The provisions of part 113 of this chapter shall apply to the manufacture, processing or packing of low-acid foods in hermetically sealed containers, and intended for use as food for animals.

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.

(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 (d) and (e) of this chapter. For animal feeds bearing or containing anthelmintic drugs covered by approved applications, the labeling revisions required for compliance with this section may be placed into effect without the submission of supplemental applications as provided for in § 514.9 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.

(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 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 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.

(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.

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.

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).

(a) Investigations by the Food and Drug Administration, the Centers for Disease Control of the U.S. Public Health Service, the Animal Health Division of the Agricultural Research Service, U.S. Department of Agriculture, and by various State public health agencies have revealed that processed fish meal, poultry meal, meat meal, tankage, and other animal byproducts intended for use in animal feed may be contaminated with Salmonella bacteria, an organism pathogenic to man and animals. Contamination of these products may occur through inadequate heat treatment of the product during its processing or through recontamination of the heat-treated product during a time of improper storage or handling subsequent to processing.

(b) Articles used in food for animals are included within the definition of food in section 201(f) of the Federal Food, Drug, and Cosmetic Act. Further, Salmonella contamination of such animal feeds having the potentiality for producing infection and disease in animals must be regarded as an adulterant within the meaning of section 402(a) of the act. Therefore, the Food and Drug Administration will regard as adulterated within the meaning of section 402(a) of the act shipments of the following when intended for animal feed and encountered in interstate commerce and found upon examination to be contaminated with Salmonella microorganisms: Bone meal, blood meal, crab meal, feather meal, fish meal, fish solubles, meat scraps, poultry meat meal, tankage, or other similar animal byproducts, or blended mixtures of these.

(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.

(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.

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.

(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.

(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.

(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:

(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.

(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. FDA guidance documents contain the procedures and protocols FDA recommends for the implementation of this subpart. These guidance documents are available from the Division of Dockets Management (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 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 act for risks other than cancer.

(d) This subpart does not apply to essential nutrients.

(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 Sm.

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 m means the concentration of the marker residue in the target tissue when the residue of carcinogenic concern is equal to Sm.

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 m means the concentration of residue in a specific edible tissue corresponding to a maximum lifetime risk of cancer in the test animals of 1 in 1 million.

S o means the concentration of the test compound in the total diet of test animals that corresponds to a maximum lifetime risk of cancer in the test animals of 1 in 1 million. For the purpose of this subpart, FDA will also assume that this So will correspond to the concentration of residue of carcinogenic concern in the total human diet that represents no significant increase in the risk of cancer to people.

Sponsor means the person or organization proposing or holding an approval by FDA for the use of a sponsored compound.

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.

(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 analyze the data from the bioassays using a statistical extrapolation procedure.

(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 So. Because the total diet is not derived from food-producing animals, FDA will make corrections for food intake. FDA will designate as Sm the concentration of residue in a specific edible tissue corresponding to a maximum lifetime risk of cancer in test animals of 1 in 1 million.

(2) From the appropriate residue chemistry data FDA will calculate the Rm as described in § 500.86(c). The sponsor must provide a regulatory method in accordance with § 500.88(b). FDA will calculate the LOD of the method from data submitted by the sponsor under § 500.88. The LOD must be less than or equal to Rm.

(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.

(a) For each edible tissue, the sponsor shall measure the depletion of the residue of carcinogenic concern until its concentration is at or below Sm.

(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 Sm.

(c) From these data, FDA will select a target tissue and a marker residue and designate the concentration of marker residue (Rm) that the regulatory method must be capable of measuring in the target tissue. FDA will select Rm such that the absence of the marker residue in the target tissue above Rm can be taken as confirmation that the residue of carcinogenic concern does not exceed Sm in each of the edible tissues and, therefore, that the residue of carcinogenic concern in the diet of people does not exceed So.

(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.

(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 Rm. FDA will determine the LOD from the submitted analytical method validation data.

