FDA 修订无菌药品工艺检查合规程序 7356.002A，实施日期为 2015 年 9 月 11 日
Sterile Drug Process Inspections (7356.002A)
FDA 将无菌药品工艺检查合规程序 7356.002A 的实施日期更新为 2015 年 9 月 11 日，本次修订涉及实施日期、完成日期及组织与程序调整。程序覆盖无菌原料药和无菌制剂的制造与检验，包括终端灭菌和无菌工艺生产的注射剂、眼科及耳用制剂等，CBER 监管产品与兽药不在覆盖范围内。按该程序，全检通常覆盖至少四个系统，其中必须包括质量体系，并要求覆盖设施设备与生产系统。
文件说明 7356.002A 适用于无菌药品工艺检查，并列出系统覆盖范围与全检、简检的选用条件。
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美国食品药品监督管理局 计划 7356.002A
合规计划指导手册
第56章 – 药品质量保证
主题： 实施日期
2015年9月11日
无菌药品工艺检查
修订说明：计划于2015年9月11日修订，以更新 完成日期
实施日期、完成日期、
组织/程序变更及计划
联系人。
数据报告
产品代码 产品/任务代码
行业代码54、56及60-66（含） 国内/国外检查：
56002A（全面检查）
56002I（简化检查）
相关PAC
56002
56002C
56002M
现场报告要求：
企业检查报告（EIR）应使用TurboEIR或替代系统中ORA和CDER均可访问的特定模块以电子方式创建和提交。
对于因未遵守适用于无菌药品工艺检查的21 CFR Part 210和211现行药品生产质量管理规范（CGMP）而被归类为官方行动指示（OAI）的常规商业生产检查，应按照《监管程序手册》（RPM）通过MARCS-CMS提交建议、行政或司法行动建议。
各辖区应根据现行FACTS、Panorama和CMS程序立即报告重大问题。这包括及时提交和变更OAI通知。
在检查期间，如果您获得有关药品不良体验（ADE）报告不充分、未经批准药品问题或批准后报告违规（申请补充、现场警示报告（FAR）等）的信息，请按照适用合规计划中的指示并在EIR中单独标题下报告。有关这些检查活动的数据系统信息应在单独的计划任务代码（PAC）下报告。将这些计划下的覆盖范围扩展至CGMP检查时，应在本合规计划下报告。
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7356.002A
要求各辖区在所有无菌药品工艺检查中使用本合规计划。
注：各辖区应确保按本计划通告的指示所执行的每项操作
均录入正确的产品代码和计划/任务代码（P/AC）。
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PROGRAM 7356.002A
目录
第一部分 背景 ................................................................................................... 4
第二部分 实施 ............................................................................................. 5
2.1 目标 ........................................................................................................5
2.2 项目管理说明 ................................................................ 5
A. 策略 ............................................................................................... 5
B. 检查计划 ............................................................................. 6
C. 概况报告 ................................................................................... 6
第三部分 检查...................................................................................................... 7
3.1 灭菌类型....................................................................................... 7
A. 终端灭菌 ........................................................................... 7
B. 无菌工艺 .............................................................................. 7
3.2 报告 .......................................................................................................8
3.3 检查方法 ................................................................................. 9
3.4 系统检查覆盖范围...................................................................... 11
3.5 质量体系 .............................................................................................. 11
3.6 设施与设备系统 ................................................................. 13
A. 设施 ............................................................................................... 13
B. 设备 ......................................................................................... 14
3.7 物料系统 .......................................................................................... 19
3.8 生产系统........................................................................................ 22
3.9 包装与标签系统 .................................................................. 28
3.10 实验室控制系统 ........................................................................... 28
3.11 取样 ....................................................................................................... 30
第四部分 分析 ....................................................................................................... 32
第五部分 监管/行政策略 .............................................. 33
第六部分 参考文献、附件与项目联系人..................... 35
6.1 参考文献 ......................................................................................................... 35
6.2 附件 ..................................................................................................... 36
6.2 联系人 ........................................................................................................ 36
第七部分 中心职责 ........................................................................... 38
附件 A .................................................................................................................A
[封面页结束]
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PROGRAM 7356.002A
第一部分 - 背景
本计划涵盖所有无菌药品的生产和检验，包括通过过滤或其他方式灭菌并进行无菌工艺处理的药品，以及最终灭菌的药品。本计划涵盖的产品类型包括无菌原料药、眼科用药、耳用剂型、小分子及已许可生物治疗药品的小容量注射剂（SVS）产品、大容量注射剂（LVP）产品，以及任何其他要求无菌或标示为无菌的药品。生物制品评价与研究中心（CBER）监管的产品和兽药产品不在本计划涵盖范围内。
本计划中的指南信息针对无菌生产操作而制定，应与《药品生产检查合规计划》（CP 7356.002）配合使用。
2004年，美国食品药品监督管理局（FDA）发布了《行业指南：无菌工艺生产的无菌药品——现行药品生产质量管理规范》，本合规计划中通称为FDA“2004年无菌工艺指南”。该文件代表了FDA对无菌工艺药品现行药品生产质量管理规范（CGMP）的当前思考。
该行业指南并未确立强制性要求，不应被援引作为检查缺陷的依据。检查缺陷的依据源自CGMP法规，即21 CFR第210和211部分。
遵循2004年无菌工艺指南的生产商通常被认为符合CGMP法规。但是，如果替代方法满足21 CFR第210和211部分的要求，也可以使用替代方法。
对于检查期间遇到的技术问题和异常情况，鼓励检查员联系其所在地区办公室、ORA医疗产品与烟草运营办公室/医疗产品与烟草计划运营处和/或CDER进行咨询。对于微生物分析、无菌及相关取样方面的问题，请联系ORA监管科学办公室/医疗产品与烟草科学人员。
[第一部分结束]
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计划 7356.002A
第二部分 - 实施
2.1 目标
本计划的主要目标是为对无菌原料药1和无菌成品制剂药品生产商开展检查提供指导，以确定其是否符合《食品、药品和化妆品法案》及现行药品生产质量管理规范（CGMPs），《联邦法规汇编》第21篇第210和211部分。
其他目标包括：
• 获取影响无菌性的操作信息，以确定需改进和
纠正的领域。
• 评估无菌药品行业的现行药品生产质量管理规范。
• 对被发现不符合要求的制造商采取适当措施。
2.2 计划管理说明
A. 策略
(1) 系统检查
对药品生产商的检查应使用本合规计划中的系统定义和组织方式进行并报告。以系统为重点将提高检查效率，因为这些系统通常适用于多个产品类别。覆盖系统的选择将由地区办公室根据企业的具体运营、以往覆盖情况、合规历史或地区办公室确定的其他优先事项作出。
检查通常应对所有产品类别作出可接受或不可接受的判定。对某一系统的覆盖应足够详细，即选择每个产品类别的一个示例，以使关于该系统控制状态的结论适用于所有产品类别。然而，对某一产品类别确定某系统得到充分控制的结论，可以扩展到另一产品类别，即使该另一产品类别未被专门审查。主导调查员必须考虑工厂各种生产情况的独特性，并在选择要审查的产品类别时运用其最佳判断。
选择系统内的具体领域或独特职能将由主导调查员自行决定。
系统覆盖的选项在 CPGM 56002 中描述。任何一次检查不必覆盖每个系统。见第三部分 - 检查。
对一个系统的完整检查可能需要进一步跟进另一系统活动中的某些项目，以充分记录检查发现。此类跟进不构成对另一系统的完整覆盖（也不能在 FACTS 中如此报告）；该跟进也不要求调查员对另一系统进行完整覆盖。
1
“无菌原料药”指无菌活性药物成分（APIs）。
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PROGRAM 7356.002A
(2) 检查范围
对无菌药品生产企业的检查，依据合规计划 7356.002《药品生产检查》第二部分——实施中所述的系统策略，以全面检查或
简化检查的形式进行。
关于这些检查选项所要求的覆盖范围的完整讨论，见本计划第三部分——检查。
B. 检查计划
当无菌药品生产企业作为常规法定检查的一部分接受检查时，实施本计划。CDER 将根据基于风险的优先排序模型，结合年度绩效目标确定受检企业，作为确保基于风险优先安排检查覆盖范围的举措的一部分。
适当时，考虑采用团队方式进行检查。使用熟悉无菌药品生产和无菌工艺的检查员，并考虑纳入具有微生物控制专长的微生物学家。具体而言，
• 所有团队成员应非常熟悉 FDA 的行业指南《无菌工艺生产的无菌药品——现行药品生产质量管理规范》（2004 年 9 月）。
• 检查员或团队成员应完全胜任无菌产品生产，并已完成注射剂生产、无菌技术、
灭菌方法及相关程序和设备的正式培训课程。参与的微生物学家应
具备无菌、内毒素检测以及生产过程中微生物控制评估方面的经验。
C. 概况报告
根据检查发现，更新 FACTS 封面页概况屏幕中所有适用的概况类别。以下是本计划实施时生效的无菌产品概况类别清单。使用与所涵盖产品和工艺类型相对应的代码。
概况 完整描述
类别
LVP 大容量注射剂是指包装在标签标示装量超过 100 mL 的容器中的无菌注射用药品。大多数采用最终灭菌，但有些可通过过滤除菌并进行无菌工艺处理。
SVT 小容量注射剂是指包装在标签标示装量小于 100 mL 的容器中、经最终灭菌的无菌注射用药品。
SVS 小容量注射剂，通过过滤除菌并进行无菌工艺处理。
SVL 小容量注射剂，通过过滤除菌、无菌灌装并冻干。
SLQ 无菌液体（混悬剂和乳剂除外）
SON 无菌软膏
SPW 无菌粉末
CSS 通过化学合成制成的无菌原料药。
CFS 通过发酵制成的无菌粗品原料药。
CRX 原料药无菌或原料药中间体/NEC 无机/矿物
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PROGRAM 7356.002A
PART III - INSPECTIONAL
3.1 灭菌类型
生产无菌药品有两种主要方法：
• 最终灭菌
• 已灭菌单元组件的无菌工艺
使用无菌工艺生产无菌药品与使用最终灭菌生产之间存在根本差异。当产品和容器/密封系统能够承受最终灭菌工艺时，应采用最终灭菌。
A. 最终灭菌 - 最终灭菌工艺通常包括在旨在最大限度减少产品微生物和颗粒物污染的高质量环境条件下灌装和密封产品容器。这种上游生物负载的最小化降低了对后续灭菌工艺的挑战。在大多数情况下，产品、容器和密封件具有低生物负载，但在灌装时并非无菌。随后产品在其最终容器中接受灭菌工艺。
最终灭菌有多种方法，包括：
• 湿热灭菌
• 辐照
• 环氧乙烷（通常用于组装组件/套件）
灭菌循环类型包括：
1. 过度杀灭法：
o 通常用于热稳定材料。
o 旨在提供显著水平的无菌保证，无论装载中实际生物负载微生物的数量和
耐受性如何。
o 导致对产品或被灭菌物品更大的热量/暴露输入。
2. 基于生物负载的循环：
o 需要开展研究以确定产品中发现的微生物的数量和耐受性，以及进厂组件和容器/密封件的生物负载量。
o 进行循环开发以杀灭微生物负载，但不降解产品。
o 对批次进行常规生物负载监测，并持续了解产品生物负载、容器/密封件生物负载和环境监测样品中发现的微生物的热/暴露耐受性。
最终灭菌参考：PDA 技术报告第 1 号（2007 年修订）《湿热灭菌工艺验证：循环设计、开发、确认和持续控制》。
B. 无菌工艺 - 无菌工艺比最终灭菌对产品造成微生物污染的风险更高。在无菌灌装工艺中，药品、容器和
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PROGRAM 7356.002A
瓶盖/密封件单独灭菌，然后在极高的环境质量标准下组合在一起，以降低出现非无菌单元的可能性。无菌工艺涉及的变量比终端灭菌更多。在无菌灌装和组装之前或期间，对已灭菌药品、容器或密封件进行的任何人工或机械操作都会带来微生物污染的风险。
某些类型的无菌工艺除了操作人员在关键区域的常规干预外，还涉及对无菌组件、容器和密封件的人工操作。在传统无菌工艺中，人员是重要的污染来源，尤其是在要求操作人员常规进入灌装线关键区域（100级、ISO 5或A级）的生产线上。基于更先进控制技术的无菌工艺系统，如限制进入屏障系统（RABS）和吹灌封系统，旨在减少灌装线关键区域的人员干预，而隔离器系统则将无菌灌装线与外部环境完全隔离，并最大限度减少员工与关键区域的接触。
注：有关隔离器技术和吹灌封系统的更多信息，见FDA 2004年无菌工艺指南。
在对无菌药品生产商进行检查时，重要的是覆盖产品污染风险最大和/或需要严格控制工艺参数的系统及系统内区域。例如，如果某企业有多条无菌生产线，应覆盖在100级（ISO 5）区域需要最多人工操作的生产线。如果该企业对多个产品进行终端灭菌，应审查一个对热敏感且需要产品特定（基于生物负载）灭菌循环的产品。
注：对于在终端灭菌前进行无菌灌装的终端灭菌产品，可考虑采用不那么严格的无菌控制。
由于境外检查往往存在时间限制，仔细的检查计划尤为重要。应根据各区域对产品质量的潜在影响确定覆盖优先顺序。
3.2 报告
在编写检查报告时，遵循现行版IOM（调查操作手册）以及《国际检查与旅行指南》中的说明。
所有报告均使用Turbo EIR，无论国内还是国际，即使未签发FDA-483或FDA-483是在Turbo EIR之外签发的。报告的“生产/设计运营”部分应按本计划所述且在检查期间覆盖的系统进行组织。根据本合规计划中概述的关键要素，简要总结你对每个已覆盖系统的审查。对于发现存在缺陷的系统，添加更多细节和支持性证据。
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计划 7356.002A
3.3 检查方式
如果被检查的无菌药品为放射性药品，则应遵循合规计划 7356.002C《放射性药品》作为补充指南。本计划不应用于正电子发射断层扫描（PET）药品的检查。合规计划 7356.002P 专门针对 PET 药品。
本计划（CP 7356.002A）还应与合规计划 7356.002M《已上市生物治疗药品的检查》结合使用，用于已上市无菌生物制品的检查。
CGMP 合规计划 7356.002 提供了关于采用基于系统的方法对药品生产商进行检查的一般信息。它描述了六大系统（质量、设施与设备、物料、生产、包装与标签、实验室）以及两种检查选项（全面检查和简化检查）。它还就何时应选择每种选项提供了指南，并讨论了与被检查系统相关的“受控状态”的含义。
对无菌药品生产商的检查以全面检查或简化检查的方式进行，采用下文概述的系统策略。
全面检查包括监督性检查或合规性检查，并对企业遵守 CGMP 的情况进行全面评估。全面检查通常包括对至少四个系统的检查，其中必须包括质量系统。根据本计划，全面检查应包括设施与设备以及生产系统，因为这些系统对成品的无菌保证起着关键作用。
全面检查（PAC 56002A）在以下情况下进行
• 当要对药品企业进行首次检查时；
• 当作为警告信、监管行动或重大 FDA 483 检查发现之后的后续检查而进行的首次检查时；
• 当在简化检查期间获得的信息显示企业在某一个或多个系统领域的做法和程序存在重大缺陷时；
• 当自上次检查以来企业的运营发生重大变化时；或
• 出于监督目的，由地区办公室酌情决定，因为企业有反复违规、在合规与不合规之间波动的历史，或者当其他信息（样品、投诉、现场警示、召回等）使人们对企业生产质量产品的能力产生疑问时。
如果满足以下两个条件，简化检查（PAC 56002I）可能是适当的：
1. 企业已实施正式的风险管理计划，确保有效的设计和控制（包括维护）。这包括其工艺生产线的风险缓解设计，该设计纳入了现代化的分离和自动化方法（例如，隔离器、封闭式 RABS），以及上游生物负载控制。企业质量系统对潜在危害的响应能力也是评估的一部分，包括企业的计划是否提供稳健的
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计划 7356.002A
通过正式的药品生命周期质量风险管理计划，依照 ICH Q9 主动发现并纠正问题，从而实现日常保证和有效的消费者保护。
2. 该企业具有持续可接受合规历史的记录以及强大的风险管理
计划。
o 该企业生产采用稳健
灭菌方法进行终端灭菌的成品制剂。（注：终端灭菌提供更为稳健的工艺以
确保无菌）；或，
o 该企业已实施稳健的风险管理，通过
其整体设计与控制计划提供日常保证；
o 在检查开始时，对自
上次全面检查以来的无菌保证数据进行广泛审查。对培养基模拟灌装、无菌检测数据、召回、
缺陷/不良事件投诉及报告的审查未发现已分销批次无菌失败的
