Container Closure

System and Component

Changes: Glass Vials
and Stoppers
Guidance for Industry

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)

July 2024
Pharmaceutical Quality/Manufacturing Standards
 Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1
II. REGULATORY APPROACHES TO CMC CHANGES ............................................. 2
III. COMMON CHANGES RELATED TO GLASS VIALS AND STOPPERS .............. 4
IV. TOOLS TO FACILITATE CHANGES TO CCS COMPONENTS ............................ 5
A. Risk-Based Considerations for Supplement Reporting Categories........................................... 5
B. Comparability Protocols ............................................................................................................... 6
REFERENCES.............................................................................................................................. 7
APPENDIX: TABLES DESCRIBING CCS CHANGES FOR PRODUCTS WITH
APPROVED ANDAS, NDAS, OR BLAS ................................................................................. 10

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Container Closure System and Component Changes: Glass Vials

and Stoppers
Guidance for Industry 1

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.

I. INTRODUCTION

FDA is issuing this guidance to collate recommendations for appropriate reporting categories and
the content of postapproval change submissions across numerous FDA guidance documents. 2
This guidance conveys recommendations to holders of approved new drug applications (NDAs),
biologics license applications (BLAs), and abbreviated new drug applications (ANDAs)
regarding the reporting and implementation of some common changes to container closure
system (CCS) components consisting of glass vials and stoppers for approved 3 sterile drug
products, including biological products, administered parenterally. This guidance also discusses
pathways available to application holders to obtain Agency feedback. Additionally, this guidance
discusses risk-based tools available to facilitate the implementation of changes to CCSs
consisting of glass vials and stoppers. This guidance does not apply to CCS types other than
glass vials and stoppers.

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 at the Food and Drug
Administration. You may submit comments on this guidance at any time. Submit comments to Docket No. FDA-
2017-D-6821 (available at https://www.regulations.gov/docket?D=FDA-2017-D-6821). See the instructions in
that docket for submitting comments on this and other Level 2 guidances.
2
In March 2021, FDA published the guidance for industry COVID-19 Container Closure System and Component
Changes: Glass Vials and Stoppers, which provided recommendations regarding the reporting and implementation
of some common changes to container closure system (CCS) components consisting of glass vials and stoppers for
approved sterile drugs. That guidance was intended to remain in effect only for the duration of the public health
emergency related to COVID-19 declared by the Secretary of Health and Human Services under section 319 of the
Public Health Service Act (section 319 public health emergency), which has now expired. FDA is issuing this final
guidance because many of the recommendations set forth in the 2021 guidance are applicable outside the context of
the section 319 public health emergency.
3
Although this guidance does not principally address data recommendations for original applications pending
approval, the risk-based regulatory approaches discussed in this guidance, other guidance documents referenced in
References, and the data recommendations provided in the tables in Appendix may be useful during product
development and for original application submission. Should an applicant need to change CCS components before
product approval, the applicant should proactively seek feedback from the appropriate FDA review division to
mitigate the effect of the change on the review timeline of the pending application.

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In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.

II. REGULATORY APPROACHES TO CMC CHANGES

As described in section 506A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356a), 21
CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12, an applicant must notify FDA about changes
in each condition (e.g., the product, production process, quality controls, equipment, facilities, or
labeling) established in an approved application beyond the variations already provided for in the
application. The reporting category for such changes depends on the potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the product as these factors may
relate to the safety or effectiveness of the product. Therefore, changes can range from those that
require approval before implementation (prior approval supplement (PAS)), those that require
notification 30 days before (changes being effected in 30 days (CBE-30)), or upon
implementation (changes being effected), and those where notification can be provided after
implementation (annual report). Some of these identified changes, depending on the
circumstances, may be more appropriately submitted as an original application instead of as
supplements. 4

FDA has conveyed additional clarification regarding reporting of CMC changes to an NDA,
BLA, and ANDA in guidance documents specific to various application types and product
dosage forms (see References). The content in section IV. Common Changes Related to Glass
Vials and Stoppers related to changes to glass vials and stoppers for finished drug and biological
products includes content derived from the referenced guidance documents.

