FDA 发布 7356.000 合规计划，规定 CDER 或 CDRH 主导组合产品的检查安排
Inspections of CDER-Led or CDRH-Led Combination Products (7356.000)
FDA 发布合规计划 7356.000，用于 CDER 或 CDRH 主导的单体式和共同包装组合产品生产场地的检查，文件签发与实施日期为 2020 年 6 月 4 日。该计划适用于上市前、上市后、监督、有因及其他基于风险的检查，重点说明基础 CGMP 加 21 CFR Part 4 指定条款的覆盖方式与报告要求。CBER 主导的组合产品不适用本计划，应参考 CBER 相应合规计划。
文件列出组合产品检查中基础 CGMP 与 21 CFR Part 4 指定条款的覆盖安排，可供核对检查类型与报告路径。
译文尚不完整，完整内容请切换到原文。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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美国食品药品监督管理局
合规计划 计划 7356.000
主题： 实施日期：
由 CDER 主导或 CDRH 主导的组合产品的检查 2020 年 6 月 4 日
数据报告
产品代码 产品/任务代码
使用适当的产品代码 使用基础合规计划的产品/任务代码
（见第 III.1.A 部分）
现场报告要求：
EIR（企业检查报告）和 FDA-483：应使用单一 EIR 以及（适用时）
FDA-483 记录在组合产品生产商1检查期间所做的所有观察
（见第 III.2 部分——报告）。遵循与牵头中心相关的
监管事务办公室（ORA）政策，例如，关于
是否对 483 进行注释以及检查惯例（另见参考文献 12，第 5 章）。
报告要求：按照组合产品基础合规计划的现场报告
要求以及本合规计划中确定的特定
预期，记录检查：
1. 对于根据简化新药申请（ANDA）或新药申请（NDA）获批的 CDER 主导组合产品的
批准前检查，按照合规计划
7346.832 的现场报告要求进行记录。对于根据生物制品许可申请（BLA）获批的 CDER 主导组合产品的
许可前检查，按照合规计划 7356.002M 的现场
报告要求进行记录。
2. 对于 CDRH 主导组合产品（上市前批准
（PMA））的批准前检查，按照合规
计划 7383.001 的现场报告要求进行记录。
3. 对于 CDER 主导的 NDA/ANDA 组合产品的监督性检查，按照
合规计划 7356.002 的现场报告要求进行记录。
对于 CDER 主导的 BLA 组合产品的监督性检查，按照
合规计划 7356.002M 的现场报告要求进行记录。
4. 对于 CDRH 主导组合产品的监督性检查，按照
合规计划 7382.845 的现场报告要求进行记录。
5. 关于其他具体的报告预期，见第 III.2 部分——报告。
与牵头中心的协调：如果在组合产品检查后考虑采取合规
措施，ORA 应在采取此类措施之前与牵头中心协调。
无论引用的是哪项现行药品生产质量管理规范（CGMP）
法规，都应联系牵头中心（例如，对于 CDRH 主导的产品，检查
仅产生药品 CGMP（21 CFR 第 211 部分）以及（如适用）21 CFR 第 600 部分
观察项，合规措施仍应通过 CDRH 协调）。
1
关于“牵头中心”以及本合规计划中通篇使用的其他斜体术语的讨论，见附件 C。
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鼓励检查员通过牵头中心申请检查前会议，以
就指令或方法达成一致。牵头中心
与 ORA 之间的沟通应按照 ORA 与该中心现有的流程进行。
CDER 牵头的组合产品使用 Profile Codes：对本计划中所述的
CDER 牵头的组合产品生产商的检查，应至少包含一个药品
profile code 和一个器械 profile code（例如，对生产
无菌灌装预充式注射器的设施进行检查时，使用 profile codes SVS——无菌灌装小容量注射剂
和 IDD——注射给药装置（注射器、自动注射器/注射笔））。另见参考文献 12，
Exhibit 5-14。
注：CBER 牵头的组合产品不在本合规计划范围内。对于
CBER 牵头的组合产品，请参阅 CBER 合规计划，网址为
https://www.fda.gov/vaccines-blood-biologics/enforcement-actions-cber/compliance-programs-
cber
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目录
第一部分 – 背景 ............................................................................................................ 4
组合产品 .......................................................................................................... 4
组合产品 CGMP ............................................................................................. 5
第二部分 - 实施.................................................................................................... 6
范围 .................................................................................................................................... 6
目标 .............................................................................................................................. 7
A. 方法 ...................................................................................................................... 7
B. 检查计划 ................................................................................................... 7
C. 人员 ...................................................................................................................... 9
项目管理说明. ..................................................................................... 9
第三部分 - 检查 ......................................................................................................... 9
运营 ............................................................................................................................ 9
A. 检查 .................................................................................................................... 9
报告............................................................................................................................ 19
第四部分 – 分析 ......................................................................................................... 20
第五部分 - 监管/行政策略 ................................................. 21
组合产品的批准前检查 ......................................................... 21
组合产品的监督性检查和基于风险的检查 ............ 22
与其他类型检查联合进行的批准前检查 ................ 22
21 CFR Part 4 中列明条款的重要发现 ............................ 22
第六部分 参考文献、附件和项目联系人 ........................ 24
参考文献 .......................................................................................................................... 24
附件 ....................................................................................................................... 24
项目联系人 ............................................................................................................... 24
第七部分 - 中心职责 ............................................................................... 25
附件 A – 21 CFR Part 211 中列明条款的组合产品检查考虑因素
..................................................................................................... 26
附件 B – 21 CFR Part 820 中列明条款的组合产品检查考虑因素
....................................................................................................................... 38
附件 C – 定义和缩略语 ......................................................................... 45
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第一部分 – 背景
2013年1月，FDA发布了一项关于组合产品现行药品生产质量管理规范（CGMP）2
要求的最终规则（21 CFR Part 4, Subpart A）。在该最终规则发布之前，已有CGMP法规
对药品、器械、生物制品以及人细胞、组织及基于细胞和组织的产品（HCT/Ps）确立了要求。
然而，当时没有任何法规来阐明和解释这些CGMP要求如何适用于组合产品。
该最终规则发布后，还附有一份最终指南文件《组合产品现行药品生产质量管理规范要求》
（参考文献9）。
组合产品
组合产品的定义。组合产品是由两种或更多不同类别的医疗产品（即药品与器械、药品与生物制品、
器械与生物制品，或三者兼有）组成的产品（见21 CFR 3.2(e)）。组合产品的组成部分是指
构成组合产品的药品、器械或生物制品。本合规计划重点关注两类组合产品：3
• 单一实体组合产品：各组成部分在物理或化学上
结合（例如，预充式注射器或药物洗脱支架）。见21 CFR 3.2(e)(1)。
• 联合包装组合产品：各组成部分包装在一起（例如，
含有器械和药品的手术包或急救包，与药品容器包装在一起的
给药装置）。见21 CFR 3.2(e)(2)。
组合产品的示例包括（另见示例清单）：
• 含有或与药品或生物制品包装在一起的预充式注射器、透皮系统、自动注射器
• 药物洗脱支架
• 涂覆/浸渍抗菌药物的植入物
• 已灌装的静脉注射（IV）袋
• 抗体药物偶联物
组合产品会被分配给某个FDA中心，由该中心对该组合产品的审评和监管拥有主要管辖权（即
牵头中心）。组合产品分配给牵头中心，依据的是哪个组成部分提供该组合产品的
主要作用方式（21 U.S.C. 351(g)）。一般而言，组合产品的申请类型（如有）
与牵头中心一致（例如，CDRH牵头的产品将
通过PMA/510(k)/De Novo获批或获准，而CDER牵头的组合产品
则通过ANDA/NDA/BLA获批）。一般而言，在需要时，牵头中心作为
与组合产品检查相关的外勤工作的主要联系点
2
见78 FR 4307。
3
还有第三类组合产品，即交叉标识组合产品，其各组成部分分别
销售（例如，光激活药品与单独销售的激光器、药物激活
装置的情况）（21 CFR 3.2(e)(3)、(4)）。交叉标识组合产品组成部分的生产商只需
遵守原本适用于该类产品的要求（例如，药品组成部分适用21 CFR Part 210和211，
器械组成部分适用21 CFR Part 820）。关于交叉标识组合产品的组成部分在同一设施生产时的
预期，另见脚注8。
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生产商。牵头中心将酌情协调 FDA 其他组织部门
（另见第 VII 部分——中心职责）。
组合产品 CGMP
对于单一实体组合产品和共同包装组合产品，21 CFR 第 4 部分
A 子部分确定了两种证明组合产品符合 CGMP 要求的方式：
1. 符合所有适用的 CGMP。证明符合组合产品中
所含各组成部分适用的所有 CGMP
法规，
或
2. 简化方法。对于同时包含药品和器械或生物制品和器械的组合产品，
实施简化方法，通过证明符合 (i) 药品 CGMP（21 CFR 第 210 和 211 部分）或器械
质量体系 (QS) 法规（21 CFR 第 820 部分）（基础 CGMP），以及 (ii) 同时符合
这两套 CGMP 要求中另一套的特定条款（称为“明确列出的条款”）。
关于适用于包含生物制品组成部分的组合产品的附加要求，见下文。
具体而言，简化方法允许组合产品生产商
通过设计和实施一套 CGMP 运行体系，证明符合以下任一要求，
从而同时满足药品 CGMP 和器械 QS 法规的要求：
• 依据 21 CFR 4.4(b)(1)，符合药品 CGMP 以及器械 QS
法规中以下明确列出的条款（基于药品 CGMP 的简化
方法）：
o 21 CFR 820.20 - 管理职责
o 21 CFR 820.30 - 设计控制（如适用）
o 21 CFR 820.50 - 采购控制
o 21 CFR 820.100 - 纠正和预防措施
o 21 CFR 820.170 - 安装（如适用）
o 21 CFR 820.200 - 服务（如适用）
或
• 依据 21 CFR 4.4(b)(2)，符合器械 QS 法规以及药品
CGMP 中以下明确列出的条款（基于器械 QS 法规的
简化方法）：
o 21 CFR 211.84 - 组份、药品
