FDA 发布上市后检查合规程序 7356.843，实施日期为 2023 年 3 月 13 日
Postapproval Inspections (7356.843)
FDA 发布合规程序 7356.843，用于对已批准 NDA、ANDA 及其原料药生产设施的上市后检查，实施日期为 2023 年 3 月 13 日，签发日期为 2023 年 1 月 27 日。
文件列出上市后检查的四个产品专属目标，可用于对照工艺验证生命周期、变更管理与数据完整性等核查范围。
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美国食品药品监督管理局
合规计划 计划 7356.843
第56章——药品质量保证
主题： 实施日期：
上市后检查 2023年3月13日
数据报告
产品代码 产品/任务代码（PAC）
人用药品 PAC 主题
行业代码： 56843 上市后检查
50, 54–56, 59, 60–66. 56R927 远程交互评估（RIE）
活动——人用药品
56R928 704a4 活动——人用药品
备注：
1. ORA应使用本合规计划对生产设施进行上市后检查，以支持已批准的新药申请（NDA）和简略新药
申请（ANDA）。1
2. 报告生物制品上市后检查时，使用本合规计划（7356.843）下的PAC 56843。
3. 报告正电子发射断层扫描（PET）上市后检查时，使用本合规计划（7356.843）下的PAC
56843。
4. 当上市后检查覆盖范围与其他合规计划下的检查覆盖范围同时进行或扩展时，应遵循相应的合规计划
进行检查，并按照适用合规计划中的说明，在企业检查报告（EIR）中以单独标题报告该覆盖范围。
现场报告要求：
1. 企业回复说明
检查员指示企业管理层将Form FDA 483回复提交至监管事务办公室（ORA）医疗产品与烟草运营办公室
（OMPTO）内指定的药品质量运营办公室（OPQO）部门，并抄送首席检查员。检查员审查Form FDA 483
回复中的上市后检查部分，如不充分，则向ORA以及药品评价与研究中心（CDER）药品质量办公室
（OPQ）内的药品生产评估办公室（OPMA）提供意见。
1 在本合规计划中，设施、企业、场所和机构等术语同义使用。
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2. 检查结果的沟通
调查员在既定的 ORA 时限内，在 eNSpect 中完成 EIR——包括封面页、附件和证明文件。2 当 EIR 在 FDA 电子存储系统中可用时，ORA 通过 OPMA 批准后计划邮箱（[email protected]）通知 OPMA。
3. 设施警报
• 如果根据合规计划 7356.002——药品生产检查第 V 部分识别出重大现行药品生产质量管理规范（CGMP）缺陷，且这些缺陷可能影响已上市药品，则不迟于检查结束日期后 2 个工作日，在 Panorama 中输入潜在的官方行动指示（pOAI）警报。3
4. 检查分类
• 如果未发现缺陷，在 eNSpect 中输入无需行动指示（NAI）分类。
• 如果所引用的缺陷未达到本合规计划第 V 部分所述的重要性水平，在 eNSpect 中输入自愿行动指示（VAI）分类。
• 在 eNSpect 中输入官方行动指示（OAI）分类，适用于：
PAC 56843，当根据本合规计划第 V 部分识别出目标药品的重大缺陷时。4
PAC 56002，当根据合规计划 7356.002 第 V 部分识别出重大 CGMP 缺陷且这些缺陷可能影响已上市药品时。
5. 企业概况分类代码更新
除非至少符合以下情形之一，否则不要更新概况分类：
• 受检查的药品或原料药（API）是该概况下生产的唯一药品或 API。
2 参见 ConOps 协议《FDA 人用药品设施评估与检查计划整合：运营概念》第 3.3 节“沟通检查发现”。
3
在极少数情况下，如果根据本合规计划（7356.843）第 V 部分观察到的目标药品重大 CGMP 缺陷可能影响其他已上市药品，但检查范围未扩展至合规计划 7356.002，则宜与 ORA 批准前计划经理协商后，视情况不迟于检查结束日期后 2 个工作日，在 Panorama 中输入 pOAI 警报。关于建议增加合规计划 7356.002 下检查范围的情形，另见第 II.3.E 部分——将检查范围扩展至合规计划 7356.002。
4
重大缺陷可包括 CGMP 缺陷和申请相关问题，本合规计划第 V 部分对此有进一步描述。
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• 监督检查覆盖范围（合规计划 7356.002）被添加到批准后
检查中。
对于 ORA 审查后被认为可接受的检查（即 PAC
56843 的 NAI 或 VAI），ORA 在 eNSpect 中酌情更新并最终确定 PAC 状态和概况。
对于 ORA 审查后初步认为不可接受的检查（即
PAC 56843 的初步 OAI），ORA 在 eNSpect 中酌情录入初步 PAC 状态和概况，并
转交至 CDER 牵头办公室，如第 V 部分所述，以进行最终审查、分类、签发 FMD-
145 信函，并在 eNSpect 中进行修改。
6. 样品相关报告要求
ORA 监管科学办公室（ORS）中指定的分析服务实验室将
完成的分析工作表上传至合规管理服务（CMS），并将
原始工作表包提交至生产设施所属的 ORA 属地地区办公室。
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目录
第一部分——背景 .................................................................................................................... 6
第二部分——实施 ........................................................................................................... 9
1. 范围 ............................................................................................................................................ 9
2. 策略 ........................................................................................................................................ 9
A. 基于风险的批准后检查确定 ..................................................................................... 9
B. 按目标进行检查 ...................................................................................................... 10
3. 计划管理说明 ............................................................................................ 11
A. 设施选择 ................................................................................................................ 11
B. 批准后检查任务请求 .................................................................................. 11
C. 检查安排与准备 ............................................................................... 12
D. 检查组 .................................................................................................................. 13
E. 将检查范围扩展至合规计划 7356.002 .................................. 13
F. 检查期间 CDER 咨询 .............................................................................. 13
G. 拒绝 ............................................................................................................................... 14
4. 申请评估整合的重要性 ................................................................... 14
第三部分――检查 ............................................................................................................... 15
1. 检查/审计策略 .......................................................................................................... 15
2. 检查/审计范围、目标和技术 .......................................................... 15
A. 目标 1：工艺验证生命周期与控制状态 ........................................ 16
B. 目标 2：调查与 CAPA 计划 ................................................................ 22
C. 目标 3：变更管理、变更有效性及与申请和其他上市后报告和要求的符合性 ................................................ 24
D. 目标 4：产品质量数据的完整性 ................................................................... 33
3. 检查报告 .................................................................................................................. 35
A. 签发 Form FDA 483 ................................................................................................. 35
B. 完成和评估企业检查报告................................ 35
4. 样品采集或样品提交请求 ................................................................. 36
第四部分——分析 ................................................................................................................. 37
第五部分――监管/行政策略 ...................................................... 38
1. 重大问题 ....................................................................................................................... 38
2. 针对检查发现的监管/行政后续行动的协调 ........ 39
A. 对 PAC 56843 视为重大的问题 .................................................... 39
B. 对 PAC 56843 不视为重大的问题 ............................................. 41
第六部分——参考文献、附件、计划联系人和缩略语 ...... 42
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1. 参考文献 .................................................................................................................................. 42
A. 美国联邦法规第 21 篇 ................................................................................ 42
B. 合规计划 ......................................................................................................... 42
C. 合规政策指南 ................................................................................................... 42
D. FDA 指南................................................................................................................... 43
E. 其他程序与参考文献 ....................................................................................... 44
2. 附件 ................................................................................................................................. 45
3. 计划联系人 ....................................................................................................................... 45
A. 监管事务办公室 ............................................................................................... 45
B. 药品评价与研究中心 .......................................................................... 46
4. 缩略语 ................................................................................................................................... 46
第七部分――CDER-ORA 职责概述 ..................................................... 48
附件 A：远程监管评估 .................................................... 49
1. 根据 FD&C 法案第 704(a)(4) 条提出的 FDA 记录及其他信息要求
（法定授权的 RRA） ........................................................................................................... 49
2. 远程交互式评估（自愿 RRA）...................................................................... 49
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第一部分——背景
《联邦食品、药品和化妆品法案》（FD&C 法案）规定，FDA 可批准 NDA 或
ANDA，前提是除其他要求外，用于药品生产、加工、包装和检验的方法以及所用设施和控制
被认定足以确保并保持其鉴别、强度、质量和纯度。5 在某些情况下，FDA 可批准
申请而无需对生产申请产品的设施进行检查
（例如，该设施具有良好的 CGMP 合规历史，申请产品不属于该设施的新
产品类别，该设施在所采用的生产方法方面有成功的历史）。
2002 年，FDA 宣布了一项名为“21 世纪药品 CGMP”的重要倡议，
以加强和现代化对药品生产和产品质量的监管。6 该
倡议鼓励实施基于风险和科学的方法，使 FDA 的关注
聚焦于关键领域，以促进监管机构做出更好、更一致的决策。根据
该倡议，本批准后合规计划包括基于科学和风险的
方法，用于检查企业的生产工艺、产品理解和质量
控制；确保产品生命周期内的质量；评估企业的生产
能力；以及核实申请数据的真实性及对已批准
申请承诺的符合性。
2017 年，CDER 和 ORA 签订了 ConOps 协议《FDA 人用药品设施评估
与检查计划整合：运营概念》，其中概述了 CDER 和 ORA 在人用药品设施评估及批准前、
批准后、监督和因由检查方面的角色和
职责。参与本
合规计划的 FDA 各组成部分——CDER 的 OPQ 和合规办公室（OC）、ORA 以及 FDA
实验室——致力于协调努力和沟通，以解决未决
质量问题。本批准后检查合规计划与该协议一致。
