COVID-19 Container Closure 
System and Component Changes: 
Glass Vials and Stoppers 
 
Guidance for Industry 
 
 
 
This guidance is intended to remain in effect until August 7, 2024, unless superseded by 
a revised final guidance before that date. For further information, refer to 88 FR 15417, 
March 13, 2023, available at https://www.federalregister.gov/documents/2023/03/13/2023-
05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19.    
COVID-19 Container Closure 
System and Component Changes: 
Glass Vials and Stoppers 
 
Guidance for Industry 
 
March 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) Contains Nonbinding Recommendations 
 
  Preface
 
Public Comment 
 
This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public 
health emergency. This guidance is being implemented without prior public comment because 
the Food and Drug Administration (FDA or Agency) has determined that prior public 
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR 
10.115(g)(2)). This guidance document is being implemented immediately, but it remains 
subject to comment in accordance with the Agencys good guidance practices. 
 
Comments may be submitted at any time for Agency consideration. Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov. 
All comments should be identified with the docket number FDA-2020-D-1136 and complete 
title of the guidance in the request. 
 
Additional Copies 
 
Additional copies are available from the FDA web page titled COVID-19-Related Guidance 
Documents for Industry, FDA Staff, and Other Stakeholders, available at 
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-related-
guidance-documents-industry-fda-staff-and-other-stakeholders and the FDA web page titled 
Search for FDA Guidance Documents, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.  You may also send an email request to 
druginfo@fda.hhs.gov or ocod@fda.hhs.gov to receive an additional copy of the guidance. 
Please include the docket number FDA-2020-D-1136 and complete title of the guidance in the 
request. 
 
Questions 
 
For questions about this document, contact (CDER) CDER-OPQ-Inquiries@fda.hhs.gov 
or (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 
240-402-8010.   Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  Introduction .......................................................................................................................... 1 
II.  Background .......................................................................................................................... 2 
III.  Regulatory Approach to CMC Changes............................................................................... 3 
IV.  Common Changes Related to Glass Vials and Stoppers ...................................................... 5 
V.  Tools to Facilitate Changes to CCS Components ................................................................ 6 
A.  Risk-Based Considerations for Supplement Reporting Categories ............................... 6 
B.  Comparability Protocols ................................................................................................ 7 
VI.  Additional Resources ........................................................................................................... 8 
VII.  References ............................................................................................................................ 8 
Appendix A: Tables Describing CCS Changes for Products With Approved ANDAs, NDAs,  
or BLAs .............................................................................................................................. 11 
 
  Contains Nonbinding Recommendations 
 
COVID-19 Container Closure 
System and Component Changes: 
Glass Vials and Stoppers  
 
Guidance for Industry 
 
 
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 staff or Office responsible for this guidance as listed 
on the title page.   
 
 
I.  Introduction 
 
FDA plays a critical role in protecting the United States from threats such as emerging infectious 
diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to 
providing timely guidance to support response efforts to this pandemic.   
 
FDA is issuing this guidance to collate recommendations for appropriate reporting category and 
the content of postapproval change submissions across numerous FDA guidance documents. 
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 approved1 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 FDA recognizes that during the COVID-19 public health emergency some injectable products, either approved or 
pending approval, may need some changes to the primary packaging components (e.g., glass vials and stoppers) due 
to supply chain issues affecting their availability. 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 section VII, References, and the data recommendations provided 
in the tables in Appendix A 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. 
  1  Contains Nonbinding Recommendations 
 
 
This policy is 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 (HHS) on January 
31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in 
accordance with section 319(a)(2) of the Public Health Service Act (42 U.S.C. 247d(a)(2)). 
 
Given this public health emergency, and as discussed in the Notice in the Federal Register of 
March 25, 2020, titled Process for Making Available Guidance Documents Related to 
Coronavirus Disease 2019, available at https://www.govinfo.gov/content/pkg/FR-2020-03-
25/pdf/2020-06222.pdf, this guidance is being implemented without prior public comment 
because FDA has determined that prior public participation for this guidance is not feasible or 
appropriate (see section 701(h)(1)(C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
(21 U.S.C. 371(h)(1)(C)) and 21 CFR 10.115(g)(2)). This guidance document is being 
implemented immediately, but it remains subject to comment in accordance with the Agencys 
good guidance practices. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in FDA 
guidances means that something is suggested or recommended, but not required. 
 