FDA applies a risk-based approach to the evaluation of proposed CMC changes to a CCS (e.g.,
changes in components, composition, container type, suppliers, and manufacturers), taking into
consideration the characteristics of the specific product. The suitability and compatibility of a
CCS depends not only on the properties of a container, but also on the properties of other CCS
components and their interactions with the drug product formulation over its intended shelf life.
Applicants must validate the effects of the change prior to distribution of the drug, 5 and, as
appropriate, conduct additional qualification tests or submit information to address product-
specific risks as part of that assessment. For example, this additional information to be submitted
to FDA could include studies to assess: the effect of formulation attributes such as high pH; the
effect of factors that increase the potential for glass delamination, particulate matter, leachables,
or interactions of labile molecules with leachables (such as susceptibility of some proteins to
interact with metal ions); or the effect of the lyophilization process on product quality. Finally,

4
Applicants can consult the appropriate Center for Drug Evaluation and Research or Center for Biologics
Evaluation and Research review division for questions regarding circumstances where an original application or
supplement should be submitted.
5
See section 506A(b) of the FD&C Act and pertinent regulations at 21 CFR 314.70(a)(2), 21 CFR 314.97(a)
(incorporating 21 CFR 314.70 by reference), and 21 CFR 601.12(a)(2).

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applicable tests and studies as outlined in United States Pharmacopeia (USP) chapters 6 should be
conducted to demonstrate the suitability of the glass vial following a change; such tests must be
conducted where needed to ensure continued compliance with compendial standards for strength,
quality, or purity of the drug. 7 FDA encourages applicants to submit the appropriate
postapproval supplement type as recommended by the existing guidance documents for proposed
changes to the CCS.

FDA may consider available risk evaluations and product quality risk mitigation strategies to
support a lower reporting category for specific changes. FDA recommends applicants use the
risk management principles described in the ICH guidance for industry Q9(R1) Quality Risk
Management (May 2023), and tools described in ICH guidance for industry Q12 Technical and
Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021),
where appropriate. Whether or not a change is required to be reported to FDA, in accordance
with applicable regulations, 8 FDA expects all changes to be appropriately managed by an
establishment’s/facility’s pharmaceutical quality system under the applicable current good
manufacturing practice regulations in 21 CFR parts 210, 211, and 600. Applicants should also
refer to the recommendations in the ICH guidance for industry Q10 Pharmaceutical Quality
System (April 2009).

A supplement for a CCS-related change should include information to support the proposed
change and can incorporate certain information by reference to a drug master file (DMF), where
appropriate. However, when incorporating information by reference to a DMF, the supplement
should also include sufficient product-specific information to support the change.

Applicants are ultimately responsible for assessing the effects of the proposed change(s) on
product quality, and ensuring that information to support the change is provided for a complete
submission of a supplement or annual report. 9 DMF holders must notify affected authorized
parties of any DMF changes, additions, or deletions. 10 DMF holders also should provide
application holders with sufficient information to determine the appropriate reporting category
for their applications based on the potential to have an adverse effect on the identity, strength,
quality, purity, or potency of the product as these factors may relate to the safety or effectiveness
of the product. This notification should occur well before making any changes to permit
authorized parties to submit application changes within an appropriate time frame. For additional
information on DMF submission guidelines, refer to 21 CFR 314.420, 21 CFR 601.51(a), and the
draft guidance for industry Drug Master Files (October 2019). 11

6
See USP General Chapters <381> Elastomeric Closure for Injections, <660> Glass Containers Used in
Pharmaceutical Packaging/Delivery Systems, <1207> Package Integrity Evaluation — Sterile Products, <1660>
Evaluation of the Inner Surface Durability of Glass Containers.
7
See section 501(b) of the FD&C Act.
8
21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
9
21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
10
21 CFR 314.420(c).
11
In June 2014, FDA issued the guidance for industry Drug Master Files: Guidelines. In October 2019, FDA issued
the revised draft guidance for industry Drug Master Files. When final, this guidance will represent FDA’s current
thinking on this topic. 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.

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This guidance is not intended to alter existing submission processes; applicants should follow the
recommendations in current guidance documents for reporting CMC changes to an approved
application (see References).

