FDA 发布合规计划 7346.832M，涵盖 CDER 监管生物制品生产商的许可前与批准前检查
Prelicense and Preapproval Inspections of CDER-Regulated Biological Product Manufacturers (7346.832M)
FDA 发布合规计划 7346.832M，用于 CDER 监管生物制品生产商的许可前检查（PLI）与批准前检查（PAI），文件签发日为 2026 年 4 月 14 日，实施日期为 2026 年 5 月 14 日。
该合规计划列出了生物制品生产场地许可前与批准前检查的风险判断、覆盖要点和回复时限，可供对照现行检查安排。
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。
第 1 页
美国食品药品监督管理局
合规计划 计划 7346.832M
第46章——新药审评
主题： 实施日期：
CDER监管的生物制品生产商许可前和批准前检查 05/14/2026
数据报告
产品代码 计划任务代码
人用药品 PAC 主题
行业代码： 国内/国外检查：
50, 55-56, 57-59, 60-66
46832M 许可前治疗性生物制品检查
46832S BLA许可前检查——生物类似药
56R927 远程交互评估（RIE）活动——人用
药品
56R928 704a4活动——人用药品
备注：
1. 药物评价与研究中心（CDER）应使用本合规计划对生产场所1进行许可前检查（PLI）和批准前检查（PAI），以支持原始及补充生物制品许可申请（BLA）的批准。
2. 在生物制品2灌装/包装操作的PLI或PAI期间评估无菌保证时，遵循合规计划7356.002A——无菌药品工艺检查中的说明。
3. 如为支持新药临床试验申请（IND）（包括治疗性IND）而需要进行检查，将启动有因任务。
报告要求：
1. CDER信息学平台相应组件中的CDER PLI和PAI请求
CDER药品质量办公室（OPQ）下属药品生产评估办公室（OPMA）的设施评估员，录入对以下对象进行PLI或PAI的决定
1
在本合规计划中，术语establishment、facility和firm同义使用，涵盖受FDA药品生产法规和法定权限约束的实体。另见21 CFR 207.1和21 CFR 600.3(w)。
2
在本合规计划中，除非另有说明，术语biological product指受《公共卫生服务法》（PHS Act；42 U.S.C. 262）第351条监管的药品子集，包括CDER监管的蛋白质原料药和制剂。
签发日期：04/14/2026 第1页，共83页
第 2 页
PROGRAM 7346.832M
在原始或补充 BLA 的评估 3 期间生产蛋白质原料药（DS）或制剂（DP）的
生产场所。
2. 企业对 Form FDA 483 回复的说明
在 PLI 或 PAI 结束时，如果签发了 Form FDA 483，检查团队负责人 4 指示
该场所的管理层在 15 个工作日内，将针对 Form FDA 483 上所列观察项的回复提交至
OPMA 邮箱 [email protected]，并抄送检查
团队负责人。
3. 检查结果的沟通
• 检查团队负责人在检查结束后 2 个工作日内沟通检查发现，
并向 OPMA 部门主任、检查团队负责人的主管以及
OPMA 邮箱 [email protected] 提供 Form FDA 483（如已签发）
及初步现场建议。
• 检查团队负责人与检查团队协作，完成
场所检查报告（EIR），其中包括附件和证物。
• 检查团队负责人通知被指派负责该检查审核的 OPMA 评估员
EIR 已完成。
4. 设施建议
当检查审核完成时，OPMA 评估员作出适当的最终建议（批准或不予批准）。
• 当不予批准的标准均不适用时，录入批准建议
（见本合规计划的第 V 部分）。
• 当存在重大缺陷时，录入不予批准建议（见本合规计划的
第 V 部分）。
5. 设施警报
• 当 PLI 或 PAI 发现的缺陷仅影响与申请中所述生物制品相关的
生产和控制操作时，不要在 CDER Informatics Platform 中录入
潜在的官方行动指示（pOAI）警报。
• 当 PLI 或 PAI 发现影响该场所生产的其他已批准产品的
生产和控制操作的关键或系统性 CGMP 缺陷（例如与数据完整性相关的缺陷）时，
应尽快将这些缺陷告知 CDER 合规办公室（OC）
（[email protected]）并讨论
3
在本合规计划中，术语 assessment 与 review 同义，指评估和
分析申请中提交的数据和信息，以确定该申请是否满足
批准要求并记录该确定结果的过程。
4
有关检查团队负责人和检查团队组成的更多信息，见第 II.1.A 部分。
签发日期：04/14/2026 第 2 页，共 83 页
第 3 页
PROGRAM 7346.832M
与 CDER 的 OC 共同确定适当的后续步骤（例如，在 CDER
Informatics Platform 中发出 pOAI 警报，或未来进行后续检查）。 5
6. 企业档案分类代码更新
企业检查期间所涵盖的档案分类代码的状态（可接受或不可接受）
依据《调查操作手册》（IOM）中的 Exhibit 5-14.6.3 进行管理。
• 除非检查涵盖新的档案
分类代码，否则不会为 PLI 或 PAI 更新档案。
• 对于具有新档案分类代码的企业的 PLI 或 PAI，检查团队
负责人可将新的档案分类代码添加到相应系统中，并且如果检查被分类为无需采取行动（NAI）或
自愿采取行动（VAI），且对该申请作出批准建议，则 OPMA
评估员可将其最终确定。
• 如果涉及新档案分类代码的 PLI 或 PAI 导致暂缓建议，则不会
作出档案分类代码建议。这确保该企业不会
被视为申请中所述生物制品（或相关产品）的可接受生产商，
直至后续检查（如需要）核实
适当纠正措施的实施，或直至通过
其他适当方式（即替代工具）核实纠正情况。 6
7. 被检查企业已上市产品的其他报告
在 PLI 或 PAI 期间，如果检查团队获得有关药品不良
反应报告不充分、未经批准药品问题或上市后报告违规（例如，未
提交申请补充、生物制品偏差报告（BPDR））的信息，检查团队
应及时通过发送电子邮件至 [email protected] 和 [email protected] 并抄送
[email protected]，通知 OPQ 的质量监督办公室（OQS）和 OC。
8. 样品相关报告要求
必要时，PLI 和 PAI 期间的样品采集依据 IOM（第
4 章）和《联邦食品、药品和化妆品法案》（FD&C Act，21 U.S.C. 372）第 702 条进行，以
确保维持证据性样品控制。采样可由企业
人员在 FDA 观察下进行。当为方法验证或
档案分析采集官方样品时，检查团队负责人应使用适当的
产品/任务代码（PAC）对其进行标识。这些样品随后被送往 OPQ 实验室进行检测（例如，
方法验证或档案分析）。
检查团队负责人可在需要时通过发送电子邮件至以下地址联系 OQS：
5
关于关键缺陷的示例，参见合规计划 7356.002M——蛋白质原料药生产商
监督检查的第 V 部分。
6
有关替代工具的更多信息，参见第 II.1.B(3) 部分。
发布日期：04/14/2026 第 3 页，共 83 页
第 4 页
PROGRAM 7346.832M
[email protected] 并抄送 [email protected]，以了解
在 PLI 或 PAI 期间采集样品的程序细节。
签发日期：04/14/2026 第 4 页，共 83 页
第 5 页
计划 7346.832M
目录
第一部分——背景 .......................................................................................................................... 7
适用法规、规章和指南 .......................................................................7
生物制品生产运营概述 ...............................9
A. 原料药 .............................................................................................................9
B. 制剂 ...............................................................................................................10
第二部分——实施 ............................................................................................................... 11
目标 ..........................................................................................................................11
A. 范围...........................................................................................................................11
B. 策略 .......................................................................................................................12
计划管理说明 ..................................................................................17
A. 场所评估与检查 ...................................................................18
B. 检查安排 ..........................................................................................18
申报审评整合的重要性 .........................................................18
第三部分——检查 ..................................................................................................................... 20
运营 ........................................................................................................................20
A. 目标1：申报承诺与适用CGMP要求
合规...........................................................................................................................20
B. 目标2：数据完整性审计 ...............................................................................63
报告..........................................................................................................................65
第四部分——分析 ....................................................................................................................... 66
第五部分——监管/行政策略 .............................................................. 67
CDER建议 ................................................................................................67
A. 批准建议 .........................................................................................67
B. 暂缓建议 ........................................................................................67
其他考虑事项 ...............................................................................................70
第六部分——参考文献、附件、计划联系人和缩略语 .......... 72
参考文献 ........................................................................................................................72
A. 美国联邦法规第21篇 ........................................................................72
B. 合规计划（CDER药品）........................................................................72
C. 指南 ...................................................................................................................72
D. FDA用户付费计划 .............................................................................................74
E. 非FDA参考文献 .................................................................................................75
计划联系人 .............................................................................................................75
A. 药物评价与研究中心 ..................................................................75
B. 检查与调查办公室 ....................................................................75
缩略语 .........................................................................................................................76
第七部分——中心职责 ............................................................................................ 78
附件A：抗体-药物偶联物产品 ................................................... 79
附件B：源自产孢微生物的产品 ......... 80
发布日期：04/14/2026 第5页，共83页
第 6 页
PROGRAM 7346.832M
附件 C：高活性或毒性产品 .......................................................... 82
附件 D：冻干或冷冻干燥 ........................................................... 83
签发日期：04/14/2026 第 6 页，共 83 页
第 7 页
PROGRAM 7346.832M
第一部分——背景
适用的法规、规章和指南
生物制品，包括由 CDER 监管的生物制品，必须符合《公共卫生服务法》第 351 条（PHS Act，42 U.S.C. 262）所阐明的要求，该要求已编入 21 CFR 第 600 和 601 部分，以确保产品安全、纯净且有效。它们还必须符合《联邦食品、药品和化妆品法》（FD&C Act）中的现行药品生产质量管理规范（CGMP）要求，以及 21 CFR 第 210 和 211 部分中适用的 CGMP 法规。此外，由生物制品和器械组成部分构成的组合产品须遵守适用于各组成部分的 CGMP 要求，包括药品 CGMP 法规（21 CFR 第 210、211、600 和 601 部分）以及器械质量管理体系法规（QMSR）（21 CFR 第 820 部分）。7
生物制品许可相关法规包括以下内容：
• 根据 601.20(a)：“生物制品许可申请只有在审查产品并确定该产品符合生物制品许可申请中确立的标准以及本章法规所规定的要求（包括但不限于本章第 210、211、600、606 和 820 部分中规定的药品生产质量管理规范要求）后，方可批准。”
• 根据 601.20(d)：“生物制品许可只有在检查生物制品许可申请中所列场所并确定该场所符合生物制品许可申请中确立的标准以及适用法规所规定的要求后，方可颁发或批准生物制品许可申请。”
因此，本合规计划下的覆盖范围及申请评估流程旨在确定这些要求是否已得到满足。
尽管 FDA 尚未发布针对 DS 的 CGMP 法规，但根据 FD&C Act 第 501(a)(2)(B) 条（21 U.S.C. 351(a)(2)(B)），所有药品均须按照 CGMP 生产。因此，FDA 关于 DS（包括蛋白质 DS）生产的 CGMP 现行思考可见于国际人用药品注册技术协调会（ICH）行业指南 Q7《原料药药品生产质量管理规范指南》（2016 年 9 月）。8 ICH
7
参见 21 CFR 第 4 部分所要求的 21 CFR 第 820 部分条款。2024 年 2 月 2 日，组合产品 CGMP 最终规则（21 CFR 第 4 部分）经修订以反映质量管理体系法规（QMSR）（21 CFR 第 820 部分）的发布，该法规取代了质量体系法规（QS 法规）（参见 89 FR 7496，见 https://www.federalregister.gov/d/2024-01709）。QMSR 修订了第 820 部分，主要通过以引用方式纳入 2016 版 ISO 13485（ISO 13485）质量管理体系要求。ISO 13485 中的要求整体而言与 QS 法规的要求基本相似，并对企业的质量管理体系提供类似水平的保证。QMSR 还以引用方式纳入 ISO 9000:2015(E)《质量管理体系——基础和词汇》第 3 条（ISO 9000）。除引用纳入 ISO 13485 和 ISO 9000 外，QMSR 还确立了附加要求和条款，以澄清 ISO 13485 中使用的某些期望和概念。这些补充内容确保引用纳入 ISO 13485 不会与其他适用的 FDA 要求产生不一致（医疗器械；质量管理体系法规技术修订（90 FR 55978，2025 年 12 月 4 日）。
8
我们会定期更新指南。如需指南的最新版本，请查阅 FDA 指南网页 https://www.fda.gov/regulatory-information/search-fda-guidance-documents。
发布日期：2026 年 4 月 14 日 第 7 页，共 83 页
第 8 页
PROGRAM 7346.832M
Q7 并未确立要求，而是为生产商在蛋白原料药（DS）生产操作中遵守
CGMP 提供指导。遵循 ICH Q7 的场所通常将被
视为符合 FD&C 法案第 501(a)(2)(B) 条的法定要求。
为了以更可预测且高效的方式管理批准后化学、生产和控制（CMC）变更，
FDA 发布了 ICH 行业指南 Q12《药品产品生命周期管理的技术与监管考量》（2021 年 5 月）及其
附件，以及行业指南草案 ICH Q12：FDA
监管产品的实施考量（ICH Q12 实施指南，2021 年 5 月）。9 当 ICH Q12 与 ICH
Q12 实施指南结合使用，并具备充分的产品和工艺知识，且在
ICH 行业指南 Q9(R1)《质量风险管理》（2023 年 5 月）所述风险管理原则以及
ICH 行业指南 Q10《药品质量体系》（2009 年 4 月）所述有效质量体系的背景下，
申请人和生产商有机会在变更实施前减少对广泛监管审评的需求，从而有效管理 CMC 变更。10
在检查场所质量体系期间评估变更管理系统，是 FDA 评估申请的重要组成部分，
尤其是那些拟使用 ICH Q12 监管工具（如既定条件（EC））的申请。对
场所变更管理系统的评估有助于 FDA 评估该场所
是否会适当管理变更，并促进申请人具备适当
报告 EC 变更的能力，这些变更需与申请人的产品生命周期管理
文件或其在申请中提交的可比性方案一致。11 可比性方案可以
独立于原始申请或补充申请中任何先前确定的 EC 而提交。
此外，FDA 采用基于风险的策略来确定为支持申请的监管行动而进行 PLI 或 PAI 的必要性、时机和实施方式。
基于风险的方法考虑从检查中获得的信息以及替代工具的使用，简化 FDA 对
药品生产场所和操作的监管，并能够及时高效地
评估场所是否准备好按申请所述开展商业化生产操作。12 有关基于风险的
检查策略的信息，见本合规计划第 II.1.B 部分。
9
ICH Q12 实施指南定稿后，将代表 FDA 对此主题的当前思考。
10
在本合规计划中，质量体系一词与 ICH Q10 所述药品质量体系（PQS）同义。
PQS 是就质量方面指导和管控制药公司的管理体系。
11
可比性方案与 21 CFR 601.12(e) 中定义的方案以及 ICH Q12 中使用的批准后变更
管理方案同义。见行业指南《NDA、ANDA 或 BLA 中化学、生产和控制信息的批准后
变更可比性方案》（2022 年 10 月）。
12
见行业指南《替代工具：评估待审申请中确定的药品生产设施》（2025 年 9 月）。
签发日期：04/14/2026 第 8 页，共 83 页
第 9 页
PROGRAM 7346.832M
生物制品生产操作概述
A. 原料药
蛋白质——PHS 法案第 351(i)(1) 条规定的生物制品法定类别之一——
可从动物或转基因动物的组织、体液或卵中提取并纯化。但在大多数
情况下，它们是在细胞培养中表达后回收并纯化的。哺乳动物细胞和
细菌细胞是用于表达生物制品蛋白质原料药的最常见宿主细胞，但
酵母、植物及其他细胞系也可用作宿主细胞。大多数通过细胞培养或
发酵重组衍生和生产的生物制品采用分级细胞库系统。首先建立表达
该蛋白质的主细胞库（MCB）。取一支 MCB 用于制备工作细胞库
（WCB）。在上游生产操作中，将来自 WCB 管瓶的细胞接种到生长
培养基中以开始细胞培养或发酵，细胞培养物依次扩增至越来越大的
容器，直至生产规模的发酵罐或生物反应器。在受控生长和表达之后，
在预定的培养持续时间结束时，从生产规模的发酵罐或生物反应器中
收获粗蛋白质原料药并进行澄清。取决于最终发酵罐或生物反应器的
类型（例如，补料分批与灌流），收获可以是连续的或分批进行的，
随后将澄清的收获液合并。
离心和过滤等收获工艺旨在停止细胞生长，并将发酵混合物中的蛋白质
产物和可溶性液体组分与宿主细胞及其他碎片分离，以使所得发酵液
适合下游纯化单元操作。当蛋白质未分泌到生长培养基中（即仍位于
细胞内）时，可对细胞使用裂解酶或机械处理（如匀浆）以释放蛋白质。
在某些情况下（通常为细菌表达系统），表达的蛋白质聚集形成包涵体；
因此，需将蛋白质变性（解折叠）并复性（重折叠）以产生可溶的、
有活性的蛋白质形式，然后通过下游生产操作对其进行进一步纯化。
纯化步骤可包括沉淀、超滤/渗滤（UF/DF）以及结合-洗脱或流穿
层析。这些步骤旨在将目标蛋白质与工艺相关和产品相关杂质分离，
例如培养基组分；聚集的、低分子量的和错误折叠的目标蛋白质；
宿主 DNA；宿主细胞蛋白质；以及内毒素）。取决于用于生产该蛋白质
的宿主表达系统，还可能有灭活或清除外源因子（如病毒）的步骤。
这些步骤包括柱纯化步骤和病毒灭活专用步骤（即去污剂灭活、低 pH
保持、病毒过滤和/或热处理）。通常，在纯化过程结束时，原料药经
配制、灌装至原料药容器密闭系统，并在适当温度下储存。然后，
将散装原料药（BDS）准备好，以便运输至制剂灌装/包装生产场所
使用。
对于某些生物制品，原料药生产遵循与上述不同的工艺：
• 在某些情况下，将各组分氨基酸通过合成偶联以生成该
蛋白质。合成后，纯化步骤通常按上述方式进行，以去除
产品相关杂质（例如异构体、降解杂质）或工艺相关杂质
（例如合成工艺中使用的有机溶剂）。
签发日期：2026 年 4 月 14 日 第 9 页，共 83 页
第 10 页
PROGRAM 7346.832M
• 在其他情况下，纯化后的蛋白质会与小分子药物偶联或化学连接（例如抗体-药物偶联物（ADC）），还可能涵盖合成来源的蛋白质与放射性分子或其他标记物偶联以用于成像目的。合成化学品如聚乙二醇也可与蛋白质偶联以延长蛋白质半衰期。在蛋白质-小分子偶联物生产操作中，纯化后的蛋白质和小分子均被视为DS中间体（DSIs）。偶联产品通常有两步生产操作：首先，按照细胞生长和纯化工艺或肽合成工艺所述生产蛋白质组分，得到蛋白质DSI。然后将该蛋白质DSI与小分子中间体偶联形成BDS，再加工成DP。蛋白质中间体生产和蛋白质-药物偶联的过程可在同一或不同场所进行（针对ADC的检查覆盖指南见附件A）。13
• 对于某些蛋白质DS，步骤包括在最终DS灌装前进行冻干或冷冻干燥以提高产品稳定性。通常，冻干首先将DS（以浆液或液体形式）倾倒入托盘，然后将托盘装入冻干机。冻干完成后，将DS研磨成均匀粉末并灌装到适当的DS容器密闭系统（例如袋或瓶）中（针对冻干或冷冻干燥的检查覆盖指南见附件D）。
• 某些蛋白质DSI会通过沉淀或结晶作为一种纯化步骤或用于减少体积。这些沉淀或结晶的中间体有时可用作中间体暂存点，或者在某些情况下可在冻干前生成。
B. 药品
在DP设施中，BDS溶液可进行合并，或者如果已冷冻则先解冻再合并。如有必要，可对BDS进行进一步配制。BDS溶液可先通过生物负载降低过滤器，然后通过0.2 µm除菌过滤器，以制成大批DP。无菌过滤后的大批DP被无菌灌装到适当的无菌容器密闭系统（例如西林瓶、预充式注射器、卡式瓶）中，灌装后的容器用无菌的合适胶塞封闭，以生产DP溶液灌装剂量单位。某些DP的生产包括冻干步骤，在此期间DP剂量单位被部分加塞，并去除水分以产生粉末，供患者在给药前复溶和稀释。DP灌装的西林瓶和卡式瓶在压盖过程中用铝盖密封。DP灌装的卡式瓶和某些预充式注射器可进一步组装成装置（例如自动注射器、贴身给药系统）。较少情况下，DP可压片或胶囊化。最后，对DP的初级容器密闭系统进行目视检查、贴标，并包装到次级包装中以便放行和分销。
13
用作中间体和连接子的小分子的商业化生产操作不在本合规计划范围内。关于其生产操作的检查覆盖，请参阅合规计划7346.832——批准前检查。
签发日期：04/14/2026 第 10 页，共 83 页
第 11 页
PROGRAM 7346.832M
PART II—IMPLEMENTATION
Objective
A. Scope
This compliance program covers PLIs and PAIs of DS and DP manufacturers 14 of CDER-regulated
biological products that meet the definition of protein articulated in 21 CFR 600.3(h)(6). 15 Some
examples of these types of products follow:
• Enzymes.
