99-25493. Supplements and Other Changes to Approved New Animal Drug Applications  

  • [Federal Register Volume 64, Number 190 (Friday, October 1, 1999)]
    [Proposed Rules]
    [Pages 53281-53294]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 99-25493]
    
    
    
    [[Page 53281]]
    
    =======================================================================
    -----------------------------------------------------------------------
    
    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    
    Food and Drug Administration
    
    21 CFR Parts 5, 25, 500, 510, 514, and 558
    
    [Docket No. 99N-1415]
    RIN 0910-AB49
    
    
    Supplements and Other Changes to Approved New Animal Drug 
    Applications
    
    AGENCY: Food and Drug Administration, HHS.
    
    ACTION: Proposed rule.
    
    -----------------------------------------------------------------------
    
    SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
    its regulations on supplements and other changes to an approved new 
    animal drug application (NADA) or abbreviated new animal drug 
    application (ANADA) to implement the manufacturing changes provision of 
    the Food and Drug Administration Modernization Act of 1997 (the 
    Modernization Act). This proposed rule would require manufacturers to 
    validate the effect of any manufacturing change on the identity, 
    strength, quality, purity, and potency of a new animal drug as those 
    factors relate to the safety or effectiveness of the product. The 
    proposal identifies changes requiring submission and approval of a 
    supplement prior to the distribution of the new animal drug made using 
    the change, changes requiring the submission of a supplement at least 
    30 days prior to the distribution of the new animal drug, changes 
    requiring the submission of a supplement at the time of distribution, 
    and changes to be described in an annual report.
    
    DATES: Written comments by December 15, 1999.
    
    ADDRESSES: Submit written comments to the Dockets Management Branch 
    (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
    Rockville, MD 20852. Submit written comments on the information 
    collection requirements to the Office of Information and Regulatory 
    Affairs, Office of Management and Budget (OMB), New Executive Office 
    Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn.: Wendy 
    Taylor, Desk Officer for FDA.
    
    FOR FURTHER INFORMATION CONTACT: Dennis M. Bensley, Jr., Center for 
    Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 
    Standish Pl., Rockville, MD 20855, 301-827-6956.
    
    SUPPLEMENTARY INFORMATION:
    
    I. Introduction
    
        On November 21, 1997, the President signed the Modernization Act 
    into law (Public Law 105-115). Section 116 of the Modernization Act 
    amended the Federal Food, Drug, and Cosmetic Act (the act) by adding 
    section 506A (21 U.S.C. 356a), which describes requirements and 
    procedures for making and reporting manufacturing changes to approved 
    NADA's and ANADA's, new drug applications (NDA's) and abbreviated new 
    drug applications (ANDA's), and to license applications for biological 
    products. This proposed rule sets forth regulations to implement 
    section 506A of the act for NADA's and ANADA's. The Center for Drug 
    Evaluation and Research (CDER) and the Center for Biologics Evaluation 
    and Research (CBER) are issuing separate proposed regulations regarding 
    manufacturing changes for NDA's and ANDA's and for licensed biological 
    products.
        Section 506A of the act makes no distinction between the 
    requirements for reporting manufacturing changes for human drug and 
    biological products regulated by CDER and CBER and for new animal drug 
    products regulated by the Center for Veterinary Medicine (CVM). CVM is 
    proposing this rule to harmonize the reporting requirements of 
    manufacturing changes for new animal drug products with those reporting 
    requirements for human drug and biological products.
        The Modernization Act, section 116, becomes effective on the 
    effective date of these final regulations or 24 months after the 
    enactment of the Modernization Act (November 21, 1999), whichever 
    occurs first. This proposed rule updates and will replace Sec. 514.8 
    (21 CFR 514.8), which provides the current requirements for 
    manufacturing changes for NADA's.
    
    II. Background
    
    A. CVM's Current Rule
    
        CVM currently evaluates all manufacturing changes to approved 
    NADA's under the regulations found in Sec. 514.8. Manufacturing changes 
    are currently submitted as permitted changes (Sec. 514.8(a)(5)), 
    changes being effected (CBE's) (Sec. 514.8(d), or changes requiring 
    approval prior to implementation (Sec. 514.8(a)(4)).
        Under current Sec. 514.8(a)(5), permitted changes may be put into 
    effect without the approval of a supplemental application but must be 
    reported in the next annual drug experience report (DER). Section 
    514.8(a)(5) lists the types of manufacturing changes that are 
    considered permitted changes.
        CBE's under current Sec. 514.8(d) include manufacturing changes 
    that would ``give increased assurance that the drug will have the 
    characteristics of identity, strength, quality, and purity which it 
    purports or is represented to possess.'' Such changes are to be placed 
    into effect at the earliest possible time with concurrent submission of 
    a supplemental application; hence such changes do not require CVM 
    approval before implementation.
        Changes requiring approval of a supplemental application prior to 
    implementation are set out in current Sec. 514.8(a)(4) of the 
    regulations. Most manufacturing changes are currently reported in 
    preapproval supplemental applications under Sec. 514.8(a)(4).
    
    B. Section 116 of The Modernization Act
    
        Many of the concepts included in the Modernization Act were 
    incorporated from earlier rulemaking and guidance documents issued by 
    CDER and CBER. A discussion of CDER's earlier rulemaking, guidance 
    documents, and their underlying rationale can be found in the preamble 
    to CDER's proposed rulemaking to comply with section 506A of the act.
        CDER had issued a series of guidance documents to ease preapproval 
    requirements for certain manufacturing changes that are unlikely to 
    have a detectable impact on a drug product's quality and performance as 
    distinguished from those that could have a significant impact. These 
    guidance documents were issued under a provision in current 21 CFR 
    314.70(a) that permits holders of an approved application to make 
    changes to the application in accordance with a guideline, notice, or 
    regulation published in the Federal Register that provides a less 
    burdensome notification of the change.
        As of this date, CDER has issued several guidances addressing the 
    requirements relating to postapproval changes in manufacturing and 
    controls. These are known as the SUPAC (Scale-Up and Postapproval 
    Changes) documents. The first of these guidance documents was published 
    in November 1995 and is entitled ``Immediate Release Solid Oral Dosage 
    Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and 
    Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence 
    Documentation'' (SUPAC-IR). This guidance provides recommendations to 
    holders of approved drug applications who intend, during the 
    postapproval period, to change: (1) The components or composition, (2) 
    the site of manufacture, (3) the scale of manufacture, and/or (4)
    
    [[Page 53282]]
    
    the manufacturing (process and/or equipment) of an immediate release 
    solid oral dosage form.
        In May 1997 and August 1997, CDER issued two related guidances 
    entitled ``Semisolid Dosage Forms Scale-Up and Postapproval Changes: 
    Chemistry, Manufacturing, and Controls; In Vitro Release Testing; In 
    Vivo Bioequivalence Documentation'' (SUPAC-SS) and ``Modified Release 
    Solid Oral Dosage Forms Scale-Up and Postapproval Changes: In Vitro 
    Dissolution Testing; In Vivo Bioequivalence Documentation'' (SUPAC-MR). 
    These two guidances cover the same general topics and use the same 
    general approaches as SUPAC-IR. The current series of guidance 
    documents relating to scale-up and postapproval changes focuses on 
    changes to manufacturing and controls for drug products. Future 
    guidances will consider changes in manufacturing and controls for the 
    drug substance, product containers and closures, and other topics as 
    well.
        The underlying rationale of these guidances already completed or in 
    preparation is that the identity, strength, quality, purity, and 
    potency of an approved drug should remain unchanged in any important 
    aspect as a result of any postapproval change in manufacturing and 
    controls. This unchanged performance extends to changes that might 
    affect in vivo bioavailability and relative bioavailability 
    (bioequivalence).
        CDER's guidance documents, described previously, originally applied 
    only to drug products approved under sections 505 (new and abbreviated 
    new drug applications) and 507 (antibiotic applications; revoked by the 
    Modernization Act) of the act (21 U.S.C. 355 and 357). However, CVM 
    adopted many of the concepts described in these guidance documents by 
    permitting the reporting of minor manufacturing changes in a biennial 
    supplement instead of in a preapproval supplement submitted in 
    accordance with the current regulation (Sec. 514.8). The biennial 
    supplement does not require CVM approval prior to the distribution of 
    the drug product made using the changes.
        CDER's and CBER's proposed rulemaking and supporting guidance 
    documents allow for many moderate manufacturing changes to be reported 
    as CBE's that are not provided for in CVM's current regulations 
    (Sec. 514.8). CVM is proposing regulations that harmonize the reporting 
    of manufacturing changes for new animal drug products with the 
    reporting of manufacturing changes for human drug products, because: 
    (1) The act makes no distinction between the requirements for the 
    reporting of manufacturing changes for human drug products and for new 
    animal drug products, (2) the act does not provide for the reporting of 
    minor manufacturing changes in biennial supplements, (3) the proposed 
    rulemaking allows for flexibility in reporting many moderate changes as 
    CBE's, and (4) CVM and the animal drug industry can benefit from CDER's 
    expertise and resources to issue specific guidances on manufacturing 
    and controls changes used for drugs, generally.
        CVM is currently collaborating with CDER on a number of guidance 
    documents addressing manufacturing and controls changes, including the 
    draft guidance document entitled ``Chemistry, Manufacturing and Control 
    Changes to an Approved NADA or ANADA'' to be made available for comment 
    along with this proposed rulemaking. On the effective date of these 
    final regulations or on November 21, 1999, whichever occurs first, 
    CVM's previous practices will be superseded by section 506A of the act 
    and/or the final regulations and the reporting of minor manufacturing 
    changes in biennial supplements will no longer be permitted. CVM 
    proposes to adopt CDER's current guidance documents for manufacturing 
    changes (SUPAC-IR, SUPAC-SS and SUPAC-MR). These documents will be 
    updated to reflect changes resulting from the proposed rulemaking, and 
    CVM intends to participate with CDER in the drafting of any guidance 
    documents covering manufacturing changes. In addition, CVM will also 
    issue guidance documents for specific new animal drug products such as 
    Type A medicated articles.
    