问题，并且
o 该企业具有令人满意的 CGMP 合规记录（例如，连续两次 NAI 或不超过
一次 VAI 检查），且无 1 类召回。
微生物控制和无菌保证应作为简略无菌药品
检查的主要重点。根据本计划，简略检查应涵盖每个系统（质量体系除外）的以下关键要素：
• 设施与设备：
o 清洁与消毒
o 设施/设备布局及空气处理系统，用于防止活性和非活性
污染
o 物料流向
o 洁净区的质量控制，包括空气压差平衡和 HEPA 过滤
o 支持洁净室质量充分性的趋势数据
o 对差异的记录调查
• 物料：
o 进厂物料和组件的微生物及细菌内毒素控制
o 供水质量、维护、确认
o 提供所需水和工艺气体的系统的运行
o 对 OOS、偏差和差异的记录调查
• 生产：
o 观察生产过程中操作人员行为和无菌技术的充分性
o 生产线操作和干预
o 人员的无菌技术培训
o 主要生产线维修或维护问题
o 微生物和细菌内毒素控制的风险评估，包括关键步骤的
保持时间
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PROGRAM 7356.002A
o 设备、容器-密封件及用品的灭菌验证
o 培养基模拟灌装设计与结果
o 对偏差、差异及 OOS 结果的书面调查记录
• 实验室：
o 对 OOS、偏差及差异的调查
o 检验方法及控制，包括对经验证方法的遵循情况
o 实验室人员的培训与资质
o 水系统检验结果的趋势分析
o 用于环境监测分离菌回收、鉴定及趋势分析的系统
3.4 系统检查覆盖范围
合规计划 7356.002《药品生产检查》列出了检查六个系统时各自应覆盖的领域。本计划按系统
针对无菌药品特别关注的领域提供了补充指南。
附件 A 是一份问题清单，旨在辅助开展检查并获取评估企业运营所需的信息。除非相关，
否则答案无需写入 EIR。该问题清单涵盖：湿热灭菌；干热灭菌/去热原；无菌灌装；冻干；隔离器；环境监测；以及
生物指示剂。
3.5 质量体系
如合规计划 7356.002 所述，质量体系的检查分两个阶段。第一
阶段是评估质量部门是否履行了其在程序审核与批准方面的职责，并确保其适用于使用。第二
阶段是评估企业收集的数据，以识别潜在的质量问题。对于无菌生产操作，后一
目标涉及大量数据，这些数据与其他检查系统相关联。企业对这类数据的
全面审核是确保产品在高度无菌保证下生产的关键要素。因此，重要的是审核企业
利用数据评估其生产操作和设施受控状态的系统。质量部门保存的数据
汇总和趋势报告应在每次检查时予以审核。在常规 CGMP 检查中，这一审核有助于确定选择哪种方式（全面或
简化）。
质量体系的检查应包括 CP7356.002 中列出的领域。对于本计划，
检查应包括审核所有可能表明产品污染和
无菌保证问题的数据与报告。
与质量有关的记录包括以下内容：
1. 定期产品评估、投诉、不良事件、调查、现场警示报告、
产品留样评估、投诉、拒收批次、稳定性及退货，这些表明
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PROGRAM 7356.002A
possible product contamination or risks to patients (for example, hazy or cloudy product,
foreign matter/particulates in injectable products, cracked, and leaky containers).
2. Discrepancy and failure investigations, such as:
o All initial positive sterility tests and endotoxin and media fill failures regardless of final
disposition.
o Unexpected results or trends.
o All failures that occurred during validation or revalidation of sterilization / depyrogenation
processes.
o All investigations involving media fills / process simulations.
o Environmental (microbial/viable and particle/non-viable counts) and personnel monitoring
results that exceed alert or action levels.
o Process deviations or equipment malfunctions that involve critical equipment, such as
sterilizers and lyophilizers.
o Out of Specification (OOS) results for assay, impurities, particulate matter, or reconstitution
time, if applicable.
o Product rejects (rejects determined during manufacturing and Quality Control test)
3. Trends reports/ summaries of quality indicators:
o For aseptic processing, summary of all media fills performed since last inspection.
o Environmental monitoring trend data (microbial and particle counts).
o Personnel monitoring trend data.
o Summary of water system test results.
4. Summary of change controls for critical utilities and equipment implemented since the last
inspection, for example:
o Sterilizers, lyophilizers, depyrogenation equipment
o Aseptic processing line
o Clean steam generator, process gas system
o WFI and / or Purified Water system
o Air handling systems
o Automated building management system
Every inspection of a sterile drug manufacturer should include a review of the type of information listed
above and observation of the manufacturing operations occurring in the critical areas. The information
can be used to select other system(s) to be covered during the inspection.
In addition, the review of summary data and observation of operations can focus the inspection on
potential problem areas and provides an overview of the effectiveness of the Quality System. The
inspection of the Quality System may necessitate follow-up within another system. However, this
coverage does not constitute or require complete coverage of these systems.
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PROGRAM 7356.002A
3.6 FACILITIES AND EQUIPMENT SYSTEM
Compliance Program 7356.002 lists the general areas to cover when inspecting the Facilities and
Equipment System. The areas are applicable to sterile drug products and should be covered if this
system is selected. The principle objective of an effective sterile drug manufacturing operation from a
facility and equipment standpoint is to provide suitable protection of product. The inspectional
evaluation of this objective is again two-part:
• Review and evaluate the firm’s rationale for, and adequacy of, the facility and equipment
design (Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance).
• Evaluate the data that provide information relevant to the state of control of the facility and
equipment.
In addition to the review of design elements and data, investigators should look for visible deficiencies in
the facility and equipment, such as cleanliness, equipment deterioration (e.g., warping, corrosion),
inaccessible and/or difficult to clean surfaces, and changes to critical equipment or systems that have not
been qualified which may impact product quality. Investigator should look for aberrant events due to
facility deterioration, a pattern of recurring and uncorrected maintenance issues, and increase or changes
in production output that exceed the capacity of the facility and equipment.
A. FACILITIES
Evaluate the design and layout of the facility (e.g., personnel/material flow, cleanroom design).
Specifications for clean room areas (layout, air filtration, appropriate air classification, pressure
differentials between rooms and areas, temperature, and humidity) should be appropriate, and based on
the risk of product contamination with particulate matter and microorganisms. Review the certification
and qualification of the clean room areas to verify the areas meet design criteria and specifications.
Certification and qualification typically includes data in support of the following: air flow pattern
studies, HEPA (High Efficiency Particulate Air) filter integrity testing, air velocity measurement, non-
viable particle, and verification of appropriate pressure differentials, temperature and humidity setpoints.
Evaluate the airflow pattern (smoke studies) conducted under dynamic conditions to verify the
unidirectional airflow and air turbulence within the critical area where sterilized drug product,
containers, and closures are exposed to environmental conditions.
• Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance.
• Routine monitoring and maintenance to assure air handling systems continue to operate within
established parameters (microbiological monitoring is discussed under the Laboratory Control
System).
o Afford special attention to facilities that are performing construction in the clean areas, or at
the vicinity of cleanroom. Because microbes (e.g., fungal spores) can be liberated from the
movement of walls and other construction activities, determine if the facility is returned to
acceptable environmental control through proper measures (environmental monitoring,
media fills) before production can resume.
o Verify that environmental monitoring of non-viable particle is occurring during operations
including sites where there is the most risk to exposed product, container and closures.
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PROGRAM 7356.002A
o Check if pressure differentials, temperature, and humidity are continuously monitored
during routine production.
o Determine if continuous monitoring systems are alarmed to alert operators of excursions.
o Check if excursions from acceptable ranges are investigated to determine impact on product
and that needed corrective actions are taken.
o Evaluate the program for periodic testing / recertification of the HEPA filters in critical
areas to maintain appropriate air flow. The tests typically include integrity testing of the
HEPA filters and air velocity checks.
• Sanitization / disinfection of clean room areas, processing lines, and non autoclavable
equipment, materials, and components should be reviewed. Focus on the areas where the
sterile product is exposed up to and including sealing operations. These critical areas represent
the highest risk to the product. The suitability, efficacy, and limitations of disinfecting agents
and adequacy of procedures should be reviewed, including the data that establishes the expiry
of the disinfection solution. (Reference: Section X.A.3 of FDA’s 2004 Aseptic Processing
Guidance)
• For multi-use facilities and non-dedicated equipment, evaluate the adequacy of the changeover
procedures and cleaning to prevent cross-contamination between products.
B. EQUIPMENT
Equipment used in the manufacture of sterile drug products may include the following:
• Production Equipment
• Container/closure processing equipment (e.g. stopper washer, glassware depyrogenation
equipment)
• Support system/material system related equipment (e.g. WFI system and related equipment,
process gas related equipment)
Specific considerations include:
(1) Production Equipment
(a) Aseptic Processing Equipment. Determine that all equipment that comes in direct contact
with product (e.g., filters, transfer lines, holding tanks, stopper bowls, filling line equipment) and
sterile components (e.g., stoppers) are sterilized and protected from contamination prior to and
during use. Equipment logs or other related information may provide insight into significant
maintenance or other problems that may increase exposure of batches to contamination risk.
(b) Stopper washer. Inspectional considerations include the qualification of the equipment,
cycle validation and supporting data, equipment preventative maintenance (maintenance
requirements and frequency), quality of water used for washing, and associated water
sampling/qualification data. The appropriateness of the air supply used in any drying operations
should also be verified.
