FDA 发布 API 工艺检查合规计划 7356.002F 修订版，纳入 ICH Q9(R1)、Q10、Q12 要素
Active Pharmaceutical Ingredient (API) Process Inspection (7356.002F)
FDA 发布 API 工艺检查合规计划 7356.002F 修订版，实施日期为 2025 年 9 月 2 日，签发日为 2025 年 8 月 1 日。修订版纳入 ICH Q9(R1) 质量风险管理、Q10 药品质量体系和 Q12 产品生命周期管理要素，并增加有害杂质控制内容。
该合规计划修订后纳入 ICH Q9(R1)、Q10 和 Q12 的要素，并列出 API 检查中质量体系等各系统的覆盖要点与检查方法，可帮助读者定位检查关注领域。
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美国食品药品监督管理局
合规计划 计划 7356.002F
第56章 – 药品质量保证
主题：原料药工艺 实施日期：
检查 2025年9月2日
修订：修订以增加国际人用药品注册技术协调会
(ICH) 行业指南 Q9(R1) 质量
风险管理（2023年5月）、Q10 药品质量
体系（2009年4月）和 Q12 药品
生命周期管理的技术与监管考量
（2021年5月）以及有害杂质控制的要素。1
数据报告
产品代码 产品/任务代码
行业代码 54、56 及 60-66（含） 境内和境外检查：
• 56002F（全面检查）
• 56002L（简化检查）
相关产品/任务代码：
• 56002 & H（药品工艺检查 (DPI)）
• 56002C & K（放射性药品的 DPI）
现场报告要求：
本合规计划 2 涵盖原料药 (API) 设施 4 的现行药品生产质量管理规范 (CGMP) 检查 3，
以确保 API 符合《联邦食品、药品和化妆品法案》(FD&C 法案) 第
501(a)(2)(B) 条。5 这包括评估 CGMP 要求符合性
并提供 API 生产和流通各方面全面监管
覆盖的程序。
检查员将创建企业检查报告 (EIR)，并使用
eNSpect 或检查与调查办公室 (OII) 和
药品评价与研究中心 (CDER) 均可访问的替代系统以电子方式提交。对于分类为
1
我们会定期更新指南。如需指南的最新版本，请查看 FDA 指南网页
https://www.fda.gov/regulatory-information/search-fda-guidance-documents。
2
合规计划可在 https://www.fda.gov/drugs/guidance-compliance-regulatory-information/drug-
compliance-programs 获取。
3
在本合规计划中，CGMP 检查包括监督性检查和有因检查。
4
本合规计划交替使用企业、场所、公司和设施等术语，以涵盖受
FDA 药品生产法规和法定权限约束的实体。
5
见 21 U.S.C. 351(a)(2)(B)。
签发日期：2025年8月1日 第 1 页，共 41 页
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PROGRAM 7356.002F
由于 CGMP 缺陷适用于原料药而被列为官方行动指示（OAI）时，CDER 将
依据《监管程序手册》，在合规管理系统中提交建议性、行政性或司法性
行动建议。
检查员应在 eNSpect 中报告重大问题。这些问题可包括分析或
检查方面的问题，或与本计划下形成的信息相关的其他问题。这
包括及时提交、变更和删除 OAI 通知。
如果美国食品药品监督管理局（FDA）工作人员在检查期间获得有关药品不良
反应报告不足、未经批准药品问题或上市后报告（例如药品申请
补充、现场警示报告）违规的信息，检查员应按照适用合规
计划中的指示，在 EIR 中以单独标题报告这些
信息。有关这些活动的信息应在单独的产品/任务
代码下报告。
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PROGRAM 7356.002F
目录
第一部分 – 背景 ............................................................................................................ 4
1. 引言 .................................................................................................................................. 4
2. 适用法规、规章和指南 ......................................................................... 4
3. 本计划涵盖的原料药范围 .................................................................................... 6
4. 定义.................................................................................................................................... 7
第二部分 – 实施 ................................................................................................... 9
1. 目标 ...................................................................................................................................... 9
2. 计划管理说明 ............................................................................................ 10
A. 选择场所 ........................................................................................................................ 10
B. 选择检查员 ........................................................................................................... 10
C. 选择检查类型..................................................................................................... 10
D. 选择系统................................................................................................................... 11
E. 选择原料药 ........................................................................................................................ 12
F. 选择特征类别 ........................................................................................................ 13
第三部分 – 检查 ....................................................................................................... 14
1. 操作 .................................................................................................................................. 14
A. 检查方法 ........................................................................................................... 14
B. 系统覆盖 .................................................................................................................... 15
C. 制定检查策略 .......................................................................................... 28
2. 报告.................................................................................................................................... 30
A. 回复 Form FDA 483 的特别说明 ...................................................... 31
第四部分 – 分析 ......................................................................................................... 32
第五部分 – 监管/行政策略 ................................................ 33
第六部分 – 参考文献、附件和计划联系人 ..................... 36
1. 参考文献 .................................................................................................................................. 36
2. 附件 – 无。 .................................................................................................................. 39
3. 计划联系人 ....................................................................................................................... 39
A. CDER ..................................................................................................................................... 39