    III. Summary of the Legislation
    
        Section 116 of the Modernization Act amended the act by adding 
    section 506A, which provides requirements for making and reporting 
    manufacturing changes to an approved application and for distributing a 
    drug made with such changes. Section 506A of the act includes the 
    following provisions:
        1. A drug made with a manufacturing change, whether a major 
    manufacturing change or otherwise, may be distributed only after the 
    applicant validates the effects of the change on the identity, 
    strength, quality, purity, and potency of the drug as these factors may 
    relate to the safety and effectiveness of the drug (section 506A(a)(1) 
    and (b) of the act). This section recognizes that additional testing, 
    beyond testing to ensure that an approved specification is met, is 
    required to ensure unchanged identity, strength, quality, purity, or 
    potency as these factors may relate to the safety or effectiveness of 
    the drug.
        2. A drug made with a major manufacturing change may be distributed 
    only after the applicant submits a supplemental application to FDA and 
    the supplemental application is approved by the agency. The application 
    is required to contain information that FDA deems appropriate and 
    include the information developed by the applicant validating the 
    effects of the change (section 506A(c)(1) of the act). The phrase 
    ``validating the effects of the change,'' as used in this proposed 
    rule, is not the same as ``validation'' required in FDA's current good 
    manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211).
        3. A major manufacturing change is a manufacturing change 
    determined by FDA to have substantial potential to adversely affect the 
    identity, strength, quality, purity, or potency of the drug as these 
    factors may relate to the safety or effectiveness of the drug. Such 
    changes include: (1) A change made in the qualitative or quantitative 
    formulation of the drug involved or in the specifications in the 
    approved application or license unless exempted by regulation or 
    guidance, (2) a change determined by FDA through regulation or guidance 
    to require completion of an appropriate clinical study demonstrating 
    equivalence of the drug to the drug manufactured without the change or 
    a reference listed drug, and (3) other changes determined by regulation 
    or guidance to have a substantial potential to adversely affect the 
    safety or effectiveness of the drug (section 506A(c)(2) of the act).
        4. FDA may establish categories of manufacturing changes, other 
    than major manufacturing changes, and require submission of a 
    supplemental application for drugs made with such manufacturing changes 
    (section 506A(d)(1)(B) and (d)(1)(C) of the act). For changes, other 
    than major changes, that require submission of a supplemental 
    application, the applicant may begin distribution of the drug 30 days 
    after FDA receives the supplemental application unless the agency 
    notifies the applicant within the 30-day period that FDA review and 
    prior approval of the application is required (section 506A(d)(3)(B)(i) 
    of the act). FDA may also designate a category of manufacturing changes 
    for which the applicant may begin distributing a drug made with such 
    changes upon receipt by the agency of the supplemental application for 
    the change (section 506A(d)(3)(B)(ii) of the act). If FDA fails
    
    [[Page 53283]]
    
    to approve a supplemental application, the agency may order the 
    manufacturer to cease the distribution of drugs that have been made 
    with the disapproved change (section 506A(d)(3)(B)(iii) of the act).
        5. FDA may authorize applicants to distribute drugs without 
    submitting a supplemental application (section 506A(d)(1)(A) of the 
    act) and may establish categories of manufacturing changes that may be 
    made without submitting a supplemental application (section 
    506A(d)(1)(C) of the act). The applicant is required to submit a report 
    to FDA on such a change, and the report is required to contain 
    information the agency deems to be appropriate and information 
    developed by the applicant when validating the effects of the change. 
    FDA may also specify the date on which the report is to be submitted 
    (section 506A(d)(2)(A) of the act). If during a single year an 
    applicant makes more than one manufacturing change subject to a 
    reporting requirement, the act permits FDA to authorize the applicant 
    to submit a single annual report containing the required information 
    for all the changes made during the year (section 506A(d)(2)(B) of the 
    act).
        Section 506A of the act recognizes that the amount of testing and 
    the data to be included in a submission and the appropriate method for 
    reporting the data are related to the scope and the type of change 
    being made. Four methods of reporting changes (i.e., supplements that 
    require FDA review and prior approval, CBE's supplements with a 30-day 
    wait, CBE's supplements with no wait, and annual reports) are discussed 
    in section 506A of the act and in this proposal. The appropriate method 
    for reporting any specific change depends on the potential for that 
    change to impact the fundamental safety or effectiveness of the product 
    by adversely affecting the basic aspects of the drug product--its 
    identity, strength, quality, purity, and potency.
        The main objective of a review of a supplemental application that 
    documents postapproval changes to an NADA or ANADA is to ensure 
    ``sameness'' or ``equivalence'' between the pre- and post-change 
    product. ``Sameness or equivalence'' do not mean ``identical'' since 
    certain manufacturing changes lead to differences. Such differences 
    should not, however, affect the safety or effectiveness of the drug 
    product. Also, a proposed manufacturing change should not be so 
    extensive that a new drug product is created. If a manufacturing change 
    does produce a fundamental alteration (i.e., a pharmaceutically 
    inequivalent dose form), a new application may be required for the 
    resulting product.
        Generally, in the case of NADA products, the pre- and post-change 
    drug product should be compared. In the case of ANADA products, the 
    pre- and post-change drug products should be compared to the reference 
    listed drug, typically the pioneer drug product. Confirmation of 
    ``sameness'' or ``equivalence'' is particularly important when changes 
    are made that involve the active pharmaceutical ingredient or affect 
    critical manufacturing steps. Examples of such changes include, but are 
    not limited to, components and overall composition of the formulation; 
    manufacturing site, scale, equipment, process, or specifications; and 
    analytical procedures.
        Many factors should be considered in determining whether a change 
    has a substantial, moderate, or minimal potential to have an adverse 
    effect on the identity, strength, quality, purity, or potency of the 
    product as they may relate to the safety or effectiveness of the 
    product. Some types of manufacturing changes have a greater potential 
    to cause unwanted or unexpected changes to the product that may be 
    difficult to assess by merely testing to specifications. The type of 
    product is also a factor to consider in determining the potential risk 
    of a manufacturing change having an adverse effect on the product. Some 
    products may be substantially affected by what appear to be small 
    manufacturing changes.
        Therefore, defining ``substantial,'' ``moderate,'' and ``minimal'' 
    in the regulations with such specificity that they exhaustively 
    describe all of the many individual changes that may occur is not 
    feasible. FDA is planning, however, to provide greater detail in 
    guidance about the types or categories of changes that the agency 
    believes should be considered ``substantial,'' ``moderate,'' or 
    ``minimal.''
        Section 506A of the act provides FDA with considerable flexibility 
    to establish required information and filing requirements for 
    manufacturing changes. There is a corresponding need to retain such 
    flexibility in the proposed regulations implementing section 506A of 
    the act to ensure that the least burdensome means for reporting changes 
    are available. FDA believes that such flexibility is necessary to be 
    responsive to increasing knowledge of and experience with certain types 
    of changes and to help ensure the effectiveness and safety of the 
    products involved. For example, a change that may currently be 
    considered to have a substantial potential to have an adverse effect on 
    the safety or effectiveness of the product may, at a later date, based 
    on new information or advances in technology, be determined to have a 
    lesser potential to have such an adverse effect. Conversely, a change 
    originally considered to have a moderate potential to have an adverse 
    effect on the safety or effectiveness of the product may later, as a 
    result of new information, be found to have an increased, substantial 
    potential to adversely affect the product.
        The agency believes it can more readily respond to knowledge gained 
    from manufacturing experience, and advances in technology by issuing 
    regulations that set out broad, general categories of manufacturing 
    changes and by using guidance documents to provide FDA's current 
    thinking on the specific changes that fall into those general 
    categories. The proposed rule would, therefore, reduce the number of 
    manufacturing changes specifically identified as being subject to 
    supplements requiring or not requiring review and approval. The agency 
    also understands that applicants expect some predictability on what 
    type of reporting will be expected for specific changes. FDA intends to 
    make available guidance documents to describe the agency's current 
    interpretation of specific changes falling into the four filing 
    categories and to modify the documents as needed to reflect changes 
    based on new information. The use of guidance documents as provided for 
    in section 506A of the act will allow FDA to more easily and quickly 
    modify and update important information. Guidance documents will be 
    developed according to the procedures set out in FDA's Good Guidance 
    Practices as published in the Federal Register of February 27, 1997 (62 
    FR 8961 at 8967 to 8972). A notice of availability for a draft guidance 
    entitled ``Chemistry, Manufacturing and Control Changes to an Approved 
    NADA or ANADA'' is published elsewhere in this issue of the Federal 
    Register. This guidance covers recommended reporting categories for 
    various postapproval manufacturing changes. FDA has published 
    guidances, including SUPAC guidances and CVM's ``Animal Drug 
    Manufacturing Guidelines,'' that provide recommendations on both 
    reporting categories and/or the type of information that should be 
    developed by the applicant to validate the effect of the change on the 
    identity, strength, quality, purity, or potency of a product as these 
    factors may relate to the safety or effectiveness of the product. To 
    the extent that the recommendations on reporting categories in this 
    proposed guidance, when finalized, are
    
    [[Page 53284]]
    
    inconsistent with previously published guidances, such as the SUPAC's, 
    the recommended reporting categories in such prior guidances will be 
    superseded by this new guidance upon its publication in final form. FDA 
    intends to update the prior published guidances to make them consistent 
    with this guidance.
    