为了以更可预测和高效的方式促进批准后化学、生产和控制（CMC）
变更的管理，FDA 于 2021 年发布了国际人用药品注册技术协调会
（ICH）行业指南 Q12《药品产品生命周期管理的技术和监管考量》
及其附件，以及行业指南草案
ICH Q12：《FDA 监管产品的实施考量》（ICH Q12 实施
指南）。7 当与增加的产品和工艺知识结合使用——并在
ICH 行业指南 Q9(R1)《质量风险管理》中的风险管理原则以及 ICH 行业
指南 Q10《药品质量体系》所述的有效药品质量体系（PQS）的
背景下——这些指南文件应增强行业
在实施前减少对广泛监管监督需求的情况下有效管理 CMC 变更的
能力。
5
见 FD&C 法案第 505(d) 和 505(j)(4)(A) 条（21 U.S.C. 355(d)(3) 和 (j)(4)(A)）。
6
见《21 世纪药品质量——基于风险的方法：进展报告》。
7
ICH Q12 实施指南定稿后，将代表 FDA 对该主题的当前思考。有关指南的
最新版本，请查看 FDA 指南网页 https://www.fda.gov/regulatory-information/search-
fda-guidance-documents。
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例如，对既定条件（EC）——为确保产品质量而认为必要的具有法律约束力的信息——的任何变更，均需按法规（如 21 CFR 314.70 和 314.97）的详细规定向 FDA 提交（PAS、CBE-30、CBE-0 或年度报告）。8 尽管这些法规并未明确规定什么构成 EC，但它们确实提出了一种基于风险的变更报告范式。此外，现有的 FDA 关于批准后变更的指南文件为如何报告广泛的批准后变更提供了建议。9 ICH Q12 及 ICH Q12 实施指南为申请人提供了一个机会，使其能够具体界定 EC，并明确其申请中的产品、生产工艺、设施与设备以及控制策略中哪些要素被视为 EC，从而在变更时需要报告。在申请中提出 EC 完全是自愿的。如果未提出具体的 EC，则 EC 将是那些（例如，参数、属性、控制、质量标准、设施以及为确保产品质量所必需的其他要素）FDA 根据法规中规定的基于风险的范式以及指南中关于批准后变更的建议通常视为 EC 的内容。
申请中识别的任何 EC，以及针对这些 EC 变更所提出的任何报告类别，均由综合质量评估（IQA）团队中的 CDER 成员进行评估。在评估具体 EC 和报告类别时，IQA 团队将考虑可能需要在批准后检查中涵盖的领域，例如关于将实施这些 EC 的场所的 PQS 的信息，以及申请人的科学论证，其中可包括开发研究。例如，ICH Q10 中所述的有效 PQS 对于使用 ICH Q12 中所述的工具至关重要。作为 PQS 的一部分，对企业变更管理系统的评估有助于确保对 EC 变更进行适当的报告，包括报告与任何批准后变更管理方案（PACMP）以及产品生命周期管理（PLCM）文件（如果在申请中提交）保持一致。根据 ICH Q12，PACMP 是监管工具，其（1）描述申请人打算在产品生命周期的商业阶段实施的 CMC 变更；（2）提出实施产品变更所需的要求和研究；（3）确定需满足的具体条件和可接受标准；（4）解释变更将如何准备和验证，包括评估拟议变更的影响；以及（5）建议通知 FDA 的报告类别。FDA 将 PACMP 称为可比性方案，其可独立于原始申请或补充申请中任何先前的 EC 识别而提交。10 在所有情况下，变更均须按照 CGMP 要求适当识别和实施。
8
PAS=事先批准补充申请；CBE=变更即刻生效。
9
参见，例如，FDA 的放大和批准后变更（SUPAC）指南以及行业指南《对特定生物技术产品和特定合成生物产品的已批准申请的变更》《对已批准 NDA 或 ANDA 的变更》《需在年度报告中记录的 CMC 批准后生产变更》以及《NDA、ANDA 或 BLA 中化学、生产和控制信息的批准后变更可比性方案》。
10
可比性方案与 21 CFR 314.70(e) 和 601.12(e) 中定义的方案同义。参见行业指南《NDA、ANDA 或 BLA 中化学、生产和控制信息的批准后变更可比性方案》。
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此外，为配合 FDA 加强药品生产和产品质量监管的举措，FDA 开发了更多工具以加强其监管监督。由于 2019 冠状病毒病（COVID-19）公共卫生紧急事件，FDA 依靠各种替代工具来推进其监管职责。这可能包括以下内容：(1) 通过互认协议（MRA）和其他保密协议，向可信赖的外国监管伙伴索取现有检查报告；11 以及 (2) 开展远程监管评估（RRA），12 包括 (a) 根据《联邦食品、药品和化妆品法案》第 704(a)(4) 条，直接向设施和其他被检查实体索取与申请相关的记录和其他信息，以及 (b) 在适当情况下开展远程互动评估（RIE）。如相关机构政策和本合规计划（包括附件 A）中进一步所述，FDA 在某些情况下可使用这些工具来评估设施并支持对申请的监管决定。
11
对于 FDA 与欧盟和英国现有的 MRA，这包括使用认可机构签发的官方检查报告，适用于位于签发机构领土内外的生产设施。更多信息，请参见 https://www.fda.gov/international-programs/international-arrangements/mutual-
recognition-agreement-mra。
12
RRA 是对 FDA 监管的机构及/或其记录进行的完全远程审查，以评估其是否符合适用的 FDA 要求。RRA 有助于保护人类健康、为监管决定提供信息，并核实向该机构提交的某些信息。
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第二部分——实施
1. 范围
ORA 与 CDER 依据本合规计划共同对已上市药品进行评估，这些药品根据已批准的 NDA 或 ANDA 或其相关 API（以下简称受
监管药品）生产。13 上市后检查与批准前检查（PAI）相似，均针对具体产品，但与 PAI 不同的是，上市后检查在申请获批后进行。
受监管药品的上市后检查由 ORA 牵头，CDER 可选择参与。
上市后检查侧重于工艺验证生命周期、变更管理、提交至申请的变更，以及按照申请承诺和
CGMP 要求执行支持性活动。14
本合规计划为检查覆盖范围提供基于风险的策略，并
明确各方角色以建立高效沟通。
CDER 利用上市后检查的信息更新受监管药品的生命周期风险概况，或
确定监管措施。
2. 策略
A. 上市后检查的基于风险判定
IQA 团队 15 采用基于风险的方法进行产品质量评估，包括设施
评估，以及在认为必要时对申请中所列生产设施进行检查。在上市申请审评和批准期间，IQA 团队评估
有关产品、工艺和设施的潜在风险，并确定是否需要进行上市后
检查。此类判定基于可表明潜在设施相关风险的全部信息。在此类情况下，ORA 批准前计划经理
（PAM）将通过 OPMA 上市后计划邮箱
（[email protected]）与 OPMA 协商，以与 IQA 团队协调并确认需要
进行上市后检查。若 IQA 团队或 ORA PAM 基于其对申请产品的风险评估，未发现任何产品质量方面的潜在关注，则
13
在本合规计划中，术语 API 与原料药同义。
14
对于 (a) PET 药品，参见 21 CFR 第 212 部分及合规计划 7356.002P——正电子发射
断层扫描（PET）CGMP 药品工艺及批准前检查/调查；(b) 药品，参见 21
CFR 第 210 和 211 部分；(c) 生物制品，参见 21 CFR 第 210、211、600 和 610 部分；(d) 一般 API，参见
ICH 行业指南 Q7《活性药用成分药品生产质量管理规范指南》中的建议；以及 (e) 按合规计划 7356.002A——无菌药品工艺
检查标注为无菌的 API，参见 21 CFR 第 210 和 211 部分。
15 就本合规计划而言，IQA 团队指由指定的主题专家团队（例如，
原料药审评员、药品审评员、生物药剂学审评员、生产审评员、ORA 批准前
计划经理或按需指定的代表）组成，其被指派评估申请提交（即
原始申请或其上市后提交）的质量方面。根据需要，它还可能包括其他角色。参见 ConOps
协议。
发布日期：2023 年 1 月 27 日 第 9 页，共 50 页
第 10 页
PROGRAM 7356.843
生产工艺以及申请中指定的设施，可能不需要对该设施进行产品特定的上市后
检查。
视情况，OPMA 将根据产品、药物类别和剂型的综合风险，并基于工艺和
设施方面的考虑，在 IQA 团队建议的任务之外确定额外任务。
此项工作的总体目的是确认产品质量问题对患者造成的风险已降至最低。
上市后检查的需求可在申请批准之前以及之后确定。例如：
• 在申请批准之前，IQA 团队可能预计在放大和持续商业化生产期间产品质量
变异性风险增加，并决定可能需要上市后检查，以替代或补充 PAI。在这些情况下，
IQA 生产评估文件或 Panorama Inspection View 中 OPMA 的最终建议应表明
应执行上市后检查。
• 在某些情况下，PAI 期间可能出现需要由未来上市后检查解决的关注事项。
• 在申请批准之后，OPMA 在制定上市后检查候选名单时评估来自多个来源的
信息。来源可包括已完成的 IQA 生产评估、OPQ 质量监督办公室（OQS）
关于场点药品质量状态的评估（例如场点档案），以及上市后申报中描述的
任何变更。
B. 按目标检查
上市后检查有四个主要的产品特定目标，每个目标都需要考虑潜在风险和已识别
关注事项的策略：
1. 目标 1：工艺验证生命周期与控制状态
确认有高度保证，商业化生产工艺处于控制状态，并持续生产出符合适用
的鉴别、含量、质量和纯度要求的目标药品。16 确保企业的
生产工艺、控制策略、检验方法以及目标药品的工艺性能和产品质量
监测系统设计良好、已实施、视情况已验证，并在产品生命周期内按需
得到确认。
2. 目标 2：调查与纠正和预防措施（CAPA）计划
确定与目标药品及相关工艺和设备相关的调查和 CAPA 是否已使用
质量风险管理作为支持持续改进的推动因素，得到彻底评估和有效实施。
16
参见 FD&C 法案第 501(a)(2)(B) 节以及 21 CFR 210.1(a) 和 211.100(a)。
发布日期：01/27/2023 第 10 页，共 50 页
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PROGRAM 7356.843
3. Objective 3: Change Management, Change Effectiveness, and Conformance to the
Application and Other Postmarketing Reports and Requirements
Determine whether implemented changes in the product, process, components, equipment,
and/or facility associated with the subject drug were implemented effectively using quality
risk management as an enabler in support of continual improvement. Verify that the subject
drug is being manufactured in accordance with the approved application or active drug
master file (DMF) referenced in the approved application, including filed postapproval
changes. Confirm that the firm is fulfilling or is on track to fulfill commitments (e.g.,
providing additional stability data) made at the time of approval (of an original application or
in subsequent submissions) and is meeting drug quality reporting requirements in a timely
manner.
4. Objective 4: Integrity of Product Quality Data
Audit manufacturing controls, test results, and the related raw data for starting materials, in-
process materials, and batches of the subject drug. Ensure that the test and production data
are authentic, computed correctly, accurate, and documented per CGMP and that they
support the associated decisions by the firm, application submissions, and lifecycle changes.
For details on inspectional and auditing techniques related to these objectives, refer to Part
III―Inspectional.
3. Program Management Instructions
A. Facility Selection
OPMA selects a subject drug and associated manufacturing facilities as described in Part II.2.A—
Risk-Based Determination for Postapproval Inspections. OPMA ensures that the manufacturing
facility selected for postapproval inspection, including a facility named in a referenced DMF, is still
named in an approved drug application. OPMA should, to the extent possible, confirm that the drug
product is marketed using the Electronic Drug Registration and Listing System (eDRLS), Online
Reporting Analysis Decision Support System (ORADSS), and the OQS site dossier, which may
contain information useful for this determination.
B. Postapproval Inspection Assignment Requests
OPMA issues postapproval inspection assignment requests to the ORA Pharmaceutical Assignment
mailbox ([email protected]) and the appropriate ORA division manager or
ORA PAM. OPMA summarizes product and process knowledge from the application and identifies
and advises on onsite coverage of potential risks to and concerns for product and process, which the
investigator can use to develop an inspection plan.
These assignment requests could involve multiple applications for one facility, with different
degrees of coverage of the four objectives. Reasons for the assignment could include the level of
manufacturing experience, risk factors that apply to two or more subject drugs, and an efficient use
of resources by covering multiple applications at one inspection, among others.
Date of Issuance: 01/27/2023 Page 11 of 50
第 12 页
PROGRAM 7356.843
Postapproval inspection assignments should include the selection rationale, a product risk
assessment based on the original application and postapproval submissions thereto, and the criteria
for choosing applications, as necessary.
OPMA expects postapproval inspection assignments to be covered by ORA field personnel as part of
ORA’s work plan for the fiscal year. Resources allocated under PAC 56843 are intended for this
compliance program. ORA notifies OPMA via the OPMA Postapproval Program mailbox
([email protected]) if ORA will be unable to complete an assignment
because of competing priorities.