(c) Capping Equipment (vials). The vial cap provides the final closure element of a sealed vial.
The capping machine folds and crimps the cap (aluminum) over the neck of the stoppered vial.
The cap on the vial protects the stopper from external damage, while firmly holding the stopper
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PROGRAM 7356.002A
in the fully seated, sealed position. Evaluate the established processing settings (crimp angles,
pressures), and preventative maintenance schedules of the capping machine. Air supply quality
to the capping units should also be evaluated.
(d) Post fill Visual Inspection/Automated Inspection Equipment. The 100% inspection of the
final filled and sealed product may occur via a manual, automated, or semi-automated inspection
process. Manual and semi-automated inspection processes involve specified viewing fields and
calibrated light sources. Semi-automated processes may use conveyor belts and rotational units
that present the filled product to an operator for visual inspection. All conveyor and rotational
speed set points should be verified against established parameters. Automated inspection systems
may inspect for one or all types of defects in a given filled product. Defect categories with
relevant action levels should be defined. The qualification of the equipment and the challenges
performed to verify equipment functionality prior to routine use should be evaluated as well as
the training program for operators performing manual visual inspections.
(e) Sterilizers. The inspection should cover the Installation and Operation Qualification of
equipment and the Performance Qualification of the process (IQ, OQ and PQ), and operation,
calibration and preventative maintenance of representative types of equipment used to sterilize
finished dosage forms, filling equipment, containers, closures, etc. Such equipment includes
autoclaves, dry heat ovens, dry heat tunnels, steam-in-place (SIP) equipment and chemical
sterilization systems (i.e., hydrogen peroxide, peracetic acid). Inspection of sterilizers should
include physical examination of the equipment. Review the engineering specifications which
may be described in the equipment’s DQ (Design Qualification). DQ is performed prior to the IQ
(Installation Qualification) and OQ (Operational Qualification), and verify that the sterilizer is
maintained, calibrated and drained properly and that it has appropriate measuring devices
(temperature sensors, pressure gauges, etc.).
Records of unplanned maintenance, as well as preventative maintenance, should be reviewed to
assure all significant changes have been evaluated and qualified as appropriate. Equipment logs
should also be reviewed. For example, repeat sterilization of loads because of cycle failures can
indicate a serious problem with a sterilizer. Impact of re-sterilization to product quality should be
evaluated. (Performance qualification is covered under the Production System).
The equipment can be computer controlled or operated in a manual mode. For computer
controlled system, programmable logic controller (PLC) or a more complex Supervisory
Controlled and Data Acquisition Management System (SCADA), may require an assessment to
determine if the computer control and/or monitoring system are Part 11 compliant.
Reference:
o PDA Technical Report No. 1 Revised 2007 Validation of Moist Heat Sterilization
Processes: Cycle Design, Development, Qualification and Ongoing Control;
o ISO 17665 Moist Heat Sterilization.
(f) Lyophilizer. Because partially sealed vials are used in the lyophilization process, sterile
product is exposed to the environment from the time of filling until the vials are fully stoppered
in the lyophilization chamber at the end of the cycle. The inspection should verify that partially
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PROGRAM 7356.002A
sealed vials are transported and loaded into the lyophilizers under Class 100 (ISO 5) protection.
Investigators should observe the transport of vials and loading of lyophilizers.
Other key equipment areas to cover include: validation of the sterilization of the lyophilization
chamber between uses, current sterilization controls, leak testing of the chamber, integrity testing
of air/gas filters, and calibration of temperature and pressure controllers.
Reference: FDA’s Guide to Inspections of Lyophilization of Parenterals.
(g) Isolators. Evaluate the design and control elements that maintain the separation or isolation
of the product. Pressure differential, glove integrity, and protection of the transfer (i.e., entry,
exit) ports are key elements for the isolators. The transfer of containers, closures and supplies
(including environmental monitoring supplies) into an isolator should be carefully controlled.
Another critical element for these systems is the effectiveness of the chamber decontamination
program. Current methods (e.g., vaporized hydrogen peroxide, steam hydrogen peroxide,
peracetic acid) used to decontaminate isolator barriers are capable of surface sterilization but
lack the penetrating capabilities of steam sterilization. Investigators should be mindful of the
limitations of these surface sterilants, including their inefficiency in penetrating obstructed or
protected surfaces. Validation of the decontamination of the interior (surfaces) of an isolator
should demonstrate a 6-log reduction of the biological indicator (BI). Quantitative measuring
devices (e.g., near infrared) or chemical indicators (qualitative test) can be used to determine the
worst case location for decontamination validation using BI. Factors to be considered in
decontamination validation include the location of the BI and the type of surfaces where the BIs
are inoculated.
Utensils and equipment surfaces inside the isolator that have direct contact with sterile product
and components should be sterilized to render them free of microorganisms. The sterilization
validation should achieve a minimum of a 6-log reduction of the BI
Reference:
o Appendix 1 of FDA’s 2004 Aseptic Processing Guidance;
o PDA Technical Report 51 (2010) Biological Indicators for Gas and Vapor Phase
Decontamination Processes: Specifications, Manufacture, Control and Use provides
general principles to be considered in decontamination by BI.
(h) Restricted Access Barrier System (RABS). In general, a RABS is a fill-finish line in a rigid
wall enclosure that provides full physical separation of the filling line from operators. It is
important to note that the inside surfaces of the RABS are disinfected with a sporicidal agent2,
but this is not accomplished using the automated decontamination cycles employed for isolators.
This requires firms to carefully supervise disinfection procedures and assure ongoing
effectiveness of the disinfection program. Operators use glove ports, half suits or automation to
access areas within the enclosure during filling. There are 2 types of RABS, “open” and “closed”
RABS. The doors to a “closed” RABS are never opened during an operation. While an “open”
RABS is designed to operate with doors closed at all times, on rare pre-defined circumstances
2
Robust disinfection of all non-product contact surfaces within the RABS should be performed with a suitable sporicidal
agent before batch manufacture. Product contact equipment should be subject to sterilization.
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PROGRAM 7356.002A
the doors of the enclosure can be opened to perform certain interventions. If doors are routinely
opened during a filling operation, the system is not considered a RABS because it no longer
restricts access to the critical areas. Typically, the cleanroom surrounding the RABS is
controlled as a Class 10,000 (ISO 7) area and operators are fully gowned.
Reference: Restricted Access Barrier Systems (RABS) for Aseptic Processing; ISPE; August 16
2005.
When inspecting a RABS:
o Determine that the gloves and gauntlets attached to the glove ports are sterile when
installed. After installation, the gloves should be disinfected or changed at appropriate
intervals to minimize the risk of contamination.
o Verify there is a well defined written procedure that describes what is done when an open-
door intervention is performed. All open-door interventions should be documented and
described in batch records, and followed by disinfection.
o RABS entry is often accompanied by an appropriate line clearance, which should be clearly
documented in batch records.
o Determine that all fluid pathways and product contact parts such as stopper bowl, feed and
placement systems are sterilized prior to the filling of each batch.
o Observe how sterile components and supplies are transferred to the RABS. Verify that the
transfer system prevents exposure of sterile surfaces to less clean environments.
o Verify that non-product contact surfaces within the RABS undergo thorough disinfection
with a sporicidal agent before each batch. The effectiveness of the overall disinfection
program should be validated and routinely evaluated by the environmental monitoring
program.
(i) Blow-fill-seal (BFS) Technology. BFS is an automated aseptic filling process in which
containers are formed, filled and sealed in a continuous operation. BFS systems can reduce the
risk of product contamination by reducing operator interventions. The systems are typically used
for filling sterile ophthalmic and respiratory care products. See Appendix 2 of FDA’s 2004
Aseptic Processing Guidance for information about BFS systems. It should be noted that the
inner surfaces of the containers can be exposed to the surrounding environment during the
formation and molding steps prior to filling. The sterile product can also be exposed to the
environment during the filling and sealing steps of the BFS process. Therefore, the air quality
should meet the microbiological level established for Class 100 (ISO 5) should be supplied to
where the sterile product or its containers are exposed during the BFS process. Some of the more
advanced BFS equipments that provide enhanced protection for the sterile product operation can
be located in a Class 100,000 (ISO 8) area. Otherwise, a Class 10,000 (ISO 7) area is
appropriate. Research has demonstrated a direct relationship between the number of
contaminated units and the level of microbial contamination in the air surrounding the machine
(see Reference #20). Typically, the product supply line and sterilizing product filters are steam
sterilized-in-place (SIP).
When inspecting BFS:
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PROGRAM 7356.002A
o Verify that HEPA-filtered or sterile air is used during steps where sterile product or
materials are exposed (e.g., parison formation, container molding, and filling steps).
o Evaluate the monitoring and preventative maintenance programs to determine the integrity
of the utilities (cooling water, heating, etc.) associated with the BFS machine is routinely
checked. Leaks in the molds or utility connections at the molds can contaminate the sterile
product or containers.
o Review the SIP system used to sterilize the product line. Determine the sterilization cycle
has been validated and the condensate properly drains from the line. The line should also be
protected between sterilization and use.
o Verify that personnel who enter the classified environment surrounding the BFS machine
are properly gowned and trained.
o If possible, observe equipment setup and any difficulties that can lead to contamination
risks.
Other control procedures (media fills, environmental monitoring, disinfection of surfaces, etc.)
are the same as discussed for conventional aseptic processing line.
(j) Reactor, Centrifuge, Dryer, Mill. This type of equipment can be used to aseptically
manufacture sterile bulk Active Pharmaceutical Ingredients (APIs). The equipment and all
transfer piping must be sterilized prior to processing. This is typically done with sterilize-in-
place (SIP) systems which use clean steam or a chemical sterilant. Review the validation, cycle
controls and the routine monitoring of the SIP system. The equipment and all transfer piping
must remain integral (no fluid or air leaks) and sterile throughout the entire manufacturing
process. Determine how the firm verifies the integrity of the equipment train throughout the
process. If a piece of equipment is opened in the process (e.g. adding seed crystals), verify the
area surrounding the open operation is robustly protected from contamination risks with a Class
100 (ISO 5) air system as well as implementing a carefully designed aseptic operation.
Reference: FDA’s Guide to Inspections of Sterile Drug Substance Manufacturers.
(2) Container/Closure Processing Equipment
Depyrogenation equipment may include a dry heat oven and/or depyrogenation tunnel.
Depyrogenation of stoppers can also be accomplished by dilution via a washing process. The
final rinse of the washing process uses Water for Injection (WFI). For more information, see
FDA’s Aseptic Processing Guidance, Section VI.B, Containers/Closures.
(3) Support Utilities
(a) Water System. Specifically, review WFI generation equipment and distribution loop(s),
including tanks, water lines, isometric diagrams, vent filters, and preventive maintenance
schedules (See also Materials System). Monitoring equipment associated with the Water System
should also be evaluated.
(b)HVAC. Refer to Section IV of FDA’s 2004 Aseptic Processing Guidance on qualification
and maintenance of the HVAC system.
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(c) Process Gases. Gases that are in contact with the drug product or components in drug
manufacturing operations are referred to as process gases. Gases used in aseptic operations, or
downstream of sterilization, must be filtered through a sterilizing grade filter to maintain asepsis.
The integrity testing of these filters (typically hydrophobic) should be evaluated. The system
used in the generation of the process gas(es) should also be evaluated including preventive
maintenance (PM) schedules, monitoring (including temperature, pressure, and humidity), and
sampling. See also under Materials System.
3.7 MATERIALS SYSTEM
Compliance Program 7356.002 lists the areas to cover when inspecting the Materials System. The areas
are applicable to sterile drug products and should be covered if this system is selected. In sterile
operations, the quality attributes of each of the materials (ingredients, WFI, containers, closures) have a
bearing on the critical attributes of the finished product. Review the firm’s procedures for receipt,
handling, sampling, testing, approval and storage of manufacturing materials to verify their fitness for
use. Emphasis should be placed on incoming materials that are represented to be sterile and / or pyrogen
free.
Areas of special concern for sterile drug products include:
(1) Water Systems. Water for Injection (WFI) is an ingredient in many sterile drugs, including
injectable products and sterile ophthalmic products. It is also used in depyrogenation (or endotoxin
removal) of equipment and stoppers and in cleaning operations. The quality of the water, and its
endotoxin levels and controls, used in the upstream process should also be evaluated in order to ensure
the removal of bacterial endotoxin to the appropriate level downstream. Purified water can be used for
some sterile non-injectable solutions.
• Observe and understand elements of the generation and distribution systems.
• Evaluate the water system “As Built” diagrams” and inspect for leaks, pipe slopes (via the
isometric diagrams and verification of the degree of the slopes), so called “dead legs”, and
non-sanitary fittings in the distribution system.
• Evaluate how microbial alert and action levels are established.
• Evaluate sampling sites, procedures, frequencies and tests performed.
• Review procedures for preventative maintenance and calibration of critical instruments,
including scheduling and equipment update procedures.
• Review raw data to verify that all of the above is completed per established procedure.
• Review and observe routine monitoring (in-line TOC and conductivity) of water system.
