(a) Definitions. (1) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) apply to those terms when used in this part.

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(2) The following definitions of terms apply to this part:

(i) Assess the effects of the change means to evaluate the effects of a manufacturing change on the identity, strength, quality, purity, and potency of a drug as these factors may relate to the safety or effectiveness of the drug.

(ii) Drug substance means an active ingredient as defined under § 210.3(b)(7) of this chapter.

(iii) Minor changes and stability report (MCSR) means an annual report that is submitted to the application once each year within 60 days before or after the anniversary date of the application’s original approval or on a mutually agreed upon date. The report must include minor manufacturing and control changes made according to § 514.8(b)(4) or state that no changes were made; and stability data generated on commercial or production batches according to an approved stability protocol or commitment.

(iv) Specification means the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of drugs including, for example, drug substances, Type A medicated articles, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug. For the purpose of this definition, the term “acceptance criteria” means numerical limits, ranges, or other criteria for the tests described.

(b) Manufacturing changes to an approved application—(1) General provisions. (i) The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about it in a supplement under paragraph (b)(2) or (b)(3) of this section or by inclusion of the information in the annual report to the application under paragraph (b)(4) of this section.

(ii) The holder of an approved application under section 512 of the act must assess the effects of the change before distributing a drug made with a manufacturing change.

(iii) Notwithstanding the requirements of paragraphs (b)(2) and (b)(3) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the drug, or by notification in the next annual report described in paragraph (b)(4) of this section).

(iv) In each supplement and amendment to a supplement providing for a change under paragraph (b)(2) or (b)(3) of this section, the applicant must include a statement certifying that a field copy has been provided to the appropriate FDA district office. No field copy is required for a supplement providing for a change made to a drug manufactured outside of the United States.

(v) A supplement or annual report described in paragraph (b)(4) of this section must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the cover letter.

(2) Changes requiring submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (i) A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.

(ii) These changes include, but are not limited to:

(A) Except those described in paragraphs (b)(3) and (b)(4) of this section, changes in the qualitative or quantitative formulation of the drug, including inactive ingredients, or in the specifications provided in the approved application;

(B) Changes requiring completion of appropriate clinical studies to demonstrate the equivalence of the drug to the drug as manufactured without the change;

(C) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation;

(D) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance;

(E) Changes in a drug product container closure system that controls the drug delivered to the animal or changes in the type or composition of a packaging component that may affect the impurity profile of the drug product;

(F) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following:

(1) Changes in the virus or adventitious agent removal or inactivation method(s),

(2) Changes in the source material or cell line, and

(3) Establishment of a new master cell bank or seed;

(G) Changes to a drug under an application that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that application.

(iii) The applicant must obtain approval of a supplement from FDA prior to distribution of a drug made using a change under paragraph (b)(2) of this section. The supplement must be labeled “Prior Approval Supplement.” Except for submissions under paragraph (b)(2)(v) of this section, the following information must be contained in the supplement:

(A) A completed Form FDA 356V;

(B) A detailed description of the proposed change;

(C) The drug(s) involved;

(D) The manufacturing site(s) or area(s) affected;

(E) A description of the methods used and studies performed to assess the effects of the change;

(F) The data derived from such studies;

(G) Appropriate documentation (for example, updated master batch records, specification sheets) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;

(H) For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section;

(I) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section; and

(J) Any other information as directed by FDA.

(iv) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover must be plainly marked: “Prior Approval Supplement-Expedited Review Requested.”

(v) Comparability Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug as these factors may relate to the safety or effectiveness of the drug. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of the drug produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect. A comparability protocol supplement must be labeled “Prior Approval Supplement—Comparability Protocol.”

(3) Changes requiring submission of a supplement at least 30 days prior to distribution of the drug made using the change (moderate changes). (i) A supplement must be submitted for any change in the drug, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug.

(ii) These changes include, but are not limited to:

(A) A change in the container closure system that does not affect the quality of the drug except as otherwise described in paragraphs (b)(2) and (b)(4) of this section;

(B) Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including:

(1) An increase or decrease in production scale during finishing steps that involves different equipment, and

(2) Replacement of equipment with that of a different design that does not affect the process methodology or process operating parameters.

(C) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.

(iii) A supplement submitted under paragraph (b)(3)(i) or (b)(3)(vi) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is made. The supplement submitted under paragraph (b)(3)(i) must be labeled “Supplement-Changes Being Effected in 30 Days.”

(iv) Pending approval of the supplement by FDA and except as provided in paragraph (b)(3)(vi) of this section, distribution of the drug made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement.

(v) The applicant must not distribute the drug made using the change if within 30 days following FDA’s receipt of the supplement, FDA informs the applicant that either:

(A) The change requires approval prior to distribution of the drug in accordance with paragraph (b)(2) of this section; or

(B) Any of the information required under paragraph (b)(3)(iv) of this section is missing. In this case, the applicant must not distribute the drug made using the change until the supplement has been amended to provide the missing information.

(vi) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved application may commence distribution of the drug involved upon receipt by the agency of a supplement for the change. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement. The supplement must be labeled “Supplement-Changes Being Effected.” These changes include, but are not limited to:

(A) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess; and

(B) A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another.

(vii) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug(s) made with the manufacturing change.