    IV. Description of the Proposed Rule
    
    A. Definitions
    
        FDA has added a new paragraph to define terms and phrases as used 
    in proposed Sec. 514.8. Proposed Sec. 514.8(a) would add definitions of 
    ``minor changes and stability report (MCSR),'' ``specification,'' 
    ``validate the effects of the change,'' `listed drug,'' and ``the 
    list.'' These definitions are necessary to implement the provisions of 
    section 506A of the act.
        FDA is proposing to define ``specification'' as the quality 
    standard (i.e., tests, analytical procedures, and acceptance criteria) 
    provided in an approved application to confirm the quality of drug 
    substances, drug products, intermediates, raw materials, reagents, and 
    other components including container closure systems, and in-process 
    controls. FDA is proposing to define ``specification'' because section 
    506A of the act includes a change ``in the specifications in the 
    approved application or license'' as a major change. To clarify the 
    meaning of the term ``acceptance criteria'' as used in the definition 
    of ``specification,'' FDA is including in the proposed definition of 
    ``specification'' the statement that ``acceptance criteria'' refers to 
    numerical limits, ranges, or other criteria for the tests described. To 
    determine if a material being tested complies with a specification, 
    there must be predetermined criteria. These criteria may include 
    numerical limits or ranges (e.g., not more than 1 percent) or other 
    criteria (e.g., white to off-white in color).
        FDA is proposing to define the phrase ``validate the effects of the 
    change'' as an assessment of the effect of a manufacturing change on 
    the identity, strength, quality, purity, or potency of a drug as these 
    factors relate to the safety or effectiveness of the drug. FDA is 
    proposing to define this phrase because section 506A of the act 
    includes a requirement that a drug made with a manufacturing change may 
    only be distributed after the applicant validates the effects of the 
    change. Validating the effects of the change is important in 
    determining whether manufacturing changes alter the identity, strength, 
    quality, purity, or potency of a drug product as these factors may 
    relate to drug safety or effectiveness, and includes testing beyond 
    that in an approved specification, such as redocumentation of the 
    pharmaceutical equivalence or bioequivalence.
        ``Minor changes and stability report'' would mean a report that is 
    submitted once each year within 60 days of the anniversary of the 
    application's original approval or a mutually agreed upon date for 
    minor manufacturing changes made according to proposed Sec. 514.8(b)(4) 
    or a statement that no changes were made, and updated stability data 
    generated on commercial or production batches according to an approved 
    stability protocol.
        The MCSR is the annual report described in section 506A(d)(2)(B) of 
    the act, and it is different and distinct from the annual report 
    described and submitted in accordance with current Sec. 510.300 (21 CFR 
    510.300) (i.e., periodic DER's). The MCSR is a type of ``annual'' 
    report for manufacturing changes only. The MCSR would be submitted to 
    and reviewed by CVM's Office of New Animal Drug Evaluation (ONADE) 
    rather than by CVM's Office of Surveillance and Compliance (OSC). The 
    MCSR must include minor manufacturing changes implemented over the past 
    year and an update of ongoing stability data generated on production 
    lots. Currently, ongoing stability data are submitted as part of DER's 
    to OSC. CVM has decided that it is more efficient to allow the 
    administrative review of information relating to manufacturing changes 
    and stability to reside in one group. Information regarding labeling 
    changes and product defects would continue to be submitted to CVM's 
    OSC.
        FDA is proposing to define ``listed drug'' and ``the list'' to 
    clarify ``reference listed drug'' cited in proposed 
    Sec. 514.8(b)(2)(ii)(B).
    
    B. Manufacturing Changes to an Approved Application
    
        Proposed Sec. 514.8(b) sets forth general requirements under which 
    an applicant must notify FDA when making a change to an approved 
    application and replaces current Sec. 514.8(a). This paragraph states 
    that an applicant must notify FDA about each change in each condition 
    established in an approved application beyond the variations already 
    provided for in the application, and that the notice is required to 
    describe the change fully. It also states that the applicant must, 
    depending on the type of change, notify FDA of the change in a 
    supplement under proposed Sec. 514.8(b)(2) or (b)(3) or by the 
    inclusion of the information in an annual report (the MCSR) under 
    proposed Sec. 514.8(b)(4). Reference in current Sec. 514.8(a)(1) to 
    current regulations, Sec. 510.300, has been deleted and, instead, 
    proposed Sec. 514.8(b)(1)(i) makes reference to annual reports 
    described under proposed Sec. 514.8(b)(4). Manufacturing changes and/or 
    updated stability data generated according to an approved stability 
    commitment would no longer be reported in periodic DER's (i.e., annual 
    reports under current Sec. 510.300) but be reported under proposed 
    Sec. 514.8(b)(4) in an MCSR. CVM intends to publish a final rule 
    revising Sec. 510.300, which will be renumbered as Sec. 514.80. Since 
    CVM expects to publish the final rule for Sec. 514.80 (Records and 
    reports concerning experience with new animal drugs for which an 
    approved application is in effect. (56 FR 65581, December 17, 1991)) 
    before the final rule for Sec. 514.8, CVM will, if necessary, amend the 
    rule for Records and reports concerning experience with new animal 
    drugs for which an approved application is in effect. after the final 
    rule for Sec. 514.8 publishes.
        Proposed Sec. 514.8(b)(1)(ii) would require the holder of an 
    approved application under section 512 of the act (21 U.S.C. 360b) to 
    validate the effects of manufacturing changes on the identity, strength 
    (e.g., assay and content uniformity), quality (e.g., physical, 
    chemical, and biological properties), purity (e.g., impurities and 
    degradation products) and potency (e.g., biological activity, 
    bioavailability, and bioequivalence) of a drug as these factors may 
    relate to the safety or effectiveness of the drug. These validation 
    requirements must be met before a product made with a manufacturing 
    change may be distributed. This amendment implements section 506A(a)(1) 
    and (b) of the act.
        Proposed Sec. 514.8(b)(1)(iii) states that notwithstanding the 
    requirements of Sec. 514.8(b)(2) and (b)(3), an applicant must report 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, a type of manufacturing change subject to review 
    and approval by FDA under proposed Sec. 514.8(b)(2) might be identified 
    in regulation or guidance as a change that could be reported in a 
    supplement not requiring review and approval or in an annual report. 
    CDER used this provision to reduce the regulatory burden for submission 
    of supplements for manufacturing changes that were not likely to 
    adversely affect drug product quality or performance in the SUPAC 
    guidance documents.
    
    [[Page 53285]]
    
        Proposed Sec. 514.8(b)(1)(iv) requires the applicant to include in 
    each supplemental application providing for a change under proposed 
    Sec. 514.8(b)(2) or (b)(3), a statement that a copy of the supplement 
    has been provided to the appropriate FDA district office whose 
    jurisdiction includes the facility where the manufacturing change is 
    implemented.
        Proposed Sec. 514.8(b)(1)(v) would add a requirement that a list of 
    all changes contained in the supplement or annual report must be 
    included in the cover letter for the supplement or annual report. For 
    many years, most supplements and annual reports have routinely included 
    such cover letters. Including a list of all changes in the cover 
    letters will enable FDA to more efficiently locate and evaluate changes 
    in what are often substantial documents, thus facilitating FDA review 
    of supplements and annual reports.
        Proposed Sec. 514.8(b)(2)(iii) describes the information that must 
    be included in a supplement. References to regulations for categorical 
    exclusion or an environmental assessment have been updated and included 
    in Sec. 514.8(b)(2)(iii)(K).
    
    C. Changes Requiring Supplement Submission and Approval Prior to 
    Distribution of the Product Made Using the Change (Major Change)
    
        Certain drug manufacturing steps are so critical that changes in 
    these steps must be subject to the submission of a supplement to FDA 
    that is approved by FDA prior to distribution of the drug product made 
    using the change. Current Sec. 514.8(a)(4) sets forth changes for which 
    such review and approval are required.
        Proposed Sec. 514.8(b)(2) would revise the current sections to 
    implement section 506A of the act. Proposed Sec. 514.8(b)(2)(i) 
    implements section 506A(c)(2) of the act and would require a 
    preapproval supplement to be submitted for any major change, i.e., any 
    change in the product, 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 
    product as these factors may relate to the safety or effectiveness of 
    the product.
        Also, there are times when manufacturing changes are demonstrated 
    to have an adverse effect on the identity, strength, quality, purity, 
    or potency of the drug product. In many cases the applicant chooses not 
    to implement these manufacturing changes, but in other cases the 
    applicant may still wish to do so. If an assessment by the sponsor 
    shows that a manufacturing change has adversely affected the identity, 
    strength, quality, purity, or potency of the drug product and the 
    sponsor wants to make the change, the change should be filed in a 
    supplement that requires review and approval by FDA before distribution 
    of the product, regardless of whether the change is listed as an 
    example of one that normally does not need FDA approval prior to 
    distribution of the product made with the change. The applicant should 
    submit this change in a supplement that requires review and approval 
    with appropriate information to demonstrate that the manufacturing 
    change has not altered the continued safety and effectiveness of the 
    product. The agency will assess the effect of any adverse change in a 
    drug product, as the change may relate to the safety or effectiveness 
    of the product, during the review of the supplement that requires 
    approval prior to distribution of the product.
        Proposed Sec. 514.8(b)(2)(ii) lists examples of those changes 
    requiring submission and approval of a supplement prior to 
    distribution, including those designated as major manufacturing changes 
    in section 506A(c)(2) of the act, and changes to certain biotechnology 
    products. These changes have a substantial potential to have an adverse 
    effect on the identity, strength, quality, purity, or potency of the 
    product as these factors may relate to the safety or effectiveness of 
    the product. The agency's continued review and approval of these 
    changes prior to product distribution is necessary to protect the 
    animals and the public from products for which safety or effectiveness 
    may have been compromised.
        FDA is proposing to describe additional specific examples of 
    changes that have substantial, moderate, and minimal potential to 
    adversely affect a product in guidance documents rather than enumerate 
    them in the proposed regulations. As discussed previously, section 506A 
    of the act expressly states that the agency, through guidance, may 
    categorize the manufacturing changes. FDA anticipates that scientific 
    advances and future experience may reduce the need for approval of 
    supplements providing for certain changes, and the agency will respond 
    to changed circumstances by revising the guidance documents. A notice 
    of availability of a draft guidance document entitled ``Guidance for 
    Industry: Chemistry, Manufacturing and Controls Changes to an Approved 
    NADA or ANADA,'' that provides more detailed recommendations on how to 
    report proposed changes, is being published elsewhere in this issue of 
    the Federal Register, and the agency is soliciting comments on the 
    draft guidance in addition to the proposed rule.
        In regard to proposed Sec. 514.8(b)(2)(ii)(B), section 506A of the 
    act also states in part that ``* * * equivalence of the drug to the 
    drug as manufactured without the change'' should be demonstrated. For 
    those generic drug products for which, at the time of approval, a 
    generic drug applicant was required to show equivalence between the 
    proposed generic drug and a reference listed drug (typically the 
    referenced pioneer drug product), a proposed manufacturing change 
    should not significantly change the equivalence demonstrated at the 
    time of approval. In addition, for the more significant manufacturing 
    changes for generic drugs the approval of which relied on a 
    demonstration of bioequivalence to a reference listed drug, the 
    applicant is required to conduct a bioequivalence study comparing the 
    drug product made with the change to the reference listed drug, 
    typically the pioneer drug product.
        Under proposed Sec. 514.8 (b)(2)(ii)(G) changes to a product under 
    an application that is subject to a validity assessment because of 
    significant questions regarding the integrity of the data supporting 
    the application require approval prior to distribution. Until questions 
    about the integrity of the data in the application have been resolved, 
    there are inadequate assurances that any change will not adversely 
    affect the safety or effectiveness of the product. Moreover, a change 
    to a product cannot be validated, as required under 506A(b) of the act, 
    until the integrity of the underlying data in such an application is 
    validated. Consequently, there is a significant potential that the 
    change will have an adverse effect on the identity, strength, quality, 
    purity, or potency of the product. After a validity assessment has been 
    completed, and data integrity questions resolved, the holder of an 
    approved application may submit supplements for manufacturing changes 
    as otherwise provided in Sec. 514.8.
        Current Sec. 514.8(a)(4)(iii), (a)(4)(iv), and (a)(4)(v) regarding 
    general manufacturing and control changes requiring approval prior to 
    distribution are not included in proposed Sec. 514.8(b)(2), because 
    some of these changes would fall into the proposed major manufacturing 
    change category while others would fall into other proposed categories 
    depending on whether the change is considered to have a substantial, 
    moderate, or minimal potential to adversely affect the
    