III. COMMON CHANGES RELATED TO GLASS VIALS AND STOPPERS

The tables in the Appendix of this guidance include information derived from existing FDA
guidance documents that contain recommendations for reporting category and submission
content related to common CMC changes to CCS components (glass vials and stoppers) for
finished drug and biological products. The tables include the type of data recommended to
support a specific change (as discussed in the guidance for industry Container Closure Systems
for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls
Documentation (May 1999)), as well as the recommended reporting category. Some
recommendations regarding data submission and reporting categories may differ based on the
nature of the product and the potential risk to product quality as it may relate to safety and
effectiveness of the product. The quantity of data that should be included in the submission
depends on the application type and available body of knowledge. 12 Changes should be
supported with confirmatory 13 batch data. To assess the change, FDA may request that the
applicant provide additional information in the supplement or referenced DMF.

An applicant seeking to make more than one related change concurrently should submit a
supplement with data appropriate to address the potential risk from the cumulative effect of
multiple changes. Where the recommended reporting categories for the individual changes differ,
the submission category selected should be the one associated with the highest risk change (e.g.,
PAS) of the categories recommended for the individual changes.

When the CCS changes described in the Appendix tables necessitate a corresponding change in
finished product specifications, 14 the applicant should provide all studies and data appropriate to
support the affected specification change(s). The reporting category depends on the potential to
have an adverse effect on the identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product. For example, tightening the
acceptance criteria for a quality attribute may warrant a lower reporting category than widening
the acceptance criteria.

12
The quantity of data recommended in the Appendix tables for NDAs, ANDAs, and BLAs is derived from related
guidance documents. For example, the number of batches is derived from principles outlined in scale-up and
postapproval changes guidance documents (e.g., 1 to 3 batches for ANDAs and NDAs depending on the body of
knowledge). Where guidance documents do not provide specific information on the quantity of data expected to
support the change, the applicant may contact FDA to obtain feedback.
13
For the purposes of this guidance, confirmatory data means comparative product batch data (on product
manufactured prior to and after the proposed change) that is sufficient to demonstrate no adverse effect on product
quality due to the proposed CCS change.
14
The ICH guidances for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances (December 2000) and Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999) define specifications
as “a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits,
ranges, or other criteria for the tests described.”

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Before introducing a new CCS component that differs from the specified CCS component
type/grade in product labeling (e.g., “packaged in type 1 glass”), a supplement to change product
labeling may be appropriate. When the CCS new component differs from that specified in the
applicable USP monograph, appropriate engagement with USP regarding an update to the
product monograph 15 may be necessary to ensure continued compliance with the monograph. 16

IV. TOOLS TO FACILITATE CHANGES TO CCS COMPONENTS

For CCS and component changes that are the subject of this guidance, FDA intends to consider
risk-based approaches using existing tools and capabilities to facilitate providing timely
feedback, guidance, and assessment of proposed changes as discussed below.

FDA may expedite the assessment of a supplement or determine that a different reporting
category is appropriate, taking into account public health priorities 17 and the applicant’s rationale
and associated risk assessment and mitigation strategy for the proposed change. Should a
different reporting category be determined to be appropriate, FDA will notify the applicant and
convey its rationale for the determination. 18

A. Risk-Based Considerations for Supplement Reporting Categories

Consistent with applicable regulations and existing guidance documents related to postapproval
CMC changes for NDAs, ANDAs, and BLAs, FDA may consider available information and
approaches to mitigate the risk to product quality when determining whether a lower reporting
category for supplements is appropriate. Applicants should consider using tools in ICH Q12
(e.g., established conditions, postapproval change management protocols (PACMPs)) to support
proposals for reduced reporting categories based on an increased understanding of the risk to
product quality when making a change related to the glass vial or stopper.

