and place of the prehearing conference, or a statement that the date, time, and place will be announced in a later notice. However, in the case of a denial of approval, the hearing must not occur more than 90 days after expiration of the 30-day time period in which to request a hearing, unless the presiding officer and the applicant otherwise agree; and in the case of withdrawal of approval, the hearing will occur as soon as practicable.
(d) The hearing will be open to the public; however, if the Commissioner finds that portions of the application which serve as a basis for the hearing contain information concerning a method or process entitled to protection as a trade secret, the part of the hearing involving such portions will not be public, unless the respondent so specifies in the request for a hearing.
§ 514.201 Procedures for hearings.
Hearings relating to new animal drugs under section 512(d) and (e) of the act shall be governed by part 12 of this chapter.
Subparts D-E [Reserved]
Subpart F—Judicial Review
§ 514.235 Judicial review.
(a) The transcript and record shall be certified by the Commissioner. In any case in which the Commissioner enters an order without a hearing pursuant to § 314.200(g) of this chapter, the request(s) for hearing together with the data and information submitted and the Commissioner’s findings and conclusions shall be included in the record certified by the Commissioner.
(b) Judicial review of an order withdrawing approval of a new drug application, whether or not a hearing has been held, may be sought by a manufacturer or distributor of an identical, related, or similar drug product, as defined in § 310.6 of this chapter, in a United States court of appeals pursuant to section 505(h) of the act.
PART 515—MEDICATED FEED MILL LICENSE
Subpart A—Applications
§ 515.10 Medicated feed mill license applications.
(a) Medicated feed mill license applications (Form FDA 3448) may be obtained from the Public Health Service, Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785, or electronically from the Center for Veterinary Medicine at: https://www.fda.gov/animal-veterinary/animal-food-feeds/medicated-feeds.
(b) A completed medicated feed mill license must contain the following information:
(1) The full business name and address of the facility at which the manufacturing is to take place.
(2) The facility’s FDA registration number as required by section 510 of the Federal Food, Drug, and Cosmetic Act (the act).
(3) The name, title, and signature of the responsible individual or individuals for that facility.
(4) A certification that the animal feeds bearing or containing new animal drugs are manufactured and labeled in accordance with the applicable regulations published under section 512(i) of the act or in accordance with the index listing published under section 572(e)(2) of the act.
(5) A certification that the methods used in, and the facilities and controls used for, manufacturing, processing, packaging, and holding such animal feeds conform to current good manufacturing practice as described in section 501(a)(2)(B) of the act and in part 225 of this chapter.
(6) A certification that the facility will establish and maintain all records required by regulation or order issued under sections 512(m)(5)(A) or 504(a)(3)(A) of the act, and will permit access to, or copying or verification of such records.
(7) A commitment that current approved or index listed Type B and/or Type C medicated feed labeling for each Type B and/or Type C medicated feed to be manufactured will be in the possession of the feed manufacturing facility prior to receiving the Type A medicated article containing such drug.
(8) A commitment to renew registration every year with FDA as required in part 207 of this chapter.
(c) Applications must be completed, signed, and submitted to the Food and Drug Administration, Center for Veterinary Medicine, Division of Food Compliance, 12225 Wilkins Ave., Rockville, MD 20852, or email (via attachment): [email protected].
(d) Applications that are facially deficient will be returned to the applicant. All reasons for the return of the application will be made known to the applicant.
(e) Upon approval, the application will be signed by an authorized employee of FDA designated by the Commissioner of Food and Drugs, and a copy will be returned to the applicant.
§ 515.11 Supplemental medicated feed mill license applications.
(a) After approval of a medicated feed mill license application to manufacture animal feed, a supplemental application shall be submitted for a change in ownership and/or a change in mailing address of the facility site.
(b) Each supplemental application should be accompanied by a fully completed Form FDA 3448 and include an explanation of the change.
(c) Within 30 working days after a supplemental application has been filed, if the Commissioner of Food and Drugs determines that the application provides adequate information respecting the change in ownership and/or postal address of the facility site, then an authorized employee of the Food and Drug Administration designated by the Commissioner shall notify the applicant that it is approved by signing and mailing to the applicant a copy of the Form FDA 3448. Supplemental applications that do not provide adequate information shall be returned to the applicant and all reasons for the return of the application shall be made known to the applicant.
Subpart B—Administrative Actions on Licenses
§ 515.20 Approval of medicated feed mill license applications.
Within 90 days after an application has been filed under § 515.10, if the Commissioner of Food and Drugs (the Commissioner) determines that none of the grounds for denying approval specified in section 512(m)(3) of the Federal Food, Drug, and Cosmetic Act (the act) applies, an authorized employee of the Food and Drug Administration designated by the Commissioner shall notify the applicant that it is approved by signing and mailing to the applicant a copy of the Form FDA 3448.
§ 515.21 Refusal to approve a medicated feed mill license application.
(a) The Commissioner of Food and Drugs (the Commissioner) shall within 90 days, or such additional period as may be agreed upon by the Commissioner and the applicant, after the filing of an application under § 515.10, inform the applicant in writing of his/her intention to issue a notice of opportunity for a hearing on a proposal to refuse to approve the application, if the Commissioner determines upon the basis of the application, on the basis of a preapproval inspection, or upon the basis of any other information before him that:
(1) The application is incomplete, false, or misleading in any particular; or
(2) The methods used in and the facilities and controls used for the manufacturing, processing, and packaging of such animal feed are not adequate to preserve the identity, strength, quality, and purity of the new animal drug therein; or
(3) The facility manufactures animal feeds bearing or containing new animal drugs in a manner that does not accord with the specifications for manufacture or labels animal feeds bearing or containing new animal drugs in a manner that does not accord with the conditions or indications of use that are published under section 512(i) or 572(e)(2) of the act.
(b) The Commissioner, as provided in § 515.30, shall expeditiously notify the applicant of an opportunity for a hearing on the question of whether such application is approvable, unless by the 30th day following the date of issuance of the letter informing the applicant of the intention to issue a notice of opportunity for a hearing the applicant:
(1) Withdraws the application; or
(2) Waives the opportunity for a hearing; or
(3) Agrees with the Commissioner on an additional period to precede issuance of such notice of hearing.
§ 515.22 Suspension and/or revocation of approval of a medicated feed mill license.
(a) The Secretary of Health and Human Services may suspend a medicated feed mill license approved under section 512(m)(2) of the Federal Food, Drug, and Cosmetic Act (the act) and give the person holding the medicated feed mill license application prompt notice of this action and afford the applicant the opportunity for an expedited hearing on a finding that there is an imminent hazard to the health of man or of the animals for which such animal feed is intended.
(b) The Commissioner of Food and Drugs (the Commissioner) shall notify in writing the person holding an application approved under section 512(m)(2) of the act and afford an opportunity for a hearing on a proposal to revoke approval of such application if the Commissioner finds:
(1) That the application contains any untrue statement of a material fact; or
(2) That the applicant has made any changes that would cause the application to contain any untrue statements of material fact or that would affect the safety or effectiveness of the animal feeds manufactured at the facility unless the applicant has supplemented the application by filing a supplemental application under § 515.11.
(c) The Commissioner may notify in writing the person holding an application approved under section 512(m)(2) of the act and afford an opportunity for a hearing on a proposal to revoke approval of such application if the Commissioner finds:
(1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain such records or to make required reports in accordance with a regulation or order under sections 512(m)(5)(A) or 504(a)(3)(A) of the act, or the applicant has refused to permit access to, or copying, or verification of, such records as required by sections 512(m)(5)(B) or 504(a)(3)(B) of the act; or
(2) That on the basis of new information before him, evaluated together with the evidence before him when such license was issued, the methods used in, or the facilities and controls used for, the manufacture, processing, packing, and holding of such animal feed are inadequate to assure and preserve the identity, strength, quality, and purity of the new animal drug therein, and were not made adequate within a reasonable time after receipt of written notice from the Commissioner specifying the matter complained of; or
(3) That on the basis of new information before him, evaluated together with the evidence before him when such license was issued, the labeling of any animal feeds, based on a fair evaluation of all material facts, is false or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Commissioner specifying the matter complained of; or
(4) That on the basis of new information before him, evaluated together with the evidence before him when such license was issued, the facility has manufactured, processed, packed, or held animal feed bearing or containing a new animal drug adulterated under section 501(a)(6) of the act, and the facility did not discontinue the manufacture, processing, packing, or holding of such animal feed within a reasonable time after receipt of written notice from the Commissioner specifying the matter complained of.
§ 515.23 Voluntary revocation of medicated feed mill license.
A license issued under section 512(m)(2) of the Federal Food, Drug, and Cosmetic Act (the act) will be revoked on the basis of a request for its revocation submitted in writing by a responsible individual holding such license on the grounds that the facility no longer manufactures any animal feed covered under § 558.4(b) of this chapter. A written request for such revocation shall be construed as a waiver of the opportunity for a hearing as otherwise provided for in this section. Revocation of approval of a medicated feed mill license under the provisions of this paragraph shall be without prejudice.
§ 515.24 Notice of revocation of a medicated feed mill license.
When a license approved under section 512 of the Federal Food, Drug, and Cosmetic Act (the act) is revoked by the Commissioner of Food and Drugs (the Commissioner), the Commissioner will give appropriate public notice of such action by publication in the
§ 515.25 Revocation of order refusing to approve a medicated feed mill license application or suspending or revoking a license.
The Commissioner of Food and Drugs (the Commissioner), upon his/her own initiative or upon request of an applicant stating reasonable grounds therefor and if the Commissioner finds that the facts so require, may issue an order approving a medicated feed mill license application that previously has had its approval refused, suspended, or revoked.
§ 515.26 Services of notices and orders.
All notices and orders under this part 515 and section 512 of the Federal Food, Drug, and Cosmetic Act (the act) pertaining to medicated feed mill licenses shall be served:
(a) In person by any officer or employee of the Department of Health and Human Services designated by the Commissioner of Food and Drugs; or
(b) By mailing the order by certified mail addressed to the applicant or respondent at the applicant or respondent’s last known address in the records of the Food and Drug Administration.
Subpart C—Hearing Procedures
§ 515.30 Contents of notice of opportunity for a hearing.
(a) The notice to the applicant of opportunity for a hearing on a proposal by the Commissioner of Food and Drugs (the Commissioner) to refuse to approve a medicated feed mill license application or to revoke the approval of a medicated feed mill license will specify the grounds upon which the Commissioner proposes to issue this order. On request of the applicant, the Commissioner will explain the reasons for the action. The notice of opportunity for a hearing will be published in the
(1) To avail himself of the opportunity for a hearing; or
(2) Not to avail himself of the opportunity for a hearing.
(b) If the applicant fails to file a written appearance in answer to the notice of opportunity for hearing, this failure will be construed as an election not to avail himself of the opportunity for the hearing, and the Commissioner without further notice may enter a final order.
(c) If the applicant elects to avail himself of the opportunity for a hearing, the applicant is required to file a written appearance requesting the hearing within 30 days after the publication of the notice, giving the reason why the application should not be refused or the medicated feed mill license should not be revoked, together with a well-organized and full-factual analysis of the information the applicant is prepared to prove in support of his opposition to the Commissioner’s proposal. A request for a hearing may not rest upon mere allegations or denials, but must set forth specific facts showing there is a genuine and substantial issue of fact that requires a hearing. When it clearly appears from the information in the application and from the reasons and factual analysis in the request for the hearing that no genuine and substantial issue of fact precludes the refusal to approve the application or the revocation of approval of the application, the Commissioner will enter an order on this information, stating his/her findings and conclusions. If a hearing is requested and is justified by the applicant’s response to the notice of opportunity for a hearing, the issues will be defined, an Administrative Law Judge will be named, and the Judge shall issue a written notice of the time and place at which the hearing will commence. In the case of denial of approval, such time shall be not more than 90 days after the expiration of such 30 days unless the Administrative Law Judge and the applicant otherwise agree; and, in the case of withdrawal of approval, such time shall be as soon as practicable.
