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。
FDA guidance: Container Closure Systems for Human Drugs and Biological Products
Status: Draft. Draft — Not for Implementation; distributed for comment.
FDA directory issue date: 2026-08-13 (MM/DD/YYYY in source).
Directory modification time is retained in source metadata; it is not a new issue date or proof that the PDF was revised.
Products: Drugs
Topics: Chemistry, Manufacturing, and Controls (CMC), Pharmaceutical Quality
Issuing offices: Center for Drug Evaluation and ResearchCenter for Biologics Evaluation and Research
Document type: Guidance Document
Official detail page: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-human-drugs-and-biological-products
Scope: public guidance PDFs from FDA's whole-agency directory, explicitly tagged Drugs/Biologics and manufacturing/quality/ICH-Quality. The complete PDF follows.
PDF 文字版；图形和原始排版请参阅官方 PDF。
第 1 页
Container Closure Systems for
Human Drugs and Biological
Products
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) [email protected];
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010;
or (OCP) [email protected].
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Combination Products (OCP)
August 2026
Pharmaceutical Quality/CMC
第 2 页
Container Closure Systems for
Human Drugs and Biological
Products
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: [email protected]
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
Phone: 800-835-4709 or 240-402-8010
Email: [email protected]
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
and/or
Office of Combination Products
Food and Drug Administration
10903 New Hampshire Ave., WO32, Hub/Mail Room #5129
Silver Spring, MD 20993
Phone: 301-796-8930; Fax: 301-847-8619
Email: [email protected]
https://www.fda.gov/combination-products/guidance-regulatory-information/combination-products-guidance-documents
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Combination Products (OCP)
August 2026
Pharmaceutical Quality/CMC
第 3 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. SCOPE ............................................................................................................................... 2
III. BACKGROUND ............................................................................................................... 3
A. Statutory and Regulatory Authority ............................................................................................ 4
B. Compendial Requirements ............................................................................................................ 5
C. Combination Products ................................................................................................................... 5
IV. RISK-BASED FRAMEWORK: FACTORS TO CONSIDER ..................................... 6
A. General Considerations ................................................................................................................. 6
1. Safety of Packaging Materials ......................................................................................................... 6
2. Protection......................................................................................................................................... 7
3. Performance..................................................................................................................................... 7
4. Impacts of Manufacturing Process .................................................................................................. 8
5. Storage and Handling ...................................................................................................................... 8
B. Risk Considerations for Common Dosage Forms of Drug Products ........................................ 8
1. Inhalation Products ....................................................................................................................... 10
2. Intranasal Products ....................................................................................................................... 11
3. Injectable Drug Products............................................................................................................... 11
4. Transdermal and Transmucosal Delivery Systems ........................................................................ 12
5. Topical Dermal Drug Products ..................................................................................................... 12
6. Ophthalmic and Otic Products ...................................................................................................... 13
7. Oral Drug Products ....................................................................................................................... 13
V. QUALITY ASSESSMENT AND CONTROL.............................................................. 14
A. Typical Quality Assessments and Control of a CCS ................................................................. 15
1. Description..................................................................................................................................... 16
2. Suitability Evaluation..................................................................................................................... 17
3. Quality Control .............................................................................................................................. 22
4. Stability Testing ............................................................................................................................. 22
5. Additional Tests for Shipping, Handling, and Storage .................................................................. 23
B. Special Considerations for Particular Packaging Components ............................................... 24
1. Secondary Packaging Components................................................................................................ 24
2. Auxiliary Packaging Components.................................................................................................. 25
3. Packaging Components for Device Constituent Parts of Combination Products ......................... 25
C. Recommendations for Bulk Containers ..................................................................................... 27
i
第 4 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
VI. CCS INFORMATION SUBMITTED IN SPECIFIC APPLICATION TYPES ....... 27
A. Marketing Applications ............................................................................................................... 28
B. Investigational Applications ........................................................................................................ 29
C. Master Files .................................................................................................................................. 30
VII. REPORTING POSTAPPROVAL CHANGES TO A CCS ........................................ 30
GLOSSARY................................................................................................................................. 32
ii
第 5 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
1 Container Closure Systems for Human Drugs and Biological
2 Products
3 Guidance for Industry 1
4
5
6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person
8 and is not binding on FDA or the public. You can use an alternative approach if it satisfies the
9 requirements of the applicable statutes and regulations. To discuss an alternative approach,
10 contact the FDA staff responsible for this guidance as listed on the title page.