ORA may find that the selected application product has not been marketed and may find a more
suitable application product for postapproval inspection coverage. In these situations, ORA can
exercise discretion and select a different application for postapproval inspection coverage than that
assigned. However, ORA should coordinate with OPMA before making any such changes in
assignment. A postapproval inspection may be combined with other programs or for-cause
inspections as necessary for efficient inspection coverage. A systems-based CGMP surveillance
inspection per compliance program 7356.002 may be added as per program management
instructions. ORA should send concerns, problems, or objections regarding the assignment request to
the OPMA Postapproval Program mailbox ([email protected]).
C. Inspection Scheduling and Preparation
During logistics planning (e.g., determining the inspection start date), and before initiating the
postapproval inspection, ORA may decide to confirm with the firm that the drug is manufactured at
the inspection site.
In addition to following the steps in section 5.5.1.1—Preparation and References—of the
Investigations Operations Manual (IOM), investigators should prepare for a postapproval inspection
by conducting the following activities:
• Review the completed DMF/drug process/micro IQA reviews and the CMC section of the
application (including the original development report), related supplements and
postapproval changes, annual reports, application postapproval commitments, and related
DMFs associated with the inspection assignment.
Note: This information can be accessed electronically via Panorama or DARRTS/Lorenz
docuBridge. Applications often contain trade secrets or confidential commercial information,
and it is essential that the information be carefully protected to prevent its release outside
FDA. ORA divisions are expected to establish a controlled access filing system to prevent
the unauthorized use or release of application information.
• Based on the assignment request, contact the drug process, microbiology, and facility
assessors assigned to the application, as applicable, to discuss special areas for coverage and
questions regarding the submitted information (e.g., test methods, data tables, raw material
attributes, justifications for finished product specifications).
• Access the application’s most current PLCM document or comparability protocols via an
OPMA request or docuBridge to ensure inspection coverage is relevant.
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PROGRAM 7356.843
• After reviewing the assignment request and the related PAI’s EIR (if performed), contact
OPMA with questions about the application and contact the ORA PAM or designee with
questions about the performed PAI, EIR, and firm history.
• In consultation with other inspection team members, develop an inspection plan that is
specific to the establishment and its compliance history and to the subject drug being
inspected and is consistent with this compliance program’s objectives and inspectional and
auditing techniques.
D. Inspection Team
ORA leads postapproval inspections and CDER participates with CDER and ORA management
concurrence. ORA investigators and CDER application assessors or CDER subject matter experts
are encouraged to jointly participate in postapproval inspections, particularly for those subject drugs
that are a new molecular entity, incorporate a new molecular entity, are a novel formulation or
dosage type, are produced using a novel unit operation or processing method, or use a novel
analytical test method or technique. While the ORA investigator is responsible for reporting
inspection findings in the EIR, all participants on an inspection team are responsible for submitting
their portion of the EIR and supporting exhibits to the lead investigator in a timely manner, as
directed by the lead investigator.
E. Expanding Inspection Coverage to Compliance Program 7356.002
The inspection team should add surveillance coverage with PAC 56002 under compliance program
7356.002 17 if it finds objectionable conditions for the assigned subject drug during the postapproval
inspection and if one of the following conditions exist:
• The subject drug is the only product manufactured at the establishment; or
• The objectionable conditions identified for the subject drug as per part V of this compliance
program could potentially impact other marketed drug products manufactured at the
establishment.
F. CDER Consultation During Inspection
When product-specific issues arise that cannot be immediately resolved by the investigator on-site
and may need the subject matter expertise of product assessors from CDER (OPQ), ORA can reach
out to the appropriate OPMA/review division representative for clarification.
17
Unless there is an assignment from the current Site Surveillance Inspection List or there is justification based on
objectionable observations that could impact marketed drug products, surveillance coverage (56002(X)) would not
typically be added to postapproval inspection assignments.
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第 14 页
PROGRAM 7356.843
G. Refusals
Under section 501(j) of the FD&C Act, a drug is adulterated that “has been manufactured, processed,
packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such
factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit
entry or inspection.” 18
Investigators should fully document the circumstances of the denial, delay, limitation, or refusal as
outlined in the IOM. The ORA program division should attempt to resolve the issue, but if initial
attempts are unsuccessful, the ORA program division should notify its Office of Chief Counsel
senior enforcement advisor, if needed, and OC for awareness and assistance. In the event a denial,
delay, limitation, or refusal occurs during an inspection where the circumstances indicate a
significant threat to humans or animals, the investigator should attempt to collect an inventory of all
drugs (components and finished products) at the establishment.
4. Importance of Application Assessment Integration
Achieving a science-based approval decision about each application from a pharmaceutical quality
perspective requires an integrated assessment of the application and associated facilities. Because
this requires input from multiple disciplines in FDA, differences of opinion may occur. FDA offices
involved in the postapproval inspection program are covered by an equal voice philosophy. Under
this philosophy, all appropriate expertise should be considered in the important decisions made about
applications, and the perspective from each FDA office assigned a role in reviewing and evaluating
drug applications is valuable. This equal voice environment is achieved, in practice, when each
organizational unit:
• Integrates each contribution to enhance the decision of the multidisciplinary team.
• Provides an environment where all team members can express their views for the areas in
which they have a recognized responsibility.
• Ensures an avenue for promptly raising unresolved differences of opinion through the
management chain for prompt resolution.
• Maintains transparency with a full and adequate record documenting decisions, including
significantly differing views.
18
See also guidance for industry Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug
Inspection for additional information.
Date of Issuance: 01/27/2023 Page 14 of 50
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PROGRAM 7356.843
PART III―INSPECTIONAL
1. Inspection/Audit Strategy
There are four primary product-specific objectives to be covered under this compliance program:
1. Objective 1: Process Validation Lifecycle and State of Control.
2. Objective 2: Investigations and CAPA Program.
3. Objective 3: Change Management, Change Effectiveness, and Conformance to the
Application and Other Postmarketing Reports and Requirements.
4. Objective 4: Integrity of Product Quality Data.
The inspection team should provide the coverage described in the assignment memo as well as
provide additional, in-depth coverage of potential issues identified during the inspection.
2. Inspection/Audit Coverage, Objectives, and Techniques
Subsequent to an application approval, the firm should have generated and collected substantially
more manufacturing and laboratory data than what is typically provided at filing and made available
during the application review. Product and process knowledge gained by analysis of such data
should help firms demonstrate their ability to consistently maintain process controls, meet quality
specifications, reliably produce subject drugs of intended quality, and adequately respond to
unexpected or aberrant results in a timely manner to prevent poor quality drug products from
reaching consumers.
Postapproval inspection focuses largely on the product lifecycle, including the process validation
lifecycle and manufacturing changes that may have occurred after approval. During a postapproval
inspection, the inspection team reviews records and processes for changes related to the subject drug
that have occurred from the time the application was approved up to the time of the inspection. The
inspection team should also confirm that manufacturing-related commitments made by applicants
during the application or supplement approval stage have been completed or are underway. It is not
uncommon for manufacturers to change production equipment, manufacturing procedures, and
associated control strategies based on scale-up, process qualification, process verification, and
capacity needs. Such modifications, which generally need to be submitted for FDA review (see 21
CFR 314.70) unless otherwise provided for as approved ECs, reflect changes to the approved
application and must conform to CGMP regulations (see 21 CFR 211.22 and 211.100).
This section further explains each postapproval inspectional objective and provides examples of
documents and processes to review, guiding points for inspectional focus areas and coverage, a
framework for assessing the firm’s performance, and references to applicable regulations and
guidance documents.
Date of Issuance: 01/27/2023 Page 15 of 50
第 16 页
PROGRAM 7356.843
A. Objective 1: Process Validation Lifecycle and State of Control
Summary: Verify that there is a high degree of assurance that the commercial
manufacturing process is in a state of control and consistently produces a subject drug
that meets the applicable requirements for identity, strength, quality, and purity. 19
Ensure that the firm’s manufacturing process, control strategy, test methods, and
process performance and product quality monitoring system for the subject drug are
well-designed, implemented, validated as applicable, and verified throughout the
product lifecycle as necessary.
Process validation is defined as the collection and evaluation of data from the process design stage
through commercial production, which establishes scientific evidence that a process is capable of
consistently delivering quality product. Process validation is grouped into three stages: (1) process
design, (2) process qualification, and (3) continued process verification. 20 Process validation
coverage during postapproval inspection primarily focuses on stages 2 and 3—process qualification
and continued process verification—for the commercial manufacture of the subject drug. Stage
1―process design―is expected to require less coverage, particularly for subject drugs for which
PAIs were conducted. During a postapproval inspection, the investigator may need to evaluate
certain aspects of process design if they observe variability in commercial manufacturing data (stage
3 data, e.g., trends, deviations, failures) or process qualification studies and data (stage 2 data).
Suggested focus areas within the three process validation stages are described below.
(1) Objective 1A: Review of Process Design (Process Validation—Stage 1)
Sufficient documentation of process design activities is necessary to ensure that process knowledge
is appropriately captured, evaluated, and leveraged for use in subsequent stages of process
validation. Product development activities, including design of experiment (DoE) studies and
appropriate application of risk analysis tools in particular, are perhaps among the best industry
practices that manufacturers can use to develop process knowledge.
Process design and development studies, in particular DoE studies, typically help reveal
relationships between variable inputs (e.g., component characteristics, process parameters) and
resulting outputs (e.g., in-process material, intermediates, subject drug). Additionally, process design
studies (e.g., laboratory or pilot-scale models, computer-based or virtual simulations of certain unit
operations or process dynamics), and in particular the scale-up studies to commercial production,
address the functionality and operational limitations of commercial equipment and the anticipated
contributions to variability posed by different component lots (e.g., impact of component particle
size on unit operations such as mixing/blending, filling, or compression), production operators,
environmental conditions, and measurement systems in the production setting. The scientific data
resulting from process design, including DoE studies, can contribute to process understanding and
19
See footnote 16.
20
See guidance for industry Process Validation: General Principles and Practices for expectations about the scope and
purpose of these three stages.
Date of Issuance: 01/27/2023 Page 16 of 50
第 17 页
PROGRAM 7356.843
thereby help manufacturers justify ranges for incoming component quality, equipment parameters,
in-process material quality attributes, and the design of manufacturing process and controls.
Inspection Coverage 21
• If objective 1A was not previously evaluated (e.g., during a PAI or during an RIE 22 or an
assessment conducted under section 704(a)(4) of the FD&C Act), or there was a quality
concern identified from the previous evaluation, review the product development activities,
experimental reports, and other supportive data and reports available—whether they were
included in the original application or they were performed as part of a research or trial batch
on a different manufacturing scale―to determine if the process was designed to produce the
subject drug meeting the established critical quality attributes before the firm initiated stage 2
process validation activities.
• Determine if the firm appropriately executed relevant process design activities in response to
deviations observed in stage 2 or 3.
(2) Objective 1B: Review of Process Performance Qualification (Process Validation—
Stage 2)
The focus of postapproval inspections during the process qualification stage is on process
performance qualification (PPQ), which is primarily concerned with achieving a level of confidence
that the commercial process and controls consistently result in high-quality product and that
commercial distribution is justified.
Firms can achieve this by (1) designing and executing a written protocol (hereinafter PPQ protocol)
that specifies manufacturing conditions, controls, testing, and expected outcomes, and (2) generating
a report (hereinafter PPQ report) that documents adherence to the PPQ protocol and draws
conclusions as to whether the process (a) meets the conditions established in the PPQ protocol and
(b) is in a state of control. 23
Inspection Coverage
• Verify that the PPQ protocol for the subject drug has been reviewed and approved by
appropriate departments, including the quality unit, before its execution as per the established
procedure.