(4) Changes and updated stability data to be described and submitted in an annual report (minor changes). (i) Changes in the drug, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug must be documented by the applicant in an annual report to the application as described under paragraph (a)(2)(iii) of this section. The report must be labeled “Minor Changes and Stability Report.”

(ii) These changes include but are not limited to:

(A) Any change made to comply with a change to an official compendium, except a change in paragraph (b)(3)(ii)(C) of this section, that is consistent with FDA statutory and regulatory requirements;

(B) The deletion or reduction of an ingredient intended to affect only the color of the drug product;

(C) Replacement of equipment with that of the same design and operating principles except for those equipment changes described in paragraph (b)(3)(ii)(B)(2) of this section;

(D) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another;

(E) A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;

(F) An extension of an expiration dating period based upon full shelf-life data on production batches obtained from a protocol approved in the application;

(G) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the drug being tested as the analytical procedure described in the approved application, or deletion of an alternative analytical procedure; and

(H) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.

(iii) For changes under this category, the applicant is required to submit in the annual report:

(A) A completed Form FDA 356V;

(B) A statement by the holder of the approved application that the effects of the change have been assessed;

(C) A detailed description of the change(s);

(D) The manufacturing site(s) or area(s) involved;

(E) The date each change was implemented;

(F) Data from studies and tests performed to assess the effects of the change;

(G) For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, relevant validation protocols and/or standard operating procedures;

(H) Appropriate documentation (for example, updated master batch records, specification sheets, etc.) including previously approved documentation (with the changes highlighted) or references to previously approved documentation;

(I) Updated stability data generated on commercial or production batches according to an approved stability protocol or commitment; and

(J) Any other information as directed by FDA.

(c) Labeling and other changes to an approved application—(1) General provisions. The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully.

(2) Labeling changes requiring the submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (i) Addition of intended uses and changes to package labeling require a supplement. These changes include, but are not limited to:

(A) Revision in labeling, such as updating information pertaining to effects, dosages, adverse reactions, contraindications, which includes information headed “adverse reactions,” “warnings,” “precautions,” and “contraindications,” except ones described in (c)(3) of this section;

(B) Addition of an intended use;

(C) If it is a prescription drug, any mailing or promotional piece used after the drug is placed on the market is labeling requiring a supplemental application, unless:

(1) The parts of the labeling furnishing directions, warnings, and information for use of the drug are the same in language and emphasis as labeling approved or permitted; and

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

(3) Prescription drug labeling not requiring an approved supplemental application is submitted in accordance with § 514.80(b)(5)(ii).

(D) Any other changes in labeling, except ones described in paragraph (c)(3) of this section.

(ii) The applicant must obtain approval of the supplement from FDA prior to distribution of the drug. The supplement must contain the following:

(A) A completed Form FDA 356V;

(B) A detailed description of the proposed change;

(C) The drug(s) involved;

(D) The data derived from studies in support of the change; and

(E) Any other information as directed by FDA.

(3) Labeling changes to be placed into effect prior to receipt of a written notice of approval of a supplemental application. (i) Labeling changes of the following kinds that increase the assurance of drug safety proposed in supplemental applications must be placed into effect immediately:

(A) The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, adverse reaction, and precaution information;

(B) The deletion from package labeling, promotional labeling, or drug advertising of false, misleading, or unsupported intended uses or claims for effectiveness; and

(C) Any other changes as directed by FDA.

(ii) Labeling changes (for example, design and style) that do not decrease safety of drug use proposed in supplemental applications may be placed into effect prior to written notice of approval from FDA of a supplemental application.

(iii) A supplement submitted under paragraph (c)(3) of this section must include the following information:

(A) A full explanation of the basis for the changes, the date on which such changes are being effected, and plainly marked on the mailing cover and on the supplement, “Supplement—Labeling Changes Being Effected”;

(B) Two sets of printed copies of any revised labeling to be placed in use, identified with the new animal drug application number; and

(C) A statement by the applicant that all promotional labeling and all drug advertising will promptly be revised consistent with the changes made in the labeling on or within the new animal drug package no later than upon approval of the supplemental application.

(iv) If the supplemental application is not approved and the drug is being distributed with the proposed labeling, FDA may initiate an enforcement action because the drug is misbranded under section 502 of the act and/or adulterated under section 501 of the act. In addition, under section 512(e) of the act, FDA may, after due notice and opportunity for a hearing, issue an order withdrawing approval of the application.

(4) Changes providing for additional distributors to be reported under Records and reports concerning experience with approved new animal drugs (§ 514.80). Supplemental applications as described under paragraph (c)(2) of this section will not be required for an additional distributor to distribute a drug that is the subject of an approved new animal drug application or abbreviated new animal drug application if the conditions described under § 514.80(b)(5)(iii) are met.

(d) Patent information. The applicant must comply with the patent information requirements under section 512(c)(3) of the act.

(e) Claimed exclusivity. If an applicant claims exclusivity under section 512(c)(2)(F) of the act upon approval of a supplemental application for a change in its previously approved drug, the applicant must include such a statement.

(f) Good laboratory practice for nonclinical laboratory studies. A supplemental application that contains nonclinical laboratory studies must include, with respect to each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

[71 FR 74782, Dec. 13, 2006]