11
12
13
14 I. INTRODUCTION
15
16 This document provides guiding principles 2 for evaluating the qualityof container closure
17 systems (CCSs) 3 used to package drugs and biological products, for human use. This includes
18 CCSs that are also device constituent parts of combination products and CCSs used to package
19 the drug or biological product constituent parts of combination products. 4 Specifically, this
20 guidance discusses FDA’s current thinking on how to evaluate CCSs according to a risk-based
21 framework that includes quality assessments and quality control of packaging materials and
22 components. 5 When final, this guidance will supersede the guidances for industry Container
23 Closure Systems for Packaging Human Drugs And Biologics (May 1999) and Container Closure
24 Systems for Packaging Human Drugs and Biologics — Questions and Answers (May 2002). 6
25 FDA intends to supplement this guidance with additional guidances to provide topic-specific
26 recommendations related to the general information described in this guidance. These topic-
27 specific guidances will address methods related to evaluating and characterizing novel CCSs and
28 provide information about specific quality attributes and testing requirements, including
1
This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in cooperation with the Center for Biologics Evaluation and Research, Center for Devices and
Radiological Health, Office of Regulatory Affairs (now known as the Office of Inspections and Investigations), and
Office of Combination Products in the Office of the Commissioner at the Food and Drug Administration.
2
This guidance does not suggest specific test methods or acceptance criteria (except for references to United States
Pharmacopeia methods), nor does it suggest comprehensive lists of tests. These details should be determined based
on good scientific principles for each specific container closure system for specific drug product formulations,
dosage forms, and routes of administration. Acceptance criteria should be based on data for specific packaging
components and container closure systems.
3
Terms bolded at first mention are defined in the Glossary.
4
See 21 CFR 3.2(e) and 21 CFR 4.2. If you have questions regarding whether a CCS is a device and your product is,
therefore, a combination product, contact the Office of Combination Products at [email protected] for
assistance.
5
FDA responds to potential drug shortages by taking actions to address their underlying causes and enhance product
availability, as appropriate. When drug shortages are caused by quality problems, including problems involving a
CCS, FDA works with the firm to address the issues. For drug shortage information and reporting, see
https://www.fda.gov/drugs/drug-shortages/frequently-asked-questions-about-drug-shortages.
6
We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
1
第 6 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
29 considerations for extractables and leachables evaluations and associated toxicological risk
30 assessments.
31
32 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
33 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
34 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
35 the word should in Agency guidances means that something is suggested or recommended, but
36 not required.
37
38
39 II. SCOPE
40
41 This guidance provides recommendations regarding pharmaceutical quality considerations (e.g.,
42 chemistry, manufacturing, and controls (CMC)) for CCSs used for human drugs and biological
43 products. 7 It discusses both general principles and specific considerations for the development
44 and assessment of CCSs for drug products, 8 and drug substances. It also applies to CCSs that are
45 device constituent parts of combination productsor that are used to hold the drug or biological
46 product constituent part(s) of these products. 9 Although the scope of this guidance excludes
47 stand-alone devices, and its focus is on CCSs that package drugs or biological products, some
48 recommendations described in this guidance also may be applicable to stand-alone devices
49 intended to deliver drugs. 10
50
51 This guidance applies to applications 11 including amendments and supplements to approved
52 applications, for human drugs and biological products, as well as for combination products. It
53 also applies to drug products legally marketed according to section 505G of the Federal Food,
7
For the purposes of this guidance, the term drug refers to drug substance and drug product, including biological
products. Biological products refer to those defined in section 351(i)(1) of the Public Health Service Act and subject
to licensure under section 351(a) or (k) of the Act. In this guidance, drug also includes drug or biological product
constituent parts of combination products.
8
For the purposes of this guidance, drug product refers to any drug in finished dosage form.
9
In accordance with 21 CFR 3.4, a combination product is assigned to an Agency center that will have primary
jurisdiction for that combination product’s premarket review and regulation. A drug or biological product
constituent part may be part of a CDER-, CBER-, or CDRH-led combination product. Combination products
composed of a device constituent part that is the CCS for a drug or biological product constituent part are typically
assigned to CDER or CBER.
10
Questions regarding whether these recommendations would apply to a specific device should be discussed with
the CDRH or CBER review division during the development process. In this guidance, the term device has the
meaning given in section 201(h) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(h)).