• Evaluate the adequacy of the PPQ protocol in terms of the essential elements it describes,
which may include but are not limited to the following:
21
Refer to the original application and IQA for information regarding manufacturing of the drug substance or drug
product, batch formula and components, unit operations, process development activities, in-process controls and
specifications, and identified lifecycle considerations.
22
For more information on this topic, see guidances for industry Remote Interactive Evaluations of Drug Manufacturing
and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency and Manufacturing, Supply
Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency: Questions and
Answers.
23
For further details, see guidance for industry Process Validation: General Principles and Practices.
Date of Issuance: 01/27/2023 Page 17 of 50
第 18 页
PROGRAM 7356.843
A reflection of the approved application.
Primary features and layout of the commercial production facilities.
Qualifications of utilities, equipment, raw material (including starting materials),
components, and personnel.
Description of manufacturing conditions, identification of relevant quality attributes,
including critical quality attributes, along with description of their controls.
Acceptance criteria for each significant processing step and for the cumulative
process.
Identification of the data to be collected and a description of when and how it will be
evaluated.
Limitations for proposed commercial manufacturing conditions, including equipment
operating parameters and processing limits.
Identification and validation status of test methods used for process measurements (e.g.,
in-process, release testing).
A representative sampling plan including sampling points, sampling strategy (frequency
and number), and acceptance criteria with an objective to provide sufficient statistical
confidence of quality both within a batch and across batches. 24
Provision for addressing deviations from expected conditions and handling of
nonconforming data.
Documentation of science-based justification if excluding PPQ data from further
consideration.
• Evaluate the adequacy of the information summarized in the PPQ report, which may include
but is not limited to the following:
Summary and analysis of data collected, as specified by the PPQ protocol.
Evaluation of unexpected observations and additional data not specified in the PPQ
protocol.
Summary and discussion of manufacturing nonconformances such as deviations, aberrant
test results, and other information that may have a bearing on the validity of the process.
Description in sufficient detail of corrective actions or changes that need to be made to
existing procedures and controls.
A conclusion that is based on a compilation of process knowledge and information from
the design stage through the process qualification stage and includes the following:
24
For FDA’s current thinking regarding sampling for blend uniformity/content uniformity, see
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm#16 rather than
relying solely on the requirements of USP General Chapter <905> Uniformity of Dosage Units or EP 2.9.6 Uniformity of
Content of Single-Dose Preparations without performing additional developmental activities. USP= United States
Pharmacopeia; EP= European Pharmacopeia.
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第 19 页
PROGRAM 7356.843
Clear establishment of the degree to which PPQ protocol study conditions, acceptance
criteria, and process performance indicators for product quality and process
consistency have been met, including a description of the control of and justification
for changes made to PPQ criteria during the study.
Sufficient description of manufacturing conditions or quality attributes identified
during the PPQ study that, per a risk analysis, will require either correction or
changes to existing procedures and controls.
Conclusion as to whether the process is in a state of control. If not, the report should
describe the conditions to be met before such a conclusion can be reached.
Approval of the PPQ report by appropriate department and quality unit personnel.
• Determine whether the conclusions on the manufacturing process’ state of control and
commercial distribution are justified and supported by the information in the PPQ report.
• Determine the accuracy and authenticity of the data and calculations generated during
execution of the PPQ protocol (e.g., raw data including laboratory notebooks, executed batch
records, internal quality decisions). Evaluate and determine the adequacy of the executed
PPQ protocol and the final written report, including deviations, results, outcomes, and
conclusions drawn.
• Evaluate the investigation reports for the firm’s resolution of product quality/process control
issues that arose during the PPQ study (e.g., specifications not met, process controls not
adequate, variability exceeding acceptance criteria, lots rejected). 25
• Evaluate the impact of recent changes to commercial manufacturing facilities, processing
conditions, or critical quality attributes in the approved application on the validity of the PPQ
study.
• Evaluate whether the equipment and utilities remain suitable for their intended use and
whether the preventive maintenance program remains appropriate based on information
collected since PPQ completion.
(3) Objective 1C: Review of Continued Process Verification (Process Validation—Stage 3)
Continued process verification provides assurance throughout the lifecycle that the commercial scale
process remains in a state of control (i.e., the validated state). During continued process verification,
manufacturers enhance, as necessary, mechanisms for detecting and monitoring signals of process
drift, shift, or loss of control to identify the source and scope of newly identified variations.
Manufacturers evaluate the commercial process and product data to identify and prevent
unacceptable variability. As manufacturers accumulate information during commercial production,
25
An unresolved PPQ processing issue may allow for variation in process parameters or in commercial product quality
that unexpectedly becomes unacceptable. The source of an unresolved PPQ processing issue may be a hitherto
unidentified process design (stage 1) defect. An unresolved PPQ processing issue may allow for episodic or persistent
process variation in process parameters or in product quality that is revealed by a careful inspection of commercial
product data and information (stage 3).
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第 20 页
PROGRAM 7356.843
component variability that was not observed during process design and development (stage 1) or
PPQ (stage 2) can manifest in the in-process materials and thereby contribute to variability in
product quality. When variability is detected, manufacturers should investigate and determine if
process parameter ranges need to be adjusted, process changes are needed to manage the variability,
or increased sampling is needed to better monitor and understand in-process material attribute
variability. Changes in operating conditions (e.g., ranges/set-points), process controls, components
or in-process material attributes/characteristics, and specifications may require additional process
design or PPQ studies to maintain compliance with 21 CFR 211.180(e) and sections 506A(a)(1) and
(b) of the FD&C Act.
Inspection Coverage
• Review and evaluate the firm’s quality management oversight and the methods used to assess
the commercial product data; determine if the firm adequately detects emerging trends
related to product quality from the information found in product data analysis reports; and
determine if the firm adequately incorporates risk analysis into decisions regarding continued
process verification data. This information may be found in:
Analysis of nonconforming product data from complaints, product rejections, recalls,
NDA/ANDA field alert reports (FARs), adverse event reports, audits, regulatory
inspections, and similar sources.
Investigations into unexpected trends recognized from the analysis of process, material,
or product variability.
Process performance and product quality monitoring data, including control charts,
process deviations, in-process batch release testing results, process yield variations,
nonconformances, and batch records.
Documentation of the appropriate statistical process control techniques applied as part of
the product and quality improvement program.
Laboratory records, including stability data trend analysis and reports, testing deviations,
nonconformances, investigations, and CAPA reports 26 with discussions of root cause
factors for out-of-trend (OOT) and out-of-specification (OOS) test results for raw
materials, in-process materials, and the subject drug.
• Determine if the firm adequately considered the need for additional process design or process
qualification studies when changes are made to the process after the initial PPQ, including
necessary adjustment of the sampling plan (e.g., frequency, sample size, location) to better
monitor and understand process variability.
• Determine if the firm evaluates production data and leverages such data to identify changes
needed in the manufacturing process, control procedures, or specifications, thereby
promoting continual improvement throughout the product lifecycle.
26
Refer to objective 2 regarding important elements to be considered for investigations and CAPAs.
Date of Issuance: 01/27/2023 Page 20 of 50
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PROGRAM 7356.843
(4) Related Resources
Regulations
• 21 CFR 211.22, 211.63, 211.84, 211.100, 211.110, 211.180
Guidance for Industry
• Analytical Procedures and Methods Validation for Drugs and Biologics (July 2015)
• Control of Nitrosamine Impurities in Human Drugs, Rev. 1 (February 2021)
• Data Integrity and Compliance With Drug CGMP Questions and Answers (December 2018)
• Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-
19 Public Health Emergency: Questions and Answers (May 2021)
• Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET)
Drugs (April 2012)
• PET Drugs—Current Good Manufacturing Practice (CGMP) (December 2009)
• PET Drugs—Current Good Manufacturing Practice (CGMP), Small Entity Compliance
Guide (August 2011)
• Process Validation: General Principles and Practices (January 2011)
• Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
• Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring
Facilities During the COVID-19 Public Health Emergency (April 2021)
• Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing
Practice (October 2004)
Draft Guidance for Industry 27
• ICH Q12: Implementation Considerations for FDA-Regulated Products (May 2021)
ICH Guidance for Industry
• Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
(September 2016)
• Q8(R2) Pharmaceutical Development (November 2009)
• Q9(R1) Quality Risk Management, Draft (June 2022)
• Q10 Pharmaceutical Quality System (April 2009)
• Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management (May 2021)
27
When final, this guidance will represent the FDA’s current thinking on this topic.
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B. Objective 2: Investigations and CAPA Program
Summary: Determine whether investigations and CAPAs associated with the subject
drug and associated processes and equipment were thoroughly evaluated and
effectively implemented using quality risk management as an enabler in support of
continual improvement.
(1) Objective 2A: Investigations
In general, the depth and breadth of investigations of any product- or process-related deviation
should be governed by a documented risk assessment and should take a structured approach to
determining the root cause of the deviation.
The level of effort, formality, and documentation of the investigation should be commensurate with
the level of risk. The firm should support its conclusions with scientific rationale and data generated
through investigations. Where applicable, the firm should use retain samples or confirmatory testing
to aid in its investigations. Laboratory error should be rare and is not sufficient to justify invalidating
data, unless there is clear evidence that it was the root cause of a failing result.
The analysis of product risk should be commensurate with the significance and risk of the
nonconformity and its perceived impact on the quality, safety, or effectiveness of the drug product.
The firm should conduct the risk assessment in a timely manner, using sound scientific and quality
risk management principles. This includes consulting subject matter experts from departments within
the organization with the expertise needed to ensure a full understanding of the scope of the problem
and its implications for product quality and risk to public health. 28
Inspection Coverage 29
• Review the firm’s response to both internal (e.g., deviation, OOT, OOS, errors) and external
(e.g., drug quality reports, recalls, complaints) signals for the subject drug. Investigations
involving released drug product should be given priority.
• Ascertain if the firm conducts or has conducted a thorough root cause investigation to
identify product quality issues for the subject drug.
• Determine if the firm’s investigations included an analysis of product risk and an evaluation
of risk to public health.
• Confirm that the firm expanded the scope of the investigation to include any and all lots of
the subject drug and any other drug products that may have been affected.
28
Departments include those involved in pharmaceutical development, manufacturing, quality, technical services,
laboratory work, materials management, regulatory affairs, and medical services.
29 During a postapproval inspection, coverage should focus on the investigations and CAPAs pertaining to the subject
drug rather than on the overall effectiveness or validity of the investigation system itself, which is the typical focus of a
surveillance-based inspection.
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(2) Objective 2B: CAPA Program
The CAPA program considers the risk that the problem poses to product quality. The level of effort,
formality, and documentation of CAPAs should be commensurate with the level of risk. The CAPA
program should also address identified problems, prevent their recurrence, and trigger improvements
through change management as necessary.
Inspection Coverage
• Based on the firm’s response to internal and external signals for the subject drug, check
whether the firm has a procedure to prioritize CAPAs based on risk and manage CAPAs for
the released subject drug in a timely manner. Through this coverage, assess the adequacy of
the firm’s approach, actions, and responses regarding the following:
Routine, proactive identification and analysis of quality data regarding product and
quality problems.
Evaluation of deviations, nonconformances, investigations, complaints, Process
Performance and Product Quality Monitoring System data/trends, and other external
reports to determine an appropriate CAPA.
Documentation of the full extent of a problem before conducting risk analysis or
determining the proper course of a CAPA.
Application of quality risk management concepts in the CAPA approach.
Review of proposed CAPAs by a cross-functional team with the necessary training and
experience before management approval.
