Changes to Disposable 
Manufacturing 
Materials:  
Questions and Answers 
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) 
Center for Veterinary Medicine (CVM) 
 
July 2022 
 
Pharmaceutical Quality/Manufacturing Standards
         
Changes to Disposable 
Manufacturing Materials: 
Questions and Answers 
Guidance for Industry 
 
 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
and/or 
Policy and Regulations Staff, HFV-6 
Center for Veterinary Medicine 
Food and Drug Administration 
7500 Standish Place, Rockville, MD  20855 
https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-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) 
Center for Veterinary Medicine (CVM) 
 
 July 2022 
 
Pharmaceutical Quality/Manufacturing Standards
      Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DISCUSSION .................................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 3 
Q1: What are some possible changes an applicant can make to disposable manufacturing 
materials and what reporting categories are applicable? ............................................................... 3 
Q2: Are there steps to lower the reporting category of a supplement? ........................................... 4 
Q3: When and how should an applicant contact FDA for feedback on a proposed change? ......... 5 
 
APPENDIX A ................................................................................................................................ 7 
APPENDIX B ................................................................................................................................ 9 
i  Contains Nonbinding Recommendations 
 
Changes to Disposable Manufacturing Materials:  
Questions and Answers 
Guidance for Industry1 
 
 
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  
 
This guidance describes chemistry, manufacturing, and controls (CMC) postapproval changes 
related to disposable manufacturing materials2 that applicants can pursue in drug and biological 
product manufacturing. This guidance applies to biologics license application (BLA) products 
licensed under section 351(a) or 351(k) of the Public Health Service Act (PHS Act); human drug 
products marketed as new drug applications (NDAs) or abbreviated new drug applications 
(ANDAs) under section 505(b)(1), 505(b)(2), or 505(j) of the Federal Food, Drug, and Cosmetic 
Act (FD&C Act); and animal drugs marketed as new animal drug applications (NADAs) or 
abbreviated new animal drug applications (ANADAs) under section 512(b)(1) or 512(b)(2) of 
the FD&C Act.3 This guidance applies to all manufacturing establishments, including those that 
perform functions under contract as defined in the guidance for industry Contract Manufacturing 
Arrangements for Drugs: Quality Agreements (November 2016).4  
 
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 
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Center for 
Veterinary Medicine (CVM). 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 For the purposes of this guidance, disposable manufacturing materials include, but are not limited to, single-use 
system assemblies and parts, filters, mixing bags, bioreactor bags, and tubing. 
 
3 This guidance also applies to combination products with device constituent parts that are the subject of BLAs, 
NDAs, ANDAs, and application supplements. 
 
4 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
  1  Contains Nonbinding Recommendations 
 
specific regulatory or statutory requirements are cited. The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
 
II.  DISCUSSION 
 
FDA receives questions about the limited availability of disposable manufacturing materials 
during periods of increased demand (e.g., public health emergencies or natural disasters). 
Limited availability of disposable manufacturing materials can affect sterile drugs and biological 
products. Applicants should use science-based and risk-based principles, and refer to current 
guidances for industry, to determine the appropriate reporting category to communicate changes 
to disposable manufacturing materials.  
 
FDA expects all changes to be appropriately managed by an establishments pharmaceutical 
quality system under the statutory requirements in section 501(a)(2)(B) of the FD&C Act and 
applicable current good manufacturing practice (CGMP) regulations in 21 CFR parts 210, 211, 
and 600-680, and part 4 for combination products. Additionally, applicants should follow the 
principles described in FDAs ICH guidances for industry: Q7 Good Manufacturing Practice 
Guidance for Active Pharmaceutical Ingredients (September 2016), Q9 Quality Risk 
Management (June 2006), Q10 Pharmaceutical Quality System (April 2009), and Q12 Technical 
and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021). 
 
Changes to disposable manufacturing materials for application products should be communicated 
to FDA through postapproval submissions  such as prior approval supplements (PAS) or 
changes being effected (CBE) supplements  or in annual reports.5, 6, 7, 8, 9, 10, 11 Regulations 
describe types of postapproval changes and associated reporting categories.12 Under CGMP, any 
changes to disposable manufacturing materials should be documented within the pharmaceutical 
 
5 Guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain 
Biological Products (June 2021).  
  
6 Guidance for industry CMC Postapproval Manufacturing Changes for Specified Biological Products to Be 
Documented in Annual Reports (December 2021). 
 
7 Guidance for industry CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports (March 
2014). 
 
8 Guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved NADA/ANADA (May 
2007). 
 
9 Guidance for industry Changes to an Approved NDA or ANDA (April 2004). 
 
10 Guidance for industry Changes to an Approved Application for Specified Biotechnology and Specified Synthetic 
Biological Products (July 1997).  
 
