Guidance for Industry
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`
`Changes to an Approved
`
`
` NDA or ANDA
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` U.S. Department of Health and Human Services
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` Food and Drug Administration
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` Center for Drug Evaluation and Research (CDER)
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`
` April 2004
`
`CMC
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`
`
`Revision 1
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` P. 1
`
`UT Ex. 2050
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`
`
`
`
`Guidance for Industry
`
`
`
`
`
`
`
`Changes to an Approved
`
`NDA or ANDA
`
`
`
`
`
`
`Additional copies are available from:
`
`
`
`Office of Training and Communications
`
`
`Division of Drug Information, HFD-240
`
`Center for Drug Evaluation and Research
`
`
`Food and Drug Administration
`
`
`5600 Fishers Lane
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`
`Rockville, MD 20857
`
`(Tel) 301-827-4573
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`
`http://www.fda.gov/cder/guidance/index.htm
`
`
`
`
`
`
`U.S. Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research (CDER)
`
`April 2004
`
`CMC
`
`
`Revision 1
`
` P. 2
`
`UT Ex. 2050
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`
`
`
` I.
`
`
`
`
` TABLE OF CONTENTS
`
`
`
`
`INTRODUCTION AND BACKGROUND...............................................................................................................1
`
`
`
`
` II. REPORTING CATEGORIES....................................................................................................................................3
`
`
`III. GENERAL REQUIREMENTS .................................................................................................................................4
`
`
`IV. ASSESSING THE EFFECT OF MANUFACTURING CHANGES........................................................................5
`
`
`
`5 A. ASSESSMENT OF THE EFFECTS OF THE CHANGE...........................................................................................................
`
`
`1.
`Conformance to Specifications...........................................................................................................................5
`
`2.
`Additional Testing...............................................................................................................................................6
`
`EQUIVALENCE............................................................................................................................................................6
`
`B.
`C. ADVERSE EFFECT .......................................................................................................................................................7
`
`
`
`
`
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` V. COMPONENTS AND COMPOSITION ..................................................................................................................7
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`
`
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` VI. MANUFACTURING SITES ......................................................................................................................................8
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`
`
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`A. GENERAL CONSIDERATIONS.......................................................................................................................................8
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`B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT)...................................................................................................9
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`10 C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................
`
`
`
`Supplement - Changes Being Effected in 30 Days............................................................................................10
`
`1.
`2.
`Supplement - Changes Being Effected..............................................................................................................11
`
`
` D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................11
`
`
`
`
` VII. MANUFACTURING PROCESS ........................................................................................................................11
`
`
`
`
`
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`A. GENERAL CONSIDERATIONS.....................................................................................................................................11
`
`B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................12
`
`C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................14
`
`
`Supplement - Changes Being Effected in 30 Days............................................................................................14
`
`1.
`
`2.
`15 Supplement - Changes Being Effected..............................................................................................................
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`D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................15
`
`
`VIII.
`
`SPECIFICATIONS ..............................................................................................................................................16
`
`
`A. GENERAL CONSIDERATIONS.....................................................................................................................................16
`
`B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................17
`
`C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................18
`
`
`Supplement - Changes Being Effected in 30 Days............................................................................................18
`
`1.
`2.
`Supplement - Changes Being Effected..............................................................................................................18
`
`
` D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................19
`
`
`
`
` IX. CONTAINER CLOSURE SYSTEM .......................................................................................................................19
`
`
`
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`A. GENERAL CONSIDERATIONS.....................................................................................................................................19
`
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`20 B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................
`
`C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................21
`
`
`Supplement - Changes Being Effected..............................................................................................................21
`
`2.
`
` D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................22
`
`
`
`
` X.
`
`LABELING................................................................................................................................................................24
`
`
`
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`A. GENERAL CONSIDERATIONS.....................................................................................................................................24
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`B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................24
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`25 C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED) ........................................................................
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` D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................26
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`
`
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` XI. MISCELLANEOUS CHANGES..............................................................................................................................26
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`
`
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`A. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................26
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`B. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................27
`
`
`Supplement - Changes Being Effected in 30 Days............................................................................................27
`
`1.
`2.