• Monoclonal antibodies.
• ADCs.
• Fusion proteins (e.g., antibody Fc region-containing fusion proteins).
• Growth factors.
• Cytokines (e.g., interleukins, interferons, tumor necrosis factors).
• Botulinum toxins.
• Insulin and insulin analogues.
• Synthetically derived proteins.
CDER is responsible for conducting PLIs and PAIs covered under this compliance program:
• A PLI is an inspection of an establishment (new or existing) 16 that manufactures a new
biological product subject to an original application. This includes inspections of
establishments that already manufacture other currently approved biological products.
• A PAI is an inspection of an establishment (new or existing) that manufactures a licensed
biological product for which the applicant has submitted a supplement for a significant
manufacturing change (e.g., prior approval supplement) that requires on-site review of the
change.
These PLIs and PAIs are conducted by CDER to evaluate establishment readiness for commercial
manufacturing operations 17 of biological products or combination products with biological product
and device constituent parts described in original and supplemental BLAs under assessment
(hereinafter products of interest), and ultimately to support regulatory decisions for these
14
21 CFR 600.3(t) defines manufacturer as “any legal person or entity engaged in the manufacture of a product subject to
license under the act” and “...any legal person or entity who is an applicant for a license where the applicant assumes
responsibility for compliance with the applicable product and establishment standards.”
15
Under 21 CFR 600.3(h)(6), a protein is any alpha amino acid polymer with a specific, defined sequence that is greater
than 40 amino acids in size.
16
In this compliance program, new establishments are those with no compliance history, and existing establishments are
those with a compliance history.
17
In this compliance program, the term commercial manufacturing operations refers to the manufacturing processes
resulting in commercial biological product.
Date of Issuance: 04/14/2026 Page 11 of 83
第 12 页
PROGRAM 7346.832M
applications. 18,19 The inspections help CDER determine whether proposed manufacturing operations
and control strategies ensure product quality and conform with licensing requirements, including
standards established in applications and applicable CGMP requirements. 20 The compliance program
can be used in conjunction with compliance program 7356.002A to cover the evaluation of certain
sterile manufacturing operations (e.g., aseptic filling operation).
Under this compliance program, inspection teams within CDER (in collaboration with the Office
of Inspections and Investigations (OII), when needed) conduct PLIs and PAIs using the strategy
described in Part II.1.B and cover the objectives detailed in Part III. Inspectional coverage
outlined in Part III applies to both DS and DP unless specifically noted. Inspection teams include
an inspection team lead (typically from OPMA) and, as needed, assessors from other OPQ offices
(e.g., Office of Product Quality Assessment III (OPQA III). 21
If the inspection team discovers systemic CGMP deficiencies during a PLI or PAI, the inspection
coverage may be expanded to cover the commercial manufacture of other FDA approved products at
the establishment, as time permits. This expanded coverage would generate evidence and appropriate
documentation of these deficiencies 22 to support potential enforcement actions for marketed products
and to inform future inspection planning and strategy. 23
B. Strategy
(1) Risk-Based Inspection Determination
In general, PLIs and PAIs are performed to provide assurance that data and information submitted in
original and supplemental BLAs under review are accurate and complete and to evaluate whether
establishment operations are performed as described in applications under review and in conformance
with applicable requirements.
The CDER integrated quality assessment (IQA) team 24 takes a holistic, risk-based approach to
determine whether a PLI or PAI is needed for an establishment listed in a BLA. In conducting the risk
assessment, the IQA team assesses the manufacturing operations and activities of the facility as
described in the application in relation to those previously evaluated or inspected in the facility (e.g.,
profile codes), evaluates the information about the facility’s compliance with CGMP (e.g.,
18
For the purpose of this compliance program, there is no distinction between inspectional approaches to support approval
of original or supplemental 351(a) or 351(k) BLAs. Throughout the rest of this compliance program, the term application
is used to describe both original and supplemental BLAs, unless a distinction between the two is necessary.
19
This compliance program covers certain combination products containing both biological and device constituent parts,
with coverage determined by the risk of the device component.
20
See 21 CFR parts 210, 211, and 610 and 21 CFR 600.21, 601.2, 601.20, and 601.22, and 21 CFR parts 4.
21
Inspections are conducted by officers or employees duly designated by the Secretary who are authorized to conduct
inspections under 704(a)(1) under FD&C Act.
22
See footnote 5.
23
See Facility Alerts in the Reporting Requirements section for additional pOAI details for U.S.-marketed products
manufactured at the establishment being inspected.
24
The IQA team consists of assessors from OPMA and OPQA III but can also include assessors from other disciplines as
needed.
Date of Issuance: 04/14/2026 Page 12 of 83
第 13 页
PROGRAM 7346.832M
compliance status, inspection history), and identifies potential risk associated with the operations for
the proposed product (e.g., complexity of the operation, the product itself, or both). Using the
knowledge of the facility along with the understanding of the proposed manufacturing operations and
activities, as well as relevant hazard signals (e.g., BPDRs, recalls), the IQA team assesses the overall
risk of the operations and determines the preparedness of the facility and necessity of an inspection.
Based on the risk assessment, the IQA team decides whether existing information is sufficient to
demonstrate that the facility meets applicable approval standards, or there is a need for an inspection,
a further assessment through alternative tools (see Part II. 1.B(3)), or both, to determine whether the
facility is in compliance with applicable statutory and regulatory requirements to meet the approval
standards for the BLA. 25 The holistic, risk-based approach used to facilitate a prompt decision on the
necessity of a PLI or PAI is illustrated in the flow diagram below:
25
351 PHS Act, 42 U.S.C. 262, and 21 CFR parts 4, 210, 211, 600, and 601.
Date of Issuance: 04/14/2026 Page 13 of 83
第 14 页
PROGRAM 7346.832M
Flow Diagram: Risk-Based Inspection Determination
Risk assessment of the facility's preparedness to conduct commercial manufacturing of the product as
described in the application - factors to be considered such as:
• Profile code status
• Compliance history
• Inspection history
• Product characteristics (e.g., novel or complex drugs)
• Manufacturing operations and activities
• Hazard signals (BPDRs, recalls, complaints, FARs, MedWatch)
Risk assessment Yes
PLI or PAI Not
supports facility’s Needed
preparedness
No
No Risk assessment supports
potential use of
Alternative Tools (ATs) in
lieu of inspection
Yes
Use of ATs support facility’s preparedness such as:
• Assessment of inspection records from MRA partner
• Assessment of inspection records from regulatory partner under
Confidentiality Agreements
• Records request under 704(a)(4)
• Remote Interactive Evaluations
No Yes
PLI or PAI ATs’ information
Needed supports facility’s
preparedness*
*Information from ATs may also be used in support of a regulatory action.
Date of Issuance: 04/14/2026 Page 14 of 83
第 15 页
PROGRAM 7346.832M
(2) Risk-Based Determination of the Inspection Scope and Depth
Once the IQA determines that a PLI or PAI is needed, the IQA team and the inspection team will
determine the scope and depth of the inspection by considering the following:
• The novelty and complexity of the product of interest and manufacturing operations and
activities described in the application (e.g., combination products with biological and device
constituent parts 26).
• The inherent risk of the product of interest (e.g., a biological product that is classified as
highly potent).
• For supplemental applications, the novelty and complexity of the proposed manufacturing
change(s), and the risk of the proposed change(s) to the product quality.
• Other considerations (e.g., significance of issues identified during the application assessment,
type of inspections (PLI versus PAI)).
The scope and depth of coverage can be adjusted during an inspection based on the inspection team’s
findings.
(3) Alternative Tools
FDA can use alternative tools to support evaluation of establishments and regulatory decisions
regarding applications, such as the following 27: (1) requesting existing inspection reports and other
information from trusted foreign regulatory partners through Mutual Recognition Agreements
(MRAs) and other confidentiality agreements; 28 and (2) conducting remote regulatory assessments, 29
including (a) requesting records and other information directly from establishments and other
inspected entities related to the application under section 704(a)(4) of the FD&C Act (21 U.S.C.
374(a)(4)), and (b) conducting remote interactive evaluations where appropriate. 30 With regards to
this compliance program, a request of records under section 704(a)(4) can be used in lieu of or in
advance of a PLI or PAI to support assessment of an application. 31
26
For inspections of combination products with biological and device constituent parts, per compliance program
7356.000– Inspections of CDER‐led or CDRH‐led Combination Products, the lead center will engage expertise from
other agency components, including other center(s), as needed.
27
For these and other alternative tools, see guidance for industry Alternative Tools: Assessing Drug Manufacturing
Facilities Identified in Pending Applications (September 2025).
28
For existing FDA MRAs with the European Union, United Kingdom, and SwissMedic, this includes the use of official
inspection reports issued by a recognized authority for manufacturing establishments located inside and outside the
territory of the issuing authority. For more information, see https://www.fda.gov/international-programs/international-
arrangements/mutual-recognition-agreement-mra.
29
A remote regulatory assessment is an examination of an FDA-regulated establishment or its records, conducted entirely
remotely, to evaluate compliance with applicable FDA requirements. For more information, see guidance for industry
Conducting Remote Regulatory Assessments: Questions and Answers (June 2025).
30
See draft guidance for industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring
Facilities (October 2023). When final, this guidance will represent FDA’s current thinking on this topic.
31
See Staff Manual Guide 6001.1, Agency Program Directives, Volume IV – Food and Drug Administration Inspection,
Date of Issuance: 04/14/2026 Page 15 of 83
第 16 页
PROGRAM 7346.832M
(4) Inspection by Objectives
The objectives identified in this compliance program reflect FDA’s risk-based inspectional approach
described in Part II.1B(1), building on the knowledge acquired by FDA over decades of inspections.
PLIs and PAIs incorporate this risk-based approach in the systematic evaluation of a facility to
determine its ability to produce a biological product that meets the identity, strength, quality, safety,
purity, and potency standards described in the application.
The primary objectives to be covered on every PLI and PAI follow:
• Objective 1: Application Commitments and Applicable CGMP Requirements Compliance 32
• Objective 2: Data Integrity Audit
The following table outlines high-level examples of the areas under each objective that should be
evaluated during an inspection. Knowledge about the establishment and its capabilities, such as that
gained from previous inspections or assessments through alternative tools, should inform the breadth
of coverage needed to assess the establishment in support of the subject application(s). Coverage
under each objective is described in more detail in Part III of this compliance program. Part V
provides administrative/regulatory guidance regarding the evaluation of inspectional findings and
examples of Form FDA 483 observations.
High-Level Examples of Areas To Evaluate, by Objective
Objectives Examples
Objective 1: Application Commitments and
Applicable CGMP Requirements
Compliance
• Deviation reports and associated corrective actions and
preventive actions
Objective 1a: Evaluation of the • Personnel training and qualification
Effectiveness of Quality System • Document control and distribution records (including
Oversight batch records) and procedures
• Change control activities
• Quality and contract agreements
FDA Remote Regulatory Assessment Standard Practices (January 2025). See also guidance for industry Alternative Tools:
Assessing Drug Manufacturing Facilities Identified in Pending Applications (September 2025).
32
Inspectional coverage described in Objective 1 is organized following the six-system inspection model. For more
information about the six-system inspection model, see guidance for industry Quality Systems Approach to
Pharmaceutical CGMP Regulations (September 2006) and compliance program 7356.002—Drug Manufacturing
Inspections.
Date of Issuance: 04/14/2026 Page 16 of 83
第 17 页
PROGRAM 7346.832M
High-Level Examples of Areas To Evaluate, by Objective
Objectives Examples
• Design and layout of the facility to include qualification
and maintenance of room classification
Objective 1b: Evaluation of the
• Critical equipment operations, qualification, and cleaning
Suitability of Facilities and Equipment
• Product cross-contamination preventive measures
• Water and clean steam systems
• Raw material/component testing, examination, release,
Objective 1c: Evaluation of Material and documentation
Management to Support Commercial • Critical raw material supplier qualification
Manufacturing
• Storage, distribution, and quarantine of materials
(including cell banks)
• Relevant procedures and records of commercial
Objective 1d: Evaluation of manufacturing operations
Production and Process Controls in • Manufacturing unit operations
Commercial Manufacturing Operations • Microbial monitoring and control
• Process performance qualification results
• Out-of-specification investigation and procedures
Objective 1e: Evaluation of the • Test sample and reference standard tracking and storage
Laboratory Control System • Laboratory equipment qualification, maintenance, and
calibration
• Stability testing program and records
Objective 1f: Evaluation of • Packaging and labeling procedures and controls
Packaging, Labeling, Storage, and • Storage of in-process and final material
Shipping Operations
• 21 CFR 610.14 identity test fulfillment
Objective 2: Data Integrity Audit • Computerized systems validation
• Completeness and accuracy of CGMP data
• Computerized systems access control and audit trail
Program Management Instructions
Inspection activities conducted under this compliance program involve a collaborative effort between
the IQA team and the inspection team. Both teams should be knowledgeable of the manufacturing
operations, testing methodologies, and control strategies used to manufacture the product of
interest. 33 They should also be knowledgeable of the applicable statutory and regulatory requirements,
including CGMP requirements. When applicable, the OPMA invites investigators from OII to
participate in the inspection. The inspection team has access to electronic product applications and
should refer to these applications when appropriate. If needed, the inspection team lead can ask
product specialists to assist in obtaining copies of relevant sections of paper-based product
applications.
33
See 21 CFR 600.20.
Date of Issuance: 04/14/2026 Page 17 of 83
第 18 页
PROGRAM 7346.832M
A. Establishment Evaluation and Inspection
• The OPMA assessor verifies that relevant establishments listed in the application are entered
in the appropriate component of the CDER Informatics Platform.
• The OPMA assessor places a request in the appropriate component of the CDER Informatics
Platform for a PLI or PAI.
o If a PLI or PAI is not needed based on the risk assessment, the OPMA assessor enters
appropriate justification in the appropriate component of the CDER Informatics Platform.
• The inspection team lead schedules the date for the inspection.
• During the inspection, the inspection team documents significant CGMP deficiencies
regarding the manufacturing of the product of interest on Form FDA 483, as applicable, with
sufficient supporting evidence. Deficiencies that are solely application assessment issues are
not included on Form FDA 483.
• All participants on the inspection team are responsible for writing and submitting their portion
of the EIR to the inspection team lead, along with supporting exhibits.
B. Scheduling the Inspection
FDA expects the establishment to be ready for an inspection at the time of application submission,
and, in general, to be operational and manufacturing the complete product for which a biologics
license is sought at the time of inspection. 34 Because of the complexity and duration of biological
product manufacturing operations, in most cases, the inspection is scheduled to observe operations
considered to be relatively high risk from a quality perspective.
When scheduling a PLI or PAI, the OPQ inspection team considers the manufacturing schedule at the
establishment to be inspected as provided by the applicant. The IQA team or inspection team lead, as
applicable, generally contacts applicants and establishments to confirm the establishment’s
manufacturing schedule for the product of interest and to coordinate inspectional logistics,
respectively. For original applications, FDA’s goal is to notify the applicant of its intent to inspect a
manufacturing facility at least 60 days before the inspection and no later than midcycle. 35 For any
application, FDA reserves the right to conduct inspections of the manufacturing establishment at any
time during the assessment cycle, whether or not the Agency has communicated to the establishment
the intent to inspect. If the proposed manufacturing schedule changes, applicants and establishments
have been advised to immediately provide a written explanation and provide a new proposed
manufacturing schedule.
Importance of Application Assessment Integration
Achieving a science- and risk-based approval decision for each application from a pharmaceutical
quality perspective requires an integrated assessment of the application and inspection of the
34
See 21 CFR 600.21 and 601.20(b)(2).
35
See the PDUFA VII and BsUFA III commitment letters, available on the FDA User Fee Programs website.
Date of Issuance: 04/14/2026 Page 18 of 83
第 19 页
PROGRAM 7346.832M
establishments named in the application. Because multiple disciplines within the FDA contribute to
the integrated assessment, differences of opinion might occur. FDA offices involved in PLIs or PAIs
supporting regulatory decisions for applications are covered by an “equal voice” philosophy. Under
this philosophy, all appropriate expertise should be considered in the important decisions made about
applications, and the perspective from each FDA office assigned a role in assessing and evaluating
drug applications is valuable. 36
36
See MAPP 4151.8, Rev. 2, Equal Voice: Collaboration and Regulatory and Policy Decision-Making in CDER (August
12, 2025).
Date of Issuance: 04/14/2026 Page 19 of 83
第 20 页
PROGRAM 7346.832M
PART III—INSPECTIONAL
Operations
This section provides instructions for the inspection team on evaluating whether establishments
comply with licensing requirements, including standards established in applications and applicable
CGMP requirements, 37 and on confirming the integrity of data submitted in applications.
The instructions fall under two primary objectives, as listed below. The IQA team and inspection
team decide the scope and depth of coverage for each objective based on the risk-based approach and
considerations described in Part II.1.B(1) of this compliance program. While conducting inspectional
activities related to each objective, the inspection team focuses on the product of interest as defined in
the Scope section of this compliance program (Part II.1.A).