Before submitting a supplement with a lower reporting category than what is required in existing
regulations and recommended in existing guidance, applicants should contact FDA for feedback
and concurrence. For Center for Drug Evaluation and Research (CDER)-regulated products,
applicants should contact the regulatory project management staff (regulatory project manager or

15
For additional information, see the draft guidance for industry Harmonizing Compendial Standards With Drug
Application Approval Using the USP Pending Monograph Process (July 2019). When final, this guidance will
represent FDA’s current thinking on this topic.
16
See section 501(b) of the FD&C Act.
17
For additional information, see 21 CFR 314.70(b)(4). For FDA policies describing expedited review requests
related to prior approval supplements to NDAs and BLAs, see MAPP 5310.3 Rev 1 Requests for Expedited Review
of New Drug Application and Biologics License Application Prior Approval Supplements Submitted for Chemistry,
Manufacturing, and Controls Changes; for FDA policies describing prioritization of the review related to original
ANDAs, amendments, and supplements thereof, see MAPP 5240.3 Rev. 5 Prioritization of the Review of Original
ANDAs, Amendments, and Supplements; for FDA policies on drug shortage management, see MAPP 4190.1 Rev. 3
Drug Shortage Management. MAPPs are available at https://www.fda.gov/about-fda/center-drug-evaluation-and-
research-cder/cder-manual-policies-procedures-mapp.
18
Depending on the regulatory jurisdiction of the product, the applicant can contact the responsible review division
within CDER or CBER (as applicable) to gain additional feedback on specific changes, the information needed to
support the change, and the filing approach, as needed.

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regulatory business process manager) within the appropriate CDER review office responsible for
the subject product application. For Center for Biologics Evaluation and Research (CBER)-
regulated products, applicants should contact the appropriate CBER review office. Additionally,
if the CDER- or CBER-regulated product could enter, or is currently in, drug shortage, then the
respective applicant should include [email protected] for products regulated by CDER
and [email protected] for products regulated by CBER on those communications.

B. Comparability Protocols

As explained in the guidance for industry Comparability Protocols for Postapproval Changes to
the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA (October
2022), a comparability protocol (CP) is a comprehensive, prospectively written plan for
assessing the effect of a proposed CMC postapproval change(s) on the identity, strength, quality,
purity, and potency of a drug product or a biological product. It is a tool for applicants to obtain
feedback from FDA on prospective scientific approaches, submitted as a part of an original
application or PAS, to facilitate expeditious implementation of postapproval changes. CPs allow
FDA to review a description of one or more proposed CMC postapproval changes, supporting
information (including any analysis and risk assessment activities), the plan for implementing the
change(s), and, if appropriate, the proposed reduced reporting category for the change(s). By
delineating the specific approach to be used to evaluate one or more future changes and the
rationale for that approach, the applicant can gain the Agency’s approval of the plan well in
advance of the need to implement the change(s). This process can facilitate a more efficient
submission process for the applicant and review process for FDA.

If the original application or PAS containing the CP is approved, the change usually can be
implemented under a lower reporting category than would normally be expected based on
recommendations in guidance (e.g., changes otherwise requiring a prior approval supplement
could be implemented under a CBE-30). A CP can then be used for a one-time change(s) or be
used repeatedly for a specified type of change over the life cycle of a product. A CP can also be
submitted to cover an identical change(s) that affects multiple applications (grouped
supplements, trans-BLA submissions). 19 A CP is a well-suited tool for making changes to glass
vials and stoppers, because a change to one component can be implemented to many products
sharing that container or closure, and the protocol could be used multiple times as the need arises
for additional changes to accommodate the dynamic supply chain evolution.

19
See the guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application:
Certain Biological Products (June 2021).

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REFERENCES 20

Draft and Final Guidances 21

• Changes to an Approved Application for Specified Biotechnology and Specified Synthetic

Biological Products (July 1997)

• Changes to an Approved NDA or ANDA (April 2004)

• Changes to an Approved NDA or ANDA; Questions and Answers (January 2001)

• Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain

Biological Products (June 2021)

• Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing,

and Controls Information in an NDA, ANDA, or BLA (October 2022)

• Container Closure Systems for Packaging Human Drugs and Biologics (May 1999)

• 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)

• Drug Master Files (October 2019) 22

• Harmonizing Compendial Standards With Drug Application Approval Using the USP
Pending Monograph Process (July 2019) 23

• ICH Q12 Implementation Considerations for FDA-Regulated Products (May 2021) 24

• Manufacturing Changes and Comparability for Human Cellular and Gene Therapy
Products (July 2023) 25

• PAC-ATLS: Postapproval Changes — Analytical Testing Laboratory Sites (April 1998)

20
MAPPs can be found on the CDER Manual of Policies & Procedures web page at https://www.fda.gov/about-
fda/center-drug-evaluation-and-research/cder-manual-policies-procedures-mapp, and SOPPs can be found on the
Biologics Procedures (SOPPs) web page at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-procedures-sopps.
21
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.
22
When final, this guidance will represent the FDA’s current thinking on this topic.
23
Ibid.
24
Ibid.
25
Ibid.