(d) The hearing will be open to the public; however, if the Commissioner finds that portions of the application which serve as a basis for the hearing contain information concerning a method or process entitled to protection as a trade secret, the part of the hearing involving such portions will not be public, unless the respondent so specifies in the appearance.
§ 515.31 Procedures for hearings.
Hearings relating to new animal drugs under section 512(m)(3) and (m)(4) of the Federal Food, Drug, and Cosmetic Act (the act) shall be governed by part 12 of this chapter.
Subpart D—Judicial Review
§ 515.40 Judicial review.
The transcript and record shall be certified by the Commissioner of Food and Drugs (the Commissioner). In any case in which the Commissioner enters an order without a hearing under § 314.200(g) of this chapter, the request(s) for hearing together with the data and information submitted and the Commissioner’s findings and conclusions shall be included in the record certified by the Commissioner.
PART 516—NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES
Subpart A—General Provisions
§ 516.1 Scope.
(a) This part implements section 573 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360ccc-2) and contains the following subparts:
(1) Subpart A—General Provisions.
(2) Subpart B—Designation of a Minor Use or Minor Species New Animal Drug.
(3) Subpart C [Reserved]
(4) Subpart D [Reserved]
(b) References in this part to regulatory sections of the Code of Federal Regulations are to Chapter I of Title 21, unless otherwise noted.
§ 516.2 Purpose.
This part establishes standards and procedures for implementing section 573 of the act, including designation of minor use or minor species new animal drugs and associated exclusive marketing rights.
§ 516.3 Definitions.
(a) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321) apply to those terms when used in this part.
(b) The following definitions of terms apply to all subparts of part 516:
Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the pharmacological action of the drug substance.
Functionally superior means that a drug has been shown to provide a significant therapeutic or physiologic advantage over that provided by a conditionally-approved or approved MUMS drug, that is otherwise the same drug, in one or more of the following ways:
(i) The drug has been shown to be more effective, as assessed by effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials, than a conditionally approved or approved MUMS drug, that is otherwise the same drug. Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials will be necessary; or
(ii) The drug has been shown to be safer than a conditionally-approved or approved MUMS drug, that is otherwise the same drug, in a substantial portion of the target population, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary.
Infrequently, as used in the minor use definition, means a disease or condition that is uncommon or that occurs only sporadically on an annualized basis.
Limited geographical areas, as used in the minor use definition, means regions of the United States distinguished by physical, chemical, or biological factors that limit the distribution of a disease or condition.
Major species means cattle, horses, swine, chickens, turkeys, dogs, and cats.
Minor species means animals, other than humans, that are not major species.
Minor use means the intended use of a drug in a major species for an indication that occurs infrequently and in only a small number of animals or in limited geographical areas and in only a small number of animals annually.
MUMS drug means a new animal drug, as defined in section 201 of the act, intended for a minor use or for use in a minor species.
Same dosage form means the same as one of the dosage form categories specified in the following parts of this chapter:
(i) Part 520: Oral dosage form new animal drugs (excluding use in animal feeds as specified in part 558 of this chapter).
(ii) Part 522: Implantation or injectable dosage form new animal drugs.
(iii) Part 524: Ophthalmic and topical dosage form new animal drugs.
(iv) Part 526: Intramammary dosage forms.
(v) Part 529: Certain other dosage form new animal drugs.
(vi) Part 558: New animal drugs for use in animal feeds.
Same drug means a MUMS drug for which designation, indexing, or conditional approval is sought that meets the following criteria:
(i) If it is a MUMS drug composed of small molecules and contains the same active moiety as a prior designated, conditionally-approved, or approved MUMS drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate or clathrate is not the same, it is considered the same drug; except that, if the prior MUMS drug is conditionally approved or approved and the second MUMS drug is shown to be functionally superior to the conditionally approved or approved MUMS drug for the same intended use, it is not considered the same drug.
(ii) If it is a MUMS drug composed of large molecules (macromolecules) and contains the same principal molecular structural features (but not necessarily all of the same structural features) as a prior designated, conditionally approved, or approved MUMS drug, it is considered the same drug; except that, if the prior MUMS drug is conditionally approved or approved and the second MUMS drug is shown to be functionally superior to the conditionally approved or approved MUMS drug for the same intended use, it is not considered the same drug. This criterion will be applied as follows to different kinds of macromolecules:
(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the subsequent drug is shown to be functionally superior.
(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug is shown to be functionally superior.
(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug is shown to be functionally superior.
(D) Closely related, complex partly definable drugs with similar pharmacologic intent would be considered the same unless the subsequent drug is shown to be functionally superior.
Same intended use means an intended use of a MUMS drug, for which designation, indexing, or conditional approval is sought, that is determined to be the same as (or not different from) a previously designated, conditionally approved, or approved intended use of a MUMS drug. Same intended use is established by comparing two intended uses and not by simply comparing the specific language by means of which the intent is established in labeling in accordance with the following criteria:
(i) Two intended uses are considered the same if one of the intended uses falls completely within the scope of the other.
(ii) For intended uses associated with diseases or conditions with multiple causative organisms, two intended uses are not considered the same when they involve different causative organisms or different subsets of causative organisms of that disease or condition when the causative organisms involved can reliably be shown to be clinically significant causes of the disease or condition.
(iii) Two intended uses of a drug are not considered the same if they involve different intended species or different definable subpopulations (including “production classes”) of a species.
Small number of animals means equal to or less than 50,000 horses; 80,000 dogs; 150,000 cats; 310,000 cattle; 1,450,000 pigs; 14,000,000 turkeys; and 72,000,000 chickens.
Sponsor means the person requesting designation for a MUMS drug who must be the real party in interest of the development and the intended or actual production and sales of such drug (in this context, the sponsor may be an individual, partnership, organization, or association). Sponsor also means the person responsible for an investigation of a new animal drug (in this context, the sponsor may be an individual, partnership, corporation, or Government agency or may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new animal drugs). Sponsor also means the person submitting or receiving approval for a new animal drug application (in this context, the sponsor may be an individual, partnership, organization, or association). In all contexts, the sponsor is responsible for compliance with applicable provisions of the act and regulations.
Subpart B—Designation of a Minor Use or Minor Species New Animal Drug
§ 516.11 Scope of this subpart.
This subpart implements section 573 of the act. Specifically, this subpart sets forth the procedures and requirements for submissions to FDA of requests for designation of a new animal drug for a minor use or a minor species.
§ 516.12 Purpose.
This subpart establishes standards and procedures for determining eligibility for designation and the associated incentives and benefits described in section 573 of the act, including a 7-year period of exclusive marketing rights.
§ 516.13 Definitions.
The following definitions of terms apply only in the context of subpart B of this part:
Director means the Director of the Office of Minor Use and Minor Species Animal Drug Development of the FDA Center for Veterinary Medicine.
Intended use means the intended treatment, control or prevention of a disease or condition, or the intention to affect the structure or function of the body of animals within an identified species, subpopulation of a species, or collection of species.
MUMS-designated drug means a new animal drug, as defined in section 201 of the act, intended for a minor use or for use in a minor species that has been designated under section 573 of the act.
MUMS-drug exclusive marketing rights or exclusive marketing rights means that, effective on the date of FDA conditional approval or approval as stated in the approval letter of an application for a MUMS-designated drug, no conditional approval or approval will be given to a subsequent application for the same drug, in the same dosage form, for the same intended use for 7 years, except as otherwise provided by law or in this subpart.
§ 516.14 Submission of requests for designation.
All correspondence relating to a request for designation of a MUMS drug must be addressed to the Director of the Office of Minor Use and Minor Species Animal Drug Development. Submissions not including all elements specified in § 516.20 will be returned to the sponsor without review.
§ 516.16 Eligibility to request designation.
The person requesting designation must be the sponsor and the real party in interest of the development and the intended or actual production and sales of the drug or the permanent-resident U.S. agent for such a sponsor.
§ 516.20 Content and format of a request for MUMS-drug designation.
(a) A sponsor that submits a request for designation of a new animal drug intended for a minor use or minor species must submit each request in the form and containing the information required in paragraph (b) of this section. While a request for designation may involve multiple intended uses, each request for designation must constitute a separate submission. A sponsor may request MUMS-drug designation of a previously unapproved drug, or a new intended use or dosage form for an already conditionally approved or approved drug. Only one sponsor may receive MUMS-drug designation of the same drug, in the same dosage form, for the same intended use.
(b) A sponsor must submit two copies of a completed, dated, and signed request for designation that contains the following information:
(1) A request for designation of a new animal drug for a minor use or use in a minor species, which must be specific.
(2) The name and address of the sponsor; the name of the sponsor’s primary contact person and/or permanent-resident U.S. agent including title, address, and telephone number; the established name (and proprietary name, if any) of the active pharmaceutical ingredient of the drug; and the name and address of the source of the active pharmaceutical ingredient of the drug.
(3) A description of the proposed intended use for which the drug is being or will be investigated.
(4) A description of the drug and dosage form.
(5) A discussion of the scientific rationale for the intended use of the drug; specific reference, including date(s) of submission, to all data from nonclinical laboratory studies, clinical investigations, copies of pertinent unpublished and published papers, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive.
(6) A specific description of the product development plan for the drug, its dosage form, and its intended use.
(7) If the drug is intended for a minor use in a major species, documentation in accordance with § 516.21, with appended authoritative references, to demonstrate that such use is a minor use.
(8) A statement that the sponsor submitting the request is the real party in interest of the development and the intended or actual production and sales of the product.
(9) A statement that the sponsor acknowledges that, upon granting a request for MUMS designation, FDA will make information regarding the designation publicly available as specified in § 516.28.
§ 516.21 Documentation of minor use status.
So that FDA can determine whether a drug qualifies for MUMS-drug designation as a minor use in a major species under section 573 of the act, the sponsor shall include in its request to FDA for MUMS-drug designation under § 516.20 documentation demonstrating that the use is limited to a small number of animals (annualized). This documentation must include the following information:
(a) The estimated total number of animals to which the drug could potentially be administered on an annual basis for the treatment, control, or prevention of the disease or condition for which the drug is being developed, including animals administered the drug as part of herd or flock treatment, together with a list of the sources (including dates of information provided and literature citations) for the estimate.
(b) The estimated total number of animals referred to in paragraph (a) of this section may be further reduced to only a subset of the estimated total number of animals if administration of the drug is only medically justified for this subset. To establish this, requestors must demonstrate that administration of the drug to animals subject to the disease or condition for which the drug is being developed other than the subset is not medically justified. The sponsor must also include a list of the sources (including dates of information provided and literature citations) for the justification that administration of the drug to animals other than the targeted subset is medically inappropriate.
§ 516.22 Permanent-resident U.S. agent for foreign sponsor.
Every foreign sponsor that seeks MUMS-drug designation shall name a permanent resident of the United States as the sponsor’s agent upon whom service of all processes, notices, orders, decisions, requirements, and other communications may be made on behalf of the sponsor. Notifications of changes in such agents or changes of address of agents should preferably be provided in advance, but not later than 60 days after the effective date of such changes. The permanent-resident U.S. agent may be an individual, firm, or domestic corporation and may represent any number of sponsors. The name and address of the permanent-resident U.S. agent shall be provided to the Director of the Office of Minor Use and Minor Species Animal Drug Development.
§ 516.23 Timing of requests for MUMS-drug designation.
A sponsor may request MUMS-drug designation at any time in the drug development process prior to the submission of an application for either conditional approval or approval of the MUMS drug for which designation is being requested.
§ 516.24 Granting MUMS-drug designation.
(a) FDA may grant the request for MUMS-drug designation if none of the reasons described in § 516.25 for refusal to grant such a request apply.
(b) When a request for MUMS-drug designation is granted, FDA will notify the sponsor in writing and will give public notice of the MUMS-drug designation in accordance with § 516.28.
§ 516.25 Refusal to grant MUMS-drug designation.
(a) FDA will refuse to grant a request for MUMS-drug designation if any of the following reasons apply:
(1) The drug is not intended for use in a minor species or FDA determines that there is insufficient evidence to demonstrate that the drug is intended for a minor use in a major species.