The inspection coverage outlined in Part III applies generally to both DS and DP, unless stated
otherwise. DP-specific inspection coverage elements are clearly identified in the narrative, when
appropriate. 38
• Objective 1: Application Commitments and Applicable CGMP Requirements Compliance
o Objective 1a: Evaluation of the Effectiveness of Quality System Oversight
o Objective 1b: Evaluation of the Suitability of Facilities and Equipment
o Objective 1c: Evaluation of Material Management to Support Commercial Manufacturing
o Objective 1d: Evaluation of Production and Process Controls in Commercial
Manufacturing Operations
o Objective 1e: Evaluation of the Laboratory Control System
o Objective 1f: Evaluation of Packaging, Labeling, Storage, and Shipping Operations
• Objective 2: Data Integrity Audit
This section explains objectives 1 and 2 in more detail, provides coverage instructions for the
inspection team, and includes applicable references.
A. Objective 1: Application Commitments and Applicable CGMP Requirements Compliance
(1) Objective 1a: Evaluation of the Effectiveness of Quality System Oversight
Under this objective, the inspection team evaluates the establishment’s quality system to determine its
ability to provide effective oversight of the commercial manufacturing operations described in the
application and to ensure that the quality of the product of interest consistently meets established
specifications.
37
See 21 CFR parts 4, 210, 211, and 610 and 21 CFR 600.21, 601.2, 601.20, and 601.22.
38
In this compliance program, the inspection coverage specific to DS follows ICH Q7 for meeting statutory CGMP
requirements. Inspection coverage specific to DP follows the requirements set forth in 21 CFR parts 4, 210, 211, 600, and
601.
Date of Issuance: 04/14/2026 Page 20 of 83
第 21 页
PROGRAM 7346.832M
Parts III.1.A(1)(a) through (o) below outline specific areas under Objective 1a that should be verified
by the inspection team as they relate to the product of interest.
(a) Quality Unit
The establishment’s quality system includes the quality unit, which is responsible for, among other
duties 39:
• Establishing a system to release or reject materials, including DS, DP, intermediates,
packaging, and labeling materials.
• Approving specifications and instructions provided in master production records.
• Reviewing and approving validation protocols and reports and completed batch production
and laboratory control records before release or distribution of materials.
• Ensuring that product quality-related complaints, unexplained excursions, adverse trends,
deviations, and failures are fully investigated and resolved.
• Ensuring that there are stability data, generated through an adequate stability program, to
support expiry dates and storage conditions.
• Performing product quality reviews.
• Overseeing facilities and equipment, including manufacturing and laboratory testing. This
includes ensuring that systems are in place that are used for maintaining and calibrating
equipment used in establishments to manufacture or test materials.
• Ensuring that regular internal audits (self-inspections) are performed to confirm that
operations conform with CGMP requirements. 40
• Approving contractors and relevant quality agreements between the applicant and contractors
that define in detail the responsibilities of each party.
The inspection team should, at a minimum:
• Verify that the quality unit:
o Reviews and approves relevant documents—including validation protocols and reports,
operating procedures, manufacturing records, laboratory control records, associated
deviations, corrective actions and preventive actions (CAPAs), and change controls—
before lots are released or distributed.
o Reviews and approves changes that potentially affect the quality of intermediates or
products before implementation.
o Ensures that there is an adequate number of trained personnel, training programs are
periodically assessed, and training is adequate.
• Verify that an effective system is in place for maintaining and calibrating critical equipment.
39
See 21 CFR 211.22 and ICH Q7, section II.B, Responsibilities of the Quality Unit(s).
40
See ICH Q7, section II.D, Internal Audits (Self Inspection).
Date of Issuance: 04/14/2026 Page 21 of 83
第 22 页
PROGRAM 7346.832M
• Verify that an effective system is in place to release or reject materials, including raw
materials, intermediates, DS or DP, packaging, and labeling materials.
• Verify that the establishment has adequate oversight in place to detect potential quality issues
and respond appropriately to ensure defective products are not released to the market. This
includes determining whether the establishment is operating in a state of control employing
conditions and practices that ensure compliance with regulatory requirements.
• Verify that the establishment has adequate oversight and a robust change management system
to evaluate manufacturing changes and risks associated with them.
FDA can consider the outcomes of these evaluations when assessing whether appropriate regulatory
oversight can be maintained for products for which flexible regulatory approaches have been
proposed (e.g., in applications with proposed ECs as described in ICH Q12), or when assessing how
effectively establishments are applying principles of continual improvement.
References:
• 21 CFR 211.22, 211.25, 211.28, 600.10, 600.12, and parts 601 and 610
• ICH Q7, section II, Quality Management
• ICH Q10
• ICH Q12
• Guidance for industry ICH Q12 Implementation Considerations for FDA-Regulated Products
(May 2021)
• Guidance for industry Advancement of Emerging Technology Applications for
Pharmaceutical Innovation and Modernization (September 2017)
• Guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations
(October 2006)
(b) Senior Management Responsibility
Senior management should demonstrate a commitment to quality. This includes a commitment to
meeting applicable regulatory requirements (e.g., supporting the quality management system
addressing specific requirements for combination products that include device constituent parts (e.g.,
conducting management reviews to assess the suitability and effectiveness of the quality management
system at defined intervals)), developing quality policy, among other aspects.
The inspection team should, at a minimum:
• Evaluate whether the responsibilities and authority of operations and quality organization
units are clearly delineated by senior management.
• Evaluate whether management commits appropriate resources (e.g., investigate quality issues
and implement appropriate CAPAs, upgrading facilities and equipment, adequate staffing
levels).
References:
Date of Issuance: 04/14/2026 Page 22 of 83
第 23 页
PROGRAM 7346.832M
• 21 CFR 4.4
• ICH Q10, section III, Management Responsibility
• Guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations
(c) Internal Audits
The establishment should perform regular internal audits to confirm that manufacturing operations
are in conformance with CGMP requirements.
The inspection team should, at a minimum:
• Evaluate whether there are written procedures to conduct regular internal audits and critical
review of processes and procedures pertaining to manufacturing operations are reviewed and
approved by the quality unit and that they are in place and being followed.
• Evaluate whether internal audits are conducted regularly according to an approved, defined
schedule.
• Evaluate whether the reporting procedures ensure the internal audit results are reported to
management.
Reference:
• ICH Q7, section II.D, Internal Audits (Self Inspection)
(d) Contract Agreements
Applicants and contract manufacturing organizations (CMOs) share the responsibility of ensuring that
manufacturing operations are conducted in compliance with CGMP. CMOs are subject to CGMP
requirements and may not violate them at the direction of applicants.
Contract agreements can be extremely valuable in delineating the activities of all parties involved.
For contract agreements in place, the inspection team should, at a minimum:
• Verify that there is a written and approved contract or formal agreement between the applicant
and CMO and other contracted parties (e.g., testing laboratories) defining in detail the CGMP
responsibilities of each party, including quality measures and other considerations relevant to
the contract agreement.
• Confirm that the contract agreement describes each party’s involvement in investigations,
CAPAs, and product disposition.
• Verify that the contract agreement indicates that the applicant should be notified by the
contracted party of deviations or changes pertaining to or affecting the product or its
established conditions.
• Verify that batch production records have been reviewed and approved for batch release in
accordance with the quality agreement.
• Confirm that the contract agreement allows for on-site audits of contracted establishments.
Date of Issuance: 04/14/2026 Page 23 of 83
第 24 页
PROGRAM 7346.832M
References:
• 21 CFR 210.2(b), 211.22(b) and 211.22(d)
• ICH Q7, section XVI, Contract Manufacturers (Including Laboratories)
• Guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements
(November 2016)
(e) Personnel Training
The establishment is expected to provide adequate training to ensure that personnel are trained and
qualified to perform their functions.
The inspection team should, at a minimum:
• Verify that there is an adequate number of trained personnel, including supervisors, for
assigned functions and operations.
• Verify that the establishment has adequate standard operating procedures (SOPs) and other
training procedures in place to appropriately train personnel on essential documents, including
training on changes to SOPs, batch production records, or other pertinent work instructions.
• Verify that training is regularly conducted by qualified individuals and that it covers, at a
minimum, the particular operations that the employee performs and applicable CGMP
requirements as they relate to the employee’s functions.
• Verify that personnel are trained in appropriate sanitation and health habits for the
establishment’s production processes.
• Verify that training records are maintained.
• Confirm that training is periodically assessed.
References:
• 21 CFR 211.25 and 600.10(b)
• ICH Q7, section III, Personnel
(f) Personnel Gowning and Qualifications
Commercial manufacturing operators are expected to be trained in proper gowning technique.
The inspection team should, at a minimum:
• Evaluate whether appropriate gowning procedures, including those governing hygiene,
behavior, and health, have been established and are followed by observing personnel during
the inspection. Focus on personnel who might have direct contact with product intermediates
or manufacturing operations.
• Verify that personnel with apparent illnesses or open lesions are excluded from manufacturing
activities.
Date of Issuance: 04/14/2026 Page 24 of 83
第 25 页
PROGRAM 7346.832M
• Verify that the establishment’s gowning procedure is adequate to prevent cross-contamination
when operators move from one product suite to another within the establishment, especially
when operators pass from highly potent or toxic compound manufacturing areas to other
areas.
References:
• 21 CFR 211.25, 211.28, and 600.10(c)(2)
• ICH Q7, section III.B, Personnel Hygiene
(g) Document Control Procedures
Production, control, and distribution records are expected to be maintained for not fewer than 5 years
after the batch records have been completed or 6 months after the latest expiry date of the batch.
These records should be readily available during an inspection.
The inspection team should, at a minimum:
• Evaluate whether master production and control records are completed to ensure uniformity
from batch to batch according to approved procedure.
• Verify the adequacy of the document control procedures, including issuance, version control,
accessibility to manufacturing personnel, and archiving.
• For combination products with biological product and device constituent parts, verify that the
manufacturer has established and maintained a design and development file for the device
constituent part.
References:
• 21 CFR 211.186, 600.12, and Clause 7.3 and its subclauses of ISO 13485:2016, as required by
21 CFR parts 4.4(b)(1)(ii)
• ICH Q7, section VI, Documentation and Records
(h) Batch Production Record Review and Control
Master and batch production records are expected to include complete information related to batch
production and control. The quality unit should review and approve these batch production records to
determine compliance with established, approved written procedures before a batch is released or
distributed.
The inspection team should, at a minimum:
• Verify that manufacturing operations use the same unit operations and control strategies
described in the batch production records. (The inspection team should do this while
observing the manufacturing operations being performed, if possible.)
• Confirm that the batch production records submitted in the application correspond to the batch
production records used at the establishment (as appropriate; batch production records can be
updated following application submission).
Date of Issuance: 04/14/2026 Page 25 of 83
第 26 页
PROGRAM 7346.832M
• Verify that the methods listed in the batch production records align with those described in the
application (including those used to assess the quality and stability of the batch, in-process
materials, intermediates, and raw materials, as applicable).
• Verify that the master production record provides sufficient instructions for manufacturing
operations if such information is not provided in other procedures. In addition, confirm that
there are no operations or procedures performed that are not described in the batch production
records or incorporated by reference in other quality unit-approved procedures.
• Verify that manufacturing unit operations recorded in the batch production records are within
validated operational parameters as described in the application.
• Verify that all equipment is listed in the batch production records and that the equipment
meets performance parameters.
• Verify that the quality unit has reviewed deviation, investigation, and out-of-specification
(OOS) reports as part of the batch production record review.
• Verify that the documentation system for batch production records is appropriately validated
and controlled to prevent unauthorized access and changes to data.
• For computerized batch production records that list exceptions that will not be part of a
deviation investigation, review the exceptions for their potential impact on the product.
• Verify that the quality unit reviews and approves relevant documents, including
manufacturing and laboratory control records, before releasing lots for distribution.
• For combination products with biological product and device constituent parts, verify that the
quality unit has procedures to conduct formal documented reviews of design and development
results to ensure that the device constituent parts design meet the established standards. Also,
verify that the design and development reviews are conducted by personnel with expertise in
relevant operational functions for the design and development stage being reviewed, as well
as specialists and the individual(s) who does/do not have direct responsibility for the design
and development stage being reviewed. In addition, verify that the results of a design and
development review, including identification of the design, date, and individuals performing
the review, are documented appropriately in the design and development file.
See Objective 1d in Part III.1.A(4) of this compliance program for further inspectional activities
regarding batch production records.
References:
• 21 CFR 211.180(e), 211.188, 211.192, and Clause 7.3 and its subclauses of ISO 13485:2016,
as required by 21 CFR parts 4.4(b)(1)(ii)
• ICH Q7, section VI.E, Batch Production Records (Batch Production and Control Records)
Date of Issuance: 04/14/2026 Page 26 of 83
第 27 页
PROGRAM 7346.832M
(i) Computerized Systems
Computerized systems used to support commercial manufacturing operations are expected to have
controls to ensure that data generated by these systems are reliable, accurate, complete, and secure. 41
They should have sufficient controls to prevent unauthorized access and unauthorized changes to
data. If changes are made, computerized systems should be able to trace the change, who made it, and
when it was made and should also be able to capture the original entry before the change was made.
Changes to computerized systems should be made according to an approved change procedure and
should be formally authorized, documented, and validated. Records should be kept of changes,
including modifications and enhancements made to hardware, software, and other critical components
of the system.
The inspection team should, at a minimum:
• Confirm that computerized systems involved in product manufacturing operations are
validated for their intended use. 42
• Verify that written procedures are available for the operation and maintenance of
computerized systems.
• Verify that user access controls to computerized systems are appropriately configured and
enforced to prohibit unauthorized access, unauthorized changes to data, and deletion of data.
• Verify that the system administrator role and any rights to alter files and settings are assigned
to personnel independent from those responsible for the record content and verify that the
quality unit maintains and controls a list of authorized individuals for each system.
• Verify that audit trail functionalities for computerized systems are properly configured,
enabled, and locked and that audit trails for critical data are independently reviewed during
data review and batch release. Verify that the production and control records, which include
audit trails, have been reviewed and approved by the quality unit. Verify that aborted or
incomplete analyses/runs are captured in audit trails and that they have been investigated and
justified.
• Verify that changes to computerized systems are authorized, documented, and validated and
that records of changes are maintained to ensure that the computer system remains in a
validated state.
• Verify that original manufacturing and testing data and relevant metadata, including audit
trails, are backed up periodically using a secure and commercial process, and confirm that
efficient, reliable restoration of the backup/archived data is verified.
References:
• 21 CFR 211.68(b) and 211.192
41
Computerized or related systems can refer to computer hardware, software, peripheral devices, networks, cloud
infrastructure, personnel, and associated documents (e.g., user manuals, SOPs).
42
See ICH Q7, which defines validation as providing assurance that a specific process, method, or system will
consistently produce results meeting predetermined acceptance criteria.
Date of Issuance: 04/14/2026 Page 27 of 83
第 28 页
PROGRAM 7346.832M
• ICH Q7, section V.D, Computerized Systems
• Guidance for industry Data Integrity and Compliance With Drug CGMP: Questions and
Answers (December 2018)
• Guidance for industry and FDA staff General Principles of Software Validation (January
2002)
(j) Change Management
Changes to manufacturing operations, controls, materials, analytical methods, computer hardware and
software, facilities, and equipment are expected to be evaluated for their potential to impact product
quality. CGMP-related changes that can potentially affect product identity, strength, quality, safety,
purity, and potency should be implemented following approval by the quality unit and other relevant
disciplines.
Evaluation and verification of an establishment’s change management system are particularly
important when an applicant proposes specific ECs for the application, comparability protocols to
modify ECs, or the reporting categories for ECs differ from FDA regulations and guidance.
The inspection team should, at a minimum:
• Determine whether there is a strategy for evaluating the effect that changes in manufacturing
operations have on the product’s identity, strength, quality, safety, purity, and potency.
• Verify that changes are reviewed and approved by the quality unit and relevant disciplines and
that if the establishment conducts additional testing and validation studies, they are
appropriate to justify the changes.
• Verify that there is a robust change control system and major changes made to manufacturing
operations after process validation are reported with the appropriate reporting category to
FDA.
• For combination products with biological product and device constituent parts, verify that the
quality unit and relevant disciplines review and approve procedures for the identification,
documentation, validation, and, where appropriate, review and approve design and
development changes of device constituent parts before their implementation.
References:
• 21 CFR 211.100, 211.160, 601.12, and Clause 7.3 and its subclauses of ISO 13485:2016, as
required by 21 CFR parts 4.4(b)(1)(ii)
• ICH Q7, section XIII, Change Control
• ICH Q9(R1)
• ICH Q10
• ICH Q12
• Guidance for industry Changes to an Approved Application for Specified Biotechnology and
Specified Synthetic Biological Products (July 1997)
Date of Issuance: 04/14/2026 Page 28 of 83
第 29 页
PROGRAM 7346.832M
• Guidance for industry CMC Postapproval Manufacturing Changes To Be Documented in
Annual Reports (March 2014)
(k) Validation Protocols and Reports
Manufacturing and testing in conformance with CGMP requirements require validation activities;
manufacturers are expected to collect and evaluate data demonstrating that equipment, processes, and
test methods are capable of consistently performing as intended to produce high-quality product for
commercial distribution. For biological products, applications need to include sufficient data and
information demonstrating that the commercial manufacturing process consistently delivers a product
that is safe, pure, and potent. The demonstration of consistency is supported by data and information
derived from process validation Stage 2 – process performance qualification (PPQ). For combination
products with biological product and device constituent parts, pharmaceutical development practices
such as Quality by Design 43 can be used and built upon to demonstrate compliance with design and
development requirements. However, the manufacturer should have documentation supporting their
claim that the device constituent part design and control procedures are in alignment with the design
and development requirements.
The quality unit is responsible for overseeing validation activities, including reviewing and approving
validation protocols and reports.
The inspection team should, at a minimum:
• Verify that the quality unit reviews and approves validation protocols and reports and ensures
that procedures are executed as written.
• Verify that validation reports contain results that meet predetermined acceptance criteria as
submitted to FDA.
• Determine whether deviations or investigations occurred during execution of the validation
protocol and, if so, whether the deviation investigations and associated CAPAs and change
controls were adequate. Consider the potential impact of the deviation on FDA’s assessment
of validation data submitted to the application.
• Determine whether associated change management activities are indicative of inadequate
validation efforts.
• For combination products with biological product and device constituent parts, verify that the
manufacturer has procedures that describe the process for design and development verification
and design and development validation for each device constituent part specific to its use and
ensure that the procedures are executed as written. 44
References:
43
See the guidance for industry Q8(R2) Pharmaceutical Development (November 2009).
44
Design and development verification and design and development validation data are evaluated during BLA
assessment.
Date of Issuance: 04/14/2026 Page 29 of 83
第 30 页
PROGRAM 7346.832M
• 21 CFR part 211, subparts F—Production and Process Controls and I—Laboratory Controls,
21 CFR 601.2(a), and Clause 7.3 and its subclauses of ISO 13485:2016, as required by 21
CFR parts 4.4(b)(1)(ii)
• ICH Q7, section XII, Validation
• Guidance for industry Process Validation: General Principles and Practices (January 2011)
(l) Product Review
Products are expected to be regularly reviewed for quality with the objective of verifying the
consistency of manufacturing operations after approval. These product reviews are expected to be
performed and documented at least annually and generally include a review of the following:
• Critical in-process controls.