 
II.  Background 
 
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus 
has been named SARS-CoV-2 and the disease it causes has been named Coronavirus Disease 
2019 (COVID-19). On January 31, 2020, HHS issued a declaration of a public health 
emergency related to COVID-19 and mobilized the Operating Divisions of HHS.2 In addition, on 
March 13, 2020, there was a Presidential declaration of a national emergency in response to 
COVID-19.3   
 
Many FDA-regulated human drugs (finished pharmaceuticals and biological products) related to, 
and products being developed for, the treatment and prevention of COVID-19 use glass vials and 
stoppers as their primary CCS. The supply of CCS components for FDA-regulated products 
generally may become constrained as manufacturers respond to the public health emergency 
related to COVID-19. As a result, manufacturers of FDA-regulated products may need to update 
their approved applications to make changes to CCS components to meet current product 
demand or increase supply resilience. In response to this public health emergency, FDA will 
 
2 Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued 
Jan. 31, 2020, and subsequently renewed), available at 
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.  
3 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) 
Outbreak (Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. 
  2  Contains Nonbinding Recommendations 
 
consider risk-based approaches to facilitate implementation of chemistry, manufacturing, and 
controls (CMC) changes to a CCS in an effort to mitigate the disruptive effect of the COVID-19 
pandemic. These measures may include, but may not be limited to, recommendations for 
adjustments to submission content and reduction in reporting categories for CMC changes. 
 
 
III.  Regulatory Approach to CMC Changes 
 
As described in 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 section VII., 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). 
  3  Contains Nonbinding Recommendations 
 
applicable tests and studies as outlined in United States Pharmacopeia (USP) chapters6 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. 
 
As discussed in section V., Tools to Facilitate Changes to CCS Components, of this guidance 
and the guidance for industry Manufacturing, Supply Chain, and Drug and Biological Product 
Inspections During COVID-19 Public Health Emergency; Questions and Answers (August 
2020),8 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 
Quality Risk Management (June 2006) where appropriate. Whether or not a change is required to 
be reported to FDA, in accordance with applicable regulations,9 FDA expects all changes to be 
appropriately managed by an establishments/facilitys 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). 
 
The 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.10 DMF holders must notify affected authorized 
parties of any DMF changes, additions, or deletions.11 DMF holders also should provide 
application holders with sufficient information to determine the appropriate reporting procedure 
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).12 
 
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 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. 
9 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12 
10 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12 
11 21 CFR 314.420(c) 
12 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 FDAs current 
thinking on this topic. 
  4  Contains Nonbinding Recommendations 
 
 
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 section VII., References).   
 
 
IV.  Common Changes Related to Glass Vials and Stoppers  
 
The tables in Appendix A 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 submission 
data recommendations 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.13 Changes should be supported with confirmatory14 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 tables in Appendix A necessitate a corresponding 
change in finished product specifications,15 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, 
 
13 The quantity of data recommended in the tables in Appendix A 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. 
14 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. 
15 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. 
  5  Contains Nonbinding Recommendations 
 
tightening the acceptance criteria for a quality attribute may warrant a lower reporting category 
than widening the acceptance criteria. 
 
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 monograph16 may be necessary. 
 
 
V.  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 under existing tools and capabilities to facilitate providing 
timely feedback, guidance, and assessment17 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 priorities18 and the applicants 
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. 
 
A.  Risk-Based Considerations for Supplement Reporting 
Categories 
 
During this public health emergency, FDA will consider requests to submit certain changes to 
CCS using a lower reporting category than that recommended in existing guidance if the 
applicants are experiencing constrained supply of CCS or components thereof, and if the relevant 
NDAs, ANDAs, or BLAs are related to the treatment or prevention of COVID-19 or other drugs 
in shortage, as appropriate. Consistent with applicable regulations and existing guidance 
documents related to postapproval CMC changes for drug applications 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 
 
16 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 FDAs current thinking on this topic. 
17 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 For additional information, see 21 CFR 314.70(b)(4) and 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. 
  6  Contains Nonbinding Recommendations 
 
wishing to request a lower supplement reporting category should provide (1) their rationale, 
(2) supporting information, and (3) risk-mitigation approaches, for FDA to consider whether the 
requested reduction in reporting category is appropriate.  
 
