FDA 发布人用药品与生物制品容器密封系统指南草案
FDA Draft: Container Closure Systems for Human Drugs and Biological Products
FDA 发布《人用药品与生物制品容器密封系统》指南草案征求意见，意见应在联邦公报发布可及性通知后 90 天内提交。草案以风险为基础框架，涉及包装材料安全性、保护、性能、生产工艺影响及储存和处理，并按吸入、鼻用、注射、透皮和透黏膜等给药途径与剂型列出包装关注程度。
草案给出容器密封系统的风险分级框架及常见剂型关注点，可帮助读者对照评估现有包装材料与提交资料。
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FDA 指南：人用药品和生物制品的容器密封系统
状态：草案。草案——不得用于实施；发布以征求意见。
FDA 目录发布日期：2026-08-13（源文件中为 MM/DD/YYYY）。
目录修改时间保留在源元数据中；它不是新的发布日期，也不能证明 PDF 已被修订。
产品：药品
主题：化学、制造和控制（CMC）、药品质量
发布办公室：药物评价与研究中心、生物制品评价与研究中心
文件类型：指南文件
官方详情页：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-human-drugs-and-biological-products
范围：来自 FDA 全机构目录的公开指南 PDF，明确标记为药品/生物制品及生产/质量/ICH-质量。完整 PDF 如下。
PDF 文字版；图形和原始排版请参阅官方 PDF。
第 1 页
人用药品和生物制品的
容器密闭系统
行业指南
草案指南
草案指南
本指南文件仅为征求意见目的分发。
关于本草案文件的意见和建议应在《联邦公报》发布宣布该草案指南可获取的通知后90天内提交。
电子意见请提交至 https://www.regulations.gov。书面意见请提交至 Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852。所有意见均应注明在《联邦公报》上发布的
可获取通知中列出的案卷编号。
关于本草案文件的问题，请联系 (CDER) [email protected]；
(CBER) Office of Communication, Outreach and Development，800-835-4709 或 240-402-8010；
或 (OCP) [email protected]。
美国卫生与公众服务部
食品药品管理局
药品评价与研究中心 (CDER)
生物制品评价与研究中心 (CBER)
组合产品办公室 (OCP)
2026年8月
药品质量/CMC
第 2 页
人用药品和生物制品
容器密闭系统
行业指南
更多副本可从以下地址获取：
通讯办公室，药品信息处
药品评价与研究中心
美国食品药品监督管理局
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
电话：855-543-3784 或 301-796-3400；传真：301-431-6353
电子邮件：[email protected]
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
和/或
通讯、外联与发展办公室
生物制品评价与研究中心
美国食品药品监督管理局
电话：800-835-4709 或 240-402-8010
电子邮件：[email protected]
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
和/或
组合产品办公室
美国食品药品监督管理局
10903 New Hampshire Ave., WO32, Hub/Mail Room #5129
Silver Spring, MD 20993
电话：301-796-8930；传真：301-847-8619
电子邮件：[email protected]
https://www.fda.gov/combination-products/guidance-regulatory-information/combination-products-guidance-documents
美国卫生与公众服务部
美国食品药品监督管理局
药品评价与研究中心（CDER）
生物制品评价与研究中心（CBER）
组合产品办公室（OCP）
2026年8月
药品质量/CMC
第 3 页
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目录
I. 引言............................................................................................................. 1
II. 范围 ............................................................................................................................... 2
III. 背景 ............................................................................................................... 3
A. 法定与监管权限 ............................................................................................ 4
B. 药典要求 ............................................................................................................ 5
C. 组合产品 ................................................................................................................... 5
IV. 基于风险的框架：需考虑的因素 ..................................... 6
A. 一般考虑 ................................................................................................................. 6
1. 包装材料的安全性 ......................................................................................................... 6
2. 保护......................................................................................................................................... 7
3. 性能..................................................................................................................................... 7
4. 生产工艺的影响 .................................................................................................. 8
5. 贮存与处理 ...................................................................................................................... 8
B. 药品常见剂型的风险考虑 ........................................................................ 8
1. 吸入产品 ....................................................................................................................... 10
2. 鼻用产品 ....................................................................................................................... 11
3. 注射用药品............................................................................................................... 11
4. 经皮和经黏膜给药系统 ........................................................................ 12
5. 局部皮肤用药品 ..................................................................................................... 12
6. 眼用和耳用产品 ...................................................................................................... 13
7. 口服药品 ....................................................................................................................... 13
V. 质量评估与控制.............................................................. 14
A. CCS 的典型质量评估与控制 ................................................................. 15
1. 描述..................................................................................................................................... 16
2. 适用性评价..................................................................................................................... 17
3. 质量控制 .............................................................................................................................. 22
4. 稳定性试验 ............................................................................................................................. 22
5. 运输、处理和贮存的附加试验 .................................................................. 23
B. 特定包装组件的特殊考虑 ............................................... 24
1. 次级包装组件................................................................................................ 24
2. 辅助包装组件.................................................................................................. 25
3. 组合产品器械组成部分的包装组件 ......................... 25
C. 大容量容器的建议 ..................................................................................... 27
i
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VI. 特定申请类型中提交的 CCS 信息 ....... 27
A. 上市申请 ............................................................................................................... 28
B. 研究性申请 ........................................................................................................ 29
C. 主文件 .................................................................................................................................. 30
VII. 向 CCS 报告批准后变更 ........................................ 30
术语表................................................................................................................................. 32
ii
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1 人用药物和生物制品的容器密封系统
2 产品
3 行业指南 1
4
5
6 本指南草案在定稿后，将代表美国食品药品监督管理局
7 （FDA 或本局）对该主题的当前思考。它不为任何人确立任何权利，
8 对 FDA 或公众均不具有约束力。如果替代方法满足
9 适用法规和规章的要求，你可以使用替代方法。如需讨论替代方法，
10 请按标题页所列联系方式联系负责本指南的 FDA 工作人员。
11
12
13
14 I. 引言
15
16 本文件提供了用于评估人用药物和生物制品包装所用容器密封
17 系统（CCS）2 的质量的指导原则 3。这包括
18 同时作为组合产品器械组成部分的 CCS，以及用于包装
19 组合产品中药物或生物制品组成部分的 CCS。4 具体而言，本
20 指南讨论了 FDA 当前关于如何根据基于风险的
21 框架评估 CCS 的思考，该框架包括包装材料和
22 组件的质量评估和质量控制。5 定稿后，本指南将取代行业指南《用于包装人用药物和生物制品的容器
23 密封系统》（1999 年 5 月）和《用于包装人用药物和生物制品的容器密封
24 系统 — 问答》（2002 年 5 月）。6
25 FDA 打算通过其他指南补充本指南，以针对本指南所述一般信息提供特定主题
26 建议。这些特定主题
27 指南将涉及评估和表征新型 CCS 的相关方法，并
28 提供有关特定质量属性和检测要求的信息，包括
1
本指南由药品评价与研究中心药品质量办公室
与生物制品评价与研究中心、器械与放射健康中心、
监管事务办公室（现称为检查与调查办公室）以及
美国食品药品监督管理局局长办公室组合产品办公室合作编写。
2
本指南不建议具体检测方法或接受标准（提及《美国
药典》方法除外），也不建议全面的检测清单。这些细节应
根据针对特定药品制剂、剂型和给药途径的每个具体容器密封系统的