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• Submission Documentation for Sterilization Process Validation in Applications for

Human and Veterinary Drug Products (November 1994)

Scale-Up and Postapproval Changes Guidances

• SUPAC: Manufacturing Equipment Addendum (December 2014) 26

• SUPAC-IR: Questions and Answers about SUPAC-IR Guidance (February 1997)

• SUPAC-MR: Modified Release Solid Oral Dosage Forms; Scale-Up and Postapproval
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In
Vivo Bioequivalence Documentation (September 1997)

• SUPAC-IR: Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval
Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation (November 1995)

• SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes:

Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo
Bioequivalence Documentation (May 1997)

ICH Guidances

• Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances (December 2000)

• Q6B Specifications: Test Procedures and Acceptance Criteria for

Biotechnological/Biological Products (August 1999)

• Q9(R1) Quality Risk Management (May 2023)

• Q10 Pharmaceutical Quality System (April 2009)

• Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle

Management (May 2021)

Manual of Policies and Procedures 27

• MAPP 4190.1 Rev. 3 Drug Shortage Management

26
When final, this guidance will represent the FDA’s current thinking on this topic.
27
MAPPs can be found on the CDER Manual of Policies & Procedures web page at https://www.fda.gov/about-
fda/center-drug-evaluation-and-research/cder-manual-policies-procedures-mapp.

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• MAPP 5240.3 Rev. 6 Prioritization of the Review of Original ANDAs, Amendments, and
Supplements

• MAPP 5310.3 Rev. 2 Requests for Expedited Review of New Drug Application and
Biologics License Application Prior Approval Supplements Submitted for Chemistry,
Manufacturing, and Controls Changes

Standard Operating Procedures and Policies 28

• SOPP 8506 Management of Shortages of CBER-Regulated Products

28
SOPPs can be found on the CBER Biologics Procedures (SOPPs) web page at https://www.fda.gov/vaccines-
blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-procedures-sopps.

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APPENDIX: TABLES DESCRIBING CCS CHANGES FOR PRODUCTS WITH

APPROVED ANDAS, NDAS, OR BLAS

The following tables include information derived from existing FDA guidance documents
containing FDA recommendations for reporting categories and submission content for common
chemistry, manufacturing, and controls changes to glass vials and stoppers, the container closure
system (CCS) components of finished pharmaceuticals and biological products. These tables
provide baseline recommendations for the information to be submitted and the reporting category
for specific changes, and do not consider the cumulative effect of concurrent changes. As stated
in sections III and IV of the guidance, FDA may request more information to support the change,
and determine that a different reporting category is appropriate based on risk assessment
information related to the specific change proposed.

These tables do not include all possible CCS changes that would necessitate a submission as
described in applicable regulations. 1 Application holders should consult existing guidance
documents for further information on CCS change recommendations. Depending on regulatory
jurisdiction of the product application, the applicant can contact the responsible review division
within the Center for Drug Evaluation and Research (CDER) 2 or the Center for Biologics
Evaluation and Research (CBER) (as applicable) to gain additional feedback on specific
changes, the information needed to support the change, and the filing approach, as needed.

For the following tables, the term confirmatory data means comparative data that demonstrate no
adverse impact on product quality due to the proposed CCS change.

1
21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
2
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 (November 2020) and Controlled Correspondence Related
to Generic Drug Development (December 2020).