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 send an email to CDER-OPQ-Inquiries@fda.hhs.gov should circumstances 
resulting from the COVID-19 pandemic warrant the use of atypical or flexible submission 
strategies as described in this section.19 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 CDER DRUG SHORTAGES 
(DRUGSHORTAGES@FDA.HHS.GOV) for products regulated by CDER and 
cbershortage@fda.hhs.gov for products regulated by CBER on those communications. 
 
For more information, refer to the guidance for industry Manufacturing, Supply Chain, and Drug 
and Biological Product Inspections During COVID-19 Public Health Emergency; Questions and 
Answers. 
 
B.  Comparability Protocols  
 
As explained in the draft guidance for industry Comparability Protocols for Human Drugs and 
Biologics: Chemistry, Manufacturing, and Controls Information (April 2016),20 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 Agencys 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 
 
19 Regarding a pending supplement for a CDER-regulated product, applicants should contact the regulatory project 
management staff (regulatory project manager or regulatory business process manager) within the appropriate 
CDER review office responsible for the subject product application. 
20 See this guidance for additional information. When final, this guidance will represent FDAs current thinking on 
this topic. 
  7  Contains Nonbinding Recommendations 
 
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).21 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 in reaction to 
COVID-19.  
 
 
VI.  Additional Resources 
 
For additional questions about this guidance, contact CDER at CDER-OPQ-
Inquiries@fda.hhs.gov, or contact the CBER office responsible for the products regulation. The 
text COVID-19 Container Closure System and Component Changes should be included in the 
subject line of the email. 
 
Depending on regulatory jurisdiction of the product application, 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. 
 
 
VII. References22,23,24 
 
Draft and Final Guidances 
 
  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) 
 
 
21 See the draft guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application: 
Certain Biological Products (December 2017). When final, this guidance will represent the FDAs current thinking 
on this topic.  
22 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. 
23 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. 
24 For a comprehensive list of COVID-19 guidance documents, see the COVID-19-Related Guidance Documents for 
Industry, FDA Staff, and Other Stakeholders web page at (https://www.fda.gov/emergency-preparedness-and-
response/coronavirus-disease-2019-covid-19/covid-19-related-guidance-documents-industry-fda-staff-and-other-
stakeholders). 
  8  Contains Nonbinding Recommendations 
 
  Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain 
Biological Products (December 2017)25 
 
  Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry, 
Manufacturing, and Controls Documentation (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 (August 2017)26 
 
  Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, 
and Controls Information (April 2016)27 
 
  Drug Master Files (October 2019)28  
 
  Harmonizing Compendial Standards With Drug Application Approval Using the USP 
Pending Monograph Process (July 2019)29 
 
  Manufacturing, Supply Chain, and Drug and Biological Product Inspections During 
COVID-19 Public Health Emergency; Questions and Answers (August 2020) 
 
  PAC-ATLS: Postapproval Changes  Analytical Testing Laboratory Sites (April 1998) 
 
  Submission Documentation for Sterilization Process Validation in Applications for 
Human and Veterinary Drug Products (November 1994) 
 
Scale-Up and Postapproval Changes Guidances 
 
  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) 
 
  Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, 
Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence 
Documentation (May 1997) 
 
  SUPAC: Manufacturing Equipment Addendum (December 2014) 
 
25 When final, this guidance will represent the FDAs current thinking on this topic. 
26 Ibid. 
27 Ibid. 
28 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 FDAs current 
thinking on this topic. 
29 When final, this guidance will represent the FDAs current thinking on this topic. 
  9  Contains Nonbinding Recommendations 
 
 
  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) 
 
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 Quality Risk Management (June 2006) 
 
  Q10 Pharmaceutical Quality System (April 2009) 
 
Manual of Policies and Procedures 
 
  MAPP 4190.1 Rev. 3 Drug Shortage Management 
 
  MAPP 5240.3 Rev. 5 Prioritization of the Review of Original ANDAs, Amendments, and 
Supplements 
 