11
For the purposes of this guidance, the term application refers to investigational new drug applications, new drug
applications, abbreviated new drug applications, and biologics license applications. It also includes investigational
device exemption applications, premarket approval applications, De Novo requests, and premarket notifications (as
described in sections 515, 513(f)(2), and 510(k) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360e,
360c(f)(2), and 360(k)), respectively) for combination products covered by this guidance.
2
第 7 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
54 Drug, and Cosmetic Act (FD&C Act) 12 without an approved application under section 505 of the
55 FD&C Act. 13,14
56
57 This guidance is not intended to address packaging operations (e.g., processes of filling,
58 packaging, and labeling) associated with drug product manufacture.
59
60 This guidance does not cover standards and recommendations for child-resistant packaging.
61 Regulations issued under the Poison Prevention Packaging Act of 1970 (PPPA) 15 establish the
62 standards and test procedures for child-resistant packaging. 16 For applications that propose child-
63 resistant packaging statements in product labeling, the applicant should follow the
64 recommendations in the guidance for industry Child-Resistant Packaging Statements in Drug
65 Product Labeling (August 2019), which include submitting written verification to FDA that the
66 drug product’s child-resistant packaging meets the standards under 16 CFR part 1700.
67
68
69 III. BACKGROUND
70
71 A CCS is the sum of packaging components that together contain and protect a drug. It includes
72 the primary packaging components, and it also includes the secondary packaging
73 components if their purpose is to further protect the drug. A CCS must provide adequate
74 protection in storage and use without altering the safety, identity, strength, quality, or purity of
75 the drug beyond the official or established requirements. 17 For example, packaging components
76 should be constructed of materials that will not leach harmful or undesirable amounts of
77 substances to which patients could be exposed directly or indirectly.
78
79 In recent years, the development of novel drug products and new container closure technologies
80 has led to advancements in the design, construction, and evaluation of CCSs. For example,
81 technological advancements in pharmaceutical therapies can introduce additional functional
82 purposes for CCSs, as with products that use the CCS to prepare the final dosage or to deliver the
83 product. In such cases, additional control measures and testing should be conducted to ensure
84 that the additional functions of the CCS do not adversely impact the safety, identity, strength,
85 quality, and purity of the product.
86
87 To accommodate the advancements in the design, construction, and evaluation of CCSs, several
12
See 21 U.S.C. 355h.
13
See 21 U.S.C. 355.
14
Drugs marketed pursuant to section 505G of the FD&C Act must also meet the general requirements for
nonprescription drugs, which include requirements that these drugs contain only safe and suitable inactive
ingredients and are manufactured according to current good manufacturing practice. It is the manufacturer’s
responsibility to comply with these requirements and to document and maintain supporting data in its files.
15
Authority under the PPPA is vested in the Consumer Product Safety Commission by section 30(a) of the
Consumer Product Safety Act. Special packaging is defined under 15 U.S.C. 1471(4), 16 CFR 1700.1(b)(4), and 21
CFR 310.3(l). Regulations issued under the PPPA establish performance standards and test methods that determine
if a packaging system is child-resistant and adult-use-effective (16 CFR 1700.15 and 16 CFR 1700.20). The written
verification to FDA discussed in this guidance is separate from the certification required to be provided to the
Consumer Product Safety Commission under 15 U.S.C. 2063 and 16 CFR 1110.
16
See 16 CFR part 1700.
17
See 21 CFR 211.84 and 211.94.
3
第 8 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
88 general chapters within the United States Pharmacopeia and the National Formulary (USP-NF)
89 provide new or updated information relevant to the storage and distribution of pharmaceutical
90 products, including more comprehensive and advanced testing to characterize packaging
91 materials and components. Other FDA and International Conference on Harmonization (ICH)
92 guidances 18,19 that outline specific recommendations relevant to CCS assessments have also been
93 issued since the 1999 publication of the guidance for industry Container Closure Systems for