• Evaluate the firm’s CAPAs to ensure they were implemented in a timely manner and that
they are effective and prevent recurrence. Through this coverage, assess the adequacy of the
firm’s CAPA approach, actions, and responses regarding the following:
Documentation of effectiveness check criteria (e.g., implementation timeline and
milestones, collection of feedback, validations, other evidence of the success of the
corrections made).
Monitoring for recurring deviations.
Evaluation and mitigation of new or recurring risks derived from the CAPA effectiveness
check, with management review and approval.
Management assurance that responsible parties will follow through on CAPA
commitments, including reporting as postapproval changes, as applicable.
Timely filings of regulatory submissions and postmarketing reports.
(3) Related Resources
Regulations
• 21 CFR 211.22(c), 211.84, 211.100, 211.110(a)
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Guidance for Industry
• Current Good Manufacturing Practice Requirements for Combination Products (January
2017)
• Investigating Out-of-Specification Test Results for Pharmaceutical Production (October
2006)
• Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
ICH Guidance for Industry
• Q9(R1) Quality Risk Management, Draft (June 2022)
• Q10 Pharmaceutical Quality System (April 2009)
C. Objective 3: Change Management, Change Effectiveness, and Conformance to the
Application and Other Postmarketing Reports and Requirements
Summary: Determine whether implemented changes in the product, process,
components, equipment, and/or facility associated with the subject drug were
implemented effectively using quality risk management as an enabler in support of
continual improvement. Verify that the subject drug is being manufactured in
accordance with the approved application or active DMF referenced in the approved
application, including filed postapproval changes. Confirm that the firm is fulfilling
or is on track to fulfill commitments (e.g., providing additional stability data) made at
the time of approval (original application or subsequent submissions) and is meeting
drug quality reporting requirements in a timely manner.
It is not uncommon for manufacturers to change facilities (e.g., add a new facility or replace an
existing facility), introduce changes within a facility, or change production equipment or
manufacturing and control procedures because of scale-up, process qualification, process
verification, capacity needs, or improvement plans. The impetus for change may originate from
internal sources (e.g., the outputs of process performance and product quality monitoring, CAPAs,
product reviews, audits, adverse trends, OOS results, adoption of advanced manufacturing) or
external sources (e.g., adverse event reports, FDA inspections, compendia modifications). Change
management ensures the appropriate execution of changes so that information relevant to the subject
drug is fed back into the process and control strategy to effect continual improvement and ensure the
maintenance of a state of control.
A change management system:
• Controls and implements proposed changes that are expected to improve product quality,
process performance, and robustness.
• Ensures that proposed changes that might impact product quality (and thereby potentially
product safety, effectiveness, or both) are evaluated commensurate with the level of risk to
patients by using sound scientific and quality risk management principles.
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• Documents how the assessed risk was categorized and how it will be managed, controlled, or
mitigated in the event the proposed change is not implemented.
• Ensures that implementation takes place in a timely manner with the approval of the quality
unit.
• Monitors the effects of changes to ensure that they have the intended effect and that there are
no unintended consequences.
The change control process should involve input from departments with the expertise needed to
assess the specific change and to ensure a full understanding of the scope of the change and its
implications for the process and control strategy.
Subject matter experts from the relevant departments responsible for implementing a specific change
determine the type and extent of data (existing or to be newly generated) needed to support the
change, and develop study protocols describing the methods, prospective acceptance criteria, and
additional post-implementation process performance or product quality monitoring as necessary.
As mentioned above, the change control process should also verify that changes have been effective
in achieving the desired outcome with no unintended consequences. For example, a sufficient
number of post-implementation commercial batches may be identified for review and evaluation. As
another example, increasing data-gathering efforts (e.g., evaluating stability batches), as needed,
confirms that the change objectives are achieved, that there is no deleterious impact on product
quality, and that the knowledge gained is captured. The impact of each implemented change should
be evaluated before the affected batches are released.
During a postapproval inspection, coverage should focus on changes pertaining to the subject drug
under evaluation rather than on the overall effectiveness or validity of the change control or change
management system, which is the typical focus of a surveillance-based inspection.
(1) Objective 3A: Change Management and Change Effectiveness
The change management system ensures that appropriate science- and knowledge-based risk
assessments are performed and documented for changes, taking into account the points below:
• The level of rigor, effort (e.g., testing, validation, review), and documentation is
commensurate with the level of risk associated with each change, and each change is
appropriately categorized according to the associated level of risk as defined by the site.
• Risk assessment adequately evaluates the potential risks and benefits of changes to product
quality, safety, and effectiveness.
• Changes and their risks are assessed using current product and process knowledge, including
appropriate data (available or generated, if needed), to identify current and needed risk
controls for each change.
The change management system also ensures that appropriate time and effort have been considered
in change planning, prioritization, and implementation, taking into account the points below:
• The outcomes of risk assessments and the assigned risk levels drive change planning,
prioritization, and implementation expectations.
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• Data to support the change, as well as acceptance criteria and change effectiveness criteria,
are predefined in change planning. These may include continued process verification and
statistical assessments, including process capability and process performance indices—Cpk
and Ppk—to aid with the quantitative assessment of risk control.
• Risks with the current state (until changes are implemented) and risks that might be
temporarily introduced during the change process are adequately assessed.
• Interim controls (short-term measures) are identified and implemented in a timely manner to
monitor and mitigate risks associated with the current state.
• Identified risk control measures are adequately implemented in a timely manner.
• Approval to proceed with change implementation or rejection of the change is documented
with appropriate justification.
• Relevant risk assessments are reviewed and are updated after the implementation of changes.
• Relevant and timely updates are made to regulatory filings, when appropriate (e.g., annual
reports must include all changes of relevance to filings; see 21 CFR 314.81 and 314.98).
In addition to general inspection coverage considerations regarding change management and
effectiveness, this section includes considerations covering product quality review (PQR) through
the PQS as an input to change management, ECs, comparability protocols, PLCM documents, and
supply chain-related changes. 30 For example, changes in the supply chain for APIs, excipients, and
primary packaging components that occur after approval should be thoroughly evaluated, approved,
and documented to ensure that they are unlikely to pose an adverse risk to product quality and
thereby to patients.
Inspection Coverage
• Evaluate changes to facility, product, process, and practices that have occurred since the
application was approved, or since the last inspection providing coverage of changes for this
product, that may have affected product quality. Evaluate the scientific justification for and
implementation of the changes and compare them to the changes contained in postapproval
submissions.
• Determine whether:
The factors or reasons triggering changes and the related evidence are clearly
documented. 31
30
See ICH Q12. The PQR is also referred to as an annual product review, which is a regulatory requirement per 21 CFR
211.180(e).
31 Examples of common lifecycle factors that trigger change include but are not limited to the following: upgrades to
equipment or facilities; changes in raw material quality or sourcing; improvements in manufacturing performance and
consistency (to reduce variability, improve yield, etc.); enhancements in manufacturing capacity; corrections of quality
issues; and addressing of signals from the PQS such as deviations, complaints/adverse events, CAPAs, product quality
review, operational review metrics, management review, new regulations, compliance gaps, implementing innovation,
and continual improvement initiatives.
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Proposed changes for the subject drug have been adequately evaluated using quality risk
management principles 32 and have been validated (if needed) and approved for
implementation through a formal change control system.
Proposed changes have been adequately justified with a scientific rationale and data.
Confirm that the evaluation of each change has been completed before affected batches
were released. 33
Relevant experts and stakeholders (e.g., subject matter experts, specific departments) are
involved in change proposal development and approval. 34
The objectives, scope, expected outcomes, and anticipated benefits of proposed changes
are documented.
Changes are proposed and formally evaluated in a timely manner, and a decision to
accept or reject the proposal is documented. For rejected change proposals, the rationale
for rejection is adequately documented.
Before change closure, the firm has ensured that:
Changes have met their intended objectives and predefined effectiveness criteria.
Deviations from those criteria are adequately assessed, approved, and managed or
justified. Whenever possible, quantitative data are leveraged to objectively determine
change effectiveness (e.g., statistical confidence and coverage).
As part of the quality risk management activities, residual risks are assessed and
managed to acceptable levels, and appropriate adaptations of procedures and controls
are implemented.
Unintended consequences or risks introduced as a result of changes are evaluated,
documented, approved, handled adequately, and are subject to a predefined
monitoring time frame.
Before or after change closure, the firm has ensured that:
Post-implementation actions (including those for deviations from predefined
acceptance criteria or CAPAs) are identified and completed adequately.
Relevant risk assessments are updated after changes are implemented and their
effectiveness is assessed. New product/process knowledge resulting from risk
assessments are captured in the appropriate quality and operations documents (e.g.,
standard operating procedures, reports, product control strategy documents).
32 See ICH Q9(R1), and Annex II in particular. Bear in mind that an impact assessment, typically performed within the
change control system, may not be as comprehensive as a risk assessment for proposed changes. Impact assessments
often assign categorization and determine the change’s regulatory filing but may not always fully address what might go
wrong or would be improved in the context of current product and process knowledge, the control strategy, and the
product lifecycle.
33 See footnote 32 with regard to impact assessment.
34
See footnote 28.
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The effects of implemented changes are actively monitored (e.g., use of additional
samples for in-process or stability testing, review of data results after completion of a
prespecified number of batches) to confirm that change objectives are achieved and
that there is no deleterious impact on product quality.
Changes are monitored via ongoing monitoring systems to ensure maintenance of a
state of control, 35 and lessons learned are captured and communicated. When
deviations associated with postapproval changes are detected:
o Risk-mitigating steps are developed in the case of deviations from acceptance
criteria or identification of unanticipated risks.
o The issue is managed via the firm’s deviation management process and
appropriate CAPAs are identified and undertaken via the firm’s CAPA program.
• Confirm that implemented changes, as appropriate, were captured and assessed as part of the
PQR procedures, which are described in further detail under objective 3B in Part III.2.C(2) of
this compliance program. (Also see “Inspection Coverage—Pharmaceutical Quality System
Assessment” below.)
Inspection Coverage—Pharmaceutical Quality System Assessment
• Through the review of PQR procedures, confirm that senior management is responsible for
PQS governance through periodic management review to ensure its continuing suitability and
effectiveness. 36 When confirming that periodic management reviews are occurring:
Determine whether management reviews include:
Measurement of achievement of PQS objectives.
Assessment of performance indicators used to monitor the effectiveness of processes
within the PQS (e.g., complaints, deviations, CAPAs, self-assessments, external
assessments).
Determine whether outcomes of management review of the PQS and monitoring of
internal and external factors include:
Improvements to the PQS and related processes.
Allocation or reallocation of resources and personnel training.
Revisions to quality policy and quality objectives, as appropriate.
Documentation and timely and effective communication of the results of the
management review and actions, including escalation of appropriate issues to senior
management.
35
The inspection coverage related to state of control under this objective may overlap with the inspection coverage
recommended for stages 2 and 3 of process validation under objectives 1B and 1C, respectively.
36
See ICH Q10.
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Inspection Coverage—Comparability Protocols and Product Lifecycle Management
• Determine whether the applicant has an approved comparability protocol or specified and/or
categorized postapproval changes in a PLCM document.
If there is an approved comparability protocol, verify the implementation status of any
change.
Review that the change as implemented aligns with the comparability protocol.
Verify whether the data generated demonstrate that the change objective and
acceptance criteria were met.
If there is an approved PLCM document:
Verify that changes to all ECs are handled per the approved PLCM and changes to
parameters unrelated to ECs are managed appropriately under the firm’s PQS.