B. OII .......................................................................................................................................... 40
第七部分 – 中心职责 .............................................................................. 41
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PROGRAM 7356.002F
第一部分 – 背景
1. 引言
本合规程序对原料药生产设施监督检查采用基于风险的检查策略。本合规程序中的程序可最大限度利用资源，并实现高效的检查覆盖。检查深度应基于与特定公司运营相关的适当风险。这些风险可包括公司的合规历史、所采用的技术、原料药的声称特性，以及原料药在药品中的预期用途（如已知）。本合规程序还提供了对因由检查的覆盖程序。
原料药是指：
[任何]旨在在疾病的诊断、治愈、缓解、治疗或预防中提供药理活性或其他直接作用，或影响人或其它动物身体结构或任何功能的组分。该术语包括那些在药品生产中可能发生化学变化，并以经修饰的形式存在于药品中、旨在提供特定活性或作用的组分。6
原料药生产过程通常包括一系列操作。原料药生产过程中的主要操作或步骤可包括多步化学合成和发酵、纯化、结晶、干燥、粉碎、包装、贴标和检测。本合规程序适用于该场所的所有原料药生产操作，包括物料的接收、生产、包装、再包装、贴标、再贴标、质量控制、放行、合同检测、原料药的储存和分销，以及相关控制。
2. 适用法规、规章和指南
根据FD&C法案第510条，7 原料药生产商必须向FDA注册其场所，并列出其商业分销的原料药，除非根据21 CFR 207.13获得豁免。外国药品生产商也须注册其场所，并列出所有进口或拟进口至美国的药品。有关外国药品场所注册要求的更多信息，请参阅21 CFR 207.25(h)。
原料药受FD&C法案第501(a)(2)(B)条掺假条款的约束，该条款要求所有药品均按照CGMP要求生产。FD&C法案未对原料药和药品作出区分，如果其中任一者不符合CGMP要求，即违反FD&C法案。尽管FDA已发布针对药品的CGMP法规，但FDA尚未发布专门针对原料药或药物组分的CGMP法规。因此，本文件中术语CGMP要求指FD&C法案的要求，而非第210和211部分（21 CFR第210和211部分）中针对药品的要求。
6
见21 CFR 210.3(b)(7)。
7
见21 U.S.C. 360。
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PROGRAM 7356.002F
FDA 长期以来一直认识到，第 210 部分和第 211 部分中药品 CGMP 要求中的概念对原料药生产是有效且适用的。这些概念包括：(1) 通过使用合适的设备以及聘用具备适当资质并经过培训的人员来确保药品质量；(2) 建立充分的书面程序和控制系统，以确保生产工艺和控制措施有效；(3) 建立对中间物料和药品的检验体系；以及 (4) 确保药品在其预期使用期内保持稳定。
FDA 期望原料药生产商：(1) 从使用起始物料开始，将 CGMP 应用于原料药生产过程；以及 (2) 验证影响最终原料药质量和纯度的关键工艺步骤。适当的控制水平高度取决于生产工艺，并随着工艺从早期步骤推进到最终分离和纯化步骤而不断提高。适当的控制水平取决于与每个具体工艺步骤相关的风险或关键性。
2001 年，FDA 发布了 ICH 行业指南 Q7《原料药药品生产质量管理规范指南》。8 ICH Q7 代表了 FDA 当前对原料药 CGMP 的看法。因此，遵循本指南的原料药及相关生产和检验设施通常将被视为符合法定 CGMP 要求。9 但是，如果替代方法满足《联邦食品、药品和化妆品法案》第 501(a)(2)(B) 条的要求，并确保原料药符合其声称的纯度、鉴别和质量特性，则可采用替代方法。
ICH Q7 就原料药在适当质量体系下生产的 CGMP 范围和应用向行业提供指导。ICH Q7 中的建议还旨在帮助确保原料药符合其声称或宣称具有的质量和纯度特性。检查员应将 ICH Q7 作为检查原料药生产商及相关设施的指南。
作为 FDA 持续推进“21 世纪药品质量”倡议的一部分，FDA 正在推行相关策略，以确保实施 ICH 行业指南 Q10《药品质量体系》（2009 年 4 月）中所述的有效药品质量体系。此外，FDA 发布了 ICH 行业指南 Q9(R1)《质量风险管理》（2023 年 5 月），以提供可应用于产品生命周期各个方面以确保药品质量的质量风险管理工具的原则和示例。为了以更可预测且高效的方式促进对批准后化学、生产和控制变更的管理，FDA 发布了 ICH 行业指南 Q12《药品生命周期管理的技术和监管考虑》及其附件（2021 年 5 月）以及行业指南草案 ICH Q12：《FDA 监管产品的实施考虑》（2021 年 5 月）。10 应将知识管理、变更管理和质量风险管理原则整体应用于原料药生产运营，以帮助确保原料药质量。除 ICH Q9(R1)、Q10 和 Q12 外，这些原则还在行业指南《药品 CGMP 法规的质量体系方法》（2006 年 9 月）中有所描述。
8
ICH Q7 修订版 1 于 2016 年 9 月发布。
9
参见 ICH 行业指南 Q7《原料药药品生产质量管理规范指南：问答》（2018 年 4 月）。
10
本指南定稿后，将代表 FDA 当前对该主题的看法。
发布日期：2025 年 8 月 1 日 第 5 页，共 41 页
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为加强 FDA 对原料药生产及质量的监管，FDA 可能使用其他信息来源为其监管监督提供依据。这可能包括以下内容：(1) FDA 开展的其他检查（例如，批准前检查和批准后检查）；(2) 通过互认协议及其他保密协议，向可信赖的境外监管伙伴索取的现有检查报告；11 以及 (3) 远程监管评估，12 包括 (a) 依据《联邦食品、药品和化妆品法案》第 704(a)(4) 条直接向生产设施及其他被检查实体索取的记录或其他信息，13 以及 (b) 在适当情况下开展的远程交互式评估。
3. 本计划涵盖的原料药范围
本合规计划适用于用于人用药品的原料药的生产，包括：
• 通过化学合成生产的小分子原料药及关键中间体
• 通过化学合成或发酵生产的、由最多 40 个氨基酸组成的多肽
• 通过微生物发酵生产的抗生素及其他小分子原料药
本合规计划不涵盖用于血液、疫苗、过敏原、组织以及细胞和基因治疗的原料药。14 这些产品由生物制品评价与研究中心监管。对属于蛋白质的原料药15 的 CGMP 检查，使用合规计划 7356.002M——《蛋白质原料药生产商监督检查》开展。含有属于蛋白质的原料药的生物制品示例包括但不限于：
• 酶
11
对于 FDA 与欧盟、瑞士和英国现有的互认协议，这包括使用由认可机构签发的官方检查报告，适用于位于签发机构领土之内和之外的生产设施。更多信息，请参见 https://www.fda.gov/international-
programs/international-arrangements/mutual-recognition-agreements-mra。
参见行业指南草案《开展远程监管评估 问答》（2024 年 1 月）。
12
该指南定稿后，将代表 FDA 对该主题的当前看法。
13
参见 21 U.S.C. 374(a)(4)。
14
术语 drug substance 用于生物制品中的原料药。
15
参见 21 CFR 600.3(h)(6) 中蛋白质的定义。蛋白质是依据《公共卫生服务法》第 351 条定义并获得许可的生物制品。
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PROGRAM 7356.002F
• 单克隆抗体
• 抗体药物偶联物
• 融合蛋白（例如，含抗体 Fc 区的融合蛋白）。
• 生长因子
• 细胞因子（例如，白细胞介素、干扰素、肿瘤坏死因子）
• 肉毒毒素
• 胰岛素及胰岛素类似物
• 合成来源的蛋白质
本合规计划适用于预期无菌的原料药的生产，但仅涵盖至原料药被致无菌之前的环节。然而，本合规计划与
ICH Q7 均未提供关于无菌原料药灭菌和无菌工艺的指南。检查员
在检查声称无菌的原料药的无菌工艺（包括配制无菌制剂）时，应使用合规计划 7356.002A——无菌药品工艺检查，以及行业指南《无菌工艺生产的无菌药品——现行
药品生产质量管理规范》（2004 年 9 月）。
散装成品与原料药的生产方式类似，但其在合成、发酵或提取后不再经过进一步
加工或配制，而是重新包装进入上市容器。散装成品须符合第
210 和 211 部分的要求。产生此类原料药的合成和发酵工艺由本
计划涵盖，而非剂型计划（即合规计划 7356.002——药品
生产检查）。
4. 定义
原料药：“[任何]旨在在疾病的诊断、治愈、缓解、治疗或预防中提供药理
活性或其他直接作用，或影响人或其它动物身体的结构或任何功能的组分。该术语包括那些
在药品生产中可能发生化学变化，并以经修饰的形式存在于药品中，旨在提供特定活性或作用的
组分。” 16
FDA 和业界也使用术语 drug substance 来指代原料药。
原料药生产工艺：导致原料药制备的一系列相关操作。原料药生产工艺中的主要操作或步骤可能包括
多步化学合成和发酵、纯化、结晶、干燥、粉碎、包装、
贴标和检测。
原料药起始物料：用于原料药生产并作为重要结构片段并入原料药结构的
原材料、中间体或原料药。原料药
16
见 § 210.3(b)(7)。
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起始物料可以是商品，也可以是根据合同或商业协议从一个或多个供应商处采购的物料，
还可以是内部生产的物料。原料药起始物料通常具有
明确的化学性质和结构。
大宗成品：一种与原料药类似方式生产的药物物料，但在其合成、发酵或提取后
不再经过进一步加工或配制，而是
重新包装到上市容器中。
中间体：在原料药加工步骤中产生的物料，在成为原料药之前
会经历进一步的分子变化或纯化。中间体可能被分离，也可能不被分离。
（注：本合规程序仅涉及在设施已界定的
原料药生产开始点之后产生的那些中间体。）
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PART II – IMPLEMENTATION
1. Objective
The primary objective of this compliance program is to provide comprehensive CGMP inspectional
coverage of API manufacturing establishments. This is done through system-based inspections that
represent all profile classes (i.e., types of API manufacturing processes) and determine whether a
manufacturer is operating in a state of control. An API manufacturer is operating in a state of control
when it employs conditions and practices that ensure compliance with section 501(a)(2)(B) of the
FD&C Act. A firm that is in a state of control produces APIs that have an adequate level of assurance
of quality, identity, and purity.