94 Packaging Human Drugs and Biologics.
95
96 A. Statutory and Regulatory Authority
97
98 The FD&C Act contains packaging requirements for drug products. A drug is deemed
99 adulterated “if its container is composed,in whole or in part, of any poisonous or deleterious
100 substance which may render the contents injurious to health” (see section 501(a)(3) 20). A drug is
101 also deemed adulterated if the methods, facilities, or controls used for its manufacture,
102 processing, packing, or holding do not conform to or are not operated or administered according
103 to current good manufacturing practice (CGMP, see section 501(a)(2)(B) 21). Additionally, under
104 section 502, 22 a drug is deemed misbranded if its packaging, including labeling, does not meet
105 other requirements set forth in the Act. An application must include a description of the
106 manufacturing and packing procedures as described in 21 CFR 314.50(d)(1) for new drug
107 applications, in 21 CFR 314.94(a)(9) for abbreviated new drug applications, and in 21 CFR
108 601.2 for biologics license applications. For a device-led combination product reviewed in an
109 appropriate device application, such a description as noted is among the types of information that
110 would typically be necessary to support the safety and effectiveness of the combination
111 product. 23 For all drug products and combination products, information to demonstrate
112 compliance with CGMP with respect to the CCS (e.g., 21 CFR 4, subpart A, 21 CFR 211 subpart
113 E, 21 CFR part 820) 24 must be available on inspection or upon a request under section 704(a)(4)
114 of the FD&C Act.
115
18
See, for example, the guidance for industry Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products — Chemistry, Manufacturing, and Controls Documentation (July 2002). See also 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.
19
See, for example, the ICH guidance for industry Q8(R2) Pharmaceutical Development (November 2009).
20
See 21 U.S.C. 351(a)(3).
21
See 21 U.S.C. 351(a)(2)(B).
22
See 21 U.S.C. 352.
23
As explained in the guidance for industry and FDA staff Principles of Premarket Pathways for Combination
Products (January 2022), in determining what is needed to demonstrate the safety and effectiveness of the
combination product, FDA takes into account the questions and considerations, reflected in the statutory and
regulatory provisions associated with each constituent part in its review of the combination product as a whole and
its constituent parts. This includes how the constituent parts may interact and interrelate. For example, for a device-
led combination product reviewed in an appropriate device application that includes a drug constituent part (that
would otherwise be reviewed in an NDA), nonclinical pharmacology and toxicology and clinical pharmacology
(including pharmacokinetic) data and chemistry, manufacturing, and controls (CMC) information are among the
types of information that would typically be necessary.
24
On February 2, 2024, FDA issued a final rule amending the device quality system regulation, 21 CFR part 820, to
align more closely with international consensus standards for devices and conforming amendments were also made
to 21 CFR part 4 (89 FR 7496, available at https://www.federalregister.gov/d/2024-01709). This final rule took
4
第 9 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
116 B. Compendial Requirements
117
118 Section 201(j) of the FD&C Act 25 recognizes the USP-NF as an official compendium of the
119 United States. Under section 501(b) of the FD&C Act, 26 a drug is deemed to be adulterated if it
120 purports to be or is represented as a drug the name of which is recognized in the USP-NF and its
121 strength differs from, or its quality and purity falls below, the standards set forth in the
122 compendium. Under section 502(g) of the FD&C Act, 27 a drug with a name recognized in the
123 USP-NF is deemed misbranded unless it is packaged and labeled as described in the
124 compendium. Standards for an article recognized in a USP-NF official monograph, general
125 chapter, or general notice apply for the article’s entire life cycle (production to expiration).
126 Various USP general chapters define requirements for materials of construction (MOC),
127 components, and CCSs. For new or newly revised standards, USP allows, and FDA generally
128 encourages, early adoption of revised standards in advance of the official date unless otherwise
129 specified at the time of publication. 28
130
131 C. Combination Products
132
133 A combination product is a human medical product composed of two or more types of medical
134 products (i.e., drug and device, drug and biological product, device and biological product, or all
135 three together). 29 The drugs, devices, and biological products included in combination products
136 are referred to as constituent parts of the combination product. A CCS may also be a device
137 constituent part if it has more than one function (e.g., to be a container closure and to deliver the
138 drug). Examples of CCSs that may also be a device constituent part of a combination product
139 include piston syringes, pumps, metered dose inhalers (MDIs), and intravenous bags.
140 Combination products raise additional premarket review considerations relating, for example, to
141 performance of the device, engineering, and user interface, all of which may be affected by
142 interactions (e.g., adsorption) between the device and drug or biological product it holds. 30
143 Combination products are also subject to additional postmarket regulatory requirements,
144 including 21 CFR part 4 subparts A and B. 31 Some considerations for CCSs that are device
145 constituent parts are addressed in this guidance (see section V.B.3). However, sponsors should
effect on February 2, 2026. This rule revised or removed certain provisions in part 820 and incorporated by
reference the 2016 edition of the International Organization for Standardization (ISO) 13485, Medical devices –
Quality management systems – Requirements for regulatory purposes, in part 820. As stated in the preamble to the
final rule, the requirements in ISO 13485 are, when taken in totality, substantially similar to the requirements of the
current part 820, providing a similar level of assurance in a firm’s quality management system and ability to
consistently manufacture devices that are safe and effective and otherwise in compliance with the Federal Food,
Drug, and Cosmetic Act (FD&C Act). See 89 FR 7496, available at https://www.federalregister.gov/d/2024-01709.