    [[Page 53286]]
    
    identity, strength, quality, purity, or potency of the drug as they may 
    relate to the safety or effectiveness of the drug. FDA plans to provide 
    recommendations on how to submit the supplements in guidance documents, 
    including the draft guidance document mentioned previously. Current 
    Sec. 514.8(a)(4)(v) relating to identification of distributors has been 
    updated and reproposed as Sec. 514.8(c)(4).
        Proposed Sec. 514.8(b)(2)(iii) states that the applicant must 
    obtain approval of a supplement from FDA before distributing a product 
    using a change under Sec. 514.8(b)(2), and it specifies information to 
    be included in the supplement.
        Proposed Sec. 514.8(b)(2)(iv) permits a request for an expedited 
    review of a supplement for public health reasons or if a delay in 
    making the change described in the supplement would impose an 
    extraordinary hardship on the applicant. FDA is including this 
    provision for expedited review for extraordinary hardship reasons but 
    wishes to clarify that these requests should focus on manufacturing 
    changes made necessary by catastrophic events (e.g., fire) or by events 
    that could not be reasonably foreseen and for which the applicant could 
    not plan. Requests for expedited review will be assessed on a case-by-
    case basis. All requests may not be granted.
        Under proposed Sec. 514.8(b)(2)(v), an applicant may submit one or 
    more protocols describing specific tests, validation studies, and 
    acceptable limits to be achieved to demonstrate the lack of an adverse 
    effect for specified types of manufacturing changes on the identity, 
    strength, quality, purity, or potency of the drug as these factors may 
    relate to the safety or effectiveness of the drug. Such protocols, or 
    changes to a protocol, would be submitted as a supplement requiring 
    approval from FDA prior to distribution. If approved, the use of such a 
    protocol in making the specified changes may justify a reduced 
    reporting category for the change because of the reduced risk of an 
    adverse effect.
        Generally, when considering a change in the manufacture of a 
    product, the manufacturer will prepare a protocol, often called a 
    ``comparability protocol,'' identifying tests to be performed in 
    evaluating the change and its effect on the product and defining the 
    criteria against which the impact of the change will be evaluated. By 
    providing FDA an opportunity to review and approve the comparability 
    protocol before it is used by the applicant to evaluate a change, FDA 
    can have a greater assurance that the change is being properly 
    evaluated and there is, therefore, less potential for the change to 
    have an adverse effect on the safety or effectiveness of the product.
    
    D. Changes Requiring Supplement Submission at Least 30 Days Prior to 
    Distribution of the Drug Product Made Using the Change (Moderate 
    Changes)
    
        Current Sec. 514.8(d)(3) provides for manufacturing changes that 
    give an increased assurance that the drug will have the characteristics 
    of identity, strength, quality, and purity that it purports or is 
    represented to possess to be placed into effect at the earliest 
    possible time. Proposed Sec. 514.8(b)(3) implements section 
    506A(d)(1)(B) and (d)(3) of the act and provides that products made 
    using the changes listed under this section may only be distributed not 
    sooner than 30 days after receipt of a supplement by FDA. FDA 
    recognizes that animal and the public health can be adequately 
    protected without requiring approval of certain manufacturing changes 
    prior to distribution of the product made with the change. FDA 
    continues to believe that it is important that such changes be 
    documented and validated so that there is a mechanism for assessing the 
    consequences of the change and that the agency approve such changes. 
    The requirement to submit a supplement 30 days before distribution of 
    the product balances FDA's need to review applications to protect 
    against the distribution of unsafe or ineffective products and the need 
    to make improved products available.
        Proposed Sec. 514.8(b)(3)(i) would require that a supplement be 
    submitted for any change in the product, 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 product as these factors may relate to the safety or 
    effectiveness of the product. Proposed Sec. 514.8(b)(3)(iii) states 
    that a supplement submitted under Sec. 514.8(b)(3)(i) is required to 
    give a full explanation of the basis for the change and identify the 
    date on which the change is to be made, and that the supplement must be 
    labeled ``Supplement--Changes Being Effected in 30 Days.''
        Proposed Sec. 514.8(b)(3)(ii) describes the types of changes that 
    require submission of a supplement 30 days before distribution.
        Proposed Sec. 514.8(b)(3)(iv) states that distribution of a product 
    made using a change listed under this section may not begin until 30 
    days after receipt of a supplement by FDA. This section would also 
    require that the same information listed in proposed 
    Sec. 514.8(b)(2)(iii), discussed previously, must be contained in the 
    supplement required under proposed Sec. 514.8(b)(3).
        According to proposed Sec. 514.8(b)(3)(v), during the 30-day period 
    following receipt of the supplement, FDA would perform a preliminary 
    review to determine whether the supplement is complete and whether the 
    type of change is appropriate for review as a supplement under proposed 
    Sec. 514.8(b)(3). If the proposed change is determined to be a major 
    change that should appropriately be submitted under proposed 
    Sec. 514.8(b)(2), the agency would inform the applicant and the 
    applicant would be required to receive FDA's approval before a product 
    produced with the change could be distributed. If FDA determines that 
    the change is properly submitted as a supplement under 
    Sec. 514.8(b)(3)(i), but the required information is incomplete, the 
    applicant would be required to supply the missing information and wait 
    until FDA has determined that the supplement is in compliance before 
    distributing the product.
        Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a 
    supplemental application under this section, the agency may order the 
    manufacturer to cease distribution of the drug products made with the 
    manufacturing change. This amendment would implement section 
    506A(d)(3)(B)(iii) of the act.
    
    E. Changes That May Be Implemented When FDA Receives a Supplement 
    (Moderate Changes)
    
        Section 506A(d)(3)(B)(ii) of the act gives FDA authority to 
    designate a category of changes for which the holder of an approved 
    application making such change may begin distribution of the drug upon 
    receipt by FDA of a supplemental application for the change. FDA 
    recognizes that animals and the public can be adequately protected 
    without requiring approval of certain manufacturing changes prior to 
    distribution of the product made with the change. FDA continues to 
    believe that it is important that such changes be documented and 
    validated so that there is a mechanism for assessing the consequences 
    of the change and that the agency approve such changes. However, based 
    on FDA's experience, certain changes may be implemented when FDA 
    receives the supplement, rather than delaying distribution for 30 days 
    because, in general, these changes provide the same or increased 
    assurance that the product will have the characteristics of identity, 
    strength,
    
    [[Page 53287]]
    
    quality, purity, or potency that it purports or is represented to have. 
    Submission of a supplement gives FDA ready access to information 
    regarding such changes. The requirement for approval of such 
    supplements allows FDA to protect against the distribution of unsafe or 
    ineffective products while allowing products that are likely to be 
    improved to be available more quickly. Examples of such changes are 
    listed in proposed Sec. 514.8(b)(3)(vi). The supplement submitted under 
    this paragraph is required to give a full explanation of the basis for 
    the change and the supplement must be labeled ``Supplement--Changes 
    Being Effected.''
        Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a 
    supplemental application under this section, the agency may order the 
    manufacturer to cease distribution of the drug products made with the 
    manufacturing change.
        Current Sec. 514.8(d) describes the types of changes that can be 
    placed into effect at the earliest possible time. Such changes are 
    being described in proposed Sec. 514.8(b)(3)(vi) and (c)(3).
    