良好科学原则确定。接受标准应基于特定包装
组件和容器密封系统的数据。
3
首次提及时以粗体显示的术语在术语表中定义。
4
参见 21 CFR 3.2(e) 和 21 CFR 4.2。如果你对 CCS 是否属于器械以及你的产品
因此是否属于组合产品有疑问，请联系组合产品办公室 [email protected]
寻求帮助。
5
FDA 通过采取适当行动解决潜在药品短缺的根本原因并提高产品
可及性来应对潜在药品短缺。当药品短缺由质量问题引起，包括涉及
CCS 的问题时，FDA 会与企业合作解决问题。有关药品短缺信息和报告，参见
https://www.fda.gov/drugs/drug-shortages/frequently-asked-questions-about-drug-shortages。
6
我们会定期更新指南。如需指南的最新版本，请查看 FDA 指南网页
https://www.fda.gov/regulatory-information/search-fda-guidance-documents。
1
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29 可提取物和浸出物评估及相关毒理学风险
30 评估的考虑因素。
31
32 一般而言，FDA 的指南文件不确立具有法律强制执行力的责任。
33 相反，指南描述的是本机构对某一主题的当前思考，应仅
34 视为建议，除非引用了具体的监管或法定要求。在
35 本机构指南中使用 should 一词，意味着某事是被建议或推荐的，但
36 并非必需。
37
38
39 II. 范围
40
41 本指南就用于人用药品和生物制品的 CCS 的药品质量考虑因素（例如，
42 化学、生产和控制（CMC））提供建议。7 它讨论了用于
43 药品8和原料药的 CCS 的开发
44 和评估的一般原则和具体考虑因素。它还适用于作为
45 组合产品器械组成部分的 CCS，或用于盛装这些产品中
46 药品或生物制品组成部分的 CCS。9 尽管本指南的范围不包括
47 独立器械，且其重点在于包装药品或生物制品的 CCS，本指南中
48 所述的一些建议也可能适用于旨在
49 递送药品的独立器械。10
50
51 本指南适用于申请11，包括对已批准
52 申请的修订和补充，适用于人用药品和生物制品，以及组合产品。它
53 也适用于根据《联邦食品、药品和化妆品法》第 505G 节合法上市的药品，
7
就本指南而言，术语 drug 指原料药和药品，包括生物
制品。生物制品指《公共卫生服务法》第 351(i)(1) 节所定义并根据
该法第 351(a) 或 (k) 节须获得许可的产品。在本指南中，drug 也包括组合产品的
药品或生物制品组成部分。
8
就本指南而言，药品指任何制成最终剂型的药品。
9
根据 21 CFR 3.4，组合产品被分配给对该组合产品上市前
审评和监管拥有主要管辖权的机构中心。药品或生物制品
组成部分可以是 CDER、CBER 或 CDRH 主导的组合产品的一部分。由作为药品或生物制品组成部分 CCS 的
器械组成部分构成的组合产品通常
分配给 CDER 或 CBER。
10
关于这些建议是否适用于特定器械的问题，应在开发过程中与
CDRH 或 CBER 审评部门讨论。在本指南中，术语 device 具有
《联邦食品、药品和化妆品法》第 201(h) 节（21 U.S.C. 321(h)）所赋予的含义。
11
就本指南而言，术语 application 指研究性新药申请、新药
申请、简化新药申请和生物制品许可申请。它也包括研究性
器械豁免申请、上市前批准申请、De Novo 请求和上市前通知（分别如
《联邦食品、药品和化妆品法》第 515、513(f)(2) 和 510(k) 节所述（21 U.S.C. 360e、
360c(f)(2) 和 360(k)）），适用于本指南涵盖的组合产品。
2
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54 FD&C 法案）12，且未根据 FD&C 法案第 505 条获得批准申请
55 FD&C 法案。13,14
56
57 本指南无意涉及与药品生产相关的包装操作（例如，灌装、
58 包装和贴标过程）。
59
60 本指南不涵盖防儿童开启包装的标准和建议。
61 根据 1970 年《防毒包装法》（PPPA）15 发布的法规确立了
62 防儿童开启包装的标准和测试程序。16 对于在产品标签中提出防儿童
63 开启包装声明的申请，申请人应遵循
64 行业指南《药品标签中的防儿童开启包装声明》（2019 年 8 月）中的
65 建议，其中包括向 FDA 提交书面验证，证明
66 该药品的防儿童开启包装符合 16 CFR 第 1700 部分的标准。
67
68
69 III. 背景
70
71 CCS 是共同容纳和保护药品的包装组件总和。它包括
72 初级包装组件，如果次级包装
73 组件的目的是进一步保护药品，则也包括次级包装组件。CCS 必须在
74 储存和使用中提供充分保护，且不得改变药品的安全性、鉴别、强度、质量或纯度
75 超出官方或既定要求。17 例如，包装组件
76 应采用不会浸出患者可能直接或间接接触到的有害或不良量
77 物质的材料制成。
78
79 近年来，新型药品和新容器密封技术的发展
80 推动了 CCS 在设计、构造和评估方面的进步。例如，
81 药物疗法的技术进步可为 CCS 引入额外的功能性
82 用途，例如使用 CCS 配制最终剂型或递送
83 产品的产品。在此类情况下，应实施额外的控制措施和检测，以确保
84 CCS 的额外功能不会对产品的安全性、鉴别、强度、
85 质量和纯度产生不利影响。
86
87 为适应 CCS 在设计、构造和评估方面的进步，若干
12
见 21 U.S.C. 355h。
13
见 21 U.S.C. 355。
14
根据 FD&C 法案第 505G 条上市的药品还必须符合非处方药的
一般要求，其中包括这些药品仅含有安全且合适的非活性
成分，并按照现行药品生产质量管理规范生产。制造商有责任
遵守这些要求，并在其文件中记录和保存支持性数据。
15
PPPA 下的权力依据《消费品安全法》第 30(a) 条授予
消费品安全委员会。特殊包装的定义见 15 U.S.C. 1471(4)、16 CFR 1700.1(b)(4) 和 21
CFR 310.3(l)。根据 PPPA 发布的法规确立了性能标准和测试方法，用于确定
包装系统是否防儿童开启且对成人使用有效（16 CFR 1700.15 和 16 CFR 1700.20）。本指南中讨论的向 FDA 提交的书面
验证，不同于根据 15 U.S.C. 2063 和 16 CFR 1110 要求向
消费品安全委员会提供的认证。
16
见 16 CFR 第 1700 部分。
17
见 21 CFR 211.84 和 211.94。
3
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88 《美国药典》和《国家处方集》（USP-NF）中的各通用章节
89 提供了与药品储存和流通相关的新信息或更新信息，
90 包括更全面、更先进的检测，以表征包装
91 材料和组件。自1999年发布行业指南《人用药品和生物制品
92 容器密封系统》以来，其他FDA和国际人用药品技术要求协调理事会（ICH）
93 指南 18,19 也相继发布，其中概述了与CCS评估相关的具体建议。
94
95
96 A. 法定和监管权限
97
98 《联邦食品、药品和化妆品法案》（FD&C Act）包含针对药品的包装要求。如果药品
99 的“容器全部或部分由任何有毒或有害物质构成，而该物质可能使内容物
100 危害健康”，则该药品被视为掺假（见第501(a)(3)条 20）。如果药品
101 生产、加工、包装或保存所使用的方法、设施或控制不符合、
102 或未按照现行药品生产质量管理规范（CGMP，见第501(a)(2)(B)条 21）运行或管理，
103 则该药品同样被视为掺假。此外，根据
104 第502条 22，如果药品的包装（包括标签）不符合该法案规定的
105 其他要求，则该药品被视为贴错标签。申请必须包含
106 21 CFR 314.50(d)(1)中针对新药申请所述的生产和包装程序说明，
107 21 CFR 314.94(a)(9)中针对简化新药申请，以及21 CFR
108 601.2中针对生物制品许可申请。对于在
109 适当器械申请中审评的以器械为主导的组合产品，上述此类说明属于通常
110 支持组合产品安全性和有效性所必需的信息类型
111 。 23 对于所有药品和组合产品，证明
112 CCS符合CGMP的信息（例如21 CFR 4 A子部分、21 CFR 211 E子部分、
113 21 CFR 820） 24 必须在检查时或根据FD&C Act第704(a)(4)条
114 提出要求时可供查阅。
115
18
例如，参见行业指南《鼻喷雾剂和吸入溶液、混悬液及喷雾药品——化学、生产和控制文件》（2002年7月）。另见行业指南草案《透皮和局部给药系统——产品开发和质量考量》
（2019年11月）。该指南定稿后，将代表FDA对该主题的当前思考。
19
例如，参见ICH行业指南Q8(R2)《药品研发》（2009年11月）。
20
见21 U.S.C. 351(a)(3)。
21
见21 U.S.C. 351(a)(2)(B)。
22
见21 U.S.C. 352。
23
如行业和FDA工作人员指南《组合产品上市前路径原则》（2022年1月）所述，在确定证明组合产品安全性和有效性所需内容时，FDA在将组合产品作为一个整体及其各组成部分进行审评时，会考虑与各组成部分相关的法定和监管条款所反映的问题和考量。这包括各组成部分可能如何相互作用和相互关联。例如，对于在适当器械申请中审评的、包含药物组成部分（否则将在NDA中审评）的以器械为主导的组合产品，非临床药理学和毒理学以及临床药理学（包括药代动力学）数据和化学、生产和控制（CMC）信息属于通常必需的信息类型。
24
2024年2月2日，FDA发布了一项最终规则，修订器械质量体系法规21 CFR 820，以更贴近器械的国际共识标准，并对21 CFR第4部分作出了相应修订（89 FR 7496，见https://www.federalregister.gov/d/2024-01709）。该最终规则
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116 B. 药典要求
117
118 《联邦食品、药品和化妆品法案》（FD&C Act）第 201(j) 条 25 承认 USP-NF 为美国的法定药典。
119 根据 FD&C Act 第 501(b) 条，26 如果某药品声称是或标示为 USP-NF 中已收载名称的药品，
120 而其规格与药典规定不同，或其质量和纯度低于药典规定的标准，则该药品被视为掺假。
121 根据 FD&C Act 第 502(g) 条，27 名称已收载于 USP-NF 的药品，
122 除非其包装和标签符合药典所述，否则被视为贴错标签。
123 USP-NF 官方各论、通则或一般公告中收载物品的标准适用于该物品的整个生命周期（从生产到有效期）。
124 USP 各通则规定了构建材料（MOC）、
125 组件和 CCS 的各项要求。对于新标准或新修订标准，
126 除发布时另有规定外，USP 允许、且 FDA 通常鼓励在正式日期之前提前采用修订后的标准。28
127
128 C. 组合产品
129
130 组合产品是由两种或多种类型的医疗产品（即药品与器械、药品与生物制品、器械与生物制品，或三者兼有）
131 组成的人用医疗产品。29 组合产品中所包含的药品、器械和生物制品
132 被称为组合产品的组成部分。如果 CCS 具有一种以上功能（例如，既作为容器密封件，又用于
133 输送药品），则其也可能成为器械组成部分。可能同时作为组合产品器械组成部分的 CCS 示例
134 包括活塞式注射器、泵、定量吸入器（MDI）和静脉输液袋。
135 组合产品会引发额外的上市前审查考量，例如涉及
136 器械性能、工程学和用户界面，所有这些都可能受到
137 器械与其所盛装的药品或生物制品之间相互作用（例如吸附）的影响。30
138 组合产品还须遵守额外的上市后监管要求，
139 包括 21 CFR 第 4 部分 A 分部和 B 分部。31 本指南中讨论了作为器械
140 组成部分的 CCS 的一些考量（见第 V.B.3 节）。然而，申办者应
于 2026 年 2 月 2 日生效。该规则修订或删除了第 820 部分中的某些条款，并通过引用
将 2016 年版国际标准化组织（ISO）13485《医疗器械——质量管理体系——
法规用途要求》纳入第 820 部分。正如最终规则序言所述，
ISO 13485 的要求从整体来看与现行第 820 部分的要求基本相似，
为企业质量管理体系及持续生产安全有效且符合《联邦食品、
药品和化妆品法案》（FD&C Act）的器械的能力提供了类似水平的保证。见 89 FR 7496，
可访问 https://www.federalregister.gov/d/2024-01709。
25
见 21 U.S.C. 321(j)。
26
见 21 U.S.C. 351(b)。
27
见 21 U.S.C. 352(g)。
28
关于 USP 提前采用政策，参见参考时的 USP 通则与要求 <3.10> 标准的适用性。
29
见脚注 4 和 9。
30
更多信息，参见行业和 FDA 工作人员指南《组合产品上市前路径原则》（2022 年 1 月）。
31
更多信息，参见行业和 FDA 工作人员指南《组合产品现行药品生产质量管理规范
要求》（2017 年 1 月）和《组合产品上市后安全性报告》
（2019 年 7 月）。
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146 参考其他相关指南，包括本指南中引用的指南，他们可以联系其组合产品的
147 审评部门，咨询支持上市许可所需的数据和信息
148 相关问题。
149
150
151 IV. 基于风险的框架：需考虑的因素
152
153 药品 CCS 的选择取决于药品和 CCS 两者的特性。不能
154 假定某一 CCS 适用于一种药品，就自动
155 适用于另一种产品。CCS 的关键质量属性，32 尤其是其可浸出物
156 谱，可能受到生产工艺差异、材料
157 供应商变化，甚至药品处方细微变化的影响。
158
159 用于评估 CCS 质量的合适框架应采用风险管理
160 流程。33 该流程应始于对特定药品所用 CCS 的评估，
161 包括 CCS 所选用的 MOC、药品的生产工艺以及药品的临床
162 使用。应基于这些评估充分识别和
163 表征与 CCS 相关的潜在风险。例如，药品与
164 包装材料之间的相互作用可能产生可浸出物，导致非预期的化学毒性。或者，这些
165 可浸出物可能导致药品质量发生不良变化（例如，稳定性降低、
166 杂质谱变化、颗粒物增加、抗原性改变），从而导致
167 药品预期治疗作用发生不可接受的改变。包装组件的确认和
168 质量控制应包括缓解策略，以解决
169 通过检测和其他评估所识别的知识空白和风险。
170
171 A. 一般考虑
172
173 使用基于风险的方法评估 CCS 时，应考虑以下因素。
174 本清单并非详尽无遗；在产品
175 开发和生命周期中可能需要评估其他风险因素。
176
177 1. 包装材料的安全性
178
179 包装组件应采用不会浸出有害或
180 不良量物质的材料制成，以免患者在接受
181 该药品治疗时暴露于这些物质。主要 CCS 最可能是可浸出物的来源，因为包装
182 组件与药品直接接触，但可浸出物也可能来自次要
183 CCS（例如，保护性包装、油墨、标签、粘合剂）以及
184 药品生产中使用的生产设备。对安全性和相容性相关风险的评估应
32
关键质量属性是指物理、化学、生物或微生物学性质或特征，其
应处于适当的限度、范围或分布内，以确保所需的产品质量。参见 ICH
行业指南 Q8(R2) 药品研发（2009 年 11 月）。
33
参见 ICH 行业指南 Q9(R1) 质量风险管理（2023 年 5 月）和 FDA 指南草案，
产品质量评估的获益-风险考量（2022 年 5 月）。本指南定稿后，将代表
FDA 对该主题的当前思考。
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185 relevant to the drug’s intended use (e.g., route of administration, delivery mechanism) and the
186 dosage form (e.g., solid- or liquid-based).