A firm is not in a sufficient state of control if any system is significantly noncompliant with CGMP
requirements such that the quality, identity, and purity of the API cannot be adequately ensured.
Documented CGMP deficiencies provide the evidence for concluding that a system is not operating
in a state of control. See Part V - Regulatory/Administrative Strategy, for a discussion of compliance
actions based on inspection findings that demonstrate that a system or multiple systems are not in a
state of control.
Profile classes generalize inspectional coverage from a small number of specific APIs to all APIs in
that class. This compliance program uses a systems-based approach to further generalize inspectional
coverage from a small number of profile classes to an overall evaluation of the firm. This allows
preapproval inspections to focus on the specific issues related to a given drug application and
improves the assessment process by providing timely and efficient support for drug application
decisions.
Investigators should use this compliance program’s system definitions and organization when
inspecting API manufacturers and reporting the results. Focusing on systems, rather than just profile
classes, increases the efficiency of inspections, because the systems are often applicable to multiple
profile classes. An inspection under this program is profileable and will result in a determination of
acceptability or nonacceptability for all API profile classes specified in this compliance program.
Inspection coverage should represent all of the API profile classes that are manufactured by the firm.
The other objectives of this compliance program include:
• Determining whether inspected establishments are operating in compliance with applicable
CGMP requirements to aid in FDA’s enforcement of the FD&C Act.
• Initiating appropriate action against manufacturers that are found to be out of compliance.
• Obtaining information that may affect other drug manufacturing or compounding operations
(e.g., sterilization, drug product manufacturing, drug product compounding).
Date of Issuance: 08/01/2025 Page 9 of 41
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• 在检查期间向生产商提供指导，以在适用情况下提高对 CGMP 要求的符合性。
2. 计划管理说明
A. 选择场所
CDER 使用基于风险的场所选择模型来确定 API 企业，以供 OII 进行常规监督
检查。CDER 和 OII 依据《调查操作手册》(IOM) 第 5 章维护药品档案。17
除非 CDER 特别指示，OII 负责使用本合规计划的说明确定对每家 API 企业的检查
覆盖深度。本计划下的 CGMP 检查覆盖范围将足以评估每家企业的合规状态。
B. 选择检查员
API 生产商的检查应由经验丰富的检查员进行，这些检查员应具备与 API 生产商所进行的
API 生产工艺类型（例如发酵、化学合成）相关的充分教育和培训。18 应酌情考虑将
化学师和微生物学家纳入 API 检查团队，特别是用于评估实验室操作（例如分析方法评价、
分析数据、实验室程序、仪器）以及评估用于建立杂质谱的分析方法、
发酵生产工艺和化学合成的复杂多步工艺。
进行 API 检查的检查员必须了解用于生产 API 的工艺与用于生产
成品剂型的工艺之间的基本差异。API 通常通过化学合成或通过细胞培养和提取
生产。因此，API 生产通常涉及通过各种化学、
物理和生物处理步骤对起始物料或中间体进行显著改变。一般而言，API 生产的最终目标是
获得具有特定身份的纯化合物。相比之下，成品
剂型生产的最终目标通常是在各给药单位中实现 API 的均匀分布，以
递送精确量的 API。
C. 选择检查类型
CGMP 检查有两种基本类型：监督检查和有因检查。监督检查
定期进行，以履行 FDA 检查药品生产
设施的职责。有因检查是针对违规的监督检查以及
因特定事件或信息而需要对设施进行检查时进行的。
17
见 https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-
references/investigations-operations-manual。
18
关于发酵的更多检查指南，见合规计划 7356.002M。
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有因检查包括：(1) 在采取监管行动后，为核实纠正措施而进行的后续 CGMP 合规检查；以及 (2) 针对特定事件或信息（例如现场警示报告、生物制品缺陷报告、行业投诉、召回、其他缺陷产品迹象）而开展的 CGMP 检查，这些事件或信息使某项生产规范、设施、工艺或 API 的合规性或质量受到质疑。
后续 CGMP 合规检查提供有针对性的覆盖范围，包括关注领域、针对受影响运营提出的纠正措施计划、任何已实施的纠正措施，和/或上次检查中 Form FDA 483–检查观察记录上注明的缺陷。系统覆盖范围可根据具体情况逐案增加。针对警告信或其他重大监管行动的后续 CGMP 合规检查也属于有因检查，因此，相关的有因任务可要求全面系统覆盖或单个系统覆盖。此外，经 OII 酌情决定，可在检查前或检查期间根据具体情况逐案增加覆盖范围。
其他有因检查（例如因行业投诉或其他缺陷 API 迹象而进行的检查）可以启动，但这些检查可扩展至包括 CGMP 覆盖范围，以更新企业的整体合规状态。
D. 选择系统
这是检查 API 生产商的系统总体方案：
1. 质量体系确保整体符合 CGMP 要求以及内部程序和标准。健全的质量体系依赖于文件记录以及高级管理层对 CGMP 运营和质量相关事项的有力监督，支持并促进在全部六个系统下开展的活动，监测其有效性，并确保对既定质量方针的承诺。19
2. 设施与设备系统包括为 API 生产提供适当物理环境和设备的活动。
3. 物料系统包括控制起始物料、中间体和容器的措施和活动。它包括计算机化及库存控制流程、储存和分销控制的验证。
4. 生产系统包括控制 API 生产的措施和活动，包括过程取样、检测和工艺验证。
19
质量方针定义为组织与质量相关的总体意图和方向，由高级管理层正式表达。参见 ICH Q10。
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5. Packaging and Labeling System includes measures and activities that control the packaging
and labeling of intermediates and APIs.
6. Laboratory Control System includes measures and activities related to laboratory
procedures, testing, analytical methods development, analytical methods validation or
verification, and the stability program.
Inspectional Section III.1.B has detailed inspection coverage guidance for these systems.
An inspection under this program is defined as audit coverage of two or more systems, including
mandatory coverage of the quality system. Inspecting at least two systems (i.e., the quality system
and one other system), or more systems if deemed necessary by OII, will provide the basis for an
overall inspection classification decision.
Coverage of a system should be sufficiently detailed and specific examples should be selected.
Sufficient coverage ensures that the system inspection outcome reflects the system’s state of control
for every profile class. If a particular representative system is adequate, it should be adequate for all
drug profile classes manufactured by the firm. In some circumstances, it may not be possible to
generalize certain deficiencies in a system to all API profile classes. If so, the unaffected profile
classes may be considered acceptable if they are otherwise acceptable.