    F. Changes and Updated Stability Data to Be Described and Submitted in 
    an Annual Report (Minor Changes)
    
        Minor manufacturing changes are currently submitted in an annual 
    report under Sec. 510.300(b)(6) as referenced in current 
    Sec. 514.8(a)(5) or in a biennial supplement. Proposed Sec. 514.8(b)(4) 
    would provide that changes to the product, 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 as these factors may relate to the safety or effectiveness of 
    the product be documented by the applicant in the next annual report, 
    i.e., ``Minor Changes and Stability Report,'' as described under 
    proposed Sec. 514.8(b)(4). FDA recognizes that there are manufacturing 
    changes that have a minimal potential to have an adverse affect on a 
    product's safety or effectiveness. FDA believes that agency approval of 
    these changes prior to product distribution is unnecessary and is 
    proposing in Sec. 514.8(b)(4) that such changes would not be required 
    to be approved by the agency. FDA continues to believe that it is 
    important that such changes be documented and validated so that FDA can 
    assess the consequences of the change. FDA can effectively assess 
    compliance with this section and CGMP requirements for changes that 
    have a minimal potential to adversely affect the product's safety or 
    effectiveness by having ready access to information regarding such 
    changes through submission of an annual report and by inspection.
        Section 506A(d)(1)(C) of the act authorizes FDA to establish 
    reporting categories (i.e., annual report) of manufacturing changes 
    (i.e., minor changes) that may be made without submitting a 
    supplemental application. Section 506A(d)(2)(A) of the act permits 
    minor changes to be reported separately or in an annual report. Section 
    506A of the act has no provisions for reporting minor manufacturing 
    changes in biennial supplements as permitted by CVM's pilot program. 
    Therefore, all minor manufacturing changes described in regulations or 
    guidance should be submitted in an MCSR to the application annually. 
    The MCSR will be reviewed by the appropriate CVM office that reviews 
    manufacturing supplements. No manufacturing changes or updated 
    stability data are to be reported in the periodic DER that is submitted 
    to CVM's OSC. But reports of manufacturing defects must continue to be 
    submitted to OSC. The MCSR must be submitted each year within 60 days 
    of the anniversary of approval of the application or mutually agreed 
    upon date. Proposed Sec. 514.8(b)(4)(ii) lists examples of changes that 
    can be reported in the MCSR.
        Proposed Sec. 514.8(b)(4)(iii) states that the MCSR must list all 
    products to which minor changes were made.
        Proposed Sec. 514.8(b)(4) replaces current Sec. 514.8(a)(5).
    
    G. Labeling and Other Changes Requiring Submission and Approval of a 
    Supplement Prior to Distribution of the Product Made Using the Change 
    (Major Changes)
    
        Labeling changes addressed in current Sec. 514.8(a) and (b) are 
    newly addressed by proposed Sec. 514.8(c). Proposed Sec. 514.8(c)(1) 
    describes when an applicant must notify FDA that the applicant is 
    making such a change to an approved application. This section states 
    that an applicant must notify FDA about each change in each condition 
    established in an approved application beyond the variations already 
    provided for in the application, and that the notice is required to 
    describe the change fully.
        Proposed Sec. 514.8(c)(2) updates current Sec. 514.8(a)(3), 
    (a)(4)(i) and (a)(4)(ii) regarding labeling changes and addition of 
    intended use requiring preapproval supplements. Labeling and other 
    changes requiring submission of a supplemental application are 
    described in proposed Sec. 514.8(c)(2)(i).
        Proposed Sec. 514.8(c)(2)(ii) requires an applicant to obtain 
    approval of a supplement by FDA before distributing a product subject 
    to a change listed under Sec. 514.8(c)(2)(i), and specifies information 
    to be included in the supplement.
        Current Sec. 514.8(a)(3) regarding mailing or promotional pieces 
    for a prescription drug has been updated and is included under proposed 
    Sec. 514.8(c)(2). Current Sec. 514.8(a)(4)(i) and (a)(4)(ii) regarding 
    revisions in labeling and addition of claim, respectively, have been 
    updated and included under proposed Sec. 514.8(c)(2)(i)(A) and 
    (c)(2)(i)(B).
    
    H. Labeling Changes To Be Placed Into Effect Prior to Receipt of a 
    Written Notice of Approval of a Supplemental Application
    
        Proposed Sec. 514.8(c)(3) updates and redesignates current 
    Sec. 514.8(d) regarding labeling changes to be placed into effect prior 
    to receipt of a written notice of approval of a supplemental 
    application.
        Proposed Sec. 514.8(c)(3)(i) requires labeling changes that 
    increase the assurance of product safety, such as additional warnings, 
    contraindications, or side effects or deletions of false, misleading, 
    or unsupportive statements; and any other changes as directed by FDA to 
    be placed into effect immediately. These changes, proposed 
    Sec. 514.8(c)(3)(i)(A) and (c)(3)(i)(B), are listed in current 
    Sec. 514.8(d)(1) and (d)(2).
        Proposed Sec. 514.8(c)(3)(ii) permits labeling changes to the style 
    and format that do not decrease the safety of product approved in 
    supplemental applications to be placed into effect prior to written 
    notice of approval from FDA of a supplemental application.
        Proposed Sec. 514.8(c)(3)(iii) updates current Sec. 514.8(e) and 
    describes what must be included in a supplement submitted under 
    Sec. 514.8(c)(3). FDA will not take action against products or sponsors 
    solely because a change in labeling described in Sec. 514.8(c)(3) is 
    implemented prior to FDA receipt and approval of a supplement if the 
    information listed in Sec. 514.8(c)(3)(iii) has been submitted to the 
    agency.
        Proposed Sec. 514.8(c)(4) would require applicants to notify CVM of 
    additional designated distributors under proposed Sec. 514.80(a)(2), 
    (b)(3), and (b)(5)(iii) (Records and reports concerning experience with 
    new animal drugs for which an approved application is in effect.--as 
    noted in section IV.B of this document, CVM expects to publish the 
    final rule for Sec. 514.80 before the final rule for this document). 
    This notification will be accompanied by a Form FDA 2301, submitted to 
    DER, and reported at the time of initial product distribution by the 
    new distributor. This type of change is not considered a
    
    [[Page 53288]]
    
    manufacturing change, rather a type of labeling change to be reported 
    to the Division of Epidemiology and Surveillance in the OSC, CVM.
        In addition to section 506A of the act, other sections of the act 
    authorize FDA to propose Sec. 514.8. Section 501 of the act (21 U.S.C. 
    351) prohibits the manufacture, processing, packing, or holding of 
    drugs that do not conform to CGMP; the use of an unsafe new animal drug 
    under the meaning of section 512 of the act; the use of unsafe color 
    additives in or on a drug under section 721 of the act (21 U.S.C. 
    379e); and the distribution of a drug that differs in the strength, 
    purity, or quality that it purports or is represented to possess. 
    Section 502 of the act (21 U.S.C. 352) prohibits false or misleading 
    labeling of drugs, drugs that lack adequate directions for use and 
    adequate warnings, and the distribution of drugs that are dangerous to 
    health when used in the manner suggested in the labeling. Under section 
    512 of the act, FDA will approve an application for a new intended use 
    of a new animal drug if, among other things, the methods used in, and 
    the facilities and controls used for, the manufacture, processing, and 
    packing of such drug are adequate to preserve its identity, strength, 
    quality, and purity. Section 701 of the act (21 U.S.C. 371) authorizes 
    FDA to issue regulations for the efficient enforcement of the act.
    
    I. Other Information.
    
        Proposed Sec. 514.8(d) regarding patent information is included to 
    comply with section 512(c)(3) of the act. Proposed Sec. 514.8(e) 
    regarding claimed exclusivity is included to comply with section 
    512(c)(2)(F) of the act. Proposed Sec. 514.8(f) regarding good 
    laboratory practice for nonclinical laboratory studies is redesignated 
    as current Sec. 514.8(l).
    
    J. Sections Proposed for Removal
    
        The agency is proposing that a number of paragraphs be removed 
    after reevaluation of the regulations covering changes to an approved 
    application because the agency has determined that these paragraphs are 
    no longer relevant to current practices. These regulations are 
    described in the next two paragraphs.
        FDA has determined that the regulations covering special 
    circumstances of NADA's effective prior to October 10, 1962, are no 
    longer needed. Thus FDA is proposing to eliminate current 
    Sec. 514.8(g), (k), and (j).
        Current Sec. 514.8(h) stating that nothing in Sec. 514.8 limits the 
    Secretary of Health and Human Services's authority to suspend or 
    withdraw approval of a new animal drug application is adequately 
    addressed in section 512(c)(1)(F) of the act and need not be addressed 
    in the proposed regulations. Similarly, FDA is removing current 
    Sec. 514.8(i) that provides for a deferral of final action on 
    supplemental applications as described under current Sec. 514.8(d), 
    (e), and (g).
    
    K. Section 514.106 Approval of Supplemental Applications
    
        This proposal would modify Sec. 514.106(b) regarding the 
    administrative categorization of supplemental applications to provide 
    for proper references to proposed Sec. 514.8.
    
    V. Conforming Amendments
    
        A number of sections in the regulations covering new animal drugs 
    are affected by these proposed changes. Conforming changes are being 
    proposed in Secs. 5.83, 25.33, 500.25, 510.300, 514.106, and 558.5 
    because of the reorganization of the existing information or 
    introduction of new requirements.
    
    VI. Environmental Impact
    
        The agency has determined under 21 CFR 25.24(h) that this action is 
    of a type that does not individually or cumulatively have a significant 
    effect on the human environment. Therefore, neither an environmental 
    assessment nor an environmental impact statement is required.
    
