FDA发布第7356.040号配药外包设施检查合规程序
Outsourcing Facility Inspections
FDA发布编号7356.040的配药外包设施检查合规程序，签发日为2025年1月15日，实施日期为2025年2月15日。程序规定全面检查与简略检查两种监督性检查选项，简略检查通常覆盖至少三个系统，且必须包含质量系统与生产系统。检查依据为21 CFR第210和211部分及FD&C法案503B、501(a)(2)(A)、501(a)(2)(B)等条款。
该程序说明FDA对配药外包设施的检查选项、系统覆盖范围、检查依据及实施日期，可帮助了解其检查框架。
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美国食品药品监督管理局
合规计划 计划 7356.040
第56章——药品质量保证
主题： 实施日期：
外包设施检查 2025年2月15日
数据报告
产品代码 产品/任务代码
所有人用药品 PAC 主题
行业代码： 56040 外包设施检查
54–56, 60–66 56040A 简化外包设施
检查
现场报告要求：
1. 建立检查报告（EIR）应使用 eNSpect 或替代系统中可供检查与调查办公室（OII）及药品评价与研究中心（CDER）双方访问的特定模块以电子方式创建和提交。
2. 对于因未能遵守《食品、药品和化妆品法》（FD&C 法）第 503B 条、FD&C 法第 501(a)(2)(A) 条，或 FD&C 法第 501(a)(2)(B) 条中适用于人用药品的、21 CFR 第 210 和 211 部分所规定的现行药品生产质量管理规范（CGMP）要求，而被分类为官方行动指示（OAI）的外包设施检查，OII 各分部应尽快按照《调查操作手册》（IOM）将重大检查问题报告至 eNSpect，并按照《监管程序手册》批准对检查采取建议、行政或司法行动。
3. 请 OII 各分部对所有外包设施检查均使用本合规计划。
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PROGRAM 7356.040
目录
第一部分 – 背景…... .......................................................................................................... 4
第二部分 – 实施 ........................................................................................................ 6
目标 ...................................................................................................................................... 6
策略 ........................................................................................................................................ 6
A. 外包设施检查 ..................................................................................... 6
B. 系统检查 ........................................................................................................... 6
C. 药品生产系统方案 ...................................................... 7
项目管理说明 .............................................................................................. 9
A. 定义 ............................................................................................................................ 9
B. 检查计划 ............................................................................................................ 11
第三部分 – 检查 ........................................................................................................... 12
操作 .................................................................................................................................. 12
A. 检查方法 ....................................................................................................... 13
(1) 检查选项…………………………………………………………………...13
(a) 全面检查…….……………………………………………………………….13
(b) 简化检查…………………………………………………………....13
(2) 检查覆盖范围………………………………………………………………....14
(3) 系统检查覆盖范围………………………………………………………...14
(a) 质量体系…………………………………………………………………….14
(b) 设施与设备系统…….………………………………………..…..18
(c) 物料系统…………………………………………………………………..27
(d) 生产系统…………….……………………………………………...……29
(e) 包装与标签系统…….………………………………….………….39
(f) 实验室控制系统…….………………………………………………….41
B. 取样 ............................................................................................................................. 45
C. 检查团队 ................................................................................................................ 46
报告.................................................................................................................................... 46
第四部分 – 分析 .............................................................................................................. 47
分析实验室 .............................................................................................................. 47
应进行的分析.......................................................................................................... 47
第五部分 – 监管/行政策略 .................................................... 48
第六部分 – 参考文献、附件和项目联系人 .......................... 49
参考文献 .................................................................................................................................. 49
A. 美国联邦法规第21篇 ................................................................................ 49
B. 合规项目......................................................................................................... 49
C. FDA指南 .................................................................................................................. 49
D. ICH指南 ................................................................................................................... 49
E. 其他参考文献 ................................................................................................................. 49
附件 ................................................................................................................................. 50
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计划联系人 ....................................................................................................................... 50
A. 执法相关指南或政策.................................................................... 50
B. CGMP 或任何质量相关政策问题 ....................................................... 50
缩写 ................................................................................................................................... 50
第七部分 – CDER 和 OII 职责概述.................................................. 52
监督检查职责 ................................................................................... 52
复检职责 .................................................................................................... 52
有因检查职责....................................................................................... 52
附件 A – 示例…………………………………………………………………53
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第一部分——背景
《药品质量与安全法案》于2013年11月27日签署成为法律，在《联邦食品、药品和化妆品法案》（FD&C法案）中新增了第503B条。根据第503B(b)条，1 配制方可选择向FDA注册为外包设施。在外包设施中配制的药品，若满足第503B条规定的条件，可豁免FD&C法案第505条关于须获得上市申请批准的要求、2 FD&C法案第502(f)(1)条关于药品标签须载有充分使用说明的要求，3 以及FD&C法案第582条规定的药品供应链安全要求。外包设施由FDA按照基于风险的检查计划进行检查，且必须遵守FD&C法案的其他条款，包括第501(a)(2)(A)条、第501(a)(2)(B)条下的CGMP要求及其实施法规。
根据第501(a)(2)(A)条，药品在下列情形下被视为掺假：
其制备、包装或保存的条件不卫生，因而可能已被污物污染，或因而可能已变得危害健康。
根据第501(a)(2)(B)条，药品在下列情形下被视为掺假：
其生产、加工、包装或保存所采用的方法，或所使用的设施或控制措施，不符合或未按照现行药品生产质量管理规范运行或管理，以确保该药品在安全性方面符合本[法案]的要求，并具有其声称或标示所具有的鉴别特征和效价，且符合其声称或标示所具有的质量和纯度特性。
此外，经《食品药品管理局安全与创新法案》修订的FD&C法案第501条规定：
就第(a)(2)(B)款而言，“现行药品生产质量管理规范”一词包括对药品生产实施监督和控制以确保质量，包括管理风险并确立原材料、药品生产所用物料及成品药品的安全性。
成品药品的CGMP法规（PET药品和医用气体除外）4 规定于21 CFR第210和211部分。如行业指南草案《现行药品生产质量管理规范——FD&C法案第503B条下人用药品配制外包设施指南》（2020年1月）5 所述，FDA拟为外包设施颁布更具体的CGMP法规。在这些最终法规颁布之前，外包
1
21 U.S.C. 353b。
2
21 U.S.C. 355。
3
21 U.S.C. 352(f)(1)。
4
医用气体的CGMP法规（21 CFR 213）计划于2025年12月实施。
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我们会定期更新指南。本指南定稿后，将代表FDA对该主题的当前看法。如需指南的最新版本，请查阅FDA指南网页 https://www.fda.gov/regulatory-
information/search-fda-guidance-documents。
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计划 7356.040
设施须符合第 210 和 211 部分的 CGMP 要求。本合规计划的主要关注点是 21 CFR 第 211 部分中与无菌和非无菌配制药品质量相关的方面，包括无菌保证、效价（例如，效价不足、效价过高）、标签、交叉污染或药品混淆，因为外包设施运营的这些方面如果不按照 CGMP 及其他法定和监管要求执行，将对患者安全构成最大风险。
为配合 FDA 加强对外包设施生产和产品质量监管的举措，FDA 可能使用额外信息来源为其监管监督提供依据。这可能包括以下内容：(1) FDA 开展的其他检查；(2) 远程监管评估（RRA）6，包括 (a) 根据 FD&C 法案第 704(a)(4) 条直接向设施和其他被检查实体索取的记录或其他信息，以及 (b) 在适当情况下开展的远程互动评估（RIE）。
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见合规计划 7356.002，附件 A。
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计划 7356.040
第二部分——实施
目标
本合规计划活动的目标是确保各场所持续生产质量可接受的药品，并尽量减少消费者接触掺假药品。
根据本合规计划，开展检查、调查、取样、样品分析以及监管或行政后续行动，以识别场所的质量问题和不良趋势，
从而使 FDA 能够制定缓解这些问题的策略。本计划的目标是：
• 确定被检查场所 7 是否按照适用的 CGMP 要求运行，以生产无菌和非无菌配制药品。如果不符合要求，
则提供证据以对责任人采取行动，并采取适当措施防止掺假产品进入市场或将掺假产品从市场中移除。
• 在检查期间向场所提供意见，以改进其对联邦法规的符合性。
• 了解外包设施的当前实践，以更新 CGMP 要求、监管政策和指南文件。
策略
A. 外包设施的检查
药品生产使用许多物理操作，将组分、容器和密封件组合在一起，制成可放行分销的产品。历史上，FDA 对药品生产的检查
被组织为若干组操作及相关活动，称为系统。为与此保持一致，FDA 对外包设施生产活动的检查
也将按系统组织。对所有系统的控制有助于确保企业生产出具有其所声称或标示拥有的鉴别、强度、质量和纯度特性的