If a selected API has a unique processing or control function that is part of a system that was not
chosen for coverage, the unique function can be covered for that API. However, the system for the
unique function does not need to be given full coverage. For example, if an API chosen for coverage
uses only high purity water in its manufacture, the water purification system can be inspected without
giving full inspection coverage to the materials system. Selecting unique functions within a system
will be at the discretion of the investigator.
Complete inspection of one system may require follow up of certain aspects of another system to
fully document the findings. However, this coverage does not constitute nor require complete
coverage of the other system.
E. Selecting APIs
Inspections should cover any APIs referenced in the assignment and, as appropriate, any other
representative APIs based on their level of risk. For foreign API firms, investigators should cover
only APIs that are marketed or intended to be marketed in the United States.
Investigators should select APIs so that the coverage represents the establishment’s overall ability to
manufacture in compliance with CGMP requirements. API selection should also be based on the level
of risk, including selection of APIs that are:
• Used in approved drug products
• Therapeutically significant
• Difficult to manufacture
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• Intended for use in parenteral or modified-release products or in combination products 20
• Documented as having past compliance problems
However, this does not prevent investigators from selecting less therapeutically significant APIs to
evaluate specific APIs (or profile classes) that were not previously given in-depth coverage at the
facility. Inspection coverage depth and intensity can be reduced for these APIs unless deficiencies are
identified.
When a system is inspected, the inspection of that system generally applies to all API products that
use the system. Because API manufacturers are often referenced in multiple drug applications, each
inspection should cover an adequate number and type of APIs to cover the selected systems. For
example, if an inspection covers the production system for a site making one API by fermentation and
another by synthesis, the inspection should include both types of processing in the physical inspection
and the records that are sampled during the audit. This strategy, together with the classification of all
applicable profile classes after the inspection, will maximize the use of FDA resources and avoid
repeated visits to the same manufacturing site to cover different API profile classes.
F. Selecting Profile Classes
Profile class codes 21 or APIs selected for coverage should represent all of the APIs manufactured at
the firm. Profile class codes may also be grouped by similarity, such that coverage of one profile class
is sufficient to demonstrate the CGMP conditions for another profile class. For example, inspecting a
profile class code of CSS 22 could provide surrogate coverage of CSN. Similarly, inspecting a profile
class code of CBI could provide surrogate coverage of other profile classes, such as CFN, CFS, and
perhaps CEX.
The inspection findings will be used to update all applicable profile classes. 23 Normally, an inspection
under this system approach will result in all applicable profile classes being updated. For more
information, see Exhibit 5-14 Profiling a Firm’s CGMP/QS Compliance Status in the IOM.
20
Combination products are subject to the CGMP requirements outlined in 21 CFR part 4. See the guidance for industry
and FDA staff Current Good Manufacturing Practice Requirements for Combination Products (January 2017) and
compliance program 7356.000—Inspections of CDER-led or CDRH-led Combination Products.
21
A profile classification scheme is used to categorize APIs by the nature of their processing.
22
This compliance program applies to the manufacture of sterile APIs only up to the point immediately before the APIs
are rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this compliance program.
Investigators should use the finished pharmaceuticals regulations (parts 210 and 211) and follow compliance program
7356.002A when inspecting the sterile processing of APIs.
23
Profile classes are not updated for a preapproval inspection of an API unless the preapproval inspection covers a new
profile. See also compliance program 7346.832—Preapproval Inspections.
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PART III – INSPECTIONAL
1. Operations
Investigators conducting API inspections should understand the general inspection strategy in this
compliance program. API firms vary greatly in size, diversity of operations, and quality assurance
systems, so investigators should carefully plan their inspection strategy at each firm. See Part III.1.C
for the procedures for preparing an inspection strategy.
Investigators should also review the firm’s rationale for the point at which API production begins, as
described in ICH Q7 and the ICH guidance for industry Q11 Development and Manufacture of Drug
Substances (November 2012). This point may vary based on the type of process used for the API
(e.g., synthesis, fermentation, extraction, purification).
A. Inspection Approaches
Surveillance inspections have two inspection options: a full inspection and an abbreviated inspection.
For-cause inspections can provide focused coverage, or they can be expanded to abbreviated or full
inspections on a case-by-case basis, at OII’s discretion.
(1) Full Inspection Option
The full inspection option is a CGMP inspection that provides a broad and in-depth evaluation of the
establishment’s conformance with CGMP requirements. A full inspection may change to an
abbreviated inspection with concurrence from OII.
During the course of a full inspection, coverage in other systems may be needed to verify quality
system activities. The full inspection option should include an inspection of at least four systems, one
of which must be the quality system.
A full inspection is appropriate for the following cases:
• For an initial inspection of a newly registered establishment. Inspection coverage should
include all the systems that are appropriate for the operations.
• When the establishment has a history of fluctuating into and out of compliance. To determine
if the establishment meets this criterion, OII should use all of the information at its disposal.
This information can include inspection results, results of sample analyses, complaints,
defects, drug quality reports, field alert reports, adverse event reports, and recalls, in addition
to any compliance actions resulting from these types of information or from past inspections.
• To evaluate whether important changes have occurred by comparing current operations
against the EIR from the last full inspection. The following are typical types of changes that
warrant the full inspection option:
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– Changes that introduce a new potential for cross-contamination through the type of
materials that use the same equipment or the type of processing.
– Use of new technology requiring new expertise, significant equipment changes, or new
facilities.
• When OII management or CDER requests this option.
• To follow up on a warning letter or other regulatory actions.
• When, at OII’s discretion, a full inspection needs to be conducted based on CGMP findings.
(2) Abbreviated Inspection Option
The abbreviated inspection option is a CGMP inspection that efficiently updates the evaluation of and
provides documentation for an establishment’s conformance with CGMP requirements. The
abbreviated inspection option should include an inspection audit of two to three systems, one of
which must be the quality system. OII’s division management should ensure that the optional systems
are rotated in successive abbreviated inspections. During the course of an abbreviated inspection,
verification of quality system activities may require limited coverage in other systems.
An abbreviated inspection is appropriate when a full inspection is not warranted. This option involves
inspecting the manufacturer to: (1) maintain surveillance over the establishment’s manufacturing
practices and quality performance; and (2) evaluate whether the establishment is maintaining and
improving the CGMP level of assurance for the quality of its APIs. Select the abbreviated inspection
option (with OII concurrence) when an establishment has:
• A record of sustained acceptable compliance history
• A strong risk management program
• A lack of significant marketed API quality defects.
An abbreviated inspection may be changed to a full inspection at OII’s discretion.
B. System Coverage
This section provides a complete description of each system and the areas for coverage. Investigators
should take the firm’s specific operating conditions, history of previous coverage, and history of
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PROGRAM 7356.002F
CGMP compliance into consideration when selecting systems and determining the relative depth of
the audit’s coverage.
The organization and personnel (including appropriate qualifications and training), employed in any
given system, will be evaluated as part of that system’s operation. Production, control, or distribution
records are required to maintain CGMP compliance, and the records selected for review should be
included for inspection audit within the context of each of the systems. Inspection of contract
companies should include (1) coverage within the system for which the intermediate, API, or service
is contracted; and (2) evaluation of their quality system.
Each of the following system descriptions has a bulleted list of areas. The firm should have written
and approved procedures and documentation for each of these areas. Whenever possible, investigators
should verify (through observation) if firms are adhering to written procedures. For each system, the
areas are not limited to the final API but may also include starting materials and intermediates. All
areas under each system should be covered; however, the depth of coverage may vary from the
planned inspection strategy depending on inspectional findings.