  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  
 
Standard Operating Procedures and Policies 
 
  SOPP 8506 Management of Shortages of CBER-Regulated Products 
 
  10  Contains Nonbinding Recommendations 
 
Appendix A:  
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 IV and V 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) 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 
  11  Contains Nonbinding Recommendations 
 
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 
Support the Change   Reporting  Current  for Reporting Category 
  Category   Guidance1  
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 on 
glass2   (accelerated and real time), and    Changes to an  the circumstances of the 
  data to support sterility assurance  Approved NDA or  specific change2 
    ANDA 
continued 
  12  Contains Nonbinding Recommendations 
 
Table A, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change   Reporting  Current  for Reporting Category 
  Category   Guidance1  
Change between  Description, composition, drawing,  CBE-30   Section IX.C.1.a.  Changes in vial properties 
molded and tubing glass  and specification of vial     of Changes to an  that affect manufacturing 
    PAS for  Approved NDA or  processes (e.g., thicker 
CCS suitability tests and  lyophilized  ANDA  glass affecting 
determinations as recommended in  products (refer    lyophilization processes) 
USP General Chapter <660> and  to Specific    pose a higher risk to quality 
principles of USP General Chapter  Considerations    and therefore may trigger a 
<1660> (required for compendial  for Reporting  higher reporting category 
products)3  Category)  with additional data needed 
    to assess the effects of the 
Confirmatory batch data, including  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 
  13  Contains Nonbinding Recommendations 
 
Table A, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current  for 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 
  14  Contains Nonbinding Recommendations 
 
Table A, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current  for 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 
 
  15  Contains Nonbinding Recommendations 
 
 
Table A, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current  for 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 
 
  16  Contains Nonbinding Recommendations 
 
Table A, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current  for Reporting Category 
  Category   Guidance1  
Changes in how the  Sterilization and depyrogenation  CBE-30  Section IX.C.1.a.   
stopper is supplied (e.g.,  validation  of Changes to an 
unprocessed, RTS, and    Approved NDA or 
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 A 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.   
 
  17  Contains Nonbinding Recommendations 
 
Table B: Changes to the Properties for Glass Vials and Stoppers: Biologics License Applications* 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change from glass to a  Extractables and leachables risk  PAS  Changes to an   
new material (e.g.,  assessment and supporting data  Approved 
plastic)    Application for 
Confirmatory batch data,  Specified 
including release and stability  Biotechnology and 
data (accelerated and real time),  Specified Synthetic 
and data to support sterility  Biological Products 
assurance  (July 1997)  
   
  Section 3.2.P.7. of 
  the Appendix in 
  Chemistry, 
  Manufacturing, and 
Controls Changes to 
an Approved 
Application: Certain 
Biological Products 
(December 2017)2 
continued 
  18  Contains Nonbinding Recommendations 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change to different  Confirmatory batch data,  PAS  BLA: Changes to an  FDA may consider a 
composition or type of  including release and stability    Approved  lower reporting category 
glass3   data (accelerated and real time),    Application for  based on the 
and data to support sterility  Specified  circumstances of the 
assurance  Biotechnology and  specific change (e.g., if 
  Specified Synthetic  the new vial type or 
Biological Products   composition was 
  previously used in a 
Section 3.2.P.7. of  licensed product) 
the Appendix in 
Chemistry, 
Manufacturing, and 
Controls Changes to 
an Approved 
Application: Certain 
Biological Products  
continued 
  19  Contains Nonbinding Recommendations 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change between molded  Description, composition,  AR   Section 3.2.P.7., due  Changes in vial 
and tubing glass  drawing, and specification of vial    to expected change  properties that affect 
     PAS for  in properties, of the  manufacturing processes 
CCS suitability tests and  lyophilized  Appendix in  (e.g., thicker glass 
determinations as recommended  products with  Chemistry,  affecting lyophilization 
in USP General Chapter <660>  molded vials  Manufacturing, and  processes) pose a higher 
and principles of USP General  (refer to  Controls Changes to  risk to quality and 
Chapter <1660> (required for  Specific  an Approved  therefore may trigger a 
compendial products)4  Considerations  Application: Certain  higher reporting category 
  for Reporting  Biological Products   with need for additional 
CCIT data   Category)    data to assess the effects 
    Section 5.2 of the  of the change 
Confirmatory batch data,    Appendix in CMC 
including release and stability    Postapproval 
data (accelerated and real time),    Manufacturing 
and data to support sterility  Changes for 
assurance  Specified Biological 
  Products To Be 
Lyophilization cycle verification  Documented in 
or validation if process is  Annual Reports 
modified (refer to Specific  (August 2017)5 
Considerations for Reporting   
Category)  Changes to an 
  Approved Application 
  for Specified 
Biotechnology and 
Specified Synthetic 
Biological Products  
continued 
  20  Contains Nonbinding Recommendations 
 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change in vial  CCIT data  PAS  BLA: Changes to an  For vials with the same 
dimensions     Approved Application  nominal fill volume but 
Representative media fill   for Specified  slight changes to 
  Biotechnology and  dimensions, a CBE-30 
Confirmatory batch data,  Specified Synthetic  may be considered 
including release and stability  Biological Products  
data (accelerated and real time),   
and data to support sterility  Section 3.2.P.7. of 
assurance  the Appendix in 
  Chemistry, 
Additional accelerated and real  Manufacturing, and 
time stability data as needed (e.g.,  Controls Changes to 
concurrent stopper change)  an Approved 
  Application: Certain 
Biological Products 
Switch from amber glass  Confirmatory batch data,  PAS  Same as above    
to clear glass (with or  including release and stability 
without additional  data (accelerated and real time), 
photoprotective  and data to support sterility 
measures)  assurance 
   
