FDA 发布 MAPP 5016.8 Rev. 1，规定质量相关沟通采用四部分结构
MAPP 5016.8 Using Four-Part Harmony in Quality-Related Assessment Communications
FDA 药品质量办公室发布 MAPP 5016.8 Rev. 1，规定审评人员在质量相关沟通中采用四部分结构，该文件于 2023 年 9 月 22 日生效。四部分依次为已提供什么、问题是什么、需要什么以及为何需要，可依问题性质合并、省略或调整顺序。文件适用于 IND、NDA、BLA、ANDA、EUA 及被其引用的 DMF 等提交在审评中的质量相关沟通。
该 MAPP 说明 FDA 药品质量办公室在质量相关沟通中采用四部分结构，并附稳定性与灭菌验证等示例。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5016.8 Rev. 1
POLICY
OFFICE OF PHARMACEUTICAL QUALITY
Using Four-Part Harmony in Quality-Related Assessment Communications
Table of Contents
PURPOSE ...........................................................................1
BACKGROUND ................................................................2
POLICY ..............................................................................2
RESPONSIBILITIES ........................................................4
REFERENCES...................................................................4
DEFINITIONS ...................................................................4
EFFECTIVE DATE ...........................................................5
CHANGE CONTROL TABLE.........................................5
ATTACHMENT – Examples of Quality-Related
Communications ...............................................................6
PURPOSE
This MAPP describes how the Office of Pharmaceutical Quality (OPQ) product quality
assessors can follow the principles of Four-Part Harmony 1 to enhance the clarity of quality-
related communications. 2 This MAPP applies to quality-related communications that are sent
1
Four-Part Harmony is a format recommendation adopted by several FDA centers. Efforts that align with or
describe Four-Part Harmony include:
• The Prescription Drug User Fee Act VII goals letter titled “PDUFA Reauthorization Performance Goals
and Procedures Fiscal Years 2023 Through 2027” available on the FDA website at
https://www.fda.gov/media/151712/download.
• The Center for Biologics Evaluation and Research Standard Operating Procedure and Policy 8401.1
Issuance of and Review of Responses to Information Request Communications to Pending Applications
available at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-procedures-sopps.
• The guidance for industry and Food and Drug Administration staff Developing and Responding to
Deficiencies in Accordance with the Least Burdensome Provisions (October 2022). We update guidances
periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
• The Medical Device User Fee Amendments V goals letter titled “MDUFA Performance Goals and
Procedures, Fiscal Years 2023 Through 2027” available on the FDA website at
https://www.fda.gov/media/158308/download.
2
Quality-related communications include, but are not limited to, complete response letters, deficiency letters,
discipline review letters, and information requests.
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 1 of 7
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5016.8 Rev. 1
to applicants 3 during assessments 4 across the product life cycle. These communications
identify deficiencies or request information during the assessment of submissions related to
human drugs, including:
• Investigational new drug applications (INDs), new drug applications (NDAs),
biologics license applications (BLAs), abbreviated new drug applications (ANDAs),
and emergency use authorizations (EUAs), as well as drug master files (DMFs) that
are referenced by INDs, NDAs, ANDAs, and other DMFs.
• Amendments and supplements to the applications listed above.
• Other submissions including, but not limited to, annual reports, postmarketing
commitments, and submissions that involve intercenter consults with OPQ for drug
quality assessment.
The attachment provides examples of quality-related communications.
BACKGROUND
• To promote efficient communication between assessment teams and applicants, FDA
has committed to ensuring the use of Four-Part Harmony in quality-related
communications. 5,6 This commitment includes revising and publishing this MAPP
and conducting internal training. 7
• Four-Part Harmony is intended to ensure that assessors draft clear quality-related
communications and provide a basis for each communication that is consistent with
FDA’s policy. This may help applicants provide adequate information to address
identified quality issues.
POLICY
• Four-Part Harmony recommends that all quality-related communications address the
following four essential components:
3
For the purposes of this MAPP, the term applicants refers to sponsors, submitters, and holders of INDs,
NDAs, BLAs, ANDAs, and EUAs, as well as DMFs that are referenced in INDs, NDAs, ANDAs and other
DMFs.