• Trending of release data.
• Batches that failed to meet established specifications.
• Critical deviations or nonconformances and related investigations.
• Changes introduced to commercial manufacturing and testing operations.
• Results of the stability monitoring program.
• Environmental monitoring data.
• Utility systems (e.g., water, gas) monitoring data.
The inspection team should, at a minimum:
• Verify that the establishment has developed procedures or will sufficiently incorporate the
pending drug into existing procedures to conduct product reviews at least annually.
• Determine whether the product review procedure is comprehensive and covers relevant
quality reports.
References:
• 21 CFR 211.180(e)
• ICH Q7, section II.E, Product Quality Review
(m) Stability Program
A stability monitoring program is expected to be in place to confirm product stability. In general, at
least one product batch is subjected to stability testing annually, and additional batches should be
placed on stability following major deviations or anomalies that occur during production.
The inspection team should, at a minimum:
• Verify that stability records are aligned with data and information submitted in the
application.
Date of Issuance: 04/14/2026 Page 30 of 83
第 31 页
PROGRAM 7346.832M
• Verify that procedures are in place and are followed within the establishment, as appropriate,
for the storage and testing of stability samples as specified in the application.
• Verify that validation and continuous monitoring of stability chambers used for storage of
stability samples are operated and maintained at storage conditions specified in the
application. Review deviations related to stability chambers.
• During PAIs, verify that adequate investigation and documentation of stability failures occur
and, if necessary, stability failures are reported through BPDRs.
References:
• 21 CFR 211.137, 211.166, 211.170, 211.194, and 610.50
• ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products
(November 2003)
• ICH guidance for industry Q5C Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products (July 1996)
• ICH Q7, section XI.E, Stability Monitoring of APIs 45
(n) Deviation and Failure Investigations
The effectiveness of the establishment’s quality system is in part evaluated based on the established
practices in place to mitigate and prevent excursions, adverse trends, deviations, failures, and changes
in product quality. When excursions, adverse trends, deviations, or failures occur, the establishment’s
quality system is expected to conduct thorough and meaningful investigations with scientifically
supported conclusions, relevant CAPAs, and associated change controls as needed. The effectiveness
of CAPAs is expected to be documented and evaluated by the quality unit in a timely manner.
The inspection team should, at a minimum:
• Verify that the quality unit reviews production records to investigate unexplained excursions,
adverse trends, deviations, and failures and that it fully investigates errors. Verify that the
quality unit’s investigation includes an evaluation of relevant product batches, including
aborted batches.
• Verify that the establishment has and follows quality unit-approved procedures for handling
deviation-and-failure investigations.
• Evaluate a sufficient number of investigation records across multiple systems for commercial
manufacturing operations to confirm the adequacy of investigations, product disposition
decisions, and CAPA implementations.
• For combination products with biological product and device constituent parts, verify that the
manufacturer has established and maintained procedures for implementing analysis of data,
improvement, and complaint handling to address nonconformance associated with the device
constituent part and the combination product as a whole. Verify that there are effectiveness
45
API=active pharmaceutical ingredient.
Date of Issuance: 04/14/2026 Page 31 of 83
第 32 页
PROGRAM 7346.832M
checks that consider the combination product as a whole even if the analysis of data,
improvement, and complaint handling applies only to a single constituent part.
References:
• 21 CFR 211.192, and Clause 7.3 and its subclauses of ISO 13485:2016, as required by 21
CFR parts 4.4(b)(1)(iv)
• ICH Q7, section II.A, Principles
• ICH Q9(R1)
(o) Product Complaints, Adverse Event Reports, BPDRs, Recalls, and Returns
Adequate procedures are expected to be in place to handle product complaints, adverse event reports
(AERs), BPDRs, recalls, and returns.
The inspection team should, at a minimum:
• Verify that adequate procedures are in place for proper handling of product complaints, AERs,
BPDRs, recalls, and returns.
• If applicable, review records of product complaints, AERs, BPDRs, recalls, and returns and
verify if approved procedures were followed, adequate investigations were conducted, and
CAPAs were implemented.
References:
• 21 CFR 7.40, 211.180(e)(2), 211.198, 600.14, and 600.80
• ICH Q7, section XV, Complaints and Recalls
• Guidance for industry Biological Product Deviation Reporting for Licensed Manufacturers of
Biological Products Other than Blood and Blood Components (October 2006)
• Compliance program 7356.002M—Surveillance Inspections of Protein Drug Substance
Manufacturers 46
(2) Objective 1b: Evaluation of the Suitability of Facilities and Equipment
Under this objective, the inspection team evaluates a facility’s design, layout, and equipment—
including utilities and equipment qualification, calibration, and maintenance—supporting the
commercial operations described in the application. During the inspection, the inspection team
observes the commercial manufacturing operations related to the product of interest and verifies that
they are performed in the areas and with the equipment as described in the application.
Facilities might conduct aseptic processing operations (e.g., DP filling operations) where product
sterility must be maintained. 47 In such cases, the inspection team should refer to compliance program
46
Compliance program 7356.002M applies only to surveillance inspections of CDER-regulated protein DS
manufacturers.
47
21 CFR 211.113(b).
Date of Issuance: 04/14/2026 Page 32 of 83
第 33 页
PROGRAM 7346.832M
7356.002A to appropriately evaluate aseptic processing operations performed for DP operations and,
when appropriate, for DS operations. In addition, the inspection team should refer to FDA’s
recommendations regarding aseptic processing in the guidance for industry Sterile Drug Products
Produced by Aseptic Processing—Current Good Manufacturing Practice (September 2004).
Parts III.1.A(2)(a) through (c) below outline specific areas under Objective 1b that should be verified
by the inspection team as they relate to the product of interest.
(a) Facilities
The buildings and facilities housing manufacturing operations are expected to be of suitable size and
design and are expected to be constructed to facilitate cleaning, maintenance, and operations that are
appropriate for the type of manufacturing being performed. Facilities are expected to be designed to
minimize potential exposure of the product stream to contaminants. Adequate changeover activities
are critical when commercial manufacturing operations are conducted in a multiproduct
establishment.
The inspection team should, at a minimum:
• Review the design and layout of the facility (e.g., personnel flow, material flow, equipment
flow, product flow, waste flow, area classifications) on paper and on the manufacturing floor
to confirm their suitability.
• Verify: (a) appropriate segregation with adequate space to prevent mix-ups, (b) appropriate
area classification, and (c) adequate pressure differential controls (e.g., cascades, sinks, or
bubbles for personnel/material airlocks) are established to prevent cross-contamination and
microbiological contamination.
• Verify that pertinent buildings and facilities are in an appropriate state of repair during the
inspection walk-through.
• Verify the suitability of the type of water used in manufacturing.
• Verify that clean utilities are qualified and monitored and that actions are taken when limits
are exceeded.
• Verify that cleaning and disinfecting procedures are sufficiently detailed (e.g., concentrations
of cleaning and disinfectant solutions, contact time, use of sporicidal agents) and that they
adequately ensure microbial control based on environmental monitoring data.
• Evaluate whether a response plan is in place to guide decontamination activities during
catastrophic spills and potential viral contamination events.
References:
• 21 CFR 211.42 through 211.58, 211.63 through 211.72, and 600.11(a) and (b)
• ICH Q7, sections IV.A, Design and Construction, and V, Process Equipment
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, section IV, Buildings and Facilities
Date of Issuance: 04/14/2026 Page 33 of 83
第 34 页
PROGRAM 7346.832M
i. HVAC system/Area classifications
Heating, ventilation, and air conditioning (HVAC) systems are essential for providing suitable
manufacturing environments for biological products, which are usually manufactured using
mammalian cell cultures that are susceptible to contamination by adventitious agents (e.g., viruses,
mycoplasma). HVAC systems are expected to be designed to contain or protect biological products
from risks of contamination and cross-contamination.
The inspection team should, at a minimum:
• Determine if the HVAC system, including air-handling unit segregation, area classifications,
and pressure differential controls, is appropriately designed to prevent cross-contamination
and the spread of adventitious agents.
• Review environmental monitoring data (see Part III.1.A(2)(a)(v)—Environmental monitoring
for more details) and pressure differential data to determine whether there is adequate
establishment control.
• Verify that the cell culture/fermentation microbial contamination rates and in-process
bioburden and endotoxin data for harvesting and purification confirm the suitability of the
environmental classifications for production areas.
• Determine whether there is environmental segregation of manufacturing operations that occur
before viral clearance/inactivation and those that occur after viral clearance/inactivation, with
separate air handling units or a once-through HVAC system. In the case where there is no
physical segregation of pre- and post-viral operations, evaluate whether procedural controls or
other controls are in place to sufficiently mitigate viral contamination risks and that available
information and data support this practice.
• Determine whether there is physical segregation of live cell and cell-free areas for microbial-
derived products.
• Determine whether there are adequate records on the HVAC system’s installation,
qualification, and recertifications (e.g., documentation of testing for flow laminarity, air
velocity, particle counts, leaks). Review the qualification and recertification data and confirm
that high-efficiency particulate air (HEPA) filters are tested for integrity at installation and
recertified at least annually.
References:
• 21 CFR 211.46(a) through (c) and 600.11(a)
• ICH Q7, section IV.B, Utilities
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, section IV, Buildings and Facilities
ii. Water system and clean steam system
Water used in manufacturing is expected to be suitable for its intended use. In general, water for
injection (WFI) is used in the production of biological products. Purified water can be used for initial
equipment rinses when cleaning. Purified water can also be used in fermentation and early-stage
Date of Issuance: 04/14/2026 Page 34 of 83
第 35 页
PROGRAM 7346.832M
purification steps for microbial processes using Gram-negative organisms. The downstream
purification process is generally designed to remove levels of endotoxin generated by the microbial
cultures, after which it is more appropriate to use WFI. It may also be possible to justify the
suitability of purified water in other cases, such as fermentation processes for fungal or Gram-positive
host organisms. However, WFI should generally be used for all DS manufacturing steps of
mammalian cell-derived products. WFI is expected to have appropriate specifications for
physical/chemical attributes, total microbial counts, objectionable organisms, and endotoxins.
Clean steam condensate quality specifications should not be inferior to compendial (United States
Pharmacopeia (USP)) standards for WFI for physical/chemical attributes and endotoxins.
The inspection team should, at a minimum:
• Verify that the primary source of water complies with applicable standards (e.g., U.S.
Environmental Protection Agency, World Health Organization, European Union) and that
water production systems (including purified water and WFI) produce water of a quality that
is suitable for its intended use.
• Verify the adequacy of the water system’s design (e.g., no dead legs) and qualification.
• Evaluate the adequacy of the facility’s water system maintenance program (e.g., no visible
leaks) and related procedures to determine whether the program maintains a constant state of
control over the system.
• Verify the adequacy of the facility’s water monitoring program and associated procedures and
data. Similarly, determine whether the establishment adequately investigates and documents
water and clean steam monitoring excursions and implements appropriate CAPAs in a timely
manner.
• Determine whether the level of steam saturation or dryness, amount of non-condensable gas,
and amount of superheat are suitable for the intended pure steam application.
References:
• 21 CFR 211.48, 211.63, 211.67(b), 211.100(a) and (b), and 211.192
• ICH Q7, section IV.C, Water
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, section VI, Components and Containers/Closures
• USP General Chapter <1231> Water for Pharmaceutical Purposes
iii. Other utilities
Other utilities (such as process gases) that can impact product quality are expected to be qualified and
appropriately monitored as actions need to be taken when limits are exceeded. These utilities can be
used in both upstream and downstream manufacturing operations.
The inspection team should, at a minimum:
• Review the sampling points, frequency of testing, acceptance criteria, monitoring data, and
maintenance records.
Date of Issuance: 04/14/2026 Page 35 of 83
第 36 页
PROGRAM 7346.832M
• Verify the locations of the filters used to remove bioburden and particulates (if applicable)
from process gases during manufacturing operations and verify the frequency of integrity
testing and replacement of these filters.
References:
• 21 CFR 211.46 and 600.11
• ICH Q7, section IV.B, Utilities
iv. Pest control
A pest control program is necessary to prevent infestations and contamination of raw materials,
equipment, and other components that can impact manufacturing operations.
The inspection team should, at a minimum:
• Verify the adequacy of the establishment’s pest control program.
• Evaluate the adequacy of pest monitoring limits and determine whether the frequency of trap
inspections is adequate.
• Evaluate the establishment’s pest control data, pest control deviations, and associated
investigations and CAPAs.
References:
• 21 CFR 211.56
• ICH Q7, section IV.G, Sanitation and Maintenance
v. Environmental monitoring
Establishments should use appropriate environmental controls to minimize the risk of contamination.
When determining acceptance criteria for air quality and monitoring frequency, establishments
should factor in the stages of production and the types of operations conducted in specific areas
(open, closed, or contained systems).
The inspection team should, at a minimum:
• Determine the adequacy of the establishment’s environmental monitoring program, including
monitoring methods, locations, frequency, and alert and action limits. Confirm monitoring
methods and locations on the manufacturing floor.
• Review environmental monitoring data and trend reports to verify that the HVAC control and
cleaning and sanitization programs are adequate and effective (see Part III.1.A(2)(a)(i)—
HVAC system/Area classifications for more details).
• Determine whether the establishment promptly responds to, adequately investigates, and
documents environmental monitoring excursions and performs appropriate CAPAs in a timely
manner.
References:
• ICH Q7, section XVIII.A, General
Date of Issuance: 04/14/2026 Page 36 of 83
第 37 页
PROGRAM 7346.832M
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, section X.A, Environmental Monitoring
(b) Equipment
Manufacturing equipment is expected to be of appropriate design and size and be suitable for its
intended use. A cleaning, sterilization/sanitization (where appropriate), and maintenance program is
expected to be in place and followed at appropriate intervals to prevent equipment malfunctions and
contamination.
The inspection team should, at a minimum:
• Confirm that product contact surfaces are constructed from materials that are not reactive,
additive, or absorptive.
• Confirm that substances associated with equipment operation, such as lubricants, heating
fluids, and coolants, do not contact products directly or alter their quality.
• Confirm that equipment failures and deviations related to equipment function are evaluated
for their impact on product quality.
• Verify that critical equipment specified in the application is the same equipment used during
commercial manufacturing operations.
• Confirm that the establishment has effective preventive maintenance and calibration programs
for its equipment.
• Review records associated with the qualification, requalification, preventive maintenance,
calibration, cleaning, and sterilization/sanitization of manufacturing and laboratory testing
equipment, as applicable.
• Verify the effectiveness of microbial control and equipment sterilization/sanitization
procedures as demonstrated by low rates of cell culture/fermentation process contamination
and acceptable in-process harvesting and purification bioburden and endotoxin data.
• Verify that deviations related to manufacturing equipment have been appropriately
investigated and CAPAs implemented in a timely manner. Confirm that the effectiveness of
CAPAs after implementation has been evaluated and documented. As appropriate, verify the
adequacy of the implemented CAPAs on the manufacturing floor.
• For protein DS manufacturing using critical equipment with specialized qualification
activities (e.g., fermentors or bioreactors, centrifuges, depth filtration, UF/DF, column
chromatography equipment), evaluate the verification activities related to equipment
maintenance and requalification/continued performance. 48 This includes:
o Adhering to chromatography resin or UF/DF membrane lifetimes as established and
concurrently validated at commercial scale, including a periodic review of the qualified
state and requalification of these lifetimes as needed.
48
Information on qualification activities is also evaluated as part of the application assessment.
Date of Issuance: 04/14/2026 Page 37 of 83
第 38 页
PROGRAM 7346.832M
o Ensuring that instruments used to measure or monitor critical in-process parameters such
as pH or dissolved oxygen are maintained and calibrated at appropriate intervals using
appropriate standards. These calibration procedures should also contain limits for accuracy
over the relevant range and limits for precision.
References:
• 21 CFR 211.63, 211.65, 211.67, and 211.113
• ICH Q7, section V.A, Design and Construction
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing —Current Good
Manufacturing Practice, section IX.C, Sterilization of Equipment, Containers, and Closures
• Compliance program 7356.002A—Sterile Drug Process Inspections
• International Organization for Standardization (ISO) 17665, Sterilization of Health Care
Products—Moist Heat —Requirements for the Development, Validation and Routine Control
of a Sterilization Process for Medical Devices (2024)
i. Equipment cleaning
Equipment used to manufacture products are expected to be cleaned, stored, and, where appropriate,
sanitized or sterilized to prevent contamination or carryover of a material that would alter product
identity, strength, quality, safety, purity, and potency. Equipment cleaning validation studies are
expected to include an evaluation of the cleaning efficacy for dedicated and shared equipment. In
general, cleaning validation includes preestablished residual limits assessed by assays demonstrated
to detect residues. For shared equipment and utensils, the cleaning validation ensures that there is no
carryover between products such that product safety and efficacy are compromised. A periodic
monitoring program is expected to be in place to verify that equipment and utensils continue to be
effectively cleaned.
The inspection team should, at a minimum:
• Review equipment cleaning validation data to determine the adequacy of the cleaning-in-place
system, washer cycles, and manual cleaning operations in removing cleaning agents and
product residues. Highest priority should be placed on equipment shared with other products
and on equipment used to process high-risk products (e.g., spore-forming organisms or highly
potent or toxic products). 49 If cleaning validation has not been completed, evaluate whether
the establishment has adequate cleaning verification procedures in place. Verify that cleaning
validation and verification includes a visual inspection (e.g., for lyophilizers, a periodic
monitoring for leaks of silicon oil or alternate shelf heat fluids).
• Verify that the cleaning validation acceptance criteria are suitable for the equipment’s
intended use.
• Verify that the validated cleaning procedures are followed during routine equipment cleaning.
• Review the frequency of and resulting data for periodic equipment cleaning verification.
49
See Attachments B and C of this compliance program.
Date of Issuance: 04/14/2026 Page 38 of 83
第 39 页
PROGRAM 7346.832M
• Review the validation of equipment’s dirty and clean hold times, if applicable. Confirm
adherence to the validated dirty and clean hold times.
• Visually check equipment cleanliness.
References:
• 21 CFR 211.67 and 600.11(b)
• ICH Q7, section V.B, Equipment Maintenance and Cleaning
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, sections VI, Components and Containers/Closures, and VII,
Endotoxin Control
ii. Equipment sanitization and sterilization
Establishments are expected to use sterile equipment for cell culture and fermentation processes.
Equipment used in purification processes can be sterilized or sanitized to prevent cross-
contamination.
The inspection team should, at a minimum:
• Review the validation and requalification records of sterilization processes for cell culture and
fermentation equipment as detailed in the application to determine whether there is effective
equipment sterilization.
• Verify the sterilization and/or sanitization validation and requalification of purification
equipment to determine whether there is effective microbial control of equipment.
References:
• 21 CFR 211.67
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Practice, sections VI, Components and Containers/Closures, and VII,
Endotoxin Control
• ICH Q7, sections XVIII, Specific Guidance for APIs Manufactured by Cell
Culture/Fermentation
iii. Equipment maintenance and calibration
Equipment used in the manufacture and testing of raw materials, in-process materials, intermediates,
and products are expected to be calibrated according to written procedures and an established
schedule. The equipment maintenance and calibration schedule should be based on the criticality of
the equipment or the frequency of the equipment use to ensure that relevant range and limits for
precision are maintained as appropriate. Equipment calibrations are expected to be performed using
certified standards or equipment manufacturer’s recommended standards. Deviations from approved
standards of calibration involving critical instruments should be investigated to determine if those
deviations could have influenced the determination of the product quality.