(1) Quality System
The quality system is assessed in two phases. In phase one, investigators evaluate whether the quality
unit has fulfilled the responsibility to review and approve all procedures related to production, quality
control, and quality assurance. Additionally, investigators will evaluate if the quality unit has ensured
that the procedures and the associated record keeping systems are adequate for their intended use. In
phase two, investigators assess the data and identify any quality problems. This phase may link to
other major systems for inspectional coverage.
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Quality oversight of contracted operations and material suppliers
– An effective monitoring strategy has been implemented; incoming material monitoring,
life cycle qualification program, quality agreements, and timely communication
mechanisms are implemented.
• Management oversight of the development, implementation, monitoring, and continual
improvement of the quality system 24
– Quality risk management 25 and knowledge management 26 are incorporated (e.g., timely
and effective communication, appropriate resource allocation, reviews of process
performance and API quality).
24
See ICH Q10.
25
See ICH Q9(R1).
26
Effective knowledge management (e.g., acquiring, analyzing, storing, and disseminating information) supports effective
risk management, along with timely risk review, corrective actions and preventive actions, and change management.
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• Quality oversight of hazards (e.g., cross-contamination, adulteration, hazardous impurities 27
such as nitrosamines 28 and nitrosating agents)
– Hazards are documented, identified, evaluated, addressed, communicated, and continually
reviewed (as needed) throughout the API’s life cycle.
– Hazardous impurity risks are assessed, and control strategies are implemented to mitigate
the risks (e.g., actions to address sources of variability, release testing, reduction or
elimination of impurities, cleaning validation); control strategies are reviewed following
changes and throughout the API’s life cycle.
• Adequate staffing to ensure fulfillment of quality unit duties
• Periodic quality reviews as described in ICH Q7
– Reviews are complete and conducted at least annually; API quality is reviewed to assess
risk and determine the need for changes, such as changes in API specifications,
manufacturing, or control procedures; statistical analysis is conducted to identify areas
(e.g., trends, patterns, correlations, anomalies) for action and improvement.
• Complaint reviews (quality and medical)
– Reviews are documented, evaluated, and investigated in a timely manner; corrective
action is included when appropriate.
• Discrepancies, failures, and critical deviations related to manufacturing and testing
– These issues are documented and investigated in a timely manner using scientific evidence
to identify the root cause; corrective actions and preventive actions are included, and the
effectiveness of the corrective and preventative actions is evaluated; investigations are
expanded to include any related APIs or materials.
• Stability failures
– Investigation is expanded where warranted; disposition is documented; stability data
supports the API retest dates and storage conditions.
27
See the ICH guidance for industry M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals to Limit Potential Carcinogenic Risk (July 2023).
28
See the guidance for industry Control of Nitrosamine Impurities in Human Drugs (September 2024).
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• Change management for the manufacturing of all APIs
– Changes are documented (with justification), reviewed by subject matter experts,
approved before implementation, and evaluated for effectiveness; changes are revalidated,
reverified, and requalified as needed; quality risk management 29 is used to evaluate
proposed changes for potential risks (e.g., hazardous impurities) and impact on API
quality; changes are reported to FDA by the drug application or drug master file (DMF)
holder, as appropriate.
• Reporting of changes for approved drug application products
– Changes to established conditions are documented and communicated to the drug
application holder, as appropriate. This enables reporting that is compliant with relevant
regulations 30 and consistent with the product life cycle management document in the drug
application or recommendations in relevant guidance. 31
• Rejects
– Investigations are expanded when warranted; corrective actions and preventative actions
are implemented, when appropriate.
• Quality oversight system for the release or rejection of raw materials
29
See ICH Q10.
30
See 21 CFR 314.70 and 314.97.
31
See the following guidances for industry:
• Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing,
and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (November 1995)
• SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation
(September 1997)
• Nonsterile Semisolid Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and
Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997)
• Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products
(July 1997)
• Changes to an Approved NDA or ANDA (April 2004)
• Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products
(June 2021)
• CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March 2014)
See also ICH Q12, its annexes, and the draft guidance ICH Q12: Implementation Considerations for FDA-Regulated
Products.
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• Batches manufactured since the last inspection to evaluate any rejections or conversions (e.g.,
from drug to nondrug use) because of processing problems
• Recalls (including any attempt to recover distributed API not meeting its specifications or
purported quality)
– The cause was determined; corrective actions were taken.
• Validation
– The statuses of validation and revalidation activities (e.g., computer, manufacturing
process, laboratory methods) are documented (e.g., reviews and approvals of validation
protocols and reports).
• Contemporaneous and complete documentation 32
• CGMP training and qualification for employees on a continuing basis and with sufficient
frequency
– Training includes coverage of quality functions, risk management, and the specific CGMP
operations assigned to individual employees.
• Programs for the ongoing monitoring of process performance and API quality throughout the
API’s life cycle
– Significant issues are escalated to senior management.
• Reprocess and rework
– Evaluation is conducted; approval is documented; impact on validation and stability is
assessed.
• Returns and salvages
– Assessment is conducted; investigation is expanded where warranted; disposition is
completed.
32
See the guidance for industry Data Integrity and Compliance With Drug CGMP: Questions and Answers (December
2018).
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(2) Facilities and Equipment System
(a) Facilities
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Responsible personnel’s oversight of the facility infrastructure and the suitability of
manufacturing operations
• Change management system for implementing changes in the facility
• Facility layout, material flow, and personnel flow that prevent cross-contamination, including
cross-contamination from processing of nondrug materials
• Complete and comprehensive separation of the manufacturing operations for highly
sensitizing agents (e.g., penicillin, beta-lactams, steroids, hormones, and cytotoxics)
• Qualified and appropriately monitored utilities (e.g., steam, gas, compressed air, heating,
ventilation, air conditioning) 33
• Lighting, potable water, washing and toilet facilities, and sewage and refuse disposal
• Cleaning and maintenance that potentially affect API quality
• Sanitation of the facility and use of rodenticides, fungicides, insecticides, and cleaning and
sanitizing agents
• Training and qualification of personnel
(b) Equipment
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
Note that this system includes only those utilities whose output is not intended to be incorporated into the API, such as
33
water used in cooling or heating jacketed vessels.
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• Equipment installation
– Equipment is operational; performance is qualified, when appropriate.
• Adequate equipment design, size, and location
• Controls to prevent contamination, including appropriate design provisions to ensure
separation from pesticides, other toxic materials, or nondrug chemicals
• Equipment surfaces that are not reactive, additive, or absorptive in a way that could alter
material quality
• Appropriate identification of equipment (e.g., reactors, storage containers) and permanently
installed processing lines
• Prevention of contact between substances associated with the operation of equipment (e.g.,
lubricants, heating fluids, coolants) and starting materials, intermediates, final APIs, and
containers
• Cleaning procedures and cleaning validation and sanitization studies to verify that residues,
microbial contamination, and, when appropriate, endotoxin contamination are brought below
scientifically appropriate levels
• Calibrations that use standards that can be traced to certified standards (e.g., National Institute
of Standards and Technology, United States Pharmacopeia (USP))
• Qualification, calibration, and maintenance of storage equipment (e.g., refrigerators, freezers)
to ensure that materials (e.g., standards, raw materials, reagents) are stored under appropriate
conditions
• Equipment (including computers) qualification, validation, calibration, maintenance, and
security
• Control system for implementing changes to equipment
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• Documentation of any discrepancies (critical discrepancy investigations are covered under the
quality system)
• Training and qualification of personnel
(3) Materials System
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Training and qualification of personnel
• Identification of starting materials and containers
• Storage conditions
• Quarantine of all materials and APIs (including reprocessed materials) until they are tested or
examined and released
• Collection of representative samples for testing or examination
– Appropriate means are used; comparisons are against appropriate specifications.