(2) The drug is the same drug in the same dosage form for the same intended use as one that already has a MUMS-drug designation but has not yet been conditionally approved or approved.
(3) The drug is the same drug in the same dosage form for the same intended use as one that is already conditionally approved or approved. A drug that FDA has found to be functionally superior is not considered the same drug as an already conditionally approved or approved drug even if it is otherwise the same drug in the same dosage form for the same intended use.
(4) The sponsor has failed to provide:
(i) A credible scientific rationale in support of the intended use,
(ii) Sufficient information about the product development plan for the drug, its dosage form, and its intended use to establish that adherence to the plan can lead to successful drug development in a timely manner, and
(iii) Any other information required under § 516.20.
(b) FDA may refuse to grant a request for MUMS-drug designation if the request for designation contains an untrue statement of material fact or omits material information.
§ 516.26 Amendment to MUMS-drug designation.
(a) At any time prior to conditional approval or approval of an application for a MUMS-designated drug, the sponsor may apply for an amendment to the designated intended use if the proposed change is due to new and unexpected findings in research on the drug, information arising from FDA recommendations, or other unforeseen developments.
(b) FDA will grant the amendment if it finds:
(1) That the initial designation request was made in good faith;
(2) That the amendment is intended to make the MUMS-drug designated intended use conform to the results of new and unexpected findings in research on the drug, information arising from FDA recommendations, or other unforeseen developments; and
(3) In the case of a minor use, that as of the date of the submission of the amendment request, the amendment would not result in the intended use of the drug no longer being considered a minor use.
§ 516.27 Change in sponsorship.
(a) A sponsor may transfer sponsorship of a MUMS-designated drug to another person. A change of sponsorship will also transfer the designation status of the drug which will remain in effect for the new sponsor subject to the same conditions applicable to the former sponsor provided that at the time of a potential transfer, the new and former sponsors submit the following information in writing and obtain permission from FDA:
(1) The former sponsor shall submit a letter to FDA that documents the transfer of sponsorship of the MUMS-designated drug. This letter shall specify the date of the transfer. The former sponsor shall also certify in writing to FDA that a complete copy of the request for MUMS-drug designation, including any amendments to the request, and correspondence relevant to the MUMS-drug designation, has been provided to the new sponsor.
(2) The new sponsor shall submit a letter or other document containing the following information:
(i) A statement accepting the MUMS-drug designated file or application;
(ii) The date that the change in sponsorship is intended to be effective;
(iii) A statement that the new sponsor has a complete copy of the request for MUMS-drug designation, including any amendments to the request and any correspondence relevant to the MUMS-drug designation;
(iv) A statement that the new sponsor understands and accepts the responsibilities of a sponsor of a MUMS-designated drug established elsewhere in this subpart;
(v) The name and address of a new primary contact person or permanent resident U.S. agent; and
(vi) Evidence that the new sponsor is capable of actively pursuing approval with due diligence.
(b) No sponsor may relieve itself of responsibilities under the act or under this subpart by assigning rights to another person without:
(1) Assuring that the new sponsor will carry out such responsibilities; and
(2) Obtaining prior permission from FDA.
§ 516.28 Publication of MUMS-drug designations.
FDA will periodically update a publicly available list of MUMS-designated drugs. This list will be placed on file at the FDA Dockets Management Staff, and will contain the following information for each MUMS-designated drug:
(a) The name and address of the sponsor;
(b) The established name and trade name, if any, of the drug;
(c) The dosage form of the drug;
(d) The species and the proposed intended use for which MUMS-drug designation was granted; and
(e) The date designation was granted.
§ 516.29 Termination of MUMS-drug designation.
(a) The sponsor of a MUMS-designated drug must notify FDA of any decision to discontinue active pursuit of conditional approval or approval of such MUMS drug. FDA must terminate the designation upon such notification.
(b) A conditionally-approved or approved MUMS-designated drug sponsor must notify FDA at least 1 year before it intends to discontinue the manufacture of such MUMS drug. FDA must terminate designation upon such notification.
(c) MUMS designation shall terminate upon the expiration of any applicable period of exclusive marketing rights under this subpart.
(d) FDA may terminate designation if it independently determines that the sponsor is not actively pursuing conditional approval or approval with due diligence. At a minimum, due diligence must be demonstrated by:
(1) Submission of annual progress reports in a timely manner in accordance with § 516.30 that demonstrate that the sponsor is progressing in accordance with the drug development plan submitted to the agency under § 516.20 and
(2) Compliance with all applicable requirements of part 511 of this chapter.
(e) Designation of a conditionally approved or approved MUMS-designated drug and the associated exclusive marketing rights may be terminated if the sponsor is unable to provide sufficient quantities of the drug to meet the needs for which it is designated.
(f) FDA may also terminate MUMS-drug designation for any drug if the agency finds that:
(1) The request for designation contained an untrue statement of material fact; or
(2) The request for designation omitted material information required by this subpart; or
(3) FDA subsequently finds that the drug in fact had not been eligible for MUMS-drug designation at the time of submission of the request;
(4) The same drug, in the same dosage form, for the same intended use becomes conditionally approved or approved for another sponsor; or
(5) FDA withdraws the conditional approval or approval of the application for the new animal drug.
(g) For a conditionally approved or approved drug, termination of MUMS-drug designation also terminates the sponsor’s exclusive marketing rights for the drug but does not withdraw the conditional approval or approval of the drug’s application.
(h) Where a drug has been MUMS-designated for a minor use in a major species, its designation will not be terminated on the grounds that the number of animals to which the drug could potentially be administered on an annual basis for the treatment, control, or prevention of the disease or condition for which the drug is being developed, including animals administered the drug as part of herd or flock treatment, subsequently increases.
(i) When a MUMS-drug designation is terminated, FDA will notify the sponsor in writing and will give public notice of the termination of the MUMS-drug designation.
§ 516.30 Annual reports for a MUMS-designated drug.
Within 14 months after the date on which a MUMS drug is granted designation and annually thereafter until approval, the sponsor of a MUMS-designated drug shall submit a brief progress report on the drug to the investigational new animal drug file addressed to the Director of the Office of Minor Use and Minor Species Animal Drug Development that includes the following information:
(a) A short account of the progress of drug development including a description of studies initiated, ongoing, and completed, and a short summary of the status or results of such studies;
(b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and
(c) A brief discussion of any changes that may affect the MUMS-designated drug status of the product. For example, situations in which testing data demonstrate that the proposed intended use is inappropriate due to unexpected issues of safety or effectiveness.
§ 516.31 Scope of MUMS-drug exclusive marketing rights.
(a) After conditional approval or approval of an application for a MUMS-designated drug in the dosage form and for the intended use for which MUMS-drug designation has been granted, FDA will not conditionally approve or approve another application or abbreviated application for the same drug in the same dosage form for the same intended use before the expiration of 7 years after the date of conditional approval or approval as stated in the approval letter from FDA, except that such an application can be conditionally approved or approved sooner if, and at such time as, any of the following occurs:
(1) FDA terminates the MUMS-drug designation and associated exclusive marketing rights under § 516.29; or
(2) FDA withdraws the conditional approval or approval of the application for the drug for any reason; or
(3) The sponsor with exclusive marketing rights provides written consent to FDA to conditionally approve or approve another application before the expiration of 7 years; or
(4) The sponsor fails to assure a sufficient quantity of the drug in accordance with section 573 of the act and § 516.36.
(b) If an application for a MUMS drug cannot be approved until the expiration of the period of exclusive marketing of a MUMS-designated drug, FDA will so notify the sponsor in writing.
§ 516.34 FDA recognition of exclusive marketing rights.
(a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely written notice recognizing exclusive marketing rights when an application for a MUMS-designated drug has been conditionally approved or approved. The written notice will inform the sponsor of the requirements for maintaining MUMS-designated drug exclusive marketing rights for the full 7-year term. This notice will generally be contained in the letter conditionally approving or approving the application.
(b) When an application is conditionally approved or approved for a MUMS-designated drug that qualifies for exclusive marketing rights, FDA will publish this information in the
§ 516.36 Insufficient quantities of MUMS-designated drugs.
(a) Under section 573 of the act, whenever FDA has reason to believe that sufficient quantities of a conditionally-approved or approved, MUMS-designated drug to meet the needs for which the drug was designated cannot be assured by the sponsor, FDA will so notify the sponsor of this possible insufficiency and will offer the sponsor the following options, one of which must be exercised by a time that FDA specifies:
(1) Provide FDA information and data regarding how the sponsor can assure the availability of sufficient quantities of the MUMS-designated drug within a reasonable time to meet the needs for which the drug was designated; or
(2) Provide FDA in writing the sponsor’s consent for the conditional approval or approval of other applications for the same drug before the expiration of the 7-year period of exclusive marketing rights.
(b) If, within the time that FDA specifies, the sponsor fails to consent to the conditional approval or approval of other applications and if FDA finds that the sponsor has not shown that it can assure the availability of sufficient quantities of the MUMS-designated drug to meet the needs for which the drug was designated, FDA will issue a written order terminating designation of the MUMS drug and the associated exclusive marketing rights. This order will state FDA’s findings and conclusions and will constitute final agency action. An order terminating designation and associated exclusive marketing rights may issue whether or not there are other sponsors that can assure the availability of alternative sources of supply. Such an order will not withdraw the conditional approval or approval of an application. Once terminated under this section, neither designation, nor exclusive marketing rights may be reinstated.
§ 516.52 Availability for public disclosure of data and information in requests.
(a) FDA will not publicly disclose the existence of a request for MUMS-drug designation under section 573 of the act prior to final FDA action on the request unless the existence of the request has been previously publicly disclosed or acknowledged.
(b) Whether or not the existence of a pending request for designation has been publicly disclosed or acknowledged, no data or information in the request are available for public disclosure prior to final FDA action on the request.
(c) Except as provided in paragraph (d) of this section, upon final FDA action on a request for designation, the public availability of data and information in the request will be determined in accordance with part 20 of this chapter and other applicable statutes and regulations.
(d) In accordance with § 516.28, FDA will make a cumulative list of all MUMS-drug designations available to the public and update such list periodically. In accordance with § 516.29, FDA will give public notice of the termination of all MUMS-drug designations.
Subpart C—Index of Legally Marketed Unapproved New Animal Drugs for Minor Species
§ 516.111 Scope of this subpart.
This subpart implements section 572 of the act and provides standards and procedures to establish an index of legally marketed unapproved new animal drugs. This subpart applies only to minor species and not to minor use in major species. This index is only available for new animal drugs intended for use in a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals and for new animal drugs intended for use only in a hatchery, tank, pond, or other similar contained man-made structure in an early, nonfood life stage of a food-producing minor species, where safety for humans is demonstrated in accordance with the standard of section 512(d) of the act (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance). The index shall not include a new animal drug that is contained in, or a product of, a transgenic animal. Among its topics, this subpart sets forth the standards and procedures for:
(a) Investigational exemptions for indexing purposes;
(b) Submissions to FDA of requests for determination of eligibility of a new animal drug for indexing;
(c) Establishment and operation of expert panels;
(d) Submissions to FDA of requests for addition of a new animal drug to the index;
(e) Modifications to index listings;
(f) Publication of the index; and
(g) Records and reports.
§ 516.115 Definitions.
(a) The following definitions of terms apply only in the context of subpart C of this part:
Director OMUMS means the Director of the Office of Minor Use and Minor Species Animal Drug Development of the FDA Center for Veterinary Medicine.
Holder means the requestor of an index listing after the request is granted and the new animal drug is added to the index.
Index means FDA’s list of legally marketed unapproved new animal drugs for minor species.
Intended use has the same meaning as that given in § 516.13 of this chapter.
Qualified expert panel means a panel that is composed of experts qualified by scientific training and experience to evaluate the target animal safety and effectiveness of a new animal drug under consideration for indexing.
Requestor means the person making a request for determination of eligibility for indexing or a request for addition to the index.
Transgenic animal means an animal whose genome contains a nucleotide sequence that has been intentionally modified in vitro, and the progeny of such an animal, provided that the term ‘transgenic animal’ does not include an animal of which the nucleotide sequence of the genome has been modified solely by selective breeding.