187
188 Containers and closures must not interact with a drug product to cause unacceptable changes in
189 the quality of either the drug product or the packaging components. 34 Similarly, packaging
190 components should not interact with the drug substance to compromise quality. Examples of
191 adverse outcomes caused by incompatibility between a CCS and a drug include:
192
193 • Increased degradation of the active pharmaceutical ingredient
194 • Decreased effectiveness of key excipients (e.g., antioxidants or preservatives)
195 • Changes in physicochemical properties of drugs (e.g., precipitation, pH, appearance)
196 • Compromise of packaging materials or their performance (e.g., glass delamination,
197 formation of particulates)
198 • Change in product stability caused by interactions between a packaging component and
199 a drug (e.g., the types and amounts of leachables could increase over storage time as a
200 result of such interactions)
201 • Change in a biological product’s effectiveness and safety caused by leachables
202 interacting or reacting with a drug that alters its properties (e.g., reacting with a protein
203 and causing changes to its tertiary structure)
204
205 2. Protection
206
207 A CCS must protect against ingress from external contaminants and should prevent leakage. 35 A
208 CCS must also protect against external factors that can cause deterioration or contamination of
209 the drug product, 36 such as exposure to light, loss of solvent, physical stress during transportation
210 and storage, exposure to reactive gases (e.g., oxygen), absorption of water vapor, and ingress of
211 microbial contaminants.
212
213 3. Performance
214
215 A CCS’s performance is its ability to function in the manner for which it was designed. A CCS
216 can have functional features in addition to containing and protecting drugs. For example, for a
217 multiple-dose product, the elastomeric closures of the CCS are pierced multiple times; it is
218 important to evaluate the performance of the closure during the piercing process. Specifically,
219 the functional parameters that include penetrability, fragmentation, and self-sealing efficiency
220 should be evaluated. 37 As another example, an MDI CCS consists of the device constituent part,
221 which plays an important role in generating aerosol particles, determining the aerosol
222 characteristics, and controlling the amount of medication delivered to the patient. Tests to
223 characterize the delivery performance are an important part of evaluating an MDI. 38 The risk
34
See 21 CFR 211.84 and 211.94.
35
See 21 CFR 211.94.
36
Ibid.
37
See USP General Chapter <381> Elastomeric Components in Injectable Pharmaceutical Product
Packaging/Delivery Systems.
38
See the draft guidance for industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products —
Quality Considerations (April 2018). When final, this guidance will represent FDA’s current thinking on this topic.
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224 assessment should account for the functionality of the CCS and discuss the mitigations for the
225 risks that may prevent the CCS from performing those functions.
226
227 A CCS that performs drug delivery should deliver the drug to the intended delivery site in the
228 amount and rate described in the drug labeling. 39 As appropriate, data should be provided to
229 demonstrate that the CCS operates as designed (see sections III.C and V.B.4 for additional
230 information).
231
232 Integrity failures in primary packaging components could cause dimensional incompatibility
233 among the packaging components (e.g., closures with imperfect seals, plunger-syringe
234 incompatibility, variation in dimensional parameters between stopper and container neck). These
235 incompatibilities can further affect CCS performance. 40
236
237 4. Impacts of Manufacturing Process
238
239 The risk assessment should include an evaluation of any potential effects of direct or indirect
240 treatment (e.g., washing, coating, lyophilization, sterilization) of the CCS during the drug
241 manufacturing process. The compatibility of a CCS with a given treatment (a pre- or post-
242 processing method) should be evaluated to ensure that these processes will not adversely affect
243 the CCS’s suitability, compatibility, or functionality. Terminal sterilization and depyrogenation
244 processes that employ high heat, irradiation, or exposure to reactive gases (e.g., ethylene oxide,
245 vaporized hydrogen peroxide) could negatively affect the CCS’s quality. For example, these
246 processes could cause glass to delaminate, which could result in particulate matter in the drug
247 product, and insufficient aeration during sterilization by vapor hydrogen peroxide or ethylene
248 oxide, which could cause leaching of harmful chemicals from the packaging components to the
249 drug.
250
251 5. Storage and Handling
252
253 The risk assessment should account for the product’s intended storage and handling conditions to
254 ensure that the CCS can maintain integrity and functional performance. For example, if the final
255 product is stored at very low temperatures (e.g., frozen temperature of -20°C or cryotemperature
256 of less than -160°C), the integrity and functionality of a CCS should be assessed after storage
257 under worst-case conditions. One way to conduct this type of assessment is to use freeze-thaw
258 cycles or thermal cycling to simulate the storage and handling of the product (see section V.A.5).
259
260 B. Risk Considerations for Common Dosage Forms of Drug Products
261
262 The Agency recognizes that certain drug products pose higher risk than others. The type and
263 extent of information (e.g., testing data) that should be provided for assessments of a CCS is
264 based on the risk identified. Because the level of risk associated with a CCS depends on multiple
39
See draft guidance for industry Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and
Biological Products (June 2024), When final, this guidance will represent FDA’s current thinking on this topic.
40
If a CCS integrity failure is detected, manufacturers must investigate the root cause. Based on a robust quality risk
assessment, manufacturers must also implement appropriate corrective actions, which may include changes to the
manufacturing process to reduce or prevent further CCS integrity failures (see 21 CFR 211.22(a) and 211.192).
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265 and complex factors, risk assessments should be product-specific. For example, an assessment
266 for leachables should account for the safety of the CCS’s MOC, the likelihood that leachables
267 would release into the product from the CCS, and the potential toxicity of the leachables.
268
269 Table 1 provides examples of packaging concerns for common dosage forms of drug products
270 categorized by the route of administration (ROA) and the likelihood of interaction between the
271 packaging components and the drug product. The columns reflect the relative degree of concern
272 associated with each listed ROA, and the rows reflect the likelihood of interaction between the
273 packaging components and drug product. This table is meant to illustrate that not all CCSs have
274 the same degree of packaging concerns; however, it should not be viewed as justification for not
275 adequately assessing the safety of a particular proposed CCS. CCSs with higher risk generally
276 require greater scrutiny to ensure safe use. However, even low-risk drug products present some
277 risk and an adequate assessment for potential leachables is important for these particular drug
278 products (e.g., topical and oral dosage forms).
279
280 Table 1 is not a complete list of all possible dosage forms and ROAs, but the general principles
281 used to determine risk levels in this table apply to other dosage forms and ROAs.. The risk
282 assessments and extent or adequacy of recommended testing of a CCS for any given product
283 should not be determined based solely on the examples in the table. All risk factors for a specific
284 product should be taken into consideration (e.g., dosage forms, CCS MOC and design, drug
285 formulation, ROA) in the overall risk evaluation of a CCS. Factors that are not specified in the
286 table can significantly affect the level of concern, which may differ even among drug products
287 with the same ROA or dosage forms. For example, drug formulation information including
288 cosolvent, physicochemical properties of drug substance and excipients, drug load, pH,
289 surfactants, chelating agents, preservatives, stabilizers, and lipids should be considered in the risk
290 assessment as applicable, along with any additional relevant factors that may affect risk. Risk
291 considerations for common dosage forms of drug products are further discussed in detail
292 following the table.
293
294 Table 1. Examples of Packaging Concerns for Common Dosage Forms of Drug Productsa
Degree of Likelihood of interaction between the packaging components and dosage formb
concern
associated with
the route of High Medium Low
administrationb
Injectable solutions and
Inhalation aerosols suspensions Inhalation powders
Highest
(propellant based) Inhalation solutions and Powders for injection
suspensionsc
Ophthalmic solutions and
Transdermal products and
suspensions
delivery systems
High Nasal sprays —
Nasal aerosols (propellant-
Otic solutions and
based)
suspensions
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Topical dermal products Buccal/sublingual tablets
Medium Lingual and buccal sprays
(liquid and semisolid) Topical powders
Oral solutions and
Oral tablets and capsules
Low d
suspensions (liquid and —
Oral powders
semisolid)
295 a This table provides examples of the general level of packaging concern for several common dosage forms of drug products. The
296 risk associated with a CCS and the extent or adequacy of recommended testing for any given product should not be determined
297 solely based on the examples provided in the table. For combination products, the risk and extent and adequacy of testing should
298 also take into account whether interactions between a CCS that is a device constituent part and the drug or biological product
299 constituent part it holds (such as adsorption of the drug or biological product constituent part by the CCS) might negatively affect
300 device performance.
301 b Factors that are not specified in the table, such as drug formulation composition (e.g., aqueous vs. nonaqueous), can
302 significantly affect the level of concern even compared to other drug products with the same ROA or dosage form. All risk
303 factors (e.g., dosage forms, CCS material and design, drug formulation) should be considered based on the specific product in the
304 overall risk evaluation of a CCS.
305 c The term suspension is used here to describe a mixture of two immiscible phases (e.g., solid in liquid, liquid in liquid). It
306 encompasses a wide variety of dosage forms, including creams, ointments, gels, and emulsions.
307 d Low-risk dosage forms are not free of risk. Though interaction of these dosage forms with packaging components is less likely
308 than for the other listed forms, risks should be assessed and controlled as appropriate.
309
310 1. Inhalation Products
311
312 Inhalation products have one of the highest degrees of concern based on ROA because patients
313 with compromised lung function (e.g., asthma, chronic obstructive pulmonary disease) can
314 inhale leachables from packaging materials directly into their lungs. However, the risk levels
315 concerning product interaction with the CCS vary based on the products’ dosage forms.
316
317 MDI drug formulations contain drug substances (dissolved or suspended) in a propellant; a
318 mixture of propellants; or a mixture of solvents, propellants, or other excipients. The CCS for an
319 MDI consists of the device constituent parts of the combination product (i.e., the canister, the
320 actuator, and the metering valve), including any additional features (e.g., integrated spacer,
321 integrated dose counter), 41 and can also include protective secondary packaging. Device
322 constituent parts and their materials that may come into contact with the drug constituent part
323 should also be considered in the risk assessment. MDIs have the highest risk of interactions
324 between packaging components and the drug because they include a propellant. The presence of
325 an organic propellant in MDI formulations could enhance leaching of compounds from the valve
326 or canister components into the formulation.
327
328 Inhalation solutions and suspensions are intended for delivery to the lungs by oral inhalation for
329 local and/or systemic effects and are used with a nebulizer. Inhalation solutions and sprays are
330 typically aqueous-based formulations and have a medium risk of interactions between packaging
331 components and the drug . Unit-dose presentation is recommended for these drug products to
332 prevent microbial contamination during use. The CCS for these products can also include
333 protective packaging such as foil overwrap (see section V.B.1).
334
See the draft guidance for industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products —
41
Quality Considerations (April 2018). When final, this guidance will represent FDA’s current thinking on this topic.
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335 Dry powder inhaler (DPI) drug formulations typically contain the drug substance and excipients,
336 including a drug carrier (e.g., lactose) that improves the flow of the drug. Because the drug
337 product is a solid powder, this dosage form has a lower risk of interactions between packaging
338 components and the dosage form compared to liquid formulations.
339
340 2. Intranasal Products
341
342 Nasal sprays are applied to the nasal cavity for local and/or systemic effects. Nasal spray
343 combination products contain drug substances dissolved or suspended in solutions or mixtures of
344 excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffering agents) in
345 nonpressurized dispensers that deliver a spray containing a metered dose of the drug substance.
346 The formulation and the CCS (container, closure, pump, and any protective packaging)
347 collectively constitute the product. The drug formulations are typically aqueous-based and have a
348 medium risk of interactions between packaging components and the drug.
349
350 Propellant-based nasal aerosols (nasal MDIs) have a high risk of interactions between packaging
351 components and the drug. However, these products are not included in the highest risk portion of
352 the table because (unlike inhalation MDIs) they are not intended for delivery to the lungs.
353
354 3. Injectable Drug Products
355
356 An injectable drug is intended for injection through the skin or other external boundary tissue
357 (rather than for ingestion through the alimentary canal) so that drug substances are administered
358 directly into a blood vessel, organ, tissue, or lesion. There are many routes for administration of
359 injectable drug products (e.g., subcutaneous, intramuscular, intravenous). Injectable drug
360 products may be liquids in the form of solutions, emulsions, or suspensions, or they may be dry
361 solids that are to be combined with an appropriate vehicle to yield a solution or suspension.