(c) FDA will publish in the Federal Register the complete regulatory method for ascertaining the marker residue in the target tissue in accordance with the provisions of sections 409(c)(3)(A), 512(d)(1)(I), and 721(b)(5)(B) of the act.

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.

(a) This subpart E applies to all new animal drug applications, food additive petitions, and color additive petitions 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.

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.

(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.

(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.

(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.

(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.)

(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.

(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 1/2 oz.

(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.

(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.

(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.

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.

(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 1/16 inch in height on packages the principal display panel of which has an area of 5 square inches or less.

(2) Not less than 1/8 inch in height on packages the principal display panel of which has an area of more than 5 but not more than 25 square inches.

(3) Not less than 3/16 inch in height on packages the principal display panel of which has an area of more than 25 but not more than 100 square inches.

(4) Not less than 1/4 inch in height on packages the principal display panel of which has an area of more than 100 square inches, except not less than 1/2 inch in height if the area is more than 400 square inches.

(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 11/2 pounds weight shall be expressed as Net Wt. 24 oz. (1 lb. 8 oz.), Net Wt. 24 oz. (11/2 lb.), or Net Wt. 24 oz. (1.5 lb.).

(2) A declaration of 3/4 pound avoirdupois weight shall be expressed as Net Wt. 12 oz.

(3) A declaration of 1 quart liquid measure shall be expressed as Net 32 fl. oz. (1 qt.).

(4) A declaration of 13/4 quarts liquid measure shall be expressed as Net contents 56 fluid ounces (1 quart 11/2 pints) or as Net 56 fluid oz. (1 qt. 1 pt. 8 oz.), but not in terms of quart and ounce such as Net 56 fluid oz. (1 quart 24 ounces).

(5) On a random package, declaration of 3/4 pound avoirdupois may be expressed as Net Wt. .75 lb.

(6) A declaration of 21/2 gallons liquid measure shall be expressed as Net contents 21/2 gallons, Net contents 2.5 gallons, or Net contents 2 gallons 2 quarts and not as 2 gallons 4 pints.

(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 (except the requirement that food falling below the applicable standard of fill of container shall bear the general statement of substandard fill specified in § 564.14(b) of this chapter), the mislabeled food product, including any food product that fails to bear the general statement of substandard fill specified in § 564.14(b) of this chapter, 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.

(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.

(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.

(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 Federal Register as soon as practicable thereafter. The notice shall call attention to the material supporting the action level which shall be on file with the Division of Dockets Management before the notice is published. The notice shall invite public comment on the action level.

(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.

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 Federal Register for comment if it contains reasonable grounds for the proposed regulation.

(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.

(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.

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) The term sponsor means the person responsible for an investigation of a new animal drug, including responsibility for compliance with applicable provisions of the act and regulations. 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.

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.

(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.

(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.

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.

(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 Federal Register of August 23, 1966 (31 FR 11141), asking sponsors of drugs containing any antibiotic intended for use in food-producing animals to submit data to establish whether such antibiotic and its metabolites are present as residues in edible tissues, milk, and eggs from treated animals. The data on the residues of antibiotics in milk from intramammary infusion preparations were requested within 60 days and the data on all other products were requested within 180 days following the date of publication of § 510.112 in the Federal Register.

(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.

(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 Federal Register; except that in the case of data on intramammary infusion preparations the data shall be submitted within 60 days of such publication. Data demonstrating the absence in milk of residues of intramammary infusion preparations when used as directed in their labeling are needed within the 60-day period because of the importance of milk in the human diet.

(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.

(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:

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.

(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 types of approvals are required for new animal drugs intended for use in free-choice feed? New animal drugs 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)), as:

(1) An original new animal drug application (NADA),

(2) A supplemental NADA, or

(3) An abbreviated NADA.

(c) What are the approval requirements for new animal drugs intended for use in free-choice feed? (1) An approval under section 512 of the act is required for any new animal drug intended for use in a free-choice feed.