(b) The definitions of the following terms are given in § 514.3 of this chapter:
Adverse drug experience.
Product defect/manufacturing defect.
Serious adverse drug experience.
Unexpected adverse drug experience.
(c) The definitions of the following terms are given in § 516.3 of this chapter:
Same dosage form.
Same drug.
Same intended use.
§ 516.117 Submission of correspondence under this subpart.
Unless directed otherwise by FDA, all correspondence relating to any aspect of the new animal drug indexing process described in this subpart must be addressed to the Director, OMUMS. The initial correspondence for a particular index listing should include the name and address of the authorized contact person. Notifications of changes in such person or changes of address of such person should be provided in a timely manner.
§ 516.119 Permanent-resident U.S. agent for foreign requestors and holders.
Every foreign requestor and holder shall name a permanent resident of the United States as their agent upon whom service of all processes, notices, orders, decisions, requirements, and other communications may be made on behalf of the requestor or holder. Notifications of changes in such agents or changes of address of agents should preferably be provided in advance, but not later than 60 days after the effective date of such changes. The permanent resident U.S. agent may be an individual, firm, or domestic corporation and may represent any number of requestors or holders. The name and address of the permanent-resident U.S. agent shall be submitted to the Director, OMUMS, and included in the index file.
§ 516.121 Meetings.
(a) A requestor or potential requestor is entitled to one or more meetings to discuss the requirements for indexing a new animal drug.
(b) Requests for such meetings should be in writing, be addressed to the Director, OMUMS, specify the participants attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting.
(c) Within 30 days of receiving a request for a meeting, FDA will attempt to schedule the meeting at a time agreeable to both FDA and the person making the request.
§ 516.123 Informal conferences regarding agency administrative actions.
(a) Should FDA make an initial decision denying a request for determination of eligibility for indexing, terminating an investigational exemption, determining that a qualified expert panel does not meet the selection criteria, denying a request for addition to the index, or removing a new animal drug from the index, FDA will give written notice that specifies the grounds for the initial decision and provides an opportunity for an informal conference for review of the decision.
(b) The written notice will include information for scheduling the informal conference and state that a written request for a conference must be made within 60 days of the date FDA sends its notice.
(c) Within 45 days of receiving a request for an informal conference, FDA will schedule and hold the informal conference at a time agreeable to both FDA and the person making the request.
(d) Such an informal conference will be conducted by a presiding officer who will be the Director of the Center for Veterinary Medicine or his or her designee, excluding the Director of the Office of Minor Use and Minor Species Animal Drug Development and other persons significantly involved in the initial decision.
(e) The person requesting an informal conference must provide a written response to FDA’s initial decision at least 2 weeks prior to the date of the scheduled meeting. Generally, this written response would be attached to the request for an informal conference. At the option of the person requesting an informal conference, such written response to FDA’s initial decision may act in lieu of a face-to-face meeting. In this case, the informal conference will consist of a review by the presiding officer of the submitted written response.
(f) The purpose of an informal conference is to discuss scientific and factual issues. It will involve a discussion of FDA’s initial decision and any written response to that decision.
(g) Internal agency review of a decision must be based on the information in the administrative file. If the person requesting an informal conference presents new information not in the file, the matter will be returned to the appropriate lower level in the agency for reevaluation based on the new information.
(h) Informal conferences under this part are not subject to the separation of functions rules in § 10.55 of this chapter.
(i) The rules of evidence do not apply to informal conferences. No motions or objections relating to the admissibility of information and views will be made or considered, but any party to the conference may comment upon or rebut all such data, information and views.
(j) [Reserved]
(k) The presiding officer will prepare a written report regarding the subject of the informal conference that states and describes the basis for his or her findings. Whenever time permits, the parties to the informal conference will have 30 days to review and comment on the report.
(l) The administrative record of the informal conference will consist of:
(1) The notice providing an opportunity for an informal conference and the written response to the notice.
(2) All written information and views submitted to the presiding officer at the conference or, at the discretion of the presiding officer, thereafter.
(3) The presiding officer’s written report.
(4) All correspondence and memoranda of any and all meetings between the participants and the presiding officer.
(m) The administrative record of the informal conference is closed to the submission of information at the close of the conference, unless the presiding officer specifically permits additional time for further submission.
(n) The administrative record of the informal conference specified herein constitutes the exclusive record for decision.
§ 516.125 Investigational use of minor species new animal drugs to support indexing.
(a) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug intended solely for investigational use in minor species shall meet the requirements of part 511 of this chapter if the investigational use is for the purpose of:
(1) Demonstrating human food safety under section 572(a)(1)(B) of the act;
(2) Demonstrating safety with respect to individuals exposed to the new animal drug through its manufacture and use under section 572(c)(1)(F) of the act;
(3) Conducting an environmental assessment under section 572(c)(1)(E) of the act; or
(4) Obtaining approval of a new animal drug application or abbreviated new animal drug application under section 512(b) of the act.
(b) Correspondence and information associated with investigations described in paragraph (a) of this section shall not be sent to the Director, OMUMS, but shall be submitted to FDA in accordance with the provisions of part 511 of this chapter.
(c) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug intended solely for investigational use in minor species, other than for an investigational use described in paragraph (a) of this section, shall meet the requirements of this section. For such investigations, all provisions of part 511 of this chapter apply with the following modifications:
(1) Under § 511.1(a)(1) of this chapter, the label statement is as follows:
“Caution. Contains a new animal drug for investigational use only in laboratory animals or for tests in vitro in support of index listing. Not for use in humans.”
(2) Under § 511.1(b)(1) of this chapter, the label statement is as follows:
“Caution. Contains a new animal drug for use only in investigational animals in clinical trials in support of index listing. Not for use in humans. Edible products of investigational animals are not to be used for food for humans or other animals unless authorization has been granted by the U.S. Food and Drug Administration or by the U.S. Department of Agriculture.”
(3) Under § 511.1(b)(4) of this chapter, the notice is titled “Notice of Claimed Investigational Exemption for a New Animal Drug for Index Listing” and is submitted in duplicate to the Director, OMUMS.
(4) Under § 511.1(c)(3) of this chapter, if an investigator is determined to be ineligible to receive new animal drugs, each “Notice of Claimed Investigational Exemption for a New Animal Drug for Index Listing” and each request for indexing shall be examined with respect to the reliability of information submitted by the investigator.
(5) Under § 511.1(c)(4) and (d)(2) of this chapter, with respect to termination of exemptions, the sponsor of an investigation shall not be granted an opportunity for a regulatory hearing before FDA pursuant to part 16 of this chapter. Instead, the sponsor shall have an opportunity for an informal conference as described in § 516.123.
(6) Under § 511.1(c)(5) of this chapter, if the Commissioner of Food and Drugs determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are such that a request for addition to the index would have been denied, FDA will remove the new animal drug from the index in accordance with § 516.167.
(d) The investigational use of a new animal drug or animal feed bearing or containing a new animal drug subject to paragraph (c) of this section shall not be subject to the good laboratory practice requirements in part 58 of this chapter.
(e) Correspondence and information associated with investigations described in paragraph (c) of this section shall be sent to the Director, OMUMS, in accordance with the provisions of this section.
§ 516.129 Content and format of a request for determination of eligibility for indexing.
(a) Each request for determination of eligibility:
(1) May involve only one drug (or one combination of drugs) in one dosage form;
(2) May not involve a new animal drug that is contained in or a product of a transgenic animal;
(3) May not involve the same drug in the same dosage form for the same intended use as a drug that is already approved or conditionally approved; and
(4) Must be submitted separately.
(b) A request for determination of eligibility for indexing may involve multiple intended uses and/or multiple minor species. However, if a request for determination of eligibility for indexing that contains multiple intended uses and/or multiple minor species cannot be granted in any part, the entire request will be denied.
(c) A requestor must submit two copies of a dated request signed by the authorized contact person for determination of eligibility for indexing that contains the following:
(1) Identification of the minor species or groups of minor species for which the new animal drug is intended;
(2) Information regarding drug components and composition;
(3) A statement of the intended use(s) of the new animal drug in the identified minor species or groups of minor species;
(4) A statement of the proposed conditions of use associated with the stated intended use(s) of the new animal drug, including the proposed dosage, route of administration, contraindications, warnings, and any other significant limitations associated with the intended use(s) of the new animal drug;
(5) A brief discussion of the need for the new animal drug for the intended use(s);
(6) An estimate of the anticipated annual distribution of the new animal drug, in terms of the total quantity of active ingredient, after indexing;
(7) Information to establish that the new animal drug is intended for use:
(i) In a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals; or
(ii) In a hatchery, tank, pond, or other similar contained man-made structure in (which includes on) an early, non-food life stage of a food-producing minor species, and information to demonstrate food safety in accordance with the standards of section 512(d) of the act and § 514.111 of this chapter (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance);
(8) A description of the methods used in, and the facilities and controls used for, the manufacture, processing and packing of the new animal drug sufficient to demonstrate that the requestor has established appropriate specifications for the manufacture and control of the new animal drug and that the requestor has an understanding of current good manufacturing practices;
(9) Either a claim for categorical exclusion under § 25.30 or § 25.33 of this chapter or an environmental assessment under § 25.40 of this chapter;
(10) Information sufficient to support the conclusion that the new animal drug is safe under section 512(d) of the act with respect to individuals exposed to the new animal drug through its manufacture and use; and
(11) The name and address of the contact person or permanent-resident U.S. agent.
§ 516.131 Refuse to file a request for determination of eligibility for indexing.
(a) If a request for determination of eligibility for indexing contains all of the information required by § 516.129, FDA shall file it, and the filing date shall be the date FDA receives the request.
(b) If a request for a determination of eligibility lacks any of the information required by § 516.129, FDA will not file it, but will inform the requestor in writing within 30 days of receiving the request as to what information is lacking.
§ 516.133 Denying a request for determination of eligibility for indexing.
(a) FDA will deny a request for determination of eligibility for indexing if it determines upon the basis of the request evaluated together with any other information before it with respect to the new animal drug that:
(1) The same drug in the same dosage form for the same intended use is already approved or conditionally approved;
(2) There is insufficient information to demonstrate that the new animal drug is intended for use:
(i) In a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals, or
(ii) In a hatchery, tank, pond, or other similar contained man-made structure in (which includes on) an early, non-food life stage of a food-producing minor species, and there is insufficient evidence to demonstrate safety for humans in accordance with the standard of section 512(d) of the act and § 514.111 of this chapter (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance);
(3) The new animal drug is contained in or is a product of a transgenic animal;
(4) There is insufficient information to demonstrate that the requestor has established appropriate specifications for the manufacture and control of the new animal drug and that the requestor has an understanding of current good manufacturing practices;
(5) The requester fails to submit an adequate environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.33 of this chapter;
(6) There is insufficient information to determine that the new animal drug is safe with respect to individuals exposed to the new animal drug through its manufacture or use; or
(7) The request for determination of eligibility for indexing fails to contain any other information required under the provisions of § 516.129.
(b) FDA may deny a request for determination of eligibility for indexing if it contains any untrue statement of a material fact or omits material information.
(c) When a request for determination of eligibility for indexing is denied, FDA will notify the requestor in accordance with § 516.137.
§ 516.135 Granting a request for determination of eligibility for indexing.
(a) FDA will grant the request for determination of eligibility for indexing if none of the reasons described in § 516.133 for denying such a request applies.
(b) When a request for determination of eligibility for indexing is granted, FDA will notify the requestor in accordance with § 516.137.
§ 516.137 Notification of decision regarding eligibility for indexing.
(a) Within 90 days after the filing of a request for a determination of eligibility for indexing based on § 516.129(c)(7)(i), or 180 days for a request based on § 516.129(c)(7)(ii), FDA shall grant or deny the request, and notify the requestor of FDA’s decision in writing.
(b) If FDA denies the request, FDA shall provide due notice and an opportunity for an informal conference as described in § 516.123 regarding its decision. A decision of FDA to deny a request for determination of eligibility for indexing following an informal conference shall constitute final agency action subject to judicial review.