362 These products typically have a medium risk of interactions between packaging components and
363 the drug product. However, the risk can be elevated for certain injectable products if the
364 excipients used in the drug product promote the leaching of chemicals from the CCS. Injectable
365 products that contain organic solvents (e.g., ethanol or dimethyl sulfoxide in a depot injection
366 drug product) in their formulations have high potential to interact with their packaging materials.
367 Drug products administered by the intravenous route are 100% bioavailable; therefore, any
368 leachables in the product would be administered with the intended dosage form and have wide
369 access to organs and tissues. Similar concerns exist for leachables in drug products administered
370 by the subcutaneous and intramuscular routes, given the potential for significant exposure to
371 organs and tissues. For injectable products that are delivered into specific tissues (e.g., ocular,
372 perineural, intra-articular), local tissue toxicity should be considered in the safety evaluation.
373 Drug products intended for administration into uniquely vulnerable tissues, such as the central
374 nervous system or the intrathecal/epidural space, generally represent the highest level of
375 toxicological concerns for leachables because these tissues have limited or no ability to recover
376 from toxicity. 42
377
42
FDA encourages manufacturers to communicate with the Agency regarding leachables studies and the design of
toxicology study protocols for intracerebral, intrathecal, epidural, and other high-risk routes.
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378 The risk of interactions between packaging components and the drug product is generally lower
379 for powder for injection than it is for liquid-based products (e.g., solutions) because interaction
380 between the powder and the primary CCS is minimal. However, some risk factors may enhance
381 the potential for interactions between the product and the primary CCS and lead to elevated
382 levels of leachables. For example, an elastomeric stopper may interact with the organic solvent
383 vapor during the lyophilization process, or it may interact with the organic solvent present in the
384 reconstituted solution.
385
386 4. Transdermal and Transmucosal Delivery Systems
387
388 Transdermal delivery systems are combination products that deliver drug across the skin and into
389 systemic circulation. 43 They present a high risk with respect to the ROA because of the systemic
390 exposure achieved through this route. These products typically have prolonged contact with the
391 skin. Transdermal delivery systems also frequently contain multiple components, including
392 excipients such as penetration enhancers, solubilizers, or plasticizers/softeners, as well as
393 adhesives or tackifiers. These components are often composed of nonpolar or organic
394 compounds (e.g., alcohols, dimethyl sulfoxide), which increase the risk of leaching of potentially
395 harmful substances from the CCS and increase the likelihood of interaction between the
396 packaging components and the drug product. Excipients and components such as penetration
397 enhancers, or mechanical features such as microneedles, are typically used to increase systemic
398 drug absorption, but they could also facilitate skin absorption and penetration of leachables from
399 the CCS as well as other impurities (e.g., residual monomers, solvents, degradants) from the drug
400 product.
401
402 Transmucosal delivery systems are designed to result in significant absorption of the drug across
403 a mucous membrane (e.g., nasal, buccal, sublingual, vaginal, rectal), which can result in
404 avoidance or significant reduction of first-pass hepatic metabolism. Some transmucosal routes
405 may result in increased risk of toxicity or irritation to local tissues (e.g., reproductive tissues for
406 vaginal delivery systems, rectal tissue). Each product may present different risks based on the
407 tissues exposed and the specific formulation and ROA.
408
409 5. Topical Dermal Drug Products
410
411 Topical dermal drug products are administered to the outer surface of the body (e.g., skin). These
412 products are dispensed from the same CCS repeatedly (often by the end user), and they can
413 include a variety of CCSs that facilitate drug application (e.g., rigid bottle or jar, collapsible tube,
414 flexible pouch).
415
416 Topical dermal solutions and suspensions include products that are liquid or semisolid in nature.
417 Liquid-based products typically have a fluid or semisolid consistency and are marketed in a
418 single- or multiple-unit container (e.g., a rigid bottle or jar, a collapsible tube, a flexible pouch).
419 Packaging components like a dropper or spray device may be combined into a closure at the time
420 of initial packaging. There is an increased risk for interactions between the topical dermal
43
See the draft guidance for industry Transdermal and Topical Delivery Systems — Product Development and
Quality Considerations (November 2019). When final, this guidance will represent FDA’s current thinking on this
topic.
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421 solutions and suspensions and the CCS because they may remain in contact with the drug
422 product solution during storage and after the product is initially opened. Additional factors to
423 consider during the risk assessment of such products include how those products are opened,
424 reuse of the same closure system, and the accuracy and repeatability of dose disbursement from
425 the dispensing orifice.
426
427 Risk assessments of topical dermal drug products should account for both systematic and local
428 effects. Topical dermal solutions and suspensions have medium-to-high potential to interact with
429 their packaging materials because nonpolar solvents or organic compounds (e.g., alcohol) are
430 usually added to the formulation to enhance penetration into the skin. Several factors determine
431 the degree of penetration for topical dermal products. For example, if a low dose is applied (e.g.,
432 through a low concentration, low body surface area, or low frequency of application), the drug
433 product does not include dermal penetration enhancers, and the drug product is applied to intact
434 skin, there could be limited systemic exposure to potential leachables. Topical dermal solutions
435 and suspensions that contact sensitive mucosal membranes or skin that has been broken or
436 compromised have increased safety concerns.
437
438 6. Ophthalmic and Otic Products
439
440 Ophthalmic and otic products are intended for administration into the eye and ear, respectively;
441 they present a high risk associated with ROA based on the vulnerability of the tissues to which
442 the drug product is applied. Local tissue toxicity assessments are essential, with toxicity
443 determination based partly on the concentration of leachables in the solution applied to uniquely
444 vulnerable tissues. Ophthalmic and otic products are typically solutions and suspensions
445 designed to minimize local tissue irritation. Although ophthalmic and otic drug product solutions
446 may be less likely to contain solvents or have pHs that are known to enhance the release of
447 leachables, the CCSs are often manufactured with materials, such as low-density polyethylene,
448 that are soft to facilitate squeezing the product out of the container for application. These soft
449 and semipermeable materials are vulnerable to potential leachables and ingress of volatile
450 chemicals. Further, many of these CCSs need to be sterilized, and that process could contribute
451 to an increase in leachables from the CCS. 44
452
453 7. Oral Drug Products
454
455 Depending on the packaging components, the risk of interactions of drug products with the CCS
456 can vary for oral drug products. The risk of interactions between packaging components and a
457 solid oral dosage form like powders, capsules, or tablets is generally considered low.
458 Appropriately referencing the indirect food additive regulations 45 and demonstrating compliance
459 with relevant USP standards within an application or, for products not requiring an application,
460 within the relevant documentation at the manufacturing site, may be sufficient to establish safety
461 and compatibility of the MOC for packaging components, provided any limitations specified in
462 the regulations are taken into consideration. 46 However, if powders are reconstituted in their final
44
See also the guidance for industry Certain Ophthalmic Products: Policy Regarding Compliance With 21 CFR
Part 4 (March 2022).
45
See 21 CFR parts 174–186.
46
See MAPP 5015.5 Rev. 1, CMC Reviews of Type III DMFs for Packaging Materials.
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463 containers in the presence of organic solvents, they are at increased risk for interactions between
464 the packaging components and the reconstituted solution or suspension. In addition, the CCS can
465 interact with solid oral drug products containing hygroscopic excipients such as polyethylene
466 oxides or with the glycerin present in softgel capsules, affecting the stability of both the
467 packaging components and the drug product.
468
469 Compared to solid oral products, oral solutions and suspensions are at higher risk of interactions
470 between the packaging components and the drug product. As with solid oral dosage forms,
471 referencing the indirect food additive regulations 47 and demonstrating compliance with relevant
472 USP standards may be acceptable for oral solutions and suspensions if those regulations’
473 limitations and use conditions are met. However, if the risk assessment identifies additional
474 safety or compatibility concerns, such as products containing cosolvents or organic compounds
475 that are expected to extract greater amounts of substances from plastic packaging components
476 than the food products using the same packaging materials per 21 CFR parts 174–186,
477 extractables/leachables assessments and a safety evaluation should be performed. 48
478
479
480 V. QUALITY ASSESSMENT AND CONTROL
481
482 For finished pharmaceuticals, the requirements for drug product containers and closures
483 described in 21 CFR part 211 subpart E must be met to ensure that CCS and packaging
484 components are suitable and safe for their intended use. For drug substances, an appropriate
485 qualification and quality control program should be implemented as described in the ICH
486 guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical
487 Ingredients (September 2016). The overall quality evaluation of a CCS, including a variety of
488 tests and assessments, should employ appropriate risk-based approaches. Procedures regarding
489 the receipt, identification, storage, handling, sampling, testing (e.g., methods and analytical
490 reference standards, acceptance criteria or specifications, and validation information for studies
491 and evaluations), and approval or rejection of components and drug product containers and
492 closures must be written and followed for a drug product’s CCS. 49 For containers of drug
493 substances, FDA recommends the analytical test methods and criteria for accepting and releasing
494 each packaging component also be written and followed. FDA’s Emerging Technology Program
495 can help address concerns or challenges related to acceptance criteria for novel container closure
496 or packaging components. 50
497
498
499
47
See 21 CFR parts 174–186.
48
We note that ICH has a new guideline currently under development, Q3E Impurity: Assessment and Control of
Extractables and Leachables for Pharmaceuticals and Biologics, that will address the evaluation and
characterization of extractables and leachables, as well as associated toxicological risk assessments.
49
See 21 CFR 211.80. See also, 21 CFR 211.84, and 211.94(d), for additional requirements on the testing of
containers.
50
For more information, see https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-
technology-program. See the guidance for industry Advancement of Emerging Technology Applications for
Pharmaceutical Innovation and Modernization (September 2017) for information on meeting requests.
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500 A. Typical Quality Assessments and Control of a CCS
501
502 Tests (including methods and acceptance criteria) described in the USP are typically considered
503 minimum standards for establishing properties and characteristics of MOC or packaging
504 components. Use of non-USP tests may be acceptable with justification. Data supporting use of a
505 non-USP test should include a demonstration of the test’s suitability for its intended use and
506 method validation. 51,52 If a related USP test is available and a non-USP method is used instead,
507 supporting data should demonstrate the equivalency or superiority of the non-USP method to the
508 USP method.
509
510 Tests and evaluation methods for CCS quality assessments and controls should be selected
511 based on the identified risks and potential methods of mitigating these risks. Table 2 provides
512 an overview of the typical quality assessments for qualification and quality control of CCSs for
513 different classes of drug products, including packaging components. The following sections
514 describe these assessments in greater detail.
515
516 Table 2. Typical Quality Assessments of a CCS 53
Oral drug Injectable drug Inhalation drug Topical/transdermal/transmucosal
products products products products
Dosage
forms
suspensions) and topical and
DPIs) and inhalation sprays
Creams, ointments, lotions,
(powders, topical solutions,
Transdermal drug delivery
Inhalation aerosols (MDIs,
Powders for reconstitution
suspensions, otic solutions
Solutions and suspensions
Ophthalmic solutions and
Topical dermal products
Oral powders, tablets,
Inhalation solutions
Inhalation powders
(lyophilized cakes)
Oral solutions and
and suspensions
lingual aerosols
suspensions
capsules
systems
l
Characteristics
Description For each packaging component:
• Name, product code (if available), manufacturer, physical description
• Identity and specifications of MOC
• Description of any additional treatments (e.g., procedures for sterilizing or depyrogenating packaging
components)
Suitability
Protection Light exposure Light exposure Light exposure Light exposure
(for each
component Reactive gas Reactive gas Reactive gas Moisture permeation (for transdermal
and/or the delivery system and powder)
CCS, as Moisture Moisture permeation Moisture permeation
appropriate) permeation Container closure integrity
Container closure Container closure
Container closure integrity integrity Solvent loss or leakage
integrity
Solvent loss or Solvent loss or leakage
Solvent loss or leakage (except for powders)
leakage (except
for powders)
51
See the ICH guidance for industry Q2(R2) Validation of Analytical Procedures: Text and Methodology (March
2024).