The inspection team should, at a minimum:
Date of Issuance: 04/14/2026 Page 39 of 83
第 40 页
PROGRAM 7346.832M
• Determine if the procedures and schedules of the equipment maintenance program are
adequate to support the equipment’s intended use.
• Confirm that appropriate documentation is maintained.
• Verify that appropriate and timely actions are taken in response to identified or potential
equipment issues or deviations.
• For manufacturing and laboratory equipment, verify that the establishment follows a
calibration SOP that includes:
o Specific directions on how to conduct the equipment calibration.
o Limits for the equipment’s accuracy and precision.
o A schedule for the equipment calibration that details its frequency.
o Provisions for implementing CAPAs and an evaluation of the impact on product quality
involving batches affected by calibration deviations.
• Verify that calibration standards are maintained, and that current calibration status is known
and verifiable.
• Evaluate calibration records.
• For disposable or single-use equipment:
o Verify that disposable equipment has been appropriately qualified (e.g., for
extractables/leachables, compatibility, and other suitability issues).
o Verify that appropriate and timely actions are taken in response to disposable equipment
leakage incidents and that the incidents are not recurring.
o Confirm that there is an approved SOP to address leakage incidents involving disposable
containers. Verify that the SOP includes provisions for evaluating and addressing
contamination and cross-contamination of buffers, media, cell cultures, in-process
intermediates, and DS affected by the leakage.
References:
• 21 CFR 211.58, 211.67, and 211.68
• ICH Q7, section V.C, Calibration
(c) Cross-Contamination Prevention
Cross-contamination is a risk to product safety. Cross-contamination can occur through mix-ups,
retention, mechanical transfer, and airborne transfer in a multiproduct establishment.
The inspection team should, at a minimum:
• Evaluate the establishment’s cross-contamination prevention measures, including HVAC
design and area segregation as described in Part III.1.A.(2)(a)i of this compliance program.
Date of Issuance: 04/14/2026 Page 40 of 83
第 41 页
PROGRAM 7346.832M
• Determine whether changeover procedures (e.g., personnel, equipment, product) are
appropriate to prevent cross-contamination and mix-ups.
o Obtain a list of changeover activities and determine whether procedures are followed and
are adequate. Verify that shared equipment and areas are cleaned and released for use
according to quality unit-approved procedures to prevent mix-ups and cross-contamination
of raw materials, equipment, and products.
o Verify that adequate cleaning procedures for shared product contact equipment are in
place to prevent product carryover. Verify that acceptance criteria for residuals are
adequately calculated and justified. Pay special attention to changeover of production
areas from one product with a higher risk profile (e.g., highly potent or toxic product) to
another product.
o For products for which cleaning validation has not been completed, confirm that cleaning
verification is conducted for shared equipment during changeover. Verify that cleaning
verification data from previous changeover processes are documented in sufficient detail.
• Verify that adequate procedures are in place to govern the flow of products, raw materials,
personnel, waste, and equipment to prevent cross-contamination. Evaluate product crossover
points that might allow cross-contamination between different products.
• Observe personnel working in more than one area and verify that employees are following
appropriate cross-contamination measures and have been trained to take adequate precautions
to prevent cross-contamination when they pass from one area to another.
• Evaluate crossover points that might allow cross-contamination between different process
steps. Of particular importance are crossover points between upstream and downstream steps
and crossover points between pre- and post-viral clearance steps.
References:
• 21 CFR 211.42(b) and (c)
• ICH Q7, section IV.D, Containment
• International Society for Pharmaceutical Engineering (ISPE) Baseline Guide Volume 7, Risk
Based Manufacture of Pharmaceutical Products (Risk-MaPP) (2017)
(3) Objective 1c: Evaluation of Material Management to Support Commercial
Manufacturing
Under this objective, the inspection team evaluates the control of materials (e.g., raw materials, cell
lines) used in the commercial manufacturing operations described in the application. 50
References:
• 21 CFR 211.42(a), 211.58, 211.80, 211.82, 211.84 through 211.94, 600.11(h), and 601.2
• ICH Q7, section VII, Materials Management
50
Coverage of the water system and process gases is provided under Objective 1b of this compliance program.
Date of Issuance: 04/14/2026 Page 41 of 83
第 42 页
PROGRAM 7346.832M
Parts III.1.A(3)(a) through (d) below outline specific areas under Objective 1c that should be verified
by the inspection team as they relate to the product of interest.
(a) Receipt, Inventory, and Storage of Materials
The establishment is expected to have adequate written procedures for the receipt, identification,
quarantine, handling, sampling, storage, and approval or rejection of materials. Materials to be used
in commercial manufacturing operations should be stored under conditions that are appropriate to
prevent degradation, contamination, and cross-contamination. The establishment’s warehouses and
storage areas are expected to be maintained in a clean and orderly manner and should be of suitable
size and design to accommodate appropriate materials management.
Materials are expected to be stored off the warehouse floor and, when appropriate, suitably spaced to
permit cleaning and inspection. Inappropriate storage conditions increase the risk that critical
materials (e.g., raw materials) or equipment can become the source of unintended variability, which
could affect the product’s identity, strength, quality, safety, purity, and potency.
The inspection team should, at a minimum:
• Observe receiving, quarantine, sampling, and storage areas to verify the appropriate handling
and inventory of materials coming into the establishment as specified in the application.
o Verify that materials are stored under conditions (e.g., light exposure, temperature,
humidity) that are appropriate to prevent deterioration and contamination (microbial or
otherwise) and that they are protected from rodents and other pests.
o Verify that the unpacking and handling of materials, instruments or equipment is
performed following approved procedures that safeguard equipment integrity (e.g.,
protecting from damage by sharp tools, preventing damaging or kinking flexible tubing).
o Confirm that storage areas are appropriately sized and spaced to allow for cleaning and
inspection.
o Verify that appropriate expiry or retest dates have been assigned to materials in storage
areas and that they are clearly identifiable.
• Confirm during an inspection walk-through that rejected materials are clearly identified and
controlled under a quarantine system that prevents unauthorized use.
• Verify that there are inventory control processes that account for material storage, distribution
controls, quarantine practices, and documentation for incoming materials. Confirm that the
control processes adequately ensure the traceability of material lots used in commercial batch
production and prohibit the use of quarantined, expired, or rejected material.
• Confirm that the establishment maintains an inventory of critical materials and that it includes
their source, use, and criticality ranking for their potential to introduce contaminants or alter
the final product, if their sourcing is altered.
• Verify that the establishment has a plan to address potential supply chain vulnerabilities in a
timely manner.
References:
Date of Issuance: 04/14/2026 Page 42 of 83
第 43 页
PROGRAM 7346.832M
• 21 CFR 211.80, 211.82, and 211.84
• ICH Q7, section VII, Materials Management
• ICH Q10
(b) Supplier Qualifications
The establishment is expected to have adequate procedures for selecting, qualifying, and monitoring
raw material suppliers. Supplier qualification includes an evaluation of whether a supplier is able to
consistently provide material meeting the quality unit-approved specifications. Complete analyses of
the supplier material should be conducted on at least three batches of each acquired material before
reducing its in-house testing provisions. At a minimum, a complete analysis needs to be performed at
appropriate intervals and compared with the certificates of analysis (COAs) of the acquired material
to verify the reliability of COAs at regular intervals. Where appropriate, establishments can rely on
COAs from the supplier once the reliability of the supplier’s analysis has been established and one
specific identity test is conducted (if applicable) upon receiving the raw material.
The inspection team should, at a minimum:
• Verify that there are adequate procedures in place to select, qualify, and monitor raw material
suppliers. Confirm that critical and high-risk materials, including disposable equipment, are
sourced and supported by an appropriate risk-based qualification program.
• If the establishment relies on COAs in lieu of testing every lot of materials for conformance to
specifications, confirm that the reliability of the supplier’s analysis has been established
through initial and periodic verification of the supplier’s test results.
• Evaluate the establishment’s raw material and component supplier qualification program.
Determine whether the approach, including initial and ongoing audits, is appropriately risk-
based, considering the criticality of materials and their potential impact on product quality.
Note any materials for which an initial on-site audit of the supplier was not conducted by the
establishment or a qualified third party and determine the establishment’s justification for not
doing so, including their documented risk-based assessment.
• Verify that quality agreements between the manufacturer and suppliers include supplier
qualification and auditing that are appropriately performed considering material risks.
• Note if there were recent changes in the supply of critical raw materials and verify that the
changes were handled per established and appropriate change management procedures.
Confirm that an evaluation of the potential impacts to product quality was conducted.
References:
• 21 CFR 211.84
• ICH Q7, section VII, Materials Management
Date of Issuance: 04/14/2026 Page 43 of 83
第 44 页
PROGRAM 7346.832M
(c) Raw Material and Component Testing, Examination, Release, and
Documentation
Manufacturers are expected to purchase raw materials and components against agreed specifications,
from suppliers, approved by the quality unit.
The inspection team should, at a minimum:
• Verify that there are appropriate written specifications approved by the quality unit for raw
materials noted in the application.
• Confirm that released materials meet specifications through testing of representative samples
or through the examination of a COA from an appropriately qualified vendor. Confirm that
materials intended for release that do not meet the specifications are rejected and documented.
• Verify that procedures are in place and are followed for the quarantine, testing, and release of
raw materials.
• Verify that source materials of animal origin are tested as described in the application.
Specifically:
o Verify that the establishment has determined, through testing or verification by
manufacturer COA, that biological raw materials are free from adventitious agents.
o Verify that raw materials with the potential for microbiological contamination undergo
microbiological tests before use.
• If the establishment administered a conditional release of material or components, verify that
the material or components were confirmed to be fit for use before distribution. Note that
conditional release of DP components is not allowed (21 CFR 211.84(a) and (b)), including
BDS (ICH Q7).
• For synthetic processes, if the starting material is not commercially supplied, confirm that
processes exist and are followed to ensure changes in the defined chemical properties and
structures did not occur before use in manufacturing operations.
• For combination products with biological product and device constituent parts, verify that the
device constituent parts (or their components) are purchased from a supplier that meets
purchasing requirements as described in Compliance Program 7356.000 Attachment B.
References:
• 21 CFR 211.84, 600.11, and 21 CFR part 4.4
• ICH Q7, section VI.C, Records of Raw Materials, Intermediates, API Labeling and Packaging
Materials
• Compliance program 7356.000—Inspections of CDER-led or CDRH-led Combination
Products
Date of Issuance: 04/14/2026 Page 44 of 83
第 45 页
PROGRAM 7346.832M
(d) Cell Banks
Storage conditions for cell banks (MCB or WCB) are expected to be clearly defined, with control
systems in place to maintain viability and prevent contamination and mix-ups. Monitoring of
temperature readings and a working alarm system are essential to ensure that cell banks are stored
within established storage conditions. Additionally, to maintain the integrity of the cell banks, it is
essential to have a system in place to maintain records of cell bank inventory and the consistency of
storage conditions. Limiting access to authorized personnel is critical for maintaining the security and
integrity of cell banks.
The inspection team should, at a minimum:
• Review records for inventory and handling of cell banks. Confirm that the records trace the
use of specific WCB vials and lots, including whether the vial was used in a completed or
failed manufacturing campaign. Also confirm that the establishment investigates whether
manufacturing campaign failures correlate with cell bank-related issues.
• If cell banks are not stored on-site but are received from other establishments, verify that
adequate procedures are in place to (1) confirm the identity of received cell bank vials, (2)
verify that cell bank vials are appropriately controlled to prevent temperature excursions
during shipping, and (3) verify that adequate storage conditions are used until production as
specified elsewhere in this section.
• Verify that procedures are in place to adequately segregate cell banks used for production
from uncharacterized or quarantined cell banks. For multiproduct establishments, verify that
there is adequate segregation of cell lines either physically or through controlled procedures to
prevent misuse of other products’ cell bank vials in production.
• Determine whether there are procedures in place to address resupply or requalification of cell
banks when a specific point in the inventory of cell bank vials is met. Verify that the
procedures ensure timely resupply or requalification of cell banks.
• Verify that storage conditions for cell banks are adequately monitored, and review freezer
temperature logs and maintenance activities to confirm that freezers are appropriately
maintained to protect cell banks. Confirm these storage conditions and monitoring activities
on-site during the cell bank storage area inspection.
References:
• 21 CFR 610.18
• ICH guidance for industry Q5A(R2) Viral Safety Evaluation of Biotechnology Products
Derived From Cell Lines of Human or Animal Origin (January 2024)
• ICH Q7, section XVIII.B, Cell Bank Maintenance and Record Keeping
• ICH guidance for industry Q11 Development and Manufacture of Drug Substances
(November 2012)
Date of Issuance: 04/14/2026 Page 45 of 83
第 46 页
PROGRAM 7346.832M
(4) Objective 1d: Evaluation of Production and Process Controls in Manufacturing
Operations
Under this objective, the inspection team evaluates whether the product of interest is being
manufactured in accordance with the validated commercial manufacturing operations described in the
application. This objective directs the inspection team to evaluate validated manufacturing operations
associated with critical quality attributes and process controls, such as clearance of impurities, viral
clearance, microbial control, and contamination and cross-contamination controls (see also Objective
1b of this compliance program) to verify their conformance to the standards described in the
application. For biological products, data demonstrating the process performance qualification (PPQ)
of the commercial process is submitted in the application.
References:
• 21 CFR 211 subpart F—Production and Process Controls
• ICH Q7, section VIII, Production and In-Process Controls
Parts III.1.A(4)(a) through (k) below outline specific areas under Objective 1d that should be verified
by the inspection team as they relate to the product of interest. Not all biologics-related unit
operations are covered in this compliance program; contact the IQA team for additional information
regarding unit operations not described in this document.
(a) Process Validation
Process validation data are evaluated during application assessment. During the inspection, the
inspection team observes the ongoing commercial manufacturing operations to verify that they are
consistent with the commercial process as described in the application.
The inspection team should, at a minimum:
• Verify that deviation investigations related to process validation activities follow established
procedures.
• Determine whether the establishment has pending change management activities that might be
indicative of incomplete/inadequate process validation.
• Verify that all failed campaigns during the PPQ batch manufacturing were reported in the
application.
• Verify that the establishment is capable of manufacturing commercial batches using the
validated process that produced the PPQ batches, (e.g., manufacturing equipment used to
produce the PPQ batches remains in a qualified state).
• For commercial manufacturing operations, verify that the process is as described in the
application and follows quality standards by reviewing records, observing, and verifying
critical manufacturing steps.
References:
• 21 CFR 211.100
Date of Issuance: 04/14/2026 Page 46 of 83
第 47 页
PROGRAM 7346.832M
• Guidance for industry Process Validation: General Principles and Practices
• ICH Q7, section XII, Validation
(b) In-Process Sampling and Controls
The establishment is expected to have written procedures to monitor the performance of
manufacturing operations.
The inspection team should, at a minimum:
• Review the records of in-process testing and confirm that test results are recorded as described
in the application.
• If a material failed an in-process test, verify that the establishment conducted appropriate
investigations, identified actual or potential root causes, implemented appropriate CAPAs, and
properly disposed of the failed material.
• Review the records of in-process control trends and excursions from established action limits
and determine whether procedures are in place to monitor the maximum number of exceeded
alerts and action limits before implementation of appropriate CAPAs.
• If the material that failed an in-process test was used in a finished product, review the records
of the justification for disposition of the batch in question and verify that the establishment
had adequate justification.
References:
• 21 CFR 211.110
• ICH Q7, section VIII.C, In-Process Sampling and Controls
(c) Manufacturing Operations
Manufacturing of commercial biological products in compliance with CGMP requirements and in
accordance with approved processes, as appropriate, exercising appropriate change controls, and
ensuring adequate microbial control are important concepts in the manufacture of biological products.
These concepts take on added relevance for biological product manufacturing due to the increased
likelihood for failures in these areas. Accordingly, they deserve increased scrutiny during inspection.
It is of particular importance that biological product manufacturing operations are being executed as
described in the application because it is possible for manufacturing changes presumed to be
inconsequential to result in a product change that might not be detectable. For example, a change in a
cell culture parameter could potentially shift DS post-translational modification in a way that affects
product safety and efficacy.
The inspection team should, at a minimum:
• Verify that instructions related to batch production records are followed for different unit
operations.
Date of Issuance: 04/14/2026 Page 47 of 83
第 48 页
PROGRAM 7346.832M
• Verify that unit operations are conducted as currently defined in the application, including
that:
o Operating ranges for process parameters and hold times for process intermediates are not
wider or longer than those listed in the application, respectively. If not, determine whether
these changes were reported to FDA, as appropriate.
o If manufacturing operations include steps for pooling of sub-batches, they are performed
according to validated protocols described in the application and include confirmation that
pooled sub-batches met defined criteria (identical to the application) before pooling.
• Review release and in-process testing data for product batches manufactured to date to
determine the consistency of manufacturing. If release and in-process testing limits were
exceeded, determine whether the establishment followed approved procedures for
investigation; conducted an appropriate, scientifically based investigation; and implemented
CAPAs, as needed. Determine whether the product disposition decision is adequate.
• Review deviations to determine whether there are recurring problems or negative trends in
manufacturing operations.
• If automated systems are used during the production process, verify that the systems were
appropriately qualified and calibrated.
• Verify that there are no open operations during which the DS or DP is exposed to the
immediate environment. If the process described in the application includes open operation(s),
confirm that the open operation is conducted in a suitable environment and manner to prevent
contamination and cross-contamination of the in-process material.
• For combination products with biological product and device constituent parts, verify that the
manufacturer has established and maintained procedures for the transfer of the device
constituent part design (or design of the components thereof) to manufacturing, including
procedures to ensure that the device constituent part design is suitable for manufacturing
before becoming final product specifications and production capability can meet commercial
production specifications.
References:
• 21 CFR 211.42, and Clause 7.3 and its subclauses of ISO 13485:2016, as required by 21 CFR
parts 4.4(b)(1)(ii)
• ICH Q7, section VIII.A, Production Operations
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
Date of Issuance: 04/14/2026 Page 48 of 83
第 49 页
PROGRAM 7346.832M
(d) Weighing and Dispensing
Raw materials used for the manufacturing of biological products (including product intermediates)
are expected to be weighed or measured under appropriate conditions that do not affect their
suitability for use.
The inspection team should, at a minimum:
• Verify that SOPs for tracking and weighing of materials are complete and accurate. This
should include procedures for release of materials and components before use and accurate
recording of information in batch production records.
• Verify that changeover procedures between the handling of different raw materials are
adequate to prevent cross-contamination and are followed in weighing and dispensing areas.
• Observe weighing, measuring, and subdividing operations when feasible to verify that the
materials are those specified in the batch production record for the product and its
intermediate and that there is adequate segregation, tracking, and recording.
• Verify that storage containers are appropriate to maintain material suitability and that they are
clearly labeled.