Verify the maintenance status of the document in terms of when and how the
document is updated.
Review that the document was updated after the change was implemented to capture
new product/process knowledge gained during implementation.
Verify whether subsequent regulatory filings for the subject drug have been included
in the document.
• If the applicant/manufacturer is not using an approved PLCM document for the subject drug,
assess and report whether the changes are being reported in a manner that is consistent with
the appropriate regulations (see 21 CFR 314.70 and 314.97) and guidance documents 37 to
provide continued assurance of quality for the subject drug over the product lifecycle.
Inspection Coverage—Supplier/Vendor Qualification and Agreements Assessment
• Assess the adequacy of the firm’s supplier qualification program by ensuring that the firm:
Evaluated supplier changes for the raw materials, intermediates, or components of the
subject drug, as applicable, using the site change management system, evaluated the risk
of the supplier change before implementation, and evaluated the quality of the drug and
its individual characteristics (such as the impurity profile).
Evaluated changes to individual raw material and qualified component suppliers before
authorizing the material from those suppliers for use, and reevaluates the reliability of the
supplier’s analyses through appropriate validation of the supplier’s test results at
appropriate intervals.
Maintains defined sampling plans for components to obtain samples that are
representative of the shipment and defined acceptance levels to detect unacceptable
component variability.
37
See footnote 9.
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Has appropriate controls in place to measure and control variability, such as by
periodically challenging the accuracy of the certificate of analysis via performing
independent confirmatory testing at a defined frequency.
• If the firm has a quality agreement in place with other facilities, including drug applicants,
for either critical inputs (e.g., ingredients, raw materials) or outputs (e.g., bulk API for
micronization, bulk in-process material or bulk finished product for further processing such
as packaging), confirm that it defines communication roles and CGMP responsibilities of
suppliers, contract manufacturers, and drug manufacturers regarding the notification and
impact of changes in or deviations from processes or acceptance criteria for the inputs or
outputs.
(2) Objective 3B: Conformance to the Application and Other Postmarketing Reports and
Requirements
In accordance with statutory and regulatory requirements, 38 applicants must notify FDA of
manufacturing changes to approved applications before distributing drug products made with such
changes. Under 21 CFR 314.70 and 314.97, applicants must notify FDA about changes made to the
conditions and the variations in the conditions that were established in approved applications. These
regulations identify three broad reporting categories: major changes, which require submission of a
prior approval supplement (PAS); moderate changes, which require submission of a changes being
effected in 30 days (CBE-30) supplement or a CBE-0 supplement; and minor changes, which must
be reported in an annual report. The reporting category for a change is based on the potential risk for
the change to have an adverse effect on the identity, strength, quality, or purity of the drug product
as these factors may relate to its safety or effectiveness. If an application includes approved ECs
with specified reporting categories (see Part 1—Background), the reporting category reflected in the
PLCM document is considered the appropriate submission type for a postapproval change to that
EC.
Applicants of NDAs and ANDAs are required to file FARs for relevant quality issues concerning
distributed product batches pursuant to 21 CFR 314.81. A failure to file a report is considered a
significant violation and subject to a Form FDA 483 citation. 39
Firms conduct periodic PQRs—annually at a minimum or more frequently on a rolling basis—to
verify reliability and performance of the existing process in delivering quality product, verify the
appropriateness of current specifications for raw materials (including starting materials),
components, and the subject drug, and identify trends in product quality and process performance
that warrant change. 40
PQRs, taking into account previous reviews, include at least the following for the subject drug, as
applicable:
38 See section 506A of the FD&C Act (21 U.S.C. 356a).
39
See compliance program 7356.021—Drug Quality Reporting System (DQRS) (MedWatch Reports) NDA Field Alert
Reporting (FARs) and guidance for industry Field Alert Report Submission: Questions and Answers.
40
See 21 CFR 211.180(e).
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• Review of quality specifications for raw materials, intermediates, components, container
closure systems, and packaging materials as pertain to the subject drug, especially those from
new sources.
• Review of supplier qualification or requalification reports for supplied materials,
components, or other outsourced contract manufacturing activities or services.
• Review of critical in-process controls, tests, in-process specifications, test results for in-
process materials, and the final specifications and test results for the subject drug.
• Review of batches that failed to meet established specifications and their related
investigations.
• Review of significant deviations or nonconformances, their related investigations, and the
effectiveness of resultant CAPAs taken.
• Review of changes to processes or analytical methods.
• Review of supplements approved or issued a complete response action.
• Review of the results of the stability monitoring program and adverse trends.
• Review of quality-related returns, complaints, and recalls and the investigations performed at
the time.
• Review of the adequacy of previous product process or equipment corrective actions.
• The qualification status of relevant equipment and utilities (e.g., HVAC, water, compressed
gases).
Inspection Coverage 41
• Review the timeliness of notification via FARs for issues that have the potential to impact
product on the market.
• Evaluate the status of defined postmarketing commitments or postmarketing reporting
requirements that the applicant had agreed to fulfill in a timely manner as part of the
authorization for the initial approval of the NDA. 42
• Review changes that have been implemented since approval for the drug product and
determine whether the changes were properly reported to FDA.
• Evaluate if the firm has underestimated changes in terms of their potential impact on product
quality and type of change to the regulatory filing (e.g., as a minor change requiring an
annual report submission instead of as a moderate change requiring a CBE-30 supplement).
41See footnote 21.
42
Postmarketing commitments are otherwise known as quality postmarketing agreements (QPAs) as defined in the draft
guidance for industry Benefit-Risk Considerations for Product Quality Assessments. Postmarketing reporting
requirements refer to “Other postmarketing reports” as required under 21 CFR 314.81—in particular 314.81(b)(2)(iv),
(vii), (viii), and (ix) for NDAs—and the same for ANDAs under 21 CFR 314.98—in particular 314.98(c).
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• Evaluate if the firm manufactured and improperly distributed any batches with changes that
required prior FDA approval.
• Determine whether manufacturing is consistent with what was included in the application
(e.g., if manufacturing and analytical equipment, manufacturing process, process controls, in-
process and release tests, specifications, and methods employed are the same as those
documented in the application).
• Confirm and as necessary report back whether the commitments made by the applicant, at the
time the application or application supplement was approved, have been completed or are
underway.
• Verify that the firm:
Evaluates PQR results and assesses whether to undertake CAPAs, change proposals, or
process revalidation for continual improvement.
Uses quality risk management to evaluate proposed CAPAs, changes, or process
revalidation.
Completes actions that are undertaken as a result of a PQR in a timely and effective
manner.
Has procedures for the ongoing management and review of actions undertaken as a result
of PQRs and verifies the effectiveness of these procedures during self-inspection.
Reviews the effectiveness of actions undertaken as a result of a PQR at the next PQR.
(3) Related Resources
Regulations
• 21 CFR 211.198, 310.305, 314.70, 314.80, 314.81, 314.97, 314.98
Guidance 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)
• Changes to an Approved NDA or ANDA: Questions and Answers (January 2001)
• CMC Postapproval Manufacturing Changes for Specified Biological Products to be
Documented in Annual Reports (December 2021)
• CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March
2014)
• Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and
Controls Information in an NDA, ANDA, or BLA (October 2022)
• Field Alert Report Submission: Questions and Answers (July 2021)
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• SUPAC-IR: 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)
• SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo
Bioequivalence Documentation (May 1997)
Draft Guidance for Industry 43
• ICH Q12: Implementation Considerations for FDA-Regulated Products (May 2021)
• Postapproval Changes to Drug Substances (September 2018)
• SUPAC: Manufacturing Equipment Addendum (December 2014)
ICH Guidance for Industry
• Q10 Pharmaceutical Quality System (April 2009)
• Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management (May 2021)
D. Objective 4: Integrity of Product Quality Data
Summary: Audit manufacturing controls, test results, and the related raw data for
starting materials, in-process materials, and batches of the subject drug. Ensure that
the test and production data are authentic, computed correctly, accurate, and
documented per CGMP and that they support the associated decisions by the firm,
application submissions, and lifecycle changes.
This section emphasizes the importance of data integrity when it has been specifically requested as
part of inspectional coverage in the assignment. Additionally, at the discretion of the lead
investigator, data integrity coverage may be added when problems are found. Sufficient coverage
should be afforded to confirm the integrity of data relating to process performance and product
quality.
During routine production, firms generate a substantial amount of manufacturing and laboratory
data. Analysis of these data and evaluation of analytical methods ensures that firms are capable of
consistently maintaining process control, meeting quality specifications, and reliably producing
product of intended quality. Complete, consistent, and accurate data should be attributable, legible,
43
When final, these guidances will represent the FDA’s current thinking on these topics.
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contemporaneously recorded, original or a true copy, and accurate (ALCOA). 44 Analysis of product
quality data (e.g., release and stability data) also ensures that the quality unit adequately responds to
unexpected or aberrant results in a timely manner so as to prevent poor quality drug products from
reaching the marketplace.
If a pattern of data reliability issues is identified during the inspection, the investigator should consider
expanding the coverage to surveillance of marketed products manufactured in the facility using
compliance program 7356.002. If data reliability issues are documented for other products during an
expanded inspection, this suggests a broader pattern that implicates all products manufactured at the
facility. If so, ORA should consider submitting a recommendation that CDER consider invoking the
Application Integrity Policy (AIP) or that a for-cause inspection be planned to further define the scope of
the data reliability issues. 45
Inspection Coverage
• Assess the firm’s ability to effectively manage hard copy (paper), computerized, and hybrid
data systems by having user access control mechanisms and verifiable audit trails, where
appropriate, for collection, reporting, and archiving of information for the subject drug.
Determine whether data are calculated and reported using reliable and verifiable
mechanisms, interpreted using sound scientific rationale, and maintained using validated
systems.
Determine if there were data not reported in the submission, supplement, or annual report
that should have been.
Evaluate whether there were inaccurate, misleading, manipulated, or incomplete data in
CGMP documents and submissions.
• Evaluate representative raw data relating to process performance and product quality,
including the raw data from the in-process, release, and stability testing, to determine if there
is a pattern of data reliability issues that impact:
The quality specifications of the subject drug.
The retest or expiry date or labeled expiration dating.
44
These characteristics are important to ensuring data integrity and are addressed throughout the CGMP regulations for
drug products. For attributable, see 21 CFR 211.101(d), 211.122, 211.186, 211.188(b)(11), and 212.50(c)(10); for
legible, see 21 CFR 211.180(e) and 212.110(b); for contemporaneously recorded (at the time of performance), see 21
CFR 211.100(b) and 211.160(a); for original or a true copy, see 21 CFR 211.180 and 211.194(a); and for accurate, see
21 CFR 211.22(a), 211.68, 211.188, and 212.60(g).
45
Contact information and procedures for OC’s Office of Manufacturing Quality are on the AIP website at
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-
activities/application-integrity-policy. See also CPG Sec 120.100 Fraud, Untrue Statements of Material Facts, Bribery,
and Illegal Gratuities, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cpg-sec-120100-
fraud-untrue-statements-material-facts-bribery-and-illegal-gratuities.