`Supplement - Changes Being Effected..............................................................................................................27
`
`
` C. MINOR CHANGES (ANNUAL REPORT)......................................................................................................................27
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`
`
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` XII. MULTIPLE RELATED CHANGES...................................................................................................................28
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`
`ATTACHMENT A: MANUFACTURING SITES...........................................................................................................29
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`
`ATTACHMENT B: TYPE OF OPERATION AND CGMP INSPECTIONS................................................................31
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`
`ATTACHMENT C: CDER-APPROVED DRUG PRODUCTS......................................................................................34
`
`
`GLOSSARY.........................................................................................................................................................................35
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` Contains Nonbinding Recommendations*
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`
`
` Guidance for Industry1
`
`
`Changes to an Approved NDA or ANDA
`
`
`
`
`
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
`topic. It does not create or confer any rights for or on any person and does not operate to
`bind FDA or the public.** You can use an alternative approach if it satisfies the
`requirements of the applicable statutes and regulations. If you want to discuss an alternative
`approach, contact the FDA staff responsible for implementing this guidance. If you cannot
`identify the appropriate FDA staff, call the appropriate number listed on the title page of this
`guidance.
`
`
`** Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and
`Cosmetic Act and 21 CFR 314.70, it does have binding effect. If you have any questions about the effect of any portion
`of this guidance, contact the Office of Pharmaceutical Science, Center for Drug Evaluation and Research (HFD-003),
`
` Food and Drug Association, 5600 Fishers Lane, Rockville, MD 20857.
`
`
`
`
`
`
`INTRODUCTION AND BACKGROUND
`
`
`I.
`
`This guidance provides recommendations to holders of new drug applications (NDAs) and
`abbreviated new drug applications (ANDAs) who intend to make postapproval changes in
`accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and
`§ 314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for
`postapproval changes for drugs other than specified biotechnology and specified synthetic
`biological products. It supersedes the guidance of the same title published November 1999.
`Recommendations are provided for postapproval changes in (1) components and composition, (2)
`manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system,
`
`and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes.
`
`
`
`Recommendations on reporting categories for changes relating to specified biotechnology and
`specified synthetic biological products regulated by CDER are found in the guidance for industry
`
`1 This guidance has been prepared under the direction of the Chemistry, Manufacturing and Controls Coordinating Committee in
`the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA).
`
`Paperwork Reduction Act Public Burden Statement: This guidance contains information collection provisions that are subject
`to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C.
`3501-3520). The collection(s) of information in this guidance were approved under OMB Control No. 0910-0538 (until August
`31, 2005).
`
` *
`
` Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`and 21 CFR 314.70, it does have binding effect.
`
`
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`entitled Changes to an Approved Application for Specified Biotechnology and Specified
`Synthetic Biological Products (July 1997).2
`
`
`On November 21, 1997, the President signed the Food and Drug Administration Modernization
`Act of 1997 (the Modernization Act).3 Section 116 of the Modernization Act amended the the Act
`by adding section 506A, which provides requirements for making and reporting manufacturing
`changes to an approved application and for distributing a drug product made with such changes.
`The FDA has revised its regulations on supplements and other changes to an approved application
`
` (21 CFR 314.70) to conform to section 506A of the Act.
`
`This guidance does not provide recommendations on the specific information that should be
`developed by an applicant to assess the effect of the change on the identity, strength (e.g., assay,
`content uniformity), quality (e.g., physical, chemical, and biological properties), purity (e.g.,
`impurities and degradation products), or potency (e.g., biological activity, bioavailability,
`bioequivalence) of a drug product as these factors may relate to the safety or effectiveness of the
`drug product. An applicant should consider all relevant CDER guidance documents for
`recommendations on the information that should be submitted to support a given change.4
`
`
`CDER has published guidances, including the SUPAC (scale-up and postapproval changes)
`guidances, that provide recommendations on reporting categories. To the extent that the
`recommendations on reporting categories in this guidance are found to be inconsistent with
`guidances published before this guidance was finalized, the recommended reporting categories in
`such previously published guidances are superseded by this guidance. This guidance does not
`provide extensive recommendations on reporting categories for components and composition
`changes (see section V). Therefore, recommended reporting categories for components and
`composition changes provided in previously published guidances, such as the SUPAC guidances,
`still apply. Section 506A of the Act and § 314.70(c) provide for two types of changes-being­
`effected supplements (see section II), while previously there was only one type. It is important for
`applicants to use this guidance to determine which type of changes-being-effected supplement is
`recommended. CDER intends to update the previously published guidances to make them
`
`consistent with this guidance.