11 FDA ICH guidance for industry Q12 Technical and Regulatory Considerations for Pharmaceutical Product 
Lifecycle Management (May 2021). 
 
12 See 21 CFR  314.70, 314.97, 514.8, and 601.12. 
  2  Contains Nonbinding Recommendations 
 
quality system13 and available upon request during an inspection, including when the element 
being changed is not specifically described in an application. Changes to drug products for 
administration to humans or animals must be approved by the quality unit.14  
 
Changes to disposable manufacturing materials for nonapplication products, including 
nonprescription drug products, should be documented under the pharmaceutical quality system15 
and must be approved by the quality unit.16  
 
III.  QUESTIONS AND ANSWERS 
 
The following questions and answers provide information about making changes to disposable 
manufacturing materials.  
 
Q1: What are some possible changes an applicant can make to disposable 
manufacturing materials and what reporting categories are applicable? 
 
A1: Changes to disposable manufacturing materials can include, but are not limited to, the 
following: (1) changing suppliers, with or without a change in product-contacting material; 
(2) using similar materials that differ in composition or design; (3) reducing the number of 
materials used or extending the use of materials in manufacturing by increasing throughput; 
and (4) reusing a disposable manufacturing material. Current guidances for industry provide 
examples of relevant changes and corresponding reporting categories.17 Refer to Appendix A 
and Appendix B of this guidance for a summary of examples. These examples are not 
intended to be comprehensive.  
 
Factors to be considered when assessing risks to product quality and determining the 
reporting category for the change include the following: (1) intended use of the disposable 
manufacturing material in the manufacturing process; (2) whether a disposable 
manufacturing material is used upstream or downstream; (3) use of redundant steps within 
the manufacturing process; (4) enhanced product and process knowledge gained since 
application approval; (5) whether in-process and release/stability controls meet current 
regulations for detecting differences in product quality attributes; and (6) the extent of 
existing validation data.  
 
For approved BLAs, NDAs, ANDAs, NADAs, and ANADAs, applicants should consider 
factors such as those described above to determine the potential scope and risk to product 
quality of the proposed change (i.e., major, moderate, or minor), considering the specific 
 
13 FDA ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009). 
 
14 21 CFR 211.22 
 
15 See footnote 13. 
 
16 See footnote 14. 
 
17 See footnotes 5-11.  
 
  3  Contains Nonbinding Recommendations 
 
product and/or process affected by the change to disposable manufacturing material. The 
outcome of this assessment, in conjunction with regulations and guidances for CMC changes, 
can help determine which reporting category is appropriate for a proposed change. Changes 
that require an application supplement should be filed at the appropriate reporting category, 
commensurate with the level of risk to product quality. Additionally, as described in the FDA 
ICH guidance for industry Q9 Quality Risk Management (June 2006), the robustness of the 
data submitted in support of such a supplement should be commensurate with the level of 
risk to product and process. For a description of major, moderate, and minor changes, see 21 
CFR  601.12 (BLAs), 314.70 (NDAs), 314.97 (ANDAs), and 514.8 (NADAs and 
ANADAs). For elaboration on the potential risk to product quality for different changes to 
disposable manufacturing materials, including high-risk changes that could potentially affect 
critical quality attributes such as product sterility, see Appendix A and Appendix B of this 
guidance. Applicants should review the FDA ICH guidance for industry Q12 Technical and 
Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021) 
and the draft guidance for industry ICH Q12: Implementation Considerations for FDA-
Regulated Products (May 2021)18 for risk-based tools to facilitate streamlined change 
implementation. 
 
Q2: Are there steps to lower the reporting category of a supplement? 
 
A2: A comparability protocol (CP) could be used as a tool for making changes to disposable 
manufacturing materials because a change to one material can be implemented to many 
products. As described in the guidance for industry Comparability Protocols  Chemistry, 
Manufacturing, and Controls Information for New Animal Drugs (April 2016) and draft 
guidance for industry Comparability Protocols for Human Drugs and Biologics: Chemistry, 
Manufacturing, and Controls Information (April 2016),19 a CP is a comprehensive, 
prospectively written plan for assessing the effect of a proposed CMC postapproval change 
on the identity, strength, quality, purity, or potency of a drug product or a biological 
product.20  
 
Applicants can use a CP to obtain feedback from FDA on prospective scientific approaches 
submitted as 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 covering approved products at one or more manufacturing 
establishments, supporting information (including any developmental batch data, analysis 
and risk assessment activities), the plan for implementing the change(s), and, if appropriate, a 
proposed reduced reporting category. If the original application or PAS containing the CP is 
approved, the change can be implemented under a lower reporting category than would 
 
18 When final, this guidance will represent the FDAs current thinking on this topic.  
 
19 When final, this guidance will represent the FDAs current thinking on this topic.  
 
20 Additional information specific to biological products can be found in the FDA ICH guidance for industry Q5E 
Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (June 
2005).  
 