(2) An approved NADA for a Type A medicated article intended for use in free-choice feed must contain the following information:

(i) 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

(ii) Data, or reference to data in a 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.

Animal feeds that bear or contain penicillin, chlortetracycline, feed grade zinc bacitracin, and bacitracin methylene disalicylate, with or without added suitable nutritive ingredients are exempt from the certification requirements of section 512 of the act provided they are the subject of and in compliance with regulations for their use in this subchapter E, part 558 of this chapter, or any one of the paragraphs of this section:

(a) Where indicated in paragraph (b) of this section it is manufactured with or without one, but only one, of the following ingredients in a quantity, by weight of feed, as hereinafter indicated:

(1) Arsanilic acid: Not less than 0.005 percent and not more than 0.01 percent.

(2) Sodium arsanilate: Not less than 0.005 percent and not more than 0.01 percent.

(3) 3-Nitro-4-hydroxyphenylarsonic acid: Not less than 0.0025 percent and not more than 0.0075 percent except in chicken or turkey feed which shall contain not less than 0.0025 percent and not more than 0.005 percent.

(b) It is intended for use in any one of the following conditions set forth in this paragraph:

(1) It is intended for use solely in the treatment of chronic respiratory disease (air-sac infection), infectious sinusitis, and blue comb (nonspecific infectious enteritis) in poultry and/or bacterial swine enteritis; its labeling bears adequate directions and warnings for such use; and it contains, per ton of feed, the equivalent of 100 grams of penicillin. When intended for uses specified in this paragraph, it may also contain, in the amount specified, one, but only one, of the ingredients prescribed by paragraph (a) of this section.

(2) It is intended for use solely in the treatment of chronic respiratory disease (air-sac infection) and infectious sinusitis in poultry; its labeling bears adequate directions and warnings for such use; and it contains not less than 0.1 percent para-aminobenzoic acid or the sodium or potassium salt or para-aminobenzoic acid.

(3)-(29) [Reserved]

(c) It is intended for use as follows:

(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:

(a) Applications to be filed under section 512(b) of the act shall be submitted in the form described in paragraph (b) of this section. 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:

(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 the format described under § 558.6(a)(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.

(d) Minor use applications. Applications for minor use new animal drugs:

(1) Definitions. For the purpose of this section:

(i) Minor use means the use of: (a) New animal drugs in minor animal species, or (b) new animal drugs in any animal species for the control of a disease that (1) occurs infrequently or (2) occurs in limited geographic areas.

(ii) Minor species means animals other than cattle, horses, swine, chickens, turkeys, dogs, and cats.

(2) Animal safety, effectiveness, human food safety, and environmental considerations. Guidance documents for the preparation and submission of data to satisfy the requirements of section 512 of the act regarding animal safety, effectiveness, human food safety, and environmental considerations for new animal drugs intended for a minor use (as defined in paragraph (d)(1)(i) of this section) are available from the Industry Information Staff (HFV-11), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.

(i) Animal safety and effectiveness. Where the guidance documents do not specifically provide for a particular minor use, the Center for Veterinary Medicine, upon request, will advise interested persons on the effectiveness and animal safety data regarding the minor use that will be needed to satisfy the requirements of section 512 of the act. Where scientifically appropriate, the Center for Veterinary Medicine will allow the use of animal models and the extrapolation of data from a major species to a minor species to satisfy the requirements of the act.

(ii) Human food safety and environmental considerations. These guidance documents do not specifically provide for a particular minor use. Therefore, the Center for Veterinary Medicine will, upon request, advise interested persons of the data that will be needed. Where scientifically appropriate, the Center for Veterinary Medicine will allow the extrapolation of data from a major species to a minor species to satisfy the requirements of the act.

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.

(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.

(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.

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.

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.

(a)(1) After a new animal drug application is approved, a supplemental new animal drug application may propose changes. A supplemental application may omit statements made in the approved application concerning which no change is proposed. Each supplemental application shall include up-to-date reports of any of the kinds of information required by § 514.80 that has not previously been submitted. A supplemental application shall be accompanied by 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.