• Review trend data for chemistry, microbiological and endotoxin tests.
• Review investigation of results that are at or over alert and action levels.
Reference: FDA’s Guide to Inspections of High Purity Water Systems.
(2) Process Gas. Process gas and related equipment controls may be covered in conjunction with the
Facilities and Equipment System. Specific considerations include controls over final filtration of the
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PROGRAM 7356.002A
processed gas and filter integrity testing. Gas used as a component in a finished product may include the
Nitrogen gas overlay for Oxygen sensitive products.
(3) Pre-washed / Ready to Sterilize Closures. The CGMP regulation (21 CFR 211.94(c)) states that,
where indicated, containers and closures must be processed to remove pyrogenic substances. Many
manufacturers of small volume parenterals purchase stoppers that are ready-to-sterilize, (i.e., they are
pyrogen-free). No washing or depyrogenation is done by the dosage form manufacturers but these firms
are still responsible for assuring the stoppers are of acceptable quality for use in manufacturing. The
pyrogen requirements should be included in specifications for the stoppers and, if the manufacturer does
not conduct testing of each incoming lots for pyrogen/endotoxin, they should establish the reliability of
the supplier’s test results by qualification of the vendor, followed by periodic testing.
(4) Microbiological and Endotoxin Testing of Component, Container and Closure. 21 CFR
211.84(d) specifies that each lot of component, container or closure that is liable to microbial
contamination which is objectionable in view of its intended use shall be subjected to microbiological
tests before use. Evaluate the firm’s system for determining if microbiological or endotoxin testing is
required and the rationale for setting acceptance criteria. Review test data to verify that the materials
meet test criteria and, if not, verify that investigations were conducted to determine the cause and
corrective actions were implemented.
(5) Verification of Container and Closures. The physical and chemical characteristics of containers
and closures can be critical to the sterility and stability of the finished product. Many containers and
closures look alike (color and dimensions), but are made of different materials or have a different
surface treatment such as silicone on stoppers and ammonium sulfate on Type I glass. Evaluate the
firm’s procedures for assuring containers and closure consistently meet appropriate specifications.
Determine what tests and examinations are done to verify the containers and closures are made of the
correct materials with the correct dimensions (critical to ensuring continuing container-closure integrity)
and are free of critical defects.
(6) Container / Closure Integrity. The integrity of the container / closure system is critical to assuring
that all units of drug products remain sterile through shipment, storage and use. Leaking containers or
closures lead to product contamination.
Reference: FDA’s 1994 Guidance for Industry for the Submission of Sterilization Process Validation in
Applications for Human and Veterinary Drug Products.
Evaluate the tests and studies performed to demonstrate the integrity of container / closure systems for
all sterile drugs, including:
• Verify that all incoming container-closure components meet specifications, including all
appropriate dimensions.
• Determine studies adequately simulate the stress conditions of the sterilization process,
handling and storage.
• Verify that the units tested in validation are appropriate (e.g., for terminally sterilized drug
product, the units selected should be exposed to the maximum sterilization cycles using the
production process).
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• Sensitivity of the test is specified.
• Container-closure integrity is demonstrated during validation and as part of the stability
program (in lieu of sterility testing), over the shelf life of the product.
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3.8 PRODUCTION SYSTEM
Compliance Program 7356.002 lists areas to cover when inspecting the Production System. The listed
areas are applicable to sterile drug products and should be covered during inspections.
Production practices and conditions can have a direct and significant adverse impact on drug sterility
assurance. The Production System, as well as the Quality System, should be included in all Full
Inspections. Coverage of critical elements, which are typically defined by the firm of the Production
System, should be part of all inspections (full and abbreviated) of aseptically processed sterile drug
manufacturers.
The risk of contamination posed by an operation depends greatly on the design of the overall
manufacturing operation. Observation of manufacturing is a critical part of evaluating the adequacy of
an aseptic processing operation. The following should be carefully observed.
• adequacy of aseptic technique [See section V of FDA aseptic processing guidance]
• personnel behavior and practices in the cleanroom [See section V of FDA aseptic processing
guidance]
• movement of people and materials before and during the aseptic operation
• robustness of production process design (e.g., process performance, validation, impact of
equipment configuration on ergonomics of aseptic manipulations) [See section IV of FDA
aseptic processing guidance]
• disinfection practices [See section X.A.3 of FDA aseptic processing guidance]
More specifically, the inspection must include real time observation of the higher risk operations
including but not limited to (these are examples and not an all inclusive list):
• Set-up of filling lines, especially difficult to assemble lines (e.g. powder filling lines), and lines
that require multiple aseptic assemblies or do not employ SIP of the product pathway.
• Cleaning and disinfection of the line and room to ensure all difficult to access surfaces are
consistently and properly cleaned and disinfected.
• Protection of critical contact surfaces to ensure their sterility throughout operations and post
sterilizations.
• Aseptic technique and cleanroom behavior during operations, including handling of equipment
jams and stoppages.
• Personnel flow in relation to microbial control of the environment.
• Material flow (e.g., whether materials are moved from a lesser controlled area to a cleaner area
without disinfection), including number of staff and their activities in the aseptic filling room.
• Filling operations, especially personnel gowning technique, gown integrity, strict adherence to
SOPs), the nature and frequency of interventions (interventions are also performed during the
media fill simulations), and overall condition of the critical filling area.
• Atypical interventions associated with unplanned events (e.g., operator attempts to change the
filling pump during operations).
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• Extra manipulations during filling operations for assembly of sterile filtration apparatus that is
not SIP sterilized.
• Handling (transfer, storage, loading) of partially stoppered vials in lyophilization processes.
Note that for lyophilized products, vials of sterile products are stoppered but not fully sealed
until the lyophilization process is completed. The sterile product is exposed to the environment
during filling, half-stoppering, transport, loading of the lyophilizer, and the lyophilization
cycle. Complete seating of stoppers typically occurs in the chamber after the cycle is
completed. All of these manipulations must be performed under Class 100 conditions.
• Preparation of equipment for sterilization (cleaning, the type of wrapping to ensure protection
while still allowing for penetration as part of the validated sterilization cycle with defined
loading patterns).
• Environmental monitoring (while the monitoring program is considered a Laboratory System,
inspection should include observation of the actual monitoring operations and rationale for
sample site locations).
• Proper placement and sealing of stoppers on vials as applicable, and the capping (aluminum
crimp) is performed in a protected area under unidirectional flow.
• Production of sterile suspensions and sterile bulk powders (e.g., antibiotics) where sterile
filtration of the final bulk is not feasible. These are typically formulated and manufactured
under aseptic conditions. This requires the sterilization of large pieces of production equipment
(e.g., tanks, reactors, dryers and associated lines) and assurance that these pieces of equipment
retain their integrity and remain sterile.
Critical operations that should be covered during an inspection of the Production System include:
(1) Media fills or process simulations. Media fills are used to validate aseptic processing operations,
including those employing newer technologies, such as isolators, BFS or RABS systems. Media fills
representing manually intensive aseptic operations should equal or approach the size and duration of a
commercial production lot. In contrast, a process conducted in an isolator is designed to have a lower
risk of microbial contamination because of the lack of direct human intervention and can be simulated
with a lower number of units as a proportion of the overall operation. All media fills should closely
simulate manufacturing operations, incorporating, as appropriate, worst-case activities and conditions as
well as operator interventions. FDA’s current expectations for media fills are discussed in Section IX.A
of the 2004 Aseptic Processing Guidance.
• Verify Media Fills represent actual manufacturing operations by comparing observed
operations to those documented in Media Fill batch records.
• Determine if media fills are conducted semi-annually for each processing line. The activities
and interventions representative of each shift should be included in the semi-annual media fill
program. This may require more than one media fill per line every 6 months, if aseptic
processing is performed during more than one shift. With the exception of isolator operations,
at least one semi-annual media fill is performed per line per shift. Determine if the aseptic
filling of all types of containers are supported by the media fills performed. If a matrix
approach is used, evaluate the firm’s justification for selecting the worst case container /
closure configurations for each line.
• Determine accountability of all filled units (units filled vs. units incubated).
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• Verify that all units that were discarded during and after filling have a reasonable and
assignable cause for rejection (e.g., rubber stopper missing, aluminum cap missing).
• Determine that cracked and leaking units found after incubation are investigated, counted and
all rejected units properly justified (e.g., is there an assignable cause that is reasonable for the
rejection?).
• Determine how and who examines units after incubation. If the examination is not performed
by a microbiologist, determine if it is overseen by the quality unit and if the operators doing
the exam are properly trained by a microbiologist.
Reference:
• FDA’s 2004 Aseptic Processing Guidance, Section IX A.
• PDA Technical Report No. 28, revised 2006, Process Simulation Testing for Sterile Bulk
Pharmaceutical Chemicals.
• PDA Technical Report No. 22, revised 2011, Process Simulation for Aseptically Filled
Products.
(2) Sterile filtration (aseptic processing).
• Verify filters used in production are identical to those used in validation studies (i.e., those
submitted in drug applications)
• Verify that actual operating parameters and allowable extremes are covered in the validation
studies.
• Determine that validation of filter sterilization has been performed for all products. Pay special
attention to legacy products. These include older products and those for which applications
have not been submitted.
• Observe filter integrity testing to verify procedures are followed.
• Review investigations of any integrity test failures.
Reference:
• FDA’s 2004 Aseptic Processing Guidance, Section IX.B; and
• PDA Technical Report #26, 2008, Sterilizing Filtration of Liquids.
(3) Sterilization and depyrogenation of containers, closures and processing equipment.
• Review the validation or revalidation of sterilization and depyrogenation processes used for
containers, closures and, in the case of aseptic processing, equipment that comes in contact
with the sterile product or sterile components.
• Check if firm verifies that validated parameters (loading patterns, cycle parameters) are met for
each load.
• Rubber stoppers that are not purchased pre-sterilized or pre-siliconized may require
depyrogenation and siliconization prior to use. As previously noted, depyrogenation may be
achieved via a washing dilution process with the use of repeated WFI washing steps. The
validation should demonstrate a successful 3-log reduction of bacterial endotoxin. When the
firm performs its own siliconization of stoppers, silicon level after wash should be validated to
meet the predetermined acceptance criteria.
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• Stoppers are sterilized by steam sterilization. Verify that the clean steam used to provide the
sterilization is acceptable and has been assayed for endotoxin.
• Review the practices and procedures to determine if a firm needs to revalidate the sterilization
and depyrogenation process.
• Review change control procedures.
• Determine if reprocessing is performed.
• Evaluate bioburden level: Evaluate the firm’s understanding of process bioburden (e.g., from
incoming components/container/closure) and determine if the firm has adequately validated
hold time for critical steps. It is important to note that increased bioburden can lead to the
degradation of the drug product as well as contributing impurities (including endotoxin) to the
drug product. Sampling points (location in process flow) and methods should be evaluated
based on product quality risks.
(4) Lyophilization.
• Review the validation of lyophilization cycles established for selected products.
• Verify the firm confirms all critical cycle parameters are met for each lot.
• Determine environmental monitoring is routinely performed in the areas of loading and
unloading of the product from the lyophilizer. In addition, ensure personnel monitoring is
conducted on those operators who perform the loading and unloading operations.
• Observe the transport of the partially stoppered vials and the loading of the lyophilization
chambers to verify it is done under proper environmental conditions (Class 100) and to verify
that proper aseptic techniques are used.
Reference: FDA’s Guide to Inspections of Lyophilization of Parenterals.
(5) Sealing of vials.
• A vial is not sealed until the aluminum overseal is placed over the rubber stopper and crimped
in place.
• If stoppered vials exit the aseptic processing zone prior to capping, verify proper safeguards
are in place, such as HEPA filtered air protection and qualified in-line detectors that reject
vials with improperly seated stoppers.
(6) Terminal sterilization.
• Determine what type of sterilization cycles are used (bioburden based or overkill).
• Review validation / revalidation / or periodic evaluation of terminal sterilization cycles for
representative types of products.
• For selected products, verify that the parameters and loading patterns used in production are
the same as those used in validation studies.
• Determine the minimum acceptable cycle allowed in the SOP (as opposed to the nominal or
routine cycle) and compare that to the validated cycle (using BI) to verify it has been properly
qualified.
• Determine how sterilization cycles are documented, monitored and reviewed.
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• Review deviations or atypical data from sterilization operations that indicate inconsistencies in
process performance.
(7) Parametric release of terminally sterilized drug product. This is defined as a sterility assurance
release based on demonstrated control of the sterilization process. It enables a firm to use defined
critical process control data, in lieu of the sterility test to fulfill the intent of 21 CFR 211.167(a). It is
allowed only for products that are terminally sterilized by heat and it must be identified in the
appropriate regulatory filing as the release method. Parametrically released product must have an
approved application.
• If encountered during an inspection, verify the parametric release method has been submitted
and approved in the appropriate drug application. If the drug is not the subject of an approved
application, collect pertinent information and validation data for evaluation by the Center.
• Verify that the conditions described in FDA’s Compliance Policy Guide Section 490.200,
Parametric Release – Drug Products Terminally Sterilized by Heat, are met.