质量药品。
B. 系统检查
外包设施的检查应使用本合规计划中的系统定义和行业代码进行和报告。聚焦系统将提高
检查效率，因为这些系统通常适用于多种药品。
对某一系统的覆盖应足够详细，并选择具体示例，以便
该系统的检查结果反映该系统的受控状态。如果某一特定系统
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在本合规计划中，场所、人员、场地、企业和设施这些同义术语涵盖受 FDA 人用药品法规和法定权限约束的实体。
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充分，则应当足以覆盖该企业生产的所有配制药产品。例如，某机构接收、检验以及接受或拒收原材料的方式，应当对所有产品类型都相同。同样，在生产系统中，也存在一些通用要求，例如使用 SOP（标准操作规程）、组分的投料、设备标识，以及过程取样和检验，这些都可以通过选择处于不同生产阶段的多个产品来进行评估。在每个系统下，可能存在某些特定工艺所独有的内容：例如，生产用于药品生产的 USP（美国药典）注射用水，对软膏粉碎生产工艺的验证，或溶出度检测的实施。在系统内选择哪些独特功能进行覆盖，将由主检查员自行决定。 8
对一个系统的完整检查，可能需要对其他系统活动中的某些项目进行进一步跟进，以充分记录检查发现。然而，这种覆盖并不构成也不要求对这些其他系统进行完整覆盖。
C. 药品生产系统方案
任何特定系统中所聘用的组织和人员，包括适当的资质和培训，都将作为该系统运行的一部分进行评估。CGMP 法规要求保存并选定供审查的生产、控制和分销记录，应当纳入以下每个系统的检查审计范围内。对合同公司的检查，应当在其产品或服务所涉系统以及其质量系统范围内进行。
对外包设施药品生产进行审计的总体系统方案包括以下内容：
(1) 质量系统
该系统确保整体符合 CGMP 要求和内部程序及质量标准。稳健的质量系统依赖于文件记录以及高级管理层对 CGMP 运营和质量相关事项的有力监督，支持并促进在六个系统下开展的活动，监测其有效性，并确保对既定质量方针的承诺。 9 该系统包括质量部门及其审核和批准职责（例如，质量协议、变更管理、风险管理、批放行、年度记录审核、调查、持续工艺确认、验证方案和报告）。该系统还包括质量控制部门及其审核和批准职责（例如，变更控制、返工、批放行、年度记录审核、验证方案和报告）。它包括所有产品缺陷评估以及对退回和回收药品的评估。参见 CGMP 法规，21 CFR 第 211 部分，B、E、F、G、I、J 和 K 子部分。
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参见第三部分——检查。
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就本合规程序而言，质量方针定义为组织与质量相关的总体意图和方向，由高级管理层正式表达。参见 ICH 行业指南 Q10 药品质量体系。
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(2) 设施与设备系统
该系统包括为药品生产提供适当物理环境和资源的措施与活动。它包括：
• 厂房与设施设计、建造材料、维护及正确操作。
• 公用工程，其产出不拟纳入产品，例如
供暖、通风与空调（HVAC）系统、压缩气体、蒸汽及
水系统（例如注射用水系统）。
• 设备设计、建造材料、校准及维护。
• 设备确认（安装确认和运行确认）。注意，工艺
性能确认将作为生产系统下工艺验证的一部分进行评价。
清洁工艺，以及适当时的清洁验证。
参见 CGMP 法规，21 CFR 第 211 部分，B、C、D 和 J 子部分。
(3) 物料系统
该系统包括控制成品、组分（包括纳入产品的
水或气体）、容器及密封件的措施与活动。它包括计算机化库存控制流程、
药品储存、分销控制及记录的验证。参见
CGMP 法规，21 CFR 第 211 部分，B、E、H 和 J 子部分。
(4) 生产系统
该系统包括控制药品生产的措施与活动，包括
批配料、剂型生产、中控取样与检测及工艺验证。
它还包括建立、遵循并记录已批准生产
规程的执行情况。参见 CGMP 法规，21 CFR 第 211 部分，B、F 和 J 子部分。
(5) 包装与标签系统
该系统包括控制药品包装与标签的措施与活动。
它包括书面规程、标签检查与使用、标签储存与发放、包装
与标签操作控制，以及这些操作的验证。参见 CGMP 法规，21
CFR 第 211 部分，B、G 和 J 子部分。
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(6) 实验室控制系统
该系统包括与实验室程序、检验、分析方法开发、验证或确认以及稳定性计划相关的措施和活动。参见 CGMP
法规，21 CFR 第 211 部分，B、I、J 和 K 子部分。
计划管理说明
A. 定义
(1) 监督检查
(a) 全面检查选项
全面检查选项是一种监督检查，旨在对企业的药品生产进行广泛而深入的
评估，以确保有充分的控制措施防止污染，收集有关含量测定和稳定性检验实践的信息，并评估其是否符合 CGMP
要求。全面检查选项将包括对所有六个系统的检查审核。经 OII 和 OCQC 共同
同意，全面检查可改为简略检查选项。
(b) 简略检查选项
简略检查选项是一种监督检查，旨在对 CGMP 要求的符合性提供高效的最新评估。如果外包设施具有令人满意的 CGMP 合规记录，生产运营几乎没有或
没有变化，且自上次监督检查以来没有重大产品召回、产品缺陷或
重大报告事件或投诉，则可以使用简略检查选项。参见第 III.1.A
(1)(b) 部分——简略检查选项。经 OII 和
OCQC 共同同意，若在一个或多个系统中发现不良情况（如第 V 部分所列），简略检查可改为全面检查。简略检查选项通常将包括对至少三个系统的检查审核，并且必须包括质量系统和生产系统。
可选系统应在连续的简略检查中轮换。在简略检查期间，质量系统活动的确认可能需要对其他系统进行有限覆盖。
(c) 选择覆盖的系统
简略检查选项的系统选择将基于企业的
具体运营、以往覆盖历史、合规历史，或经 OII 和 OCQC 共同同意确定的其他优先事项。
(2) 复检
当 FDA 评估检查证据并确定检查发现“与[FD&C 法案]适用要求[存在]重大相关的
不合规”时，即进行复检，
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属于《联邦食品、药品和化妆品法案》第 744J(4) 条所指的范围，且 FDA 进一步认定，基于
所收集的检查证据，其应当进行复检，“专门确定是否已达到令[其]满意的合规状态。”将针对复检
签发检查任务备忘录，并应与外包设施合规计划配套使用。
(3) 有因检查
有因检查是针对特定事件或信息（例如收到严重不良事件报告、投诉、召回及其他缺陷产品
迹象）而开展的定向检查，这些事件或信息使人们对某项生产实践、设施、工艺或药品的合规性
或质量产生疑问。有因检查聚焦于所关注的领域、针对受影响运营提出的纠正措施计划，或为
解决此前检查中 Form FDA 483（检查观察记录）所列缺陷而实施的任何纠正措施。将针对有因
检查签发检查任务备忘录，并应与外包设施合规计划配套使用。如果有因检查同时也是复检
（即此前检查为 OAI），将收取复检费用。
(4) 受控状态
当外包设施采用能够确保符合所有适用法规和规章（包括该法案第 503B、501(a)(2)(A) 和
501(a)(2)(B) 条）的条件和做法时，即处于受控状态运行。处于受控状态的企业所生产的
成品制剂，其质量、效价、鉴别和纯度具有充分水平的保证。
如果任何一个系统失控，则整个场所即处于失控状态。如果一个或多个系统所产出的药品
的质量、鉴别、效价和纯度无法得到充分保证，则该系统处于失控状态。有记录的 CGMP
缺陷或未能满足《联邦食品、药品和化妆品法案》的某些条件，可作为认定某系统未在受控
状态下运行的证据。关于基于表明系统失控的检查发现而采取的合规措施，参见第五部分
监管/行政策略。
(4) 药品生产
药品生产是一系列相关操作，其结果是制得药品或药品制剂。生产工艺中的主要操作或步骤
可能包括混合、封装、压片、无菌灌装、灭菌、冻干、包装、贴标、检验等。
(5) 外包设施检查
外包设施检查是一种场所检查，其中对包括质量系统和生产系统在内的三个或更多系统进行
评估，以确定生产和 CGMP 合规是否在受控状态下进行。检查的目的是评估外包设施是否
符合生产配制的无菌和非无菌药品制剂的最低标准，并防止在以下条件下生产的药品的生产
签发日期：2025 年 1 月 15 日 第 10 页，共 54 页
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PROGRAM 7356.040
可能对患者安全构成重大风险的情形。除本程序所规定的各系统覆盖范围外，检查期间还可评估对
FD&C 法案第 503B 条某些条款的符合情况。
B. 检查计划
在 CDER 指派后，OII 将采用基于风险的方法确定检查优先次序。CDER 和
OII 负责确定对每个场所的覆盖深度。检查
覆盖深度应根据企业的合规历史、所采用的
生产技术、预期患者人群以及产品特性来确定。CGMP
检查覆盖范围必须足以评估每个企业的控制状态和合规情况。
当对某一系统进行检查时，对该系统的检查可视为适用于该系统所适用的所有
产品。检查员应选择足够数量和适当类型的产品，以
完成对该系统的覆盖。产品的选择应使覆盖范围能够
代表企业按照 CGMP
要求及其他适用的法定和监管要求生产药品的整体能力。
检查员应选择对公众
健康风险组合最大的产品。应考虑诸如窄治疗范围药品、工艺风险、投诉、
产量、分销以及使用期限/有效期过长的产品等因素。10
10
参见《调查操作手册》(IOM) 第 5.1.2 节——检查方法
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PROGRAM 7356.040
PART III—INSPECTIONAL
Operations
The investigator should review and use the CGMP regulations for finished pharmaceuticals (21 CFR
210 and 211), 11 sections 503B, 501(a)(2)(A), and 501(a)(2)(B) of the FD&C Act, and the
recommendations in related guidance for industry to evaluate manufacturing processes and
compliance.
The investigator should conduct inspections according to the STRATEGY section 12 of this
compliance program. Recognizing that Outsourcing Facilities vary greatly in size and scope, and
production systems are complex, the approach to inspecting each firm should be carefully planned.
The complexity and variability of Outsourcing Facilities necessitate a flexible inspection approach
that allows the investigator to choose the inspection focus and depth appropriate for a specific
facility, but also one that directs the performance and reporting on the inspection within a framework
which will provide for a uniform level of assessment. For example, an investigator could conduct a
walk-through of the facility and observe production as soon as possible, all while concurrently
evaluating the quality system. In some cases, it may be more appropriate for the investigator to
review the quality system thoroughly before the walk-through. Furthermore, this inspection approach
will provide for fast communication and evaluation of findings.
Inspectional observations noting CGMP deficiencies should be related to a regulatory requirement.
CGMP and other requirements for the manufacture of drug products (dosage forms) are in sections
501(a)(2)(A) and 501(a)(2)(B) of the FD&C Act and the regulations in 21 CFR part 210 and 211.
CGMP requirements apply to the production of human drugs compounded by Outsourcing Facilities.
Guidance documents are not to be referred to as the basis for an inspectional observation.
Observations of noncompliance are based requirements established in the statute and the CGMP
regulations. Current Inspection Guides and guidance to industry documents provide interpretations of
requirements, which may assist in the evaluation of the adequacy of CGMP systems. Guidance
documents do not establish requirements.
Current inspectional observation policy as stated in the IOM is that the Form FDA 483, when issued,
should be specific and contain only significant items. For this program, inspection observations
should be organized under separate captions by the systems defined in this program. List the
observations in order of importance within each system. Where repeated or similar observations are
made, they should be consolidated under a unified observation. A limited number of observations can
be common to more than one system (e.g., organization and personnel, including appropriate
qualifications and training). In these instances, put the observation in the first system reported on the
Form FDA 483 and in the text of the EIR, referencing the applicability to other systems where
appropriate. This approach is used to accommodate the structure of eNSpect, which allows an
individual citation only once per Form FDA 483. Refrain from using unsubstantiated conclusions. Do
11
FDA intends to promulgate more specific CGMP regulations for Outsourcing Facilities. Until these final regulations are
promulgated, Outsourcing Facilities are subject to the CGMP requirements in parts 210 and 211.