容器和密封件的检测及批准或拒收
o 21 CFR 211.103 - 收率计算
o 21 CFR 211.132 - 非处方 (OTC) 人用药品的
防篡改包装要求
o 21 CFR 211.137 - 有效期标注
o 21 CFR 211.165 - 检测和放行销售
o 21 CFR 211.166 - 稳定性试验
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o 21 CFR 211.167 - 特殊检测要求
o 21 CFR 211.170 - 留样
无论是否采用简化方法，此外，对于包含生物制品的组合产品，生产商必须证明其符合 21 CFR 第 600 至 680 部分（21 CFR 4.3(c)）中所有适用的生物制品 CGMP 要求（包括标准）。对于包含任何 HCT/P 的组合产品，生产商必须证明其符合 21 CFR 第 1271 部分中所有适用的法规。
第二部分 - 实施
范围
本合规程序侧重于对 CDER 或 CDRH 主导4 的单一实体和共包装成品组合产品（包含药物和器械或生物制品和器械组成部分）的组合产品生产商（见附件 C 中的定义）的检查，并有限地参考了包含生物制品或人类细胞、组织或基于细胞或组织的产品（HCT/P）组成部分的组合产品的检查考虑因素。本合规程序应用于批准前、批准后、监督、有因检查及其他基于风险的检查。5 本合规程序不涵盖 CBER 为主导中心的组合产品的检查。6
本组合产品合规程序不应用于：
1. 仅生产7 组合产品一种类型组成部分（例如，仅药物、器械或生物制品）的设施。此类设施应根据该产品现有的特定商品合规程序进行检查（见附件 C 以及关于交叉标识组合产品的脚注 3）。例如，如果某设施仅生产药物组成部分，然后将其送至另一设施灌装到注射器中，则生产药物组成部分以运至灌装设施的设施将根据相应的药物合规程序进行检查；而本组合产品合规程序将用于检查将药物组成部分灌装到注射器中以生产单一实体组合产品的设施。8
4
使用术语“CDRH 主导”或“CDER 主导”是指哪个中心是该组合产品的主导中心。
5
第三方审计、评估或检查计划（例如，医疗器械单一审核程序（MDSAP））可能会影响本合规程序的实施。如有疑问，请联系主导中心。
6
对于 CBER 监管的产品，请参阅 CBER 合规程序，网址为 https://www.fda.gov/vaccines-
blood-biologics/enforcement-actions-cber/compliance-programs-cber。CBER 将酌情与其他中心协商，以评估组合产品的检查观察结果。见 SMG 4101 中心间咨询请求流程。
7
请注意，“生产”包括与组合产品设计相关的活动（21 CFR 4.2）。任何参与组合产品设计控制（包括记录保存）的设施均为组合产品生产商。见参考文献 9 的第 III.C 节和本合规程序的附件 C。
8
如组合产品 CGMP 指南（参考文献 9）所述，对于在同一设施生产的交叉标识组合产品，本局不打算反对对该组合产品的生产使用简化的 CGMP 运行体系，而非对该设施正在进行的每种组成部分的生产使用不同的体系。如果在检查期间遇到此类情况，请联系主导中心。另见脚注 3。
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2. 仅生产“组分9”的设施。21 CFR Part 4 不改变针对组分生产商的 CGMP
监管要求。仅生产
器械组分的设施不受 QS 法规（21 CFR 820.1(a)）约束，同样，
原料药、其他组分（例如辅料）
或药品的容器/密封件10 的生产商也不受 21 CFR Part 211 约束（尽管此类
生产商须遵守 FD&C 法案第 501 条（21 U.S.C. 351）下的法定 CGMP 要求）。
然而，将组分组装成
组合产品的设施须遵守组合产品 CGMP，并属于
本合规计划的范围。
目标
本合规计划的目标是提供一个框架，用于对
单一实体和联合包装组合产品生产设施进行检查。本合规
计划依赖药品、器械和生物制品特定合规计划中
相关的 CGMP 检查流程，并处理组合产品特有的
考虑事项。
A. 方法
通常，牵头中心和基础合规
计划的检查与行政实践将作为组合产品检查的基础。然而，本合规计划
中概述的方法还广泛依赖与组合产品
组成部分相关的其他品类特定合规计划（见第三部分——检查），
以指导组合产品检查的实施。
由于大多数组合产品生产商采用简化方法，本合规
计划侧重于检查对基础 CGMP 以及 21 CFR Part 4 中
所列特定条款的符合情况。
B. 检查计划
对于监督性检查，监管事务办公室（ORA）下属的医疗器械与放射健康运营办公室
（OMDRHO）、生物制品运营办公室（OBPO）和药品
质量运营办公室（OPQO）将比较
组合产品的工作计划任务，并将利用基于风险的
产品评估和生产复杂性评估来确定各计划的角色。
对于除 BLA 以外的批准前检查，与牵头中心一致的 ORA 计划
将主导检查。例如，对于 CDER 牵头的 NDA 批准前检查
9
根据药品 CGMP，“组分”定义为“任何拟用于生产药品
的原料，包括可能不会出现在该药品中的原料。”（21 CFR 210.3）。根据器械 QS
法规，“组分”一词定义为“任何拟作为已成品、已包装和已贴标器械的一部分
纳入的原材料、物质、件、零件、软件、固件、
标签或组件。”（21
CFR 820.3(c)）。
10
如果容器/密封件作为成品器械提供，则生产该器械的设施将
受 21 CFR Part 820 要求约束。
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产品，OPQO 将作为检查的主导方。对于 CDER 主导的 BLA 许可前检查，CDER 将作为检查的主导方。
鼓励检查员通过主导中心申请检查前会议，以统一指令或方法。这些会议可通过检查任务联系人（如有）申请，或使用第 VI.3 部分——项目联系人中的联系方式。11
如果尚未获得，检查员应在检查前向主导中心申请以下信息，和/或在检查为预先通知时向企业申请。组合产品的申请持有人对组合产品 CGMP 负有并保持全面责任，并应能够描述在参与组合产品生产的每个设施中如何满足所有适用的 CGMP。如果以下信息无法在检查前获得，则应在检查早期予以处理。
• CGMP 运行体系方法。确定组合产品制造商所选择的 CGMP 运行体系。大多数组合产品制造商选择遵循与主导中心/申请类型一致的简化方法（例如，根据 PMA 批准的组合产品通常遵循基于 QS 法规的简化方法，符合所有 21 CFR Part 820 要求以及药品 CGMP 中指定的明确条款）。然而，无论申请类型如何，组合产品制造商都可以选择遵循任一简化方法或全面合规。
• 实体之间的关系。申请有关参与组合产品生产的设施（包括设计活动，另见脚注 7）的信息，以及被检查设施的 CGMP 职责范围。组合产品的 CGMP 活动可能在多个设施进行。例如，如果另一场所负责组合产品的设计控制（例如，与组合产品制造商签约并具有文件化设计责任的规格开发者），则在该另一场所进行额外检查可能更高效或必要。检查期间确定的有关职责的额外信息或澄清应反馈给主导中心。
• 文件的可用性。对于预先通知的检查，确认检查期间审查所需的文件将在被检查场所可用或可获取。文件应包括能够审查明确条款合规性的材料，包括在设施 CGMP 运行体系的相关、更广泛要素中何处可找到与明确条款有关的考虑内容（参见例如附件 A，关于扩充 21 CFR 820.80 验收活动以满足 21 CFR 211.84 要求的讨论）。
11
如果在检查准备期间或检查期间，检查员认为某产品可能是未被如此识别的组合产品，检查员可联系组合产品办公室（[email protected]）寻求协助。
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C. 人员
本合规程序所述涵盖两套 CGMP 体系的组合产品检查，可由双程序人员配置（例如，一名药品检查员和一名器械检查员）实施，或由在组合产品 CGMP 方面受过培训并具有经验的检查员实施。无论组合产品检查的人员配置如何，检查都将按照本合规程序中所述的方法进行。
程序管理说明。
由 CDER 主导和由 CDRH 主导的组合产品检查，应按照本合规程序中的说明，使用所述特定品类合规程序（例如，药品、生物制品和器械）中的内容进行。本合规程序描述了针对参与组合产品生产的设施特有的检查考虑事项。例如，第三部分——检查描述了组合产品生产商的全面检查和简化检查选项，这些选项不同于仅药品或仅器械设施检查的选项。
在适当情况下，牵头中心将通过既定的信息沟通机制，传达检查需涵盖或重点关注的任何特定产品。
现场与各中心之间就组合产品检查进行的任何互动，都应包括牵头中心。牵头中心将根据需要，吸纳包括其他中心在内的其他机构部门的专业知识，包括支持对检查发现的审核（见第七部分——中心职责）。
第三部分——检查
运营
A. 检查
检查期间的组合产品 CGMP 覆盖范围。如下文所述，组合产品检查期间 CGMP 的覆盖范围取决于检查类型、基础 CGMP、设施生产活动的范围、牵头中心提供的检查说明，以及被检查产品的申请类型。鼓励检查员通过牵头中心和 ORA 主管人员申请检查前会议，以讨论检查覆盖范围、中心说明或本合规程序中所述的方法。可通过检查请求中提供的联系方式（如有）与牵头中心沟通，或使用第六部分第 3 节——程序联系人中的联系人。
有些设施仅参与组合产品 CGMP 活动的一小部分（例如，仅管理组合产品设计活动的设施，或仅对组合产品进行灭菌的设施）。检查覆盖范围应针对该设施所发生的那些 CGMP 活动。如果对哪个设施负责特定 CGMP 要求存在疑问，请联系牵头中心寻求帮助。
组合产品 CGMP 检查的方法。下文所述的检查方法包括：(i) 根据与基础 CGMP 和检查类型相关的特定品类合规程序进行检查（即，根据基础合规
发布日期：2020 年 6 月 4 日 第 9 页，共 46 页
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program) plus (ii) coverage of the relevant called-out provisions of 21 CFR Part 4 (see PART
II.2 - Objective above).
Base CGMPs. Use of inspectional elements from the base program should include
evaluation of CGMP considerations for the combination product as a whole. For
example, during coverage of the production system at a facility that uses a drug CGMP-
based streamlined approach, the investigator should evaluate production and process
controls as directed in the associated drug compliance program. This evaluation should
include evaluation of production and process controls for each constituent part and the
combination product. Any observations related to these types of controls would be
deficiencies in the 21 CFR Part 211 requirements (e.g., 21 CFR 211, Subpart F).
Conversely, for a facility that uses a device QS-based streamlined approach, the
investigator should evaluate production and process controls for the constituent parts and
the combination product as directed in the associated device compliance program. Any
observations related to these types of controls would be deficiencies in the 21 CFR Part
820 requirements (e.g., 21 CFR 820.70, 820.72, 820.75).
Called-out Provisions. Regarding called-out provisions (covered as described in Table 1
or Table 2 below), any observations related to these provisions would be deficiencies
against the associated 21 CFR Part 820 or 21 CFR Part 211 requirements. Additional
information on combination product inspectional considerations for called-out provisions
is contained in Attachment A and Attachment B.
Other Inspectional Considerations for Combination Products: When conducting inspections of a
combination product manufacturer, consider:
• The terminology (for example the definitions used in different quality system or
regulatory documents) used by combination product manufacturers may vary (e.g.,
because they otherwise manufacture drugs or devices). Terminology differences should
not be the basis of 483-observations as long as the combination product manufacturer
can explain how their practices meet the requirements of the CGMP regulations
applicable to the facility.
• FDA has signaled some flexibility in the CGMP approach for combination products in
areas including testing and release for distribution (21 CFR 211.165), stability testing (21
CFR 211.166), special testing requirements (21 CFR 211.167), reserve samples (21 CFR
211.170), and design controls (21 CFR 820.30). See Reference 9. If a combination
product manufacturer is using such approaches, appropriate evidence and an explanation
of the rationale to support the approach should be accessible for review during facility
inspections.