(8) 100% inspection of injectable products including: cracks, visible particles and other significant
defects.
• Verify the firm has written procedures that define the defects to be removed from the lot and
actions to take if the number of critical defects exceeds a pre-determined level.
• Significant defect categories should be identified. Results of inspection of each batch should be
compared to established action levels.
• Evaluate the appropriateness of and the rationale or justification for pre-determined action
levels.
• Evaluate the firm’s investigation into the cause of rejects, including units rejected for cracks
and visible particulates (e.g., foreign matter).
• Observe the inspection process.
• Challenge visual/manual inspection rates through observation.
• Evaluate the adequacy of written procedures for visual inspection.
• Evaluate personnel qualification and requalification and equipment qualifications according to
established procedures. Evaluate personnel qualification including the use of reference samples
for qualification.
o If a manual system is used, determine if employees are trained and qualified to verify they
can recognize and remove defects under actual or simulated production conditions.
o If an automated or semi-automated system is used, determine the equipment is qualified and
the software program or equipment settings have been validated for all types of products
being inspected (e.g., clear vials, amber vials, colored solution, suspensions). If the
equipment is an automatically controlled computer based system, an assessment of the
system and validation is warranted.
• Evaluate the firm’s program for sampling and examination of inspected vials and evaluate the
effectiveness of inspection and action taken if the reject level is reached.
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• Evaluate the firm’s assessment of units rejected during filling operations (any separate
inspection prior to the 100% inspection stage), established alert/action limits, and
investigations where appropriate.
(9) Personnel (gowning, training, aseptic techniques). The type of gowns and personal protective
equipment (PPE) worn by employees should be appropriate for the areas in which they work. There
should be detailed written procedures that describe the gowning requirements for each processing area.
Evaluate the following:
• For aseptic processing, determine the gowns (which typically include face masks, hoods,
protective goggles, gloves, and boots) are sterilized and made of non-particle shedding
material. Ensure that the gowns cover all skin, hair and facial hair.
• Review how the incoming sterile gowns/garb are accepted or rejected for use.
• Evaluate the firm’s program for training, testing and qualifying and re-qualifying employees
who work in the controlled areas, especially those who set-up and operate aseptic processing
lines.
• Evaluate the aseptic techniques of employees by observing aseptic processing operations.
• For selected employees, verify the training, testing, qualifying, and re-qualifying were done as
specified in procedures.
• Verify the training is done on a continuing basis.
Reference: FDA’s 2004 Aseptic Processing Guidance, Section V.
(10) Batch records.
• Review of environmental and personnel monitoring data, as well as other data relating to
acceptability of support systems (e.g., HEPA / HVAC, WFI, steam generator) and
manufacturing equipment. This review is considered essential to batch release decisions. The
batch record should include documentation that assures this type of holistic review is done
before the release of a lot for distribution.
• For aseptic processing, verify interventions into critical areas (Class 100/ ISO 5) are
documented so they can be reviewed and evaluated by the Quality Unit.
• Review batch records to verify they include complete information for all sterilization
processes.
Reference: FDA Aseptic Processing Guidance, Section XII.
(11) Environmental and personnel monitoring.
• See section below under “Laboratory Control System”.
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3.9 PACKAGING AND LABELING SYSTEM
Compliance Program 7356.002 lists the areas to cover when inspecting the Packaging and Labeling
Control System. All of the areas that are applicable to sterile drug products and should be covered if this
system is selected for coverage. Areas of special concern for sterile products include:
• Determine that packaging and labeling operations do not introduce risk to product integrity (for
example, damage to the container or closure that could affect the integrity of the unit).
• Determine that the container, closure and packaging systems provide adequate protection
against foreseeable external factors in storage, shipment, and use that can cause contamination
or deterioration (e.g. cracked vials during shipment if not properly protected; pinhole leaks in
bags, frozen drug products, tears or holes in overwraps of sterile bulk antibiotics and large
volume parenterals; and unseating of stoppers in aluminum cans containing sterile bulk APIs
due to pressure changes during shipment by air).
• It is not unusual for filled containers of sterile products to be stored unlabeled for a period of
time. The firm must have adequate controls to assure proper identification of the unlabeled
product at all times.
• Tracking of refrigerated or temperature controlled units for room temperature exposure times
(e.g. warm up of refrigerated units prior to label application).
• Tracking and investigation (as specified and appropriate) of rejected units culled during
packaging and labeling operations.
3.10 LABORATORY CONTROL SYSTEM
Compliance Program 7356.002 lists general areas to cover when inspecting laboratories. Inspections of
sterile drug manufacturers should also cover microbiology laboratories. Quality control tests (sterility
and Limulus Amebocyte Lysate or LAL test) and the collection of environmental and personnel
monitoring samples should be observed to verify that acceptable techniques are used and written
procedures are followed. The inspection of microbiology laboratory should evaluate the following:
• Sterility testing, including the collection of samples that are representative of the entire lot and
processing conditions; adequate control and monitoring of the testing environment; validation
of the method for specific products; growth promotion testing of the media; and incubation
times and temperature. It is important to note that increasing the number of samples or the
number of tests does not greatly increase the probability of detecting contamination if it is
present at a very low level in a lot. Reference: FDA’s Guide to Inspections of Microbiology
Pharmaceutical Quality Control Laboratories and FDA’s 2004 Aseptic Processing Guidance,
Section XI.
• LAL testing, including product specific validation; collection of representative samples of raw
materials, components/containers, in-process, and finished product, where appropriate; and
adequate laboratory facilities for conducting the tests. Verify the rationale of sample size of
endotoxin test relative to the production batch. Reference: Bacterial endotoxins – Test
methodologies, routine monitoring, and alternatives to batch testing. ANSI/AAMI ST
72:2002/ (R) 2010, Association for the Advancement of Medical Instrumentation.
• Environmental monitoring, which includes: a well defined written program that covers all
production shifts and includes air, floors, walls, equipment surfaces, and, in aseptic process
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PROGRAM 7356.002A
operations, critical surfaces that come in contact with sterile product, containers and closures;
establishment of appropriate alert and action levels, use of sampling (contact plates, swabs,
active air samplers) and testing methods (media, plate exposure times, incubation times and
temperatures) that are designed to detect environmental isolates. Evaluation of the validity of
the sampling locations and sampling methods. Reference: FDA 2004 Aseptic Processing
Guidance, Section X. Note: environmental monitoring is performed during the processing of
all types of sterile drug products, including an appropriate program for terminally sterilized
products.
• Personnel monitoring which includes: a routine program for daily/shift monitoring of operators
gloves and an appropriate schedule for monitoring gowns; establishment of limits that are
based on the contamination risk to the product; and investigations of results that exceed the
established levels or demonstrate an adverse trend. Personnel monitoring is important in all
sterile product operations, but it is especially critical in aseptic processing, and inspectional
emphasis should be risk based, focusing on those operations that require employees to enter
the critical areas of the processing line. Reference: FDA’s 2004 Aseptic Processing Guidance,
Section V.C.
• Efficacy of disinfectants, including assessment of the suitability, efficacy and limitations of the
disinfecting agents used in the controlled area, production equipment and laboratories. The
firm’s assessment typically includes laboratory studies that test the effectiveness of agents on
different surface materials. Material coupons are usually used with surfaces types as found in
production. The studies should be done with the same disinfecting agents, contact times (which
should be clearly defined in written procedures). It is also important to understand that
disinfectants have limitations and most are not effective against every type of microorganism.
For this reason, firms should normally use more than one type of disinfectant. Reference:
FDA’s 2004 Aseptic Processing Guidance, Section X.A.3.
• Identification of microorganisms, including procedures that require identification of organisms
found in positive sterility tests, media fills, and environmental monitoring (environmental and
personnel) samples as specified by the firm. The program should assure routine identification
of microorganisms found in samples are taken in critical areas, surrounding areas and from
personnel in the production area. Review the procedures, equipment and controls used in
identification activities of the contaminants.
• Microbiological media, including the preparation, sterilization and growth promotion testing of
the media used in performing tests (sterility tests, raw material testing, pre-filtration bioburden,
environmental monitoring, media fills, etc.). Where appropriate, inactivating agents for
disinfectants or product residuals should be added to allow detection of contaminants.
• BIs and biological cultures used in sterilization validation studies should be used and stored
under appropriate conditions. Typically, the conditions are described in the literature received
with the BI, if supplied by a vendor. The microbial population should be confirmed by testing
each lot. Spore counts should be verified prior to use in validation studies. The D-value should
be determined for each lot of a BI if it is used in a way not described by the vendor. If used
specifically as directed, the D-value supplied by the vendor can be accepted if the reliability of
the Certificate of Analysis has been established, but D-value of incoming batches should be
periodically verified. Reference: 2004 FDA Aseptic Guidance.
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• Microorganisms (e.g., ATCC) are used for growth promotion tests of media. Organisms
isolated from environmental monitoring samples can also be used to perform growth
promotion test.
• Monitoring, calibration and maintenance programs for microbiology laboratory equipment,
such as incubators.
• Training of microbiologists and evaluation of microbiologists or technicians that perform
sterility, LAL and environmental monitoring tests.
• Documented investigations into out-of-specification results. Evaluate positive sterility tests and
media fill and LAL failures investigations. Also review environmental / personnel monitoring
results at alert and action levels to identify and determine the firm’s response to the significant
incidents or trends. Because of the limited sensitivity of the sterility tests to detect batch
contamination, any positive is a serious issue and should be thoroughly investigated by the
firm with quality unit oversight and approval. The investigation and followed should be
reviewed during inspections to assess the decision making process. An initial positive can be
found invalid only if there is clear documented evidence that the microbial growth was
unequivocally a laboratory error. Reference: Section XI.C of FDA’s 2004 Aseptic Processing
Guidance.
21 CFR 211.180(e) requires that records be maintained in such a manner that the data can be used to
evaluate adherence to quality standards. The evaluation of data generated by the microbiology lab plays
an integral role in establishing the sterility assurance of the finished product. The inspection should
determine if the firm generates and reviews testing data and product quality related data (e.g., trend
reports) to make timely, informed and science-based decisions to assure an ongoing state of control.
3.11 SAMPLING
Samples of sterile drug products should be collected to document suspected contamination, adulteration
or misbranding encountered during an inspection. The samples can be physical or documentary. In the
event of a for-cause assignment where in-process samples are being requested, collect the samples
aseptically at points where such contamination might occur. These samples should be collected by the
firm under the observation of the investigator. Great care shall be taken to prevent the possibility of
contamination and/or compromising the integrity of the sample for all physical samples of raw
materials, in-process samples or finished drug products. Consult the district management and/or Center
as well as the servicing laboratory for guidance on sample size and sampling techniques. A production
lot with an initial sterility failure result that was invalidated by the firm may be considered a good
candidate for sampling.
Physical sample analysis is not necessary to document CGMP deficiencies. Documentary samples may
be submitted when the documentation illustrates the deficiencies and to obtain evidence of interstate
shipment. Please be aware to collect the appropriate number of sample units in order to accommodate
the 702(b) section of the Act.
For finished products requiring sterility testing, collect 48 units of product. For finished products
requiring endotoxin testing, collect 20 units of product.
For additional sampling guidance, refer to Investigations Operations Manual (IOM) Chapter 4.
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[end Part III]
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PART IV - ANALYTICAL
In general, samples will be submitted to your District's designated servicing laboratory, except as
requested in a special assignment or your supervisor.
4.1 . ANALYZING LABORATORIES
For Sterility and Bacterial Endotoxin testing:
Region Examining Laboratory
NER NRL
SER SRL
CER NRL
PAR SAN-DO
SWR DEN-DO
For particulate matter in injectables analysis, contact the ORA/Office of Regulatory Science/Medical
Products and Tobacco Staff to determine the most appropriate laboratory for this test.
4.2 ANALYSIS
Sterility testing methods should be based on current editions of USP <71> Sterility Tests and the
Sterility Analytical Manual (SAM). The SAM provides supplemental information to the USP. The SAM
has the goal of standardizing the performance of testing for pharmaceutical microbiology in FDA
laboratories.
Bacterial endotoxin testing methods should be based on current editions of USP <85> Bacterial
Endotoxin Test and the Sterility Analytical Manual (SAM).
Particulate matter testing methods should be based on current editions of USP <78>.
Other microbiological examinations should be based on appropriate sections of USP and the SAM.
[end Part IV]
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PART V - REGULATORY/ADMINISTRATIVE STRATEGY
A recommendation for regulatory action should be submitted by the District Office when a judgment is
made that the firm is not operating in a state of control and management of the firm is unwilling or
unable to make adequate corrective actions in an appropriate time frame. The therapeutic use of the drug
product and the potential adverse effect of the CGMP deviations on the finished product must be
considered in determining the appropriate action needed.
When deciding the type of action to recommend, the initial decision should be based on the seriousness
of the problem and the most effective way to protect the consumer (i.e., when non-sterile parenterals are
found, injunction/seizure, recall would be the action(s) of choice). Instructions in the Regulatory
Procedures Manual (RPM) should be followed.