§ 516.141 Qualified expert panels.
(a) Establishment of a qualified expert panel. Establishing a qualified expert panel is the first step in the process of requesting the addition of a new animal drug to the index. A qualified expert panel may not be established until FDA has determined that the new animal drug is eligible for indexing. The requestor must choose members for the qualified expert panel in accordance with selection criteria listed in paragraph (b) of this section and submit information about these proposed members to FDA. FDA must determine whether the proposed qualified expert panel meets the selection criteria prior to the panel beginning its work. Qualified expert panels operate external to FDA and are not subject to the Federal Advisory Committee Act, as amended, 5 U.S.C. App.
(b) Criteria for the selection of a qualified expert panel. (1) A qualified expert panel member must be an expert qualified by training and experience to evaluate a significant aspect of target animal safety or effectiveness of the new animal drug under consideration.
(2) A qualified expert panel member must certify that he or she has a working knowledge of section 572 of the act (the indexing provisions of the statute) and this subpart, and that he or she has also read and understood a clear written statement provided by the requestor stating his or her duties and responsibilities with respect to reviewing the new animal drug proposed for addition to the index.
(3) A qualified expert panel member may not be an FDA employee.
(4) A qualified expert panel must have at least three members.
(5) A qualified expert panel must have members with a range of expertise such that the panel, as a whole, is qualified by training and experience to evaluate the target animal safety and effectiveness of the new animal drug under consideration.
(6) Unless FDA makes a determination to allow participation notwithstanding an otherwise disqualifying financial interest, a qualified expert panel member must not have a conflict of interest or the appearance of a conflict of interest, as described in paragraph (g) of this section.
(c) Requestor responsibilities. (1) The requestor must:
(i) Choose members for the qualified expert panel in accordance with selection criteria listed in paragraph (b) of this section.
(ii) Provide each potential expert panel member a copy of section 572 of the act (the indexing provisions of the statute) and this subpart and obtain certification that he or she has a working knowledge of the information.
(iii) Provide each potential expert panel member a written statement describing the purpose and scope of his or her participation on the qualified expert panel and obtain certification that he or she has read and understood the information. The written statement should describe the duties and responsibilities of qualified expert panels and their members established by paragraphs (e) and (f) of this section, including the need to prepare a written report under § 516.143.
(iv) Obtain information from each potential expert panel member demonstrating that he or she is qualified by training and experience to evaluate the target animal safety and effectiveness of the new animal drug under consideration. This information can be obtained from a comprehensive curriculum vitae or similar document.
(v) Notify each potential expert panel member that he or she must submit information relating to potential conflict of interest directly to FDA in a timely manner, as required in paragraph (e)(6) of this section.
(2) The requestor must submit, in writing, the names and addresses of the proposed qualified expert panel members and sufficient information about each proposed member for FDA to determine whether the panel meets the selection criteria listed in paragraphs (b)(1) through (b)(5) of this section.
(3) After FDA has determined that the qualified expert panel meets the selection criteria, the requestor must provide to the panel all information known by the requestor that is relevant to a determination of the target animal safety and the effectiveness of the new animal drug at issue. In addition, the requestor must notify FDA of the name of the qualified expert panel leader.
(4) The requestor must immediately notify FDA if it believes a qualified expert panel member no longer meets the selection criteria listed in paragraph (b) of this section or is otherwise not in compliance with the requirements of this section.
(5) If a qualified expert panel member cannot complete the review for which he or she was selected, the requestor must either choose a replacement or justify the continued work of the panel in the absence of the lost panelist. In either case, the requestor must submit sufficient information for FDA to determine whether the proposed revised qualified expert panel meets the selection criteria listed in paragraphs (b)(1) through (b)(5) of this section.
(6) The requestor must keep copies of all information provided to, or received from, qualified expert panel members, including the written report, for 2 years after the completion of the report, or the product is added to the index, whichever occurs later, and make them available to a duly authorized employee of the agency at all reasonable times.
(d) FDA responsibilities. (1) FDA will determine whether the requestor’s proposed qualified expert panel meets the selection criteria listed in paragraph (b) of this section. FDA will expeditiously inform the requestor, in writing, of its determination. If FDA determines that the qualified expert panel does not meet the selection criteria, FDA will provide due notice and an opportunity for an informal conference as described in § 516.123. A determination by FDA that a proposed qualified expert panel does not meet the selection criteria following an informal conference shall constitute final agency action subject to judicial review.
(2) If FDA determines that a qualified expert panel no longer meets the selection criteria listed in paragraph (b) of this section or that the panel or its members are not in compliance with the requirements of this section, the agency will expeditiously inform the requestor, in writing, of this determination and provide due notice and an opportunity for an informal conference as described in § 516.123. A determination by FDA, following an informal conference, that a qualified expert panel no longer meets the selection criteria listed in paragraph (b) of this section or that the panel or its members are not in compliance with the requirements of this section shall constitute final agency action subject to judicial review.
(e) Responsibilities of a qualified expert panel member. A qualified expert panel member must do the following:
(1) Continue to meet all selection criteria described in paragraph (b) of this section.
(2) Act in accordance with generally accepted professional and ethical business practices.
(3) Review all information relevant to a determination of the target animal safety and effectiveness of the new animal drug provided by the requestor. The panel should also consider all relevant information otherwise known by the panel members, including anecdotal information.
(4) Participate in the preparation of the written report of the findings of the qualified expert panel, described in § 516.143.
(5) Sign, or otherwise approve in writing, the written report. Such signature or other written approval will serve as certification that the written report meets the requirements of the written report in § 516.143.
(6) Provide the information relating to potential conflict of interest described in paragraph (g) of this section to FDA for its consideration. Such information should be submitted directly to the Director, OMUMS, when notified by the requestor.
(7) Immediately notify the requestor and FDA of any change in conflict of interest status.
(8) Certify at the time of submission of the written report that there has been no change in conflict of interest status, or identify and document to FDA any such change.
(f) Additional responsibilities of a qualified expert panel leader. (1) The qualified expert panel leader must ensure that the activities of the panel are performed efficiently and in accordance with generally accepted professional and ethical business practices.
(2) The qualified expert panel leader serves as the principal point of contact between representatives of the agency and the panel.
(3) The qualified expert panel leader is responsible for submitting the written report and all notes or minutes relating to panel deliberations to the requestor.
(4) The qualified expert panel leader must maintain a copy of the written report and all notes or minutes relating to panel deliberations that are submitted to the requestor for 2 years after the report is submitted. Such records must be made available to a duly authorized employee of the agency for inspection at all reasonable times.
(g) Prevention of conflicts of interest. (1) For the purposes of this subpart, FDA will consider a conflict of interest to be any financial or other interest that could impair a person’s objectivity in serving on the qualified expert panel or could create an unfair competitive advantage for a person or organization.
(2) Factors relevant to whether there is a conflict of interest or the appearance of a conflict of interest include whether the qualified expert panel member, their spouse, their minor children, their general partners, or any organizations in which they serve as an officer, director, trustee, general partner or employee:
(i) Is currently receiving or seeking funding from the requestor through a contract or research grant (either directly or indirectly through another entity, such as a university).
(ii) Has any employment, contractual, or other financial arrangement with the requestor other than receiving a reasonable fee for serving as a member of the qualified expert panel.
(iii) Has any ownership or financial interest in any drug, drug manufacturer, or drug distributor which will benefit from either a favorable or unfavorable evaluation or opinion.
(iv) Has any ownership or financial interest in the new animal drug being reviewed by the qualified expert panel.
(v) Has participated in the design, manufacture, or distribution of any drug that will benefit from either a favorable or unfavorable opinion of the qualified expert panel.
(vi) Has provided within 1 year any consultative services regarding the new animal drug being reviewed by the qualified expert panel.
(vii) Has entered into an agreement in which fees charged or accepted are contingent upon the panel member making a favorable evaluation or opinion.
(viii) Receives payment for services related to preparing information the requestor presents to the qualified expert panel, other than for services related to the written report described in § 516.143.
(3) To permit FDA to make a decision regarding potential conflict of interest, a potential qualified expert panel member must submit to the Director, OMUMS, the following information relating to themselves, their spouse, their minor children, their general partners, or any organizations in which they serve as an officer, director, trustee, general partner or employee, regarding the following issues to the extent that they are, in any way, relevant to the subject of the review of the qualified expert panel:
(i) Investments (for example, stocks, bonds, retirement plans, trusts, partnerships, sector funds, etc.), including for each the following: Name of the firm, type of investment, owner (self, spouse, etc.), number of shares / current value.
(ii) Employment (full or part time, current or under negotiation), including for each the following: Name of the firm, relationship (self, spouse, etc.), position in firm, date employment or negotiation began.
(iii) Consultant/advisor (current or under negotiation), including for each the following: Name of the firm, topic/issue, amount received, date initiated.
(iv) Contracts, grants, Cooperation Research and Development Agreement (CRADAs) (current or under negotiation), including for each the following: Type of agreement, product under study and indications, amount of remuneration (institution/self), time period, sponsor (government, firm, institution, individual), role of the person (site investigator, principal investigator, co-investigator, partner, no involvement, other), awardee.
(v) Patents/royalties/trademarks, including for each the following: Description, name of firm involved, income received.
(vi) Expert witness (last 12 months or under negotiation), including for each the following: For or against, name of firm, issue, amount received.
(vii) Speaking/writing (last 12 months or under negotiation), including for each the following: Firm, topic/issue, amount received (honorarium/travel), date.
(viii) Whether the potential qualified expert panel member, their spouse, their minor children, their general partners or any organizations in which they serve as an officer, director, trustee, general partner or employee, have had, at any time in the past, involvement of the kind noted in paragraph (g)(3)(i) through (g)(3)(vii) of this section with respect to the animal drug that is the subject of the qualified expert panel review.
(ix) Whether there are any other involvements (other kinds of relationships) that would give the appearance of a conflict of interest which have not been described in paragraph (g)(3)(i) through (g)(3)(viii) of this section.
(x) In all cases, a response of “no,” “none,” or “not applicable” is satisfactory when there is no relevant information to submit.
(xi) A certification statement signed by the potential qualified expert panel member to the effect that all information submitted is true and complete to the best of their knowledge, that they have read and understood their obligations as an expert panel member, and that they will notify FDA and the requestor of any change in their conflict of interest status.
(4) The fact that a qualified expert panel member receives a reasonable fee for services as a member of the qualified expert panel, provided that the fee is no more than commensurate with the value of the time that the member devotes to the review process, does not constitute a conflict of interest or the appearance of a conflict of interest.
§ 516.143 Written report.
The written report required in § 516.145(b)(3) shall:
(a) Be written in English by a qualified expert panel meeting the requirements of § 516.141;
(b) Describe the panel’s evaluation of all available target animal safety and effectiveness information relevant to the proposed use of the new animal drug, including anecdotal information;
(c) For all information considered, including anecdotal information, include either a citation to published literature or a summary of the information;
(d) State the panel’s opinion regarding whether the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm being caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;
(e) Be signed, or otherwise approved in writing, by all panel members, in accordance with § 516.141; and
(f) If the panel unanimously concludes that the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm being caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question, the written report shall:
(1) Provide draft labeling that includes all conditions of use and limitations of use of the new animal drug deemed necessary by the panel to assure that the benefits of use of the new animal drug outweigh the risks, or provide narrative information from which such labeling can be written by the requestor; and
(2) Include a recommendation regarding whether the new animal drug should be limited to use under the professional supervision of a licensed veterinarian.
§ 516.145 Content and format of a request for addition to the index.
(a) A requestor may request addition of a new animal drug to the index only after the new animal drug has been granted eligibility for indexing.