Additional tests based on results of 
comparative photostability study 
 
Labeling change accounting for 
different storage conditions (e.g., 
protect from light) 
continued 
  21  Contains Nonbinding Recommendations 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change in primary CCS  Description of the container  PAS  BLA: Changes to an   
type (e.g., switching from  properties and composition  Approved 
vial to ampule)6    Application for 
  Container suitability7  Specified 
  Biotechnology and 
Manufacturing and controls   Specified Synthetic 
  Biological Products  
Sterilization validation   
  Section 3.2.P.7. of 
CCIT data  the Appendix in 
  Chemistry, 
Confirmatory batch data,  Manufacturing, and 
including release and stability  Controls Changes to 
data (accelerated and real time),  an Approved 
and data to support sterility  Application: Certain 
assurance  Biological Products  
continued 
  22  Contains Nonbinding Recommendations 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Change in stopper  Description of new stopper  PAS  BLA: Changes to an   
rubber/elastomer    Approved 
material8  Composition  Application for 
    Specified 
Closure suitability9  Biotechnology and 
  Specified Synthetic 
Manufacturing and controls  Biological Products  
   
CCIT data  Section 3.2.P.7. of 
  the Appendix in 
Confirmatory batch data,  Chemistry, 
including release and stability  Manufacturing, and 
data (accelerated and real time),  Controls Changes to 
and data to support sterility  an Approved 
assurance  Application: Certain 
Biological Products  
Change in stopper  Confirmatory batch data,  CBE-30    Same as above    
dimensions   including release and stability 
  data (accelerated and real time), 
and data to support sterility 
assurance 
 
CCIT data 
continued 
  23  Contains Nonbinding Recommendations 
 
Table B, continued 
Proposed Change   Recommended Information to  Recommended  Reference to  Specific Considerations 
Support the Change  Reporting  Current Guidance1   for Reporting Category 
Category  
Changes in how the  Sterilization and depyrogenation  CBE-30  Section 3.2.P.7. of  For certain biological 
stopper is supplied (e.g.,  validation     the Appendix in  products, FDA may 
unprocessed, RTS, and      Chemistry,  consider AR depending 
RTU)  Confirmatory batch data,    Manufacturing, and  on the circumstances of 
  including data to support sterility    Controls Changes to  the change (e.g., change 
assurance  an Approved  is occurring at a vendor 
  Application: Certain  that provides pre-
  Biological Products   processed stoppers) 
 
Changes to an 
Approved 
Application for 
Specified 
Biotechnology and 
Specified Synthetic 
Biological Products 
* PAS = prior approval supplement; BLA = biologics license application; CCIT = Container Closure Integrity Test; AR = annual report; CBE-30 = changes 
being effected in 30 days; RTS = ready to sterilize; RTU = ready to use 
 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 When final, this guidance will represent the FDAs current thinking on this topic. 
3 This change can be reported in an annual report if there is no change in the product-contact material or dimensions (size and shape) per 3.2.P.7 of the Appendix 
in the draft guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products. 
4 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 
5 When final, this guidance will represent the FDAs current thinking on this topic. 
6 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.   
7 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. 
  24  Contains Nonbinding Recommendations 
 
8 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. 
9 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. 
 