References:
• 21 CFR 211.101
• ICH Q7, section VIII.A, Production Operations
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
(e) Media and Buffers
Growth media is used at all stages of cell culture unit operations. The media can be of different
composition at different stages and can be supplemented by various components, including salts,
sugars, and antifoaming agents. Process buffers are used throughout manufacturing, but their use is
prominent for the biological product purification and formulation steps. Particular care should be
taken for formulation buffers with excipients. Excipient sourcing and storage conditions are of high
importance.
The inspection team should, at a minimum:
• Confirm that buffers and media are used as defined in the application and are accurately
described in the master production record.
• Evaluate whether adequate procedures are in place to prepare, label, store, and trace buffers
and media throughout manufacturing operations.
• Evaluate whether, in production, the predefined hold times for buffers and media are
supported by microbiological and chemical stability data.
Date of Issuance: 04/14/2026 Page 49 of 83
第 50 页
PROGRAM 7346.832M
• If contamination control procedures are used for cell culture media such as high-temperature,
short-time treatment, confirm that validated parameters (e.g., temperature, time, flow rate) are
used.
• Confirm that the buffer and media preparation process includes adequate environmental and
procedural controls to prevent contamination.
References:
• ICH Q7, section VIII.A, Production Operations
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
(f) Cell Culture Processes
Upstream manufacturing operations such as cell culture processes are considered high risk from a
microbial contamination perspective, and it is essential that they are conducted in a manner to avoid
contamination events. 51 Manufacturers are expected to test unprocessed bulk from the end of the
upstream manufacturing steps for the presence of adventitious agents. This testing is critical for
detecting microbial contaminants (e.g., viruses, mycoplasma) early in the manufacturing process to
ensure the product purity and safety.
The inspection team should, at a minimum:
• Review available cell culture performance trends such as cell growth and titer to identify
issues with cell culture performance. Gross deviations in cell culture parameter profiles can be
indicative of raw material failures or adventitious agent contamination.
• Evaluate the success rate for the cell culture or the fermentation process starting from cell
bank thawing. Confirm that the establishment investigates instances of a WCB failing to
generate the growth necessary for production.
• Review bioburden data and determine whether acceptance criteria or limits are met as
specified in the application. Verify that the batch is rejected in the case of a confirmed culture
contamination. Confirm that an investigation was conducted to identify root causes and that
subsequent CAPAs were implemented. Verify that procedures were followed to
decontaminate the contaminated equipment and establishment (if applicable) as described in
Objective 1b.
• Verify that unprocessed bulk safety tests (viral or microbial as relevant) were conducted using
the assays and acceptance criteria outlined in the application.
• Confirm that in-process parameters and controls for each step—from initial thaw of the cell
bank vial to production of the bioreactor culture—adhere to application commitments.
• Verify that procedures exist and are followed to maintain and expand cell cultures with
appropriate controls to minimize the risk of contamination and cross-contamination during
51
See Part I.2 of this compliance program for a description of steps involved in typical upstream manufacturing
operations.
Date of Issuance: 04/14/2026 Page 50 of 83
第 51 页
PROGRAM 7346.832M
cell culture expansion. Evaluate changeover procedures to determine whether they are
appropriate to prevent cross-contamination between different products.
• Verify that appropriate records for cell culture activities include cell passage numbers that are
consistent with the end of production or limits of in vitro cell age specified in the application.
References:
• 21 CFR 211.42
• ICH Q7, sections VIII.A, Production Operations, and XVIII, Specific Guidance for APIs
Manufactured by Cell Culture/Fermentation
• ICH Q5A(R2)
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
• USP General Chapter <1237> Virology Test Methods
(g) Final Fermentor/Bioreactor Harvesting
Harvesting can include centrifugation, filtration, or both of these unit operations, resulting in a
clarified liquid that can be more readily purified.
The inspection team should, at a minimum:
• Evaluate whether the end-of-production adventitious agent samples were taken before
harvesting.
• Evaluate whether cell culture end-of-production procedures, harvesting storage temperatures,
and elapsed times were within the ranges as specified in the application.
• Determine whether unanticipated clogging or fouling events initiated the need for unplanned
additional depth filtration or filtration steps; this can be indicative of an upstream cell culture
issue not detected by viability or cell number.
References:
• ICH Q7, section XVIII.D, Harvesting, Isolation and Purification
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use
(h) Homogenization
Some biological products produced in microorganisms might require liberation of the protein product
intermediate from the bacterial cells after harvesting and before downstream processing. This can be
accomplished through the disruption of cell walls by sonication or mechanical homogenization of the
cells followed by physical separation, such as centrifugation.
The inspection team should, at a minimum:
Date of Issuance: 04/14/2026 Page 51 of 83
第 52 页
PROGRAM 7346.832M
• Confirm that operating temperatures of the cellular disruption do not exceed the validated
range.
References:
• ICH Q7, section XVIII.D, Harvesting, Isolation and Purification
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
(i) Purification Processes
Special considerations for purification manufacturing steps are listed below, organized by overall unit
operation.
i. Chromatography
Although chromatography resins or adsorbers can be reused, they should be product-dedicated.
Chromatography column housing (the hardware containing the purification resins) need not be
product-dedicated; however, the establishment should have adequate cleaning validation and
changeover procedures for nondedicated column housing. The resin or adsorber lifetimes can be
initially validated using small-scale models, but concurrent validation at commercial scale is expected
to be ongoing at the time of approval. The effectiveness of cleaning, sanitization, and storage of
resins should be verified at scale.
The inspection team should, at a minimum:
• Confirm that the establishment reviews and trends column chromatography traces, step yields,
impurities, and other measures of performance to ensure the column chromatography steps are
consistent batch to batch, as described in the application.
• Confirm that column housings are clean and free of leaks. Visually confirm that packed
columns are free from discoloration, channels throughout the column, or pockets of air at
seals.
• Confirm that resins are product-dedicated and consistent with the application.
• Evaluate whether appropriate cleaning validation and changeover procedures for column
housings exist and whether they are followed if column housings are not product-dedicated.
• Review protocols for packing and unpacking of columns and determine whether packing
criteria are adequate (e.g., post-use resin/adsorber testing is conducted and demonstrates
adequate column performance). Evaluate whether segregation and changeover procedures at
the resin packing/unpacking area are adequate to prevent mix-up and cross-contamination.
Evaluate whether the packing/unpacking procedures are as closed as possible to reduce resin
exposure to the environment and prevent resin microbial contamination.
• Review and evaluate whether procedures for cleaning, sanitizing, and storing resins are
adequate and followed. From a microbial control perspective, review available data from
validation/verification studies of the sanitization and storage solution for chromatography
resins.
Date of Issuance: 04/14/2026 Page 52 of 83
第 53 页
PROGRAM 7346.832M
• If full-scale lifetime validation studies were completed, determine whether resins were used
within their validated lifetimes. If not, evaluate whether protocols and reports, including
interim reports, are available for full-scale lifetime studies that support the performance of the
resins.
References:
• ICH Q7, section XVIII.D, Harvesting, Isolation and Purification
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
ii. Viral clearance/inactivation
During cell expansion or while in the final fermentor or bioreactor, the cell culture can be
contaminated by adventitious agents, potentially posing a safety risk to patients. Materials, personnel,
or contaminated equipment can be the source of adventitious agents. The downstream process has
multiple orthogonal viral reduction unit operations (e.g., column chromatography), and separating the
desired product from the culture medium can also reduce adventitious agent load. Furthermore, the
manufacturing process will contain unit operations that are designed specifically to inactivate or
remove adventitious agents, such as viruses. These unit operations can include a low pH treatment
step, a detergent or solvent treatment step, a heating step, and a specific viral nanofiltration step.
The inspection team should, at a minimum:
• Confirm that the minimum exposure times for treatment steps are met.
• Confirm that column chromatography and nanofiltration steps are performed within their
validated parameters, as described in the application.
• Evaluate whether the viral filters pass the integrity testing.
• Evaluate whether process pauses in nanofiltration steps, which can impact clearance of
viruses, were validated during small-scale viral clearance studies.
• Evaluate whether deviations associated with adventitious agent clearance or inactivation unit
operations are thoroughly investigated and resolved.
References:
• ICH Q7, section XVIII.E, Viral Removal/Inactivation Steps
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
iii. Precipitation/Crystallization
A protein DS intermediate can be concentrated, or purified, using precipitation or crystallization unit
operations. This process can be induced by the addition of salts or polymers and the alteration of a
solution’s temperature, pH, or ionic strength. The resulting crystals or precipitates can be collected by
decanting, centrifugation, or other physical/mechanical separation methods.
The inspection team should, at a minimum:
Date of Issuance: 04/14/2026 Page 53 of 83
第 54 页
PROGRAM 7346.832M
• Evaluate whether temperatures, agitation rates, and reaction times during the precipitation or
crystallization incubation period are within validated ranges.
• Evaluate whether the resulting intermediate manual transport and decanting are conducted in a
suitable environment and manner to prevent contamination and cross-contamination if
conducted in open environmental conditions.
References:
• ICH Q7, section VIII.D, Blending Batches of Intermediates or APIs
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
iv. UF/DF
UF/DF can be used at any point in the production process where volume reduction (product
concentration) or buffer exchange is desired. As such, it might be used before, in between, or after
column chromatography steps. UF/DF membranes can be reused but should be product-dedicated,
and membrane lifetimes are expected to be validated, and can be done concurrently during
commercial production. The effectiveness of cleaning, sanitization, and storage are expected to be
verified at scale.
The inspection team should, at a minimum:
• Determine whether establishments that reuse UF/DF membranes confirm their suitability with
supporting data. Confirm that UF/DF membranes are not used beyond the qualified lifetime
supported by the UF/DF membrane lifetime qualification protocol outlined in the application,
as applicable. If not, determine whether protocols and reports, including interim reports, are
available for full-scale lifetime studies that support the performance of the membranes.
• Confirm that the establishment complies with the minimum number of buffer exchanges as
defined in the application.
• Confirm that the UF/DF membranes are product-dedicated and that the cleaning, sanitizing,
and storage procedures are followed between manufacturing operations. From a microbial
control perspective, review available data from validation/verification studies of the
sanitization and storage solution.
Reference:
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
(j) BDS Filtration and Fill
Most protein BDS is not typically tested for sterility. However, liquid forms are typically filtered
using 0.22 µm filtration to reduce bioburden to predefined acceptance levels. The bulk fill process
should be conducted under conditions designed to ensure microbial control during storage and
handling. The environment where the bulk fill process takes place is evaluated on a case-by-case
basis based on risk, typically during the PLI or PAI. Factors affecting microbial control include use of
Date of Issuance: 04/14/2026 Page 54 of 83
第 55 页
PROGRAM 7346.832M
open or closed systems, the growth promoting potential of the BDS, and the storage temperature of
the protein DS.
The inspection team should, at a minimum:
• Evaluate whether sensitive excipients (e.g., Polysorbate-80) are within their validated expiry
dates before compounding the BDS.
• Evaluate whether adequate procedures are in place for integrity testing of the bioburden
reduction filter used during final DS filling and that these procedures outline an appropriate
course of action if the integrity test fails. Confirm that adequate investigation and
documentation of integrity test failures occurs and appropriate CAPAs are performed in a
timely manner.
• If filling processes are not closed, evaluate whether the fill procedure is adequate to prevent
contamination and cross-contamination, and microbiology samples represent the worst-case
scenario.
• Confirm that the DS container closure system used is as indicated in the application and is
closed as described in the application (e.g., to a specified torque for screw-cap containers).
• As applicable, confirm that the manufacturer investigates leakage events, evaluates their
potential impact on the product, and provides sound, scientific reasoning for the related
disposition decision.
• Confirm that sampling is performed on representative homogeneous DS.
• For lyophilized DS milling and fill 52:
o Evaluate whether the validation was confirmed by appropriate lyophilized DS tray
sampling to ensure homogenous lyophilized DS is filled into BDS container closure
systems.
o Evaluate whether the transfer of BDS after lyophilization is conducted in a manner that
does not increase risk of contamination.
Reference:
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
(k) Reworking and Reprocessing
Manufacturers are expected to identify products or in-process materials or intermediates that fail to
meet established limits or specifications. Adequate investigation and documentation of discrepancies
and failures that prompted reprocessing steps are essential to ensure that the root causes are properly
identified and corrected. 53 Reprocessing steps are expected to be appropriately justified through
52
See Attachment D for inspection coverage guide specific to lyophilization or freeze-drying.
53
Reprocessing of a biological intermediate is defined as the repetition of a unit operation when the process has shifted
out of the validated operating ranges. Reworking is defined per ICH Q7 as “Subjecting an intermediate or API that does
Date of Issuance: 04/14/2026 Page 55 of 83
第 56 页
PROGRAM 7346.832M
validation studies, including when the reprocessing was done according to a previously approved
protocol. The final disposition of reprocessed or reworked material is expected to be recorded as per
the establishment’s written procedures. Reprocessing steps for biological products should be a rare
occurrence and generally limited to exigent circumstances, such as to avoid a drug shortage situation.
Reprocessing must be performed with the review and approval of the quality unit. If reprocessing
activities have been approved in a prior approval supplement, reprocessing can be performed without
an approved protocol, prior to releasing the reprocessed batch(es). If reprocessing is performed with
an approved protocol, the reprocessing activities should be submitted in an annual report. 54
The inspection team should, at a minimum:
• Verify that the manufacturer has established quality unit-approved procedures for
reprocessing, if applicable. Review updates to concurrent reprocessing validation reports if
available.
• If evidence of reprocessing activities is found for approved processes, verify that these
activities have been communicated to FDA in a timely manner or that material was
reprocessed per the products’ FDA-approved and validated procedures. Confirm that batches
manufactured using reprocessing steps meet specifications. If unapproved reprocessing is
discovered, notify the IQA team, in a timely manner.
• Release of reworked material should not occur for biological intermediates unless reworking
has been approved by FDA. If reworked material for marketed product is discovered, confirm
that FDA has approved such reworking. If reworked material for marketed product has been
distributed or is intended for distribution to the United States without FDA notification,
immediately contact OQS by emailing [email protected] and cc’ing
[email protected], providing evidence of distributed reworked material, as
applicable.
References:
• 21 CFR 211.115
• ICH Q7, section XIV, Rejection and Re-Use of Materials
(5) Objective 1e: Evaluation of the Laboratory Control System
Under this objective, the inspection team evaluates the establishment’s laboratory control system,
which includes evaluating various activities related to laboratory procedures, validation and
verification of analytical methods, and sample testing associated with the product of interest.
Parts III.1.A.(5)(a) through (g) outline specific areas under Objective 1e that should be verified by the
inspection team as they relate to the product of interest.
not conform to standards or specifications to one or more processing steps that are different from the established
manufacturing process to obtain acceptable quality intermediate or API.”
54
For additional information on the adequate reporting categories for reprocessing activities, see guidance for industry
Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products (June 2021).
Date of Issuance: 04/14/2026 Page 56 of 83
第 57 页
PROGRAM 7346.832M
(a) General Laboratory Operations
The establishment is expected to have documented procedures describing sampling, testing, approval
or rejection of materials, and recording and storage of laboratory data, among other aspects, to
routinely track method performance parameters and effectively manage trends. In addition, laboratory
equipment used in analytical testing is expected to be appropriately qualified for its intended use.
The inspection team should, at a minimum:
• Verify that the laboratory raw data match the data that are formally recorded in a laboratory
information management system or other computer data storage system.
• Verify that laboratory record-keeping practices align with record-keeping principles outlined
in Objective 2 of this compliance program.
• Verify that the noncompendial method validation data are consistent with the data provided in
the submission. Confirm that compendial methods were verified under actual conditions of
use.
• Verify that there is adequate test sample tracking and that there is an adequate system in place
to ensure that samples are stored appropriately and that correct samples are tested within the
appropriate time frames per the SOP.
• Verify that laboratory analysts and management staff are qualified to analyze, review, and
evaluate data.
• Review laboratory equipment qualification, maintenance, and calibration records (see Part
III.1.A(2)(b) of this compliance program for more details).
• Evaluate the establishment’s management of laboratory reagents and chemicals, including
adherence to storage conditions and expiry dates, as outlined in Part III.1.A(3)(a) of this
compliance program.
References:
• 21 CFR 211.160(a), 211.194, 610.9, 610.12 through 610.15, and 610.18
• ICH guidance for industry Q6B Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products (August 1999)
• ICH Q7, section XI, Laboratory Controls
• Guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics
(July 2015)
• Guidance for industry Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, Revision 1 (May 2022)
(b) Biochemical and Microbiology Methods
In general, biological products are tested for potency, sterility, and identity, among other biochemical
and microbiological characteristics. Because of the nature of biological product manufacturing, the
Date of Issuance: 04/14/2026 Page 57 of 83
第 58 页
PROGRAM 7346.832M
inspection team should expect to see protein-specific testing as well as microbiological testing,
including in-process control, release, and stability testing. It is common for some testing, such as
adventitious agent testing (e.g., mycoplasma testing, viral safety testing) to be conducted at
establishments other than the product manufacturer.
The inspection team should, at a minimum:
• Corroborate that data (e.g., release data, stability data) collected for batches manufactured and
tested using the validated commercial-scale process and laboratory testing methods align with
data and information submitted in the application (see Objective 2 for additional details).
• Confirm that methods are consistently executed within their validated ranges and performance
parameters and that they meet their predetermined system suitability criteria.
• Evaluate repeat incidents of failed or invalid test results and confirm they were resolved
appropriately (Assay failure rates are important indicator of assay performance and cannot be
determined solely by reviewing OOS investigations).
• Verify that laboratory method/test investigations or deviations that occurred during or after
validation were appropriately documented.
• Review discrepancies in the method validation or technical transfer results from those
submitted in the application, verify that the analytical methods described in the application
have not changed or that changes are justified, and confirm that the establishment intends to
notify FDA during submission assessment and amend the pending submission accordingly.
• Confirm that off-site testing laboratories have quality agreements that detail the
responsibilities for reporting deviations, reviewing and reporting OOS results, reviewing the
raw data, and validating test methods and on-site audits.
References:
• 21 CFR 610.10, 610.12, and 610.14
• ICH Q7, section XII.H, Validation of Analytical Methods
• Guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements
(November 2016)
(c) Sampling
Laboratory and production documents are expected to include procedures on sampling, sampling
frequency, and testing (in-line or off-line) of raw materials, in-process materials, intermediates, and
DS and DP.
The inspection team should, at a minimum:
• Verify that procedures for sampling and testing of raw materials are adequate to ensure their
proper control and disposition. Confirm implementation of procedures on the manufacturing
floor and in the raw materials testing laboratory.
Date of Issuance: 04/14/2026 Page 58 of 83
第 59 页
PROGRAM 7346.832M
• Confirm that in-process material sampling and sampling plans for product release are
consistent with the established sampling plan in the application, which should be
appropriately justified.
• Verify that the procedures in place for tracking samples (raw material, in-process, or release)
are adequate to ensure that samples are stored appropriately and that the correct samples are
tested within the time frames specified by SOPs. Storage conditions for microbial and
endotoxin samples generally should not be longer than 24 hours at 2-8°C. Review supporting
data of these microbial and endotoxin samples if stored otherwise.