(b) A requestor shall submit two copies of a dated request signed by the authorized contact for addition of a new animal drug to the index that contains the following:
(1) A copy of FDA’s determination of eligibility issued under § 516.137;
(2) A copy of FDA’s written determination that the proposed qualified expert panel meets the selection criteria provided for in § 516.141(b);
(3) A written report that meets the requirements of § 516.143;
(4) A proposed index entry that contains the information described in § 516.157;
(5) Proposed labeling, including representative labeling proposed to be used for Type B and Type C medicated feeds if the drug is intended for use in the manufacture of medicated feeds;
(6) Anticipated annual distribution of the new animal drug, in terms of the total quantity of active ingredient, after indexing;
(7) A written commitment to manufacture the new animal drug and animal feeds bearing or containing such new animal drug according to current good manufacturing practices;
(8) A written commitment to label, distribute, and promote the new animal drug only in accordance with the index entry;
(9) The name and address of the contact person or permanent-resident U.S. agent; and
(10) A draft Freedom of Information summary which includes the following information:
(i) A general information section that contains the name and address of the requestor and a description of the drug, route of administration, indications, and recommended dosage.
(ii) A list of the names and affiliations of the members of the qualified expert panel, not including their addresses or other contact information.
(iii) A summary of the findings of the qualified expert panel concerning the target animal safety and effectiveness of the drug.
(iv) Citations of all publicly-available literature considered by the qualified expert panel.
(v) For an early life stage of a food-producing minor species animal, a human food safety summary.
(c) Upon specific request by FDA, the requestor shall submit the information described in § 516.141 that it submitted to the qualified expert panel. Any such information not in English should be accompanied by an English translation.
§ 516.147 Refuse to file a request for addition to the index.
(a) If a request for addition to the index contains all of the information required by § 516.145(b), FDA shall file it, and the filing date shall be the date FDA receives the request.
(b) If a request for addition to the index lacks any of the information required by § 516.145, FDA will not file it, but will inform the requestor in writing within 30 days of receiving the request as to what information is lacking.
§ 516.149 Denying a request for addition to the index.
(a) FDA will deny a request for addition to the index if it finds the following:
(1) The same drug in the same dosage form for the same intended use is already approved or conditionally approved;
(2) On the basis of new information, the new animal drug no longer meets the conditions for eligibility for indexing;
(3) The request for indexing fails to contain information required under the provisions of § 516.145;
(4) The qualified expert panel fails to meet any of the selection criteria listed in § 516.141(b);
(5) The written report of the qualified expert panel and other information available to FDA is insufficient to permit FDA to determine that the benefits of using the new animal drug for the proposed use in a minor species outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;
(6) On the basis of the report of the qualified expert panel and other information available to FDA, the benefits of using the new animal drug for the proposed use in a minor species do not outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question; or
(7) The request contains any untrue statement of a material fact or omits material information.
(b) When a request for addition to the index is denied, FDA will notify the requestor in accordance with § 516.153.
§ 516.151 Granting a request for addition to the index.
(a) FDA will grant the request for addition of a new animal drug to the index if none of the reasons described in § 516.149 for denying such a request applies.
(b) When a request for addition of a new animal drug to the index is granted, FDA will notify the requestor in accordance with § 516.153.
§ 516.153 Notification of decision regarding index listing.
(a) Within 180 days after the filing of a request for addition of a new animal drug to the index, FDA shall grant or deny the request and notify the requestor of FDA’s decision in writing.
(b) If FDA denies the request for addition of a new animal drug to the index, FDA shall provide due notice and an opportunity for an informal conference as described in § 516.123. A decision of FDA to deny a request to index a new animal drug following an informal conference shall constitute final agency action subject to judicial review.
§ 516.155 Labeling of indexed drugs.
(a) The labeling of an indexed drug that is found to be eligible for indexing under § 516.129(c)(7)(i) shall state, prominently and conspicuously: “LEGAL STATUS—In order to be legally marketed, a new animal drug intended for a minor species must be Approved, Conditionally Approved, or Indexed by the Food and Drug Administration. THIS PRODUCT IS INDEXED—MIF # (followed by the applicable minor species index file number and a period).” “Extra-label use is prohibited.” “This product is not to be used in animals intended for use as food for humans or food-producing animals.”
(b) The labeling of an indexed drug that is found to be eligible for indexing for use in an early, non-food life stage of a food-producing minor species animal, under § 516.129(c)(7)(ii), shall state, prominently and conspicuously: “LEGAL STATUS—In order to be legally marketed, a new animal drug intended for a minor species must be Approved, Conditionally Approved, or Indexed by the Food and Drug Administration. THIS PRODUCT IS INDEXED—MIF # (followed by the applicable minor species index file number and a period).” “Extra-label use is prohibited.”
(c) The labeling of an indexed drug shall contain such other information as may be prescribed in the index listing.
§ 516.157 Publication of the index and content of an index listing.
(a) FDA will make the list of indexed drugs available through the FDA Web site at http://www.fda.gov. A printed copy can be obtained by writing to the Freedom of Information Staff or by visiting FDA’s Freedom of Information Staff’s Public Reading Room at the address listed on the Agency’s Web site at http://www.fda.gov.
(b) The list will contain the following information for each indexed drug:
(1) The name and address of the person who holds the index listing;
(2) The name of the drug and the intended use and conditions of use for which it is indexed;
(3) Product labeling; and
(4) Conditions and any limitations that FDA deems necessary regarding use of the drug.
§ 516.161 Modifications to indexed drugs.
(a) After a drug is listed in the index, certain modifications to the index listing may be requested. Any modification of an index listing may not cause an indexed drug to be a different drug (or different combination of drugs) or a different dosage form. If such modification is requested, FDA will notify the holder that a new index listing is required for the new drug or dosage form.
(b) Modifications to the indexed drug will fall under one of three categories and must be submitted as follows:
(1) Urgent changes. (i) The following modifications to an indexed drug or its labeling should be made as soon as possible, and a request to modify the indexed drug should be concurrently submitted:
(A) The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, side effect, or cautionary information.
(B) The deletion from package labeling, promotional labeling, and drug advertising of false, misleading, or unsupported indications for use or claims for effectiveness.
(C) Changes in manufacturing methods or controls required to correct product or manufacturing defects that may result in serious adverse drug events.
(ii) The modifications described in paragraph (b)(1)(i) of this section must be submitted to the Director, OMUMS, in the form of a request for modification of an indexed drug, and must contain sufficient information to permit FDA to determine the need for the modification and whether the modification appropriately addresses the need.
(iii) FDA will take no action against an indexed drug or index holder solely because modifications of the kinds described in paragraph (b)(1)(i) of this section are placed into effect by the holder prior to receipt of a written notice granting the request if all the following conditions are met:
(A) A request to modify the indexed drug providing a full explanation of the basis for the modifications has been submitted, plainly marked on the mailing cover and on the request as follows: “Special indexing request— modifications being effected;”
(B) The holder specifically informs FDA of the date on which such modifications are to be effected and submits two printed copies of any revised labeling to be placed in use, and
(C) All promotional labeling and all drug advertising are promptly revised consistent with modifications made in the labeling on or within the indexed drug package.
(2) Significant changes. (i) The following modifications to an indexed drug or its labeling may be made only after a request has been submitted to and subsequently granted by FDA:
(A) Addition of an intended use.
(B) Addition of a species.
(C) Addition or alteration of an active ingredient.
(D) Alteration of the concentration of an active ingredient.
(E) Alteration of dose or dosage regimen.
(F) Alteration of prescription or over-the-counter status.
(ii) Each modification described in paragraph (b)(2)(i) of this section must go through the same review process as an original index listing and is subject to the same standards for review.
(iii) Each submission of a request for a modification described in paragraph (b)(2)(i) of this section should contain only one type of modification unless one modification is actually necessitated by another, such as a modification of dose necessitated by a modification of the concentration of an active ingredient. Submissions relating to addition of an intended use for an existing species or addition of a species should be submitted separately, but each such submission may include multiple additional intended uses and/or multiple additional species.
(3) Minor changes. All modifications other than those described in paragraphs (b)(1) and (b)(2) of this section including, but not limited to, formulation, labeling, and manufacturing methods and controls (at the same level of detail that these were described in the request for determination of eligibility for indexing) must be submitted as part of the annual indexed drug experience report or as otherwise required by § 516.165.
(c) When changes affect the index listing, it will be updated accordingly.
§ 516.163 Change in ownership of an index file.
(a) A holder may transfer ownership of a drug’s index file to another person.
(1) The former owner shall submit in writing to FDA a statement that all rights in the index file have been transferred, giving the name and address of the new owner and the date of the transfer. The former owner shall also certify that a complete copy of the following, to the extent that they exist at the time of the transfer of ownership, has been provided to the new owner:
(i) The request for determination of eligibility;
(ii) The request for addition to the index;
(iii) Any modifications to the index listing;
(iv) Any records and reports under § 516.165; and
(v) All correspondence with FDA relevant to the indexed drug and its index listing.
(2) The new owner shall submit the following information in writing to FDA:
(i) The date that the change in ownership is effective;
(ii) A statement that the new owner has a complete copy of all documents listed in paragraph (a)(1) of this section to the extent that they exist at the time of the transfer of ownership;
(iii) A statement that the new owner understands and accepts the responsibilities of a holder of an indexed drug;
(iv) The name and address of a new primary contact person or permanent-resident U.S. agent; and
(v) A list of labeling changes associated with the change of ownership (e.g., a new trade name) as draft labeling, with complete final printed labeling to be submitted in the indexed drug annual report in accordance with §§ 516.161 and 516.165.
(b) Upon receiving the necessary information to support a change of ownership of a drug’s index file, FDA will update its publicly-available listing in accordance with § 516.157.
§ 516.165 Records and reports.
(a) Scope and purpose. (1) The recordkeeping and reporting requirements of this section apply to all holders of indexed drugs, including indexed drugs intended for use in medicated feeds.
(2) A holder is not required to report information under this section if the holder has reported the same information under § 514.80 of this chapter.
(3) The records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations in parts 211, 225, and 226 of this chapter.
(4) FDA will review the records and reports required in this section to determine, or facilitate a determination, whether there may be grounds for removing a drug from the index under section 572(f) of the act.
(b) Recordkeeping requirements. (1) Each holder of an indexed drug must establish and maintain complete files containing full records of all information pertinent to the safety or effectiveness of the indexed drug. Such records must include information from foreign and domestic sources.
(2) The holder must, upon request from any authorized FDA officer or employee, at all reasonable times, permit such officer or employee to have access to copy and to verify all such records.
(c) Reporting requirements—(1) Three-day indexed drug field alert report. The holder must inform the appropriate FDA District Office or local FDA resident post of any product or manufacturing defects that may result in serious adverse drug events within 3 working days of first becoming aware that such a defect may exist. The holder may initially provide this information by telephone or other electronic communication means, with prompt written followup. The mailing cover must be plainly marked “3-Day Indexed Drug Field Alert Report.”
(2) Fifteen-day indexed drug alert report. The holder must submit a report on each serious, unexpected adverse drug event, regardless of the source of the information. The holder must submit the report within 15 working days of first receiving the information. The mailing cover must be plainly marked “15-Day Indexed Drug Alert Report.”
(3) Annual indexed drug experience report. The holder must submit this report every year on the anniversary date of the letter granting the request for addition of the new animal drug to the index, or within 60 days thereafter. The report must contain data and information for the full reporting period. Any previously submitted information contained in the report must be identified as such. The holder may ask FDA to change the date of submission and, after approval of such request, file such reports by the new filing date. The report must contain the following:
(i) The number of distributed units of each size, strength, or potency (e.g., 100,000 bottles of 100 5-milligram tablets; 50,000 10-milliliter vials of 5- percent solution) distributed during the reporting period. This information must be presented in two categories: Quantities distributed domestically and quantities exported. This information must include any distributor-labeled product.
(ii) If the labeling has changed since the last report, include a summary of those changes and the holder’s and distributor’s current package labeling, including any package inserts. For large-size package labeling or large shipping cartons, submit a representative copy (e.g., a photocopy of pertinent areas of large feed bags). If the labeling has not changed since the last report, include a statement of such fact.
(iii) A summary of any changes made during the reporting period in the methods used in, and facilities and controls used for, manufacture, processing, and packing. This information must be presented in the same level of detail that it was presented in the request for determination of eligibility for indexing. Do not include changes that have already been submitted under § 516.161.