    VII. Analysis of Impacts
    
        FDA has examined the impacts of the proposed rule under Executive 
    Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
    Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
    Order 12866 directs agencies to assess all costs and benefits of 
    available regulatory alternatives and, when regulation is necessary, to 
    select regulatory approaches that maximize net benefits (including 
    potential economic, environmental, public health and safety, and other 
    advantages; distributive impacts; and equity). Executive Order 12866 
    classifies a rule as significant if it meets any one of a number of 
    specified conditions, including having an annual effect on the economy 
    of $100 million or adversely affecting in a material way a sector of 
    the economy, competition, or jobs. The agency believes that this 
    proposed rule is consistent with the regulatory philosophy and 
    principles identified in the Executive Order. The Office of Management 
    and Budget (OMB) has determinied that this proposed rule is a 
    significant regulatory action subject to review under the Executive 
    Order.
        The agency is proposing to amend current Sec. 514.8 to implement 
    section 116 of the Modernization Act. This section establishes 
    reporting procedures and requirements for making major and other 
    manufacturing changes to an approved NADA or ANADA. The intent of 
    section 506A of the act and this proposed rule is to permit sponsors to 
    use a less burdensome notification procedure for some types of changes, 
    while also clarifying the regulations and harmonizing them, where 
    possible, with CDER's and CBER's regulations. Downgrading the level of 
    agency review for some of these supplements will lead to compliance 
    cost savings due to the resulting improvement in manufacturing 
    efficiencies.
        The agency has not estimated the value of the expected improvements 
    in manufacturing efficiencies due to the myriad of factors affecting 
    the production schedules of new animal drugs. FDA believes, however, 
    that these changes will result in shorter average lag times between the 
    decision to make certain minor changes to the manufacturing process for 
    a new animal drug and the time at which that change can be implemented. 
    A report by the Eastern Research Group, an FDA contractor, on the 
    effects of the human drug scale-up and postapproval change guidance for 
    immediate release solid oral dosage form (SUPAC-IR), concluded that 
    this type of supplement change can result in significant net savings to 
    industry. In particular, the report found that companies gain greater 
    control over their production resources and ``shorter waiting times for 
    changes that can now be filed as Changes Being Effected (CBE's) or 
    annual reports.''
        The proposed rule contains four reporting categories for 
    supplemental chemistry, manufacturing and control (CMC) changes, 
    whereas the current regulation Sec. 514.8 contains three. The first 
    category concerns those changes requiring approval prior to 
    implementation and defines what is included in a ``major'' change. 
    These requirements are very similar to those in the existing 
    regulation, but clarify some of the existing language. The second 
    category is a new ``30-day changes being effected,'' or 30-day CBE 
    category. The purpose of this new category is to provide for a less 
    burdensome method of reporting some ``moderate'' CMC changes that 
    previously were reported as major changes requiring approval before 
    implementation. The firm submitting the supplement will be able to 
    implement the change more quickly
    
    [[Page 53289]]
    
    as it will no longer require agency approval before implementation.
        The third category concerns those supplement changes that can be 
    effected upon the agency's receipt of submission of the supplemental 
    application. The current regulation concerning this reporting category 
    contained language that allowed for the change ``at the earliest 
    possible time,'' while the act specifically dictates the change be 
    allowed at the time of agency receipt of the supplement. The fourth 
    category concerns the minor manufacturing changes and updated stability 
    data to be submitted in an MCSR. This annual MCSR replaces the current 
    regulation that also requires an annual report of these changes. 
    Nevertheless, those firms currently reporting these CMC changes in the 
    biennial supplement described previously in this document, will incur 
    the additional burden of an extra report every other year.
        Based on prior years' submissions, the agency estimates that it 
    will receive about 906 CMC supplements. According to estimates from 
    agency reviewers, about 755 of these would have required preapproval 
    under the current regulation. Under the proposed rule, the number 
    requiring preapproval is estimated at 154. The difference of 601 
    supplements represents the approximate number of additional changes 
    that can be made without agency approval. Companies submitting these 
    supplements will have the opportunity to make quicker changes and 
    realize increased manufacturing efficiencies.
        Further savings are expected from another provision of the rule 
    that concerns labeling supplements. Currently, labeling supplements are 
    required to include nine copies of the labeling in the submission. The 
    proposed rule would lower this requirement to two copies, providing 
    further small savings for industry. Although the proposal also 
    reorganizes the rules for labeling supplements, the agency does not 
    expect these changes to alter the number of labeling supplements 
    submitted annually.
        The creation of the MCSR may provide additional opportunity for 
    savings because it may include minor manufacturing changes that were 
    previously submitted as CBE's or other supplement types that require a 
    higher level of review. Under the proposal, each firm will be able to 
    accumulate and submit them together each year, rather than 
    individually.
    
    A. Regulatory Flexibility Analysis
    
        The Regulatory Flexibility Act requires agencies to analyze 
    regulatory options to minimize any significant impact on small 
    entities. The proposed rule implements section 506A of the act. The 
    intent of the rule is to clarify the regulations for submitting 
    supplemental applications for new animal drugs, harmonize the 
    regulations with those for CDER and CBER, and lessen the compliance 
    burden for some supplements by reducing the level of agency review 
    necessary before implementation of certain changes. The effects of the 
    proposed rule will be spread across all firms that submit supplements, 
    regardless of their size. The Small Business Administration defines 
    small businesses as businesses with fewer than 750 employees. Because 
    these are the firms that are most likely to be submitting reports of 
    minor changes as prior approval supplements, even though not required 
    to do so by current regulations, rather than as biennial supplements as 
    allowed under CVM's pilot project, they are even more likely to realize 
    a benefit from this regulation than the larger industry members that 
    participated in CVM's pilot project. At worst, a few small firms 
    participating in CVM's pilot project may have to submit an annual 
    report rather than a biennial supplement. Because the burden of 
    submitting one additional report every other year will not impose a 
    significant cost on small businesses, the agency certifies that the 
    rule will not have a significant effect on a substantial number of 
    small entities.
    
    B. Unfunded Mandates Reform Act
    
        Section 202 of the Unfunded Mandates Reform Act requires that 
    agencies prepare an assessment of anticipated costs and benefits before 
    proposing any rule that may result in expenditure by State, local, and 
    tribal governments, in the aggregate, or by the private sector of $100 
    million or more (adjusted annually for inflation) in any one year. 
    Because the agency estimates that the proposed rule will not result in 
    expenditures of funds by State, local, and tribal governments or the 
    private sector in excess of $100 million or more in any one year, but 
    will result in only insignificant expenditures by the industry, and in 
    fact should provide a net savings, it is not required to perform a 
    cost/benefit analysis according to the Unfunded Mandates Reform Act.
    
    VIII. Paperwork Reduction Act of 1995
    
        This proposed rule contains information collection provisions that 
    are subject to review by the OMB under the Paperwork Reduction Act of 
    1995 (44 U.S.C. 3501-3520). The title, description, and respondent 
    description of the information collection provisions are shown below 
    with an estimate of the annual reporting burden. Included in the 
    estimate is the time for reviewing instructions, searching existing 
    data sources, gathering and maintaining the data needed, and completing 
    and reviewing each collection of information.
        FDA invites comments on: (1) Whether the proposed collection of 
    information is necessary for the proper performance of FDA's functions, 
    including whether the information will have practical utility; (2) the 
    accuracy of FDA's estimate of the burden of the proposed collection of 
    information, including the validity of the methodology and assumptions 
    used; (3) ways to enhance the quality, utility, and clarity of the 
    information to be collected; and (4) ways to minimize the burden of the 
    collection of information on respondents, including through the use of 
    automated collection techniques, when appropriate, and other forms of 
    information technology.
        Title: Supplements and Other Changes to Approved New Animal Drug 
    Applications.
        Description: As directed by the Modernization Act, FDA is proposing 
    regulations to describe reporting procedures and requirements for 
    making major and other manufacturing changes to an approved NADA. The 
    proposed regulations also describe reporting procedures and 
    requirements for making labeling changes to an approved NADA. Under 
    proposed Sec. 514.8(b)(2) and (c)(2), the agency will continue to 
    require an approved supplemental application prior to distribution of a 
    product made with a major manufacturing or labeling change to an 
    approved NADA. Major manufacturing changes are those determined to have 
    substantial potential to adversely affect the identity, strength, 
    quality, purity, or potency of the drug. For moderate manufacturing 
    changes, as defined in proposed Sec. 514.8(b)(3), sponsors would be 
    required to submit a supplemental application at least 30 days prior to 
    distribution of the product made using the change. Under proposed 
    Sec. 514.8(b)(4), sponsors would not be required to submit supplemental 
    applications for minor manufacturing changes, but would describe these 
    changes in annual reports. Additionally, under proposed 
    Sec. 514.8(c)(3), certain labeling changes would require supplemental 
    applications, but would be placed into effect immediately.
        Under current regulations, CVM evaluates all manufacturing and 
    labeling changes to approved NADA's whether they are submitted as 
    permitted changes, CBE's, or those requiring approval prior to 
    implementation. CVM provided greater flexibility to the
    
    [[Page 53290]]
    
    current regulations by permitting the reporting of minor manufacturing 
    changes in a biennial supplement, as discussed earlier in this 
    document. Changes mandated by the Modernization Act will supersede this 
    practice, replacing the biennial supplement with an annual report, the 
    MCSR.
        The proposed rule is expected to lessen paperwork burden by 
    requiring: (1) Fewer copies of labels for labeling changes, (2) fewer 
    submissions because certain changes that are submitted under the 
    current rule as individual CBE's or other supplement types may now be 
    accumulated and submitted together once a year in the MCSR, and (3) 
    agency approval of fewer types of changes.
        Listed in Table 1 of this document is an estimate of the burden 
    placed on industry for the various types of submissions discussed in 
    the proposed regulation. FDA based the number of respondents upon the 
    total number of potential sponsors. The number of total annual 
    responses was derived from agency reviewers' estimates based upon prior 
    years' submissions. The number of responses per respondent is an 
    estimate that the agency arrived at by dividing the number of total 
    responses the agency expects to receive by the total number of 
    potential responses. Changes under Sec. 514.8(b)(2) through (b)(4) and 
    (c)(2) through (c)(3) are submitted on FDA Form 356V (OMB approval 
    number 0910-0032). Labeling changes under Sec. 514.8(c)(4) are made on 
    FDA Form 2301 (OMB approval number 0910-0019).
        Description of Respondents: Sponsors of new animal drug 
    applications.
        In compliance with section 3507(d) of the Paperwork Reduction Act 
    of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information 
    collection provisions of this proposed rule to OMB for review. 
    Interested persons are requested to send comments regarding this 
    information collection by November 1, 1999, to the Office of 
    Information and Regulatory Affairs, OMB, New Executive Office Bldg., 
    725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Wendy Taylor, 
    Desk Officer for FDA.
        FDA estimates the burden of this collection of information as 
    follows:
    