`
`If guidance for either recommended reporting categories or information that should be submitted to
`support a particular change is not available, the appropriate CDER chemistry or microbiology
`
`review staff can be consulted for advice.
`
`FDA's guidance documents, in general, do not establish legally enforceable responsibilities.
`Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as
`recommendations, unless specific regulatory or statutory requirements are cited. The use of the
`word should in Agency guidances means that something is suggested or recommended, but not
`required. Insofar as this guidance adjusts reporting categories pursuant to section 506A of the
`Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70, it does have binding effect. If you
`
` FDA is currently revising the 1997 guidance and intends to issue it in draft for public comment.
`3 Public Law 105-115.
` 4 A list of CDER guidances is available on the Internet at http://www.fda.gov/cder/guidance/index.htm.
`
`
`
`
`
`2
`
`* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`
` and 21 CFR 314.70, it does have binding effect.
`
`
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` Contains Nonbinding Recommendations*
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`have any questions about the effect of any portion of this guidance, contact the Office of
`Pharmaceutical Science, Center for Drug Evaluation and Research (HFD-003), Food and Drug
`
` Association, 5600 Fishers Lane, Rockville, MD 20857.
`
`
`
`
`REPORTING CATEGORIES
`
`
`II.
`
`Section 506A of the Act and § 314.70 provide for four reporting categories that are distinguished
`
`in the following paragraphs.
`
`A major change is a change that has a substantial potential to have an adverse effect on the
`identity, strength, quality, purity, or potency of a drug product as these factors may relate to the
`safety or effectiveness of the drug product. A major change requires the submission of a
`supplement and approval by FDA prior to distribution of the drug product made using the change.
`
`This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement (§
`314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for
`public health reasons (e.g., drug shortage) or if a delay in making the change described in it would
`impose an extraordinary hardship on the applicant. This type of supplement is called, and should
`
`be clearly labeled, a Prior Approval Supplement - Expedited Review Requested (§
`314.70(b)(4)).5 FDA is most likely to grant requests for expedited review based on extraordinary
`hardship for 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.
`
`A moderate change is a change that has a moderate potential to have an adverse effect on the
`identity, strength, quality, purity, or potency of the drug product as these factors may relate to the
`safety or effectiveness of the drug product. There are two types of moderate change. One type of
`moderate change requires the submission of a supplement to FDA at least 30 days before the
`distribution of the drug product made using the change. This type of supplement is called, and
`should be clearly labeled, a Supplement - Changes Being Effected in 30 Days (§ 314.70(c)(3)).
`The drug product made using a moderate change cannot be distributed if FDA informs the
`applicant within 30 days of receipt of the supplement that a prior approval supplement is required
`(§ 314.70(c)(5)(i)). For each change, the supplement must contain information determined by
`FDA to be appropriate and must include the information developed by the applicant in assessing
`the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days
`of receipt of the supplement that information is missing, distribution must be delayed until the
`
`supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)).
`
`FDA may identify certain moderate changes for which distribution can occur when FDA receives
`the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled,
`a Supplement - Changes Being Effected. If, after review, FDA disapproves a changes-being­
`effected-in-30-days supplement or changes-being-effected supplement, FDA may order the
`
`
` 5 Internal Agency policies and procedures relating to processing requests for expedited review of supplements to approved
`ANDAs and NDAs are documented in CDER's Manual of Policies and Procedures (MAPP) at 5240.1 and 5310.3,
`
` respectively. MAPPs can be located on the Internet at http://www.fda.gov/cder/mapp.htm.
`
`
`* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`
` and 21 CFR 314.70, it does have binding effect.
`
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`
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` manufacturer to cease distribution of the drug products made using the disapproved change (§
`
` 314.70(c)(7)).
`
`A minor change is a change that has minimal potential to have an adverse effect on the identity,
`strength, quality, purity, or potency of the drug product as these factors may relate to the safety or
`effectiveness of the drug product. The applicant must describe minor changes in its next Annual
`
` Report (§ 314.70(d)).