12
Refer to section II.2.
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PROGRAM 7356.040
not use the term "inadequate" without explaining why and how. 13 Specific specialized inspectional
guidance may be provided as attachments to this program, or in requests for inspection.
A. Inspection Approaches
This compliance program provides two surveillance inspection options: full inspection and
abbreviated inspection. See the definitions of the inspection options in Part II of this program.
A full inspection may change to the abbreviated inspection option with OII and OCQC joint
concurrence.
(1) Inspection Options
(a) Full Inspection
The full inspection option includes inspection of all six of the systems listed in Part II of this program.
Select the full inspection option if:
• This is an initial FDA inspection of a newly registered Outsourcing Facility. Inspection
coverage should include all systems as appropriate to the operations.
• The Outsourcing Facility has a history of fluctuating into and out of compliance. To determine
if the firm meets this criterion, OII should utilize all information at its disposal, including
compliance history, results of sample analyses, complaints, Drug Quality Reporting System
(DQRS) reports, adverse event reports, and recalls.
• Evaluate if important changes have occurred by comparing current operations against
operations documented in the EIR for the previous full inspection. The following types of
changes are typical of those that warrant the full inspection option:
− New potential for cross-contamination arising through change in process or product line.
− Use of new technology, process, or analytical method requiring new expertise,
significant new equipment, or new facilities.
• A full inspection may also be conducted on a surveillance basis at OII’s discretion.
• A full inspection may change to the abbreviated inspection option with OII and OCQC joint
concurrence and where appropriate.
(b) Abbreviated Inspection
The abbreviated inspection option may be selected with OII and OCQC joint concurrence, and
normally will include coverage of at least three systems. Coverage of the quality system and
13
Refer to policy in the IOM, Chapter 5, Section 5.5.10 – Reports of Observations for further guidance on the content of
Inspectional Observations.
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PROGRAM 7356.040
production system is mandatory. During an abbreviated inspection, verification of quality system
activities may require limited coverage in other systems. This option involves an inspection of the
firm to maintain surveillance over the Outsourcing Facility’s activities and to provide input to the
facility on maintaining and improving the level of assurance of the quality of its compounded drug
products. Abbreviated inspection coverage may be changed to the full inspection option with OII and
OCQC joint concurrence. Select the abbreviated inspection option if:
• An establishment has a record of sustained acceptable compliance history (e.g., NAI or VAI
inspection classifications), a strong risk management program, and a lack of significant
marketed product quality defects.
(2) Inspection Coverage
It is not anticipated that full inspections can be conducted every time. To build comprehensive
information on the firm's production activities, OII should consider selecting different systems for
inspection coverage during successive abbreviated inspections. In addition, coverage can be added on
a case-by-case basis by OII prior to or during the inspection in consultation with OCQC. Inspections
conducted to follow-up on a warning letter or other significant regulatory actions are considered
reinspections, and as a result, the related reinspection may include full systems coverage.
(3) System Inspection Coverage
(a) Quality System
For the purposes of this compliance program, quality system refers to the system (i.e., policies,
procedures, controls, activities, etc.) satisfying the specific quality control and quality assurance
requirements outlined under 21 CFR 211.22, as well as other quality-related requirements in 21 CFR
part 211 and under the FD&C Act.
The quality system, typically described in a quality manual, should provide for effective senior
management oversight of drug quality, and support the establishment’s quality unit. This includes,
but is not limited to, quality policies, quality planning, quality resource management, and quality
management review. When effectively implemented with an established quality policy endorsed by
senior management, a quality system provides for coordination and direction of the facility’s
activities related to producing quality drugs, helps establish and maintain a state of control, promotes
robust risk management, and facilitates continual improvement. To ensure the implementation of a
CGMP-compliant quality system, manufacturers should use knowledge management and quality risk
management tools to conduct operations, in whole or in part, consistent with recommendations in the
guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations (October
2006). 14
Additionally, an inspection conducted under this compliance program provides an opportunity for
investigators to observe and document examples of mature quality practices that exceed CGMP
See also the ICH guidances for industry Q9(R1) Quality Risk Management (May 2023) and Q10 Pharmaceutical
14
Quality System (April 2009).
Date of Issuance: 01/15/2025 Page 14 of 54
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PROGRAM 7356.040
requirements and are indicative of an advanced quality system. To aid investigators, Attachment A
provides some examples of these practices that, when properly implemented, are indicators of an
advanced quality system. The information from this compliance program, when combined with
information on mature quality practices gathered from other sources, provides FDA with a more
comprehensive understanding of a facility’s quality system.
Inspectional assessment of the quality system is two-phased. The first phase is to evaluate whether
the quality unit has fulfilled the responsibility to review and approve all procedures related to
production, quality control, and quality assurance and assure the procedures are adequate for their
intended use as outlined under 21 CFR 211.22(a) and 211.22(c). This also includes the associated
recordkeeping systems. The second phase is to assess the data collected to identify quality problems
which may link to other major systems for inspectional coverage. For sterile compounding operations,
this latter objective involves large amounts of data that link to the other inspectional systems. The
comprehensive review of such data by the firm is an essential element in assuring that products are
produced with a high degree of sterility assurance. It is therefore important to review the firm’s system
for using the data to assess the state of control of their manufacturing operations and facility. The data
summaries and trend reports maintained by the quality unit should be reviewed during every inspection.
All data should be attributable, legible, contemporaneous, original, and accurate. During a routine
surveillance inspection, this review can help determine which option (Full or Abbreviated) to select.
The firm should have written and approved procedures and documentation that assure product quality.
Procedures or documentation may apply to components, containers, closures, in-process materials,
compounded drug products, production or analytical equipment, and facilities. The firm's adherence
to written procedures should be verified through observation whenever possible. These areas are not
limited to finished products but may also incorporate components and in-process materials. These
areas may indicate deficiencies not only in this system but also in other major systems that would
warrant expansion of coverage.
The inspection of the quality system must include a review of all data and reports that may indicate
product contamination and sterility assurance issues. For sterile compounded drugs the inspection
should also include:
• Quality oversight of contracted operations (e.g., laboratories) and material suppliers to include
an: effective monitoring strategy for incoming materials or services, qualification programs,
quality agreements, and timely communication channels.
• Management oversight of the development, implementation, monitoring, and continual
improvement of the quality system and the incorporation of quality risk management and
knowledge management principles.
• Documentation and implementation procedures to ensure hazards (e.g., cross-contamination,
adulteration, hazardous impurities such as nitrosamines, nitrosating agents, nitrites, nitrates,
and azides) are identified, evaluated, addressed, communicated (to the establishment’s
management and FDA), and continuously reviewed as needed throughout a product’s
lifecycle.
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PROGRAM 7356.040
• Hazardous impurity risk is assessed, and control strategies are implemented to mitigate the
risk (e.g., actions to address sources of variability, release testing, reduction or elimination of
impurities, cleaning validation); control strategies are reviewed following changes and
throughout a product’s lifecycle.
Product reviews, completed at least annually, should include information from areas listed below as
appropriate:
• Batches reviewed for each product are representative of all batches produced, and trends are
identified.
• Evaluations of complaints, adverse events, investigations, retain sample evaluations, rejected
lots, stability data, and returned goods that indicate possible product contamination or risks to
patients (for example, hazy or cloudy product, foreign matter or particulates in injectable
products, cracked or leaky containers).
• Complaint reviews (quality and medical) are documented, evaluated, and investigated in a
timely manner. Corrective and preventive actions are implemented when appropriate.
• Discrepancy and failure investigations related to production and testing are documented,
evaluated, and investigated in a timely manner using scientific evidence to identify the root
cause (or most probable root cause). Corrective and preventive actions (CAPAs) are
implemented when appropriate and the effectiveness of the CAPAs is evaluated.
• Discrepancy and failure investigations, such as:
− All positive sterility tests, and endotoxin and media fill failures regardless of final
batch disposition.
− Unexpected results or trends.
− All failures that occurred during validation or revalidation of sterilization or
depyrogenation processes.
− All investigations involving media fills (aseptic process simulations).
− Environmental (microbial/viable and particle/nonviable counts) and personnel
monitoring results that exceed alert or action levels.
− Process deviations or equipment malfunctions that involve critical equipment, such as
sterilizers and lyophilizers.
− Out-of-Specification (OOS) results for assay, impurities, particulate matter, or
reconstitution time, if applicable.
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− Product rejects (rejects determined during manufacturing and quality control testing).
• Trends, reports, or summaries of quality indicators:
− For sterile compounded drugs produced by aseptic processing, a summary of all media
fills performed since last inspection.
− Environmental monitoring trend data (microbial and particle counts)
− Personnel monitoring trend data
− Summary of water system test results
• Documentation of change management, including justification for changes, for the
manufacturing of all products. Quality risk management principles are used to evaluate
proposed changes for potential risks (e.g., hazardous drugs and microbial contamination) and
impact on product quality. Proposed changes should be reviewed by subject matter experts
and approved before implementation and any necessary (re)evaluation, or (re)qualification
should be completed. Changes should be evaluated for effectiveness.
• Summary of change controls for critical utilities and equipment implemented since the last
inspection, for example:
− Sterilizers, lyophilizers and depyrogenation equipment
− Aseptic processing line(s) (e.g., automated filling equipment, ISO 5 laminar air flow
hoods)
− Clean steam generator, process gas system
− Water for Injection (WFI) system and Purified Water system
− Air handling systems
− Automated building management system
• Investigation of rejects, and the investigation should be expanded when warranted. CAPAs
should be implemented when appropriate.
• Investigation of stability failures, and the investigation should be expanded when warranted.
The need for recalls should be evaluated and impacted products should be appropriately
dispositioned.
• Quarantine products.
• Validation: Approval of required validation or revalidation (e.g., computer, production
process, laboratory methods) is documented.
• Training and qualification of employees in CGMP: Includes coverage of quality functions,
risk management, and specific CGMP operations assigned to individual employees.
• Programs for the ongoing monitoring of process performance and product quality. Significant
issues are escalated to senior management.
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• Assessment of returns/salvaged products are assessed; investigations are expanded when
warranted, and these products are appropriately dispositioned.