• A system for auditing and monitoring the suppliers of critical materials (e.g., raw materials,
starting materials, intermediates) and containers
• Rejected materials
– Decisions to keep or reject materials that do not meet acceptance requirements (e.g.,
starting materials, intermediates, containers) are documented and justified; rejected
materials are promptly quarantined and disposed.
• Appropriate retesting or reexamination of starting materials, intermediates, and containers
• First in, first out use of materials and containers
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• Suitability of process water used to manufacture APIs, including the water system design,
maintenance, validation, and operation, as appropriate
• Suitability of process gas used in the manufacture of APIs (e.g., gas use to sparge a reactor),
including the gas system design, maintenance, validation, and operation, as appropriate
• Containers and closures that are not additive, reactive, or absorptive
• Change management system for implementing changes in material handling operations
– Changes in the supply chain for critical materials and containers are thoroughly evaluated,
approved, and documented to ensure that they are unlikely to pose an adverse risk to API
quality.
• Qualification, validation, and security of computerized or automated processes
• Distribution records by batch for all materials (e.g., the finished API, intermediates), including
records for exported materials
• Documentation of any discrepancies (critical discrepancy investigations are covered under the
quality system)
• Risk management program for starting materials, intermediates, and containers
– Unacceptable hazards (e.g., impurities) are addressed; risks are assessed, as needed,
throughout the API’s life cycle.
(4) Production System
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Training and qualification of personnel
• Establishment of, adherence to, and documented performance of approved manufacturing
procedures
• Controls for critical activities and operations
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• Documentation and investigation of critical deviations
• Comparison of actual yields with expected yields at designated steps
• Process validation 34 program that ensures a state of control across the life cycle (i.e., process
design, process qualification, and continued process verification stages)
• Establishment of adequate control steps to ensure that APIs are suitable and safe for their
intended use
– For APIs intended to be used in parenteral dosage forms, pyrogenic (e.g., endotoxin)
contamination can be reduced or prevented through the use of appropriate water quality,
input materials, and process steps.
• Established time limits for completion of phases of production, when appropriate
• Appropriate identification of major equipment used in the production of intermediates and the
API
• Justification and consistency of intermediate specifications and API specifications
• Implementation and documentation of process controls, testing, and examinations (e.g., pH,
temperature, purity, actual yields, clarity)
• In-process sampling that is conducted using procedures designed to prevent contamination of
the sampled material
• Recovery (e.g., from mother liquor or filtrates) of reactants
– Approved procedures and recovered materials meet specifications that are suitable for
their intended use.
34
See the guidance for industry Process Validation: General Principles and Practices (January 2011).
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• Recovery of solvents
– Recovered solvents should be used only in the same step or in an earlier step (if there is
sufficient purification) of the same processes from which they were collected.
• Precautions to prevent or minimize the potential for cross-contamination when APIs are
micronized on multiuse equipment
• Validation and security of computerized or automated processes
• Ongoing statistical evaluations (e.g., batch control data, periodic capability analysis) to
identify processes that exhibit high variability and trigger needed improvements
• Change management system for production changes, including evaluation of the need for
additional validation studies
• Master batch production and control records that include instructions and processes of
appropriate specificity that enable production operators to reproducibly execute the same
manufacturing processes each time the API is produced
• Batch production and control records
• Contemporaneous and complete documentation of batch production
• Documentation of any discrepancies (critical discrepancy investigations are covered under the
quality system)
• Establishment of effective control strategies for manufacturing operations that may potentially
pose a risk of forming hazardous impurities
(5) Packaging and Labeling System
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Training and qualification of personnel
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PROGRAM 7356.002F
• Acceptance operations for packaging and labeling materials
• Establishment of, adherence to, and documented performance of approved packaging and
labeling procedures
• Change management system for implementing changes in packaging and labeling operations
• Adequate storage for labels and labeling, both approved and returned after issued
• Control of labels with similar sizes, shapes, and colors that are used for different APIs
• Adequate packaging records that include specimens of all labels used
• Control of issuance of labeling, examination of issued labels, and reconciliation of used labels
• Examination of the labeled finished APIs
• Adequate inspection (i.e., proofing) of incoming labeling
• Use of lot numbers and destruction of excess labeling bearing lot or control numbers
• Adequate separation and controls when more than one batch is labeled at a time
• Adequate expiration or retest dates on the label
• Validation of packaging and labeling operations including validation and security of
computerized processes
• Documentation of any discrepancies (critical discrepancy investigations are covered under the
quality system)
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• Repackaged APIs and intermediates
– The name of and information about the original API or intermediate manufacturer,
repacker, and relabeler are provided.
(6) Laboratory Control System
Evaluate each of the areas listed below. If there are additional considerations for the area, they are
listed in sub-bullets.
• Training and qualification of personnel
• Adequate staffing for laboratory operations
• Adequate equipment and facility for the intended use
• Calibration and maintenance programs for analytical instruments and equipment
• Validation and security of computerized or automated processes
• Source and purity of reference standards
– Assays and tests are used to establish equivalency to current official reference standards,
as appropriate.
• System suitability tests for chromatographic systems
• Specifications, standards, and representative sampling plans
• Validation or verification of analytical methods, including suitability of microbiological test
methods
• Adequate test methods for establishing complete impurity profiles for each API production
process 35
35
Note that impurity profiles are often process-related.
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PROGRAM 7356.002F
• Reassessment of impurity profiles after changes that could affect the impurity profile (e.g.,
new sources of raw materials or reagents)
• Change management strategy for hazardous impurities if any hazardous impurities have been
identified: (1) in any starting material, intermediate, container, or the API; or (2) as a
degradant during the API’s life cycle
• Change management system for implementing changes in laboratory operations
• Required testing of the correct samples using the approved or filed methods or equivalent
methods
• Documentation of any discrepancies (critical discrepancy investigations are covered under the
quality system)
• Complete analytical records from all tests and summaries of results
• Contemporaneous and complete laboratory records
• Quality and retention of raw data (e.g., chromatograms, spectra)
• Correlation of result summaries to raw data; presence and disposition of unused data
• Adherence to an adequate out of specification procedure that includes timely completion of
investigations
• Adequate reserve samples and documented examination of reserve samples
• Stability testing program, including demonstration that the analytical methods are stability-
indicating
C. Preparing the Inspection Strategy
These procedures are in addition to those in the IOM.
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1. Select two or more systems for inspection coverage, as appropriate (see Part III.1.A).
2. If APIs are not specified in the assignment, select significant APIs for inspection coverage.
APIs are considered significant based on risk. Significant APIs include: (1) APIs that broadly
use all of the systems in the firm or use special manufacturing features (e.g., complex
chemical synthesis); and (2) APIs that are highly sensitizing materials, infectious materials, or
new chemical entities made under approved drug applications. Review the firm’s inspection
history, compliance history, DMF, or drug application files.