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The analytical methods employed as part of the approved control strategy (e.g., methods
do not conform to those approved in the application). 46
(1) Related Resources
Guidance for Industry
• Analytical Procedures and Methods Validation for Drugs and Biologics (July 2015)
• Data Integrity and Compliance With Drug CGMP: Questions and Answers (December 2018)
• Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production
(October 2006)
Other FDA Resources
• Compliance program 7346.832―Preapproval Inspections, III.1.B(3) Data Integrity Audit
(October 2022)
• Guide to Inspection of Microbiological Pharmaceutical Quality Control Laboratories (July
1993)
• Guide to Inspection of Pharmaceutical Quality Control Laboratories (July 1993)
3. Inspection Reporting
The inspection team performs the inspection following this compliance program and provides
coverage in the areas of concern.
A. Issuance of Form FDA 483
Consistent with instructions in the IOM, use Form FDA 483 to communicate reportable observations
and CGMP deficiencies pertaining to the subject drug.
Refer to Part V—Regulatory/Administrative Strategy―for a list of issues that may result in a 483
observation.
If the postapproval inspection is concurrent with or expanded to CGMP surveillance, organize Form
FDA 483 according to compliance program 7356.002 and the IOM.
B. Completion and Assessment of the Establishment Inspection Report
The inspection team prepares a narrative EIR per instructions in the IOM (chapter 5). In all cases,
ORA and CDER (OPMA, Office of Manufacturing Quality (OMQ), or both as described in Part V)
collaboratively evaluate the inspection team’s report within the context of the application and
communicate relevant findings or concerns to the IQA team.
46
FDA expects the quality unit to control and approve changes made to these methods and, based on the significance of
the change in the method, communicate those changes to FDA.
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For postapproval inspections with significant deficiencies, CDER (OPMA, OMQ, or both as
described in Part V) evaluates the inspection team’s findings and the firm’s response and makes a
final recommendation on the adequacy of the firm’s response for the covered application and/or the
facility. CDER (OPMA or OMQ as appropriate) communicates the final recommendation
(concurrence/nonconcurrence) to ORA.
4. Sample Collection or Sample Submission Requests
Investigators should not routinely collect samples during the postapproval inspection. Samples of
potentially defective subject drugs may be collected to constitute persuasive evidence that significant
CGMP problems exist. Physical samples may be an integral part of a CGMP inspection where
control deficiencies are observed. Physical samples should be correlated with observed control
deficiencies. Contact a program coordinator in the ORS Office of Medical Products, Tobacco, and
Specialty Laboratory Operations ([email protected]) for guidance
on the types of samples to be collected (in-process or drug product) and for the appropriate analytical
servicing laboratory. Documentary samples may be submitted when the documentation illustrates the
deficiencies better than a physical sample. ORA divisions may elect to collect, but not analyze,
physical samples, or to collect documentary samples to document CGMP deficiencies. Physical
sample analysis is not necessary to document CGMP deficiencies. For sampling guidance, refer to
IOM chapter 4—Sampling.
If an official sample is collected at an establishment, use the PACs on the assignment to report
sample collection/analysis time.
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PART IV—ANALYTICAL
Contact ORS’ Office of Medical Products, Tobacco, and Specialty Laboratory Operations
([email protected]) for the analytical servicing laboratories for
chemical and microbiological testing. When contacting ORS for analytical servicing laboratories,
provide the product description, lots to be tested, analyses to be performed, and reason for the
sample collection.
The analytical servicing laboratory uploads completed analytical worksheets for the product samples
analyzed to CMS and submits the original worksheet package to the ORA home district office of the
manufacturing facility.
If warranted, ORA division offices will recommend an appropriate regulatory action to CDER.
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PART V―REGULATORY / ADMINISTRATIVE STRATEGY
ORA inspects the establishment named in an application and provides an initial recommendation on
its acceptability. If there are significant issues that would adversely impact the establishment’s
ability to perform its designated functions as described in the application, the lead investigator
documents the nature and scope of significant deviations and observations found during the
postapproval inspection for the subject drug.
1. Significant Issues
Examples of significant issues for the subject drug include but are not limited to the following 47:
1. Lack of or inadequate process validation (e.g., unsuitable equipment, inadequate process
performance qualification, unreliable state of control) to support distribution of the subject
drug.
2. Lack of or inadequate validation of test methods for raw materials, in-process materials, or
the subject drug.
3. Release or distribution of batches that deviated from the site’s established procedures as well
as the controls in the approved application (e.g., reprocessing or rework operations, process
controls, test methods, raw material, in-process material specifications, and subject drug
specifications).
4. Failure to investigate and resolve quality problems (e.g., manufacturing issues, including
stability failures, OOS or OOT results, consumer complaints) for distributed batches.
5. Failure to investigate and document the root cause of deviations, failure to initiate CAPAs to
correct deviations and prevent them from recurring, and failure to assess the impact on
product quality.
6. Failure of the quality unit to adequately review, assess, and approve changes relevant to the
subject drug.
7. A finding of data integrity problems. 48
8. Failure to meet application commitments by the agreed-upon timeline without a reasonable
justification and with no or inadequate communication to FDA.
9. Failure to report or inadequate reporting of changes made to the subject drug, as applicable
(e.g., changes made to approved ECs).
47
In general, issues 1 to 7 are considered typical examples of CGMP deficiencies, whereas issues 8 and 9 are typical
examples of application-related issues. Issues related to drugs that have already been distributed are considered more
significant for potential negative impact to patients or consumers.
48
Findings related to raw data integrity or falsification of data generated at the manufacturing site and used in support of
product quality decisions relevant to the subject drug should be considered for a systemic CGMP impact on current
operations (e.g., across all manufacturing operations or across all manufactured products as applicable) at the
establishment.
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If significant issues are identified during the postapproval inspection, the lead ORA investigator, as
indicated in Part II.3.E of this compliance program, should consider expanding the scope of the
inspection to include compliance program 7356.002 coverage.
2. Coordination for Regulatory/Administrative Follow-Up Actions to Inspection Findings
Inspection findings that demonstrate that the manufacturing process is not operating under a state of
control may be used as evidence for taking appropriate advisory, administrative, or judicial actions.
The initial classification of the inspection should be based on the ORA division’s assessment of the
seriousness of the inspectional issues observed.
The endorsement of the inspection report will point out the actions by the firm that have been or will
be taken and the timeline for the actions. All deficiencies noted in inspections under this compliance
program must be addressed by stating the firm’s corrective actions, accomplished or projected, for
each deficiency as established in the discussion with the firm’s management at the close of the
inspection.
If an inspection report documents significant deficiencies for the subject drug or finds one or more
systems at the establishment that are not in a state of control with or without the expanded inspection
coverage under compliance program 7356.002, consider an initial OAI classification for impacted
PACs.
A. Issues That Are Considered Significant for PAC 56843
The issues that are considered significant for PAC 56843 may impact other drug products or APIs
besides the subject drug under inspection. OMQ and OPMA, when appropriate (i.e., specifically for
the subject drug), will collaborate on the determination of combined actions (e.g., regulatory,
advisory, enforcement). OMQ, ORA, and OPMA will subsequently collaborate on related
communication with the firm or applicant, as appropriate.
When the postapproval inspection identifies the presence of significant CGMP deficiencies for the
subject drug, as described in Part V of this compliance program, or if the postapproval inspection is
combined with surveillance inspection coverage and there are significant deficiencies identified as
described in Part V—Regulatory/Administrative Strategy of compliance program 7356.002, the
inspection should result in an initial OAI classification recommendation to OMQ.
In these instances, OMQ will act as the lead office tasked with completing the final assessment,
providing a compliance recommendation, and issuing the FMD-145 letter to the firm. To support
OMQ’s efforts, OPMA may assign a point of contact to actively assist in the review of the inspection
report and the firm’s responses to the 483 observations. When appropriate, OMQ can also initiate a
product-specific consult to OPMA (such as to solicit subject matter expert opinion on the impact of
identified microorganisms or other complex manufacturing process or facility issues). When
necessary, OPMA will reach out to appropriate OPQ suboffices in response to the OMQ consult.
Regulatory, advisory, or enforcement actions may include one or more of the following:
• Hold a regulatory meeting (or meetings) with the manufacturer.
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• Issue a warning letter (or other advisory notice).
• Pursue an import alert (for foreign manufacturers).
• Order a cease distribution or product recall or recommend a product recall. 49
• Pursue product seizure.
• Pursue establishment injunction.
• Suspend product approval.
• Withdraw or revoke product approval (following the opportunity for a hearing or an
opportunity to demonstrate compliance).
• Withhold the approval of pending applications and application supplements requiring an
evaluation of the establishment.
• Invoke FDA’s Application Integrity Policy.
• Pursue prosecution.
• Pursue the imposition of civil money penalties.
• Initiate an administrative detention of the subject drug, per 21 CFR 1.980.
The postapproval inspection may find no significant CGMP deficiencies but may identify
application-related issues with an initial OAI classification for PAC 56843 requiring CDER’s
follow-up. 50 In these instances, OPMA will lead the assessment of the inspection outcomes on the
subject drug application, coordinate with the IQA team for subsequent follow-up actions or
communications with the applicant or the facility as necessary, and act as the lead office tasked with
completing the final assessment and issuing the FMD-145 letter to the firm. To support OPMA’s
efforts, OMQ may assign a point of contact to actively assist in the review of the inspection report as
well as other relevant inspectional documents. When appropriate, OPMA can also initiate a
compliance-specific consult to OMQ. When necessary, OMQ will reach out to appropriate OC
suboffices in response to the OPMA consult. OPQ can ask the applicant, site, and related programs,
as needed, to undertake follow-up actions regarding subject drug-related issues. Follow-up actions
may include, but are not limited to:
• Requesting that an applicant submit a supplement to modify ECs named in the application.
• Notifying the applicant that the reporting categories previously approved in the application
related to the facility subject to the postapproval inspection will revert to reporting categories
consistent with the risk-based paradigm in the regulations and as recommended in guidance
until adequate corrections have been verified.
Lack of follow-up on these application-focused corrections may also impact pending applications.
49
For a cease distribution or product recall of a controlled substance, refer to section 569D of the FD&C Act.
50
Examples of application-related issues include an inappropriate change reporting category, failure to meet application
commitments relevant to drug quality, failure to submit annual reports, and concerns about the PQS that impact an
approved PLCM document or suggest that additional ECs should be included in the application.
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OPMA works with other offices (e.g., Office of Combination Products (OCP) and Office of the
Chief Counsel (OCC), Office of Generic Drugs (OGD), OMQ) to determine the appropriate
administrative actions, which may include but are not limited to the following:
• FDA-initiated request to the applicant to update an existing approved application.
• Withdrawal of approval status of the application (NDA and ANDA) or its suspension under
section 505(e) of the FD&C Act (see also 21 CFR 314.150(b), 314.151, and 314.153).
After the final classification of the inspection has been completed, OQS updates the surveillance risk
model, when appropriate, with the information gained from the inspection.
B. Issues That Are Not Considered Significant for PAC 56843
If the facility inspection indicates an NAI or VAI classification and no further action is
recommended, ORA issues an FMD-145 letter within the predefined timeline based on the date of
the inspection closing. 51 OPQ suboffices (e.g., OPMA) may assist ORA divisions as requested.
51
See FMD-145—Release of the Establishment Inspection Report (EIR).