If the nature of the CGMP deviations is determined to pose minimal risks when considered in relation to
the intended use of the drug, the primary action should normally be voluntary corrections by the firm.
The District should require that all commitments for achieving voluntary compliance by firm
management be submitted in writing and contain a time schedule for completion. The District should
determine if the schedule is a reasonable time frame and should monitor the progress.
When voluntary action is not accomplished or when the deviations observed pose a serious risk to the
consumer, regulatory and / or administrative action should be recommended.
NOTE: Regulatory action is independent of the collection of a violative physical
sample. The lack of a violative physical sample is not a barrier to pursuing
regulatory and/or administrative action providing the CGMP deficiencies have
been well documented. Physical samples found to be in compliance likewise
are not a barrier to pursuing action under CGMP charges.
The following list of deficiencies represents examples of practices that CDER believes could warrant
regulatory and/or administrative action (please note the following is not intended to be an inclusive list):
1. Contamination with filth, objectionable microorganisms, toxic chemicals or other drug
chemicals; or a reasonable potential for product contamination, with demonstrated avenues of
contamination such as poor aseptic methods, contact with unclean equipment, or airborne
contamination.
2. Failure to assure that each batch conforms to label claims or established specifications, such as
NDA, ANDA, USP monographs, and the firm’s finished product specifications.
3. Distribution of product which does not conform to established specifications.
4. Lack of adequate validation of critical steps in sterilization processes, including sterilization by
filtration; sterilization cycles used for drug products; and, for aseptically processed products,
sterilization processes used to sterilize components (formulation and/or its ingredients, as well as
containers and closures), or to sterilize equipment surfaces that contact sterile product or any
elements of the product.
5. Lack of adequate validation of aseptic processing operations (media fills).
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6. Failure to appropriately conduct and document investigations of discrepancies and failures of
drug products or any of their components to meet specifications, especially inadequate
investigations of sterility test failures, media fill failures and repeated or significant
environmental or personnel monitoring results that meet or exceed action levels.
7. Facilities and equipment which do not provide adequate protection for aseptically processed
product while the sterile product or sterile components are exposed to the environment. This
includes both lack of robustness due to poor design, as well as failure to maintain equipment as
sterile (e.g., by providing proper barriers as well as assuring adequate sterilization frequency).
8. Failure to assure a robust cleanroom disinfection program. This may include the failure to assure
sufficiently detailed cleaning procedures to assure repeatability in cleaning, or failure to
demonstrate the suitability and efficacy of the disinfecting agents used for the critical controlled
areas and production equipment.
9. Failure of a WFI system to deliver water that consistently meets chemical, microbiological and
endotoxin specifications.
10. For aseptic processing, poor employee practices that increase the risk of product contamination.
11. Failure to provide adequate training to employees who work in critical operations, such as
operators on aseptic processing lines, operators responsible for initiating and checking
sterilization cycles and those who perform the 100% inspection of filled injectable products.
12. Failure to perform adequate 100% inspections of injectable products for particulate matter and
other defects.
13. Failure of batch records to include complete information related to the production and control of
each batch, including documentation that assures environmental and personnel monitoring data
and data related to the support systems, and assure quality unit review of these records prior to
approval of a lot for distribution and release. For aseptically processed product, batch
documentation includes records of purposeful operator interventions into critical (Class 100 /
ISO 5) areas of the line. Operator intervention should be minimized as much as possible to
preclude and control contamination.
14. Use of test methodology (sterility test, endotoxin test) that is not adequate or validated.
15. Lack of an adequate environmental monitoring program, that is, one that does not include
dynamic monitoring during all production shifts or has not established appropriate alert and
action levels and, in the case of aseptic processing, does not include representative critical
surfaces that come in contact with sterile product, containers and closures.
16. Lack of an adequate personnel monitoring program for aseptic processing operations. For
example, the program does not include daily monitoring of operators’ gloves and periodic
monitoring of gowns; has not established appropriate limits or does not require investigations
and corrective actions when limits are exceeded.
[end Part V]
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PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS
6.1 REFERENCES
All of the references listed below, with the exception of number 17 through 26, are available on FDA’s
internet website.
1. Code of Federal Regulations, Title 210 and 211 as revised, including the preamble.
2. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good
Manufacturing Practice; FDA; September 2004.
3. Guidance for Industry for the Submission Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products; FDA; November 1994.
4. Guidance for Industry Process Validation: General Principles and Practices of Process; FDA;
January 2011.
5. Guide to Inspections of Lyophilization of Parenterals; FDA; July 1993.
6. Guide to Inspections of Microbiology Pharmaceutical Quality Control Laboratories: FDA; July
1993.
7. Guide to Inspections of High Purity Water Systems, FDA; July 1993.
8. Guide to Inspections of Sterile Drug Substance Manufacturers; FDA; July 1994.
9. Guide to Inspection of Dosage Form Drug Manufacturers; FDA; Oct. 1993.
10. Compliance Policy Guide 7132a.13, Parametric Release – Drug Products Terminally Sterilized
by Heat; FDA.
11. Compliance Program 7356.002, Drug Manufacturing Inspections.
12. Compliance Program 7356.002C, Radioactive Drugs.
13. Compliance Program 7356.002M, Inspection of Licensed Biological Therapeutic Drug Products.
14. Investigations Operations Manual
15. Guide to the International Inspections and Travel
16. Regulatory Procedures Manual
17. Restricted Access Barrier Systems (RABS) for Aseptic Processing ISPE Definition; ISPE; August
16 2005.;
18. ISO 17665 Moist Heat Sterilization.
19. ISO 14644 Cleanrooms and Associated Controlled Environments.
20. ISO 14698 Cleanrooms and Associated Controlled Environments- Biocontamination Control.
21. PDA Technical Report No. 1 (Revised 2007) Validation of Moist Heat Sterilization Processes:
Cycle Design, Development, Qualification and Ongoing Control.
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22. PDA Journal of Pharmaceutical Science & Technology; Vol. 49, No. 6; November – December
1995 Performance of Blow/Fill/Seal Equipment under Controlled Airborne Microbial
Challenge.
23. PDA Technical Report 51 (2010) Biological Indicators for Gas and Vapor-Phase
Decontamination Processes: Specifications, Manufacture, Control and Use.
24. PDA Technical Report No. 22, revised 2011, Process Simulation for Aseptically Filled Products.
25. PDA Technical Report No. 28, revised 2006, Process Simulation Testing for Sterile Bulk
Pharmaceutical Chemicals.
26. PDA Technical Report #26, 2008, Sterilizing Filtration of Liquids.
27. Bacterial endotoxins – Test Methodologies, Routine Monitoring, and Alternatives to Batch
Testing. ANSI/AAMI ST 72:2002/ (R) 2010, Association for the Advancement of Medical
Instrumentation.
28. CGMP Q&As. FDA website.
29. Sterility Analytical Manual (SAM); FDA May 2012.
6.2 ATTACHMENTS
A “Inspections: Points to Consider” This attachment includes a list of questions intended to be an aid
in conducting inspections and obtaining information needed to assess a firm’s operations. This list of
questions and/or considerations is not intended to be an all inclusive or an exhaustive list of
concerns. They are intended to assist focusing of the inspection and include areas worthy of
consideration and evaluation during an inspection. The answers do not have to be reported in the
EIR unless they are relevant. The list of questions covers: Moist Heat Sterilization; Dry Heat
Sterilization / Depyrogenation; Aseptic Filling; Lyophilization; Isolators; Environmental
Monitoring; and Biological Indicators. CDER welcomes feedback and any additional questions to
this list.
6.3 CONTACTS
Office of Regulatory Affairs (ORA)
For technical questions concerning inspections contact:
Office of Regulatory Affairs (ORA)
Office of Medical Products and Tobacco Operations (OMPTO)
Division of Medical Products and Tobacco Program Operations (DMPTPO)
Telephone number: 301-796-0358
Email: [email protected]
For questions concerning particulate matter in injectables analysis and appropriate testing laboratory
contact:
Office of Regulatory Affairs (ORA)
Office of Regulatory Science (ORS)
Medical Products and Tobacco Scientific Staff (MPTSS)
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Bruce Harris
Telephone number: 301-796-3030
E-mail: [email protected]
For questions concerning microbiological analysis, sterility issues and related sampling concerns
contact:
Office of Regulatory Affairs (ORA)
Office of Regulatory Science (ORS)
Medical Products and Tobacco Scientific Staff (MPTSS)
Angele Smith
Telephone number: 301-796- 4200
E-mail: [email protected]
Center for Drug Evaluation and Research (CDER)
CGMP or any Quality-Related Policy Questions
For CGMP or any quality-related policy question, technical or scientific questions or
information needs, including questions about this program, please send an email to the
following address and it will be handled as a top priority:
[email protected]
Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence need and sufficiency,
citations, and case evaluation/recommendation advice, please send an email
to the following address and it will be handled as a top priority:
CDER OMQ Compliance Policy: [email protected]
Labeling Requirements and Policies
Office of Unapproved Drugs and Labeling Compliance, see intranet home page for
contacts
[CDER | Office of Compliance | Office of Unapproved Drugs and Labeling Compliance]
Registration and Drug Listing Requirements
CDER Office of Compliance, see “CDER: Who’s the Lead” intranet page for contacts
[CDER | Office of Communications | CDER: Who’s the Lead]
[end Part VI]
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PART VII - CENTER RESPONSIBILITIES
A. COMPLIANCE
The CDER Office of Product Quality (OPQ), Office of Quality Surveillance (OQS) will evaluate the
operations under this Compliance Program. Reports of these evaluations will be shared with the ORA
Headquarters offices, field offices and CDER headquarters offices.
The Center reviews enforcement recommendations and provides the agency’s technical decisions in
coordination with District Offices and Office of Chief Counsel
B. DRUG SHORTAGES
If a violative conditions are identified that may result in a shortage, field staff should notify CDER drug
shortage staff at [email protected] and ensure the company also contacts this staff. This
notification should occur as soon as the District becomes aware of a possible shortage or through
communication with the firm.
CGMPs are a preventive system intended to preclude to the occurrence of critical product defects and
loss of assurance of quality. A warning letter is an advisory action meant to notify a manufacturer that
significant violative conditions compromising the assurance of quality, safety, and/or efficacy were
observed and must be promptly corrected by an appropriate and timely action plan. In situations where
the firm’s corrective actions may reduce the supply of medically necessary products, the agency will
work closely with the firm to assure the medically necessary drugs remain available and the CGMP
deficiencies are corrected in a timely manner.
[end Part VII]
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PROGRAM 7356.002A ATTACHMENT A
Inspections: Points to Consider
Below is an extensive list of questions provided as an aid in conducting inspections and obtaining
information needed to assess a firm’s operations.
o This list of questions and/or considerations is not intended to be an all inclusive or an
exhaustive list of concerns. They are intended to assist focusing of the inspection and include
areas worthy of consideration and evaluation during an inspection.
o The answers do not have to be reported in the EIR unless they are relevant.
TOPICS:
Moist Heat Sterilization Dry Heat Sterilization / Depyrogenation Aseptic Filling
Lyophilization Isolator Barrier Technology Environmental Monitoring (Non-viable)
Environmental and Personnel Monitoring – Microbiology Biological Indicators.
CDER welcomes feedback and any additional questions to this list.
MOIST HEAT STERILIZATION
Reference: PDA Technical Report No. 1 Revised 2007 Validation of Moist Heat Sterilization Processes:
Cycle Design, Development, Qualification and Ongoing Control; and
General.
1. Who is the manufacturer of the steam sterilizer (autoclave)?
2. What is the model number, age, and internal volume of the autoclave?
3. What is the sterilizing agent? (e.g., steam, air over pressure, superheated water, gamma irradiation)?
4. If jacketed, what pressure/temperature is maintained in the jacket as opposed to the chamber?
5. What types of vent filters are used and how often are they integrity tested?
6. Are vent filters hydrophobic? Are the vent filter housings heated to prevent condensation?
7. Are cycles controlled manually or automatically?
8. What type of monitoring and controlling sensors are used (e.g., mercury-in-glass thermometer,
thermocouple, RTD, pressure gauge)?
9. How are these sensors calibrated? Are the standards NIST traceable (or traceable to a National
standards for foreign firms), where appropriate?
10. Is the autoclave equipped with a steam spreader (more than one steam entry line would be
considered in this category)?
11. If more than one autoclave is used by the firm, what is the system's capacity for steam production in
relation to all autoclaves being in operation at the same time?
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12. What are the sterilization cycle parameters? (Compare Master Process Record / SOP specifications
against processing records completed for selected drug products)
13. What are the firm's specifications and observed parameters for:
• Time
• Temperature
• Pressure (psi, in. Hg)
14. Where is the cycle controller sensor located?
15. How are each of the sterilization (#13) parameters monitored? Are the come-up times for chamber
temperature during sterilization reproducible when compared to the come-up time achieved in
validation studies?
16. Is the slowest to heat spot ("cold spot") in each load monitored during each autoclave cycle?
17. Have any changes in the steam sterilization system occurred since the last EI? Have these changes
been evaluated for the need for re-validation?
