近日，FDA发布了政策文件FDA MAPP 5021.5《将设施缺陷从主要缺陷重新分级为微小缺陷的申请评估》，该文件自2023年6月27日生效。如下：
PURPOSE 目标
This MAPP describes the policies and procedures used in the Office of Pharmaceutical Quality (OPQ), the Office of Compliance, and the Office of Generic Drugs (OGD) for the assessment of requests for reclassification of facility-based major complete response (CR) letter amendments (referred to as facility-based deficiency major-to- minor reclassification requests elsewhere) for original abbreviated new drug applications (ANDAs) and associated prior approval supplements (PASs).
本 MAPP 描述了药品质量办公室（OPQ）、合规办公室，以及仿制药办公室（OGD），对初始 ANDA 和相关 PAS 中设施的主要完整回复（CR）函修订的重新分类请求的评估方针和流程（在其他地方称为基于设施的主要缺陷重新分类为微小缺陷的请求）。
This MAPP applies to reclassification requests received as part of a single amendment that consists of both a reclassification request for facility-based deficiencies1 and a response to a CR letter in which the only major deficiency(ies) in the CR letter resulted from a facility inspection(s) or assessment.
本 MAPP 适用于作为单一修订的一部分收到的重新分类请求，该申请包括对设施缺陷的重新分类申请和对 CR 函的回复，其中 CR 函中唯一的主要缺陷是由设施检查或评估引起的。
This MAPP applies only to requests for major-to-minor reclassifications for CR letters issued on or after October 1, 2022 (the implementation date of the Generic Drug User Fee Amendments of 2022 program (GDUFA III)).1 2
本 MAPP 仅适用于 2022 年 10 月 1 日（《2022 年仿制药使用费修正案》（GDUFA III）的实施日期）当天或之后发布的 CR 信函的主要到微小重新分类请求。
BACKGROUND 背景
The Generic Drug User Fee Amendments of 2012 (GDUFA I)3 amended the Federal Food, Drug, and Cosmetic Act to authorize FDA to assess and collect user fees to provide FDA with resources4 to help ensure patients have access to quality, affordable, safe, and effective generic drugs. GDUFA fee resources bring greater predictability and timeliness to the review of generic drug applications. GDUFA has been reauthorized every 5 years to continue FDA’s ability to assess and collect GDUFA fees, and this user fee program has been reauthorized two times since GDUFA I, most recently in the Generic Drug User Fee Amendments of 2022.5 As described in the GDUFA III commitment letter applicable to this latest reauthorization,6 FDA has agreed to performance goals and program enhancements regarding aspects of the generic drug assessment program that build on previous authorizations of GDUFA. New enhancements to the program are designed to maximize the efficiency and utility of each assessment cycle, with the intent of reducing the number of assessment cycles for ANDAs and facilitating timely access to generic medicines for American patients.
2012 年《仿制药用户费修正案》（GDUFA I）修订了《联邦食品、药品和化妆品法》，授权FDA 评估和收取使用费，为 FDA提供资源，帮助确保患者获得优质、负担得起、安全有效的仿制药。GDUFA 费用资源为仿制药申请的审查带来了更大的可预测性和及时性。GDUFA 每 5 年重新授权一次，以继续 FDA 评估和收取 GDUFA 费用的能力，自 GDUFA I 以来，该用户费用计划已被重新授权两次，最近一次是在 2022 年的《仿制药用户费用修正案》中。如适用于此次最新重新授权的 GDUFA III 承诺书中所述， FDA 已同意在 GDUFA 先前授权的基础上，就仿制药评估计划的各个方面制定绩效目标和计划改进。该计划的最新改进旨在最大限度地提高每个评估周期的效率和效用，目的是减少 ANDA 的评估时长，并促进美国患者及时获得仿制药。
In accordance with the GDUFA III commitment letter, when OPQ and OGD staff receive an amendment that consists of a facility-only major-to-minor reclassification request and a response to the CR letter, they work collaboratively to determine whether to grant or deny the request.