In addition, the review of summary data and observation of operations can focus the inspection on
potential problem areas and provide an overview of the effectiveness of the quality system. The
inspection of the quality system may necessitate follow-up coverage within another system. However,
this coverage may not constitute or require complete coverage of these systems.
(b) Facilities and Equipment System
The principal objective of an effective Outsourcing Facility operation from a facility and
equipment standpoint is to provide suitable protection of compounded drug products. The
inspectional evaluation of this objective is also two-phased:
• Review and evaluate the firm’s rationale for, and adequacy of, the facility and
equipment design.
• Evaluate the data that provides information relevant to the state of control of the facility
and equipment.
The firm should have written and approved procedures and documentation for process equipment, the
design of the facilities (e.g., unidirectional vs. two-way personnel, materials, equipment, and product
flows, designated vs shared areas) and utility systems that support the critical physical and chemical
requirements of compounded drug products (e.g., design and construction, installation qualification,
operation qualification, calibration, and maintenance, controls, and automation). The firm's adherence
to written procedures should be verified through observation whenever possible. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant expansion of
coverage. When this system is selected for coverage, all areas listed below should be covered.
However, the depth of coverage may vary depending upon inspectional findings.
In addition to the review of design elements and data, investigators should look for visible
deficiencies in the facility and equipment, such as uncleanliness, equipment deterioration (e.g.,
warping, corrosion, staining), inaccessible or difficult to clean surfaces, and changes to critical
equipment or systems that have not been qualified and which may impact product quality.
Investigators should look for aberrant events due to facility deterioration, a pattern of recurring
and uncorrected maintenance issues, and an increase or changes in production output that
exceed the capacity of the facility and equipment.
i. Facilities
The inspectional evaluation should:
• Evaluate the design and layout of the facility (e.g., personnel and material flow, cleanroom
design and material of construction, air filtration and exhaust) for the prevention of cross-
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PROGRAM 7356.040
contamination 15 (e.g., HVAC system designed to prevent the influx of poor-quality air or
penicillins, non-penicillin beta-lactams, steroids, hormones, or cytotoxic or highly sensitizing
drugs).
• Review the certification and qualification of the clean room areas to verify these areas meet
the established design criteria and specifications. Certification and qualification typically
include data in support of the following: airflow pattern studies (unidirectional airflow where
applicable), HEPA (High Efficiency Particulate Air) filter integrity testing, air velocity
measurements, nonviable particle counts, and verification of appropriate pressure
differentials, temperature, and humidity setpoints.
• Assess if specifications for clean room areas (e.g., air classification, pressure differentials
between rooms and areas, temperature, and humidity) are appropriate, and based on the risk of
product contamination with particulate matter and microorganisms.
− Evaluate the airflow pattern studies (smoke studies) conducted under dynamic
conditions to verify the unidirectional airflow and any air turbulence observed within
the critical area where sterilized drug product, containers, and closures are exposed to
environmental conditions. If possible, review video recordings for airflow pattern
studies (smoke studies).
• Ensure routine monitoring and maintenance to assure air handling systems continue to operate
within established parameters (microbiological monitoring is discussed under the Laboratory
Control System):
− Afford special attention to facilities that are performing construction in the clean areas,
or at the vicinity of a 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
(e.g., environmental monitoring, media fills) before production is allowed to resume.
− Verify that environmental monitoring of viable and nonviable particles is occurring
during operations including locations where there is the most risk to exposed product,
container, and closures.
− Check if pressure differentials, temperature, and humidity are monitored during
routine production.
− Determine if monitoring systems have alarms to alert operators of excursions.
− Check if excursions from acceptable ranges are investigated to determine impact on
product and that needed corrective actions are taken.
See the draft guidance for industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-
15
Contamination (June 2022). When final, this guidance will represent the FDA’s current thinking on this topic.
Date of Issuance: 01/15/2025 Page 19 of 54
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− Check if critical equipment (e.g., laminar airflow hoods, restricted access barrier
systems, isolators, etc.) that has been moved is requalified before use.
• Evaluate cleaning and maintenance.
− Review sanitation of the building, use of appropriate rodenticides, fungicides,
insecticides, cleaning, and sanitizing agents. Controls are established to prevent
contamination, particularly with any pesticides or any other toxic materials, or other
drug or non-drug chemicals.
− For multiuse facilities and non-dedicated equipment, evaluate the adequacy of the
changeover procedures and cleaning to prevent cross-contamination between products.
− Sanitization or disinfection of clean room areas, processing lines, and non-
autoclavable equipment, materials, and components should be reviewed to ensure they
are suitable for their intended use (e.g., non-sterile disinfectants or shedding wipes
would not be appropriate to sanitize or disinfect cleanrooms). Investigators should
focus on the areas where the sterile product is exposed up to and including sealing
operations. These critical areas represent the highest risk to products that are intended
to be sterile. The suitability, efficacy, and limitations of disinfecting agents and
adequacy of cleaning procedures should be reviewed, including the data that
establishes the expiry of the disinfection solution. Note: published literature and
supplier certificates of analysis can be relied on when initially determining the
effectiveness of agents used to clean and disinfect, as necessary, the facility and
equipment surfaces, provided that the supplier’s cleaning procedures are followed.
Examples of insanitary conditions 16 include but are not limited to:
Visible signs of filth, dirt, dust, mold or mildew, insects, inappropriate
items/debris, trash, or other signs of inadequate cleanliness on floors, ledges,
and other surfaces
In processing areas: peeling paint, chipped drywall, or ceiling tiles in disrepair,
perforated, unsealed or difficult to clean.
− Control system for implementing changes in the building.
− Lighting, potable water, washing and toilet facilities, sewage and refuse disposal.
− Oversight of facility infrastructure and suitability of manufacturing operations by
responsible operations manager.
16
See the guidance for industry Insanitary Conditions at Compounding Facilities (November 2020).
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ii. Equipment
The investigators should evaluate:
• Equipment installation qualification, operational qualification, performance qualification,
calibration, and maintenance where appropriate (e.g., smoke studies or airflow visualization
for ISO 5 environments, HEPA certification).
• Adequacy of equipment design, size, and location (e.g., equipment for ISO areas, cleanroom
activities, and cleanability).
• Equipment surfaces to determine whether they are reactive, additive, or absorptive.
• Product risk from equipment within production areas (e.g., equipment stored or operated in
ISO 5 areas that could compromise the air quality).
• Appropriate use of equipment, lubricants, coolants, refrigerants, etc. that may contact
products, containers, or closures.
• Qualification, calibration, and maintenance of storage equipment (e.g., refrigerators, freezers)
to ensure that reference standards, raw materials, reagents, or other materials are stored at the
proper temperature.
• Equipment qualification, calibration, and maintenance (e.g., autoclave, incubators, and water
baths qualification and maintenance records), including computer qualification and computer
system validation.
• Sterilizing filters are appropriately sourced and checked for integrity post-use.
• Equipment identification practices (where appropriate).
• Documented investigation into any unexpected discrepancy.
• Control system for implementing changes to equipment.
Equipment used in the manufacture of sterile drug products may include, but not limited to, the
following: 1) production equipment, 2) container/closure processing equipment (e.g., stopper washer,
glassware depyrogenation equipment), 3) support system/material system related equipment (e.g.,
WFI system and related equipment, process gas related equipment).
(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,
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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 preventive
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 in the fully seated, sealed position.
Evaluate the established processing settings (crimp angles, pressures), and
preventive maintenance schedules of the capping machine. Air supply quality to
the capping units should also be evaluated. Ensure that containers are fully
sealed/capped before exposing to less than ISO 5 quality air.
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 more types of defects in each 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. 17
e. Sterilizers. The inspection should cover the Installation and Operation
Qualification of equipment, the performance qualification of the process
(Installation Qualification (IQ), Operational Qualification (OQ) and Performance
Qualification (PQ)), and operation, calibration, and preventive 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 equipment, and chemical sterilization
systems (i.e., hydrogen peroxide, peracetic acid). Inspection of sterilizers should
17
See the draft guidance for industry Inspection of Injectable Products for Visible Particulates (December 2021). When
final, this guidance will represent the FDA’s current thinking on this topic.
Date of Issuance: 01/15/2025 Page 22 of 54
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PROGRAM 7356.040
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 and OQ. Verify that the sterilizer is
maintained, calibrated, and drained properly and that it has appropriate measuring
devices (temperature sensors, pressure gauges, etc.). 18
i. Records of unplanned maintenance, as well as preventive 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. (PQ is covered under the production system).
ii. The equipment can be computer-controlled or operated in a manual mode.
For computer-controlled systems, programmable logic controller 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.
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 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. Isolator. 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
See PDA Technical Report No. 1 (Revised 2007) Validation of Moist Heat Sterilization Processes: Cycle Design,
18
Development, Qualification and Ongoing Control; and ISO 17665 Moist Heat Sterilization.
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chemical indicators (qualitative test) can be used to determine the worst-case
location for decontamination validation using a BI. Factors to be considered in
decontamination validation include the location of the BI and the type of surfaces
where the BIs are inoculated.
i. 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. 19
h. Restricted Access Barrier System (RABS). 20 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 agent, 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 two 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 always
closed, on rare pre-defined circumstances 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. When
inspecting a RABS:
i. 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.
ii. 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.
iii. RABS entry is often accompanied by an appropriate line clearance, which
should be clearly documented in batch records.
iv. 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
19
See PDA Technical Report 51 (2010), Biological Indicators for Gas and Vapor Phase Decontamination Processes:
Specifications, Manufacture, Control and Use. This document provides general principles to be considered in
decontamination by BI.
20
See Restricted Access Barrier Systems (RABS) for Aseptic Processing, ISPE (August 2005).
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PROGRAM 7356.040
batch.
v. 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.
vi. 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. Laminar Flow Hoods (LFHs). LFHs must provide ISO 5 or better conditions and
unidirectional airflow must be ensured to reduce the risk of product contamination.
Inspectional considerations include review of: IQ, OQ, PQ, and validation of the
LFH; evaluation for continuous monitoring of nonviable particle counts and air
quality; regular maintenance, including a routine preventative maintenance
program and evaluation of the HEPA filter(s); and environmental monitoring for
viable and nonviable particles. Airflow patterns should be performed under
dynamic conditions and evaluated for turbulence or eddy currents that can act as a
channel or reservoir for air contaminants.
j. 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. 21 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)
and should be supplied to where the sterile product or its containers are exposed
during the BFS process. Some of the more advanced BFS equipment that provide
enhanced protection for the sterile product operation can be 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. 22
Typically, the product supply line and sterilizing product filters are steam sterilized
in place. When inspecting BFS:
i. 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).