  25  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  Reporting  Guidance1   Considerations for 
the Change  Category     Reporting Category 
Site of vial or stopper  Name and address of the  AR   Section VI.A. of Changes   
manufacture or processing  new site     to an Approved NDA or 
(no change in supplier)      ANDA (April 2004) 
  Comparative information   
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. 
 
  26  Contains Nonbinding Recommendations 
 
Table D: Changes to the Source or Site of Manufacture for Glass Vials and Stoppers: Biologics License Applications* 
Proposed Change  Recommended  Recommended  Reference to Current  Specific 
Information to Support  Reporting  Guidance1  Considerations for 
the Change  Category    Reporting Category 
Site of vial or stopper  Name and address of the  AR   Section 3.2.P.7. of the  For certain biological 
manufacture or  new site     Appendix in Chemistry,  products, a higher 
processing (no change in    Manufacturing, and  reporting category may 
supplier)  Comparative information  Controls Changes to an  be appropriate if vial or 
  on the CCS between the old  Approved Application:  stopper manufacturing 
and the new source  Certain Biological Products  or processing will be 
  (December 2017)2   done by the drug 
Commitment to place    product manufacturer 
batches on stability  Changes to an Approved 
  Application for Specified 
  Biotechnology and Specified 
  Synthetic Biological 
  Products (July 1997) 
continued 
  27  Contains Nonbinding Recommendations 
 
Table D, continued 
Proposed Change  Recommended  Recommended  Reference to Current  Specific 
Information to Support  Reporting  Guidance1  Considerations for 
the Change  Category    Reporting Category 
Site of vial or stopper  Name and address of the  CBE-30  Section 3.2.P.7. of the  For certain biological 
sterilization    new site     Appendix in Chemistry,  products, FDA may 
      Manufacturing, and  consider AR depending 
Validation data to support  Controls Changes to an  on the circumstances of 
the vial/stopper sterilization  Approved Application:  the change (e.g., vendor 
  Certain Biological Products   provides pre-sterilized 
    stoppers and is 
  Section 5.2 of the Appendix  changing site of 
  in CMC Postapproval  sterilization). 
  Manufacturing Changes for   
  Specified Biological 
Products To Be Documented 
in Annual Reports (August 
2017)3  
 
Changes to an Approved 
Application for Specified 
Biotechnology and Specified 
Synthetic Biological Products  
Site of vial or stopper  Name and address of the  AR  CMC Postapproval   
testing   new site  Manufacturing Changes for 
    Specified Biological 
Full description of the  Products To Be Documented 
testing to be performed by  in Annual Reports 
the new facility  
* 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 
2 When final, this guidance will represent the FDAs current thinking on this topic. 
3 Ibid. 
  28  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  method change  Approved NDA or 
(e.g., changing from    ANDA (April 2004) 
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 process    Changes to an 
depyrogenation process  change  Approved NDA or 
parameters    ANDA 
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 
 
  29  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 process  Changes to an 
(e.g., from moist heat  change  Approved NDA or 
to irradiation)    ANDA 
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 process    Changes to an 
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. 
 