25
See 21 U.S.C. 321(j).
26
See 21 U.S.C. 351(b).
27
See 21 U.S.C. 352(g).
28
See USP General Notices and Requirements <3.10> Applicability of Standards for USP early adoption policies at
the time of reference.
29
See footnotes 4 and 9.
30
For further information, see the guidance for industry and FDA staff, Principles of Premarket Pathways for
Combination Products (January 2022).
31
For further information, see the guidance for industry and FDA staff, Current Good Manufacturing Practice
Requirements for Combination Products (January 2017), and Postmarketing Safety Reporting for Combination
Products (July 2019).
5
第 10 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
146 refer to other relevant guidance including those cited in this guidance, and they may contact the
147 review division for their combination product with questions regarding data and information
148 needed to support marketing authorization.
149
150
151 IV. RISK-BASED FRAMEWORK: FACTORS TO CONSIDER
152
153 Selection of the CCS for a drug depends on the characteristics of both the drug and the CCS. It
154 cannot be assumed that because a CCS was suitable for one drug product, it is automatically
155 appropriate for another product. A CCS’s critical quality attributes, 32 particularly its leachables
156 profile, can be affected by differences in manufacturing processes, variations in materials
157 suppliers, or even subtle changes in the drug product’s formulation.
158
159 A suitable framework for evaluating the quality of a CCS should use a risk management
160 process. 33 The process should begin with an assessment of the CCS used for a specific drug,
161 including the CCS’s selected MOC, the drug’s manufacturing processes, and the drug’s clinical
162 use. The potential risks associated with the CCS should be adequately identified and
163 characterized based on these assessments. For example, interactions between drugs and
164 packaging materials could produce leachables that cause unintended chemical toxicity. Or, these
165 leachables could cause undesirable changes in the drug’s quality (e.g., reduced stability,
166 variations in the impurity profile, increased particulate matter, altered antigenicity) that result in
167 an unacceptable alteration of the drug’s intended therapeutic effects. The qualification and
168 quality control of packaging components should include mitigation strategies that address
169 knowledge gaps and risks identified through testing and other evaluations.
170
171 A. General Considerations
172
173 The following factors should be considered when using a risk-based approach to evaluate a CCS.
174 This list is not exhaustive; additional risk factors may need to be evaluated during the product’s
175 development and life cycle.
176
177 1. Safety of Packaging Materials
178
179 Packaging components should be constructed of materials that will not leach harmful or
180 undesirable amounts of substances to which a patient will be exposed when being treated with
181 the drug. The primary CCS is the most likely source of leachables because the packaging
182 components are in direct contact with the drug, but leachables can also come from secondary
183 CCSs (e.g., protective packaging, inks, labels, adhesives) and from manufacturing equipment
184 used in drug production. Assessments of safety- and compatibility-related risks should be
32
A critical quality attribute is a physical, chemical, biological, or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution to ensure the desired product quality. See the ICH
guidance for industry Q8(R2) Pharmaceutical Development (November 2009).
33
See the ICH guidance for industry Q9(R1) Quality Risk Management (May 2023) and FDA draft guidance,
Benefit-Risk Considerations for Product Quality Assessments (May 2022). When final, this guidance will represent
FDA’s current thinking on this topic.
6
第 11 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
7
第 12 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
8
第 13 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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
9
第 14 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
10
第 15 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
11
第 16 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
12
第 17 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
13
第 18 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
14
第 19 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
15
第 20 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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
16
第 21 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
17
第 22 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
18
第 23 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
19
第 24 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
20
第 25 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
21
第 26 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
22
第 27 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
23
第 28 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
73
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.
24
第 29 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
25
第 30 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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
26
第 31 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
27
第 32 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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).
28
第 33 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
29
第 34 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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)).
30
第 35 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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.
31
第 36 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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
32
第 37 页
Contains Nonbinding Recommendations
Draft — Not for Implementation
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