52
See USP general notice 6.30 for use of alternative tests.
53
This table does not address all quality considerations relevant to the assessment of device constituent parts of
CCSs. See sections III.C and V.B.3 for related information.
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Oral drug Injectable drug Inhalation drug Topical/transdermal/transmucosal
products products products products
Dosage
forms
suspensions) and topical and
DPIs) and inhalation sprays
Creams, ointments, lotions,
(powders, topical solutions,
Transdermal drug delivery
Inhalation aerosols (MDIs,
Powders for reconstitution
suspensions, otic solutions
Solutions and suspensions
Ophthalmic solutions and
Topical dermal products
Oral powders, tablets,
Inhalation solutions
Inhalation powders
(lyophilized cakes)
Oral solutions and
and suspensions
lingual aerosols
suspensions
capsules
systems
l
Characteristics
For sterile products:
• Container closure integrity testing (CCIT), see section V.A.2.a.i and Table 3 for further information.
Compatibility Chemical Chemical Chemical composition Chemical composition
and safety composition composition
(for each Physicochemical tests Physicochemical tests (e.g., for elastomer,
component Physicochemical Physicochemical tests (e.g., for elastomer, plastic, or glass)
and/or the tests (e.g., for (e.g., for elastomer, plastic, or glass)
CCS, as elastomer, plastic, plastic, or glass) Extractables and leachables
appropriate) or glass) Extractables and
Extractables and leachables Impact on product quality
Appropriate leachables
reference to Impact on product Biocompatibility (biological reactivity)
indirect food Impact on product quality
additive quality Particulate matter
regulations (see Biocompatibility
section IV.B.7) Biocompatibility (biological reactivity) Coating integrity test (e.g., for coatings on
(biological reactivity) metal tubes)
Extractables and Particulate matter
leachables Particulate matter
Impact on product
quality
Performance For the assembled CCS:
• Functionality tests
• Drug delivery assessments, as appropriate
Quality For packaging components received by the manufacturer (at release of packaging components during manufacturing):
control • Tests and acceptance criteria (e.g., appearance, identification of material, microbiological and physiochemical
tests)
• Dimensional (drawing) and performance (e.g., functionality) criteria
• Methods to monitor consistency in composition, as appropriate
Stability Considerations of CCS evaluation as part of stability testing:
• Drug product stored in final CCS is tested.
• An evaluation of the CCS should be included in the stability protocol, as appropriate.
• CCIT is recommended in lieu of sterility testing for sterile products.
• Postapproval changes of CCS may require stability studies, as applicable.
Additional For the assembled CCS, if applicable:
tests • Stress test (e.g., shipping validation or qualification)
• Freeze-thaw and thermal cycling tests
517
518
519 1. Description
520
521 The general description of each packaging component of a CCS should include the following
522 information:
523
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524 • The product name, name and address of the manufacturer, and a physical description of
525 the packaging component (e.g., type, MOC, dimensions and drawing, shape, color).
526 • The MOC (e.g., plastics, paper, metal, glass, elastomers, coatings, adhesives) identified
527 by a specific product designation and source (name of the manufacturer). 54 Alternate
528 MOC should also be identified. Postconsumer recycled plastic should not be used in the
529 manufacture of a primary packaging component. If it is used for a secondary packaging
530 component, then the safety and compatibility of the material for its intended use should
531 be addressed appropriately.
532 • Descriptions of any processes or preparations that are performed on a packaging
533 component (e.g., washing, coating, sterilization, depyrogenation). 55
534
535 2. Suitability Evaluation
536
537 The suitability evaluation is, collectively, the tests and studies used and accepted to qualify a
538 CCS or packaging components for their intended use. Every proposed CCS for a drug product
539 must meet certain requirements, including that it provide adequate protection against foreseeable
540 external factors in storage and use, be composed of materials that do not alter the quality of the
541 drug, be clean, and (when appropriate given the nature of the drug) be sterilized and
542 depyrogenated. 56 Containers for drug substances should provide adequate protection against
543 deterioration or contamination during transportation and recommended storage; be cleaned and
544 sanitized to ensure that they are suitable for their intended use; and not be reactive, additive, or
545 absorptive so as to alter the quality of drug substance. 57 Generally, the suitability evaluation
546 includes tests to demonstrate protection, compatibility, safety, and performance of packaging
547 components and systems. If the CCS has a performance feature such as drug delivery, the
548 evaluation should also show that the assembled CCS functions properly.
549
550 a. Protection
551
552 USP tests 58 for light exposure or transmission, moisture permeation, and container closure
553 integrity are generally considered sufficient for evaluating a CCS’s ability to protect the drug.
554 Testing for properties other than those described in the USP (e.g., gas transmission, solvent loss,
555 leakage) should also be performed when appropriate. For all sterile products, container closure
556 integrity testing (CCIT) and related data should demonstrate that the proposed CCS maintains
557 product sterility.
558
54
When possible, this information should be included in the application. Alternatively, trade secret, confidential data
or information not known to the applicant may be provided by referencing a drug master file (see section VI.C).
55
For further information, see the guidance for industry Submission of Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products (November 1994).
56
See 21 CFR 211.84, and 211.94.
57
See the ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients (September 2016).
58
See, e.g., USP General Chapter <659> Packaging and Storage Requirements.
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559
560 i. Recommendations for CCIT
561
562 CCIT is used to evaluate CCS integrity to ensure the product is protected from ingress of
563 environmental factors. For sterile products, CCIT is used:
564
565 • To demonstrate that the CCS selected is suitable to provide an adequate sterile barrier
566 • To validate related manufacturing parameters (e.g., capping parameters) for the selected
567 CCS and as an in-process test for appropriate CCS closure
568 • To demonstrate that the CCS maintains its integrity at the labeled storage conditions
569 over expiry ensuring protection of the product quality and sterility, if applicable
570
571 The selected method for CCIT should include method validation for the specific CCSs,
572 sensitivity information, and negative and positive controls. Factors to consider when selecting a
573 method for evaluating the container’s integrity include the suitability of the method for the type
574 of CCS, the intended use of the CCS, the sensitivity of the test method, and the storage
575 conditions of the drug product. Worst-case conditions should be considered and represented
576 when selecting an appropriate CCIT method. In some instances, the CCS’s seal integrity can be
577 transiently compromised at extreme storage conditions or during shipping and handling, which
578 could affect product quality and safety. For example, rubber stoppers can lose their elastic
579 properties at extreme low temperatures, and this transient loss in seal integrity can lead to
580 overpressure in the container caused by accumulation of ingressed gas during storage. The
581 ingressed gas can then become trapped when the elastomers reseal after being removed from the
582 extreme temperature. This transient loss of integrity would not be captured when the CCIT is
583 conducted after the container is removed from the extreme conditions. Therefore, a test method
584 that can be performed at extreme temperature conditions (e.g., freezing) should be considered.
585
586 Table 3 lists examples of commonly used CCIT methods organized by specific CCS type. The
587 list does not represent the only tests that can be performed to demonstrate container integrity for
588 these specific CCSs. FDA encourages innovative, advanced, and deterministic integrity testing
589 technologies. While probabilistic integrity testing methods could be acceptable, these testing
590 methods can be challenging to design, develop, validate, and implement. All CCIT methods have
591 advantages and disadvantages that should be considered prior to test selection. 59
592
593 Table 3. Examples of CCIT for Common Types of CCSs
CCS MOC CCIT
Vials or bottles Glass or plastic Helium leak testing
with closure Pressure and/or vacuum decay
Dye ingress
Mass extraction test
For a thorough discussion of the merits of various test methods for different types of CCSs, see USP General
59
Chapter <1207> Package Integrity Evaluation — Sterile Products and its subchapters.
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CCS MOC CCIT
Ampoules Glass Helium leak testing
Pressure and/or vacuum decay
Dye ingress
High voltage leak detection
Plastic blow fill seala Helium leak testing
Pressure and/or vacuum decay
Dye ingress
High voltage leak detection
Pre-filled Glass or plastic Helium leak testing
syringes/ Pressure and/or vacuum decay
cartridges Dye ingress
Mass extraction test
Tubes Plastic or Aluminum Dye ingress
Flexible bags Plastic Helium leak testing
Pressure and/or vacuum decay
Dye ingress
Mass extraction test
Internal pressurization (bubble emission test)
Blister Plastic, aluminum foil Helium leak testing
Dye ingress
Seal integrity testing
Burst/creep testing
Sachets/pouches Foil/paper Pressure and/or vacuum decay
Plastic Pressure and/or vacuum decay
Dye ingress
594 a Container closure defects can be a major problem for blow-fill-seal operations. A reliable, sensitive leak detection test should be
595 used to inspect each unit of each batch. Several leak detection methods, including high voltage leak detection or vacuum leak
596 detection, can be adapted easily for in-line leak detection to ensure product container integrity. For more information, see the
597 guidance for industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice
598 (September 2004).
599
600 All sterile products must be tested to verify the maintenance of sterility over the drug product’s
601 shelf life. 60 Because of the limitations of sterility testing, the Agency encourages performing
602 CCIT in lieu of sterility testing as a component of a stability program to ensure that containers
603 are able to maintain sterility throughout the drug product’s shelf life. 61
604
605 b. Safety and compatibility
606
607 To ensure that the CCS is safe and compatible with the drug, packaging components and MOC
608 should be well characterized. Characterization should include the complete chemical
609 composition of every material used in the manufacture of each packaging component and should
See 21 CFR 211.166, 21 CFR 211.167(a), and 21 CFR 610.12.
60
See the guidance for industry Container and Closure System Integrity Testing in Lieu of Sterility Testing as a
61
Component of the Stability Protocol for Sterile Products (February 2008).
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610 include results of appropriate qualification and characterization tests (e.g., USP tests for
611 elastomers, plastic, or glass). 62 For application products, this information may be provided as a
612 reference to Type III master files.
613
614 For drugs that are unlikely to interact with the CCS, other tests or information (e.g., appropriate
615 reference to the indirect food additive regulations at 21 CFR parts 174–186) can be used to
616 address the issue of safety and compatibility. For example, safety and compatibility of the CCS
617 for an oral solid could be addressed by meeting compendial requirements (e.g., USP tests for
618 glass and plastic containers) and conforming to the requirements for indirect food additives
619 provided in the CFR (e.g., 21 CFR 177.1520 for olefin polymers).
620
621 i. Extractables and leachables assessments
622
623 Extractables and leachables assessment is an integral part of a CCS’s suitability evaluation. 63
624 These studies and associated toxicological assessments should be performed for any drug that is
625 likely to interact with its packaging components, leading to introduction of leached substances
626 into the patient. A risk-based approach should be used when designing and assessing extractables
627 and leachables studies for a CCS and when making changes to packaging components during the
628 product’s life cycle. Risk assessment for leachables should be performed on a case-by-case basis
629 (i.e., it should be product-specific).