根据 GDUFA III 承诺书，当 OPQ 和 OGD 工作人员收到一份修正案，该修正案包括仅针对主要至微小设施缺陷重新分类的请求和对 CR 信函的回复时，他们将共同决定是批准还是拒绝该请求。
POLICY方针
FDA will accept for review a request for reclassification from major to minor if:
如果满足以下条件，FDA 将接受将主要缺陷重新定级为微小缺陷的审查申请：
The CR letter was issued on or after October 1, 2022 (the implementation date of GDUFA III).7
CR 信函于 2022 年 10 月 1 日（GDUFA III 实施日期）或之后签发。
The reclassification request is submitted with a CR letter response amendment in a single submission.
重新分类请求与 CR 信函回复修订一起提交。
The facility issue is the only major deficiency.
设施问题是唯一的主要缺陷。
The CR letter’s major amendment classification is based on observations from a surveillance inspection (e.g., official action indicated (OAI) classification of a facility from a surveillance inspection). This includes surveillance inspections conducted by foreign regulatory authorities where the information is shared under a mutual recognition agreement.8
CR 信函的主要修订分类基于监管检查的观察结果（例如，监管检查对设施的强制行动指示（OAI）分类）。这包括根据互认协议共享信息的外国监管机构进行的监督检查。
The reclassification request is easily identified in the cover letter for the amendment submitted in response to the CR letter.
在针对 CR 信函提交的修正案的封面函中，可以很容易地确定重新分类请求。
FDA determines that the words “Facility-Only Reclassification Request” are included in the submission and verifies that the submission includes the voluntary action indicated (VAI) or the no action indicated (NAI) current good manufacturing practice (CGMP) classification letter issued by FDA to the facility or facilities subsequent to the OAI classification referenced in the CR letter.8 9
FDA 确定在提交文件中包含“仅设施重新分类请求”，并验证提交文件是否包括 FDA 在 CR 信函中引用的 OAI 分类之后向设施或设施发布的自愿行动指示（VAI）或无行动指示（NAI）CGMP 分类信函。
The CR letter is less than 1 year old10 11 (from the date the CR letter was signed) or it is more than 1 year old and one of the following applies:
CR 信函自签发起不到 1 年（自签署 CR 信函之日起）或超过 1 年，且适用以下情况之一：
The product is on the drug shortage list or is a public health emergency product.
该产品被列入药品短缺名单或是突发公共卫生事件产品。
The facility deficiency is the only deficiency in the CR letter (i.e., the facility issue is the only (i.e., single) major deficiency, and there are no minor deficiencies).
设施缺陷是 CR 函中唯一的缺陷（即，设施问题是唯一的（即，单一的）主要缺陷，不存在微小缺陷）。
If accepted for review based on the above criteria, FDA will grant the request for reclassification only when FDA determines that the facility issues have been addressed (e.g., facility has been classified as an NAI or a VAI), and there is no need for an inspection or an alternative tool to resolve facility issues for the subject drug.11
如果根据上述标准接受审查，只有当 FDA 确定设施问题已经得到解决（例如，设施已被归类为 NAI 或 VAI），并且不需要检查或替代工具来解决受试药物的设施问题时， FDA 才会批准重新分类请求。
FDA will generally deny a request a request for reclassification from major to minor if:
如果出现以下情况，FDA 通常会拒绝从主要缺陷改为微小缺陷的请求：
The facility CR deficiency was issued based on an inspection other than a surveillance inspection or assessment (e.g., a withhold recommendation based on a preapproval inspection (PAI) or the use of alternative tools).12
设施 CR 缺陷是基于监督检查或评估以外的检查发布的（例如，基于批准前检查（PAI）或使用替代工具的拒绝批准建议）。
The facility deficiency has not been adequately resolved for the subject drug (e.g., FDA intends to conduct additional follow-up to verify that a corrective and preventive action(s) plan(s) was appropriate and fully implemented).
受试药物的设施缺陷尚未得到充分解决（例如，FDA 打算进行后续检查，以验证纠正和预防措施计划是否适当并得到充分实施）。
The submission does not include the VAI or the NAI CGMP classification letter issued by FDA.