(iv) Nonclinical laboratory studies and clinical data not previously reported under this section.
(v) Adverse drug experiences not previously reported under this section.
(vi) Any other information pertinent to safety or effectiveness of the indexed drug not previously reported under this section.
(4) Distributor’s statement. At the time of initial distribution of an indexed drug by a distributor, the holder must submit a report containing the following:
(i) The distributor’s current product labeling. This must be identical to that in the index listing except for a different and suitable proprietary name (if used) and the name and address of the distributor. The name and address of the distributor must be preceded by an appropriate qualifying phrase such as “manufactured for” or “distributed by.”
(ii) A signed statement by the distributor stating:
(A) The category of the distributor’s operations (e.g., wholesale or retail);
(B) That the distributor will distribute the drug only under the indexed drug labeling;
(C) That the distributor will promote the indexed drug only for use under the conditions stated in the index listing; and
(D) If the indexed drug is a prescription new animal drug, that the distributor is regularly and lawfully engaged in the distribution or dispensing of prescription products.
(5) Other reporting. FDA may by order require that a holder submit information in addition to that required by this section or that the holder submit the same information but at different times or reporting periods.
§ 516.167 Removal from the index.
(a) After due notice to the holder of the index listing and an opportunity for an informal conference as described in § 516.123, FDA shall remove a new animal drug from the index if FDA finds that:
(1) The same drug in the same dosage form for the same intended use has been approved or conditionally approved;
(2) The expert panel failed to meet the requirements in § 516.141;
(3) On the basis of new information before FDA, evaluated together with the evidence available to FDA when the new animal drug was listed in the index, the benefits of using the new animal drug for the indexed use do not outweigh its risks to the target animal, taking into account the harm caused by the absence of an approved or conditionally-approved new animal drug for the minor species in question;
(4) Any of the conditions in § 516.133(a)(2), (5), or (6) are present;
(5) The manufacture of the new animal drug is not in accordance with current good manufacturing practices;
(6) The labeling, distribution, or promotion of the new animal drug is not in accordance with the index listing;
(7) The conditions and limitations of use associated with the index listing have not been followed; or
(8) Any information used to support the request for addition to the index contains any untrue statement of material fact.
(b) The agency may partially remove an indexing listing if, in the opinion of the agency, such partial removal would satisfactorily resolve a safety or effectiveness issue otherwise warranting removal of the listing under section 572(f)(1)(B) of the act.
(c) FDA may immediately suspend a new animal drug from the index if FDA determines that there is a reasonable probability that the use of the drug would present a risk to the health of humans or other animals. The agency will subsequently provide due notice and an opportunity for an informal conference as described in § 516.123.
(d) A decision of FDA to remove a new animal drug from the index following an informal conference, if any, shall constitute final agency action subject to judicial review.
§ 516.171 Confidentiality of data and information in an index file.
(a) For purposes of this section, the index file includes all data and information submitted to or incorporated by reference into the index file, such as data and information related to investigational use exemptions under § 516.125, requests for determination of eligibility for indexing, requests for addition to the index, modifications to indexed drugs, changes in ownership, reports submitted under § 516.165, and master files. The availability for public disclosure of any record in the index file shall be handled in accordance with the provisions of this section.
(b) The existence of an index file will not be disclosed by FDA before an index listing has been made public by FDA, unless it has previously been publicly disclosed or acknowledged by the requestor.
(c) If the existence of an index file has not been publicly disclosed or acknowledged, no data or information in the index file are available for public disclosure.
(d) If the existence of an index file has been publicly disclosed or acknowledged before an index listing has been made public by FDA, no data or information contained in the file will be available for public disclosure before such index listing is made public, but the agency may, at its discretion, disclose a brief summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.
(e) After FDA sends a written notice to the requestor granting a request for addition to the index, the following data and information in the index file are available for public disclosure unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information previously disclosed to the public, as defined in § 20.81 of this chapter.
(2) A summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the index file. Such summaries do not constitute the full information described under section 572(c) and (d) of the act on which the safety or effectiveness of the drug may be determined. Such summaries will be based on the draft Freedom of Information summary submitted under § 516.145, which will be reviewed and, where appropriate, revised by FDA.
(3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61 of this chapter.
(4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of the following:
(i) Names and any information that would identify the person using the product.
(ii) Names and any information that would identify any third party involved with the report, such as a veterinarian.
(5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as defined in § 20.81 of this chapter.
(6) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established in § 20.61 of this chapter.
(7) All correspondence and written summaries of oral discussions relating to the index file, in accordance with the provisions of part 20 of this chapter.
(f) The following data and information in an index file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter, or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control procedures.
(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(g) Subject to the disclosure provisions of this section, the agency shall regard the contents of an index file as confidential information unless specifically notified in writing by the holder of the right to disclose, to reference, or otherwise utilize such information on behalf of another named person.
(h) For purposes of this regulation, safety and effectiveness data include all studies and tests of an animal drug on animals and all studies and tests on the animal drug for identity, stability, purity, potency, and bioavailability.
(i) Safety and effectiveness data and information that have not been previously disclosed to the public are available for public disclosure at the time any of the following events occurs unless extraordinary circumstances are shown:
(1) No work is being or will be undertaken to have the drug indexed in accordance with the request.
(2) A final determination is made that the drug cannot be indexed and all legal appeals have been exhausted.
(3) The drug has been removed from the index and all legal appeals have been exhausted.
(4) A final determination has been made that the animal drug is not a new animal drug.
Subpart D [Reserved]
Subpart E—Conditionally Approved New Animal Drugs For Minor Use and Minor Species
§ 516.498 Crofelemer.
(a) Specifications. Each delayed-release tablet contains 125 milligrams (mg) crofelemer.
(b) Sponsor. See No. 086149 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer 1 tablet orally twice daily for 3 days for dogs weighing ≤140 pounds. Administer 2 tablets orally twice daily for 3 days for dogs weighing >140 pounds.
(2) Indications for use. For the treatment of chemotherapy-induced diarrhea in dogs.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.1012 Fuzapladib.
(a) Specifications. The drug is provided as a powder for injection that is reconstituted with 3.5 milliliter (mL) of provided diluent to a final concentration of 4 milligrams (mg) fuzapladib sodium per mL.
(b) Sponsor. See No. 064642 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer at a dosage of 0.4 mg (0.1 mL) per kilogram of body weight once daily for 3 consecutive days by intravenous (IV) injection over 15 seconds to 1 minute.
(2) Indications for use in dogs. For the management of clinical signs associated with acute onset of pancreatitis in dogs.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.1449 Molidustat oral suspension.
(a) Specifications. Each milliliter (mL) of suspension contains 25 milligrams (mg) molidustat sodium.
(b) Sponsor. See No. 058198 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer orally at a dosage of 5 mg/kg of body weight (2.3 mg/lb) daily for up to 28 consecutive days.
(2) Indications for use. For the control of nonregenerative anemia associated with chronic kidney disease in cats.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.1760 Phenobarbital.
(a) Specifications. Each tablet contains 15, 16.2, 30, 32.4, 60, 64.8, 97.2 or 100 milligrams (mg) phenobarbital.
(b) Sponsor. See No. 064950 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer phenobarbital as tablets given orally twice a day at the minimum dosage of 2.5 mg per kilogram of body weight (mg/kg) and may be titrated to effect to a maximum dosage of 5 mg/kg. The dosage of phenobarbital tablets should be adjusted based on monitoring the clinical response of the individual patient.
(2) Indications for use. For the control of seizures associated with idiopathic epilepsy in dogs.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.1780 Pimobendan.
(a) Specifications. Each chewable tablet contains 1.25, 2.5, 5, or 10 milligrams (mg) pimobendan.
(b) Sponsor. See No. 000010 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer orally at a total daily dose of 0.23 mg per pound (0.5 mg per kilogram) body weight, using a suitable combination of whole or half tablets. The total daily dose should be divided into two portions administered approximately 12 hours apart.
(2) Indications for use in dogs. For the delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease (2019 ACVIM Consensus Statement). Stage B2 preclinical myxomatous mitral valve disease (MMVD) refers to dogs with asymptomatic MMVD that have a moderate or loud mitral murmur due to mitral regurgitation and cardiomegaly.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.1858 Potassium bromide.
(a) Specifications. Each chewable tablet contains 250 or 500 milligrams (mg) potassium bromide.
(b) Sponsor. See No. 055246 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer 25 to 68 mg per kilogram (11 to 31 mg per pound) of body weight once daily. The dosage can be divided and should be adjusted to clinical response.
(2) Indications for use. For the control of seizures associated with idiopathic epilepsy in dogs.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.2475 Torsemide.
(a) Specifications. Each milliliter of solution contains 0.2 milligrams (mg) torsemide.
(b) Sponsor. See No. 017030 in § 510.600(c) of this chapter.
(c) Conditions of use in dogs—(1) Amount. Administer orally once daily at a dose of 0.05 to 0.2 mg/lb (0.11 to 0.44 mg/kg) of bodyweight.
(2) Indications for use. For use as concurrent therapy with pimobendan, spironolactone, and an angiotensin converting enzyme (ACE) inhibitor for the management of pulmonary edema in dogs with congestive heart failure caused by myxomatous mitral valve disease (MMVD).
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
§ 516.2980 Verdinexor.
(a) Specifications. Each tablet contains 2.5, 10, or 50 milligrams (mg) verdinexor.
(b) Sponsor. See No. 086121 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer verdinexor tablets orally at an initial dose of 1.25 mg per kilogram (mg/kg) of body weight twice per week with at least 72 hours between doses. If tolerated after 2 weeks, increase the dose to 1.5 mg/kg twice per week with at least 72 hours between doses.
(2) Indications for use. For the treatment of lymphoma in dogs.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian. It is a violation of Federal law to use this product other than as directed in the labeling.
PART 520—ORAL DOSAGE FORM NEW ANIMAL DRUGS
§ 520.23 Acepromazine.
(a) Specifications. Each tablet contains 10 or 25 milligrams (mg) acepromazine maleate.
(b) Sponsors. See Nos. 000010 and 086117 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Dogs—(i) Amount. 0.25 to 1.0 mg per pound (/lb) body weight orally.
(ii) Indications for use. As an aid in tranquilization and as a preanesthetic agent.
(iii) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
(2) Cats—(i) Amount. 0.5 to 1.0 mg/lb body weight orally.
(ii) Indications for use. As a tranquilizer.
(iii) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.28 Acetazolamide.
(a) Specifications. A powder containing acetazolamide sodium, USP equivalent to 25 percent acetazolamide activity.
(b) Sponsor. See No. 054771 in § 510.600(c) of this chapter.
(c) Conditions of use in dogs—(1) Amount. Administer orally at a dosage of 5 to 15 milligrams per pound of body weight daily.
(2) Indications for use. As an aid in the treatment of mild congestive heart failure and for rapid reduction of intraocular pressure.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.35 Afoxolaner, moxidectin, and pyrantel.
(a) Specifications. Each chewable tablet contains 9.375 milligrams (mg) afoxolaner, 45 micrograms (mcg) moxidectin, and 18.75 mg pyrantel; 18.75 mg afoxolaner, 90 mcg moxidectin, and 37.5 mg pyrantel; 37.5 mg afoxolaner, 180 mcg moxidectin, and 75 mg pyrantel; 75 mg afoxolaner, 360 mcg moxidectin, and 150 mg pyrantel; or 150 mg afoxolaner, 720 mcg moxidectin, and 300 mg pyrantel.
(b) Sponsor. See No. 000010 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer orally once a month at the minimum dose of 1.14 mg/lb (2.5 mg/kg) afoxolaner, 5.45 mcg/lb (12 mcg/kg) moxidectin, and 2.27 mg/lb (5.0 mg/kg) pyrantel. For heartworm disease prevention, give once monthly for at least 6 months after last exposure to mosquitoes.