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PART VI—REFERENCES, ATTACHMENT, PROGRAM CONTACTS, AND ACRONYMS
1. References
A. Code of Federal Regulations, Title 21
https://www.ecfr.gov/current/title-21
21 CFR part 1
21 CFR part 210
21 CFR part 211
21 CFR part 212
21 CFR part 310
21 CFR part 314
B. Compliance Programs
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/drug-compliance-programs
7346.832—Preapproval Inspections
7356.002—Drug Manufacturing Inspections
7356.002A—Sterile Drug Process Inspections
7356.002C—Radioactive Drugs
7356.002F—Active Pharmaceutical Ingredients
7356.002P—Positron Emission Tomography (PET) CGMP Drug Process and Pre-approval
Inspections/Investigations
7356.021—Drug Quality Reporting System (DQRS) (MedWatch Reports) NDA Field Alert
Reporting (FARs)
C. Compliance Policy Guide
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-
manuals/manual-compliance-policy-guides
CPG Sec. 120.100 Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities
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D. FDA Guidances
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
(1) Guidance for Industry
Analytical Procedures and Methods Validation for Drugs and Biologics (July 2015)
Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological
Products (July 1997)
Changes to an Approved NDA or ANDA (April 2004)
Changes to an Approved NDA or ANDA: Questions and Answers (January 2001)
Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection
(October 2014)
CMC Postapproval Manufacturing Changes for Specified Biological Products to be Documented in
Annual Reports (December 2021)
CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March 2014)
Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls
Information in an NDA, ANDA, or BLA (October 2022)
Control of Nitrosamine Impurities in Human Drugs, Rev. 1 (February 2021)
Current Good Manufacturing Practice Requirements for Combination Products (January 2017)
Data Integrity and Compliance With Drug CGMP: Questions and Answers (December 2018)
Field Alert Report Submission: Questions and Answers (July 2021)
Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (October
2006)
Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19
Public Health Emergency: Questions and Answers (May 2021)
Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs
(April 2012)
PET Drugs—Current Good Manufacturing Practice (CGMP) (December 2009)
PET Drugs—Current Good Manufacturing Practice (CGMP), Small Entity Compliance Guide
(August 2011)
Process Validation: General Principles and Practices (January 2011)
Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
Questions and Answers on Current Good Manufacturing Practices for Drugs (March 2018)
Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities
During the COVID-19 Public Health Emergency (April 2021)
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Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice
(October 2004)
SUPAC-IR: 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)
SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation
(May 1997)
Draft guidance 52
Benefit-Risk Considerations for Product Quality Assessments (May 2022)
Conducting Remote Regulatory Assessments: Questions and Answers (July 2022)
ICH Q12: Implementation Considerations for FDA-Regulated Products (May 2021)
Postapproval Changes to Drug Substances (September 2018)
SUPAC: Manufacturing Equipment Addendum (December 2014)
(2) ICH Guidance for Industry
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September
2016)
Q8(R2) Pharmaceutical Development (November 2009)
Q9(R1) Quality Risk Management, Draft (June 2022)
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
(May 2021)
E. Other Procedures and References
Application Integrity Policy, https://www.fda.gov/inspections-compliance-enforcement-and-
criminal-investigations/compliance-actions-and-activities/application-integrity-policy
FMD-145—Release of the Establishment Inspection Report (EIR) (July 2019),
https://www.fda.gov/media/83055/download
52
When final, these guidances will represent the FDA’s current thinking on these topics.
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Inspection Guides, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/inspection-references/inspection-guides
• Pharmaceutical Quality Control Laboratories (July 1993)
• Microbiological Pharmaceutical Quality Control Laboratories (July 1993)
Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of
Operations (June 2017), https://www.fda.gov/drugs/pharmaceutical-quality-resources/integration-
fda-facility-evaluation-and-inspection-program-human-drugs-concept-operations
Investigations Operations Manual (2021), https://www.fda.gov/inspections-compliance-
enforcement-and-criminal-investigations/inspection-references/investigations-operations-manual
Pharmaceutical Quality for the 21st Century—A Risk-Based Approach: Progress Report (May
2007), https://www.fda.gov/about-fda/center-drug-evaluation-and-research/pharmaceutical-quality-
21st-century-risk-based-approach-progress-report
Points to Consider for Internal Reviews and Corrective Action Operating Plans (June 1991),
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/application-
integrity-policy/points-consider-internal-reviews-and-corrective-action-operating-plans-june-1991-
food-and-drug
Regulatory Procedures Manual (July 2021), https://www.fda.gov/inspections-compliance-
enforcement-and-criminal-investigations/compliance-manuals/regulatory-procedures-manual
Staff Manual Guide 9004.1, Policy and Procedures for Requesting Records in Advance of or in Lieu
of a Drug Inspection (August 2017), https://www.fda.gov/media/124338/download
United States Pharmacopeia (USP), https://www.uspnf.com
An Update to the Resiliency Roadmap for FDA Inspectional Oversight (November 2021),
https://www.fda.gov/media/154293/download
2. Attachment
Attachment A: Remote Regulatory Assessments
3. Program Contacts
A. Office of Regulatory Affairs
Office of Medical Products and Tobacco Operations
Office of Pharmaceutical Quality Operations, Division of Pharmaceutical Quality Programs,
Pharmaceutical Quality Initiatives Branch
ORA program coordinators: See the ORA Directory in the IOM for updated references,
https://www.fda.gov/files/inspections,%20compliance,%20enforcement,%20and%20criminal
%20investigations/published/ORA--Directory.pdf
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PROGRAM 7356.843
Office of Regulatory Science
Office of Medical Products, Tobacco, and Specialty Laboratory Operations
Staff Director
[email protected]
B. Center for Drug Evaluation and Research
CGMP or Quality-Related Policy Questions
For CGMP or quality-related policy, technical, or scientific questions or information needs,
including questions about this program, send an email to the following address and it will be
handled as a top priority:
[email protected]
Product-Specific Inspection-Related Questions:
For questions about a product-specific postapproval inspection under this program, contact
the OPMA Postapproval Program mailbox:
[email protected]
Office of Compliance: Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence need and sufficiency,
citations, and case evaluation/recommendation advice related to marketed products or
surveillance coverage, send an email to the following address and it will be handled as a top
priority:
[email protected]
4. Acronyms
ALCOA attributable, legible, CDER Center for Drug Evaluation and
contemporaneously recorded,
Research
original or a true copy, and
accurate CGMP current good manufacturing
practice
ANDA abbreviated new drug application
CMC chemistry, manufacturing, and
API active pharmaceutical ingredient controls
CAPA corrective action and preventive CMS Compliance Management
action Services
CBE changes being effected Cpk process capability index
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DMF drug master file OPMA Office of Pharmaceutical
Manufacturing Assessment
DOE design of experiment
OPQ Office of Pharmaceutical Quality
EC established condition
OPQO Office of Pharmaceutical Quality
eDRLS Electronic Drug Registration and
Operations
Listing System
OQS Office of Quality Surveillance
EIR establishment inspection report
ORA Office of Regulatory Affairs
FAR field alert report
ORA PAM ORA preapproval program
FD&C Act Federal Food, Drug, and Cosmetic
manager
Act
ORADSS Online Reporting Analysis
ICH International Council for
Decision Support System
Harmonisation
ORS Office of Regulatory Science
IOM Investigations Operations Manual
PAC product/assignment code
IQA integrated quality assessment
PACMP postapproval change management
MRA mutual recognition agreement
protocol
NAI No Action Indicated
PAI preapproval inspection
NDA new drug application
PET positron emission tomography
OAI Official Action Indicated
PLCM product lifecycle management
OC Office of Compliance
pOAI potential Official Action Indicated
OCC Office of the Chief Counsel
Ppk process performance index
OCP Office of Combination Products
PPQ process performance qualification
OGD Office of Generic Drugs
PQR product quality review
OMPTO Office of Medical Products and
PQS pharmaceutical quality system
Tobacco Operations
RIE remote interactive evaluation
OMQ Office of Manufacturing Quality
RRA remote regulatory assessments
OOS out-of-specification
SUPAC Scale-Up and Postapproval
OOT out-of-trend
Changes
VAI Voluntary Action Indicated
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PART VII―OVERVIEW OF CDER-ORA RESPONSIBILITIES
CDER and ORA redefined their roles and responsibilities regarding application assessments and
inspections of human drugs facilities under the ConOps agreement Integration of FDA Facility
Evaluation and Inspection Program for Human Drugs: A Concept of Operations. This ConOps
operating model applies to pre- and postapproval, surveillance, and for-cause inspections.
Postapproval facility inspections are led by ORA with CDER participation. The roles and
responsibilities for postapproval inspections as laid out in ConOps are subject to this compliance
program.
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ATTACHMENT A: REMOTE REGULATORY ASSESSMENTS
In addition to its inspectional authority, FDA may conduct remote regulatory assessments (RRAs),
under certain circumstances, to support oversight of FDA-regulated products and establishments. 1
An RRA is an examination of an FDA-regulated establishment and/or its records, conducted
remotely, to evaluate compliance with applicable FDA requirements. RRAs assist in protecting
human health, informing regulatory decisions, and verifying certain information submitted to the
Agency.
RRAs used in lieu of or in advance of inspections have allowed FDA to remotely evaluate drug
manufacturing establishments to mitigate risks. However, RRAs are not the same as an inspection as
described in section 704(a)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and FDA
does not consider them to satisfy the statutory requirement for an inspection under section 510(h) of
the FD&C Act.
The following RRAs, along with applicable FDA policies, can be used to support the objectives of
this compliance program when, in the opinion of FDA experts, they would enable FDA to determine
whether the establishment meets applicable requirements for the product’s identity, strength, quality,
and purity for an application subject to section 505 of the FD&C Act.
1. FDA Records and Other Information Requests Under Section 704(a)(4) of the FD&C Act
(Statutorily Authorized RRA)
In 2012, with the passage of the Food and Drug Administration Safety and Innovation Act to amend
the FD&C Act, Congress gave FDA the authority to request “any records or other information” in
advance of or in lieu of an inspection related to human or animal drugs, including human biological
drug products. Section 704(a)(4) of the FD&C Act requires “a person that owns or operates an
establishment that is engaged in the manufacture, preparation, propagation, compounding, or
processing of a drug” to provide FDA, upon request, records or other information that FDA may
inspect under section 704(a)(1).
With regards to this compliance program, a 704(a)(4) request may be used in lieu of or in advance of
a postapproval inspection to support preparation and assessment of product-specific inspection
coverage. 2 The use of 704(a)(4) authority does not prevent an FDA investigator from requesting
records or other information on inspection.
2. Remote Interactive Evaluation (Voluntary RRA)
A remote interactive evaluation (RIE) is an evaluation of a firm’s compliance with regulations
1
See FDA’s An Update to the Resiliency Roadmap for FDA Inspectional Oversight, section 704 of the Federal Food,
Drug, and Cosmetic Act, and draft guidance for industry Conducting Remote Regulatory Assessments: Questions and
Answers.
2
Staff Manual Guide 9004.1, Policy and Procedures for Requesting Records in Advance of or in Lieu of a Drug
Inspection.
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PROGRAM 7356.843
and/or conformance with an application submission that a firm participates in voluntarily. 3 RIEs are
defined as FDA’s use of any combination of remote interactive tools (e.g., remote livestreaming
video of operations, teleconferences, screen sharing) to evaluate facilities where drugs are
manufactured, processed, packaged, or held. FDA may request to conduct an RIE whenever a
program office determines it is appropriate based on mission needs.
With regards to this compliance program, an RIE may be used in lieu of or in advance of a
postapproval inspection to evaluate marketed drug products manufactured under approved new drug
applications or abbreviated new drug applications or their associated active pharmaceutical
ingredients. During an inspection, FDA may collect copies of previously received documents and
other documents not previously requested.
3
See guidance for industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring
Facilities During the COVID-19 Public Health Emergency.
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来源：FDA Pharmaceutical Quality Documents · fda.gov