21
See Appendix 2 of the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Process (October 2004).
22
ISO 14698 Cleanrooms and Associated Controlled Environments Biocontamination Control.
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ii. Routinely evaluate the monitoring and preventive maintenance programs to
determine the integrity of the utilities (cooling water, heating, etc.)
associated with the BFS. Leaks in the molds or utility connections at the
molds can contaminate the sterile product or containers.
iii. Review the sterilize in place (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.
iv. Verify that personnel who enter the classified environment surrounding the
BFS machine are properly gowned and trained.
v. If possible, observe equipment setup and any difficulties that can lead to
contamination risks.
vi. Other control procedures (media fills, environmental monitoring,
disinfection of surfaces, etc.) should be the same as discussed for a
conventional aseptic processing line.
(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 WFI. Evaluate depyrogenation processes to ensure they are
appropriately validated for destroying or removing pyrogens (e.g., endotoxins). 23
(3) Support System Equipment
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 the guidance for industry Sterile Drug Products
Produced by Aseptic Processing—Current Good Manufacturing Process (October
2004), specifically the part on qualification and maintenance of the HVAC system.
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
23
See the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing
Process (October 2004).
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PROGRAM 7356.040
(typically hydrophobic) should be evaluated. The system used in the generation of
the process gas(es) should also be evaluated including preventive maintenance
schedules, monitoring (including temperature, pressure, and humidity), and
sampling. See also under Materials System.
(c) Materials System
The principal objective of an effective Outsourcing Facility operation from a materials standpoint is
to provide suitable components, containers, and closures. 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. Each Outsourcing Facility is expected to implement procedures and controls
for the components, containers, and closures to ensure compounded drug products meet all
established quality specifications over the expiry period.
The suitability of containers and closures should be evaluated by the Outsourcing Facility using
scientifically sound and appropriate criteria to verify suitability and conformance to all relevant
quality specifications. 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. Evaluate the firm’s efforts to ensure containers and closures protect
the product throughout the marketed shelf life and are also not reactive, additive, or absorptive.
Review the firm’s procedures and practices for handling and storing container/closures to protect
them from deterioration or contamination. Evaluate the firm’s adherence to the supplier’s expiration
date or in-use/retest date. Assess if containers/closures are re-examined/retested after stored for long
periods or exposed conditions that may adversely affect the container/closure. Evaluate the firm’s
procedures for cleaning and where applicable sterilizing and depyrogenating container/closures.
Appropriate controls are expected for all components (sterile and non-sterile) to ensure the quality of
the finished compounded drugs. Scientifically sound and appropriate specifications must be
established for each component to address all necessary quality attributes of the finished drug product
given the intended use, route of administration, and any other conditions specified in the drug product
directions for use.
In general, component quality attributes may include but are not limited to identity, strength, purity,
particle size, sterility, bacterial endotoxin level, content uniformity, sterility (or for non-sterile
products, microbial enumeration, tests for specified microorganisms) and other characteristics (e.g.,
product-specific tests established by official compendium) that could affect the quality of the final
drug product. Review the firm’s established specifications for components as well as the firm’s
scientific basis for establishing specifications for each component. Evaluate the firm’s controls for
examining, testing, and accepting components.
Determine if the firm tests, examines, or verifies the acceptability of each lot of components, and
each shipment if shipped separately, and if conformity with all specifications is evaluated before use.
Evaluate the firm’s procedures and practices for storing components (e.g., stored under the supplier’s
labeled storage conditions or otherwise established using scientifically sound and appropriate
criteria). Assess if components are used within expiry or retested and re-examined, where
appropriate. In the absence of supplier’s labeled expiration (or retest) date, review the firm’s internal
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PROGRAM 7356.040
controls for setting expiration (or retest) date, or use by dates.
When this system is selected for coverage, all areas 24 listed below should be evaluated:
• Qualification of suppliers and vendors.
• Identification, including labeling, of components, containers, closures.
• Examination, including package integrity, of components, containers, closures.
• Storage conditions of components, containers, closures.
• Storage under quarantine until tested or examined and released.
• Representative samples collected, tested, or examined using appropriate means for each lot.
• Each lot of containers and closures is examined to ensure conformity with appropriate
specifications before use or in lieu of, verification of the supplier's test results (certificate of
analysis or conformity) for components, containers, and closures.
• Evaluate the tests and studies performed to demonstrate the integrity of container closure
systems for all sterile drugs, including confirming that 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.
• Where applicable, conformance to compendial standards (i.e., applicable USP/NF general
chapters and monographs).
• For sterile drug products: a validated sterilization and depyrogenation process for
container/closures (if not using presterilized, and depyrogenated containers and closures); and
where applicable, validated washing prior to sterilization in-house.
• Water produced onsite and used as an ingredient or processing aid tested for appropriate
quality given the intended use to include:
− Design and qualification of the water generation and distribution system
− Offline and in-line monitoring (e.g., pH, TOC, conductivity), trending of data
− Sampling sites, procedures, microbial alert, and action levels
− Preventive maintenance, periodic cleaning, and calibration
− Investigations for discrepancies and excursions
24
For each of the listed areas, the firm should have written and approved procedures and/or documentation resulting
therefrom. These areas are not limited to finished products but may also incorporate in-process materials. The firm's
adherence to written procedures should be verified through observation whenever possible. However, the depth of
coverage may vary depending upon inspectional findings.
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PROGRAM 7356.040
• Process gas supply, design, maintenance, validation, and operation.
• Appropriate handling and protection of sterile containers and closures (i.e., packaging
integrity maintained during storage or movement in non-aseptic environments).
• Rejection of any component, container, closure not meeting acceptance requirements
including any supplier established expiration or in-use period.
• Appropriate retesting/reexamination of components, containers, closures.
• First in – first out use of components, containers, closures.
• Where necessary, retesting and reexamination of components for identity, strength, quality,
and purity.
• Quarantine of rejected materials.
• Documented investigation into any unexpected discrepancy.
(d) Production System
The principal objective of an effective production system is to ensure process controls are designed
and followed to ensure the drug products manufactured have the identity, strength, quality, and purity
they purport or are represented to possess. Each Outsourcing Facility is expected to have written and
approved procedures, documentation, and controls. The establishment’s adherence to written
procedures should be verified through observation whenever possible. These areas are not limited to
finished products but may also incorporate components and in-process materials. These areas may
indicate deficiencies not only in this system but also in other systems that would warrant expansion of
coverage. The inspectional evaluation for this objective includes:
• Review and evaluate the firm’s personnel, material, equipment, product, and process flow.
• Evaluate the data that provides information relevant to the state of control of the Outsourcing
Facility’s manufacturing operations.
Production practices and conditions can have a direct and significant adverse impact on drug sterility
assurance. Coverage of critical elements of the production system, which are typically defined by the
firm, should be part of all inspections of Outsourcing Facilities.
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. Before use in production, equipment, components, containers, and
closures should be visually examined for indications of damage, degradation, or contamination. All
aseptic manipulations, including processing of sterile materials, filling, and closing (e.g., placement
Date of Issuance: 01/15/2025 Page 29 of 54
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PROGRAM 7356.040
and sealing of stoppers on vials), should be performed under unidirectional flow that is ISO 5 or
better. 25
The following should be carefully reviewed and observed:
• Adequacy of personnel practices, aseptic technique, and adherence to documented procedures.
• 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).
• Established justifiable time limits for completion of phases of production including in-process
storage conditions and hold times (e.g., bulk in-process time/temperature, partially stoppered
vials during loading/unloading for lyophilization).
• Process validation, including validation and security of computerized or
automated processes.
• Identification of equipment with contents, and where appropriate, phase of
manufacturing and/or status.
• Adequate procedure and practice for charge-in of components (e.g., sterile operations outside
ISO 5).
• Method of sealing containers with closures (e.g., manual or automated stoppering, and
use and application of caps and crimp seals).
• Disinfection practices, including suitability and efficacy assessment of cleaning/disinfection
practices, and verification of stated product label process.
• Validation of cleaning/sterilization/depyrogenation of components including equipment,
containers, and closures (e.g., validated for bioburden reduction).
• Equipment cleaning and use logs.
• Contamination and cross-contamination controls.
• Prevention of objectionable microorganisms in non-sterile drug products.
25
See the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing
Process (October 2004) and draft guidance for industry Current Good Manufacturing Practice—Guidance for Human
Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020). When final, this
guidance will represent FDA’s current thinking on this topic. See also Compliance Program 7356.002, Drug
Manufacturing Inspections.
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PROGRAM 7356.040
• Contemporaneous and complete batch production documentation (batch production and control
records; master production and control records).
• Calculation and documentation of actual and percentage of theoretical yields.
• Formulation at not less than 100%.
• Control system for implementing changes in processes.
• Implementation and documentation of in-process controls, tests, and examinations
(e.g., Visual Inspection, pH, adequacy of mix, weight variation, clarity).
• Justification and consistency of in-process specifications and drug product
final specifications.
• Change control; the need for revalidation evaluated.
• Documented investigation into any unexpected discrepancy.
• Sterilization method and validation.
• Defects in container/closures after production.
More specifically, the inspection should include real time observation of the higher risk operations
including but not limited to (these are examples and not an all-inclusive list):
• Adherence to production procedures (e.g., setup, line clearance, aseptic processing,
environmental and personnel monitoring)
− Setup 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
sterilization (exceptions may be considered for products undergoing terminal sterilization).
− If a drug product intended to be sterile is not terminally sterilized, there must be a
validated sterilization step such as sterile filtration and it is critical that the sterilization
step occur as close to filling into the final product container as is feasible.
• Aseptic technique and cleanroom behavior during operations, including handling of
equipment jams and stoppages.
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PROGRAM 7356.040
• 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 should also be 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).
• Extra manipulations during filling operations for assembly of sterile filtration apparatus that is
not sterilized in place.
• 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. These manipulations must be performed under ISO 5 conditions.
• Preparation of equipment for sterilization (cleaning, use of 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; capping (aluminum crimp) is
performed in a classified area under unidirectional flow in ISO 5 or better conditions.