提交的材料不包括 FDA 发布的 VAI 或 NAI CGMP 分类信。
RESPONSIBILITIES职责
OGD Responsibilities OGD 职责
The Office of Regulatory Operations (ORO) will:
监管运行办公室（ORO）将
For OGD-Managed Submissions:
对于 OGD 管理的申报
Triage the facility-only major-to-minor reclassification request and assign it to OPQ’s Office of Program and Regulatory Operations (OPRO).
仅对设施的主要到微小重新分类请求进行分类，并将其分配给 OPQ 的项目和监管运营办公室（OPRO）。
Draft a formal correspondence that includes acknowledgment of the reclassification request and issue it to the applicant.
起草一份正式信函，其中包括对重新分类请求的确认，并将其发给申请人。
Provide an update to the OPQ assessment team on the prioritization decision that determines whether the request has a 30- or 60-day decisional period (referred to as decisional period elsewhere).
就确定请求是否有 30 天或 60 天的决策期（在其他地方称为决策期）的优先级决策向 OPQ 评估小组提供最新情况。
Draft the final grant or deny decision and issue it to the applicant.
起草最终批准或拒绝决定，并将其发给申请人。
OPQ Responsibilities 职责
OPRO will: OPRO将
Assign the facility-only major-to-minor reclassification request to the regulatory business process manager (RBPM).
向监管业务流程经理（RBPM）分配仅从大到小的设施重新分类请求。
For OGD-Managed Submissions:
对于 OGD 管理的申报
The RBPM will: RBPM将
Assign the reclassification request and notify OPQ’s Office of Pharmaceutical Manufacturing Assessment (OPMA) to evaluate the reclassification request.
分配重新分类请求，并通知人事部药品生产评估办公室（OPMA）对重新分类请求进行评估。
Review the rationale for OPMA’ s grant or deny decision.
审查OPMA批准或拒绝决定的理由。
For OPQ-Managed Requests for Chemistry, Manufacturing, and Controls Supplements:
对于受 OPQ 管理的 CMC 增补要求：
The RBPM will: RBPM将
Draft a formal correspondence that includes acknowledgment of the reclassification request and issue it to the applicant.
起草一份正式信函，其中包括对重新分类请求的确认，并将其发给申请人。
If applicable, provide an update to the OPQ assessment team on the prioritization decision that determines whether the request has a 30- or 60- day decisional period.
如果适用，向 OPQ 评估小组提供关于优先级决策的最新信息，以确定请求是否有 30 天或 60 天的决策期。
Draft the final grant or deny decision and issue it to the applicant.
起草最终批准或拒绝决定，并将其发给申请人。
OPMA will:
Confirm the current status of the facility or facilities identified in the reclassification request and determine whether to grant or deny the request.
确认重新分类请求中确定的一个或多个设施的当前状态，并确定是否批准或拒绝该请求。
If the reclassification request is denied, provide the rationale to the RBPM to include in the denial letter.
如果重新分类请求被拒绝，将向 RBPM 提供理由，将其包含在拒绝信中。
Office of Compliance Responsibilities 合规办公室职责
The Office of Manufacturing Quality will: 生产质量办公室将
Provide input on the classification status of the facility when requested by OPMA.
在 OPMA 要求时提供该设施的重新分类状态信息
PROCEDURES程序
Original ANDAs and OGD-Managed ANDA PASs
初始 ANDA 和 OGD 管理的 ANDA PAS
1. The ORO regulatory project manager (RPM) receives and reviews the amendment submission cover letter for the facility-only major-to-minor reclassification request.
ORO 监管项目经理（RPM）接收并审查仅针对设施的主要到微小重新分类请求的修订提交封面信。
2. The ORO RPM determines whether to accept or not accept the reclassification request for review. The ORO RPM accepts the request for review if all of the criteria in bulleted items a) through f) are met:
ORO RPM 决定是否接受重新分类请求进行审查。如果符合项目符号 a）至 f）中的所有标准，则 ORO RPM 接受审查请求：
The reclassification request is submitted with a CR letter response amendment in a single submission.
重新分类请求与 CR 函回复修订内容一起提交。
The reclassification request is submitted with the VAI or the NAI CGMP classification letter issued by FDA to the facility.