 
  30  Contains Nonbinding Recommendations 
 
Table F: Changes to the Manufacturing or Processing of Glass Vials and Stoppers: Biologics License Applications* 
Proposed  Recommended Information to  Recommended  Reference to Current  Specific 
Change  Support the Change  Reporting  Guidance1  Considerations for 
  Category    Reporting Category 
Changes in vial  Validation data to support the  PAS  Changes to an Approved   
sterilization or  sterilization or depyrogenation  Application for Specified 
depyrogenation  method change  Biotechnology and Specified 
method (e.g.,    Synthetic Biological Products 
changing from  Extractables and leachables data  (July 1997)2 
moist to dry heat)     
  Accelerated and real time   
stability data  
Changes in vial  Validation data to support the  CBE-30  Section 3.2.P.7. of the  For certain biological 
sterilization or  sterilization or depyrogenation    Appendix in Chemistry,  products, FDA may 
depyrogenation  process change    Manufacturing, and Controls  consider AR depending 
process    Changes to an Approved  on the circumstances of 
parameters  Application: Certain  the change (e.g., vial 
  Biological Products  vendor is changing the 
(December 2017)3   sterilization or 
  depyrogenation process 
Changes to an Approved  parameters) 
Application for Specified   
Biotechnology and Specified 
Synthetic Biological Products 
continued 
  31  Contains Nonbinding Recommendations 
 
Table F, continued 
Proposed  Recommended Information to  Recommended  Reference to Current  Specific 
Change  Support the Change  Reporting  Guidance1  Considerations for 
  Category    Reporting Category 
Stopper washing  Depyrogenation validation data  CBE-30  Section 5.2 of the Appendix in  For certain biological 
process   to support the stopper washing    CMC Postapproval  products, FDA may 
  process change    Manufacturing Changes for  consider AR depending 
    Specified Biological Products  on the circumstances of 
To Be Documented in Annual  the change (e.g., 
Reports (August 2017)4  vendor provides pre-
  washed stoppers and is 
Section 3.2.P.7. of the  changing the washing 
Appendix in Chemistry,  process) 
Manufacturing, and Controls   
Changes to an Approved 
Application: Certain 
Biological Products  
 
Changes to an Approved 
Application for Specified 
Biotechnology and Specified 
Synthetic Biological Products  
continued 
  32  Contains Nonbinding Recommendations 
 
Table F, continued 
Proposed  Recommended Information to  Recommended  Reference to Current  Specific 
Change  Support the Change  Reporting  Guidance1  Considerations for 
  Category    Reporting Category 
Stopper  CCIT data if a new coating is  CBE-30  Section 3.2.P.7. of the  For certain biological 
siliconization  used     Appendix in Chemistry,  products, FDA may 
process      Manufacturing, and Controls  consider AR depending 
  Extractables and leachables data  Changes to an Approved  on the circumstances of 
  Application: Certain  the change (e.g., 
Accelerated and real time  Biological Products   vendor provides pre-
stability data    siliconized stoppers 
  Changes to an Approved  and is changing the 
  Application for Specified  siliconization process) 
Biotechnology and Specified   
Synthetic Biological Products  
Changing the  Validation data to support the  PAS  Changes to an Approved  For certain biological 
method of stopper  stopper sterilization method  Application for Specified  products, FDA may 
sterilization (e.g.,  change  Biotechnology and Specified  consider AR depending 
from moist heat to    Synthetic Biological Products5  on the circumstances of 
irradiation)  Extractables and leachables data    the change (e.g., 
    vendor is changing the 
Accelerated and real time  sterilization method) 
stability data  
continued 
  33  Contains Nonbinding Recommendations 
 
Table F, continued 
Proposed  Recommended Information to  Recommended  Reference to Current  Specific 
Change  Support the Change  Reporting  Guidance1  Considerations for 
  Category    Reporting Category 
Stopper  Validation data to support the  CBE-30  Section 3.2.P.7. of the  For certain biological 
sterilization  stopper sterilization process    Appendix in Chemistry,  products, FDA may 
process  change    Manufacturing, and Controls  consider AR depending 
parameters    Changes to an Approved  on the circumstances of 
    Application: Certain  the change (e.g., 
Biological Products   vendor provides pre-
  sterilized stoppers and 
Changes to an Approved  is changing the 
Application for Specified  sterilization process) 
Biotechnology and Specified 
Synthetic Biological Products 
* PAS = prior approval supplement; CBE-30 = changes being effected in 30 days; AR = annual report; 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. 
2 See also 21 CFR 601.12(b)(2)(vi). 
3 When final, this guidance will represent the FDAs current thinking on this topic. 
4 Ibid. 
5 See also 21 CFR 601.12(b)(2)(vi). 
 
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