                                     Table 1.--Estimated Annual Reporting Burden\1\
    ----------------------------------------------------------------------------------------------------------------
                                                          No. of
             21 CFR Section               No. of       Responses per   Total Annual      Hours per         Total
                                        Respondents     Respondents      Responses       Response
    ----------------------------------------------------------------------------------------------------------------
    514.8(b)(2)(iii)                      190               0.81          154             100          15,400
    514.8(b)(2)(v)                        190               0.59          112              80           8,960
    514.8(b)(3)(i)                        190               2.64          502              60          30,120
    514.8(b)(3)(vi)                       190               1.32          250              60          15,000
    514.8(b)(4)                           190               5.17          982              24          23,568
    514.8(c)(2)                           190               0.26           50              20           1,000
    514.8(c)(3)                           190               0.26           50              60           3,000
    514.8(c)(4)                           190               0.39           74               3             222
    Total                                                               2,174                          97,270
    ----------------------------------------------------------------------------------------------------------------
    \1\ There are no capital costs or operating and maintenance costs associated with this collection of
      information.
    
    IX. Comments
    
        Interested persons may, on or before December 15, 1999, submit to 
    the Dockets Management Branch (address above) written comments 
    regarding this proposed rule. Two copies of any comments are to be 
    submitted, except that individuals may submit one copy. Comments are to 
    be identified with the docket number found in brackets in the heading 
    of this document. Received comments may be seen in the office above 
    between 9 a.m. and 4 p.m., Monday through Friday.
    
    List of Subjects
    
    21 CFR Part 5
    
        Authority delegations (Government agencies), Imports, Organization 
    and functions (Government agencies).
    
    21 CFR Part 25
    
        Environmental impact statements, Foreign relations, Reporting and 
    recordkeeping requirements.
    
    21 CFR Part 500
    
        Animal drugs, Animal feeds, Cancer, Labeling, Packaging and 
    containers, Polichlorinated biphenyls (PCB's).
    
     21 CFR Part 510
    
        Administrative practice and procedure, Animal drugs, Labeling, 
    Reporting and recordkeeping requirements.
    
    21 CFR Part 514
    
        Administrative practice and procedure, Animal drugs, Confidential 
    business information, Reporting and recordkeeping requirements.
    
    21 CFR Part 558
    
        Animal drugs, Animal feeds.
        Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
    authority delegate to the Commissioner of Food and Drugs, it is 
    proposed that 21 CFR parts 5, 25, 500, 510, 514, and 558 be amended as 
    follows:
    
    PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION
    
        1. The authority citation for 21 CFR part 5 continues to read as 
    follows:
    
        Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15 
    U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C. 
    41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35 
    U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 
    264, 265, 300u-300u-5, 300aa-l; 1395y, 3246b, 4332, 4831(a), 10007-
    10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O. 
    12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.
    
        2. Section 5.83 is amended by revising paragraph (c) to read as 
    follows:
    
    
    Sec. 5.83  Approval of new animal drug applications, medicated feed 
    mill license applications and their supplements.
    
    * * * * *
        (c) The Director, Division of Manufacturing Technologies, Office of 
    New Animal Drug Evaluation, CVM, is authorized to perform all of the 
    functions of the Commissioner of Food and Drugs with regard to the 
    approval of supplemental applications that are described by 
    Sec. 514.8(b)(2) and (b)(3) of this chapter.
    * * * * *
    
    PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS
    
        3. The authority citation for 21 CFR part 25 continues to read as 
    follows:
    
        Authority: 21 U.S.C. 321-393; 42 U.S.C. 262, 263b-264; 42 U.S.C. 
    4321, 4332; 40 CFR parts 1500-1508; E.O. 11514, 35 FR 4247, 3 CFR, 
    1971 Comp., p. 531-533 as amended by
    
    [[Page 53291]]
    
    E.O. 11991, 42 FR 26967, 3 CFR, 1978 Comp., p. 123-124 and E.O. 
    12114, 44 FR 1957, 3 CFR, 1980 Comp., p. 356-360.
    
    Sec. 25.33  [Amended]
    
        4. Section 25.33 Animal drugs is amended in paragraph (a)(4) by 
    removing ``514.8(a)(5), (a)(6), or (d)'' and by adding in its place 
    ``514.8(b)(3), (b)(4), or (c)(3)''.
    
    PART 500--GENERAL
    
        5. The authority citation for 21 CFR part 500 continues to read as 
    follows:
    
        Authority: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 
    360b, 371.
    
    
    Sec. 500.25  [Amended]
    
        6. Section 500.25 Anthelmintic drugs for use in animals is amended 
    in the first sentence of paragraph (c) by removing ``514.8(d) and (e)'' 
    and by adding in its place ``514.8(c)(3)''.
    
    PART 510--NEW ANIMAL DRUGS
    
        7. The authority citation for 21 CFR part 510 continues to read as 
    follows:
    
        Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.
    
    
    Sec. 510.300  [Amended]
    
        8. Section 510.300 Records and reports concerning experience with 
    new animal drugs for which an approved application is in effect is 
    amended by removing paragraph (a)(6).
    
    PART 514--NEW ANIMAL DRUG APPLICATIONS
    
        9. The authority citation for 21 CFR part 514 is revised to read as 
    follows:
    
        Authority: 21 U.S.C. 351, 352, 356a, 360b, 371, 379e, 381.
        10. Section 514.8 is revised to read as follows:
    
    
    Sec. 514.8  Supplements and other changes to an approved application.
    
        (a) Definitions. (1) The definitions and interpretations contained 
    in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) 
    apply to those terms when used in this part.
        (2) The following definitions of terms apply to this part:
        (i) Listed drug means a new animal drug product that has an 
    effective approval under section 512 of the act, which has not been 
    withdrawn or suspended under section 512 of the act, and which has not 
    been withdrawn from sale for what the Food and Drug Administration 
    (FDA) has determined are reasons for safety or effectiveness. Listed 
    drug status is evidenced by the new animal drug product's 
    identification as a new animal drug with an effective approval in the 
    current edition of FDA's ``FDA Approved Animal Drug Products'' (the 
    list) or any current supplement thereto, as a new animal drug with an 
    effective approval. A new animal drug product is deemed to be a listed 
    drug on the date of effective approval of the application or 
    abbreviated application for that new animal drug product.
        (ii) Minor changes and stability report means an annual report that 
    is submitted to the new animal drug application or abbreviated new 
    animal drug application once each year within 60 days of the 
    anniversary of the application's original approval or a mutually agreed 
    upon date. The report must include minor manufacturing and controls 
    changes made according to Sec. 514.8(b)(4) or state that no changes 
    were made; and update stability data generated on commercial or 
    production batches according to the approved stability protocol/
    commitment.
        (iii) Specification means the quality standard (i.e., tests, 
    analytical procedures, and acceptance criteria) provided in an approved 
    new animal drug application or abbreviated new animal drug application 
    to confirm the quality of drug substances, drug products, 
    intermediates, raw materials, reagents, and other components including 
    container closure systems, and in-process controls. For the purpose of 
    this definition, acceptance criteria means numerical limits, ranges, or 
    other criteria for the tests described.
        (iv) Validate the effects of the change means to assess the effect 
    of a manufacturing change on the identity, strength, quality, purity, 
    or potency of a new animal drug as these factors relate to the safety 
    or effectiveness of the new animal drug.
        (v) The list means the list of new animal drug products with 
    effective approvals published in the current edition of FDA's 
    publication ``FDA Approved Animal Drug Products'' and any current 
    supplement to the publication.
        (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 include the information in the 
    annual report to the application described in paragraph (b)(4) of this 
    section.
        (ii) The holder of an approved application under section 512 of the 
    act must validate the effect of the change on the identity, strength, 
    quality, purity, or potency of the new animal drug as these factors may 
    relate to the safety or effectiveness of the new animal drug 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 product or by notification in the next annual 
    report described in paragraph (b)(4) of this section).
        (iv) The applicant must include in each supplemental application 
    providing for a change under paragraph (b)(2) or (b)(3) of this 
    section, a statement certifying that a copy of the supplement has been 
    provided to the appropriate FDA district office.
        (v) The cover letter for 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.
        (2) Changes requiring submission and approval of a supplement prior 
    to distribution of the product made using the change (major changes). 
    (i) A supplement must be submitted for any change in the product, 
    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 product as these factors 
    may relate to the safety or effectiveness of the product.
        (ii) These changes include, but are not limited to:
        (A) Except as provided in paragraphs (b)(3) and (b)(4) of this 
    section, changes in the qualitative or quantitative formulation of the 
    new animal drug, including inactive ingredients, or other 
    specifications as provided in the approved application;
        (B) Changes requiring completion of appropriate animal studies to 
    demonstrate the equivalence of the drug to the new animal drug as 
    manufactured without the change or to the reference listed drug;
        (C) Changes that may affect product sterility assurance, such as 
    changes in 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 new animal drug 
    substance that may affect the impurity
    