NOTE: If during an inspection an investigator identifies potential problems related to
registration and listing, the investigator should contact the lead center for assistance. The
investigator should contact ORA supervisory staff if there are any questions about combination
product District Use Codes (DUCs) for a facility.
(1) Pre-Approval Inspections
Pre-announcement will typically apply to pre-approval inspections for ANDA/NDA/PMA
combination products, consistent with the ORA inspectional process for the lead center (see also
Reference 12). Pre-licensing inspections for CDER-led BLAs are also typically preannounced.
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For combination product pre-approval inspections, the focus of the inspection should be on the
combination product for which marketing approval is sought. Follow any inspectional guidance
provided by the center(s), which will specify the coverage to be conducted during the pre-
approval inspection. When coverage of both the base CGMPs and called-out provisions is
specified, the base compliance program should be used to conduct the inspection, with
additional inspectional coverage of the called-out provisions as specified in Table 1. Process
validation coverage, including what process validation activities are expected to be complete at
the time of the pre-approval inspection, will be communicated from the lead center. If there are
questions on expectations for process validation, contact the lead center for assistance.
Generally, combination product manufacturers use a streamlined approach with base CGMPs
that align with the application type for which pre-approval is sought (e.g., a drug CGMP-based
streamlined approach for an NDA or ANDA, or a device QS regulation-based streamlined
approach for a PMA). Although this is the most common situation, it is also acceptable for a
combination product manufacturer to choose to operate under the other streamlined approach
(e.g., a manufacturer for a PMA combination product could choose to operate under a drug
CGMP-based streamlined approach). In these situations, the lead center will provide additional
information or instruction in pre-inspectional meetings as necessary, and the coverage may differ
from Table 1. If there are questions regarding coverage, the investigator should consult with
ORA supervisory staff and the lead center, as appropriate.
NOTE: If a facility indicates that their combination product CGMP operating system is
compliant with 21 CFR Part 820 and 21 CFR Part 211 in their entirety, conduct the inspection
consistent with the approach for the combination product’s application type as shown in Table 1.
For example, if the pre-approval inspection is for a PMA, follow the inspection approach
outlined for a PMA.
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Table 1. General Approach to Pre-Approval Inspection Coverage for Combination Product
Manufacturing Facilities
Application
Type for
Pre-Approval Base Base Compliance Additional Coverage of Called-out
Inspection CGMPs Program Provisions
NDA/BLA12/ Drug 7346.83213 Cover the following requirements in
ANDA CGMP (NDA/ANDA) accordance with Attachment B:
(21 CFR Management Controls (21 CFR 820.20)
Part 211) 7356.002M
7356.002A (BLA) Design Controls (21 CFR 820.30)
Purchasing Controls (21 CFR 820.50)
CAPA (21 CFR 820.100)
Installation (21 CFR 820.170) and/or
Servicing (21 CFR 820.200), if
appropriate14
NOTE: If the combination product includes a
CBER-regulated biological product or an
HCT/P,15 follow the relevant inspectional
instructions and compliance programs (see
Compliance Program 7345.848 and
Compliance Program 7341.002) or contact
ORA supervisory staff and the lead center for
assistance.
12
CDER-led combination products that include a biological product constituent part are subject to both the drug
CGMPs in 21 CFR Part 210 and 211 and the applicable CGMP requirements for biological products (including
standards) found in 21 CFR Parts 600 through 680. As such, a manufacturer using a drug CGMP-based streamlined
approach for such a combination product is subject to all of the requirements in 21 CFR Parts 210, 211, and 600
through 680 (as well as the called-out provisions of 21 CFR Part 820 if the combination product includes a device
constituent part). See also PART I.2 – Combination Products CGMPs.
13
Compliance Program 7346.832 is the general pre-approval inspection program for drugs. Other compliance
programs, such as Compliance Program 7356.002A for Sterile Drugs should also be used, as applicable.
14
Coverage of installation (21 CFR 820.170) and servicing (21 CFR 820.200) requirements and tamper-evident
packaging requirements (21 CFR 211.132) should be included only for those products for which the requirements
apply (i.e., combination products that require installation and servicing or OTC combination products, respectively).
15
Biological products and biologic-led combination products are assigned to either CBER or CDER, depending on
the type of biological product (see https://www.fda.gov/about-fda/about-center-biologics-evaluation-and-research-
cber/transfer-therapeutic-products-center-drug-evaluation-and-research-cder).
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Application
Type for
Pre-Approval Base Base Compliance Additional Coverage of Called-out
Inspection CGMPs Program Provisions
PMA Device 7383.001 Cover the following requirements in
QS accordance with Attachment A:
(21 CFR Testing and approval or rejection of
Part 820) components, drug product containers, and
closures (21 CFR 211.84)
Calculation of yield (21 CFR 211.103)
Tamper-evident packaging requirements
for over-the-counter (OTC) human drug
products (21 CFR 211.132)14
Expiration dating (21 CFR 211.137)
Testing and release for distribution
(21 CFR 211.165)
Stability testing (21 CFR 211.166)
Special testing requirements
(21 CFR 211.167)
Reserve samples (21 CFR 211.170)
NOTE: If the combination product includes a
biological product or an HCT/P,15 follow the
relevant inspectional instructions and
compliance programs (for CDER-led
biological products see Compliance Program
7356.002M, for CBER-led HCT/Ps see
Compliance Program 7341.002 and for CBER-
led biological products see Compliance
Program 7345.848) or contact ORA
supervisory staff and the lead center for
assistance.
(2) Surveillance Inspections
Pre-announcement will apply to surveillance inspections, as appropriate, consistent with the
process for the base compliance program. For surveillance inspections where combination
product coverage is conducted, investigators should prioritize combination products recently
approved, cleared, or significantly changed (in terms of design) or those that include complex
technology or manufacturing considerations. This applies unless there are indicators that there
are safety and effectiveness concerns with other products. In all cases, coverage should include
review of complaint trends to identify any potentially significant defects for inspectional
scrutiny.
Abbreviated Inspections. Abbreviated inspections are generally used when the facility has a
record of satisfactory CGMP compliance with no significant product defect incidents (including
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significant Field Alert Reports (FARs), biological product deviation reports (BPDRs), medical
device reports (MDRs), safety alerts, or recalls). See also Compliance Program 7356.002 and
Compliance Program 7382.845.
Abbreviated inspections should typically not be used if:
• The facility has a history of non-compliance, recent product quality problems, complaint-
handling issues, or significant defect issues, recalls, quality related consumer complaints,
failure to meet specifications, potency failures, impurity failures and/or newly discovered
impurities
• There have been significant changes in management or organization procedures (e.g., a
change in ownership)
• New technologies or equipment requiring new expertise have been implemented since the
previous inspection
An abbreviated inspection for a combination product manufacturer may be conducted in one of
two ways, depending on whether the facility has previously been inspected against the called-out
provisions:
1) Abbreviated Base Plus Full Call-outs (Abbreviated coverage of ONLY the base CGMPs
plus FULL coverage of all the called-out provisions): The Abbreviated Base Plus All
Call-outs option is appropriate when the facility has a record of satisfactory CGMP
compliance and no significant product quality issues but has never been inspected against
the called-out provisions. The abbreviated coverage applies only to the base CGMPs and
the abbreviated coverage is consistent with the underlying compliance program for the
base CGMPs. See Table 2.
2) Abbreviated Base and Abbreviated Call-outs (Abbreviated coverage of the base CGMPs
AND abbreviated coverage of the called-out provisions): The Abbreviated Base and
Abbreviated Call-outs option is appropriate when the facility has a record of satisfactory
CGMP compliance, has been inspected against the called-out provisions, and has had no
significant product quality issues. The abbreviated coverage applies to the base CGMPs
and the called-out provisions. See Table 2.
During an abbreviated inspection, verification of overall quality system activities may warrant
additional coverage in other systems. For example, for CDRH-led combination products, when
the facility manufactures a sterile drug constituent part and/or combination product, coverage of
related critical production and process control elements should be considered (see also
Compliance Program 7356.002A).
An Abbreviated Inspection may change to a Comprehensive (Full) Inspection upon findings of
objectionable conditions (see PART V – REGULATORY/ADMINISTRATIVE STRATEGY)
with ORA division concurrence.
Comprehensive (Full)16 inspections. Comprehensive (Full) inspections will be performed as
resources permit, based on a risk-based determination:
• For the first inspection of a combination product manufacturer (e.g., an initial inspection)
16
The terms “Comprehensive” and “Full” for purposes of this compliance program are equivalent. Because the
underlying compliance programs for devices and drugs, respectively, use these terms, they are both included for
completeness.
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• For the initial coverage of called-out provisions after introduction of combination product
manufacturing operations to a facility that previously manufactured only a drug, device,
or biological product.
• When directed by the assignment
• For CDRH-led combination product foreign inspections
• When an inspection, started as an abbreviated inspection, reveals postmarket information
or objectionable conditions (see PART V – REGULATORY/ADMINISTRATIVE
STRATEGY) that cannot be adequately assessed in abbreviated inspectional coverage
Conduct abbreviated and full inspections consistent with the row of Table 2 for the base CGMPs
in use at the facility.
NOTE: If a facility indicates that the combination product CGMP operating system is compliant
with 21 CFR Part 820 and 21 CFR Part 211 in their entirety, conduct the inspection described in
Table 2 for the base CGMPs that align with the application type(s) of the combination product(s)
being covered during the inspection. For example, if the inspectional coverage is of NDA
approved combination products, follow the inspection approach outlined for “Drug CGMP-
Based.” If the inspectional coverage if for PMA approved or 510(k) cleared combination
products, follow the inspectional approach outlined for “Device QS-Based.”
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Table 2. General Approach to Surveillance Inspectional Coverage for Combination Product
Manufacturing Facilities
Base Compliance
Base CGMPs Program Additional Coverage of Called-out Provisions
Drug CGMP- 7356.00217 For Comprehensive (full) AND for Abbreviated Base
Based (NDA/ANDA) Plus Full Call-outs inspections, cover in accordance
(21 CFR 211) with Attachment B:
7356.002M18
• Management Controls (21 CFR 820.20)
7356.002A
• Design Controls (21 CFR 820.30), if applicable
(BLAs)
• Purchasing Controls (21 FR 820.50)
• CAPA (21 CFR 820.100)
• Installation (21 CFR 820.170) or Servicing (21
CFR 820.200), if applicable14
For Abbreviated Base and Abbreviated Call Outs
inspections, cover in accordance with Attachment B:
• Design Controls (21 CFR 820.30), if applicable
• CAPA (21 CFR 820.100)
• Purchasing Controls (21 CFR 820.50)
NOTE: If the combination product includes a CBER-
regulated biological product or an HCT/P15, follow the
relevant inspectional instructions and compliance programs
(see Compliance Program 7345.848 and Compliance
Program 7341.002) or contact ORA supervisory staff and the
lead center for assistance.