• 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:
i. Media Fills or Process Simulations
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PROGRAM 7356.040
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; therefore, it 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. 26 The media fill program should address:
• Factors associated with the longest permitted run of the aseptic processing operation that can
pose contamination risk (e.g., operator fatigue, quality of processing environment).
• If the firm prepares its own media, determine if the firm prepares the media correctly, tests the
pH, and conducts a growth promotion test.
• Representative number, type, and complexity of normal interventions that occur with each
run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment
adjustments). The maximum number of expected interventions should be included to simulate
worst-case conditions.
Inspection actions should include:
• Review to ensure the media is within expiry at the time of use.
• Verify media fills represent actual manufacturing operations by comparing observed
operations to those documented in Media Fill batch records.
• Determine if the firm conducts media fills or process simulations under the most
stressful/challenging conditions (including simulations of environmental and personnel
monitoring).
• Review if aseptic operators are initially qualified and requalified thereafter.
• Determine if media fills are conducted semi-annually for each processing line or when process
changes occur. The activities and interventions representative of each shift should be included
in the semiannual 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. Except for
isolator operations, at least one semiannual media fill should be performed per line per shift.
Determine if the aseptic filling of all types of containers is 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.
26
FDA’s current expectations for media fills are discussed in Section IX.A of the guidance for industry Sterile Drug
Products Produced by Aseptic Processing—Current Good Manufacturing Process (October 2004).
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PROGRAM 7356.040
• Determine accountability of all filled units (units filled vs. units incubated).
• Determine if the firm takes appropriate actions for a failed media fill.
• 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). All
integral units should be incubated.
• Determine that any 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 qualified personnel.
ii. Sterile Filtration (Aseptic Processing)
If a drug product intended to be sterile is not terminally sterilized, the finished drug product should be
sterilized immediately before filling into the final product container. This is typically done by
filtration; however, other validated sterilization methods may be used. If a finished drug product
cannot be filtered (e.g., certain suspensions), components should be sterilized (e.g., by filter) at the
last possible step (e.g., before forming the suspension). Manipulations following the component
sterilization step must be designed to prevent microbial contamination of the drug product.
Inspection actions should include:
• Verify filters used in production are identical to those used in validation studies.
• Verify that actual operating parameters and allowable extremes (e.g., batch filtration volumes,
flow rate) are covered in the validation studies.
• Determine that validation of filter sterilization has been performed for all products.
• Observe filter integrity testing to verify procedures are followed.
• Review investigations of any integrity test failures.
iii. 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 contacts the sterile product
or sterile components. Check if the firm verifies that validated parameters (loading patterns, cycle
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PROGRAM 7356.040
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 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. For stoppers that are sterilized by steam sterilization, verify that
the clean steam used to provide the sterilization is acceptable and has been assayed for endotoxin.
Inspection actions should include:
• Review the practices and procedures to determine if the 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. 27
The microbiological content (bioburden) of articles and components that are subsequently sterilized
should be controlled. If materials are stored or held during processing (e.g., before sterilization, after
sterilization, before container fill), storage or holding times must be established. Production phase
hold times for a drug product should be limited, verified by testing, and based on an understanding of
the associated risk of increased bioburden and endotoxin. Hold time assessments can be performed as
part of the process for validating sterility assurance. In addition, in-process materials such as bulk
stock solutions must be stored in equipment that is protective and does not affect the quality of the
drug beyond its established specifications.
iv. Lyophilization
Inspection actions should include:
• 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 (at least daily) performed in the areas of
loading and unloading of the product from the lyophilizer. In addition, ensure personnel
27
It is important to note that increased bioburden can lead to sterilization/endotoxin failures as well as the degradation of
the drug product, contributing impurities to the drug product. Sampling points (location in process flow) and methods
should be evaluated based on product quality risks.
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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 these steps are done under proper environmental conditions (ISO 5) and to
verify that proper aseptic techniques are used.
v. Sealing of Vials
A vial is not completely 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.
vi. Terminal Sterilization
For sterile drug products that are terminally sterilized, at least a 10-6 sterility assurance level should
be demonstrated in validation studies during process development using an appropriate sterilization
load monitor, such as biological indicators and thermocouples. Validation studies should be
performed for each load size (container closure and number of vials) intended for sterilization. For
terminally sterilized drug products that are not subjected to an overkill terminal sterilization cycle,
pre-sterilization bioburden limits should be established (i.e., determining the number of
microorganisms that can be reliably killed) and measured before sterilization. Terminal sterilization
methods may include dry or moist heat, ionizing radiation, ethylene oxide (EtO) gas, or vaporized
hydrogen peroxide. The selected sterilization method should both sterilize and not have a deleterious
effect on the strength, purity, quality, and package integrity of the sterile product.
Inspection actions should include:
• 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.
• Review deviations or atypical data from sterilization operations that indicate inconsistencies
in process performance.
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vii. Parametric Release of Terminally Sterilized Drug Product
Parametric release is defined as a sterility assurance release program 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). The firm should have a sterility assurance
program in place that encompasses multiple, integrated CGMP systems that are in a state of control,
including (1) sterilization process validation and control, (2) verification by load monitor(s), (3) a
validated container closure system, and (4) an effective quality system. If using moist heat verify that
the conditions described in FDA’s Compliance Policy Guide Section 490.200, Parametric Release –
Drug Products Terminally Sterilized by Moist Heat, are met.
viii. Inspection of Injectable Products
This area covers 100% inspection of injectable products including: cracks in the primary container,
visible particles, and other significant defects. 28 Inspection actions should include:
• Verify the firm has written procedures that define the defects that cause a container to be
removed from the lot and actions to take if the number of defects exceeds a pre-determined
level. Types of defects should be comprehensive.
• 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 for pre-determined action levels.
• Evaluate the firm’s investigation into the cause of rejects, including units rejected for cracks
and visible particulates.
• Observe the inspection process, including product inspection, including visual inspection of
in-process or final product bulk solution, commercial product used for production, and
finished product.
• 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.
28
See the draft guidance for industry Inspection of Injectable Products for Visible Particulates (December 2021). When
final, this guidance will represent the FDA’s current thinking on this topic.
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− If a manual system is used, determine if employees are trained and qualified to verify
that they can recognize and remove defects under actual or simulated production
conditions.
− 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 containers and
evaluate the effectiveness of inspection and action taken if the reject level is reached.
• 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 performed where appropriate.
ix. Personnel (Gowning, Training, Aseptic Techniques)
The type of gowns and personal protective equipment worn by employees shall 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: 29
• For aseptic processing, determine whether 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.
29
See Section IX.A of the guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current Good
Manufacturing Process (October 2004) and the draft guidance for industry Current Good Manufacturing Practice—
Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020).
When final, this guidance will represent FDA’s current thinking on this topic. See also PDA Technical Report No. 28,
revised 2006, Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals, and PDA Technical Report No. 22,
revised 2011, Process Simulation for Aseptically Filled Products.
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• Verify the training is done on a continuing basis.
x. Batch Records
Master batch records should be comprehensive and thorough, with all process steps including in-
process controls accounted for. Production batch records must provide complete documentation of the
production of each batch of a drug product. The actual batch output (yield) must be compared to the
projected (calculated) output for each drug product. If the actual output is different than expected
after accounting for sampling and known process loss, this finding should be considered an indicator
of a potential problem with production and must be investigated. An acceptance level for actual
output should be established that ensures batch-to-batch consistency. Failure to meet the acceptance
criteria and production standards must be investigated before making the batch disposition decision
and may require that the batch be rejected. Inspection actions should include:
• 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.
(e) Packaging and Labeling System
Packaging of non-sterile and sterile drugs must be appropriate to the product and capable of ensuring
the integrity and sterility, if applicable, of the product until it is administered to a patient. Labels must
contain required information, and labeling operations must include controls to prevent mix-ups;
furthermore, procedures must be developed to ensure these requirements are met. The following
aspects of packaging and labeling are critical to ensure the quality of compounded drug products and
must be implemented by Outsourcing Facilities:
• The container, closure, and packaging systems provide adequate protection against
foreseeable external factors in storage, shipment, and use that could cause contamination or
deterioration of the finished drug product (e.g., cracked vials, leaks in bags). A container
closure integrity study may be required to ensure the container closure is suitable.
• Adequate controls should be established for issuing labels, examining issued labels, and
reconciliation of used labels to prevent mix-ups.
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• Controls are in place for maintaining adequate separation between the labeling and packaging
operations of different products, including ones with different strengths or containers or
closures, to prevent mix-ups.
• Adequate controls have been established to ensure proper identification of any filled
containers of non-sterile or sterile drug products that will be stored unlabeled for any period.
• Packaging records include results of examinations of all labels used and specimens of all
labeling used are retained as part of packaging records.
• The labeled finished drug product has been examined for accuracy before release.
For each of the following, the firm should have written and approved procedures and
documentation resulting therefrom. The firm's adherence to written procedures should be
verified through observation whenever possible. These areas may indicate deficiencies not only
in this system but also in other systems that would warrant expansion of coverage. When this
system is selected for coverage in addition to the quality system, all areas listed 30 below should
be covered:
• Training/qualification of personnel
• Acceptance operations for packaging and labeling materials
• Control system for implementing changes in packaging and labeling operations
• Adequate storage for labels and labeling, both approved and returned after issued
• Control of labels which are similar in size, shape, and color for different products
• Finished product cut labels for immediate containers which are similar in appearance without
some type of 100 percent electronic or visual verification system or the use of dedicated lines
• Gang printing of labels is not done, unless they are differentiated by size, shape, or color
• Control of filled unlabeled containers that are later labeled
• Adequate packaging records that include specimens of all labels used
• Control of issuance of labeling, examination of issued labels, and reconciliation of used labels
• Examination of the labeled finished product
• Adequate inspection (proofing) of incoming labeling
30
The depth of coverage may vary depending upon inspectional findings.
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• Use of lot numbers, destruction of excess labeling bearing lot/control numbers
• Physical/spatial separation between different labeling and packaging lines
• Monitoring of printing devices associated with manufacturing lines
• Line clearance, inspection, and documentation
• Adequate expiration / Beyond Use Date (BUD) dates on the label
• Validation of packaging and labeling operations including validation and security of
computerized processes
• Documented investigation into any unexpected discrepancy
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 or 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).
• The firm must have adequate controls to always ensure proper identification of unlabeled
product (e.g., when unlabeled components or unlabeled finished products are staged or stored
awaiting labeling or further processing, there should be a system in place to ensure product
mix-ups do not occur).