3. If CDER or OII request a CDER staff member to be a member of the inspection team, the lead
investigator should brief them on the intended inspection strategy and explain their supporting
role and responsibilities for the inspection. The lead investigator should consult with OPQ
assessors on any specific drug application chemistry, manufacturing, or control issues
(whether premarket or postmarket) that will be covered during the inspection.
4. Review the impurity profile for each API production process that will be covered during the
inspection. If an application or DMF was submitted, compare the firm’s impurity profiles to
the impurity profiles submitted. 36,37
5. For the APIs that will be inspected, verify conformity to any compendial monographs, as
appropriate.
6. Before or during the inspection, determine if the firm has made process changes by comparing
current operations against the EIR for the previous inspection. Also compare the current
operations with those described in the DMF or the drug application to determine whether the
firm is complying with the postapproval chemistry, manufacturing, and controls commitments
that they made to FDA. 38 The following are examples of changes that would warrant
extensive coverage during the inspection:
a. API production process changes or product-type line changes that include processing
of several APIs of varying toxicity in common equipment and/or facilities. These
changes could introduce new potential cross-contamination.
36
Investigators and chemists should be particularly familiar with USP General Chapter <1086> Impurities in Drug
Substances and Drug Products and the ICH guidances for industry Q3A Impurities in New Drug Substances, Revision 2
(June 2008), Q3C(R8) Impurities: Guidance for Residual Solvents (December 2021), and Q3D(R2) Elemental Impurities
(September 2022)
37
See the guidance for industry Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related
Impurities (NDSRIs) (August 2023).
38
See also compliance program 7346.832—Preapproval Inspections for conducting a preapproval inspection of an API.
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b. New technology that requires new expertise, significantly new equipment, or new
facilities.
c. Changes (particularly those that are not referenced in the DMF or drug application) in
starting materials, intermediates, equipment, facilities, support systems, processing
steps, packaging materials, or computer software.
7. For foreign firms, obtain file information from the appropriate CDER assessment division or
compliance unit. Investigators may also request background information about the site
directly from the U.S. Agent before the inspection.
2. Reporting
Investigators should describe their inspection coverage and findings in the EIR. Investigators should
include a sufficient level of detail for further FDA evaluation of the firm’s state of control and
conformance to CGMP requirements. ICH Q7 may be used as a guideline to describe coverage,
findings, and deficiencies. However, investigators should not reference specific sections of ICH Q7 in
the Form FDA 483 observations or in the EIR. If an investigator believes that a particular practice
consistent with ICH Q7 is deficient, the investigator or division should consult with CDER’s Office
of Manufacturing Quality (OMQ) before making an observation that conflicts with ICH Q7. The
Form FDA 483, if issued, should include sections for each of the covered systems. In addition to the
IOM format and information reporting requirements, all EIRs for API manufacturers must include:
1. A list of APIs manufactured (or categories of APIs if there are several APIs) along
with the general manufacturing process for each API (e.g., chemical synthesis,
fermentation, extraction of botanical material).
2. An explanation for the APIs selected for coverage.
3. For foreign API manufacturers, the U.S. Agent’s name, title, complete mailing
address, telephone number, and fax number or email address.
4. For foreign API manufacturers, a report of all APIs imported into the United States
in the last two years, their consignees (including in-country intermediary repackers,
relabelers, wholesalers, distributors, and shippers that import directly in the U.S.),
and an estimate of the frequency and quantity of shipments to these consignees.
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PROGRAM 7356.002F
5. A description of each of the systems selected for coverage (i.e., areas, processes,
and operations), what was covered, who was interviewed, and what manufacturing
activities were taking place during the inspection.
6. Any significant changes to a firm’s packaging, labeling, product line, or
processes, particularly changes that are not properly filed, submitted, or reported
in a DMF or drug application (including changes to APIs intended for use in
compounding).
A. Special Instructions for Responding to a Form FDA 483
Investigators should instruct management to submit an electronic response to a Form FDA 483 with
appropriate documentation via email to [email protected] or
[email protected].
For human drug inspections that include CGMP and preapproval inspectional coverage, in addition to
the address above, include: [email protected].
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PROGRAM 7356.002F
PART IV – ANALYTICAL
API samples that the investigator collects for quality evaluation should be submitted to the
appropriate servicing laboratory. Please email the Office of the Chief Scientist (OCS)/Office of
Analytical and Regulatory Laboratories (OARL) at
[email protected] to request servicing laboratories for chemical and
microbiological testing. In the request, include the API description, lot numbers to be tested, analyses
required, and the reason for sample collection. Servicing laboratories will be selected based on
specialization, technology and testing expertise, and capacity. However, it should be noted that
physical API samples are not required to support regulatory or administrative action against a
violative firm or drug.
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PROGRAM 7356.002F
PART V – REGULATORY/ADMINISTRATIVE STRATEGY
If one or more systems are documented as not in a state of control, OII should endorse an OAI
inspection report.
Normally, issuing a warning letter or taking other regulatory or administrative action should result in
all profile classes being classified as unacceptable. However, if CDER does not approve a
recommendation for a warning letter or other regulatory action, all profile classes should be classified
as acceptable.
If an establishment with approved established conditions has an inspection that is classified as OAI
and raises significant concerns about the quality system (particularly about the change management
system), CDER offices will collaboratively evaluate the significant findings and the firm’s response.
They will use this information to determine how these findings could potentially affect the approved
established conditions.
Records, documents, and other information that are requested and reviewed during remote regulatory
assessments may reveal potentially violative practices. In such cases, OMQ’s evaluation of a potential
OAI recommendation will align with the procedures in this section during review of the case.
Recommendations for regulatory action for API CGMP deficiencies should cite the statute (section
501(a)(2)(B) of the FD&C Act) and not the drug product regulations in parts 210 and 211. These
recommendations should not cite ICH Q7; however, they can use ICH Q7 as a guideline for
describing the deficiencies. The regulatory action should demonstrate how the observed deficiencies
could potentially impact or have already impacted the quality of the API. When evaluating whether to
recommend regulatory or administrative action, consider the critical attributes of the API, the
significance of its pharmacological activity, and the intended use of the drug product that will contain
the API.
Evidence that supports a significant deficiency or pattern of deficiencies within a system may indicate
system failure. The failure of a system puts all of the manufacturer’s APIs at risk and should be
promptly corrected. The following are examples of deficiencies that may result in an inspection that
is classified as OAI:
1. Contamination of APIs with filth, objectionable microorganisms, toxic chemicals, or
significant amounts of other types of chemicals, or a reasonable potential for such
contamination because of a demonstrated route of contamination (facilities and equipment
system; production system).
2. Failure to show that API batches conform to established specifications, such as specifications
in drug applications, USP specifications, customer specifications, or label claims (quality
system).
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PROGRAM 7356.002F
3. Failure to ensure the accuracy and integrity of data. 39 Complete, consistent, and accurate data
should be attributable, legible, contemporaneously recorded, original or a true copy, and
accurate. Examples of data integrity concerns include failing to scientifically justify not
reporting relevant data, altering of raw data, inconsistently documenting manufacturing
operations, backdating test results, testing into compliance, and fabricating test results.
Examples of failure to ensure the accuracy and integrity of data include systems which allow
for the alteration or deletion of raw data, systems without audit trails activated, loose raw data
forms without adequate issuance and reconciliation, and inadequate risk-based monitoring for
data integrity concerns (all systems).