17
Compliance Program 7356.002 is the general inspection program for drugs. Other compliance programs, such as
Compliance Program 7356.002A for Sterile Drugs should also be used, as applicable.
18
Compliance Program 7356.002M for inspections of licensed therapeutic biological products does not distinguish
between full and abbreviated coverage. For surveillance inspections for combination products that contain a
therapeutic biological product either full or abbreviated coverage of the call-outs may be used based on the
inspectional history and other factors as discussed in the “Abbreviated Inspections” section above.
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Base Compliance
Base CGMPs Program Additional Coverage of Called-out Provisions
Device QS- 7382.84519 For Comprehensive (full) AND for Abbreviated Base
Based Plus Full Call-outs inspections, cover in accordance
(21 CFR Part with Attachment A:
820) Materials System:
• Testing and approval or rejection of
components, drug product containers, and
closures (21 CFR 211.84)
Laboratory Controls System:
• Testing and release for distribution (21 CFR
211.165)
• Stability testing (21 CFR 211.166)
• Special testing requirements (21 CFR 211.167),
if applicable
• Reserve samples (21 CFR 211.170)
Production System
• Calculation of yield (21 CFR 211.103)
Packaging and Labeling System
• Tamper-evident packaging requirements for
over-the-counter (OTC) human drug products
(21 CFR 211.132), if applicable14
• Expiration Dating (21 CFR 211.137)
For Abbreviated Base and Abbreviated Call Outs
inspections, cover in accordance with Attachment A:
Laboratory Controls System:
• Testing and release for distribution (21 CFR
211.165)
• Stability testing (21 CFR 211.166)
• Special testing requirements (21 CFR 211.167),
if applicable
• Reserve samples (21 CFR 211.170)
NOTE: If the combination product includes a biological
product or an HCT/P, follow the relevant inspectional
instructions and compliance programs (for CDER-led
biological products see Compliance Program 7356.002M,
for CBER-led HCT/Ps see Compliance Program 7341.002,
and for CBER-led biological products see Compliance
Program 7345.848) or contact ORA supervisory staff and the
lead center for assistance.15
19
See also Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing
Practices Regulations.
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(3) For Cause and Risk-Based Inspections
These inspections are carried out in response to information that raises questions or concerns
about a combination product or a facility that manufactures a combination product. These
inspections are usually initiated at the request of the lead center for the combination product. The
inspectional assignment provided by the lead center will outline coverage. These assignments
are typically conducted to address specific issues (e.g., adequate implementation of corrective
actions to address observations from previous inspections, or in response to specific events such
as adverse events, complaints, FARs, BPDRs, or recalls).
For Cause inspections may require additional center expertise, especially for more complex
products or when investigating apparent defects that could pose a significant health hazard.
These inspections may not require coverage of all constituent parts and/or CGMP requirements
that apply to the combination product. When such inspections are related to called-out provisions
from 21 CFR Part 4, refer to Attachments A and Attachment B as resources for combination
product inspectional considerations.
(4) Post-approval / Postmarket Inspections
Post-approval/Postmarket 20 inspections may be conducted for combination products to confirm
continued compliance, including monitoring changes in the manufacturing processes that occur
after product approval.
For both CDER-led and CDRH-led combination product post-approval/postmarket inspections,
inspectional coverage should include assessment of the combination product and not just a
constituent part, as appropriate. For example, if process validation for the specific combination
product is covered during the inspection, process validation for any device, drug, or combination
product manufacturing processes occurring at the facility should be assessed. If necessary, based
on significant findings during a post-approval/postmarket inspection for a specific combination
product, the scope of the inspection may be expanded.
For CDER-led combination products, post-approval inspections will be conducted consistent
with Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A
Concept of Operations, an agreement established between CDER and ORA in 2017. Post-
approval inspections largely focus on the process validation lifecycle, change management,
changes submitted to the application, and the execution of supporting activities per application
commitments and CGMP requirements. Coverage of combination product CGMP requirements
will be described in the related inspectional assignment.
For CDRH-led combination products, PMA postmarket inspections will be conducted consistent
with Compliance Program 7383.001and coverage of combination product CGMP requirements
aligns with Table 1 above.
(5) Special Situations – Combination Product “Convenience Kit” Manufacturers
Some facilities may assemble combination product “convenience kits.”21 These are kits that
include only constituent parts that 1) are already legally marketed independently, and
20
The terms “Post-approval” and “Postmarket” are used consistent with the terminology in the underlying
compliance programs for drugs and devices, respectively.
21
The term “convenience kits” is used in other documents for other types of kits. The definition of convenience kits
in this Compliance Program is specific to combination product convenience kits (see also Reference 9, Section
VI.1).
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2) packaged in the kit consistent with how they are independently marketed (i.e., cannot include
a change to the intended use of any of the constituent parts). Combination product convenience
kit manufacturers only need to demonstrate compliance with applicable CGMP requirements
with respect to the assembly, packaging, labeling, sterilization, and further processing of the kit
itself, including purchasing controls.
If an investigator has questions about whether a combination product is a convenience kit and
what CGMP requirements apply, they should contact the lead center or Office of Combination
Products (OCP) for assistance (see PART VI.3 - Program Contacts). During review of Corrective
and Preventive Action (CAPA) and complaints for a purported convenience kit, if there are
1) indicators of safety issues or 2) other concerns that suggest a change in intended use for any
constituent part(s) as compared to the use(s) for which the constituent part(s) is legally marketed
independently, the investigator should collect supporting documents, including any instructions
for use, inserts, other product labeling, and evidence of interstate commerce for the combination
product and constituent parts. Document the content of the kit and contact the lead center for
assistance.
(6) Special Situations – Device Constituent Part Exempt from the device QS-
regulations
FDA has exempted some devices from all or certain provisions of the device QS regulations
(including Design Controls). This is not a consideration relevant to most types of devices that
may be used as constituent parts of combination products. However, if such an exemption
applies to a device type, it is also considered to apply to device constituent parts and, thereby, to
the combination products of which they are a part in cases where the device constituent part in
the combination product is of that same type (i.e., it does not have a new intended use and does
not otherwise raise different device performance-related safety and/or effectiveness questions). If
the exemptions for a device constituent part of a drug-device combination product cover all of the
21 CFR Part 820 provisions included in 21 CFR 4.4(b)(1), then the Agency will consider the
combination product manufacturer CGMP compliant so long as the CGMP operating system is
compliant with 21 CFR Part 211 (no demonstration of compliance with 21 CFR Part 820 will be
necessary). See also Reference 9.
Many devices commonly used in combination products such as syringes, autoinjectors, and
metered dose inhalers are NOT exempt. Examples of device types that may be exempt include
medicine cups and oral dosing devices such as droppers and oral syringes. If a combination
product manufacturer claims that the device constituent part and/or their combination product is
exempt from 21 CFR 820 requirements, any investigator with concerns should contact the lead
center.
Reporting
A single EIR and, when applicable, FDA 483 should be used to document all observations made
at a combination product manufacturer.
Compliance with base compliance program reporting requirements. Documentation of the
inspection should be in accordance with the reporting requirements of the base compliance
program for the combination product (see FIELD REPORTING REQUIREMENTS on the cover
page of this Compliance Program).
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Additional reporting requirements. In addition to complying with the base compliance program
reporting requirements, the EIR should include information on:
• The CGMP operating system in use at the facility for the combination product (e.g., Drug
CGMP-based streamlined approach, Device QS-based streamlined approach, or full
compliance with all drug CGMPs and device QS regulation requirements).
• A description of the manufacturing activities (including design activities, if applicable)
occurring at the facility inspected. Also describe the relationship between the facility
being inspected and other facilities that supply constituent parts or components thereof
and/or perform combination product manufacturing activities (see footnote 7). For
example, if the inspected facility is the contract manufacturer for the combination
product, but a separate facility maintains the Design History File (DHF) and handles
complaints, this should be documented in the EIR.
• Collect the evidence and samples necessary to support each observation including, where
necessary, both specific examples and related procedures. For example, if an observation
is made against the CAPA system, collect a copy of the overall CAPA procedure for the
facility in addition to collecting evidence regarding the example(s) of failure to establish
and/or maintain a CAPA system.
Citations. If a combination product manufacturer is operating under a streamlined approach,
citations should ONLY be to provisions of the base CGMPs and to the relevant called-out
provisions from the other CGMP system (e.g., for a drug-CGMP streamlined approach, citations
should be limited to 21 CFR Part 211 and the called-out provisions from 21 CFR Part 820.
Citations should not be made to other provisions of 21 CFR Part 820 that are not called-out).
Note: Observations on the FDA 483 should be limited to those related to the adequacy of, and
adherence to, the procedures and/or controls established by the firm. Do not place observations
on the FDA 483 that concern the adequacy, safety, or efficacy of a particular design. Any such
concerns should be noted in the EIR and flagged for review by the lead center. See also
Compliance Program 7382.845 “Special Instructions Concerning Design Controls.”
PART IV – ANALYTICAL
Refer to PART IV of the applicable compliance programs for discussion of sampling and
analytical testing:
• Compliance Program 7346.832 for pre-approval inspections for CDER-led combination
products
• Compliance Program 7356.002 for surveillance inspections of CDER-led combination
products
• Compliance Program 7382.845 for surveillance inspections of CDRH-led combination
products
• Compliance Program 7383.001 for pre-approval and postmarket inspections for CDRH-
led combination products
If there are questions on sampling or analytical testing, contact the lead center for assistance.
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PART V - REGULATORY/ADMINISTRATIVE STRATEGY
The risks and intended use of the combination product and the potential adverse effect of the
CGMP deviations on the finished combination product must be considered when determining the
appropriate action needed.
Official Action Indicated-OAI. The field (ORA division (OMPTO, OPQO or OMDRHO))
submits a recommendation for regulatory action (OAI) to the lead center when a judgment is
made that the combination product manufacturer is not operating in a state of control and
management is unwilling or unable to make adequate corrective actions in an appropriate
timeframe. See also PART V.2 and PART V.4 below.
Voluntary Action Indicated-VAI. If the nature of the CGMP deviations poses minimal risks
when considered in relation to the risks and intended use of the product and there is not a history
of repeat observation(s), the recommendation should normally be voluntary corrections by the
firm (VAI). When voluntary action to address observation(s) identified during a previous
inspection is not accomplished or when the deviations observed pose a serious risk to the
consumer, then regulatory and/or administrative action should be recommended.
The procedures for developing recommendations and determining the need for regulatory action
following an inspection are conducted consistent with the established process within and
between ORA and the lead center. The lead center process should be used regardless of the
types of observations (e.g., for a CDER-led product, even if the recommendation for regulatory
action is based on 21 CFR Part 820 observations, the recommendation should be managed
consistent with the CDER process). See also PART VII-CENTER RESPONSIBILITIES.
Pre-approval Inspections for Combination Products
FDA expects that a combination product manufacturer is compliant with the requirements in
21 CFR Part 4 at the time of a pre-approval inspection. After a pre-approval inspection for a
combination product manufacturer, the inspection team makes an initial recommendation to the
lead center through the Establishment Inspection Report (EIR) endorsement to approve or
withhold the application approval based on the outcome of the establishment inspection.