重新分类请求与 FDA 向设施颁发的 VAI 或 NAI CGMP 分类信一起提交。
The reclassification request is easily identified in the cover letter for the amendment submitted in response to the CR letter.
在针对 CR 信函提交的修正案的附信中，可以很容易地确定重新分类请求。
The reclassification request is specific to a facility deficiency, and that specific deficiency is the only basis for the CR letter’s major classification. (Amendment may contain other minor deficiencies, except as noted below for a CR letter that is more than 1 year old and does not meet other criteria for acceptance.)
重新分类请求是针对设施缺陷提出的，该特定缺陷是 CR 信函主要分类的唯一依据。（修订可能包含其他微小缺陷，但以下针对超过 1 年且不符合其他验收标准的 CR 函所述的情况除外。）
The CR letter was issued on or after October 1, 2022 (the implementation date of GDUFA III).13
CR 信函于 2022 年 10 月 1 日（GDUFA III 实施日期）或之后发布。
The CR letter is less than 1 year old at the time the request for reclassification is submitted (from the date the CR letter was signed) or it is more than 1 year old and one of the following applies:
在提交重新分类请求时（自 CR 信函签署之日起），CR 信函的有效期不到 1 年，或者超过 1 年，且以下情况之一适用：
The product is the subject of a response to a public health emergency as declared by the Secretary of the U.S. Department of Health and Human Services under section 319 of the Public Health Service Act (42 U.S.C. 247d).
该产品是美国卫生与公众服务部部长根据《公共卫生服务法》第 319 条（《美国法典》第 42 卷第 247d 节）宣布的公共卫生紧急事件的响应对象。
The product is on the drug shortage list under section 506E of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356e).
根据《联邦食品、药品和化妆品法》（《美国法典》第 21 卷第 356e 节）第 506E 节，该产品在药品短缺名单上。
The facility deficiency is the only deficiency in the CR letter (i.e., the facility issue is the only major deficiency (i.e., single) and there are no minor deficiencies).
设施缺陷是 CR 函中唯一的缺陷（即，设施问题是唯一的主要缺陷（即单一缺陷），不存在微小缺陷）。
3. The ORO RPM triages the CR letter amendment that includes the reclassification request. ORO RPM 对包括重新分类请求在内的 CR 信函修订进行分类。
4. The ORO RPM notifies the applicant via a formal correspondence indicating whether its reclassification request is accepted for review and provides a decisional date indicating when the reclassification request decision will be made.
ORO RPM 通过正式信函通知申请人，说明其重新分类请求是否被接受审查，并提供决定日期，说明何时做出重新分类请求决定。
5. The ORO RPM notifies OPRO of the facility-only deficiency major-to-minor reclassification request and the decisional period (based on the priority or standard designation)14 by assigning it to OPRO.
ORO RPM 通过将其分配给 OPRO，向 OPRO 通知仅设施的主要到微小缺陷重新分类请求和决策期（基于优先级或标准指定）。
6. OPRO assigns the reclassification request to the RBPM. Then, the RBPM assigns the reclassification request to an OPMA assessor(s) for review.
OPRO 将重新分类请求分配给 RBPM。然后，RBPM 将重新分类请求分配给 OPMA 评估员进行审查。
7. The assigned OPMA assessor evaluates the reclassification request by determining whether the facility deficiency, including a deficiency pertaining to the specific application, is resolved.
指定的 OPMA 评估员通过确定设施缺陷（包括与特定应用程序有关的缺陷）是否得到解决来评估重新分类请求。
8. When the archival system indicates that FDA’s evaluation of the site is ongoing (e.g., in-process remediation), although a VAI letter has been issued, the OPMA assessor contacts the assigned Office of Manufacturing Quality compliance officer to gain additional information about the scope of the open evaluation. Within 2 U.S. business days, OMQ will provide this information to OPMA.
当档案系统表明 FDA 正在对现场进行评估（例如，正在补救）时，尽管已经发布了 VAI 信函，但 OPMA 评估员会联系指定的生产质量合规办公室官员，以获得有关公开评估范围的更多信息。OMQ 将在 2个美国工作日内向 OPMA 提供此信息。
If the deficiency is resolved, the assessor determines whether a PAI or the use of alternative tools is required to complete the assessment of the facility. If further assessment via an inspection or the use of alternative tools is not required in support of the application, the request will be granted.