  4  Contains Nonbinding Recommendations 
 
ordinarily be expected based on current guidances for industry (e.g., changes otherwise 
requiring a PAS could be implemented under a CBE-30). 
 
An approved CP can be used for a one-time change or be used repeatedly for a specified type 
of change over the lifecycle of a product. A CP can also be submitted to cover an identical 
change that affects multiple applications (e.g., grouped supplements, trans-BLA 
submissions). A CP is the same as a Postapproval Change Management Protocol as described 
in the FDA ICH guidance for industry Q12 Technical and Regulatory Considerations for 
Pharmaceutical Product Lifecycle Management (May 2021).  
 
The use of CPs can be limited for certain changes (e.g., major changes), where a reduced 
reporting category is not adequate or appropriate to ensure product quality and patient safety. 
Examples of such circumstances include insufficient understanding of the effect of the 
change on the product or process; when the CGMP compliance status of an establishment at 
the time of change impacts the reporting category; or whether data from nonclinical safety, 
pharmacokinetic/pharmacodynamic, or safety and efficacy studies are needed to evaluate the 
effect of changes on product quality. Even if a reduced reporting category is not justified, 
FDA can implement flexible assessment practices, such as expediting assessment of 
supplements, when warranted.21, 22, 23, 24 
 
Q3: When and how should an applicant contact FDA for feedback on a proposed 
change? 
 
A3: Applicants should review existing regulations and guidances for industry to determine 
the appropriate reporting category for a proposed change. Because the examples in guidances 
are not comprehensive and may not address novel situations, applicants should contact FDA 
for feedback on a proposed change, especially before submitting a supplement with a lower 
reporting category than what is required in existing regulations or recommended in existing 
guidance. FDA intends to provide timely assessment of and feedback on these types of 
proposed changes to meet urgent public health needs.  
 
 
21 For FDA policies describing expedited review requests related to prior approval supplements for NDAs and 
BLAs, see 21 CFR 314.70(b)(4) and 601.12(b)(4). See also CDER Manual of Policies and Procedures (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 (April 2021).  
 
22 For FDA policies describing expedited review requests related to prior approval supplements for NADAs and 
ANADAs, see CVM Program Policy and Procedures Manual 1243.3020: Review of Submissions in the Submission 
Tracking and Reporting System (STARS) Queue (May 2021).  
 
23 For FDA policies on drug shortage management, see CDER MAPP 4190.1 Rev. 3: Drug Shortage Management 
(November 2018), and CBER SOPP 8506, Management of Shortages of CBER-Regulated Products (February 
2022). 
 
24 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 (January 2020). 
 
  5  Contains Nonbinding Recommendations 
 
When contacting FDA about initiating changes to disposable manufacturing materials, the 
applicant should be ready to provide relevant information, including: (1) any affected 
products and processes; (2) proposed changes to mitigate effects of the component shortage 
on product quality and supply; (3) involvement of other products and/or manufacturing 
establishments (including contract manufacturing organizations); and (4) any information 
related to potential or actual drug shortage concerns. BLA, NDA, NADA, and ANADA 
applicants who want to request a meeting with FDA to discuss a particular product or 
application should contact the appropriate review team.25  
 
 
25 For additional questions, contact the appropriate product center: CDER at CDER-OPQ-Inquiries@fda.hhs.gov or 
CVM at AskCVM@fda.hhs.gov. For CBER-regulated products, applicants should contact the appropriate CBER 
review office. If a regulated product could enter or is currently in drug shortage, the applicant should also 
communicate with drugshortages@fda.hhs.gov (for products regulated by CDER), cbershortage@fda.hhs.gov (for 
products regulated by CBER), or animaldrugshortages@fda.hhs.gov (for products regulated by CVM). 
  6  Contains Nonbinding Recommendations 
 