(2) Indications for use in dogs. For the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of adult hookworm (Ancylostoma caninum, Ancylostoma braziliense, and Uncinaria stenocephala) and roundworm (Toxocara canis and Toxascaris leonina) infections. Kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), Dermacentor variabilis (American dog tick), and Amblyomma americanum (lone star tick) infestations for 1 month in dogs and puppies 8 weeks of age and older, weighing 4 pounds of body weight or greater.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.38 Albendazole oral dosage forms.
§ 520.38a Albendazole suspension.
(a) Specifications. Each milliliter of suspension contains 45.5 milligrams (mg) (4.55 percent) or 113.6 mg (11.36 percent) albendazole.
(b) Sponsor. See No. 054771 in § 510.600 of this chapter.
(c) Related tolerances. See § 556.34 of this chapter.
(d) Special considerations. See § 500.25 of this chapter.
(e) Conditions of use—(1) Cattle. Administer 11.36 percent suspension:
(i) Amount. 4.54 mg/pound (lb) body weight (10 mg/kilogram (kg)) as a single oral dose using dosing gun or dosing syringe.
(ii) Indications for use. For removal and control of adult liver flukes (Fasciola hepatica); heads and segments of tapeworms (Moniezia benedeni and M. expansa); adult and 4th stage larvae of stomach worms (brown stomach worms including 4th stage inhibited larvae (Ostertagia ostertagi), barberpole worm (Haemonchus contortus and H. placei), small stomach worm (Trichostrongylus axei)); adult and 4th stage larvae of intestinal worms (thread-necked intestinal worm (Nematodirus spathiger and N. helvetianus), small intestinal worm (Cooperia punctata and C. oncophora)); adult stages of intestinal worms (hookworm (Bunostomum phlebotomum), bankrupt worm (Trichostrongylus colubriformis), nodular worm (Oesophagostomum radiatum)); adult and 4th stage larvae of lungworms (Dictyocaulus viviparus).
(iii) Limitations. Do not slaughter within 27 days of last treatment. Do not use in female dairy cattle of breeding age: Do not administer to female cattle during first 45 days of pregnancy or for 45 days after removal of bulls.
(2) Sheep. Administer 4.45 or 11.36 percent suspension:
(i) Amount. 3.4 mg/lb body weight (7.5 mg/kg) as a single oral dose using dosing gun or dosing syringe.
(ii) Indications for use. For removal and control of adult liver flukes (Fasciola hepatica and Fascioloides magna); heads and segments of common tapeworms (Moniezia expansa) and fringed tapeworm (Thysanosoma actinioides); adult and fourth stage larvae of stomach worms (brown stomach worm (Ostertagia circumcinta and Marshallagia marshalli), barberpole worm (Haemonchus contortus), small stomach worm (Trichostrongylus axei)); adult and fourth stage larvae of intestinal worms (thread-necked intestinal worm (Nematodirus spathiger and N. filicollis), Cooper’s worm (Cooperia oncophora), bankrupt worm (Trichostrongylus colubriformis), nodular worm (Oesophagostomum columbianum), and large-mouth bowel worm (Chabertia ovina)); adult and larval stages of lungworms (Dictyocaulus filaria).
(iii) Limitations. Do not slaughter within 7 days of last treatment. Do not administer to ewes during first 30 days of pregnancy or for 30 days after removal of rams.
(3) Goats. Administer 11.36 percent suspension:
(i) Amount. 4.54 mg/lb body weight (10 mg/kg) as a single oral dose using dosing gun or dosing syringe.
(ii) Indications for use. For the treatment of adult liver flukes (Fasciola hepatica) in nonlactating goats.
(iii) Limitations. Do not slaughter within 7 days of last treatment. Do not administer to does during the first 30 days of pregnancy or for 30 days after removal of bucks.
§ 520.38b Albendazole paste.
(a) Specifications. The product contains 30 percent albendazole.
(b) Sponsor. See No. 054771 in § 510.600(c) of this chapter.
(c) Related tolerances. See § 556.34 of this chapter.
(d) Conditions of use in cattle—(1) Amount. Equivalent to 4.54 milligrams per 1 pound of body weight (10 milligrams per kilogram).
(2) Indications for use. For removal and control of the following internal parasites of cattle: adult liver flukes (Fasciola hepatica); heads and segments of tapeworms (Moniezia benedeni, M. expansa); adult and 4th stage larvae of stomach worms (brown stomach worms including 4th stage inhibited larvae (Ostertagia ostertagi); barberpole worm (Haemonchus contortus, H. placei); small stomach worm (Trichostrongylus axei)); adult and 4th stages larvae of intestinal worms (thread-necked intestinal worm (Nematodirus spathiger, N. helvetianus); small intestinal worm (Cooperia punctata and C. oncophora)); adult stages of intestinal worms (hookworm (Bunostomum phlebotmum); bankrupt worm (Trichostrongylus colubriformis), nodular worm (Oesophagostomum radiatum)); adult and 4th stage larvae of lungworms (Dictyocaulus viviparus).
(3) Limitations. Administer as a single oral dose. Do not slaughter within 27 days of last treatment. Do not use in female dairy cattle of breeding age. Do not administer to female cattle during first 45 days of pregnancy or for 45 days after removal of bulls. Consult your veterinarian for assistance in the diagnosis, treatment, and control of parasitism.
§ 520.43 Afoxolaner.
(a) Specifications. Each chewable tablet contains 11.3, 28.3, 68, or 136 milligrams (mg) afoxolaner.
(b) Sponsor. See No. 000010 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Amount. Administer orally once a month at a minimum dosage of 1.14 mg/pound (2.5 mg/kilogram).
(2) Indications for use. Kills adult fleas and for the treatment and prevention of flea infestations (Ctenocephalides felis); and the treatment and control of Ixodes scapularis (black-legged tick), Dermacentor variabilis (American dog tick), Amblyomma americanum (lone star tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick) infestations in dogs and puppies 8 weeks of age and older, weighing 4 pounds of body weight or greater, for 1 month; and for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.48 Altrenogest.
(a) Specifications. Each milliliter (mL) of solution contains 2.2 milligrams (mg) altrenogest.
(b) Sponsors. See sponsors in § 510.600(c) of this chapter:
(1) Nos. 000061 and 051072 for use as in paragraph (d) of this section.
(2) No. 061133 for use as in paragraph (d)(1) of this section.
(3) No. 013744 for use as in paragraph (d)(2) of this section.
(c) Tolerances. See § 556.36 of this chapter.
(d) Conditions of use—(1) Horses—(i) Amount. 1.0 mL per 110 pounds body weight (0.044 mg/kg) daily for 15 consecutive days.
(ii) Indications for use. For suppression of estrus in mares.
(iii) Limitations. Do not use in horses intended for human consumption. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
(2) Swine—(i) Amount. Administer 6.8 mL (15 mg altrenogest) per gilt once daily for 14 consecutive days by top-dressing on a portion of each gilt’s daily feed.
(ii) Indications for use. For synchronization of estrus in sexually mature gilts that have had at least one estrous cycle.
(iii) Limitations. Do not use in gilts having a previous or current history of uterine inflammation (i.e., acute, subacute or chronic endometritis). Gilts must not be slaughtered for human consumption for 21 days after the last treatment.
§ 520.62 Aminopentamide.
(a) Specifications. Each tablet contains 0.2 milligram (mg) aminopentamide hydrogen sulphate.
(b) Sponsor. See No. 054771 in § 510.600(c) of this chapter.
(c) Conditions of use in dogs and cats—(1) Amount. Administer orally every 8 to 12 hours as follows: For animals weighing up to 10 pounds (lbs): 0.1 mg; for animals weighing 11 to 20 lbs: 0.2 mg; for animals weighing 21 to 50 lbs: 0.3 mg; for animals weighing 51 to 100 lbs: 0.4 mg; for animal weighing over 100 lbs: 0.5 mg. Dosage may be gradually increased up to a maximum of five times the suggested dosage. Oral administration of tablets may be preceded by subcutaneous or intramuscular use of the injectable form of the drug.
(2) Indications for use. For the treatment of vomiting and/or diarrhea, nausea, acute abdominal visceral spasm, pylorospasm, or hypertrophic gastritis.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.82 Aminopropazine oral dosage forms.
§ 520.82a Aminopropazine.
(a) Specifications. Each tablet contains aminopropazine fumarate equivalent to 25 percent aminopropazine base.
(b) Sponsor. See No. 000061 in § 510.600(c) of this chapter.
(c) Conditions of use in dogs and cats—(1) Amount. Administer orally at a dosage of 1 to 2 milligrams per pound of body weight, repeated every 12 hours as indicated.
(2) Indications for use. For reducing excessive smooth muscle contractions, such as occur in urethral spasms associated with urolithiasis.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.82b Aminopropazine and neomycin.
(a) Specifications. Each tablet contains aminopropazine fumarate equivalent to 25 percent aminopropazine base and neomycin sulfate equivalent to 50 milligrams (mg) of neomycin base.
(b) Sponsor. See No. 000061 in § 510.600(c) of this chapter.
(c) Conditions of use in dogs—(1) Amount. Administer orally at a dosage of 1 to 2 mg per pound of body weight, repeated every 12 hours as indicated.
(2) Indications for use. For control of bacterial diarrhea caused by organisms susceptible to neomycin and to reduce smooth muscle contractions.
(3) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.88 Amoxicillin oral dosage forms.
§ 520.88a Amoxicillin trihydrate film-coated tablets.
(a) Specifications. Each tablet contains amoxicillin trihydrate equivalent to 50, 100, 150, 200, or 400 milligrams (mg) amoxicillin.
(b) Sponsor. See No. 054771 in § 510.600(c) of this chapter.
(c) Conditions of use—(1) Dogs—(i) Amount. Administer orally 5 mg per pound (/lb) of body weight, twice a day for 5 to 7 days.
(ii) Indications for use. Treatment of infections of the respiratory tract (tonsillitis, tracheobronchitis), genitourinary tract (cystitis), gastrointestinal tract (bacterial gastroenteritis), and soft tissues (abscesses, lacerations, wounds), caused by susceptible strains of Staphylococcus aureus, Streptococcus spp., Escherichia coli, Proteus mirabilis, and bacterial dermatitis caused by S. aureus, Streptococcus spp., and P. mirabilis.
(iii) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
(2) Cats—(i) Amount. Administer orally 5 to 10 mg/lb of body weight, once daily for 5 to 7 days.
(ii) Indications for use. Treatment of infections caused by susceptible organisms as follows: upper respiratory tract due to S. aureus, Streptococcus spp., and E. coli; genitourinary tract (cystitis) due to S. aureus, Streptococcus spp., E. coli, and P. mirabilis; gastrointestinal tract due to E. coli; and skin and soft tissue (abscesses, lacerations, and wounds) due to S. aureus, Streptococcus spp., E. coli, and Pasteurella multocida.
(iii) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
§ 520.88b Amoxicillin trihydrate for oral suspension.
(a) Specifications. When reconstituted, each milliliter contains amoxicillin trihydrate equivalent to 50 milligrams (mg) amoxicillin.
(b) Sponsor. See No. 054771 in § 510.600(c) of this chapter.
(1) Conditions of use—(i) Dogs—(A) Amount. Administer orally 5 mg per pound (/lb) of body weight, twice a day for 5 to 7 days.
(B) Indications for use. Treatment of infections caused by susceptible strains of organisms as follows: respiratory tract (tonsillitis, tracheobronchitis) caused by Staphylococcus aureus, Streptococcus spp., Escherichia coli, and Proteus mirabilis; genitourinary tract (cystitis) caused by S. aureus, Streptococcus spp., E. coli, and P. mirabilis; gastrointestinal tract (bacterial gastroenteritis) caused by S. aureus, Streptococcus spp., E. coli, and P. mirabilis; bacterial dermatitis caused by S. aureus, Streptococcus spp., and P. mirabilis; and soft tissues (abscesses, lacerations, and wounds) caused by S. aureus, Streptococcus spp., E. coli, and P. mirabilis.
(C) Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.
(ii) Cats—(A) Amount. Administer orally 5 to 10 mg/lb of body weight, once daily for 5 to 7 days.
(B) Indications for use. Treatment of infections caused b