(2) A supplemental new animal drug application shall be submitted for any change beyond the variations provided for in the application, including changes in the scale of production such as from pilot-plant to production batch, that may alter the conditions of use, the labeling, safety, effectiveness, identity, strength, quality, or purity of the new animal drug, or the adequacy of the manufacturing methods, facilities, or controls to preserve them.

(3) 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:

(i) 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

(ii) Any other parts of the labeling are consistent with and not contrary to such approved or permitted labeling.

(4) The supplemental application shall be submitted as follows. A communication proposing a change in a new animal drug application should provide for any one of the following kinds of changes:

(i) Revision in labeling, such as updating information pertaining to effects, dosages, and side effects and contraindications, which includes information headed “side effects,” “warnings,” “precautions,” and “contraindications.”

(ii) Addition of claim.

(iii) Revision in manufacturing or control procedures; for example, changes in components, composition, method of manufacture, analytical control procedures, package or tablet size, etc.

(iv) Change in manufacturing facilities.

(v) Provision for outside firm to participate in the preparation, distribution, or packaging of a new animal drug (new distributor, packer, supplier, manufacturer, etc.); one firm per submission.

(5) The following kinds of changes may be placed into effect without the approval of a supplemental application, if such change is fully described in the next periodic report required under § 514.80(b)(4) or, when such a report is not required, in a written communication to the Food and Drug Administration within 60 days of the effective date of the change (this does not apply to a change proposed because of any mixup or any bacteriological or 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 its specifications):

(i) A different container size for solid oral dosage forms where container and closure are of the same materials as those provided for in the approved application.

(ii) Change in personnel not involving new facilities.

(iii) Change in equipment that does not alter the method of manufacture of a new animal drug.

(iv) Change from one commercial batch size to another without any change in manufacturing procedure.

(v) Change to more stringent specification without altering the method described in the approved application.

(vi) Inclusion of additional specifications and methods without deletion of those described in the approved application.

(vii) Alteration of specifications or methods for inactive ingredients to bring them into compliance with new or revised specifications or methods in an official compendium.

(viii) Initiation of a product identification coding system.

(ix) Addition to labeling of a reasonable expiration date where none was previously used, with related conditions of drug storage when appropriate, except when evidence shows that a significant deterioration of the drug under marketing conditions has occurred which necessitates the immediate submission of a report under § 514.80(b)(1). The report or written communication describing such change in labeling should include stability data justifying the expiration date and recommended conditions of storage.

(x) Change from paper labels to direct printing on glass or other kinds of immediate containers without a change in text.

(6) Approval of a supplemental new animal drug application will not be required to provide for an additional distributor to distribute a drug which is the subject of an approved new animal drug application if the conditions described in § 514.80(b)(5)(iii) are met before putting such a change into effect.

(b) When necessary for the safety or effectiveness of the drug, a supplemental new animal drug application shall specify a period of time within which the proposed change will be made.

(c) If a material change is made in the components' composition, manufacturing methods, facilities, or controls, or in the labeling or advertising, from the representations in an approved application for a new animal drug (except changes conforming to the conditions set forth in paragraph (a)(5) and (6) and/or paragraphs (d), (e), (f), and (g) of this section), and the drug is marketed before a supplement is approved for such change, approval of the application may be suspended or withdrawn as provided in section 512(e) of the act.

(d) Changes of the following kinds proposed in supplemental new animal drug applications should be placed into effect at the earliest possible time:

(1) The addition to package labeling, promotional labeling, and prescription drug advertising of additional warning, contraindication, side effect, and precaution information.

(2) The deletion from package labeling, promotional labeling, and drug advertising of false, misleading, or unsupported indications for use or claims for effectiveness.

(3) Changes in the methods, facilities, or controls used for the manufacture, processing, packing, or holding of the new animal drug (other than utilization of establishments 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.