630
631 In general, leachables studies are performed throughout the shelf life of a drug product. These
632 studies are conducted under specified storage conditions as part of formal stability studies in
633 which multiple batches (e.g., three batches) of the drug product are tested at multiple time points
634 under both accelerated and long-term stability conditions, as well as intermediate conditions
635 when appropriate. 64 A justification should be provided for selections of batches other than the
636 formal stability batches or if fewer than three batches are selected. The CCS (including
637 secondary components such as labels, adhesives, over-pouches, wraps, and cartons) used in
638 leachables studies should be representative of the future commercial product. The analytical
639 methods used for leachables studies are typically the same as, or similar to, those used for the
640 extractables studies and should be properly validated. A correlation between extractables and
641 leachables could be established when sufficient extractables and leachables data from the same
642 CCS are generated.
643
62
USP testing is described in USP General Chapters <381> Elastomeric Components in Injectable Pharmaceutical
Product Packaging/Delivery Systems, <660> Containers — Glass, and <661> Plastic Packaging Systems and Their
Materials of Construction. Note that USP permits early adoption of the requirements in USP General Chapters
<661>, <661.1> Plastic Materials of Construction, and <661.2> Plastic Packaging Systems for Pharmaceutical
Use.
63
We note that ICH has a new guideline currently under development, Q3E Impurity: Assessment and Control of
Extractables and Leachables for Pharmaceuticals and Biologics, that will address the evaluation and
characterization of extractables and leachables, as well as associated toxicological risk assessments. Also see USP
General Chapters <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems,
<1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, and
others also describe extractables and leachables assessments.
64
For general guidance on conducting stability studies, see the ICH guidances for industry Q1A(R2) Stability
Testing of New Drug Substances and Products (November 2003) and Q5C Quality of Biotechnological Products:
Stability Testing of Biotechnological/Biological Products (July 1996).
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644 For drug substances, as appropriate, extractables and leachables studies and associated
645 toxicological assessments should support the evaluation of leachates from the container closure
646 components.
647
648 ii. Nonclinical toxicological risk assessments
649
650 A toxicological risk assessment of the leachables from a CCS should be provided to support the
651 CCS’s safety for drugs. 65 A toxicological risk assessment addressing general toxicological
652 concerns should be provided for all leachables exceeding the recommended qualification
653 threshold (QT). A toxicological risk assessment should also be provided for any leachables with
654 identified concerns for DNA reactivity or carcinogenicity if they exceed the appropriate
655 threshold of toxicologic concern-based acceptable intake (TTC-based AI). When local tissue
656 toxicity is a primary concern, a concentration-based QT may also be appropriate. The safety
657 concern threshold (SCT) should be based on the TTC-based AI or the QT, whichever is lowest.
658 The analytical evaluation threshold (AET) should be based on the SCT established for a given
659 CCS for a drug. FDA generally recommends the following:
660
661 • An SCT of 1.5 mcg/day should be applied for most chronic-use drugs.
662 • A QT should be applied for general toxicity for all products.
663 • A QT based on concentration also applies for drugs in which local tissue toxicity is of
664 concern (e.g., ophthalmic, intrathecal, perineural).
665 • A lower SCT may be recommended if the CCS may contain compounds of specific
666 toxicological concern (e.g., polynuclear aromatic hydrocarbons, nitrosamines).
667
668 The toxicological risk assessment should be based on the highest level of confirmed leachables
669 present in the product over the proposed shelf life. Leachables exceeding the AET should be
670 identified in a leachables study that is based on the results of extraction studies performed with
671 appropriate extraction solvents. The leachables should be identified and quantified using
672 validated analytical methods.
673
674 c. Performance
675
676 Tests and acceptance criteria used to evaluate CCS performance should be appropriate for the
677 drug’s particular dosage form, ROA, and CCS design features.
678
679 To address performance, functionality tests 66 are considered sufficient if the test and acceptance
680 criteria are appropriate for the CCS’s intended purpose. Performance evaluations should include
681 an analysis of how storage conditions and potential stress from material physical form
682 transformation (such as crystallization during a lyophilization process) could affect the CCS’s
65
We note that ICH has a new guideline currently under development, Q3E Impurity: Assessment and Control of
Extractables and Leachables for Pharmaceuticals and Biologics, that will address the evaluation and
characterization of extractables and leachables, as well as associated toxicological risk assessments.
66
Recommendations for functionality tests are described in USP General Chapters, including <659> Packaging and
Storage Requirements, <381> Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery
Systems, and <671> Containers — Performance Testing.
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683 functionality. A stability program should include a performance evaluation at the end of a
684 product’s shelf life to ensure the CCS maintains functionality as designed through expiry.
685 As described in section III.C, the CCS can serve in a dual capacity: it can contain and protect the
686 drug, and it can also act to deliver the drug as a device constituent part of a combination product.
687 The type of performance testing will depend on the type of CCS and its intended function as a
688 device constituent part (see also section V.B.3). Testing with a stand-alone device may also be
689 needed if the CCS is labeled for use with a device(s) (e.g., a drug cartridge labeled for use with a
690 separate, reusable pen injector) and the CCS performance can impact overall device and drug
691 product performance.
692
693 3. Quality Control
694
695 Quality control is the use of tests and acceptance criteria to ensure that packaging components
696 and the CCS continue to possess the characteristics established in the suitability studies.67,68 A
697 manufacturer’s quality system should ensure that all container and closure suppliers are reliable
698 and that quality controls have been established for receipt, production, storage, and use. A robust
699 quality system should have a supplier qualification program that accounts for variations in
700 component specifications from different suppliers. Sufficient initial tests should be performed to
701 establish reliability, and subsequent tests should be performed periodically to verify reliability. 69
702 Manufacturers should take into account that a change to a packaging component may result in a
703 new or revised specification for the packaging component.
704
705 Dimensional information for the CCS components (including device constituent parts) typically
706 contains a detailed schematic drawing complete with target dimensions and tolerances, including
707 test methods and acceptance criteria for each CCS component. A separate drawing may not be
708 necessary for a CCS component (including device constituent parts) if it is part of a larger unit in
709 a drawing or if the component is uncomplicated in design (e.g., a cap liner). Dimension
710 information should be provided in an application, or maintained at the manufacturing site, as
711 appropriate.
712
713 4. Stability Testing
714
715 Stability testing of a drug should be conducted in the CCS proposed for marketing (including, as
716 appropriate, any secondary packaging). 70 When applicable, the stability testing protocol should
717 include evaluation of additional functionality of the CCS (e.g., dose uniformity of an MDI until
67
See 21 CFR 211.84 and 211.94.
68
A CCS that is also a device constituent part is subject to 21 CFR part 820 requirements in accordance with
21 CFR part 4, subpart A, including design controls (see section V.B.3) and purchasing controls, among other
requirements. The Agency has exempted some devices from all or certain provisions of the device quality system
regulations. Such exemptions may extend to the device constituent parts of combination products and to the
combination products of which they are a part. See the guidance for industry and FDA staff Current Good
Manufacturing Practice Requirements for Combination Products (January 2017) for more information.
69
See the ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009).
70
For general guidance on conducting stability studies, see the ICH guidances for industry Q1A(R2) Stability
Testing of New Drug Substances and Products (November 2003) and Q5C Quality of Biotechnological Products:
Stability Testing of Biotechnological/Biological Products (July 1996). See also the guidances for industry ANDAs:
Stability Testing of Drug Substances and Products (June 2013) and ANDAs: Stability Testing of Drug Substances
and Products, Questions and Answers (May 2014).
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718 expiry). Even when a formal test for quality of the CCS is not performed, the manufacturer
719 should investigate any observed change in the CCS during the stability studies. For sterile
720 products, maintenance of sterility throughout the product’s shelf life can typically be
721 demonstrated by container closure integrity testing conducted annually, and at expiry, in lieu of
722 sterility testing (see section V.A.2.a.i for more information about CCIT).
723
724 5. Additional Tests for Shipping, Handling, and Storage
725
726 A shipping study may be performed by evaluating the integrity of the CCS after the drug has
727 been shipped from its manufacturing site to its intended destination (e.g., a packaging/labeling,
728 storage, or distribution center) using the intended commercial shipping method and under the
729 recommended storage conditions. 71 The shipping study of the drug may include evaluating the
730 mechanical protective function of the CCS, which should not have been compromised or
731 otherwise affected during shipping. An integrity evaluation of a CCS should also be considered
732 after shipping sterile drugs.
733
734 Stress testing used in a shipping study ensures that a CCS adequately protects the drug from both
735 environmental stress (e.g., light, reactive gas permeation, moisture permeation) and physical
736 stress (e.g., compression, shock, vibration, change in air pressure, expansion) during
737 transportation and handling. The design may include packaging components that supplement the
738 CCS’s mechanical strength to enhance its protective function.
739
740 Stress testing may include laboratory simulation studies using appropriate test protocols 72 to
741 evaluate the CCS’s protective function. The CCS should be able to withstand simulated
742 mechanical stress in order to demonstrate it provides adequate protection for the drug and the
743 accompanying labels during shipping and handling. Both destructive and nondestructive
744 evaluation techniques could be used to measure the integrity of the CCS (see section V.A.2.a.i
745 and Table 3). Destructive evaluation techniques (e.g., opening the opaque blister pack) are
746 typically used to evaluate the physical integrity of a CCS (e.g., fragile ampules, vials, bottles,
747 device constituent parts).
748
749 For drugs shipped under cold-chain conditions (e.g., frozen or refrigerated), the shipping
750 containers should be appropriately qualified using temperature recording systems to ensure the
751 intended product temperature is maintained when the CCS is exposed to the worst-case
752 temperature and shipping time expected. The qualification of the CCS under specified
753 temperature conditions (e.g., insulated dry ice box or temperature-controlled shipping container)
754 is typically performed using temperature recording instruments as part of shipping validation.
755
756 When applicable, drug development should include freeze-thaw and thermal cycling studies to
757 demonstrate that drug quality and CCS integrity and functionality can be maintained under
758 temperatures that represent both normal and worst-case transportation, storage, and handling
71
For drugs that are sensitive to environmental stresses, the evaluation of critical quality attributes of drugs prior to
or after shipping and handling should be performed to confirm the protective function of the CCS, as applicable.
72
Refer to the American Society for Testing and Materials (ASTM)’s standards as applicable, and the International
Safe Transit Association (ISTA)’s Guidelines for Selecting and Using ISTA Test Procedures and Projects.
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759 conditions. These studies typically include exposing the drug, while in the intended
760 commercial CCS, to multiple freeze-thaw cycles or thermal cycles. The assessment of CCS
761 integrity and functionality may include the visual inspection of defects (e.g., cracks, breakage,
762 particulates) and CCIT as recommended in Table 3.
763
764 B. Special Considerations for Particular Packaging Components
765
766 While all primary packaging components of CCSs should undergo quality assessment, some
767 CCSs have additional packaging components with special considerations for quality assessment.
768 This section describes the tests and studies recommended to establish suitability and quality
769 control for secondary packaging components, auxiliary components, and packaging components
770 that are device constituent parts of a combination product.
771
772 1. Secondary Packaging Components
773
774 Secondary packaging components do not make contact with the drug, so there is less concern
775 that the drug will interact with the secondary package’s MOC (e.g., cartons made of paper or
776 plastic; overwraps made of metal foil, plastic, or paper). Secondary packaging can have an
777 additional protective function, as when it prevents external factors (e.g., moisture, light,
778 microbial contaminants) from reaching the primary CCS, or when it provides added protection
779 for a primary CCS that is flexible or subject to rough handling. For example, the CCS for
780 inhalation aerosols and inhalation powders may include overwraps or foil pouches as secondary
781 packaging in addition to the inhaler. Secondary packaging components are also used to maintain
782 surface sterility of a primary CCS intended for use in a sterile surgical field.