Significant observations from either the base CGMPs22 or called-out provisions (see PART V.4
below) should be equally considered when making a recommendation to approve or withhold.
The lead center classifies the inspection after consideration of recommendations from the
consulted center, as applicable (see PART V.3 below and also PART VII – CENTER
RESPONSIBILITIES).
22
As discussed in PART III.1.A – Inspections, inspectional elements from the base compliance program should
include evaluation of CGMP considerations for the combination product as a whole. As such, significant
observations from the base CGMPs may involve any type of constituent part or the combination product as a whole,
as appropriate. For example, under a drug-CGMP based streamlined approach, significant deficiencies related to
production and process controls for a device constituent part, drug constituent part, or the combination product as a
whole would be cited under the base CGMPs (21 CFR Part 211).
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Surveillance Inspections and Risk-Based Inspections for Combination Products
Inspection findings that demonstrate significant CGMP deficiencies or repetition of deficiencies
identified in previous inspections, in relation to either the base CGMPs22 or called-out
provisions (see PART V.4 below), are bases for an inspection being recommended as OAI.
Inspections for Pre-approval in Conjunction with Another Type of Inspection
Combination product pre-approval inspections may be conducted in conjunction with another
type of inspection that involves commercially-marketed product(s) (e.g., a pre-approval
inspection conducted in conjunction with a surveillance inspection). Separate recommendations
and associated actions may occur in these cases, as appropriate. For example, if significant
findings result in a withhold decision for the pre-approval inspection and the findings extend
beyond the pre-approval combination product, regulatory and/or administrative actions (such as
issuance of a Warning Letter) may also be taken after coordinating with the lead center.
Significant Findings from the Called-out Provisions of 21 CFR Part 4
For combination product inspections, significant findings relating to the called-out provisions
(in addition to the base CGMPs) should be considered when determining the division
recommendation as explained below.
General Considerations. Regardless of the CGMP operating system for a combination product
facility, non-correction of significant findings from previous inspections or repeat findings of
the same or similar type as those observed on previous inspections (repeat observations) are
significant findings.
Drug CGMP-Based Streamlined Approach. For a facility using a drug CGMP-based streamlined
approach, in addition to the significant findings identified in the base compliance program, the
following are examples of significant findings from the called-out provisions of the device QS
regulation that could warrant an ORA division recommendation23 to withhold approval or OAI
(the following is not intended to be an exhaustive list):
1. Existence of combination products that do not meet the manufacturer’s specifications
and/or the applicable CGMP requirements in the 21 CFR Part 4 regulation and were not
adequately addressed by the CAPA process.
2. Failure to adequately define, document, or implement Quality System Regulation
requirements that apply to combination product facilities under 21 CFR Part 4, Subpart
A. Consistent with Compliance Program 7382.845, examples include, where required:
a. No procedure(s) that address corrective and preventive action (21 CFR 820.100)
b. No procedure(s) on how quality data will be analyzed and used
(21 CFR 820.100(a)(1))
c. Where design controls are required, no design controls procedure(s) for the
combination product (21 CFR 820.30)
23
Note that for CDER-led pre-license BLA inspections, CDER is the lead for the inspection and the inspection team
submits this initial recommendation.
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d. Where design controls are required, no design change control procedure(s)
(21 CFR 820.30(i))
e. No purchasing control procedure(s) (21 CFR 820.50)
Device QS Regulation-Based Streamlined Approach. For a facility using a device QS
Regulation-based streamlined approach, in addition to significant findings identified in the base
compliance program, the following are examples of significant findings from the called-out
provisions from the drug CGMPs that could warrant an ORA division recommendation to
withhold approval or OAI (the following is not intended to be an exhaustive list):
1. Significant data integrity problems, including misrepresented data or other conditions as
related to the called-out provisions of 21 CFR Part 211. Issues related to data integrity
should typically be cited under the related 21 CFR Part 211 called-out provision with
associated discussion in the EIR narrative.
2. Incomplete or unsuccessful analytical method validation or verification for testing
methods used to comply with called-out provisions of 21 CFR Part 211 for the drug
constituent part and/or the combination product (e.g., testing methods used for stability
(21 CFR 211.166), sterility/final release testing (21 CFR 211.165, 21 CFR 211.167),
testing of reserve samples (21 CFR 211.170)).
3. Pattern of failure to follow approved analytical procedures and/or testing methods used
for called-out provisions of 21 CFR Part 211 for the drug constituent part and/or the
combination product (e.g., identity testing (21 CFR 211.84), testing methods used for
stability (21 CFR 211.166), sterility/final release testing (21 CFR 211.165, 21 CFR
211.167), testing of reserve samples (21 CFR 211.170)).
4. Significant stability concerns (21 CFR 211.166) that raise questions about the drug
constituent part such as:
a. Stability study failures under recommended storage conditions
b. Pattern of failure to follow stability programs
c. Pattern of failure to evaluate stability failures
5. Pattern of failure to conduct testing (21 CFR 211.84 - identity testing for components,
21 CFR 211.165 - testing and release for distribution), including with regard to device
constituent parts that also serve as a container/closure or part thereof.
6. An expiration date that is not supported by stability studies (21 CFR 211.137).
Particular attention should also be paid to the relationships between requirements, and to broader
implications of deficiencies in one element for other elements or the operating process. For
combination product manufacturer inspections, related deficiencies under different elements of
the CGMP and/or Quality System subsystems24 could warrant an ORA division recommendation
to withhold approval or for OAI (see PART V of Compliance Program 7382.845 and
Compliance Program 7383.001). In particular, deficiencies in requirements related to control of
supplied products and in investigation of product problems can indicate a significant problem.
For instance:
24
Subsystems refers to the 21 CFR Part 211 (drug CGMP) subsystems as described in Reference 10 and the 21 CFR
Part 820 (device Quality System) subsystems as described in Reference 9. See also Attachment C.
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• For a facility operating under a drug CGMP-based streamlined approach, deficiencies in
both purchasing controls (21 CFR 820.50) and testing and release for distribution
(21 CFR 211.165) can indicate a significant finding is warranted. Similarly, a mixture of
CAPA deficiencies (21 CFR 820.100) and complaint file (21 CFR 211.198) deficiencies
can indicate a significant finding related to the firm’s control over nonconforming
product.
• For a facility operating under a device QS-based streamlined approach, deficiencies in
both purchasing controls (21 CFR 820.50) and control of components, containers, and
closures (21 CFR 211.84) can indicate a significant finding.
PART VI REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS
References
1. Chapters II, III, V, and VII of Federal Food, Drug, and Cosmetic Act, as amended
2. Code of Federal Regulations, Title 21, Parts 4, 210, 211, and 820 as revised
3. Compliance Program 7346.832 - Pre-Approval Inspections [Drugs]
4. Compliance Program 7356.002 - Drug Manufacturing Inspections
5. Compliance Program 7356.002A - Sterile Drug Process Inspections
6. Compliance Program 7356.002M - Inspections of Licensed Biological Therapeutic Drug
Products
7. Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
8. Compliance Program 7383.001 - Medical Device Premarket Approval and Postmarket
Inspections
9. Guidance for Industry and FDA Staff - Current Good Manufacturing Practice
Requirements for Combination Products
10. Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
11. Guide to Inspections of Quality Systems, Quality System Inspection Technique
12. Investigation Operations Manual – Chapter 5
Attachments
• Attachment A - Combination product inspectional considerations for the Called-out
provisions of 21 CFR Part 211 (see 21 CFR 4.4(b)(2))
• Attachment B - Combination product inspectional considerations for the Called-out
provisions of 21 CFR Part 820 (see 21 CFR 4.4(b)(1))
• Attachment C – Definitions and Acronyms
Program Contacts
Office of Regulatory Affairs
Questions regarding inspectional requirements and/or technical assistance:
• OMDRHO: [email protected]
• OPQO: [email protected]
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Center for Drug Evaluation and Research
For questions related to CDER-led combination products:
• Pre-approval inspections: [email protected]
• Surveillance Inspections: [email protected]
• For Cause Inspections: [email protected] or
[email protected] (depending on the issuing office for the For Cause
Inspection)
• If the product includes a CDER biologic, include:
[email protected]
Center for Devices and Radiological Health
For questions related to CDRH-led combination products:
[email protected]
Center for Biologics Evaluation and Research
For questions on CDER/CDRH-led products that include a CBER biologic:
[email protected]
Office of Combination Products
For questions related to the status of a product as a combination product or cross-cutting
combination product policy questions: [email protected]
PART VII - CENTER RESPONSIBILITIES
When ORA contacts the lead center during a combination product inspection as provided in this
program, the lead center will facilitate interaction between product reviewers in that and
secondary center(s) for the product.25 When center review before an inspection identifies
manufacturing concerns or issues that need to be addressed by the combination product
manufacturer, that information will be highlighted in the inspection request. In some cases,
expert(s) from the centers may accompany the ORA investigators during an inspection.
For CDER-led combination products, following a combination product inspection, findings will
be reviewed consistent with the existing process for center review.26 For CDRH-led combination
products, a combination product inspection with findings27 should be reviewed by CDRH. In
either case, the lead center will engage other center(s) and OCP, as applicable, to ensure
application of relevant expertise, appropriate consideration of cross-cutting implications of any
action that may be taken, and consistency of Agency actions to address similar issues.
25
The lead center will consult with the other center, as needed, to evaluate inspectional observations. See SMG
4101 Inter-Center Consult Request Process.
26
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm576307.htm.
27
CDRH review of NAI inspections for PMAs and Foreign Surveillance Inspections will occur as consistent with
existing practices.
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ATTACHMENT A – Combination Product Inspectional Considerations for Called-out
Provisions of 21 CFR Part 211
This attachment provides additional information regarding the called-out provisions of the drug-
CGMPs (21 CFR Part 211) for combination product manufacturers who utilize the device QS
regulation (21 CFR Part 820) as their base CGMPs.
In addition to covering the device QS requirements according to the applicable base compliance
program, evaluate the combination product manufacturer’s compliance with the called-out
provisions of 21 CFR Part 211 as described below.
21 CFR 211.84 Testing and approval or rejection of components, drug product containers,
and closures
Combination Product Considerations for 21 CFR 211.84:
For purposes of 21 CFR 211.84, component could include active pharmaceutical ingredients,
excipients, and water or process gases that contact the drug constituent part (see 21 CFR
210.3(a)(3)). A container closure is the sum of packaging components that together contain and
protect the drug constituent part. This includes primary packaging components that contact the
drug constituent part and will also include secondary packaging components if intended to
provide additional protection to the drug constituent part.
Combination product manufacturers do not need to comply with 21 CFR 211.84 for device
constituent parts or materials used in the manufacture of a device constituent part unless the
device constituent part is also the drug container or closure or a part thereof. For example,
syringe components that are prefilled with the drug constituent part would be subject to
21 CFR 211.84, whereas materials used solely for manufacture of a device constituent part that is
not part of the drug container or closure (e.g., a co-packaged syringe with a drug vial) would not
be subject to 21 CFR 211.84.