`
`Under § 314.70(e), an applicant can submit one or more protocols (i.e., comparability protocols)
`describing tests, studies, and acceptance criteria to be achieved to demonstrate the absence of an
`adverse effect from specified types of changes. A comparability protocol can be used to reduce
`the reporting category for specified changes. A proposed comparability protocol that was not
`approved as part of the original application must be submitted as a prior approval supplement
`(314.70(e)). On February 25, 2003, FDA issued a draft guidance on comparability protocols
`entitled Comparability protocols - Chemistry, Manufacturing, and Controls Information.
`
`
`
`
`
`
`
`III. GENERAL REQUIREMENTS
`
`Other than for editorial changes in previously submitted information (e.g., correction of spelling or
`typographical errors, reformatting of batch records), 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 (§ 314.70(a)(1)).
`
`A supplement or annual report must include a list of all changes contained in the supplement or
`annual report. On the list, FDA recommends that the applicant describe each change in enough
`detail to allow FDA to quickly determine whether the appropriate reporting category has been
`used. For supplements, this list must be provided in the cover letter (§ 314.70(a)(6)). In annual
`reports, the list should be included in the summary section (§ 314.81(b)(2)(i)). The applicant must
`
`describe each change fully in the supplement or annual report (§ 314.70(a)(1)).
`
`An applicant making a change to an approved application under section 506A of the Act must also
`conform to other applicable laws and regulations, including current good manufacturing practice
`(CGMP) requirements of the Act (21 U.S.C. 351(a)(2)(B)) and applicable regulations in Title 21
`of the Code of Federal Regulations (e.g., 21 CFR parts 210, 211, 314). For example,
`manufacturers must comply with relevant CGMP validation and recordkeeping requirements and
`ensure that relevant records are readily available for examination by authorized FDA personnel
`
`during an inspection.
`
`A changes-being-effected supplement providing for labeling changes under § 314.70(c)(6)(iii)
`
`must include 12 copies of the final printed labeling (§ 314.70(c)(1)). In accordance with
`
`* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`
` and 21 CFR 314.70, it does have binding effect.
`
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`
`
` § 314.70(a)(4), an applicant also must promptly revise all promotional labeling and drug
`
` advertising to make it consistent with any labeling change implemented in accordance with §
`
` 314.70(b) or (c).
`
`Except for supplements providing only for a change in labeling, an applicant must include in each
`supplement and amendment to a supplement a statement certifying that a field copy has been
`
` provided in accordance with 21 CFR 314.440(a)(4)6 (§ 314.70(a)(5)).
`
`
`IV.
`
`
`
`ASSESSING THE EFFECT OF MANUFACTURING CHANGES
`
`
`A.
`
`
`Assessment of the Effects of the Change
`
`
`
`
`
`
`
`The holder of an approved application under section 505 of the Act must assess the
`effects of the change before distributing a drug product made with a manufacturing
`change (§ 314.70(a)(2)).7 For each change, the supplement or annual report must contain
`information determined by FDA to be appropriate and must include the information
`developed by the applicant in assessing the effects of the change (section 506A(b), (c)(1),
`(d)(2)(A), and (d)(3)(A) of the Act). The type of information that must be included in a
`supplemental application or an annual report is specified in § 314.70(b)(3), (c)(4), and
`
`(d)(3).
`
`1.
`
`
`Conformance to Specifications
`
`An assessment of the effects of a change on the identity, strength, quality, purity, and
`potency of the drug product should include a determination that the drug substance
`intermediates, drug substance, in-process materials, and/or drug product affected
`by the change conform to the approved specifications.8 A specification is a 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, components, in-process materials, container
`closure systems, and other materials used in the production of a drug substance or
`drug product. Acceptance criteria are numerical limits, ranges, or other criteria
`for the tests described (§ 314.3(b)). Conformance to a specification means that the
`
`
`6 Mailing information for field copies is provided in 21 CFR 314.440(a)(4). FDA recommends that the applicant's home FDA
`
` district office referred to in the regulations be the district office where the applicant's headquarters is located.
` 7 Assess the effects of the change means to evaluate the effects of a manufacturing change on the identity, strength, quality,
`
` purity, and potency of a drug product as these factors relate to the safety or effectiveness of the drug product. The terms assess
`
`or assessment as used in this guidance are not the same as validation. Certain validation information, such as for sterilization
`processes, is considered information that is needed to assess the effect of the change as specified in § 314.70(a)(2) and should be
`submitted in an NDA or ANDA. Unless otherwise specified by FDA, validation (e.g., process, equipment) data need not be
`submitted in the application, but should be retained at the facility and be available for review by FDA at the Agency's discretion
`
`under CGMPs.