References:
• 21 CFR 211.84, 211.110, 211.160, and 211.165(c)
• ICH Q7, section XI, Laboratory Controls
• ICH Q7, section VII.C, Sampling and Testing of Incoming Production Materials
• ICH Q7, section VIII.C, In-Process Sampling and Controls
(d) Stability Testing
The establishment’s quality system is expected to have procedures for the stability testing program to
monitor the stability characteristics of the biological product, critical intermediates, and reference
standards (see Part III.1.A(5)(e)—Reference Standards—for more detail). The stability data are
expected to be available to review if needed. Generally, stability data are submitted in the application,
and the OPQ assessment division uses the stability data to evaluate the adequacy of the proposed
long-term storage conditions and expiry date. Stability samples are expected to be stored using the
appropriate container closure system (i.e., representative of the manufacturing container closure
system) under appropriate storage conditions, supported by data or records associated with stability
chamber monitoring. In general, the manufacturer should place the first three commercial batches on
the stability monitoring program to confirm the retest or expiry date.
The inspection team should, at a minimum:
• Confirm that stability samples are collected, stored, and tested per the stability protocol
described in the application.
• Verify that the stability data collected since application submission display no new stability
trends.
• Verify that the appropriate container and storage conditions are used for stability samples and
reserve samples.
References:
• 21 CFR 211.137, 211.166, and 610.50
• ICH Q1A(R2)
• ICH Q5C
• ICH Q7, section XI.E, Stability Monitoring of APIs
Date of Issuance: 04/14/2026 Page 59 of 83
第 60 页
PROGRAM 7346.832M
(e) Reference Standards
Reference standards should be appropriately prepared, identified, tested, approved, and stored. The
establishment’s laboratory control system should document the source of each reference standard.
Each batch of the reference standard should be periodically requalified in accordance with an FDA-
approved protocol.
The inspection team should, at a minimum:
• Determine whether the reference standards used in product testing are as described in the
application and whether the establishment’s laboratory control system follows approved
procedures for reference standard storage conditions, usage conditions, and handling
instructions.
• Confirm that procedures are in place to adequately track the reference standard inventory.
• Confirm that there are reference standard requalification and stability testing protocols in
place that align with the application submission. If a new reference standard was qualified
since submission of the application, confirm that it was qualified using an FDA-approved
protocol and reported to the Agency, as appropriate.
References:
• ICH Q6B, section II.B.1, Reference Standards and Reference Materials
• ICH Q7, section XI.A, General Controls
(f) OOS Procedures and Investigations
The establishment’s laboratory control system is expected to investigate OOS results obtained from
product testing. OOS investigations should be documented according to approved procedures, which
should detail the investigation as well as the procedures in place for retesting (if any) and
conclusions. Retesting after OOS results might be allowed under an approved documented procedure.
The inspection team should, at a minimum:
• Confirm that OOS investigation procedures are followed and that they clearly outline or
reference other procedures that dictate the disposition of material that does not meet
preestablished acceptance criteria.
• Obtain a complete list of OOS results associated with the product for in-process, release, and
stability tests, including those that were invalidated, and confirm that the OOS results were
evaluated and resolved appropriately (see Objective 2 for additional details).
• If retesting is performed, verify that there are procedures in place to determine when retesting
is appropriate, how retesting should be performed (e.g., sampling, duplicates), and how results
should be interpreted.
• For contract testing laboratories, verify that the establishment has procedures in place to
ensure receipt of reports and results (including initial and confirmed OOS results) signed by
Date of Issuance: 04/14/2026 Page 60 of 83
第 61 页
PROGRAM 7346.832M
the contract testing laboratory’s quality assurance department and that the establishment is
able to obtain raw data upon request.
References:
• 21 CFR 211.160(a) and 211.192
• Guidance for industry Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, Revision 1
(g) Reserve Sample Tracking
The establishment’s laboratory control system is expected to have procedures for retaining reserve
samples of each batch. Reserve samples are for the purpose of potential future evaluation of the
product quality of batches. These procedures are in place to ensure that a sufficient quantity of each
reserve sample is retained for an appropriate length of time (e.g., 3 years after distribution of the
batch of the DS). 55
The inspection team should, at a minimum:
• Confirm that reserve samples are stored in the same container closure system and
recommended temperatures as specified for the bulk DP in the application.
• Verify that reserve samples are retained for the specified length of time.
References:
• 21 CFR 211.170 and 600.13
• ICH Q7
(6) Objective 1f: Evaluation of Packaging, Labeling, Storage, and Shipping Operations
Under this objective, the inspection team determines whether the establishment packages, labels, and
ships the product as described in the application to confirm that the quality of the product of interest
meets established standards. In addition, the inspection team verifies that the establishment has
suitable written and approved procedures describing the receipt, identification, quarantine,
disposition, sampling, examination or testing, release, and handling of packaging and labeling
materials of the product of interest.
References:
• 21 CFR 211 subparts G—Packaging and Labeling Control and H—Holding and Distribution
• ICH Q7, sections IX, Packaging and Identification Labeling of APIs and Intermediates, and
X, Storage and Distribution
Parts III.1.A.(6)(a) through (c) outline specific areas under Objective 1f that should be verified by the
inspection team as they relate to the product of interest.
55
See ICH Q7, section XI.G.
Date of Issuance: 04/14/2026 Page 61 of 83
第 62 页
PROGRAM 7346.832M
(a) Packaging and Labeling
Packaging and labeling materials (including those for DS) are expected to conform to appropriate
written specifications established by the quality unit. Those materials that do not comply with such
specifications are expected to be rejected to prevent their use in operations for which they are
unsuitable.
The inspection team should, at a minimum:
• Review the establishment’s procedures that prevent mix-ups, including those related to label
issuance, storage, removal from designated areas, and destruction.
• Verify that the numbers of labels issued and used are reconciled and that discrepancies are
investigated and corrected as appropriate.
• Verify that printed labels contain the correct information as described in the master production
record or in the application.
• Verify that containers are clearly and accurately labeled during the inspection walk-through.
For DP, the inspection team should also, at a minimum:
• Verify that the dating of each lot of DP is consistent with the final sterile filtration before the
filling of a BDS solution into the DP. This is because some bulk solutions are held after sterile
filtration and before filling.
• Verify that the contents of the final DP container of each filling of each lot are tested for
identity after labeling operations are completed.
References:
• 21 CFR part 211, subpart G; 21 CFR 610.14 and 610.50
• ICH Q7, section IX, Packaging and Identification Labelling of APIs and Intermediates
(b) Storage
Appropriate storage conditions (e.g., controlled temperature, light, humidity when necessary) for
materials are expected to be used. Maintaining and monitoring establishments and equipment storage
conditions are essential to ensure the quality of the product.
The inspection team should, at a minimum:
• Confirm that in-process or final material is stored at an appropriate temperature as described
in the application, which may be in a controlled and monitored freezer or other cooling
device.
• Confirm that containers containing in-process or final material are appropriately segregated
and stored in areas with controlled access.
• Confirm that separate storage areas are assigned for temporary storage of quarantined,
rejected, returned, or recalled materials until the decision as to their future use has been made,
unless there is an alternative system to prevent unintentional or unauthorized use.
Date of Issuance: 04/14/2026 Page 62 of 83
第 63 页
PROGRAM 7346.832M
• Confirm that records demonstrate that specified storage conditions have been maintained,
including temperature measurements at appropriate intervals.
References:
• 21 CFR 211.122 and 211.142(b)
• ICH Q7, section VII.D, Storage
(c) Shipping
Manufacturers are expected to follow validated and documented shipping procedures to ship the
product in qualified shipping containers. For each shipment of materials, records are expected to be
maintained that show receipt and examination or testing and whether the shipment was accepted or
rejected.
The inspection team should, at a minimum:
• Confirm that batches are shipped using the validated shipping processes described in the
application.
• Confirm that the product is maintained at the appropriate temperature throughout the shipping
process.
References:
• 21 CFR 211.150
• ICH Q7, section X.B, Distribution Procedures
B. Objective 2: Data Integrity Audit
Under this objective, the inspection team evaluates the integrity of data submitted in the application.
The inspection team should select a subset of data filed in the application to audit on-site for accuracy
and completeness and should audit data with issues or risks identified during the application
assessment. The subset of data should include process validation data (including in-process testing,
release, and stability data). Additional data available on-site that are useful in assessing data integrity
are identity assay results, product and process-related impurities results, reference standard
qualification testing, and critical analytical method validation packages (e.g., potency assays,
stability-indicating assays). The inspection team should note that some of the content in this section is
an extension of the content covered under Objective 1a (e.g., computerized systems).
The inspection team should verify that data selected for evaluation have factual and contextual
integrity 56 and have been reported accurately in the application. Data integrity issues, such as those
56
Factual integrity refers to the correspondence between the data and information observed during inspection and that
submitted in the application (e.g., a chromatography image in the application corresponds to the chromatographic result
on record for the specified test on the specified date). Contextual integrity refers to the information submitted in the
application as being representative of the testing or manufacturing area and related products or processes (e.g., the
chromatography results (successes and failures) for assayed samples using the described method). Missing or
Date of Issuance: 04/14/2026 Page 63 of 83
第 64 页
PROGRAM 7346.832M
below, could indicate that the information submitted in the application is neither complete nor
accurate:
• Changes of original data and records without appropriate justification.
• Inconsistencies in the documentation of manufacturing operations.
• Exclusion of specific batches from the stability program to avoid submitting failed stability
results.
• Backdating stability test results to meet required commitments.
• Reprocessing or reworking steps not described in the application.
• Manipulation of data to obtain passing results.
• Repeated testing without appropriate justification.
• Unjustified revisions to test results.
• Lack of traceability of test results reported in the application (e.g., the establishment has no
records of the testing occurrence or raw data).
• Use of test results from one batch to substitute testing for another batch.
• Test results that do not have records supporting the conduct of the test.
The inspection team should, at a minimum, conduct the following activities with the product of
interest in mind:
• Audit and evaluate the accuracy and completeness of data associated with the product.
• Evaluate validated systems (e.g., storage and accessibility controls) in place to manage data
associated with biological product manufacturing operations to verify that the data submitted in
the application are relevant, accurate, complete, and reliable.
• Verify that the original raw data collected or generated from batch production and testing and
other pertinent controls are documented by means of written records or electronic systems.
For example, compare the original raw data such as chromatograms, spectrograms, laboratory
analyst notebooks, and additional information from the laboratory with summary data filed in
the application. Original raw data files should support a conclusion that the data and
information reported by the establishment are complete and accurate.
• Confirm that access controls to computerized systems are followed.
• Review selected audit trails to confirm that analytical equipment software used to support the
application, as applicable, has verifiable audit trails for the recording and processing of raw
data. Review selected audit trails.
• Verify that electronic records have appropriately controlled electronic signatures when used in
place of handwritten signatures and that electronic signatures are not shared.
unauthorized changes to records related to the production and testing of the product of interest, as well as unexplained
losses of inventory or testing components, challenges the factual and contextual integrity of data and information provided
in the application.
Date of Issuance: 04/14/2026 Page 64 of 83
第 65 页
PROGRAM 7346.832M
• Verify that the quality unit is appropriately ensuring the integrity of data supporting CGMP
operations.
• When data discrepancies are observed, determine which actions or inactions contributed to the
data integrity problem and whether CAPAs were or are to be taken, including retraining of
personnel if needed. Document instances of failure to report data that should have been
included in the application. Depending on the severity of the data discrepancy, the issue might
result in a withhold recommendation for the application. See a discussion of withhold items
in Part V of this compliance program.
References:
• 21 CFR 211.160, 211.165, 211.166 and 211.167
• Guidance for industry Data Integrity and Compliance With CGMP: Questions and Answers
• Guidance for industry Part 11, Electronic Records; Electronic Signatures—Scope and
Application (August 2003)
• Guidance for industry Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, Revision 1(May 2022)
• ORA Laboratory Manual, Volume III Section 3—Recording of Results Analyst Worksheet,
Rev. 4 (December 2023)
Reporting
In preparing the inspection report, the inspection team should follow instructions in chapter 5 of the
IOM. A single inspection report, and, when applicable, Form FDA 483 should be used to document
all inspection observations, including those made during an inspection at a combination product with
biological and device constituent part manufacturer.
In the “Objectionable Conditions and Management’s Response” section of the inspection report, the
inspection team should summarize its findings with sufficient details, supporting evidence, and
relevance to quality/safety for each Form FDA 483 observation as appropriate.
Date of Issuance: 04/14/2026 Page 65 of 83
第 66 页
PROGRAM 7346.832M
PART IV—ANALYTICAL
Routine sample collection and analysis under this compliance program are not anticipated.
As discussed in the Reporting Requirements section of this compliance program (under 8. Sample-
Related Reporting Requirements), the inspection team should contact OQS before samples are
collected.
Date of Issuance: 04/14/2026 Page 66 of 83
第 67 页
PROGRAM 7346.832M
PART V—REGULATORY/ADMINISTRATIVE STRATEGY
CDER Recommendations
The outcome of the inspection results in either an approve or a withhold recommendation for the
facility in the appropriate component of the CDER Informatics Platform and application assessment.
A. Approve Recommendation
For a BLA to be approved, the facility in which the biological product is manufactured, processed,
packed, or held must meet standards designed to ensure that the biological product continues to be
safe, pure, and potent. OPQ makes an approve recommendation if there are no significant CGMP
issues that could adversely affect the establishment’s ability to perform the manufacturing operations
described in the application and if no data integrity concerns were observed.
B. Withhold Recommendation
OPQ makes a withhold recommendation if there are significant CGMP issues that would adversely
impact the establishment’s ability to perform its designated functions described in the application or
if significant data integrity issues are observed. Deficiencies discovered during the PLI or PAI that
are not related to the facility’s CGMP compliance or the manufacturing of the product of interest but
are solely application assessment issues can be addressed and communicated through established
assessment practices and should not be considered in PLI and PAI withhold decisions.
(1) Overarching Examples of Significant Deficiencies
Examples of significant deficiencies associated with the manufacture of the product of interest that
could result in a withhold recommendation that are not limited to a specific system or objective
follow:
• Failure to perform the manufacturing operations as described in the application or failure to
comply with applicable CGMP requirements.
• Significant documentation deficiencies impacting equipment cleaning and maintenance,
methods validation/verification, or process parameters used to produce the protein DS or DP
as described in the application (21 CFR 211.67, 211.160, 211.165, and 211.100).
• Significant data integrity issues. (See examples under Part III.1.B of this compliance
program.)
• Delaying, denying, limiting, or refusing a drug inspection. 57
57
See guidance for industry Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device
Inspection (June 2024).
Date of Issuance: 04/14/2026 Page 67 of 83
第 68 页
PROGRAM 7346.832M
(2) Examples of Significant Deficiencies, Arranged by Objective
This section includes examples of deficiencies associated with the manufacture of the product of
interest that could result in a withhold recommendation, arranged by objective. The examples are not
exhaustive.
(a) Objective 1a: Quality System
• Deficient or unsupported instructions (e.g., records, SOPs) to conduct manufacturing
operations in compliance with regulations.
• Failure of the quality unit to review and approve complete batch production records before
batch release (21 CFR 211.22(a) and ICH Q7, section VI.E).
• Failure to investigate when the suitability of a batch is in doubt, including the failure to
investigate OOS testing results (21 CFR 211.192 and ICH Q7, section II).
• Release of affected batches without appropriately reporting significant production process
changes, reprocessing (that has not been approved in the product application), or product
rework (21 CFR 211.115 and 601.20 and ICH Q7, section XIV).
• Release of affected batches with major unapproved changes to the application, including using
a process, material, or equipment that was neither submitted to the application under review
nor in an approved application (21 CFR 601.12(b)).
• Operators are or were not trained in the particular operation that they performed or in CGMP
requirements related to their job functions (21 CFR 211.25(a) and ICH Q7, section III).
• Significant stability study deficiencies or failures, which raise questions about the stability of
the DS or DP.
(b) Objective 1b: Facilities and Equipment
• Failures or deficiencies in the qualification and maintenance/calibration of utilities or other
establishment controls/operations and equipment that can lead to batch failures (21 CFR
211.58), such as water systems; HVAC systems; fermentors or bioreactors; centrifuges;
chromatography columns; UF/DF equipment; cold storage equipment used for product
intermediates, DS, and DP; and DP aseptic filling-related equipment, including restricted
access barrier systems (RABS), isolators, filling machines, and so forth (21 CFR 211.68(a)
and ICH Q7, section IV.A).
• Failure to ensure the prevention of product contamination and cross-contamination, especially
from live viruses and highly potent or toxic compounds (21 CFR 211.63, 211.130(a),
600.10(c)(1) through (3), 600.11(e)(2) and (3), and ICH Q7, section IV.D).
• Evidence that the establishment is not compliant with 21 CFR 211.56 or 211.58 due to its lack
of cleanliness or state of disrepair (see also ICH Q7, sections IV.A and V.B).
Date of Issuance: 04/14/2026 Page 68 of 83
第 69 页
PROGRAM 7346.832M
(c) Objective 1c: Material Management
• Use of raw material (including critical raw material) that does not meet specifications or was
not appropriately qualified (21 CFR 211.84(e) and ICH Q7, section VII.C).
• Failure to ensure that materials are free from adventitious agents as required (21 CFR
600.11(e)(5)).
• Failure to store cell banks under conditions that maintain the initial characteristics of the
organisms and prevent mix-ups, contamination, and deterioration (21 CFR 610.18 and ICH
Q7, section XVIII.B).
(d) Objective 1d: Production and Process Controls
• The product cannot be consistently manufactured using the proposed commercial process or
cannot meet established quality specifications described in the application (21 CFR 601.2(d)).
• Performing production steps inconsistent with written procedures involving production and
process controls designed to ensure that products have the identity, strength, quality, safety,
purity, and potency they purport or are represented to possess (21 CFR 211.100 and ICH Q7,
section VIII.A).
• Batch production and control records are or were not prepared for each product batch (21 CFR
211.188, 600.12, and ICH Q7, section VI.E).
• Significant trend of endotoxin or bioburden excursions beyond action limits (21 CFR 211.110,
and ICH Q7, section XVIII.A).
• Recurrent cell culture contaminations, including viral, mycoplasma, and bacterial
contaminations (21 CFR 211.113(b), 600.11(b), and ICH Q7, section XVIII.C).
• Release of DS produced under conditions in which viral inactivation or clearance operations
were not performed in conformance with application commitments or without data to support
DS suitability (ICH Q5A(R2)).
• Evidence that manufacturing operations, including analytical methods, are operating outside
validation/qualification acceptance criteria described in the application (21 CFR 211.110 and
ICH Q7, section XVIII).
• Lack of complete manufacturing and control instructions in the master production record or
lack of data to support those instructions (21 CFR 211.186 and ICH Q7, section VI).
• Release of DP from a facility with a history of unresolved DP media fill failures (21 CFR
211.165).
(e) Objective 1e: Laboratory Control System
• A significant, unresolved history of in-process testing results exceeding action limits (21 CFR
211.110 and ICH Q7, section XI.A).
Date of Issuance: 04/14/2026 Page 69 of 83
第 70 页
PROGRAM 7346.832M
• Failure to conduct required adventitious agent testing, including mycoplasma and viral safety
testing, in accordance with the application (21 CFR 211.113 and 600.11).
• Failure to establish an adequate OOS procedure, follow the established OOS procedure, or
provide justification for repeated testing (21 CFR 211.192, 211.194, and ICH Q7, section XI).