783
784 The amount of information needed to demonstrate a secondary packaging’s suitability depends
785 on the packaging’s purpose. Typically, a brief description of a secondary packaging component
786 is sufficient. If the secondary packaging component is intended to provide additional protection
787 or function beyond container closure (e.g., drug delivery, controlled access to the drug, electronic
788 monitoring of the drug), appropriate assessments should demonstrate that the component
789 provides the additional protection or functions as intended, without adversely interacting with the
790 drug. In such cases, relevant in-process controls should be established with additional testing,
791 including seal integrity testing, stability studies of the drug within the secondary packaging, and
792 in-use stability testing of the drug once the protective secondary packaging is opened, as
793 applicable.
794
795 If the primary CCS is relatively permeable, the drug could be contaminated by the migration of
796 an ink, an adhesive component, or a volatile substance present in the secondary packaging
73
See the ICH guidances for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November
2003); Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products (July
1996); and World Health Organization, 2018, Stability Testing of Active Pharmaceutical Ingredients and Finished
Pharmaceutical Products, In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fifty-
Second Report, Annex 10 (WHO Technical Report Series, No. 1010). Also see USP General Chapter <1079> Good
Storage and Shipping Practices. See also Parenteral Drug Association, 2005, Technical Report #39: Cold Chain
Guidance for Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products Through
the Transportation Environment, PDA J Pharm Sci Technol, 59(3 Suppl TR39):1–12.
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797 component. If the secondary packaging component is a potential source of contamination, the
798 safety of its MOC should be demonstrated.
799
800 2. Auxiliary Packaging Components
801
802 Auxiliary packaging components are articles that are used to support or enhance a CCS. These
803 articles include, but are not limited to, pharmaceutical coil (e.g., cotton, rayon), desiccants, and
804 oxygen scavengers. Pharmaceutical coil, desiccants, and oxygen scavengers included in drug
805 primary packaging prevent tablet and capsule breakage and exposure to moisture and oxygen,
806 respectively. These types of packaging components should be chosen carefully to prevent
807 unintended ingestion of desiccants by the consumer or unacceptable toxicity from any materials
808 used. The auxiliary component (e.g., desiccants) should differ in shape and/or size from the
809 dosage form (e.g., tablets, capsules) with which it is packaged. The quality standards described
810 in USP General Chapter <670> Auxiliary Packaging Components are typically considered
811 sufficient to establish the suitability of pharmaceutical coil and desiccants. If other auxiliary
812 packaging components are used, the composition and appropriate tests with acceptance criteria to
813 establish suitability should be provided (see section V.A.2 for further information about
814 suitability evaluations). Stability studies must use the final CCS in which the drug product will
815 be marketed, including any auxiliary packaging component. 74 Stability studies of the drug
816 substance should also be conducted in a CCS that is the same as or simulates the packaging
817 proposed for storage and distribution, including any auxiliary packaging components. 75
818
819 3. Packaging Components for Device Constituent Parts of Combination Products
820
821 A CCS that is also a device constituent part of a combination product is subject to certain
822 regulatory requirements that are beyond the scope of this guidance. 76 These requirements
823 include, but are not limited to, CGMP 77 and postmarketing safety reporting 78 requirements under
824 21 CFR part 4 and the submission of information in premarket applications to support the safety
825 and effectiveness of the combination product, including the performance of the device
826 constituent part. 79,80,81 For example, if the CCS is a device constituent part of a combination
827 product, the device constituent part and combination product as a whole must be designed and
74
See 21 CFR 211.166(a)(4).
75
See the ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November
2003).
76
Applicants who have questions regarding combination product requirements should contact the lead center or the
Office of Combination Products ([email protected]) for assistance.
77
For further information, see the guidance for industry and FDA staff Current Good Manufacturing Practice
Requirements for Combination Products (January 2017).
78
See the guidance for industry and FDA staff Postmarketing Safety Reporting for Combination Products (July
2019).
79
For further information, see the guidance for industry and FDA staff Principles of Premarket Pathways for
Combination Products (January 2022).
80
FDA’s approval of an abbreviated new drug application is based on demonstration of sameness to the applicable
reference listed drug, which then allows FDA to rely on its previous findings of the safety and effectiveness of the
reference listed drug. See section 505(j) of the FD&C Act.
81
FDA’s clearance of a 510(k) is based on a demonstration of substantial equivalence (which is basically a
comparative safety and effectiveness evaluation) to a legally marketed predicate device. See section 513(i) of the
FD&C Act.
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828 tested consistent with the requirements in Clause 7.3 of ISO 13485:2016, as required by 21 CFR
829 820.10(c), if applicable. 82 The design control requirements in Clause 7.3 of ISO 13485:2016, as
830 required by 21 CFR 820.10(c) may overlap with the requirements and recommendations for CCS
831 quality assessments and controls discussed in this guidance. A CCS that is a device constituent
832 part of a combination product may also be subject to purchasing controls requirements in Clause
833 7.4 of ISO 13485:2016, as required by 21 CFR 820.10(a) for any container closure components
834 that are supplied by another manufacturer. Similarly, purchasing control requirements relate to,
835 and may overlap with, CCS quality assessments and controls such as those discussed in this
836 guidance.
837
838 For a CCS that is also a device constituent part of a combination product, appropriate testing
839 should be performed to demonstrate the device’s function and delivery performance. 83
840 Evaluations should verify and validate the drug delivery performance after shipping, during
841 storage, and in use. 84 For example, pre-filled syringes serve as a delivery device by action of the
842 plunger system; the elastomeric component (i.e., the plunger) must move to empty the container
843 upon demand. Tests of this function (e.g., glide force, break force) as well as the device’s
844 container closure function (e.g., seal integrity tests), should be provided to help evaluate these
845 systems. The CCS for an MDI generally consists of the device constituent parts (i.e., the canister,
846 the actuator, and the metering valve). To characterize the delivery performance of an MDI, the
847 application should provide data to demonstrate consistent and reliable dose delivery (e.g., valve
848 delivery, delivered dose uniformity, aerodynamic particle size distribution, spray pattern). 85
849 Other assessments relating to device performance may include human factors studies to evaluate
850 the user interface of a product. 86
82
As explained in the guidance for industry and FDA staff Current Good Manufacturing Practice Requirements for
Combination Products (January 2017), the Agency has exempted some devices from all or certain provisions of the
device quality system regulations. For example, 21 CFR 880.6430 exempts liquid medication dispensers (cups,
droppers, etc.) from all provisions of the device quality system regulations with the exception of requirements
concerning records and complaint files in Clauses 4.2.5 and 8.2.2 of ISO 13485:2016, among other requirements
under 21 CFR 820.35 (recordkeeping and complaint file requirements were previously in 21 CFR 820.180 and
820.198, respectively). Such exemptions may extend to device constituent parts of combination products and to the
combination products of which they are a part. If the exemptions for a device constituent part of a drug-device
combination product cover all of the part 820 provisions included in 21 CFR 4.4(b)(1), then the Agency will
consider the combination product manufacturer CGMP compliant so long as the CGMP operating system is
compliant with part 211 (no demonstration of compliance with part 820 will be necessary). However, if a device that
would ordinarily be exempt from all or certain provisions in part 820 is incorporated into a CCS, for example, if a
dropper is incorporated into the cap of a bottle of a drug, this may be a new use of the device such that the
exemptions from part 820 may not be applicable. In any event, when incorporated into a CCS, the device must be
addressed as part of the CCS for purposes of part 211. For further information, see the guidance for industry and
FDA staff Current Good Manufacturing Practice Requirements for Combination Products (January 2017).
83
See draft guidance for industry Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and
Biological Products (June 2024) When final, this guidance will represent FDA’s current thinking on this topic.
84
Ibid.
85
See the draft guidance for industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products —
Quality Considerations (April 2018). When final, this guidance will represent FDA’s current thinking on this topic.
86
See guidance for industry and FDA staff Application of Human Factors Engineering Principles for Combination
Products: Questions and Answers (September 2023). See also the draft guidance for industry Comparative Analyses
and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an
ANDA (January 2017). When final, this guidance will represent FDA’s current thinking on this topic. The
recommendations included in this guidance generally focus on the analysis of the proposed user interface for a
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851
852 C. Recommendations for Bulk Containers
853
854 A bulk container can be used to store and ship drug substances and bulk drug products. 87 The
855 bulk container should adequately protect the drug and should be constructed of materials that are
856 safe and are compatible with the drug.
857
858 The quality assessments regarding the bulk container used for drug substances should generally
859 include:
860
861 • a detailed description of the complete CCS for the bulk drug substance (e.g., specific
862 container, closure, all liners, inner seal, desiccant)
863 • the composition of each component
864 • the analytical test methods and criteria for the acceptance and release of each packaging
865 component
866
867 A bulk container may be used to transport bulk drug products for filling, packaging, or
868 repackaging. The bulk container should meet the same requirements for protection,
869 compatibility, and safety as the final or primary CCS during the specified storage time and
870 conditions of the bulk drug products. 88
871
872
873 VI. CCS INFORMATION SUBMITTED IN SPECIFIC APPLICATION TYPES
874
875 For products that require an application, information about the CCS should be included directly
876 in the application, or in a master file that may be included by reference in an application, to show
877 that each proposed CCS and its components are suitable for their intended use. This section
878 addresses the particular types of CCS information that should be submitted in different
879 application types.
generic drug-device combination product (generic combination product) when compared to the user interface for a
reference listed drug. For information regarding the type and amount of human factor data necessary for biosimilars
and interchangeables, please contact the Division of Medication Error Prevention and Analysis within CDER’s
Office of Medication Error Prevention and Risk Management.
87
A bulk container is not the final CCS for finished drug products; instead, it is an intermediate container that holds
the bulk drug for further manufacturing or packaging, or for shipment to repackagers or contract packagers.
Pharmacy bulk packages (PBPs) and Imaging Bulk Packages (IBP) are not considered bulk containers for purposes
of this guidance because they are final containers of marketed drug products in large quantities. Designation as a
PBP or IBP is limited to injection, for injection, or injectable emulsion dosage forms as defined in USP General
Chapter <1121> Nomenclature. See USP General Chapter <659> Packaging and Storage Requirements for the
definitions of package type terms.
88
When the drug will be subject to a new drug application or a biologics license application (under section 351(a) or
(k) of the PHS Act), FDA recommends contacting the specific drug product review division with questions about
bulk containers. For further information, see the draft guidances for industry Formal Meetings Between the FDA and
Sponsors or Applicants of PDUFA Products (Rev 1) (September 2023) and Formal Meetings Between the FDA and
Sponsors or Applicants of BsUFA Products (Rev 1) (August 2023). When final, these guidances will represent
FDA’s current thinking on these topics. When the submission is an abbreviated new drug application (ANDA),
submit questions through the pre-ANDA meeting or controlled correspondence processes. See the guidances for
industry Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA (Rev 1)
(October 2022) and Controlled Correspondence Related to Generic Drug Development (Rev 1) (March 2024).
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880
881 A. Marketing Applications
882
883 All significant phases of the manufacturing and processing of a drug should be described in the
884 CMC section of the application for marketing approval or in a master file referenced in the
885 application. 89 Use of the electronic common technical document (eCTD) format is required when
886 submitting the quality section of an application to FDA. 90 Other FDA guidance provides for the
887 required formatting of device constituent part information. 91
888
889 Table 4 summarizes the general information that should be submitted for a CCS in an application
890 for marketing approval. The recommended information should also be included in supplements
891 to report changes to approved applications.