4. Failure to comply with commitments in drug applications or DMFs. All of the required
information in these commitments should be accurate and current. This includes information
about the manufacturing process, impurity profiles, and other specifications or procedures
associated with the manufacture of the API (quality system).
5. Distribution of an API that does not conform to established specifications (quality system).
6. Deliberate blending of API batches in an attempt to: (1) dilute or hide filth or other noxious
contaminants; or (2) disguise a critical quality defect and obtain a batch that meets its
specifications (production system).
7. Failure to demonstrate that all materials (including water and any other solvents used in the
final step of the API production process) are chemically and microbiologically suitable for
their intended use and do not adversely affect the quality of the API (materials system).
8. Lack of adequate validation for critical steps in the API production process, particularly for
the final separation and purification of the API or API production processes for which there is
evidence that the process is not adequately controlled. Lack of adequate control may be
indicated by repeated batch failures or wide variation in final yields compared with the
process average over time (quality system; production system). 40
9. Implementation of retrospective process validation for an existing API production process
when the process has changed significantly, the firm lacks impurity profile data, or there is
evidence of repeated batch failures because of process variability (quality system; production
system).
39
See the guidance for industry Data Integrity and Compliance With Drug CGMP: Questions and Answers.
40
See the guidance for industry Process Validation: General Principles and Practices.
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PROGRAM 7356.002F
10. Failure to establish an impurity profile for each API production process. FDA expects
manufacturers to establish complete impurity profiles for each API as part of the process
validation effort. This includes collecting data on: (1) actual and potential organic impurities
that may arise during synthesis, purification, and storage of the API; (2) actual and potential
inorganic impurities that may arise during the API production process; and (3) organic and
inorganic solvents used during the manufacturing process that are known to carry over to the
API. Impurity profile testing of each batch or after a specified number of batches may detect
new impurities that could be from a deliberate or nondeliberate change in the API
manufacturing process (laboratory control system).
11. Failure to show that a reprocessed batch complies with all of the established standards,
specifications, and characteristics (quality system; laboratory control system).
12. Failure to test for residues of organic or inorganic solvents used during manufacturing that
may carry over to the API using analytical procedures with appropriate levels of sensitivity
(laboratory control system).
13. Failure to have a formal process change control system in place to evaluate changes in starting
materials, facilities, support systems, equipment, processing steps, and packaging materials
that may affect the quality of APIs (all systems).
14. Failure to maintain batch and quality control records (quality system).
15. Incomplete stability studies to establish API stability for the intended period of use, for
example, failure to conduct forced degradation studies on APIs to isolate, identify, and
quantify potential degradants that may arise during storage (laboratory control system).
16. Use of laboratory test methods that are inadequate or have not been validated, or the use of an
inadequately qualified or untraceable reference standard (laboratory control system).
17. Packaging and labeling in a way that introduces a significant risk of mislabeling (packaging
and labeling system).
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PROGRAM 7356.002F
PART VI – REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS
1. References
• Compliance Programs
– 7346.832—Preapproval Inspections
– 7356.000—Inspections of CDER-led or CDRH-led Combination Products
– 7356.002—Drug Manufacturing Inspections
– 7356.002A—Sterile Drug Process Inspections
– 7356.002M—Surveillance Inspections of Protein Drug Substance Manufacturers
• Draft Guidances for Industry 41
– Conducting Remote Regulatory Assessments Questions and Answers (January 2024)
– ICH Q12: Implementation Considerations for FDA-Regulated Products (May 2021)
• Guidances for Industry
– Changes to an Approved Application for Specified Biotechnology and Specified Synthetic
Biological Products (July 1997)
– Changes to an Approved NDA or ANDA (April 2004)
– Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain
Biological Products (June 2021)
41
When final, these guidances will represent FDA’s current thinking on this topic.
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PROGRAM 7356.002F
– CMC Postapproval Changes To Be Documented in Annual Reports (March 2014)
– Control of Nitrosamine Impurities in Human Drugs (September 2024)
– Data Integrity and Compliance With Drug CGMP: Questions and Answers (December 2018)
– Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo
Bioequivalence Documentation (November 1995)
– Nonsterile Semisolid Dosage Forms: Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence
Documentation (May 1997)
– Process Validation: General Principles and Practices (January 2011)
– Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
– Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities
(NDSRIs) (August 2023)
– Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing
Practice (September 2004)
– SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Postapproval
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo
Bioequivalence Documentation (September 1997)
• Guidance for Industry and FDA Staff Current Good Manufacturing Practice Requirements for
Combination Products (January 2017)
• ICH Guidances for Industry
– M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals
to Limit Potential Carcinogenic Risk (July 2023)
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PROGRAM 7356.002F
– Q3A Impurities in New Drug Substances, Revision 2 (June 2008)
– Q3C(R8) Impurities: Guidance for Residual Solvents and its Appendices (December 2021)
– Q3D(R2) Elemental Impurities (September 2022)
– Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Revision
1 (September 2016)
– Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients:
Questions and Answers (April 2018)
– Q9(R1) Quality Risk Management (May 2023)
– Q10 Pharmaceutical Quality System (April 2009)
– Q11 Development and Manufacture of Drug Substances (November 2012)
– Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management and its Annexes (May 2021)
• Investigations Operations Manual, https://www.fda.gov/inspections-compliance-enforcement-
and-criminal-investigations/inspection-references/investigations-operations-manual
• Regulatory Procedures Manual, https://www.fda.gov/inspections-compliance-enforcement-and-
criminal-investigations/compliance-manuals/regulatory-procedures-manual
• USP General Chapter <1086> Impurities in Drug Substances and Drug Products
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PROGRAM 7356.002F
2. Attachments – None.
3. Program Contacts
A. CDER
(1) CGMP or Quality-Related Policy Questions
Please email CDER Office of Pharmaceutical Quality Policy ([email protected]) for
questions about the following topics:
• CGMP or quality-related policy
• Technical or scientific information needs (including questions about this compliance
program)
(2) Enforcement-Related Guidance or Policy Questions
Office of Compliance
Office of Manufacturing Quality
Please email CDER OMQ Compliance Policy ([email protected]) for
questions about the following topics:
• Enforcement-related guidance or policy, including:
– Evidence needs and sufficiency
– Citations
– Case evaluation and/or recommendation advice
(3) Labeling Requirements and Policies
CDER Office of Compliance
Office of Unapproved Drugs and Labeling Compliance
Please email [email protected] for general inquiries.
(4) Registration and Drug Listing Requirements
CDER Office of Compliance
Office of Unapproved Drugs and Labeling Compliance
Please email [email protected] for questions and assistance with registration and listings.
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B. OII
(1) Inspection-Related Questions
Office of Human and Animal Drug Inspectorate (OHADI)
Division of Human and Animal Drug Global Operations (DHADGO)
Human and Animal Drug Program Operations Branch (HADPOB)
Email: [email protected]
C. Office of the Commissioner
(1) Sampling of APIs
Office of the Chief Scientist (OCS)
Office of Analytical and Regulatory Laboratories (OARL)
Email: [email protected]
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PART VII – CENTER RESPONSIBILITIES
Compliance programs 7356.002—Drug Manufacturing Inspections and 7346.832—Preapproval
Inspections describe the responsibilities for each center.
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来源：FDA Pharmaceutical Quality Documents · fda.gov