• Failure to conduct testing as indicated in the application or a pattern of failure to perform tests
in accordance with established procedures (21 CFR 211.165, 211.166, 211.167, and ICH Q7,
section XI.B).
• Failure to properly validate/qualify test methods for assessment of quality, safety, or efficacy
attributes (21 CFR 211.194, 211.165(e), and ICH Q7, section XI.C).
(f) Objective 1f: Packaging, Labeling, Storage, and Shipping Operations
• Failure to package BDS or DP in the approved container or properly label BDS or DP
containers, respectively (21 CFR 211.94, 600.11(h), and ICH Q7, section IX.D).
• Pattern of failure to adequately investigate BDS leakage events (21 CFR 600.11(h)).
• Failure to ensure that each DP batch conforms to label claims or specifications described in
the application.
(g) Objective 2: Data Integrity
• Significant data integrity problems, including misrepresented data or other conditions related
to the batches manufactured by the proposed commercial process as described in the
application.
• Significant factual and contextual integrity of data issues, including failure to report failed test
data (21 CFR 211.68, 211.100, 211.160, 211.180, 211.188, and 211.194). For example:
o Repeated analyses of the same sample without adequate justification.
o Use of test results from previous batches to substitute testing for another batch.
o Fabrication of acceptable test results without performing the test.
• Failure to provide CGMP record traceability, failure to protect data files and systems from
changes made by unauthorized personnel, or manipulation of audit trails and data.
• Pattern of discrepancy between raw data results and formally recorded results or to maintain
complete and original copies of data, including relevant metadata.
Additional Considerations
• OPQ evaluates the inspection’s evidentiary records (e.g., EIRs, records pursuant to a request
under section 704(a)(4) of the FD&C Act, Form FDA 483s, establishment responses to
communicated deficiencies) and enters an application recommendation in the appropriate
component of the CDER Informatics Platform.
• In the case of an approve recommendation, OPMA updates the final decision and
Date of Issuance: 04/14/2026 Page 70 of 83
第 71 页
PROGRAM 7346.832M
establishment’s profile (as appropriate) in the appropriate system and shares with the IQA
team the recommendation for facilities listed in the application to support regulatory action.
• When a withhold recommendation is made for a facility that does not market FDA-regulated
products, a warning letter is not usually an appropriate regulatory action. However, if a
withhold recommendation is made for a facility on the basis of systemic CGMP deficiencies
that could impact marketed products, OPQ will discuss the deficiencies with OC in a timely
manner to determine the appropriate next steps.
• For combination products with biological and device constituent parts, the inspection team
may need to engage expertise from other agency components, including other center(s), as
needed.
Date of Issuance: 04/14/2026 Page 71 of 83
第 72 页
PROGRAM 7346.832M
PART VI—REFERENCES, ATTACHMENTS, PROGRAM CONTACTS, AND ACRONYMS
References
A. Code of Federal Regulations, Title 21
https://www.ecfr.gov/current/title-21
Part 4: Regulation of Combination Products
Part 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of
Drugs; General
Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
Part 600: Biological Products: General
Part 601: Licensing
Part 610: General Biological Products Standard
B. Compliance Programs (CDER Drugs)
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/drug-compliance-
programs
7356.000—Inspections of CDER-led or CDRH-led Combination Products
7356.002—Drug Manufacturing Inspections
7356.002A—Sterile Drug Process Inspections
7356.002M—Surveillance Inspections of Protein Drug Substance Manufacturers 58
C. Guidances
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
(1) Guidances for Industry
Advancement of Emerging Technology Applications for Pharmaceutical Innovation and
Modernization (September 2017)
Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications
(September 2025)
Analytical Procedures and Methods Validation for Drugs and Biologics (July 2015)
Biological Product Deviation Reporting for Licensed Manufacturers of Biological Products Other
than Blood and Blood Components (October 2006)
58
This compliance program applies only to surveillance inspections of CDER-regulated protein DS manufacturers.
Date of Issuance: 04/14/2026 Page 72 of 83
第 73 页
PROGRAM 7346.832M
Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological
Products (July 1997)
Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological
Products (June 2021)
Circumstances That Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device
Inspection (June 2024)
CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March 2014)
Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls
Information in an NDA, ANDA, or BLA (October 2022)
Conducting Remote Regulatory Assessments—Questions and Answers (June 2025)
Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016)
Cooperative Manufacturing Arrangements for Licensed Biologics (November 2008)
Data Integrity and Compliance With Drug CGMP: Questions and Answers (December 2018)
General Principles of Software Validation (January 2002)
Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, Revision 1
(May 2022)
Manufacturing Biological Intermediates and Biological Drug Substances Using Spore-Forming
Microorganisms (September 2007)
Part 11, Electronic Records; Electronic Signatures—Scope and Application (August 2003)
Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use
(February 1997)
Process Validation: General Principles and Practices (January 2011)
Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006)
Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice
(September 2004)
(2) Draft Guidances for Industry 59
ICH Q12: Implementation Considerations for FDA-Regulated Products (May 2021)
Inspection of Injectable Products for Visible Particulates (December 2021)
(3) ICH Guidances for Industry
Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003)
Q2(R2) Validation of Analytical Procedures (March 2024)
59
When final, these guidances will represent FDA’s current thinking on these topics.
Date of Issuance: 04/14/2026 Page 73 of 83
第 74 页
PROGRAM 7346.832M
Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or
Animal Origin (January 2024)
Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products
(July 1996)
Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological
Products (August 1999)
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016)
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients - Questions and
Answers (April 2018)
Q8(R2) Pharmaceutical Development (November 2009)
Q8, Q9 & Q10 Questions and Answers; Appendix Q&As from Training Sessions (July 2012)
Q9(R1) Quality Risk Management (May 2023)
Q10 Pharmaceutical Quality System (April 2009)
Q11 Development and Manufacture of Drug Substances (November 2012)
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management
(May 2021))
Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management
Annexes (May 2021)
Q13 Continuous Manufacturing of Drug Substances and Drug Products (March 2023)
(4) FDA Procedures and References
Investigations Operations Manual, https://www.fda.gov/inspections-compliance-enforcement-
and-criminal-investigations/inspection-references/investigations-operations-manual
MAPP 4151.8, Rev. 2, Equal Voice: Collaboration and Regulatory and Policy Decision-
Making in CDER (August 12, 2025), https://www.fda.gov/media/188211/download?attachment
ORA Laboratory Manual, Volume III Section 3—Recording of Results Analyst Worksheet, Rev.
4 (December 2023), https://www.fda.gov/media/74012/download?attachment
Staff Manual Guide 6001.1, FDA Remote Regulatory Assessment Standard Practices (January
2025), https://www.fda.gov/media/186992/download?attachment
D. FDA User Fee Programs
https://www.fda.gov/industry/fda-user-fee-programs
Prescription Drug User Fee Act (PDUFA)
Biosimilars User Fee Act (BsUFA)
Date of Issuance: 04/14/2026 Page 74 of 83
第 75 页
PROGRAM 7346.832M
E. Non-FDA References
ISO 17665, Sterilization of Health Care Products—Moist Heat—Requirements for the Development,
Validation and Routine Control of a Sterilization Process for Medical Devices (2024)
ISPE Baseline Guide Volume 7, Risk Based Manufacture of Pharmaceutical Products (Risk-MaPP)
(2017)
USP General Chapter <1231> Water for Pharmaceutical Purposes
USP General Chapter <1237> Virology Test Methods
Program Contacts
A. Center for Drug Evaluation and Research
CGMP- or Quality-Related Policy Questions
For CGMP- or quality-related policy, technical, or scientific questions or information needs,
including questions about this compliance program, send an email to the following address and it will
be handled as a top priority: [email protected].
Office of Compliance: Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence need and sufficiency, citations, and
case evaluation/recommendation advice related to marketed products or surveillance coverage, send
an email to the following address and it will be handled as a top priority:
[email protected].
Laboratories
Division of Pharmaceutical Analysis
645 South Newstead Avenue
St. Louis, MO 63110
Drug Applications
Submission information (general):
• Forms & Submission Requirements web page:
https://www.fda.gov/drugs/development-approval-process-drugs/forms-submission-
requirements
• Guidance Documents for Drug Applications web page:
https://www.fda.gov/drugs/development-approval-process-drugs/guidance-documents-
drug-applications
B. Office of Inspections and Investigations
Office of Medical Products and Tobacco Operations
Office of Pharmaceutical Quality Operations, Division of Pharmaceutical Quality Programs,
Pharmaceutical Quality Initiatives Branch
Date of Issuance: 04/14/2026 Page 75 of 83
第 76 页
PROGRAM 7346.832M
ORA program coordinators: See the ORA Directory in the IOM for updated references,
https://www.fda.gov/files/inspections,%20compliance,%20enforcement,%20and%20criminal%20inv
estigations/published/ORA--Directory.pdf
Acronyms
ADC antibody-drug conjugate FD&C Act Federal Food, Drug, and
ADE acceptable daily exposure Cosmetic Act
AER adverse event report FARs Field Alert Reports
ATs Alternative Tools HEPA high-efficiency particulate air
ANDA abbreviated new drug HVAC heating, ventilation, and air
application conditioning
API active pharmaceutical ICH International Council for
ingredient Harmonisation
BDS bulk drug substance IND investigational new drug
BLA biologics license application IOM Investigations Operations
Manual
BPDR biological product deviation
report IQA integrated quality assessment
BsUFA Biosimilar User Fee Act ISO International Organization for
Standardization
CAPA corrective action and
preventive action ISPE International Society for
Pharmaceutical Engineering
CDER Center for Drug Evaluation
and Research MAPP Manual of Policies and
Procedures
CGMP current good manufacturing
practice MCB master cell bank
CMC chemistry, manufacturing, and MRA mutual recognition agreement
controls NAI No Action Indicated
CMO contract manufacturing NDA new drug application
organization
OC Office of Compliance
COA certificate of analysis
OII Office of Inspections and
DP drug product Investigations
DS drug substance OOS out-of-specification
DSI drug substance intermediate OPMA Office of Pharmaceutical
EC established condition Manufacturing Assessment
EIR establishment inspection OPQ Office of Pharmaceutical
report Quality
Date of Issuance: 04/14/2026 Page 76 of 83
第 77 页
PROGRAM 7346.832M
OQS Office of Quality Surveillance QMSR quality management system
regulation
PAC product/assignment code
RABS restricted access barrier
PAI preapproval inspection
system
PDUFA Prescription Drug User Fee
RIE Remote Interactive
Act
Evaluations
PHS Act Public Health Service Act
SOP standard operating procedure
PLI prelicense inspection
UF/DF ultrafiltration/diafiltration
pOAI potential Official Action
USP United States Pharmacopeia
Indicated
VAI Voluntary Action Indicated
PPQ process performance
qualification WCB working cell bank
PQS pharmaceutical quality system WFI water for injection
Date of Issuance: 04/14/2026 Page 77 of 83
第 78 页
PROGRAM 7346.832M
PART VII—CENTER RESPONSIBILITIES
This Part is intentionally left blank.
Date of Issuance: 04/14/2026 Page 78 of 83
第 79 页
PROGRAM 7346.832M
ATTACHMENT A: ANTIBODY-DRUG CONJUGATE PRODUCTS
ADCs are a type of biological product whereby a recombinant protein is purified and then conjugated
to a small molecule drug via a chemical linker. Conjugation manufacturing can be performed at the
DSI manufacturer but has typically been performed at a dedicated CMO due to the specialized
manufacturing involved. The protein intermediate is purified and stored as a DSI, which is then
conjugated to the small molecule payload, either through a linker or direct conjugation. Conjugation
technologies employed are typically random conjugation processes, site-specific conjugation via
engineered cysteine or other non-natural amino acids, or enzyme-mediated, facility-specific
conjugation (e.g., transglutaminase). After conjugation, the ADC undergoes purification and
formulation for the final DS.
The inspection team should, at a minimum:
• Evaluate the identity of the recombinant protein in the DSI.
• Evaluate whether the linker-payload raw material has been stored at the validated storage
conditions before conjugation.
• When the conjugation reaction is enzyme-mediated, pay special attention to the raw material
control strategy for the enzyme, including potential contamination concerns involving the use
of animal-derived material in the production of the enzyme.
• Confirm that the conjugation procedure and subsequent quenching reaction are performed at
the appropriate temperatures and time frames as described in the application.
• Confirm that subsequent purification steps after conjugation consistently remove
unconjugated payload to appropriate safety levels as outlined in the application.
Reference:
• Guidance for industry Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use (February 1997)
Date of Issuance: 04/14/2026 Page 79 of 83
第 80 页
PROGRAM 7346.832M
ATTACHMENT B: PRODUCTS DERIVED FROM SPORE-FORMING MICROORGANISMS
Product manufacturing operations using spore-forming microorganisms conducted in a multiproduct
establishment are expected to be performed under appropriate controls to prevent contamination of
other products and areas within the establishment. Appropriate process containment control
procedures are expected to be in place to prevent the potential spread of spore-forming
microorganisms. Spore contamination prevention can be achieved by using a dedicated building or by
using process containment if manufacturing is conducted in a multiproduct manufacturing building.
The inspection team should, at a minimum:
• If spore-forming microorganisms are used for manufacturing operations, regardless of
whether production is in a dedicated building or multiproduct establishment:
o Verify that a distinct crossover point is established in manufacturing operations, after
which viable spore-forming microorganisms (both vegetative and spore forms) are not part
of the process or process solutions.
o Verify that the establishment’s design, including air-handling unit segregation, airlocks,
and pressure differentials, is appropriate to prevent the potential spread of spore-forming
microorganisms to downstream of the crossover point.
o Verify the adequacy of equipment segregation, personnel training, gowning, and flow of
products, raw materials, personnel, waste, and equipment to prevent the spread of spores
over the crossover point. Observe personnel during gowning and manufacturing
operations.
• Verify that equipment exposed to pathogenic or potentially pathogenic microorganisms (e.g.,
Clostridium botulinum) is disposable or dedicated.
• For multiproduct establishments:
o Determine whether the establishment design and procedures that are in place appropriately
ensure containment. Verify that the movement of product and personnel between the
spore-forming microorganisms manufacturing area and other manufacturing areas is
appropriately designed to prevent the introduction of spores into other areas of the
establishment.
o Confirm that major processing equipment is disposable or dedicated to a specific product
and is decontaminated and removed from the area during changeover. If equipment
dedication and removal are not feasible, verify that effective equipment decontamination
and cleaning procedures are in place. Review decontamination efficacy and cleaning
validation/verification data.
o Verify that procedures to decontaminate and remove potentially spore-contaminated
materials (including ancillary room items), equipment, waste, and disposable or product-
dedicated items during changeover are followed.
o Determine whether environmental monitoring of the spore-forming microorganisms in
adjacent areas is conducted during manufacturing operations with adequate results.
Date of Issuance: 04/14/2026 Page 80 of 83
第 81 页
PROGRAM 7346.832M
o Determine whether the environmental monitoring data demonstrate the effective removal
of spore-forming production microorganisms from the manufacturing area after cleaning
and decontamination are complete and before subsequent manufacture of other products.
o Verify that the quality unit reviews campaign changeover data (including environmental
monitoring data) and that the quality unit executes area inspections before releasing the
manufacturing area for the next product.
References:
• 21 CFR 600.11(e)(2), (3), and (5); 600.10(b); and 600.10(c)(1), (2), and (3)
• ICH Q7, section IV.D, Containment
• Guidance for industry Manufacturing Biological Intermediates and Biological Drug
Substances Using Spore-Forming Microorganisms (September 2007)
Date of Issuance: 04/14/2026 Page 81 of 83
第 82 页
PROGRAM 7346.832M
ATTACHMENT C: HIGHLY POTENT OR TOXIC PRODUCTS
Multiproduct establishments that manufacture highly potent or toxic products are expected to identify
hazards appropriately and minimize and prevent cross-contamination by having appropriate
establishment design, segregation, process containment, and procedural controls. Establishments are
expected to establish product carryover limits for shared product contact equipment based on
toxicologically-derived acceptable daily exposure (ADE)—an exposure dose unlikely to cause an
adverse effect when an individual is exposed, by any route, at or below the dose every day for a
lifetime.
The inspection team should, at a minimum:
• Evaluate the adequacy of the establishment’s strategies, including risk assessment documents,
to control identified cross-contamination risks associated with highly potent or toxic products.
• Evaluate whether the establishment updates its risk assessment and risk mitigation strategies
as new products are introduced or when new toxicological data become available indicating
additional risks for cross-contamination.
• Evaluate whether toxicologically derived ADE is used in establishing the product carryover
limits for shared product contact equipment and the analytical methods for cleaning validation
are sufficiently sensitive in recovering highly potent or toxic compounds. Confirm that
dedicated or disposable equipment is used if the predetermined product carryover limit for the
cleaning of a toxic or highly potent product cannot be achieved.
• If ADE is not used for product carryover limit calculation for shared product contact
equipment and the establishment claims product inactivation and degradation by equipment
cleaning agents as the justification for the high product carryover limit, review product
inactivation and degradation validation data using the worst-case cleaning simulation
conditions.
References:
• ICH Q7, section IV.D, Containment
• ICH Q9(R1)
• ISPE Baseline Guide Volume 7, Risk Based Manufacture of Pharmaceutical Products (Risk-
MaPP)
Date of Issuance: 04/14/2026 Page 82 of 83
第 83 页
PROGRAM 7346.832M
ATTACHMENT D: LYOPHILIZATION OR FREEZE-DRYING
Some DS and DP are lyophilized or freeze-dried to improve their storage stability. This section
outlines inspectional activities specific to the lyophilization or freeze-drying operations of DS and DP
manufacturing that are not covered in compliance program 7356.002A.
For DS operations, the inspection team should, at a minimum:
• Confirm that multiple trays were used for shelf temperature mapping during temperature
uniformity studies for bulk lyophilization of DS and evaluate the data from the worst-case
scenario mapping experiments.
• For the bulk lyophilization of DS, confirm that the volume, concentration, and fill height of
DS are within validated ranges.
• Evaluate whether DSI decanting, tray filling, tray transport, and loading conditions are
conducted as validated.
For DP operations, the inspection team should, at a minimum:
• Evaluate the establishment’s visual inspection program (100% and acceptance quality limit),
the effectiveness of inspection, and actions taken when defect limits are exceeded. Determine
whether lyophilization DP vial defects are appropriately categorized and trended.
• Confirm that visual inspectors are appropriately trained and qualified and that training and
qualification involves the use of defect libraries that incorporate relevant or expected defects
such as melt back or cracks in the cake appearance for lyophilized product.
• Evaluate whether a small sample of units is reconstituted and inspected for visible particles in
addition to the 100% inspection of the cakes for visible particles in the DP. Review the
justification for the number of samples reconstituted.
• Evaluate whether the identity of the lyophilizer manufacturer is as described in the
application.
• Confirm that the lyophilized product parameters (e.g., general appearance, cake appearance,
melt back, reconstitution time, moisture) and their acceptance criteria are those described in
the application.
References (for DP only):
• Draft guidance for industry Inspection of Injectable Products for Visible Particulates
(December 2021) 1
• Compliance program 7356.002A—Sterile Drug Process Inspections
1
When final, this guidance will represent FDA’s current thinking on this topic.
Date of Issuance: 04/14/2026 Page 83 of 83
来源：FDA Pharmaceutical Quality Documents · fda.gov