892
893 Table 4. General Information That Should Be Submitted for a CCS in an Application for
894 Marketing Approval
eCTD references Recommended information
CCS for drug substances
A brief description and discussion of the CCS information for the drug
2.3.S.6 substance (see 3.2.S.6), with summary tables and hyperlinks to related
testing reports
Description
• Identity of MOC
• Specifications
Suitability
3.2.S.6 • Choice of materials
• Protection
• Compatibility
• Safety
• Leachables and extractables assessments
• Container closure integrity for sterile substances
3.2.S.7 Stability
89
With a few exceptions, FDA does not generally permit biological products in biologics license applications to
incorporate by reference drug substance, drug substance intermediate, or drug product information in master files
(referred to as Type II drug master files) (see 21 CFR 601.2(g)(1)).
90
Electronic submission and use of the eCTD format are required for investigational new drug applications, new
drug applications, abbreviated new drug applications, biologics license applications, and most drug master files. See
section 745A(a) of the FD&C Act; guidance for industry Providing Regulatory Submissions in Electronic Format —
Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
(September 2024). For further information, see the ICH guidances for industry M4Q: The CTD — Quality (August
2001) and M4S: The CTD — Safety (August 2001). See also the guidance for industry ANDA Submissions —
Content and Format of Abbreviated New Drug Applications (June 2019).
91
For information about the device constituent part portion of the application, see the technical specifications
document eCTD Technical Conformance Guide (November 2022) and the guidance for industry Providing
Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related
Submissions Using the eCTD Specifications (February 2020).
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eCTD references Recommended information
CCS for drug products
A brief description and discussion of the CCS information for the drug
2.3.P.7 product (see 3.2.P.7), with summary tables and hyperlinks to related
testing reports
Suitability
• Choice of materials
• Protection
3.2.P.2.4 • Compatibility
• Safety
• Performancea
• Leachables and extractables assessments
Microbiological attributesb
3.2.P.2.5
• Demonstrate container closure integrity for sterile products
Process validation and/or evaluation for primary container closure
• Cleaning
3.2.P.3.5
• Depyrogenation
• Sterilization validation
Description
• Identification of MOC
3.2.P.7 • Specifications and certificate of analysis
• Engineering drawing
• Test results per USP requirements
3.2.P.8 Stability
Toxicology of Extractables and Leachables
A summary and discussion of toxicological risk assessments of
leachables and extractables from 3.2.S.6, 3.2.P.2, and 3.2.P.7, and the
2.6.6.8
rationale for conducting the studies, including summary tables and
hyperlinks to related testing reports
4.2.3.7.7 Nonclinical toxicological risk assessments
895 a If a CCS is also a device constituent part, the application should provide all appropriate additional information.
896 b For microbiological attribute considerations of nonsterile products, see the draft guidance for industry Microbiological Quality
897 Considerations in Non-Sterile Drug Manufacturing (September 2021). When final, this guidance will represent FDA’s current
898 thinking on this topic.
899
900 B. Investigational Applications 92
901
902 The CMC section of an investigational new drug application typically includes brief descriptions
903 of the packaging components, the assembled CCS, and any precautions needed to ensure that the
904 drug is protected and preserved during its use in clinical trials. The amount and depth of CMC
905 information that applicants should submit in the investigational new drug application depends on
906 the phase of the investigation, the nature of the clinical study proposed in humans, and whether
92
“Investigational applications” as used here refers to investigational new drug applications (INDs) as well as
investigational device exemption applications (IDEs) for device-led combination products. For IDEs, refer to 21
CFR 812.27 for submission requirements for nonclinical testing. The type and extent of testing appropriate for CCSs
of the drug are generally the same for both IDEs and INDs.
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907 the information is safety-related. FDA may request that additional, more comprehensive CCS
908 quality information be submitted to address specific safety concerns (e.g., proposals to employ
909 new or novel packaging materials or for atypical delivery systems). 93 Updates to the CCS
910 information should be provided if it differs from that reported in the studies for the previous
911 phase. If changes that could affect product quality are made to the CCS, the applicant should
912 submit an information amendment (e.g., CMC safety information).
913
914 C. Master Files
915
916 Drug master files (DMFs) may be used to provide confidential, detailed information about
917 packaging of drug products. DMF holders can authorize an applicant to incorporate by reference
918 information contained in the DMF without having to disclose that information to the
919 applicant. 94,95 For example, type II drug master files might be used to provide container closure
920 information for drug substances and, if applicable, CCIT information for sterile drug substances;
921 type III drug master files might be used to provide information about packaging materials,
922 including descriptions of the MOC and packaging components, controls for packaging materials
923 and components, and data (e.g., suitability evaluation) supporting acceptability of the packaging
924 material or component for its intended use. Type III drug master files can also include
925 information regarding depyrogenation and sterilization of packaging components, as applicable.
926
927
928 VII. REPORTING POSTAPPROVAL CHANGES TO A CCS
929
930 FDA’s regulations describe when a change to an approved drug product (including a biological
931 product) or its manufacturing process requires a postmarket submission. The provisions also
932 apply to changes to a CCS component, a device constituent part that is (or is part of) the CCS, or
933 a CCS component’s MOC, and to changes to a manufacturing process involving any of these
934 items. 96
935
93
For general guidance regarding the CCS information to be submitted for phase 1, 2, and 3 studies of an
investigational new drug application, see the guidances for industry Content and Format of Investigational New
Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-
Derived Products (November 1995) and INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and
Controls Information (May 2003).
94
For general information about master file format and content, see the draft guidance for industry Drug Master
Files (October 2019). When final, this guidance will represent FDA’s current thinking on this topic. For information
specific to drugs, see https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. For
information specific to biological drugs, see https://www.fda.gov/vaccines-blood-biologics/development-approval-
process-cber/master-files-cber-regulated-products. For information specific to devices and device constituent parts,
see https://www.fda.gov/medical-devices/premarket-approval-pma/master-files.
95
FDA does not approve drug master file submissions, but rather reviews the technical contents of the master file in
support of the application. An IND, NDA, or ANDA that incorporates by reference information in a drug master file
must include a letter of authorization from the drug master file holder to the application holder. See 21 CFR
314.420(b). Each incorporation by reference must describe the information being incorporated by name, reference
number, volume, and page number.
96
The requirements are specified in 21 CFR 314.70 for a new drug application, in 21 CFR 314.97 for an abbreviated
new drug application, and in 21 CFR 601.12 for a biologics license application. All manufacturing changes must be
reviewed and approved by the quality control unit (see 21 CFR 211.100(a) and 211.160(a)).
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936 Any changes to a drug’s CCS should be based on a risk assessment for potential effects on
937 identity, strength, quality, purity, or potency (see section IV). The type of information that
938 should be submitted depends on the potential for adverse effects on the safety or effectiveness of
939 the drug. In some cases, there may be substantial potential for adverse effects, even if testing was
940 conducted to establish conformance with the approved specification. A change to a packaging
941 component may result in a new or revised specification for the packaging component. 97
942
943 Multiple guidances for industry describe the Agency’s recommendations for how postapproval
944 changes to CCSs should be reported. 98 Submissions should include risk analyses and quality-
945 related evaluations as described in sections IV and V of this guidance 99 and should provide a
946 scientific justification for omitting any recommended testing. Changes to a device constituent
947 part of a combination product affect the combination product as a whole; for example, a change
948 in the device constituent may change the container closure function, device performance
949 characteristics, and the performance and labeling of the overall combination product. Therefore,
950 when considering the data to provide for a change to a device constituent part of a combination
951 product, in addition to addressing the change in the container closure (as described in the
952 referenced guidance documents), applicants should consult other relevant guidance
953 documents. 100
954
97
In accordance with the ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009), the
manufacturer’s quality system should be considered to extend to control of the quality of purchased materials. A
firm’s supplier qualification program should take into account that component specifications may vary by supplier.
98
Some of the guidances that may be relevant are: the ICH guidance for industry Q12 Technical and Regulatory
Considerations for Pharmaceutical Product Lifecycle Management (May 2021) and the guidances for industry
Changes to an Approved NDA or ANDA (April 2004), Changes to an Approved NDA or ANDA: Questions and
Answers (January 2001), CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March
2014), CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual
Reports (December 2021), and Chemistry, Manufacturing, and Controls Changes to an Approved Application:
Certain Biological Products (June 2021). See also the draft guidances for industry Postapproval Changes to Drug
Substances (September 2018), Submissions for Postapproval Modifications to a Combination Product Approved
Under a BLA, NDA, or PMA (January 2013), and ICH Q12: Implementation Considerations for FDA-Regulated
Products (May 2021). When final, these guidances will represent FDA’s current thinking on these topics.
99
See the ICH guidances for industry Q9(R1) Quality Risk Management (May 2023) and Q10 Pharmaceutical
Quality System (April 2009).
100
FDA has published the following draft guidances which may be a helpful resource: Submissions for Postapproval
Modifications to a Combination Product Approved Under a BLA, NDA, or PMA (January 2013), Bridging for Drug-
Device and Biologic-Device Combination Products (December 2019), and Essential Drug Delivery Outputs for
Devices Intended to Deliver Drugs and Biological Products (June 2024). When final, these guidances will represent
FDA’s current thinking on these topics.
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955 GLOSSARY
956
957 Analytical evaluation threshold (AET): The threshold at or above which a particular
958 extractable or leachable should be identified, quantified, and further reported for potential
959 toxicological assessment. AET is based directly on the SCT, but it is a relative value, not an
960 absolute value.
961
962 Combination product: A combination product is a human medical product composed of two or
963 more different types of medical products (i.e., drug and device, drug and biological product,
964 device and biological product, or all three together) (see 21 CFR 3.2(e)). A constituent part of a
965 combination product is a drug, device, or biological product that is a part of the combination
966 product (see 21 CFR 4.2).
967
968 Container closure system: The sum of packaging components and materials that together
969 contain and protect the article. This includes primary packaging components, and it includes
970 secondary packaging components when they are required to provide additional protection.
971
972 Critical quality attribute: A critical quality attribute is a physical, chemical, biological, or
973 microbiological property or characteristic that should be within an appropriate limit, range, or
974 distribution to ensure the desired product quality. (ICH Q8(R2))
975
976 Extractables: Organic and inorganic chemical entities that can be released from a
977 pharmaceutical packaging or delivery system, packaging component, or packaging material of
978 construction and into an extraction solvent under laboratory conditions.
979
980 Leachables: Foreign organic and inorganic chemical entities that are present in a packaged drug
981 product because they have leached into the packaged drug product from a packaging or delivery
982 system, packaging component, or packaging material of construction under normal conditions of
983 storage and use or during accelerated drug product stability studies.
984
985 Materials of construction: The materials (e.g., glass, plastic, elastomers, metal) of which a
986 packaging component consists.
987
988 Packaging component: Any single part of the package or container closure system, including
989 the container (e.g., ampules, syringes, vials, bottles), closures (e.g., screw caps, stoppers),
990 ferrules and overseals, closure liners (e.g., tube cartridge liners), inner seals, administration ports,
991 overwraps, administration accessories, labels, cardboard boxes, and shrink wrap.
992
993 Primary packaging component: A packaging component that is in direct contact with, or may
994 come into direct contact with, the drug.
995
996 Qualification threshold (QT): The threshold below which a given leachable is not considered
997 for safety qualification unless the leachable presents structure–activity relationship concerns.
998
999
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1000 Safety concern threshold (SCT): The threshold below which a leachable would have a dose so
1001 low that it presents negligible safety concerns from carcinogenic and noncarcinogenic toxic
1002 effects.
1003
1004 Secondary packaging component: A packaging component that is in direct contact with a
1005 primary packaging component and may provide additional protection for the drug (e.g., labels,
1006 adhesives, over-pouches, wraps, cartons).
33
来源：FDA 全域目录：药品／生物制品制造质量指南 · fda.gov