• 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.
(f) Laboratory Control System
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This system includes activities related to testing, analytical methods, laboratory procedures and the
stability program. 31 The principal objective of a laboratory control system is to ensure all testing and
laboratory control mechanisms are designed and followed to confirm drug products have the identity,
strength, quality, and purity they purport or are represented to possess. Whether using compendial or
alternative analytical testing methods, it is imperative that all methodologies have been demonstrated
to be suitable for the drug products for which the method is used as either a quantitative or qualitative
test or both. Whether a validated test or an established compendial test (compendial tests are
considered validated) is used, the test has been verified and documented. If using a validated or an
established compendial test procedure in a specification, the test has been verified and documented to
work under the conditions of actual use. The purpose of validation for a non-compendial method is to
ensure the method is suitable for its intended purpose and can produce valid results. When a method
is used for quantitation of drug components, accuracy, precision, specificity linearity, and range
should be established. For other determinative tests, limits of quantitation and detection may also
need to be established. All specifications, standards, sampling plans, and test procedures should be
scientifically sound and appropriate.
Each Outsourcing Facility is expected to have written and approved procedures, and documentation
for any specifications, standards, sampling plans, test procedures, or other laboratory control
mechanisms. The establishment’s adherence to written procedures should be verified through
observation whenever possible. These areas are not limited to finished products but may also
incorporate components and in-process materials. These areas may indicate deficiencies not only in
this system but also in other systems that would warrant expansion of coverage.
The inspectional evaluation of this system should include the following:
• Adequacy of staffing, equipment (including suitability), and facility, for all laboratory
operations conducted onsite.
• Calibration and maintenance programs for analytical instruments and supporting equipment
• Validation and security of computerized or automated processes
• Reference standards; source, qualification, storage (if not a compendial standard: purity and
assay, and tests to establish equivalency or superiority to current official reference standards
as appropriate)
31
USP General Chapter <51> Antimicrobial Effectiveness Testing, USP General Chapter <61> Microbial Examination of
Non-sterile Products, USP General Chapter <62> Microbial Enumeration of Non-sterile Products: Tests for Specified
Microorganisms, USP General Chapter <71> Sterility Test, USP General Chapter <788> Particulate Matter in Injections,
USP General Chapter <789> Particulate Matter in Ophthalmic Solutions, USP General Chapter <790> Visible
Particulates in Injections, USP General Chapter <771> Ophthalmic Products—Quality Tests, USP General Chapter
<1207> Package Integrity Evaluation—Sterile Products, Pyrogens and Endotoxins Testing
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• System suitability checks on chromatographic systems (e.g., Gas Chromatography or High-
Performance Liquid Chromatography) and other systems (e.g., Fourier Transform Infrared
Spectroscopy) where appropriate
• Specifications, standards, and representative sampling plans
• Adherence to the written methods of analysis for each test, and all results documented
• Validation and verification of analytical methods
• For compendial methods, documentation that the test was verified under the conditions of
actual use
• For analytical methods validated at another site, method transfers are conducted to ensure
accurate transfer of the development, qualification, and operating parameters for the method
• Control system for implementing changes in laboratory operations
• Unauthorized access and unauthorized modification of all systems and data
• Sample identified uniquely, and chain of custody maintained and documented
• Complete analytical records from all tests performed to ensure compliance with established
specifications and standards, including examinations and assays along with summaries of
results
• Quality and retention of raw data (e.g., chromatograms and spectra)
• Data integrity controls (i.e., audit trails, controlled documents, methods, procedures,
worksheets, and lab notebooks)
• Correlation of result summaries to raw data; preservation of unused data
• Adherence to an adequate OOS procedure which includes timely completion of the
investigation
• Adequate reserve samples 32; documentation of reserve sample examination
• Stability testing program (including demonstration of stability-indicating capability of the test
methods utilized to establish stability of drug product and all relevant product quality
attributes)
See the draft guidance for industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding
32
Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020). When final, this guidance will represent
FDA’s current thinking on this topic.
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• Documented investigation into any unexpected discrepancy
• Training/qualification of personnel
i. Release Testing
Appropriate specifications must be established for each drug product either by following compendial
monographs, or if no monograph is applicable, through scientifically sound and appropriate
evaluation. Established specifications should address those attributes necessary to ensure the quality
of the finished drug product. Generally, these include, where applicable: identity, purity, color clarity,
pH, content uniformity, and microbial testing. Additionally, for sterile products, sterility testing is a
CGMP requirement, and bacterial endotoxins and particulate testing may also be applicable.
However, specifications for bacterial endotoxins and particulates are dependent on the intended
dosage form of the finished drug product as well as the intended route of administration. Testing of
other quality attributes (for example: disintegration and dissolution-testing) may be necessary
depending on the dosage form. Where a compendial monograph is applicable, other special tests and
specifications may apply such as impurity testing. FDA has stated through published guidance certain
regulatory exemptions regarding certain release testing requirements. 33
Where appropriate, drug products containing antimicrobial preservatives or antimicrobial agents
(self-preserving) should be evaluated for antimicrobial effectiveness - See USP General Chapter
<51> Antimicrobial Effectiveness Testing for more information. Alternatively, other studies or
testing may be acceptable in lieu of a full antimicrobial effectiveness study. 34
ii. Stability
An appropriate stability program must be established for all marketed drug products to assess the
stability characteristics of each finished drug product and the results of such testing used to determine
storage conditions and expiration dates (or BUD) to ensure the drug product will retain its quality and
remain sterile through the labeled expiration date.
Because some compounded drugs produced by Outsourcing Facilities have small batch sizes and less
frequency of production than approved drug products, FDA generally does not intend to take
regulatory action regarding certain requirements with respect to certain CGMP requirements in parts
210 and 211 regarding stability testing. 35
33
See the draft guidance for industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020). When final, this guidance will represent
FDA’s current thinking on this topic.
34
See the draft guidance for industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020). When final, this guidance will represent
FDA’s current thinking on this topic.
35
See the draft guidance for industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the FD&C Act (January 2020). When final, this guidance will represent
FDA’s current thinking on this topic. For more information on repackaged drugs by Outsourcing Facilities see the
guidance for industry Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities (January
2017).
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However, in the case of no stability studies or reduced testing for products that meet certain criteria, a
container closure integrity test should still be used to establish the integrity of the container closure
system and the sterility of the product over the labeled shelf life. Additionally, for products labeled as
multidose, specifications that assure that the product is adequately self-preserving, or for products
containing antimicrobial preservatives, antimicrobial effectiveness testing is performed to ensure
antimicrobial activity is effective over the labeled shelf life.
iii. Contract Testing Laboratory
If contract testing laboratories are utilized by an Outsourcing Facility to perform drug testing (or any
components and in-process materials), all or in part, the Outsourcing Facility’s quality control unit is
responsible for approving and rejecting drugs tested by the contractor. Also, the contract testing lab
should be qualified by the Outsourcing Facility prior to relying on the services of the contract lab.
The Outsourcing Facility is responsible for ensuring the contract testing laboratory conforms to
CGMP. The contract testing laboratory should have documentation that whether using compendial or
alternative analytical testing methods, all methodologies have been demonstrated to be suitable for
the drug products for which the method is used. Whether a validated test or an established
compendial test is used, the test has been verified and documented, as appropriate. The following
should be evaluated when a contract lab is utilized:
• Sharing of reports of analysis, investigations, and laboratory discrepancies.
• A system for notification of OOS results (e.g., electronic notification, autogenerated or
manual), timeliness of notification of OOS; laboratory investigations reviewed before OOSs
are invalidated.
• Routine auditing to ensure the contract testing lab remains in a controlled state in accordance
with CGMP.
• Designation of all relevant responsibilities (the Outsourcing Facility’s quality control unit
should be responsible for final release or rejection).
B. Sampling
Samples may be collected to document suspected contamination, adulteration, or misbranding
encountered during an inspection. Official samples may consist of finished drug product, raw
materials, and/or components. Official samples are not necessary to document a 501(a)(2)(A) or
501(a)(2)(B) adulteration charge. Documentary samples may be submitted when the documentation
illustrates the deficiencies and to obtain evidence of interstate shipment. OII divisions may elect to
collect, but not analyze, physical samples, or to collect documentary samples to document CGMP
deficiencies. Physical sample analysis is not necessary to document CGMP deficiencies. If the
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Division believes that either official samples or environmental monitoring sampling are warranted,
please contact CDER/OC/OCQC/DCI. 36
C. Inspection Teams
An inspection team (see IOM section 5.2.8 – Team Inspections) composed of experts from within OII
Divisions, or Headquarters is encouraged when it provides needed expertise and experience. If
technical assistance is needed, contact OII Compounding. OII leads the inspection with CDER
participation when requested. Each inspection team member is responsible for preparing for,
executing, and documenting the inspection, including contributing to the establishment inspection
report, which documents the items covered during the inspection, within established timeframes.
Reporting
If OII observes critical conditions (e.g., those which may result in an imminent health hazard), as
appropriate and if feasible, they can be discussed between OII and CDER/OCQC before the
inspection closes. The OII management representative or designee, the investigator(s), and
CDER/OCQC collaboratively decide whether to continue the inspection to gather additional
information or to close the inspection to initiate prompt regulatory action.
The investigator will utilize IOM Subchapter 5.7 – Reporting for guidance in reporting of
inspectional findings. Identify systems covered in the Summary of Findings. Report and discuss in
full any adverse findings by systems under separate captions. Add additional information as needed
or desired, for example, a description of any significant changes that have occurred since previous
inspections. Each report should include a description of operations, products, and controls covered
during the inspection in sufficient detail to enable appropriate regulatory decision-making following
the inspection and to inform future inspections.
36
For sampling guidance, refer to IOM, Chapter 4 – Sampling.
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PART IV—ANALYTICAL
Analyzing Laboratories
The types of analyses that may be performed under this program include (but are not limited to):
• Routine analyses: Assay, Impurities, Dissolution, Identification
• Routine microbiological analyses: Sterility, Endotoxin, Non-sterile examination
• Other microbiological examinations
• Particulate Matter in Injectables
Email OCS/OARL at [email protected] for servicing laboratories for
chemical and microbiological testing. When contacting OARL for servicing laboratories, provide a
product description, lots to be tested, analyses to be performed, and a reason for the sample
collection. Servicing laboratories will be identified based on lab specialization, technology and
testing expertise, and laboratory capacity.