21 CFR 211.84 may be related to other supplier controls activities (see also discussion of 21
CFR 820.50, Purchasing Controls, in Attachment B).
Inspectional Approach to 21 CFR 211.84 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.84. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(b), related to the
sampling, testing, and evaluation of drug constituent part components, containers, and closures,
2) Objective 2 elements related to the analytical methods for tests of drug constituent part
components, containers, and closures described in the application, and 3) Objective 3 elements
related to the authenticity and veracity of any incoming material testing results. For surveillance
inspections, refer to Compliance Program 7356.002 “Materials System” elements related to the
drug constituent part components, containers, and closures.
It is appropriate for facilities operating under a device QS-based streamlined approach to
comply with 21 CFR 211.84 requirements by augmenting acceptance activities under 21 CFR
820.80 to incorporate 21 CFR 211.84 compliant measures.
For any active pharmaceutical ingredient and/or drug product intended for further processing into
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the drug constituent part that is supplied to the combination product manufacturer, coverage of
21 CFR 211.84 should include confirming that at least one test is conducted to verify the identity
of incoming material. If the facility relies on the supplier’s report of analysis, the facility should
have established the reliability of the supplier’s analysis through appropriate validation of the
supplier’s test results at appropriate intervals and conduct additional testing (e.g., at least one
specific identity test on components and at least visual identification for containers/closures, as
appropriate. See 21 CFR 211.84(d)).
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.1, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
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21 CFR 211.103 Calculation of Yield
Combination Product Considerations:
Yield calculation requirements apply to the drug constituent parts of combination products. For
single-entity combination products, calculation of yield must be performed on every batch of the
combination product. For co-packaged combination products, calculation of yield must be
performed on every batch of the drug constituent part(s).
Although data on the number of device constituent parts and components used and lost during
the manufacture of a combination product may be necessary to ensure appropriate control of the
manufacturing process in accordance with 21 CFR 820.70, yield calculation in accordance with
21 CFR 211.103 is not required for device constituent parts. However, problems with the device
constituent part during combination product manufacturing may affect drug yield. For example,
prefilled syringes that are rejected because of nonconformity of the syringe needle may result in
corresponding loss of drug. Any loss would be captured as part of the yield calculations for the
drug constituent part. Investigation into the cause of that loss should identify the manufacturing
problem that led to these device nonconformities.
Inspectional Approach to 21 CFR 211.103 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.103. Calculation
of yield should be determined at the conclusion of each appropriate phase of manufacturing,
processing, packaging, and holding for the drug constituent part(s) and for the combination
product as a whole. Accordingly, calculation of yield should be determined at each phase at
which drug component, in-process material, or product loss may occur, including during the
formulation of the drug, during incorporation of the drug into the combination product (e.g.,
filling or coating), and, where applicable, during the packaging process.
Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Section IV.B.2, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 211.132 Tamper-evident packaging requirements for over-the-counter (OTC)
human drug products
Combination Product Considerations for 21 CFR 211.132:
If a combination product is accessible to the public while it is for sale (i.e., non-prescription), it
should have tamper-evident packaging. If this packaging is breached or missing, the consumer
should be able to determine that tampering occurred. For single-entity combination products, the
requirement for tamper-evident packaging applies to the combination product. For co-packaged
combination products, the requirement for tamper-evident packaging applies to the drug
constituent part(s), but this requirement can be met if the entire combination product, including
the drug constituent part, has tamper-evident packaging.
Certain combination products may be exempt from over-the-counter (OTC) tamper-evident
packaging requirements, see 21 CFR 211.132(b)(1) (e.g., dentifrice products such as toothpaste
co-packaged with a toothbrush or dermatological products such as a dermatological drug pre-
filled into a delivery device, see 21 CFR 211.132(b)(1)). Certain combination products may be
exempt from bearing a statement of tamper-evident features on the package, see 21 CFR
211.132(c)(1) (e.g., propellant-based aerosols and saline nasal sprays).
Inspectional Approach to 21 CFR 211.132 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.132. Note that
21 CFR 211.132 is only applicable to OTC products and is, therefore, not applicable to many
types of CDRH-led combination products. If an investigator has questions on whether this
requirement applies, contact the lead center for assistance.
Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Section IV.B.3, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 211.137 Expiration dating
Combination Product Considerations for 21 CFR 211.137:
21 CFR 211.137 helps ensure that drug constituent parts of combination products meet applicable
standards of identity, strength, quality, and purity at the time of use, by requiring that the product
labeling bear an expiration date. Shelf-life28 expectations for device constituent parts generally
arise from design considerations (see 21 CFR 820.30). Generally, when constituent parts of a co-
packaged combination product can be used independently, expiration dating, when required,
should be listed separately for each constituent part. If a single expiration date is listed for a co-
packaged combination product, this date should be the earliest expiration date/shortest shelf-life
for any constituent part. In some cases, the drug constituent part might not have an expiration
date because current regulations exempt it from this requirement (e.g., homeopathic drug
products and investigational use products see 21 CFR 211.137(e) – (h)).
The expiration date for a combination product may be shorter than the expiration date or shelf-
life for its constituent part(s) if marketed independently. Reasons for a shorter expiration date
could include interactions between the constituent parts when combined, the effects of additional
manufacturing steps, or one constituent part having a shorter expiration date than the other(s).
Inspectional Approach to 21 CFR 211.137 for a Facility Operating under a Device QS-based
Streamlined Approach:
For pre-approval inspections, refer to Objective 2 elements of Compliance Program 7346.832
related to ensuring that the batches placed on stability for purposes of establishing expiration
date are representative of the proposed marketed product (see also discussion of stability in 21
CFR 211.166 section below). For surveillance inspections, refer to “Packaging and Labeling
System” elements of Compliance Program 7356.002 related to labeling the product with an
expiration date.
Any observations related to the shelf-life/expiration dating for only the device constituent part
should not be cited under 21 CFR 211.137. Such device constituent part considerations should
be evaluated and, when appropriate, cited under 21 CFR 820.30 and related provisions (see also
Attachment B for discussion of 21 CFR 820.30).
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.4, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
28
Expiration dating is the more commonly used term for drug constituent parts, whereas shelf life is more
commonly used for device constituent parts.
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21 CFR 211.165 Testing and release for distribution
Combination Product Considerations for 21 CFR 211.165:
Testing must be conducted to confirm whether drug constituent parts meet final specifications
prior to releasing for distribution. For single-entity combination products, laboratory testing must
be performed on every batch of the combination product. For co-packaged combination
products, laboratory testing must be performed on every batch of the drug constituent part(s).
For single-entity combination products, instead of using units from a finished combination
product batch, manufacturers may wish to use samples that are not finished combination
products but are representative of the finished combination product with respect to the
characteristics and attributes relevant to testing the drug constituent part (see Section IV.B.5,
FDA Guidance for Industry and FDA Staff - Current Good Manufacturing Practice
Requirements for Combination Products).
Inspectional Approach to 21 CFR 211.165 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.165. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(a) elements related
to out-of-specification (OOS) results during final product testing;29 2) Objective 1(b) elements
related to sampling, testing and evaluating finished products, 3) Objective 2 elements related to
analytical methods validation for testing of the finished combination product, and 4) Objective 3
elements related to the authenticity and veracity of analytical results. For Surveillance
Inspections, refer to Compliance Program 7356.002 “Materials System” elements related to
testing and release of products for distribution.
If a combination product manufacturer uses product samples that are not finished combination
products, appropriate evidence and an explanation of the rationale to support the approach should
be accessible at the manufacturing facility for review during the inspection. If samples are being
used for testing and release and there does not appear to be adequate data or justification for the
approach, contact the lead center for assistance.
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections.
• Compliance Program 7356.002 - Drug Manufacturing Inspections.
• Section IV.B.3 and IV.B.5, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
29
Quality data from OOS investigations and any related corrective actions should be addressed through the
combination product manufacturer’s quality system (see also 21 CFR 820.100 Corrective and Preventive Action
(CAPA) below)
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21 CFR 211.166 Stability testing
Combination Product Considerations for 21 CFR 211.166:
For both single-entity and co-packaged combination products, stability testing must be
performed on the drug constituent part as incorporated into the finished combination product.
For co-packaged combination products, if the drug product is purchased from another
manufacturer for inclusion in the combination product, the combination product manufacturer is
still responsible for ensuring the stability of the drug constituent part as marketed in the co-
packaged combination product through appropriate mechanisms, such as by implementing
purchasing controls to ensure the adequacy of the drug product manufacturer's stability testing or
by conducting additional stability testing (see 21 CFR 820.50). Documentation of such oversight
should be included in the CGMP records.
Combination product manufacturers may be able to use bracketing and matrixing approaches or
use stability data for a previously marketed product when a new combination product is a
modification of that already marketed product and the modification does not impact the stability
of the drug constituent part (see Section IV.B.6, FDA Guidance for Industry and FDA Staff -
Current Good Manufacturing Practice Requirements for Combination Products). Appropriate
evidence and an explanation of the rationale to support the approach should be accessible at the
manufacturing facility for review during the inspection.
Inspectional Approach to 21 CFR 211.166 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.166. For pre-
approval inspections, refer to Compliance Program 7346.832: 1) Objective 1(a) elements related
to out-of-specification (OOS) results during stability testing;30 2) Objective 1(b) elements related
to sampling, testing, release, 3) Objective 2 elements related to assurance that the batches placed
on stability for purposes of establishing expiration date will be representative of the marketed
product (see also discussion of expiration date in 21 CFR 211.137 section above), and 4)
Objective 3 elements related to assurance that the analytical results obtained are accurate. For
surveillance inspections, refer to Compliance Program 7356.002 “Laboratory Control System”
elements related to the stability program.
If the manufacturer is using stability data from a previously marketed product or bracketing or
matrixing approaches, and there does not appear to be adequate data or justification for the
approach, contact the lead center for assistance.
Reference/Resources:
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections
• Compliance Program 7356.002B - Drug Repackagers/Relabelers
• Section IV.B.6, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
30
Quality data from OOS investigations and any related corrective actions should be addressed through the
combination product manufacturer’s quality system (see also 21 CFR 820.100 Corrective and Preventive Action
(CAPA) below).
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• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
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21 CFR 211.167 Special testing requirements
Combination Product Considerations:
Special testing requirements to perform laboratory testing on each batch apply only if a
combination product or the drug constituent part thereof is: purported to be sterile and/or
pyrogen free,31 includes an ophthalmic ointment or is a controlled-release product.
Parametric release in lieu of these special testing requirements may be acceptable for some
terminally sterilized combination products and is common for some types of CDRH-led
combination products. Use of parametric release requires FDA approval for combination
products approved in an NDA, BLA, ANDA, or PMA. For some combination products (e.g.,
510(k) cleared products), it may be permissible for manufacturers to adopt parametric release
postmarket for a few well-established sterilization modalities (e.g., Ethylene Oxide Sterilization,
Gamma Irradiation Sterilization) and control such changes under their Quality System without
FDA review. If an investigator has concerns about whether a change to sterilization procedures
should have been reviewed by FDA, contact the lead center for assistance.