如果缺陷得到解决，评估员将确定是否需要PAI 或使用替代工具来完成设施评估。如果不需要通过检查或使用替代工具进行进一步评估来支持申请，则会批准申请。
If the deficiency remains unresolved (e.g., although the most recent facility inspection designation was VAI, FDA is continuing to evaluate the facility’s remediation of prior OAI deficiencies) or if a PAI or the use of alternative tools is necessary to address the current concerns, the request will be denied.
如果缺陷仍未解决（例如，尽管最近的设施检查结果为VAI，但 FDA 正在继续评估该设施对先前 OAI 缺陷的补救措施），或者如果 PAI 或使用替代工具是解决当前问题所必需的，则该请求将被拒绝。
9. The OPMA assessor communicates to the OPRO RBPM the decision regarding whether to grant or deny the request. If the decision is to grant the request, the OPMA assessor will reach out to OMQ, as needed, for input on the final classification decision. Regardless of the outcome, the OPMA assessor documents the decision and rationale in a memo and uploads the memo to the archival database. OPMA 评估员向 OPRO RBPM 传达关于是否批准或拒绝请求的决定。如果决定批准该请求，OPMA 评估员将根据需要联系 OMQ，以获得最终分类决定的意见。无论结果如何，OPMA评估员都会将决定和理由记录在备忘录中，并将备忘录上传到档案数据库。
10. OPRO informs the ORO RPM of the decision.
OPRO将该决定通知给ORO RPM。
The ORO RPM drafts and issues to the applicant the decisional letter that includes the applicable GDUFA goal date of the ANDA amendment(s)15 as stated in the GDUFA III commitment letter. See tables 1 and 2 in the Attachment, Generic Drug User Fee Amendments Submission Types and Goal Dates.
11. ORO RPM 起草并向申请人发布决定书，其中包括 GDUFA III 承诺书中规定的 ANDA 修正案的适用 GDUFA目标日期。见附件中的表 1 和表2，仿制药用户费用修正案提交类型和目标日期。
OPQ-Managed ANDA PASs 由 OPQ 管理的 ANDA PAS
1. OPRO receives the facility-only major-to-minor reclassification request and assigns it to the RBPM.
OPRO 只接收设施的大到小重新分类请求，并将其分配给 RBPM。
2. The OPRO RBPM reviews the cover letter and determines whether to accept or not accept the reclassification request for review. The OPRO RBPM accepts the reclassification request for review if all the criteria in bulleted items a) through f) are met:
OPRO RBPM 审查求职信，并决定是否接受重新分类请求进行审查。如果项目符号 a）至 f）中的所有标准都得到满足，则 OPRO RBPM 接受重新分类请求进行审查：
The reclassification request is submitted with a CR letter response amendment in a single submission.
重新分类请求与 CR 信函回复修正案一起提交。
The reclassification request is submitted with the VAI or the NAI CGMP classification letter issued by FDA to the facility.
重新分类请求与 FDA 向设施颁发的 VAI 或 NAI CGMP 分类信一起提交
The reclassification request is easily identified in the cover letter for the amendment submitted in response to the CR letter.
在针对 CR 信函提交的修正案的附信中，可以很容易地确定重新分类请求。
The reclassification request is specific to a facility deficiency, and that specific deficiency is the only basis for the CR letter’s major classification. (Amendment may contain other minor deficiencies, except as noted below for a CR letter that is more than 1 year old and does not meet other criteria for acceptance.)
重新分类请求是针对设施缺陷提出的，该特定缺陷是 CR 信函主要分类的唯一依据。（修正案可能包含其他轻微缺陷，但以下针对超过 1 年且不符合其他验收标准的 CR 信函所述的情况除外。）
The CR letter was issued on or after October 1, 2022 (the implementation date of GDUFA III).16
CR 信函于 2022 年 10 月 1 日（GDUFA III 实施日期）或之后发布。
The CR letter is less than 1 year old at the time the request for reclassification is submitted (from the date the CR letter was signed) or it is more than 1 year old and one of the following applies:
在提交重新分类请求时（自 CR 信函签署之日起），CR 信函的有效期不到 1 年，或者超过 1 年，且以下情况之一适用：
The product is the subject of a response to a public health emergency as declared by the Secretary of the U.S. Department of Health and Human Services under section 319 of the Public Health Service Act or is anticipated to be subject to the same criteria as applied to such a declaration at the time of submission.