18. Is clean steam being used (control of bacterial endotoxin)?
Validation.
19. Does the firm have written procedures for validation that include
• Design Objectives
• Installation qualification (IQ) of equipment
• Operational qualification (OQ) of equipment
• Performance qualification (PQ) with product (maximum and minimum load submitted in the
application, and any changes after)
• Description of circumstances requiring revalidation of the system
• Procedures for revalidation
20. Does validation documentation include the following?
A. Empty chamber / loaded chamber heat distribution studies:
o Number of runs?
o Was cold spot determined?
o Allowable variation?
o Actual variation found?
o What is the worst-case load?
B. Heat penetration studies
o For each type of loading pattern/for each container size utilized?
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o Number of runs per pattern?
o Was the "cold spot" determined for each pattern?
o Is the established load configuration submitted in the application followed and/or
reportable changes submitted as appropriate?
21. What type of temperature measurement system was used? Does it provide a separate printed reading
for each thermocouple?
22. What type of temperature sensors were used, and were they calibrated before and after each run?
23. If biological indicators were used during validation runs:
• Type of indicator (spore strip, inoculated product, ampule)
• Source of indicator
• Microorganism used, including concentration and D value
• Were BIs used in an "end point" or "count reductions" mode? If any positive BIs were found
(when not expected), what was the firm's response?
23. In the event a heat distribution or penetration variance was disclosed during the studies, how did the
firm correct or allow for it?
24. Has the firm determined lag times for all container sizes/mass, product viscosities, etc. and adjusted
their cycles accordingly?
DRY HEAT STERILIZATION / DEPYROGENATION
Dry heat sterilizers are used, primarily, to sterilize and depyrogenate glass containers for injectable drug
products. Both dry heat ovens and dry heat tunnels are used. An oven is a batch process and, at the end
of the cycle, the sterile vials are manually removed from the oven, transported and then manually loaded
onto the filling line. A dry heat tunnel uses a continuous, integrated process. In a tunnel, the vials move
on a belt from the wash processing through a heating zone where the vials are sterilized and
depyrogenated to a cooling zone and then directly into the Class 100 area of a filling line. Typically,
firms validate the depyrogenation of the glassware rather than the sterilization cycle. This is based on
the fact that it is generally more difficult to remove or denature pyrogenic substances than
microorganisms. Components that have undergone heat depyrogenation are rendered sterile.
General.
25. Determine what types of dry heat sterilizers are used (ovens, tunnels)?
26. Determine the location of the heat source. The heating element/device that generates the
depyrogenation temperature can affect the HEPA filters and their ability to provide the desired
filtration for non-viable particles. For example, the high temperatures create expansion and
contraction of the HEPA filters and filter housing, which can compromise the integrity and
functionality of the HEPA filters.
27. How is the heat distributed in the oven or tunnel (fan or convection)?
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28. Where are the HEPA filters located in the oven or tunnel? What zones in a tunnel are supplied with
HEPA filtered air (supply, heating, cooling zones)? Does the cool down section of the tunnel
provide a Class 100 conditions to ensure the sterility of the containers are maintained? What zones
are controlled as Class 100 areas?
29. Due to thermal dynamics (high temperature of >360 degree C leads to the expansion and contraction
of the filter housing), the HEPA filter normally undergoes integrity testing every 6 months.
However, depending on the amount of usage of the depyrogenation tunnel and data obtained from
particle monitoring in the vicinity outside the heat tunnel, integrity testings may need to be
conducted on a more frequent basis. How does the firm assure integrity of the HEPA filters? How
often are HEPA filters changed?
30. Are non-viable particle counts taken in hot air tunnel? Non-viable particle measurement for the
Class 100/ ISO-5 zone of the depyrogenation tunnel are not done during routine operation because
of high temperature. However, periodic measurement of non-viable in ISO 5 area should be verified
and they are normally measured prior to and subsequent to the manufacture of a batch/campaign
and at ambient temperature.
31. Are the sterilization / depyrogenation cycles controlled manual or automatically?
32. What type of monitoring and controlling sensors are used (e.g., thermocouple, RTD, pressure
gauge, belt speed indicators)? How often are they calibrated?
Parameters.
33. What are the sterilization / depyrogenation cycle parameters or equipment settings? Compare
master production record / SOP specifications and processing records for specific representative
products.
34. What are the firm's specifications for time, temperature, belt speed, and pressures if applicable?
35. What are the critical parameters? How were they established? How does the firm assure the critical
parameters are met for each lot or cycle?
36. Where are the sensors for the cycle controllers located?
37. How are each of the above parameters monitored? Are any of the parameters not monitored? Are
the critical parameters alarmed in continuous systems, such as those used in tunnels? What is done
when there is an alarm?
38. How does the firm assure that all critical parameters are met for each cycle in an oven or for the
continuous run of the tunnel?
39. Do dry heat tunnels have alarms to alert operators if critical parameters (heat, belt speed, pressure)
are not met? Are the alarms documented? Did the conditions that caused the alarm require the
implementation of change controls and did they impact the validated process?
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40. Have any changes in the dry heat sterilization / depyrogenation system occurred since the last
inspection? Have these changes been evaluated for the need for revalidation?
Validation.
41. Does the firm have written procedures for qualifying the dry heat sterilizers that include:
• Design Objectives
• Installation qualification of equipment
• Operational qualification of equipment
• Performance qualification with product
• Description of circumstances requiring re-validation and procedures
42. Does validation documentation include heat distribution / penetration studies?
• What is the firm's allowable temperature variation and the actual variation found in
production?
• What type of temperature measurement system was used?
• Was calibration performed before and after the validation?
• If dry heat sterilizer is an oven, was the slowest to heat area determined?
43. How was the depyrogenation cycle validated?
• Was a known amount of endotoxin added to vials?
• Was the endotoxin allowed to dry on the vials?
• Was validation conducted with recovery tests to assure the spiked endotoxin can be recovered?
Were the vials challenged with enough endotoxin to allow calculation of a 3-log reduction?
• What cycle or equipment settings were used in the validation runs?
• Was a 3 log reduction of endotoxin achieved?
44. Are the depyrogenation cycles for all vials validated or does the firm use a matrix approach? If a
matrix approach (vial sizes/mass) is used, what criteria are used to select the worst case challenges
to the system? Are all vials types and sizes bracketed?
45. Have the dry heat sterilizer cycles or equipment settings changed since the validation studies were
completed? Compare validation studies, current SOPs and processing records for recent batches.
ASEPTIC FILLING
46. When observing personnel during production, do operators practice proper cleanroom behaviors as
specified in established cleanroom SOPs?
47. Can you observe the aseptic filling processes without going into the clean room (i.e., through
window or TV monitor)?
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A. If yes, watch / observe the aseptic filling processes from preparation of bulk liquid product
to filling and sealing of final dosage form, including the environmental monitoring
performed in critical areas during actual production.
B. If not, consider observing the aseptic filling inside the clean room, for example, via a Class
10,000 (ISO-7) area. Prior to entry, consult the District.
o Do personnel enter and perform interventions at the critical Class 100 (ISO 5) areas of
the filling lines? If so, how are such entries recorded?
o How is this done (full body entry, hands only)?
o Why?
o Is this done routinely or infrequently?
o Are proper aseptic techniques used? [Reference: FDA 2004 Aseptic Processing
Guidance, Section V.A.]
o Do hands or arms go over open vials for sterile components? If yes, are the vials
discarded?
48. Does the firm have written procedures describing aseptic filling of drug products? Does it include
discussions of proper aseptic techniques and acceptable techniques for performing interventions
into the Class 100 areas?
49. Review trend reports of the non-viable, viable and personnel monitoring data.
• Have any trends been identified by the firm? If yes, what is done?
• Are investigations done of out of limit results?
Aseptic Filling Validation.
Reference: FDA’s 2004 Aseptic Processing Guidance, Section IX
50. How does the process used for media fill compare to the aseptic filling of commercial drug
products? Does the firm accurately evaluate the production operation on a routine basis (changes
over time) against the media fill design? Does the firm have detailed procedures that describe the
media fill process, including frequency, challenge conditions, personnel participation, container /
closures, interventions, duration of fill, reconciliation of vials, acceptance criteria, incubation,
examination after incubation, actions to take if positive growth is found, etc?
51. Request a summary of all media fills conducted since last inspection, including lot identification,
fill dates, production lines, number of units filled, number of units incubated, number of vials with
no growth, number of vials with positive growth, microbial identification for any containers with
growth, disposition of media fill units, etc.
• Have media fills been done at the frequency described in the procedure?
• Have any media fills showed positive growth?
• Have any media fills failed to meet acceptance criteria?
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52. Are procedures followed when positive growth is found in media filled vials? Are investigations
conducted of all positive growth found in media filled vials? What is done when a media fill fails
to meet acceptance criteria? Review investigations of any positive growth.
53. Are media fills performed on all shifts (e.g., representative of shift operations in a campaign)? Do
media fills include shift changes and breaks that occur during routine production?
54. When can media fills be aborted or units not incubated? Would production lots be rejected if the
same conditions existed during filling?
55. Are all personnel included in the media fill program? Does this include set up personnel and
mechanics who work on the aseptic filling lines? What system does the firm have for assuring all
personnel are included?
56. If end-line filters are used in actual manufacture, are they also used during media fills?
57. What size vials or ampules are used for media fills? Evaluate justification for selecting worst case
challenge if firm does not perform media fills using all the container / closure configurations filled
on the line.
58. Are vials inverted before incubation to assure media touches all inner surfaces?
59. How does the firm conduct media fills for products that are filled into amber or opaque containers?
60. How does the firm assure that all integral vials are incubated? How does the firm handle filled vials
removed during the run because of interventions?
61. Do media fills include interventions that occur during routine production? Are there written
procedures specifying removal of media fill units (type of intervention and number of units
removed) corresponding to the practice of a routine production run? Did you observe any
interventions during the filling of routine production lots that are not included in media fills?
62. Does the duration of a media fill approximate the duration of a routine production lot? If not,
evaluate firm’s justification for running shorter media fills?
63. What is the microbial growth medium?
64. Are growth promotion studies performed on each type of medium used?
65. Are growth promotion studies conducted every time a media fill is done?
66. When are the growth promotion studies performed (before/after filling; after incubation; etc.)?
67. What organisms are used to perform the growth promotion tests? Are any environmental organisms
used?
68. What temperatures and incubation times are used to incubate media filled vials?
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69. Are microorganisms from positive vials identified to genus and species? Are such microorganisms
correlated to those found during environmental monitoring?
70. Is an investigation done when cracked vials are found after incubation begins?
71. When and where are the media filled vials examined?
72. Who performs the examination of media filled vials? If production employees perform the
examination, have they been trained to recognize all types of microbial growth. Is a microbiologist
present when the examination is done?
73. What incubators are used to incubate media filled vials? How is the temperature controlled and
monitored? Have tests been done to determine if the temperature is uniform throughout the
incubator?
LYOPHILIZATION (FREEZE-DRYING)
Reference: Guide to Inspections of Lyophilization of Parenterals; FDA; July 1993
General.
74. Who is the manufacturer of the lyophilizer?
75. Describe the heating and cooling systems used in the lyophilizer; the vacuum system; gas that is
used to break the vacuum and whether it is sterile; and the temperature controlling system.
76. How are the vials transported from the filling line to the lyophilizer? How are Class 100 (ISO 5)
conditions maintained during transport, loading, and unloading of the lyophilizer?
77. Are the loading and unloading of the vials automated or manual?
78. How is the sealing of vials (final seating of stoppers) performed?
79. If the stoppering is performed automatically in the chamber at the end of the cycle, is it under
vacuum? If not under vacuum, what gas is used and how is it sterilized?
80. If the vials are stoppered outside of the chamber, how is the lyophilized product protected from
contamination during transport to the stoppering station and during the stoppering operation?
81. Describe the chamber clean-up procedures between batches of the same product and between
different products (including sterilant / cleaning agents used, monitoring for sterilant residue where
appropriate, and exposure cycle).
82. Past history has shown that the lyophilizer condenser can be a source of contamination and an
assessment of the lyophilization process should include an inspection of the condenser. How is
lyophilization cycle monitored/ documented and reviewed?
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Lyophilization Validation – Sterilization of Chamber.
81. How is the lyophilization chamber sterilized? How are all surfaces, such as all surfaces of moving
shelves, exposed to steam?
82. When is the lyophilization chamber sterilized? What is explanation / justification if it is not done
between each batch?
83. How are sterilization cycles controlled (manual, programmed)? How are cycles monitored during
production?
84. Has the sterilization of the lyophilization chamber been validated? Have the slowest to heat surfaces
in the chamber been determined and challenged in the validation runs?
85. Review current procedures and sterilization records for production lots. Are the cycle parameters
the same as those used during validation? Do production cycles meet the validated cycle
parameters?
Lyophilization Validation – Aseptic Handling.
86. Is the aseptic handling of lyophilized products validated by media fills?
87. In the aseptic process, is lyophilization simulation performed during media fill?
88. Is the maximum amount of time the vials are held prior to lyophilization simulated during media
fills? If vials are not sealed in lyophilization chamber, is the maximum hold time prior to stoppering
simulated in media fills?