It may be acceptable for the combination product manufacturer to define “batch” based on the
drug constituent part rather than the finished combination product for purposes of special testing
requirements for pyrogens and endotoxins. For example, it may be acceptable to define a batch
as a subcomponent of the combination product that incorporates the drug constituent part (see
Section IV.B.7, FDA Guidance for Industry and FDA Staff - Current Good Manufacturing
Practice Requirements for Combination Products). Appropriate evidence and an explanation of
the rationale to support the approach should be accessible at the manufacturing facility for
review during the inspection.
Inspectional Approach to 21 CFR 211.167 for a Facility Operating under a Device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.167. For
products requiring sterility and endotoxin testing prior to batch release, refer to Compliance
Program 7356.002A, Section 3.10 “Laboratory Controls System.” For manufacturers using
parametric release for sterility and endotoxins see Quality System Inspection Technique (QSIT)
Product and Process Controls Subsystem and Sterilization Process Controls. If the manufacturer
is using a parametric release approach, and there does not appear to be adequate data or
justification for the approach, contact the lead center for assistance.
Generally, for terminally-sterilized CDRH-led combination products that are labeled as sterile,
the sterility assurance level (SAL) is expected to be 10-6 (see Guidance Submission and Review
of Sterility Information in Premarket Notification (510(k) Submissions for Devices Labeled as
Sterile below). If a CDRH-led combination product or constituent part thereof labeled as sterile
has another SAL value, you may contact the lead center for assistance, as needed.
If the combination product contains a sterile biological product constituent part, the combination
product manufacturer must also comply with the requirements of 21 CFR 610.12 (Reference
Compliance Program 7345.848, “Laboratory Controls System” “Availability for Distribution and
Testing for Release for Distribution,” Compliance Program 7356.002M “Aseptic/controlled
31
Note that the appropriate terminology on the label of products may vary based on the combination product (for
example, use of “non-pyrogenic,” “meets pyrogen limit specifications” or “pyrogen free”). If an investigator has
questions related to the labeling of a combination product, contact the lead center for assistance.
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processes,” and Compliance Program 7356.002A). Note that although 21 CFR 610.12 is
specifically referenced as related to sterile product requirements, if a combination product
contains a biological product all other requirements in 21 CFR 600 through 680 also apply (see
PART I.2 – Combination Product CGMPs)
If the manufacturer is defining batch based on the drug constituent part, and there does not
appear to be adequate data or justification for the approach, contact the lead center for
assistance, as needed.
Reference/Resources
• Compliance Program 7345.848 – Inspection of Biological Drug Products (CBER)
• Compliance Program 7356.002A - Sterile Drug Process Inspections
• Compliance Program 7356.002M - Inspections of Licensed Biological Therapeutic Drug
Products
• Guide to Inspections of Quality Systems, Quality System Inspection Technique
• Compliance Policy Guide Sec. 490.200 - Parametric Release of Parenteral Drug Products
Terminally Sterilized by Moist Heat
• Section IV.B.7, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP
Regulations
• FDA Guidance for Industry - Q4B Evaluation and Recommendation of Pharmacopoeial
Texts for Use in the ICH Regions: Annex 14 Bacterial Endotoxins Test General Chapter
• FDA Guidance for Industry - Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by
Moist Heat Processes
• FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing -
Current Good Manufacturing Practice
• Guidance for Industry and Food and Drug Administration Staff - Submission and Review
of Sterility Information in Premarket Notification (510(k)) Submissions for Devices
Labeled as Sterile
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21 CFR 211.170 Reserve samples
Combination Product Considerations:
Single-entity and co-packaged combination product manufacturers must keep reserve samples of
each lot of the active ingredient, if any, that they receive, in whatever form it arrives at their
facility (e.g., as bulk active pharmaceutical ingredient or incorporated into an in-process
material) as well as reserve samples for the combination product.
For co-packaged combination products, the requirement to keep reserve samples for the
combination product can be met by maintaining samples of the drug constituent part in its
immediate container-closure system without retaining samples of the device constituent part
from the same package. For single-entity combination products, the combination product reserve
sample is generally the finished combination product, including the device constituent part or
components thereof that come into contact with the drug constituent part as packaged for
distribution. This may involve retaining the entire combination product (e.g., prefilled syringe) or
a separable portion (e.g., a cartridge).
It may be acceptable for combination product manufacturers to retain reserve samples that are
representative of, but not identical to, a finished drug constituent part or combination product, or
to maintain validated surrogates for some testing while retaining complete samples of the
combination product for other tests (see below). It may also be acceptable to retain samples that
are representative lots of a larger batch (e.g., representative samples of each size from within a
broadly defined batch that includes multiple sizes of the same family of coated combination
products such as drug eluting stents or drug coated catheters). (See Section IV.B.8, FDA
Guidance for Industry and FDA Staff - Current Good Manufacturing Practice Requirements for
Combination Products). Appropriate evidence and an explanation of the rationale to support the
approach should be accessible at the manufacturing facility for review during the inspection.
The combination product manufacturer must maintain twice the quantity of active ingredient and
combination product reserve samples necessary to perform required tests, except for sterility and
pyrogen testing (see 21 CFR 211.167 Special testing requirements above for additional
information regarding sterility and endotoxin testing). The quantity of product kept as reserve
samples should be aligned with the batch definitions in any related premarket submission for the
combination product. A sample of the device constituent part(s) may also need to be kept if, for
example, the device constituent part is needed to perform any required tests.
Inspectional Approach to 21 CFR 211.170 for a Facility Operating Under a device QS-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 211.170. For pre-
approval inspections, refer to Compliance Program 7346.832 Objective 2 to assess whether the
reserve sampling practices at the facility are consistent with what was specified in the premarket
application and/or follow any instructions provided from the lead center regarding acceptable
reserve sample approach. For surveillance inspections, refer to Compliance Program 7356.002
“Laboratory Control System” elements related to the stability program.
If a combination product manufacturer is keeping reserve samples that are representative but not
identical to the marketed product or using samples from a representative lot (see above), and
there does not appear to be adequate data or justification for the approach contact the lead center
for assistance.
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Reference/Resources
• Compliance Program 7346.832 - Pre-Approval Inspections
• Compliance Program 7356.002 - Drug Manufacturing Inspections. Refer to “Laboratory
Control System” elements related to the stability program
• Section IV.B.8, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Guidance for Industry - Quality Systems Approach to Pharmaceutical CGMP Regulations
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ATTACHMENT B – Combination product inspectional considerations for
Called-out provisions of 21 CFR Part 820
This attachment provides additional information regarding the called-out provisions for the
streamlined approach under 21 CFR 4.4(b) and information on the inspectional approach for
these provisions for combination product manufacturers who use the drug CGMP-based
streamlined approach.
In addition to covering the drug requirements according to the applicable base compliance
program, evaluate the combination product manufacturer’s compliance with the called-out
provisions of 21 CFR Part 820 as described below.
NOTE: If the combination product is exempt from the device QS regulations, this attachment
does not apply. See PART III.1.A.(6) - Special Situations – Device Constituent Part Exempt from
the device QS-regulations. If a manufacturer claims that the device used in their combination
product is exempt from 21 CFR 820 requirements and the investigator has concerns, contact the
lead center.
NOTE: Installation (21 CFR 820.170) and Servicing (21 CFR 820.200) are called-out provisions
but are not described below. These requirements are not typically a focus of inspections and do
not apply to most CDER-led combination products. If an investigator has questions on these
requirements for a particular combination product or inspection, contact the lead center for
assistance.
21 CFR 820.20 Management responsibility
Combination Product Considerations:
Although companies that traditionally manufacture drug products are subject to statutory CGMP
provisions related to management responsibility and quality management systems,32 there are
specific requirements in 21 CFR 820.20 that are not explicitly addressed in drug CGMP
requirements (e.g., conducting management reviews to assess the suitability and effectiveness of
the quality system at defined intervals). Manufacturers of a combination product that includes a
device constituent part must satisfy all elements of 21 CFR 820.20.
Inspectional Approach to 21 CFR 820.20 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.20. Refer to
QSIT section on Management Responsibility.
Reference/Resources
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to QSIT section on Management Responsibility.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
32
See Section 501(a)(2)(B) of the FD&C Act [21 USC 351(a)(2)(B)].
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• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.1, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
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21 CFR 820.30 Design controls
Combination Product Considerations:
Design controls requirements apply to the combination product as a whole, including design
considerations for each constituent part specific to its use in the combination products However,
it is appropriate for a combination product manufacturer to leverage design and development
information for any constituent part as part of the overall design controls for the combination
product. For example, design control activities for a combination product composed of a device
to be used with an already developed drug product, can leverage the drug properties as inputs for
design control activities that would focus on ensuring that the device appropriately delivers the
drug and that the drug quality is not adversely affected by its contact with the device.
Note that in some cases, design activities may occur at a separate facility from other
manufacturing activities for the combination product (see also “Special Instructions Concerning
Design Controls” in Compliance Program 7383.001 and Compliance Program 7382.845). These
facilities (often termed “specification developers”) may maintain the Design History File (DHF)
for the combination product. The combination product DHF may include cross-references to
relevant information rather than be a direct repository for all the information it needs to include.
Regardless of where DHF information is maintained, the combination product manufacturer
should be able to access necessary DHF information during the inspection to demonstrate
compliance with design control requirements. However, if another site is responsible for design
controls for the combination product, (e.g., a specification developer, see also PART II.2.B), it
may be more efficient or necessary to perform an additional inspection at that other site.
Inspectional Approach to 21 CFR 820.30 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.30. Refer to the
QSIT section on Design Controls, which discusses comprehensive coverage of design controls.
Evaluation of design controls should start with the DHF for the combination product.
In cases where the combination product manufacturer is purchasing the device constituent part
(or its components to be assembled) from another entity (e.g., buying syringe components to be
combined and filled with the drug product), the combination product DHF may reference design
information from the supplier to support design of the device constituent part. However, the
DHF should demonstrate how the constituent part’s specifications are appropriate for its use in
the combination product, addressing any interaction of the constituent parts when combined.
Similarly, if the combination product manufacturer designed the entire product, previously
developed constituent part information can also be referenced in the DHF (e.g., using
development information on a previously approved drug product that is now being developed in
a pre-filled delivery device configuration).
Pharmaceutical development practices such as Quality by Design33 can be used and built upon to
demonstrate compliance with 21 CFR 820.30. However, the combination product manufacturer
should be able to communicate to the investigator how their design practices and terminology
align with design controls requirements. The manufacturer should also communicate how the
procedures in place align with all the requirements of 21 CFR 820.30. For example, the
33
See the Guidance for Industry on Q8(R2) Pharmaceutical Development.