`
`8 If a specification needs to be revised as a result of the change, this would be considered a multiple change (see sections VIII and
`XII).
`
`
`* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`
` and 21 CFR 314.70, it does have binding effect.
`
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`material, when tested according to the analytical procedures listed in the
`
` specification, will meet the listed acceptance criteria.
`
`2.
`
`
`
` Additional Testing
`
`In addition to confirming that the material affected by manufacturing changes
`continues to meet its specification, we recommend that the applicant perform
`additional testing, when appropriate, to assess whether the identity, strength,
`quality, purity, or potency of the drug product as these factors may relate to the
`safety or effectiveness of the drug product have been or will be affected. The
`assessment should include, as appropriate, evaluation of any changes in the
`chemical, physical, microbiological, biological, bioavailability, and/or stability
`profiles. This additional assessment could involve testing of the postchange drug
`product itself or, if appropriate, the material directly affected by the change. The
`type of additional testing that an applicant should perform would depend on the
`type of manufacturing change, the type of drug substance and/or drug product, and
`the effect of the change on the quality of the drug product. For example:
`
`
`• Evaluation of changes in the impurity or degradant profile could first
`
`involve profiling using appropriate chromatographic techniques and then,
`depending on the observed changes in the impurity profile, toxicology tests
`to qualify a new impurity or degradant or to qualify an impurity that is
`above a previously qualified level.9
`
`
`
`• Evaluation of the hardness or friability of a tablet after certain changes.
`
`
`
`• Assessment of the effect of a change on bioequivalence when required
`
`under 21 CFR part 320 could include, for example, multipoint and/or
` multimedia dissolution profiling and/or an in vivo bioequivalence study.
`
`
`
`• Evaluation of extractables from new packaging components or moisture
`
`
` permeability of a new container closure system.
`
`An applicant should refer to all relevant CDER guidance documents for
`recommendations on the information that should be submitted to support a given
`change. If guidance for information that should be submitted to support a particular
`change is not available, applicants can consult the appropriate CDER chemistry or
`
` microbiology review staff for advice.
`
`B.
`
`
`Equivalence
`
`
`When testing is performed, the applicant should usually assess the extent to which the
`manufacturing change has affected the identity, strength, quality, purity, and potency of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`9 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant guidances (e.g., ICH Q3B
`
` Impurities in New Drug Products (November 1996)).
`
`* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act
`
` and 21 CFR 314.70, it does have binding effect.
`
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`drug product. Typically this is accomplished by comparing test results from pre- and
`postchange material and determining if the test results are equivalent. Simply stated: Is the
`drug product made after the change equivalent to the drug product made before the change?
` An exception to this general approach is that when bioequivalence is redocumented for
`certain ANDA postapproval changes, FDA recommends that the comparator be the
`reference listed drug. Equivalence comparisons frequently have a criterion for comparison
`with calculation of confidence intervals relative to a predetermined equivalence interval.
`For this, as well as for other reasons, equivalent does not necessarily mean identical.
`Equivalence may also relate to maintenance of a quality characteristic (e.g., stability)
`
` rather than a single performance of a test.
`
` C.
`
`
`
` Adverse Effect
`
`
`
`Some manufacturing changes 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 sometimes the applicant wishes to do so. If an assessment
`indicates that a change has adversely affected the identity, strength, quality, purity, or
`potency of the drug product, FDA recommends that the change be submitted in a prior
`approval supplement regardless of the recommended reporting category for the
`change. For example, a process change recommended for a changes-being-effected-in-30­
`days supplement could cause the formation of a new degradant that requires qualification
`and/or identification.10 The applicant's degradation qualification procedures may indicate
`that there are no safety concerns relating to the new degradant. Even so, we recommend
`that the applicant submit this change in a prior approval supplement with appropriate
`information to support the continued safety and effectiveness of the drug product. During
`the review of the prior approval supplement, the FDA will assess the impact of any
`adverse effect on the drug product as this change may relate to the safety or effectiveness of
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`the drug product.
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`Applicants are encouraged to consult with the appropriate CDER chemistry or
`microbiology review staff if there are any questions on whether a change in