89. During validation, what level of vacuum is pulled on the lyophilization chamber?
90. How long do media fill vials remain in the lyophilization chamber under vacuum? How does this
compare to commercial lots?
91. Does the process simulation result in freezing of the media? Note that this process simulation
should not include freezing of the media.
92. Is environmental monitoring performed during loading of the lyophilizer both during production
and as well as during validation?
93. Does the firm have data on growth promotion of the media? Are growth promotion tests done on
vials after incubation is completed?
94. Is environmental monitoring performed during unloading of the chamber during production as well
as during media fill validation?
95. What is used to break the vacuum during media fills (nitrogen, air, other gas)?
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Lyophilization Validation – Process.
98. Has the firm validated the lyophilization cycle (e.g., time, rate of heat input, temperatures, eutectic
melting point) for each product? Review validation records for selected drug products with different
physical and chemical characteristics.
99. Review lyophilization production records for the same products. Are the cycle parameters and
observed results within the validated cycles?
100. What are the firm’s criteria for acceptable vs. unacceptable runs, including general appearance,
cake appearance, meltback, reconstitution time, moisture, etc.?
101. Has the firm performed equipment qualification, preventative maintenance, critical instrument
calibration, and cleaning validation?
Lyophilization of sterile API: The aseptic process may include either a manual or automated transferring
process, or a combination of both, to transfer the lyophilized API out of the lyophilizer and into an SIP
holding vessel or transfer tank. It is equally important to observe and assess the manual operations of the
aseptic lyophilization process and assure that similar operations are performed during the media fill
processing steps for the API.
ISOLATOR BARRIER TECHNOLOGY
Reference: Appendix 1 of FDA’s 2004 Aseptic Processing Guidance
NOTE: Methods (e.g., hydrogen peroxide, peracetic acid) used to decontaminate isolator
barriers are capable of rendering surfaces free of viable organisms, but lack the
capabilities of steam sterilization. While these agents do not effectively penetrate
obstructed or protected surfaces, validated systems are highly effective at assuring
contamination-free internal isolator surfaces.
102. Determine:
• Model of isolator or barrier, and materials of construction
• Type of isolator (open or closed)?
• Airflow (turbulent, unidirectional)?
• Classification of surrounding room environment
• Number and location of gloves or half-suits
• Attire worn by operators (e.g., are sterile gloves worn under isolator gloves?)
• Operating parameters (pressures, air velocities, temperature, humidity)
103. Is a written maintenance program in place which requires routine documented checks or tests of
gloves, half-suits, door seals, etc. for integrity? What type of tests/checks are done and how
frequently?
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104. Do written procedures specify glove replacement frequency? If so, what is the frequency and is
the SOP followed?
105. Does the isolator maintain continuous positive pressure and at sufficient levels?
106. How are materials transferred into and out of the isolator? How robust are the transfer
mechanisms?
107. Are the equipment and surfaces that have direct contact with sterile products and components
sterilized by heat. Does it achieve a minimum of a six-log reduction of the BI spores?
108. What method is used to decontaminate the inner surface of the isolator barrier (e.g., vapor
hydrogen peroxide, steam hydrogen peroxide, chlorine dioxide, etc.)? Determine decontamination
parameters.
109. Did the surface decontamination validation study sufficiently address the ability of the sterilant to
disperse throughout the chamber and reach all surfaces? Did the decontamination process include
the use of Chemical Indicators (CI) to determine the presence or absence of the VHP on the work
surfaces and/or the worst case locations to decontaminate? The CI can assists in the evaluation
process by providing useful qualitative data. Were replicate BIs placed throughout the isolator,
including the most difficult to reach locations (e.g., underneath any items remaining in isolator
during sterilization). Are the most difficult to sterilize materials evaluated?
110. What is the isolator decontamination frequency and is it justified by validation data?
111. Is a decontamination cycle performed after a power failure or pressure reversal or other
unanticipated breach of system integrity?
112. How often is the isolator decontamination cycle revalidated?
113. Does the written environmental monitoring program include routine tests for nonviable particles,
as well as an appropriate number of microbial tests (e.g., active air and surface samples; gloves
samples) during each campaign? Evaluate the tests performed and the testing frequencies.
Testing Isolators (Sterility test).
114. Have any false positives been identified in the laboratory isolator barrier (this should be an
exceedingly rare occurrence)? Were the false positive investigated to determine and correct the
cause.
ENVIRONMENTAL MONITORING – Non-viable
Reference: FDA’s 2004 Aseptic Processing Guidance, Section IV.
115. Is the air supplied to critical areas (exposed product / filling areas) filtered through HEPA filters
under positive pressure?
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116. Is the air flow in critical areas unidirectional when delivered to the point of use? At what velocity?
Is velocity determined at the critical work height and at the filter face? Air flow pattern
evaluations (smoke studies) under dynamic conditions are performed to visualize and demonstrate
unidirectional air flow within a designated area/room [e.g., Class 100 & 10,000 (ISO5 & ISO7)].
The smoke studies may also reveal air turbulences and air eddies that could be a vector assisting
the dissemination of microbial and/or non-viable contamination within critical manufacturing
areas.
117. How is the air filtered that is supplied to critical areas (where unsterilized product, in-process
materials, and container/closures are prepared)?
118. What are the firm's air quality classifications for the following areas:
• Compounding
• Equipment preparation
• Any area where product or sterilized components are exposed
• Areas where aseptic connections are made
• Filling lines
• Room surrounding filling lines
• Capping (crimping) area
119. How often are HEPA filters integrity tested? What test method is used? What is done if leaks are
found? If done by an outside firm, are results reviewed by on-site personnel including the quality
unit?
120. How often are air flow velocities checked for each HEPA filter? What are the air velocity
specifications? What is done if velocity readings are out of specification?
121. Does the firm have a written monitoring program for classified areas that includes scientifically
sound sampling schedules; descriptions of sampling locations and frequency of sampling? How
were the locations selected?
122. What type of instrument is used to check non-viable particle counts in the classified areas? Is the
air sampled continuously? If continuous, is there an alarm when counts exceed pre-set limits or
detects cleanroom doors open for an extended time? What is done in response to the alarms? Is
there an alarm log? Are permanently installed sensors used or portable units that are taken into
and out of the critical areas? What is done if counts meet or exceed alert and action limits?
123. What are the pressure differential requirements in the sterile core area? Does this assure an air
cascade from most clean area to least clean air (by air classification)?
124. How are pressure differentials monitored? Is a continuous monitoring system used? If yes, does it
include alarms so operators are aware of excursions? Are alarm conditions documented (alarm
log)? What is done in response to an alarm? How long must a condition exist before an alarm
sounded?
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125. How are temperature and humidity monitored? What is the acceptable range? What is done if the
reading is outside of the range?
126. How are environmental excursions (readings that meet or exceed alert and action levels) handled?
Are the excursions investigated to determine impact on product, root cause and needed corrective
actions?
ENVIRONMENTAL AND PERSONNEL MONITORING – Microbiology
Reference: FDA’s 2004 Aseptic Processing Guidance, Sections V and X.A
Air.
127. Does the firm have an effective Environmental Monitoring (EM) Program in place? What is the
purpose and scope of the EM Program? Are EM sampling locations strategic, based on product
contamination risk of the process and operation? Are the microbial alert and action levels based on
the historical EM data derived from the manufacturing operations, support utilities and personnel
practices performed at the manufacturing site? What is the frequency of microbiological sampling
of air using "active" samplers (systems that sample a known volume of air) in various locations,
such as:
• Areas where product or sterile components are exposed to the environment
• Filling areas
• Loading areas for lypohilizers
• Surrounding areas
128. What are the established microbial alert and action levels or limits for quantitative air samples?
What is the length of the sampling period? Is sampling done during production or at rest?
129. What type of active air sampling equipment is used (centrifugal, impaction, membrane)? Is the
sampling equipment calibrated? What is the efficiency of the active air sampler?
130. Does the firm have data on the ability of these samplers to recover organisms without deleterious
effect on survivability such as through impact or desiccation of the media?
131. What is the actual volume of air sampled per location?
132. Are settling plates used? What is the length of exposure period? Sampling frequency? Locations
(including proximity to critical operations)? Microbial limits?
Surfaces.
133. Are there written procedures that describe the monitoring of surfaces in the clean rooms? Does it
describe locations, frequency and sampling techniques?
134. What surfaces are sampled in the critical (Class 100 / ISO 5) areas? Are critical surfaces included
(those that touch the sterile product or sterile components)?
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135. When are surface samples taken? Are critical surfaces only sampled at the end of the operation?
136. What is the frequency of sampling surfaces?
137. What types of samples are collected at each location (RODAC plate, swab samples)?
138. What are the alert and action levels / limits for the microbial sampling of critical surfaces, surfaces
in Class 100 areas and surfaces in other classified areas? How were the levels / limits established?
What is done when the samples meet or exceed alert and action levels?
Personnel.
139. Are there specific programs for training personnel who work in classified and aseptic processing
areas? Does the program include microbiological testing or qualifying employees before they are
allowed to work in these areas? Does the program include prequalification requirements?
140. How often is monitoring performed on filling room personnel? Is it done at least upon existing
the cleanroom (e.g., per shift)? How often are gloves (hands) sampled? How often are gowns
sampled? Is any sampling done after interventions are performed?
141. Who performs the sampling of personnel? Is it self-sampling? Is the sampling performed by
another production employee, a microbiologist, technician or other quality control employee?
142. What are the firm's alert and action levels / limits for personnel monitoring? How were the levels
/ limits established? What is done if the sample results reach or exceed the alert and action limits?
143. Do employees spray their hands with sanitizer or disinfectant before the sample is taken?
General.
144. What are the microbiological growth media used for environmental and personnel monitoring
samples?
145. Are the media used in the viable monitoring program shown to be capable of detecting molds and
yeasts as well as bacteria by means of growth promotion tests?
146. Is anaerobic monitoring ever performed? When?
147. Are inactivators used for antibiotics or other bactericidal / bacteriostatic substances? Has the firm
shown that these are effective? Are records available?
148. When are recovered microorganisms identified? To what level (genus, species)?
149. What are the incubation times and temperatures?
150. How are environmental and personnel monitoring data trended? How often are trend reports
prepared? How often are they reviewed? Who reviews the trend reports? What type of action is
taken based on review of trend reports?
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151. Are environmental and personnel monitoring samples that exceed action levels investigated to
determine product impact, cause and needed corrective actions? What is done when an alert level
is exceeded?
Review and assess the EM trending data, which will provide a good indication if the viable and non-
viable particles are maintained within the established levels or drifting out of control. What are the
causes of the aberrant events? Were corrective actions and preventive measures taken to preclude the
reoccurrence of the viable and non-viable particle anomalies?
BIOLOGICAL INDICATORS (BIs)
In sterile drug manufacturing, BIs are typically used to validate the cycles used for terminal sterilization,
sterilization of equipment and components. BIs are also used to validate SIP systems used to sterilize
lyophilizers, processing tanks, sterilizing filters, and product lines and systems used to decontaminate
surfaces in isolators.
152. What type of indicator is used (e.g., inoculated carrier, inoculated product, inoculated simulated
product, etc.)? Are BIs inoculated into the components (i.e., stoppers) used whenever possible?
What are their corresponding D values? Is the sterilization cycle adequate corresponding to the D
value of the BI?
153. If the source of the indicator is commercial, what is the brand name and manufacturer? What
labeling is received with the BI? If the BI is prepared in-house, determine the supplier of the
organism, how the BI is propagated and stored, and the method of preparation?
154. What organism is used (Genus, species)? Is it the appropriate microorganism used for
sterilization?
155. What is the challenge level of the biological indicator prior to exposure to sterilant?
156. Does the firm verify viable spore count on each lot of BIs before use in validation?
157. Does the firm or the BI labeling claim to meet USP performance criteria for steam or ETO
biological indicators?
158. Does the firm perform USP testing on each lot of BIs received?
159. What is the approximate D-value of the biological indicator? Is this verified prior to validation?
160. How many BIs are used per sterilizer load?
161. What procedure is used to assay the indicators after exposure? What growth media is used? What
are the optimal and actual incubation time and temperature for the BI (compare to COA received
with the BI)?
162. How are the BIs prepared for sterilization?
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163. Are biological indicators located in the most difficult to sterilize product sites (explain)? How are
these locations determined?
164. Is there a diagram of the distribution of biological indicators in the loading pattern(s) used?
165. What is the elapsed time (hrs.) between removing indicators from the sterilizer and testing? Are
there time limits established for this period? What happens if they are exceeded?
166. What is done if positive BIs are found after sterilization?
167. Describe biological indicator storage conditions:
A. Type of room, cabinet, etc. (if stored in freezer or refrigerator, state if frost-free)
B. Temperature
C. Relative humidity (if known)
D. Compare to literature received with BI or written procedures
168. Does the firm use chemical process monitor(s) to indicate cycle exposure or to measure one or
more cycle parameters?
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来源：FDA Pharmaceutical Quality Documents · fda.gov