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manufacturer should have procedures that describe the process for design verification and design
validation and should be able to explain the design verification and validation activities that were
conducted for the combination product.34
Reference/Resources
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to QSIT section on Design Controls.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.2, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• Design Control Guidance for Medical Device Manufacturers
• Guidance for Industry - Q8(R2) Pharmaceutical Development
• Guidance for Industry - Q9 Quality Risk Management
• ISO 14971 – Medical devices – Application of risk management to medical devices
34
Design validation provides objective evidence that product specifications conform with user needs and intended
uses. Design validation activities may include, for example, clinical evaluations or simulated use testing. Design
verification provides objective evidence that design outputs (e.g., diagrams, drawings, specifications and
procedures) meet design inputs (e.g., the physical and performance requirements). Design verification activities may
include, for example, tests, inspections, analyses, measurements, or demonstrations. See also Section IV.A.2, FDA
Guidance for Industry and FDA Staff Current good Manufacturing Practice Requirements for Combination
Products.
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21 CFR 820.50 Purchasing controls
Combination Product Considerations:
Purchasing controls are required for products received at the facility for use in the manufacture
of the combination product, for all suppliers of these products, and for suppliers of services
obtained (such as terminal sterilization conducted by an outside entity). Purchasing controls are
also related to acceptance activities performed to ensure that the supplied products and services
meet requirements. (Under a drug CGMP-based streamlined approach, acceptance activities are
evaluated under relevant 21 CFR Part 211 provisions including 21 CFR 211.82 and 21 CFR
211.84.)
Inspectional Approach to 21 CFR 820.50 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s compliance with 21 CFR 820.50. Evaluate the
following purchasing controls elements:
• Purchasing control and related incoming acceptance procedures.
• Purchasing data to evaluate the facility’s approach to accepting suppliers and
communicating specifications for purchased products and services.
• Actions taken in response to findings from supplier assessments.
• Relationship(s) and agreements between the combination product manufacturer and other
entities (e.g., the combination product sponsor (if not the manufacturer), constituent part
manufacturers, component suppliers). Determine how changes made by one of these
entities is communicated to the combination product manufacturer and, if applicable, to
other entities.
• How received products are tested, when needed, and controlled to ensure that
specifications are met.
Evaluation of purchasing controls should include suppliers of constituent parts and/or
components of constituent parts (note that components can include not only device components
but also drug components, as well as containers and closures, that are subject to the requirements
of 21 CFR 211.84 – see Attachment A discussion of 21 CFR 211.84). For example, if conducting
an evaluation of purchasing controls for a CDER-led combination product for which device
constituent parts (or their components) are purchased from a supplier, evaluate purchasing
controls over that supplier.
NOTE: Although constituent part suppliers may themselves be subject to premarket review and
to CGMP requirements, purchasing controls for these suppliers should still be a focus of
evaluation. For example, if supplied biological products or HCT/Ps are used in the combination
product, suppliers of the biological product and/or HCT/P should be evaluated during coverage
of purchasing controls even though the suppliers may themselves be subject to premarket review
and be subject to CGMP requirements applicable to biological products (see 21 CFR Parts 210,
211, 600 through 680) and/or current good tissue practice and donor eligibility requirements for
HCT/Ps (21 CFR Part 1271). As discussed in PART I.2, the combination product manufacturer
must also demonstrate compliance with applicable CGMP requirements under 21 CFR Parts
600 through 680 and/or 21 CFR Part 1271.
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Reference/Resources:
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.3, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
• GHTF Final Document - Quality Management System – Medical Devices – Guidance on
the Control of Products and Services Obtained from Suppliers
• FDA Guidance - Contract Manufacturing Arrangements for Drugs: Quality Agreements
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21 CFR 820.100 Corrective and preventive action
Combination Product Considerations:
Although there is flexibility in coordinating CAPA across facilities, a combination product
manufacturer must ensure that applicable 21 CFR 820.100 requirements are met for their
facility.35 The manufacturer should have appropriate mechanisms in place to ensure that issues
are identified and action(s) needed to correct and prevent recurrence are taken. The combination
product manufacturer should take appropriate measures, which may include CAPAs, with regard
to all relevant manufacturing activities, including coordinating with other manufacturers, as
needed, to correct problems with the combination product and to prevent or mitigate them going
forward. The CAPA process should consider the impact of corrective and preventive actions on
the constituent parts and for the combination product as a whole.
Inspectional Approach to 21 CFR 820.100 for a Facility Operating Under a drug CGMP-based
Streamlined Approach:
Evaluate the combination product manufacturer’s responsibility for and compliance with
21 CFR 820.100. Refer to the QSIT section on Corrective and Preventive Action (but see also
NOTE below). Confirm that the CAPA process ensures a comprehensive review of activities is
undertaken to determine the cause of existing or potential problems, which could include
manufacturing problems, deviations (including issues with product yield), or nonconformities for
a constituent part or the combination product as a whole.
The combination product manufacturer’s CAPA process should consider implications of
corrective and preventive actions for each constituent part and for the combination product as a
whole. For example, review the CAPA documentation for implications of how changes may
impact constituent parts and the product as a whole, including adequate testing/evaluation of the
change. Effectiveness checks may need to consider the product as a whole even if the corrective
action is to a single constituent part.
NOTE: QSIT contains information in the CAPA section on coverage of Medical Device
Reporting (MDR), Corrections and Removals, and Medical Device Tracking. Compliance with
these requirements should NOT be evaluated in an inspection for a CDER-led combination
product unless such coverage is specifically requested in the inspectional assignment. If you
have questions, contact the lead center.
Reference/Resources:
• Guide to Inspections of Quality Systems, Quality System Inspection Technique (QSIT).
Refer to Refer to QSIT section on CAPA.
• Compliance Program 7382.845 - Inspection of Medical Device Manufacturers
• Compliance Program 7383.001 - Medical Device PMA Preapproval and PMA
Postmarket Inspections
• Section IV.A.4, FDA Guidance for Industry and FDA Staff - Current Good
Manufacturing Practice Requirements for Combination Products
35
Relevant requirements in the drug CGMPs include 21 CFR 211.192 and 21 CFR 211.180(e). Quality data from
OOS investigations and any related corrective actions should be addressed through the combination product
manufacturer’s quality system.
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ATTACHMENT C – Definitions and Acronyms
Definitions:
Base Compliance Program: The commodity-specific (e.g., drug, device, or biological product)
compliance program that aligns with the base CGMPs and the type of inspection being
performed at combination product manufacturing facility. For example, for an NDA preapproval
inspection of a combination product facility operating under a drug CGMP-based streamlined
approach, the base compliance program would be the compliance program for pre-approval
inspection of NDAs (Compliance Program 7346.832).
Base CGMPs: For combination product manufacturers using a streamlined approach, the base
CGMPs are the drug or device CGMPs that the manufacturer will follow in their entirety. The
base CGMPs can be either the drug CGMPs (21 CFR Parts 210 and 211) or the Quality System
Regulation (21 CFR Part 820).36
Called-out Provisions: Provisions from 21 CFR Part 4 that are specified for manufacturers of
combination products using a streamlined approach. The called-out provisions are those
provisions that the manufacturer is required to comply with from the non-base CGMPs. See
PART I.2 for the specific called-out provisions.
Commodity-specific Compliance Program: Compliance programs developed for the inspection
of drugs, devices, or biological products.
Constituent Part: A drug, device, or biological product that is part of a combination product.
Cross-labeled Combination Product: A combination product for which the constituent parts are
distributed separately (as may be the case for a light-activated drug product and a separately
distributed laser drug-activation device). See 21 CFR 3.2(e)(3), (4).
Co-packaged Combination Product: The constituent parts are packaged together (e.g., a surgical
or first-aid kit containing devices and drugs, a delivery device packaged with a container of drug
product). See 21 CFR 3.2(e)(2).
Current Good Manufacturing Practice (CGMP) Operating System: The operating system within
an establishment that is designed and implemented to address and meet the current good
manufacturing practice requirements for a combination product. (21 CFR 4.2).
Lead Center: The Agency medical product center (e.g., CBER, CDER, or CDRH) that has
primary jurisdiction for a specific combination product’s review and regulation.
Combination Product Manufacturer: A combination product manufacturer is an entity (facility)
engaged in activities for a combination product that are considered within the scope of
manufacturing for drugs, devices, biological products, and HCT/Ps. Such manufacturing
activities include, but are not limited to, designing, fabricating, assembling, filling, processing,
sterilizing, testing, labeling, packaging, repackaging, holding, and storage, including a contract
manufacturing facility (see also 21 CFR 4.2 and Reference 9).
36
Note that for combination products that include a biological product, the manufacturer must demonstrate
compliance with applicable CGMP requirements for biological products that are found within the standards in parts
600 through 680 (21 CFR Parts 600 through 680). For a combination product that includes any HCT/P, the
manufacturer must demonstrate compliance with applicable regulations in part 1271 (21 CFR Part 1271).
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Single-entity Combination Product: A combination product the constituent parts of which are
physically or chemically combined (e.g., a prefilled syringe or drug-eluting stent). See 21 CFR
3.2(e)(1).
Streamlined Approach: Demonstrating compliance with either the drug CGMPs (21 CFR Parts
210 and 211) or the device Quality System (QS) regulation (21 CFR Part 820) (base CGMPs)
and also demonstrating compliance with specified provisions identified in 21 CFR Part 4 (called-
out provisions) from the other of these two sets of CGMP requirements (see PART I.2). Using
21 CFR Parts 210 and 211 as the base CGMPs with the specified called-out provisions of
21 CFR Part 820 is a “drug CGMP-based streamlined approach.” Using 21 CFR Part 820 as the
base CGMPs with the specified called-out provisions of 21 CFR Part 211 is a “device QS
regulation-based streamlined approach.”
Subsystem: The elements which together comprise the CGMP Operating System for the base
CGMPs. For 21 CFR Part 211, these subsystems include Quality System, Production System,
Facilities and Equipment System, Laboratory Controls System, Materials System, and Packaging
and Labeling System (see Reference 10). For 21 CFR Part 820, these subsystems include
Management Controls, Design Controls, Corrective and Preventive Action, and Production and
Process Controls (see Reference 11).
Acronyms:
ANDA: Abbreviated New Drug Application
API: Active Pharmaceutical Ingredient
BLA: Biologic License Applications
BPDR: Biological Product Deviation Report
CAPA: Corrective Actions and Preventive Actions or Corrective and Preventive Actions
CGMP: Current Good Manufacturing Practice
DHF: Design History File
EIR: Establishment Inspection Report
FAR: Field Alert Report
HCT/P: Human Cells, Tissues, and Cellular and Tissue-Based Products
MDR: Medical Device Report
NDA: New Drug Application
OAI: Official Action Indicated
OOS: Out-of-Specification
OTC: Over-the-Counter
PMA: Premarket Approval
QS: Quality System
QSIT: Quality System Inspection Technique
Date of Issuance: June 4, 2020 Page 46 of 46
来源：FDA Pharmaceutical Quality Documents · fda.gov