Note: The Laboratory Servicing Table Dashboard is not sufficiently detailed to accurately identify
laboratories and should not be used for selecting servicing laboratories under this compliance
program.
Analyses to be Conducted
Samples are to be examined for compliance with applicable specifications as they relate to
deficiencies noted during the inspection. All analyses will be performed by the official regulatory
methods, or when no official method exists, by other validated procedures identified by OCS/OARL.
• The presence of cross-contamination must be confirmed by a mass spectroscopic method.
• Ensure the analysis for the dissolution rate is performed by a second dissolution-testing
laboratory.
• Microbiological examinations should be based on appropriate sections of USP and
Pharmaceutical Microbiology Manual.
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PROGRAM 73000.000
PART V—REGULATORY/ADMINISTRATIVE STRATEGY
Inspection findings that demonstrate that a firm is not operating in a state of control may be used as
evidence for taking appropriate advisory, administrative, and/or judicial actions. The initial
classification should be based on the OII’s assessment of the significance of the CGMP deficiencies.
The endorsement of the inspection report should point out the actions by the firm that have been
taken or will be taken and when. All deficiencies noted in inspections under this program must be
addressed by stating the firm's corrective actions, accomplished or projected, for each, as established
in the discussion with management at the close of the inspection.
All corrective actions proposed by firms are monitored and managed collaboratively by OCQC.
These approaches may range from shut down of operations, recall of products, conducting testing
programs, development of new procedures, modifications of facilities and equipment, to simple
immediate corrections of conditions. If an inspection report documents that one or more systems at
the establishment is/are out of control, the inspection should receive an initial OAI classification.
Requests and review of records, documents, and other information from RRA activities may reveal
potentially violative practices. In such cases, OCQC’s evaluation of an OAI recommendation will use
approaches aligned with those discussed in this section during review of the case.
FDA laboratory tests that demonstrate effects of absent or inadequate CGMP are strong evidence for
supporting regulatory actions. Such evidence development should be considered as an inspection
progresses and deficiencies are found. However, the lack of violative physical samples is not a barrier
to pursuing regulatory or administrative action provided that CGMP deficiencies have been well
documented. Likewise, physical samples found to comply are not a barrier to pursuing action under
CGMP charges.
Evidence to support significant deficiencies or a trend of deficiencies within a system covered could
demonstrate system failure and should result in an OAI referral to OCQC. When deciding the type of
action to recommend, the initial decision should be based on the seriousness or frequency of the
problems.
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PART VI—REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS
References
A. Code of Federal Regulations, Title 21
• 21 CFR Part 210
• 21 CFR Part 211
B. Compliance Programs
• CP 7356.002—Drug Manufacturing Inspections.
• CP 7356.002A—Sterile Drug Process Inspections
• CP 7356.021—Drug Quality Reporting System (DQRS) (MedWatch Reports); NDA Field
Alert Reports
C. FDA Guidances
• Guidance for industry Sterile Drug Products Produced by Aseptic Processing—Current
Good Manufacturing Process (October 2004)
• Guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations
(October 2006)
• Draft guidance for industry Current Good Manufacturing Practice—Guidance for Human
Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act
(January 2020) 37
• Draft guidance for industry Inspection of Injectable Products for Visible Particulates
(December 2021) 38
D. ICH Guidances
• ICH guidance for industry Q9(R1) Quality Risk Management (May 2023)
• ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009)
E. Other Procedures and References
• Investigations Operations Manual, section 5. 1.2−Inspectional Approach
• Investigations Operations Manual, Chapter 5, Section 5.5.10 – Reports of Observations for
further guidance on the content of Inspectional Observations.
• Inspection Guide, Lyophilization of Parenteral (7/93)
• ISO 14698 Cleanrooms and Associated Controlled Environments Biocontamination
Control
37
When final, guidance will represent FDA’s current thinking on this topic.
38
When final, guidance will represent FDA’s current thinking on this topic.
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• PDA Technical Report No. 1 (Revised 2007) Validation of Moist Heat Sterilization
Processes: Cycle Design, Development, Qualification and Ongoing Control; and ISO
17665 Moist Heat Sterilization.
• PDA Technical Report 51 (2010), Biological Indicators for Gas and Vapor Phase
Decontamination Processes: Specifications, Manufacture, Control and Use.
• RABS for Aseptic Processing, ISPE (August 2005).
Attachment
• Attachment A: Examples of Indicators of an Advanced Quality System
Program Contacts
A. For Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence needed and sufficiency, citations, and
inspection endorsement advice, please send an email to the following address:
[email protected]
B. For 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 :
[email protected] with a copy to [email protected].
Acronyms
API: Active Pharmaceutical Ingredient OARL: Office of Analytical and Regulatory
Laboratories
CMS: Compliance Management System
OC: Office of Compliance
DQRS: Drug Quality Reporting System
OCS: Office of the Chief Scientist
CAPA: Corrective Action and Preventive
Action OII: Office of Inspections and Investigations
EIR: Establishment Inspection Report OMQ: Office of Manufacturing Quality
CDER: Center for Drug Evaluation and OOS: Out-of-Specification
Research OPMA: Office of Pharmaceutical
FAR: Field Alert Report Manufacturing Assessment
CGMP: Current Good Manufacturing Practice OPQ: Office of Pharmaceutical Quality
FMD: Field Management Directive PAC: Product/Assignment Code
ICH: International Council for Harmonisation PET: Positron Emission Tomography
IOM: Investigations Operations Manual PQS: Pharmaceutical Quality System
NAI: No Action Indicated RRA: Remote Regulatory Assessments
OAI: Official Action Indicated RIE: Remote Interactive Evaluation
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SOP: Standard Operating Procedure VAI: Voluntary Action Indicated
USP: United States Pharmacopeia
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PART VII—CDER AND OII RESPONSIBILITIES OVERVIEW
CDER and OII roles and responsibilities for surveillance and surveillance-related for-cause
inspections subject to this compliance program are summarized below.
Surveillance Inspection Responsibilities
Once an Outsourcing Facility is registered with FDA, the facility will be added to the list of facilities
FDA intends to inspect according to a risk-based schedule. In accordance with this compliance
program, OII schedules and leads surveillance inspections of Outsourcing Facilities, with CDER
participation as appropriate. OII will conduct an assessment to review the facts before determining an
initial classification. CDER will conduct a compliance assessment to review the facts before
progressing with any regulatory action per established procedures. Typically, the assessment will be
based upon review of the Form FDA 483, and other pertinent exhibits and documents. The review of
information requested to be collected under this compliance program may identify additional
violations not documented on the Form FDA 483.
Reinspection Responsibilities
Requests for reinspections are initiated by OCQC. Once OCQC determines a reinspection is
warranted, the office prepares an assignment memo that sets forth the areas of required coverage,
which may include surveillance program coverage. OII reviews the assignment, and if accepted,
schedules the inspection. OII leads establishment reinspections with CDER participation, as
appropriate.
OII will conduct an assessment to review the facts before determining an initial classification. CDER
will conduct a compliance assessment to review the facts before progressing with any regulatory
action per established procedures. Typically, the assessment will be based upon review of the Form
FDA 483, and other pertinent exhibits and documents. The review of information requested to be
collected under this compliance program may identify additional violations not documented on the
Form FDA 483.
For-Cause Inspection Responsibilities
Requests for for-cause inspections are initiated by OCQC. Once the OCQC determines a for-cause
inspection is warranted, the office prepares an assignment that sets forth the areas of required
coverage, which may or may not include surveillance program coverage. OII reviews the assignment,
and if accepted, schedules the inspection. OII leads for-cause inspections with OCQC participation,
as appropriate.
OII will conduct an assessment to review the facts before determining an initial classification. CDER
will conduct a compliance assessment to review the facts before progressing with any regulatory
action per established procedures. Typically, the assessment will be based upon review of the Form
FDA 483, and other pertinent exhibits and documents. The review of information requested to be
collected under this compliance program may identify additional violations not documented on the
Form FDA 483.
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第 53 页
PROGRAM 7356.040
ATTACHMENT A—EXAMPLES OF INDICATORS OF AN ADVANCED QUALITY
SYSTEM
Outsourcing Facilities can demonstrate practices that are indicative of mature quality practices that, if
effectively implemented, provide the foundation for exceeding CGMP requirements. Examples may
include a steadfast focus on implementing continual improvements, using the latest innovations to
enhance control, and creating a culture of quality where leadership demonstrates a commitment to
quality and promotes employee engagement and empowerment. Indicators of a more advanced
quality system may inform FDA’s risk-based approach to plan Outsourcing Facility inspections.
During an inspection, investigators may assess quality management practices to gain insight into an
establishment’s processes and continual system improvements. The areas below are examples of
indicators of an advanced quality system, some of which may be evaluated during an inspection.
Management Responsibility
• Communication and reward system for employees to bring quality issues to the attention of
management.
• Monitoring of external regulatory and business environments to identify unexpected risks to
quality.
• Increased levels of personnel understanding, ownership, and engagement that create
company-wide quality commitment.
• All personnel trained on the impact of poor quality on the patient.
Investigations
• Effective use of standardized tools to determine a potential root cause.
Corrective Actions and Preventive Actions
• Routine production and laboratory “shop floor” meetings (e.g., weekly) to collect employee
feedback, reduce operational risks, and ensure initiation of corrective actions and preventive
actions.
Supply Chain and Contracted Service Management
• Consistently meeting planned time frames for product delivery to the customer or internal
stock because of high manufacturing robustness (i.e., avoiding delays caused by
manufacturing quality problems)
• Active solicitation and analysis of customer feedback (beyond solely complaints) related to
quality and delivery.
Training Program
• Extensive staff training on Six Sigma and/or other advanced quality assurance tools to
improve process capability.
Quality Oversight
• Electronic systems that use analytics to optimize implementation of knowledge management
related to products, processes, and components.
Date of Issuance: 01/15/2025 Page 53 of 54
第 54 页
PROGRAM 7356.040
• Continual improvement program to optimize quality indicator metrics.
Process Parameters, Product Quality Monitoring, and Annual Product Review
• Programs to improve manufacturing processes by adopting the latest beneficial innovations and
technologies.
• Use of visuals throughout the establishment to indicate quality performance status.
Date of Issuance: 01/15/2025 Page 54 of 54
来源：FDA Pharmaceutical Quality Documents · fda.gov