(e) The Food and Drug Administration will take no action against a new animal drug or applicant solely because changes of the kinds described in paragraph (d) of this section are placed into effect by the applicant prior to his receipt of a written notice of approval of the supplemental new animal drug application if all the following conditions are met:

(1) The supplemental new animal drug application providing a full explanation of the basis for the changes has been submitted, plainly marked on the mailing cover and on the supplement, “Special new animal drug application Supplement—changes being effected.”

(2) The applicant specifically informs the Food and Drug Administration of the date on which such changes are being effected and submits to the Administration nine printed copies of any revised labeling to be placed in use, identified with the new animal drug application number.

(3) All promotional labeling and all drug advertising are promptly revised consistent with the changes made in the labeling on or within the new animal drug package.

(f) When a supplemental new animal drug application proposes changes only of the kinds described in paragraph (d) of this section, and the applicant informs the Food and Drug Administration that the changes are being put into effect, such notification will be regarded as an agreement by the applicant to an extension of the time for formal action on the application.

(g) In addition to changes as permitted by paragraphs (d) and (e) of this section, an applicant may place into effect changes proposed in a supplement to a new animal drug application that became effective prior to October 10, 1962, upon written notification from the Food and Drug Administration that such action is permitted, without approval of the supplemental application, pending the completion of the review of the effectiveness of such drug by the National Academy of Sciences-National Research Council and a determination as to whether there are grounds for refusing approval under section 512(d) of the act or for invoking section 512(e) of the act. The Food and Drug Administration will take no action against a new animal drug or an applicant solely because changes that have been permitted in a written communication are placed into effect by the applicant prior to his receipt of a written notice of approval of the supplemental new animal drug application.

(h) Except as provided in paragraphs (e) and (g) of this section, no provision of this section shall limit the authority of the Secretary or of the Commissioner to suspend or withdraw approval of a new animal drug application in accord with the provisions of section 512(e) of the act or to initiate any other regulatory proceedings with respect to a drug or applicant under provisions of the act.

(i) Changes from the conditions of an approved new animal drug application in accord with the provisions of paragraphs (d), (e), and (g) of this section are permitted on the basis of a temporary deferral of final action on the supplemental application under the provisions of section 512 (c), (d), or (e) of the act.

(j) When an applicant receives written notification from the Food and Drug Administration, under the provisions of paragraph (g) of this section, that he may place into effect changes proposed in a supplemental application without approval of the supplemental application, he may within 30 days submit a written request that the Food and Drug Administration process the supplemental application. In such case, the change shall not be put into effect until approved. Within 180 days of the receipt of such written request, the Food and Drug Administration will approve the supplemental application or furnish notice of an opportunity for a hearing under the provisions of section 512 (d) or (e), or both, of the act on a proposal to refuse approval of the supplemental application or to withdraw approval of the application and supplements thereto.

(k) A supplement to an application that became effective prior to October 10, 1962, may include a written statement to the effect that a temporary deferral of final action under the provisions of paragraph (d), (e), or (g) of this section is unacceptable to the applicant and that the applicant requests action as provided in section 512(c) of the act. Final action on such supplemental applications will be expedited in accord with applicable provisions of section 512 of the act and regulations in this subchapter E. In such cases, if the applicant places into effect any of the proposed changes prior to his receipt of a written notice of approval of the supplemental new animal drug application, such action may be regarded by the Food and Drug Administration as a basis for invoking the provisions of section 512(e)(1)(D) of the act; that is, the applicant may be furnished notice of an opportunity for a hearing on a proposal to withdraw approval of the application on the ground that the application contains an untrue statement of a material fact related to the changes from the conditions approved in the application.

(l) A supplemental application that contains nonclinical laboratory studies 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.

(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 an approval has been published in the Federal Register, unless it has previously been publicly 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 an approval has been published in the Federal Register, no data or information contained in the file is available for public disclosure before such approval is published, 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, 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 an approval has been published in the Federal Register, 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 on or 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 approval is published in the Federal Register.