4
The Office of Pharmaceutical Quality generally uses the term assessment in place of review. Assessment
means the process of both evaluating and analyzing submitted data and information to determine whether the
application meets the requirements for approval and documenting that determination.
5
See the PDUFA VII goals letter.
6
In addition, assessors should apply the CDER Style Guide to quality-related communications.
7
The prior version of this MAPP (Communication Guidelines for Quality-Related Information Requests and
Deficiencies) was internal to FDA.
Originating Office: Office of Pharmaceutical Quality
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5016.8 Rev. 1
(1) What was provided? Acknowledge the information submitted by the
applicant and provide a reference to relevant modules, sections, page
numbers, or tables unless the part of the application being referenced is
obvious from the description (e.g., “your proposed drug product
specification”).
(2) What is the issue? Identify missing information or information that FDA
considers inadequate.
(3) What is needed? Request additional information or recommend an alternative
approach to address the issue.
(4) Why is it needed? State the basis for the information request or deficiency,
and include:
a. The impact of the issue on the overall regulatory decision.
b. References to all or part of applicable regulations, statutes, guidances,
and/or FDA-recognized consensus standards, as appropriate.
• Based on the nature and extent of the issue, assessors may combine, omit, 8 or reorder
the elements.
• Quality-related communications should “request the minimum (i.e., least
burdensome) amount of information necessary to adequately address the identified
issue.” 9
• Assessors should not use mandatory language such as shall, must, required, or
requirement when referring to recommendations from guidance documents or
standards. 10 Instead, assessors should use words such as should or recommend.
Assessors may use mandatory language when referencing regulatory or statutory
requirements in the Code of Federal Regulations or a specific statute (e.g., the Federal
Food, Drug, & Cosmetic Act).
• If the applicant’s response to the quality-related communication does not resolve the
issue, assessors should consider rephrasing the quality-related communication to
clarify the basis for the request. This may help applicants provide adequate
information to address the issue.
8
Omissions are only appropriate under limited circumstances (e.g., when using templated language).
9
See the guidance for industry and Food and Drug Administration staff Developing and Responding to
Deficiencies in Accordance with the Least Burdensome Provisions (October 2022).
10
Guidance documents and standards describe FDA’s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. Applicants can use an approach
other than the one set forth in a guidance document if it complies with the relevant statutes and regulations.
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 3 of 7
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RESPONSIBILITIES
OPQ primary quality assessors will follow the principles of Four-Part Harmony when
drafting quality-related communications.
OPQ discipline-specific concurring officials 11 will ensure that quality-related
communications follow the principles of Four-Part Harmony.
REFERENCES
• Center for Biologics Evaluation and Research Standard Operating Policy and
Procedure 8401.1 Issuance of and Review of Responses to Information Request
Communications to Pending Applications (October 2022)
• Generic Drug User Fee Amendments goals letter, “GDUFA Reauthorization
Performance Goals and Program Enhancements Fiscal Years 2023-2027”
• Guidance for industry and Food and Drug Administration staff Developing and
Responding to Deficiencies in Accordance with the Least Burdensome Provisions
(October 2022)
• Medical Device User Fee Amendments goals letter “MDUFA Performance Goals and
Procedures, Fiscal Years 2023 Through 2027”
• Prescription Drug User Fee Act goals letter “PDUFA Reauthorization for Fiscal
Years 2023 Through 2027”
DEFINITIONS
• Deficiency – An outstanding issue that FDA identifies in a submission and
communicates to the applicant, sponsor, or DMF holder.
• Quality-related communication – An FDA correspondence to an applicant, sponsor,
or DMF holder that requests information or identifies deficiencies. These
communications include, but are not limited to, the following:
– Complete response letters - “usually describing all of the deficiencies that
the agency has identified in” an NDA, ANDA, BLA, supplement, or a DMF
that is referenced by an ANDA “that must be satisfactorily addressed before
[an application or supplement] can be approved” (21 CFR 314.3, 21 CFR
11
The OPQ discipline-specific concurring official can be an OPQ senior pharmaceutical quality assessor (or a
designated secondary assessor), application technical lead, branch chief, or division director, as needed.