该产品是美国卫生与公众服务部部长根据《公共卫生服务法》第 319 条宣布的公共卫生紧急事件的响应对象，或者预计在提交时应遵守与此类声明相同的标准。
The product is on the drug shortage list under section 506E of the Federal Food, Drug, and Cosmetic Act.
根据《联邦食品、药品和化妆品法》第 506E 条，该产品被列入药品短缺名单。
The facility deficiency is the only deficiency in the CR letter (i.e., the facility issue is the only major deficiency (i.e., single) and there are no minor deficiencies).
设施缺陷是 CR 函中唯一的缺陷（即，设施问题是唯一的主要缺陷（即单一缺陷），不存在微小缺陷）。
3. The OPRO RBPM triages the CR letter amendment that includes the reclassification request and assigns the request to OPMA.
OPRO RBPM 对包括重新分类请求的 CR 信函修订进行分类，并将请求分配给 OPMA。
4. After a priority or standard designation has been made, the OPRO RBPM communicates the decisional period to the OPQ assessment team.
在做出优先级或标准指定后，OPRO RBPM 将决策期传达给 OPQ 评估团队。
5. The OPRO RBPM notifies the applicant via a formal correspondence indicating whether its reclassification request is accepted for review and provides a decisional date indicating when the reclassification request will be made.
OPRO RBPM 通过正式信函通知申请人，说明其重新分类请求是否被接受审查，并提供决定日期，说明何时提出重新分类请求。
6. The assigned OPMA assessor evaluates the reclassification request and makes a grant or deny decision by determining whether the facility deficiency, including any deficiency pertaining to the specific application, is resolved.
指定的 OPMA 评估员评估重新分类请求，并通过确定设施缺陷（包括与特定申请有关的任何缺陷）是否得到解决来做出准予或拒绝的决定。
If the deficiency is resolved, the assessor determines whether a PAI or the use of alternative tools is required to complete the assessment of the facility. If further assessment via an inspection or the use of alternative tools is not necessary in support of the application, the request will be granted.
如果缺陷得到解决，评估员将确定是否需要 PAI 或使用替代工具来完成设施评估。如果不需要通过检查或使用替代工具进行进一步评估来支持申请，则会批准申请。
If the deficiency remains unresolved (e.g., although the most recent facility inspection designation was VAI, FDA is continuing to evaluate the facility’s remediation of prior OAI deficiencies) or if a PAI or the use of alternative tools is necessary to address the current concerns, the request will be denied.
如果缺陷仍未解决（例如，尽管最近的设施检查指定为 VAI，但 FDA 正在继续评估该设施对先前 OAI 缺陷的补救措施），或者如果 PAI 或使用替代工具是解决当前问题所必需的，则该请求将被拒绝。
7. The OPMA assessor communicates to the OPRO RBPM the decision of whether to grant or deny the request and documents the decision and rationale in a memo and uploads the memo to the archival database.
OPMA 评估员向 OPRO RBPM 传达是否批准或拒绝请求的决定，并将决定和理由记录在备忘录中，并将备忘录上传到档案数据库。
8. The OPRO RBPM drafts and issues to the applicant the decisional letter that includes the applicable GDUFA goal date of the ANDA amendment(s)17 as stated in the GDUFA III commitment letter. See tables 1 and 2 in the Attachment, Generic Drug User Fee Amendments Submission Types and Goal Dates.
OPRO RBPM 起草并向申请人发布决定书，其中包括 GDUFA III 承诺书中规定的 ANDA 修正案的适用 GDUFA 目标日期。见附件中的表 1 和表2，仿制药用户费用修正案提交类型和目标日期。
EFFECTIVE DATE 生效日期
This MAPP is effective on June 27, 2023.
本 MAPP 生效日期 2023 年 6 月27 日