(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.

(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.

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.

The following table outlines the purpose for each paragraph of this section:

(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.”

(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 on Form FDA 1932, and its mailing cover must be plainly marked “15-Day NADA/ANADA Alert Report.”

(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 on Form FDA 1932, and its mailing cover must be plainly marked “15-Day NADA/ANADA Alert Report Followup.” 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 should submit the report on Form FDA 1932 within 15 working days of first receiving the information.

(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 60 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. 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.

(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 § 514.80(b)(1) and (b)(2) must be reported individually on Form FDA 1932.

(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 separately from other experiences in the periodic drug experience report and clearly marked or highlighted.

(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 previously submitted Form FDA 1932, 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) Reporting forms. Applicant must report adverse drug experiences and product/manufacturing defects on Form FDA 1932, “Veterinary Adverse Drug Reaction, Lack of Effectiveness, Product Defect Report.” Periodic drug experience reports and special drug experience reports must be accompanied by a completed Form FDA 2301 “Transmittal of Periodic Reports and Promotional Material for New Animal Drugs,” in accordance with directions provided on the forms. Computer-generated equivalents of Form FDA 1932 or Form FDA 2301, approved by FDA before use, may be used. Form FDA 1932 and Form FDA 2301 may be obtained on the Internet at http://www.fda.gov/cvm/forms/forms.html, by telephoning the 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. Completed 15-day alert reports, periodic drug experience reports, and special drug experience reports 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. 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 from the Internet at http://www.fda.gov (click on “Contact FDA,” then “FDA Field Offices”).

(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.

(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.

(a) The Commissioner shall forward for publication in the Federal Register a regulation prescribing the conditions under which the new animal drug may be used, including the name and address of the applicant; the conditions and indications for use covered by the application; any tolerance, withdrawal period, or other use restrictions; any tolerance required for the new animal drug substance or its metabolites in edible products of food-producing animals; and, if such new animal drug is intended for use in animal feed, appropriate purposes and conditions of use (including special labeling requirements) applicable to any animal feed; and such other information the Commissioner deems necessary to assure safe and effective use.

(b) He shall notify the applicant by sending him a copy of the proposed publication as described in paragraph (a)(1) of this section.

(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 drug not exempted by § 514.8(a)(3)(i) and (a)(3)(ii).

(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 listed in § 514.8(d).

(xiv) Changes not requiring prior approval which are listed under § 514.8(a)(5) when submitted as supplemental applications.

(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.

(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.

(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.

(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.

(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.

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 Federal Register.

(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.

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.

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.

(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 specify the grounds upon which he proposes to issue his order. On request of the applicant, the Commissioner will explain the reasons for his action. The notice of opportunity for a hearing will be published in the Federal Register and will specify that the applicant has 30 days after issuance of the notice within which he is required to file a written appearance electing whether:

(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, his 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, he 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 should not be withdrawn, together with a well-organized and full-factual analysis of the clinical and other investigational data he 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 data in the application and from the reasons and a 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 withdrawal of approval of the application (for example, no adequate and well-controlled clinical investigations to support the claims of effectiveness have been identified), the Commissioner will enter an order on this data, stating his 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 he 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 his appearance.

Hearings relating to new animal drugs under section 512(d) and (e) of the act shall be governed by part 12 of this chapter.

(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.

(a) Medicated feed mill license applications (Forms 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 home page at http://www.fda.gov/cvm.

(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.

(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 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 §§ 207.20 and 207.21 of this chapter.

(c) Applications must be completed, signed, and submitted to the Division of Animal Feeds (HFV-220), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.

(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 original copy of 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.

(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.

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.

(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) 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 preceed issuance of such notice of hearing.

(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.

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.

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 Federal Register.

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.

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.

(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 Federal Register and will specify that the applicant has 30 days after issuance of the notice within which the Commissioner is required to file a written appearance electing whether:

(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.

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.

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.