    [[Page 53292]]
    
    profile and/or the physical, chemical, or biological properties of the 
    drug substance;
        (E) Changes in a container closure system that controls drug 
    delivery or that may affect the impurity profile of the new animal drug 
    product;
        (F) Changes solely affecting a natural product, a recombinant DNA-
    derived protein/polypeptide product, or a complex or conjugate of a new 
    animal drug 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; and
        (G) Changes to a product under an application that is subject to a 
    validity assessment because of significant questions regarding the 
    integrity of the data supporting the application.
        (iii) The applicant must obtain approval of a supplement from FDA 
    prior to distribution of a product made using a change under paragraph 
    (b)(2) of this section. Except for submissions under paragraph 
    (b)(2)(v) of this section, the following must be contained in the 
    supplement:
        (A) A completed Form FDA 356V;
        (B) A detailed description of the proposed change;
        (C) The product(s) involved;
        (D) The manufacturing site(s) or area(s) affected;
        (E) A description of the methods used and studies performed to 
    evaluate the effect of the change on the identity, strength, quality, 
    purity, or potency of the product as these factors may relate to the 
    safety or effectiveness of the product (validation);
        (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 product, or a complex or conjugate of a drug with a 
    monoclonal antibody, relevant validation protocols 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, relevant 
    validation protocols must be provided in addition to the requirements 
    in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section;
        (J) A reference list of relevant standard operating procedures 
    (SOP's) when applicable; and
        (K) A claim for categorical exclusion under Sec. 25.30 or 
    Sec. 25.33 of this chapter or an environmental assessment under 
    Sec. 25.40 of this chapter.
        (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 should be plainly 
    marked: ``Prior Approval Supplement--Expedited Review Requested.''
        (v) An applicant may submit one or more protocols describing the 
    specific tests and validation studies and acceptable limits to be 
    achieved to demonstrate the lack of adverse effect for specified types 
    of manufacturing changes on the identity, strength, quality, purity, or 
    potency of the product as these factors may relate to the safety or 
    effectiveness of the product. Any such protocols, or change to a 
    protocol, must be submitted as a supplement requiring approval from FDA 
    prior to distribution of the product. The supplement, if approved, may 
    result in the proposed change subsequently falling within a reduced 
    reporting category because the use of the protocol for that type of 
    change reduces the potential risk of an adverse effect.
        (3) Changes requiring submission of a supplement at least 30 days 
    prior to distribution of the product made using the change (moderate 
    changes). (i) A supplement must be submitted for any change in the 
    product, 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 product as these 
    factors may relate to the safety or effectiveness of the product.
        (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 final new animal drug product; and
        (B) Changes solely affecting a natural product, a recombinant DNA-
    derived protein/polypeptide product or a complex or conjugate of a new 
    animal drug with a monoclonal antibody, including:
        (1) An increase or decrease in production scale during finishing 
    steps that involves new or different equipment; and
        (2) Replacement of equipment with that of similar, but not 
    identical, design and operating principle that does not affect the 
    process methodology or process operating parameters.
        (iii) A supplement submitted under paragraph (b)(3)(i) 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 to be made. The 
    supplement 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 
    product made using the moderate change under paragraph (b)(3) of this 
    section may begin not less than 30 days after receipt of the supplement 
    by FDA. The supplement must contain the information listed in 
    paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(K) of this section.
        (v) The applicant must not distribute the product 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 
    product 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. The applicant shall not distribute the product 
    until FDA determines that compliance with this section is achieved.
        (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 
    product involved upon receipt by the agency of a supplement for the 
    change. The information listed under paragraph (b)(2)(iii) 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 new animal 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 product from one container closure 
    system to another;
        (vii) If the agency disapproves the supplemental application 
    submitted under paragraph (b)(3) of this section, it
    
    [[Page 53293]]
    
    may order the manufacturer to cease distribution of the drug products 
    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 
    product, 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 product as these 
    factors may relate to the safety or effectiveness of the product must 
    be documented by the applicant in the annual report to the application 
    in accordance with paragraph (a)(2)(ii) of this section. The report 
    shall be labeled ``Minor Changes and Stability Report.''
        (ii) These changes include but are not limited to:
        (A) Any change made to comply with an official compendium that is 
    consistent with FDA requirements and provides increased assurance that 
    the new animal drug will have the characteristics of identity, 
    strength, quality, purity, or potency that it purports or is 
    represented to possess;
        (B) The deletion or reduction of an ingredient intended to affect 
    only the color of the product;
        (C) Replacement of equipment with that of the same design and 
    operating principles except for equipment used with a natural product, 
    a recombinant DNA-derived protein/polypeptide product, or a complex or 
    conjugate of a new animal drug with a monoclonal antibody;
        (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, without 
    a change from one container closure system to another;
        (E) A change within the container closure system for a nonsterile 
    new animal drug product, based upon 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 full production batches obtained from a protocol 
    approved in the application;
        (G) The addition, deletion, or revision of an alternate analytical 
    procedure that provides the same or increased assurance of the 
    identity, strength, quality, purity, or potency of the material being 
    tested as the analytical procedure described in the approved 
    application; 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 list of all products involved; and
        (A) A statement by the holder of the approved application that the 
    effects of the change have been validated;
        (B) A full description of the manufacturing and controls changes, 
    including the manufacturing site(s) or area(s) involved;
        (C) The date each change was made;
        (D) Cross reference to relevant validation protocols and/or SOP's;
        (E) Relevant data from studies and tests performed to evaluate the 
    effect of the change on the identity, strength, quality, purity, or 
    potency of the product as these factors may relate to the safety or 
    effectiveness of the product (validation);
        (F) 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; and
        (G) Updated stability data generated on commercial or production 
    batches according to an approved stability protocol.
        (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 product made using the change 
    (major changes). (i) Addition of intended uses, changes to labeling, 
    and prescription new animal drug mailing/promotional pieces require a 
    supplement. These changes include, but are not limited to:
        (A) Revision in labeling, such as updating information pertaining 
    to effects, dosages, side effects, contraindications, which includes 
    information headed ``side effects,'' ``warnings,'' ``precautions,'' and 
    ``contraindications,'' except ones described in (c)(3) of this section;
        (B) Addition of intended use;
        (C) If it is a prescription new animal drug, any mailing or 
    promotional piece used after the drug is placed on the market is 
    labeling requiring a supplemental application, unless:
        (1) Such labeling furnishing directions, warnings, and information 
    for use of the new animal drug are the same in language and emphasis as 
    labeling approved or permitted; and
        (2) Any other such 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 
    Sec. 514.80(b)(3)(ii).\1\
    ---------------------------------------------------------------------------
    
        \1\ Sec. 514.80 was proposed at 56 FR 65581, December 17, 1991.
    ---------------------------------------------------------------------------
    
        (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 product. The supplement must contain the 
    following:
        (A) A completed Form FDA 356V;
        (B) A detailed description of the proposed change;
        (C) The product(s) involved;
        (D) The manufacturing site(s) or area(s) affected;
        (E) The data derived from studies;
        (F) A claim for categorical exclusion under Sec. 25.30 or 
    Sec. 25.33 of this chapter or an environmental assessment under 
    Sec. 25.40 of this chapter; and
        (G) 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 product 
    safety proposed in supplemental applications must be placed into effect 
    immediately:
        (A) The addition to package labeling, promotional labeling, or 
    prescription new animal drug advertising of additional warning, 
    contraindication, side effect, 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 product 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--Changes Being 
    Effected'';
    
    [[Page 53294]]
    
        (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 new animal 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, FDA may order 
    the manufacturer to cease distribution of the drug under the proposed 
    labeling.
        (4) Changes providing for additional distributors to be reported 
    under Records and reports concerning experience with new animal drugs 
    for which an approved application is in effect (Sec. 514.80)\2\. 
    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 if the conditions described under Sec. 514.80(a)(2), 
    (b)(3), and (b)(5)(iii) are met.
    ---------------------------------------------------------------------------
    
        \2\ See footnote 1.
    ---------------------------------------------------------------------------
    
        (d) Patent information. The applicant shall 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 new animal drug 
    product, the applicant shall include such a statement.
        (f) Good laboratory practice for nonclinical laboratory studies. 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.
        11. Section 514.106 is amended by removing paragraph (b)(1)(xiv) 
    and by revising paragraphs (b)(1)(vi) and (b)(1)(xiii) to read as 
    follows:
    
    
    Sec. 514.106  Approval of supplemental applications.
    
    * * * * *
        (b) * * *
        (1) * * *
        (vi) A change in promotional material for a prescription new animal 
    drug not exempted by Sec. 514.8(c)(2)(i)(C)(3).
    * * * * *
        (xiii) A change permitted in advance of approval as described under 
    Sec. 514.8(b)(3).
    * * * * *
    
    PART 558--NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS
    
        12. The authority citation for 21 CFR part 558 continues to read as 
    follows:
    
        Authority: 21 U.S.C. 360b, 371.
    
    Sec. 558.5  [Amended]
    
        13. Section 558.5  New animal drug requirements for liquid Type B 
    feeds is amended in paragraph (e) by removing ``514.8(d) and (e)'' and 
    by adding in its place ``514.8(c)(3)''.
    
        Dated: June 23, 1999.
     Margaret M. Dotzel,
     Acting Associate Commissioner for Policy.
    [FR Doc. 99-25493 Filed 9-30-99; 8:45 am]
    BILLING CODE 4160-01-F
    
    
    

Document Information

Published:
10/01/1999
Department:
Food and Drug Administration
Entry Type:
Proposed Rule
Action:
Proposed rule.
Document Number:
99-25493
Dates:
Written comments by December 15, 1999.
Pages:
53281-53294 (14 pages)
Docket Numbers:
Docket No. 99N-1415
RINs:
0910-AB49: Supplements and Other Changes to Approved New Animal Drug Applications
RIN Links:
https://www.federalregister.gov/regulations/0910-AB49/supplements-and-other-changes-to-approved-new-animal-drug-applications
PDF File:
99-25493.pdf
CFR: (12)
21 CFR 514.8(b)(2)
21 CFR 514.8(b)(3)
21 CFR 514.80(b)(3)(ii).\1\
21 CFR 5.83
21 CFR 25.33
More ...