1  APPENDIX A 
2   
3  The following are examples of potentially relevant changes1 and corresponding reporting 
4  categories for a new drug application (NDA), abbreviated new drug application (ANDA), new 
5  animal drug application (NADA), and abbreviated new animal drug application (ANADA) 
6  products. Note: this does not include biologics license application (BLA) products. These 
7  examples come from the following guidances for industry: Changes to an Approved NDA or 
8  ANDA: Questions and Answers (January 2001), Changes to an Approved NDA or ANDA (April 
9  2004), Chemistry, Manufacturing and Controls Changes to Approved NADA/ANADA (May 
10  2007), and CMC Postapproval Manufacturing Changes to be Documented in Annual Reports 
11  (March 2014).  
12   
13  Prior Approval Supplement: 
14   
15    Change from sterile filtration to moist heat sterilization for products containing heat-
16  stable active pharmaceutical ingredients. 
17   
18    Deletion or substitution of a filtration step in an aseptic processing operation.  
19   
20    Change to a product contact component in an aseptic filling line from a disposable plastic 
21  component to a reusable stainless-steel component. 
22   
23    Changes to the pore size rating of a filter used in aseptic processing.  
24   
25  Changes Being Effected (CBE): 
26   
27  CBE-30: 
28   
29    Increase of the flow rate filtration parameter for aseptic processing without a change to 
30  the filter materials or pore size rating.  
31   
32    Reduction of the number of redundant sterilizing filters in series for repeated filtration of 
33  a bulk.  
34   
35    Increase in the bulk solution storage time for a terminally sterilized drug product by more 
36  than 50 percent beyond the validated limits in the approved application when bioburden 
37  limits are unchanged.  
38   
39  CBE-0: 
40   
41    Elimination of an in-process filtration step for a terminally sterilized drug product.  
42   
 
1 For the examples listed in Appendix A, the term change refers to a change in a disposable manufacturing 
material or a change to a manufacturing process or process parameter that reduces the amount of a disposable 
manufacturing material needed to complete that process. 
  7  Contains Nonbinding Recommendations 
 
43  Annual Report: 
44   
45    Within a currently validated process parameter range, a change in the range of filtration 
46  volume for a sterile drug product. 
47   
48    Increase in the bulk solution storage time for a terminally sterilized drug product by no 
49  more than 50 percent beyond the validated limits in the approved application when 
50  bioburden limits are unchanged. 
51   
52    Deletion of a reprocessing protocol for refiltrations of a sterile drug product to control 
53  bioburden because of filter integrity test failures.  
54   
  8  Contains Nonbinding Recommendations 
 
55  APPENDIX B 
56   
57  The following are examples of potentially relevant changes1 and corresponding reporting 
58  categories for biologics license application (BLA) products. Note: this does not include new drug 
59  application (NDA), abbreviated new drug application (ANDA), new animal drug application 
60  (NADA), and abbreviated new animal drug application (ANADA) products. These examples 
61  come from the following guidances for industry: Changes to an Approved Application for 
62  Specified Biotechnology and Specified Synthetic Biological Products (July 1997), Changes to an 
63  Approved Application: Biological Products (July 1997), CMC Postapproval Manufacturing 
64  Changes for Specified Biological Products to be Documented in Annual Reports (December 
65  2021), and Chemistry, Manufacturing and Controls Changes to an Approved Application: 
66  Certain Biological Products (December 2017).  
67   
68  Prior Approval Supplement: 
69   
70  Drug substance: 
71   
72    Change from a stainless-steel to disposable (e.g., bag) bioreactor or vice versa.  
73   
74    Increase in the number of cycles of resin and membrane re-use without an approved 
75  protocol. 
76   
77    New or revised purification process (e.g., change in the resin or filter material, loading 
78  scale, column size, or elution rate of a chromatographic column).  
79   
80    Change in the method(s) for virus or adventitious agent removal or inactivation.  
81   
82  Drug product: 
83   
84    Addition, deletion, or substitution of unit operation(s) or change in their sequence.  
85   
86    Change in scale of the manufacturing process.  
87   
88    Changes that affect product sterility assurance, such as changes in product or component 
89  sterilization method(s), or an addition, deletion, or substitution of steps in an aseptic 
90  processing operation. 
91   
92    Change in a membrane material or dimensions of the final sterilization filter. 
93   
94  Changes Being Effected (CBE): 
95   
96  CBE-30: 
 
1 For the examples listed in Appendix B, the term change refers to a change in a disposable manufacturing 
material or a change to a manufacturing process or process parameter that reduces the amount of a disposable 
manufacturing material needed to complete that process. 
  9  Contains Nonbinding Recommendations 
 
97   
98  Drug substance: 
99   
100    Change in the filter or resin supplier with no change in the resin material, operating or 
101  performance parameters.  
102   
103  Drug Product: 
104   
105    Replacement of equipment with that of similar, but not identical, design and operating 
106  principle that does not affect the process methodology, process operating parameters or 
107  aseptic processing.  
108   
109    Change to a final sterilization filter supplier with no change in material, dimensions, or 
110  sterilization method.  
111   
112    Changes to sterilization cycles for sterile product contact equipment.  
113   
114  Annual Report: 
115   
116    Addition or replacement of equipment of the same size and material of construction used 
117  in harvesting and pooling with no change in the process parameters specified in the 
118  approved BLA.  
119   
120   
  10