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 4 of 7
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600.3(ll), and the Generic Drug User Fee Amendment III goals letter, 12 see
also 21 CFR 314.110 and 21 CFR 601.3).
– Deficiency letters - identifying deficiencies to a DMF holder for an
inadequate DMF referenced by an IND, NDA, or another DMF.
– Discipline review letters - conveying preliminary thoughts on possible
deficiencies found by a discipline assessor and/or assessment team for its
portion of the pending application at the conclusion of the discipline
assessment.
– Information requests - asking for further information or clarification that is
needed for or would help with completion of the discipline assessment.
EFFECTIVE DATE
• This MAPP is effective September 22, 2023.
CHANGE CONTROL TABLE
Effective Revision Revisions
Date Number
9/22/17 Initial n/a
9/22/2023 Rev. 1 Updated to fulfill PDUFA VII commitments.
12
See Generic Drug User Fee Amendments III goals letter titled “GDUFA Reauthorization Performance Goals
and Program Enhancements Fiscal Years 2023-2027” available on the FDA website at
https://www.fda.gov/media/153631/download.
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 5 of 7
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MANUAL OF POLICIES AND PROCEDURES
CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5016.8 Rev. 1
ATTACHMENT – Examples of Quality-Related Communications
The following examples are intended to demonstrate the use of Four-Part Harmony in
quality-related communications. These examples do not represent any particular aspect of
technical assessment and are not inclusive of additional recommendations that Office of
Pharmaceutical Quality suboffices may include in quality-related communications. For
demonstration purposes, the Four-Part Harmony elements are labeled in parentheses and in
bold print in each example. Assessors will not label the elements in quality-related
communications that are sent to applicants.
Example 1
For your drug product, we acknowledge the X-month accelerated and Y-month long term
stability data provided in section 3.2.P.8.3 (element 1). The provided stability data do not
support the proposed shelf life, because insufficient long-term data were provided to support
extrapolation to 2 years (element 2). Provide updated stability data to support your proposed
shelf life; otherwise, revise your proposed shelf life (element 3). For more information, see
International Council for Harmonisation (ICH) guidance for industry Q1E Evaluation of
Stability Data (June 2004), including Appendix A, which provides recommendations for
evaluating data to estimate a drug product’s shelf life (element 4). 1
Example 2
The validation information for the sterilization of the equipment and components that directly
contact the drug product provided in section 3.2.P.3.5 (element 1) corresponds to only one
run (element 2). To validate the sterilization of the production loads, you should
demonstrate the reproducibility of the process by submitting data from two additional
successful sterilization runs from either the initial validation or the most recent
requalification (element 3). For more information, refer to FDA guidance for industry
Submission Documentation for Sterilization Process Validation in Applications for Human
and Veterinary Drug Products (November 1994) (element 4).
Example 3
In the supplement, you proposed new lower strengths for drug product XXX based on the
approved higher strength (element 1). To comply with the requirements in 21 CFR 320.21,
applicants must submit in vivo bioavailability data to support the approval of the newly
proposed lower strengths, or applicants must submit a biowaiver request (element 4).
However, we cannot locate the in vivo bioavailability data or a biowaiver request in your
submission (element 2). Submit a biowaiver request with the supporting data and
information in accordance with 21 CFR 320.22 for the proposed lower strengths under eCTD
1
Do not include hyperlinks to specific guidance documents in communications. Rather, include the following
language for the first reference to a guidance in communications to the applicants: “We update guidances
periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.”
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 6 of 7
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CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5016.8 Rev. 1
section 1.12.15, Request for waiver of in vivo bioavailability studies, or provide in vivo
bioavailability data (element 3).
Originating Office: Office of Pharmaceutical Quality
Effective Date: 09/22/17; 09/22/23 Page 7 of 7
来源：FDA Pharmaceutical Quality Documents · fda.gov