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Table A: Changes to the Properties of Glass Vials and Stoppers: New Drug Applications/Abbreviated New Drug Applications*
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance 1

Change from glass to a Confirmatory batch data, including PAS Section IX.B.4. of
new material (e.g., release and stability data Changes to an
plastic) (accelerated and real time ), and

Approved NDA or
data to support sterility assurance ANDA (April 2004)

Extractables and leachables risk

assessment and supporting data
Change to different Confirmatory batch data, including PAS Sections IX.B.4. FDA may consider a lower
composition or type of release and stability data and IX.C.1.a. of reporting category based
glass2 (accelerated and real time), and Changes to an on the circumstances of
data to support sterility assurance Approved NDA or the specific change2
ANDA
continued

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Table A, continued
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance1
Change between Description, composition, drawing, CBE-30 Section IX.C.1.a. Changes in vial properties
molded and tubing and specification of vial of Changes to an that affect manufacturing
glass PAS for Approved NDA or processes (e.g., thicker
CCS suitability tests and lyophilized ANDA glass affecting
determinations as recommended products (refer lyophilization processes)
in USP General Chapter <660> and to Specific pose a higher risk to
principles of USP General Chapter Considerations quality and therefore may
<1660> (required for compendial for Reporting trigger a higher reporting
products)3 Category) category with additional
data needed to assess the
Confirmatory batch data, including effects of the change
release and stability data
(accelerated and real time), and
data to support sterility assurance

CCIT data

Lyophilization cycle verification or

validation if process is modified
(refer to Specific Considerations for
Reporting Category)
continued

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Table A, continued
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance1
Change in vial CCIT data PAS Section IX.B.4. of For vials with the same
dimensions Changes to an nominal fill volume but
Representative media Approved NDA or slight changes to
fill/bracketing data ANDA dimensions, a CBE-30 may
be appropriate
Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance
Switch from amber Confirmatory batch data, including PAS Section IX.B.6. of
glass to clear glass (with release and stability data Changes to an
or without additional (accelerated and real time), and Approved NDA or
photoprotective data to support sterility assurance ANDA
measures)
Additional tests based on results of
comparative photostability study

Labeling change accounting for

different storage conditions (e.g.,
protect from light)
continued

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Table A, continued
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance1
Change in primary CCS Description of the container PAS Section IX.B.4. of
type (e.g., switching properties and composition Changes to an
from vial to ampule)4 Approved NDA or
Container suitability5 ANDA

Manufacturing and controls

CCIT data

Sterilization validation

Confirmatory batch data, including

release and stability data
(accelerated and real time), and
data to support sterility assurance
continued

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Table A, continued
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance1
Change in stopper Description of new stopper PAS Section IX.B.4. of
rubber/elastomer Changes to an
material6 Composition Approved NDA or
ANDA
Manufacturing and controls

Closure suitability7

CCIT data

Confirmatory batch data, including

release and stability data
(accelerated and real time),
including vial orientations where
formulation is in contact with
stopper, and data to support
sterility assurance
Change in stopper CCIT data CBE-30 Section IX.C.1.a.
dimensions of Changes to an
Confirmatory batch data, including Approved NDA or
release and stability data ANDA
(accelerated and real time), and
data to support sterility assurance
continued

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Table A, continued
Proposed Change Recommended Information to Recommended Reference to Specific Considerations for
Support the Change Reporting Current Reporting Category
Category Guidance1
Changes in how the Sterilization and depyrogenation CBE-30 Section IX.C.1.a.
stopper is supplied validation of Changes to an
(e.g., unprocessed, RTS, Approved NDA or
and RTU) Representative COA, which would ANDA
include sterility and BET data if
stoppers are supplied RTU and BET
data if stoppers are supplied RTS
* PAS = prior approval supplement; CCIT = Container Closure Integrity Test; CBE-30 = changes being effected in 30 days; RTS = ready to sterilize; RTU =
ready to use; COA = certificate of analysis; BET = bacterial endotoxins testing

Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1
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.
2
A change in glass supplier without a change in glass type or coating and without a change in container/closure dimensions can be filed as an annual report as
described in section 5.4 of Appendix in the guidance for industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March
2014).
3
United States Pharmacopeia (USP) General Chapter <660> Glass Containers Used in Pharmaceutical Packaging/Delivery Systems, and USP General Chapter
<1660> Evaluation of the Inner Surface Durability of Glass Containers.
4
Some of these identified changes, depending on the circumstances, may be more appropriately submitted as an original application instead of as supplements.
This type of change may also warrant a labeling change supplement to account for a new presentation. Application holders should follow existing FDA guidance.
Applicants can consult the appropriate review division within CDER or CBER if there are questions.
5
Information about the suitability of proposed glass with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables) and
performance. Application holders should refer to USP General Chapter <660> and USP General Chapter <1660> for further information.
6
When alternate suppliers of stoppers are proposed, and if there are differences in stopper properties or manufacturing processes changes between the currently
approved and proposed supplier, because of the increased risk to quality, a higher reporting category — PAS — is warranted. However, if the differences in
stopper properties and manufacturing processes are minimal then a lower reporting category may be considered.
7
Information about the suitability of proposed stopper with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables)
and performance. Application holders should refer to USP General Chapter <381> Elastomeric Closure for Injections, for additional information.

16
 Contains Nonbinding Recommendations

Table C: Changes to the Source or Site of Manufacture for Glass Vials and Stoppers: New Drug Applications/Abbreviated
New Drug Applications*
Proposed Change Recommended Recommended Reference to Current Specific
Information to Support the Reporting Guidance1 Considerations for
Change Category Reporting Category
Site of vial or stopper Name and address of the AR Section VI.A. of Changes to
manufacture or new site an Approved NDA or ANDA
processing (no change in (April 2004)
Comparative information
supplier)
on the CCS between the
old and the new source
Commitment to place
batches on stability
Site of vial or stopper Name and address of the AR (when the Section VI.D.4. of Changes
sterilization new site process is not to an Approved NDA or
materially ANDA
Validation data to support
different from
the vial/stopper
sterilization that provided
for in the
approved
application)
Site of vial or stopper Name and address of the CBE-30 Section VI.C.1.d. of
testing new site Changes to an Approved
NDA or ANDA
Full description of the
testing to be performed by
PAC-ATLS: Postapproval
the new facility
Changes — Analytical
Testing Laboratory Sites
(April 1998)
* AR = annual report; CBE-30 = changes being effected in 30 days
1
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.

25
 Contains Nonbinding Recommendations

Table E: Changes to the Manufacturing or Processing of Glass Vials and Stoppers: New Drug Applications/Abbreviated New
Drug Applications*
Proposed Change Recommended Information to Recommended Reference to Current Specific
Support the Change Reporting Guidance1 Considerations for
Category Reporting Category
Changes in vial Validation data to support the PAS Section VII.B.2. of
sterilization or sterilization or depyrogenation Changes to an
depyrogenation method change Approved NDA or ANDA
method (e.g., changing (April 2004)
from moist to dry heat) Extractables and leachables data

Accelerated and real time stability

data
Changes in vial Validation data to support the CBE-30 Section VII.C.1.d. of
sterilization or sterilization/depyrogenation Changes to an
depyrogenation process change Approved NDA or ANDA
process parameters
Stopper washing Validation data to support the CBE-30 Section VII.C.1.a. of
process depyrogenation process change Changes to an
Approved NDA or ANDA
Stopper siliconization CCIT data if a new coating is used PAS Section IX.B.4. of
process Changes to an
Extractables and leachables data Approved NDA or ANDA

Accelerated and real time stability

data
continued

28
 Contains Nonbinding Recommendations

Table E, continued
Proposed Change Recommended Information to Recommended Reference to Current Specific
Support the Change Reporting Guidance1 Considerations for
Category Reporting Category
Changing the method Validation data to support the PAS Section VII.B.2. of
of stopper sterilization sterilization/depyrogenation Changes to an
(e.g., from moist heat process change Approved NDA or ANDA
to irradiation)
Extractables and leachables data

Accelerated and real time stability

data
Stopper sterilization Validation data to support the CBE-30 Section VII.C.1.a. of
process parameters sterilization/depyrogenation Changes to an
process change Approved NDA or ANDA
* PAS = prior approval supplement; CBE-30 = changes being effected in 30 days; CCIT = Container Closure Integrity Test

Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1
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.

29