CMC Postapproval 
Manufacturing Changes for 
Specified Biological Products 
To Be Documented in  
Annual Reports 
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) 
 
December 2021 
Pharmaceutical Quality/CMC 
 
    
CMC Postapproval 
Manufacturing Changes for 
Specified Biological Products 
To Be Documented in  
Annual Reports 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: 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 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
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 
 
 
 
 
 
 
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) 
 
December 2021 
Pharmaceutical Quality/CMC 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  RECOMMENDATIONS FOR REPORTING CERTAIN CHANGES IN AN 
ANNUAL REPORT ...................................................................................................................... 3 
IV.  CONTENTS OF ANNUAL REPORT NOTIFICATION ............................................. 4 
APPENDIX: CHANGES THAT FDA GENERALLY CONSIDERS HAVING A MINIMAL 
POTENTIAL TO HAVE AN ADVERSE EFFECT ON PRODUCT QUALITY................... 5 
i  Contains Nonbinding Recommendations 
 
CMC Postapproval Manufacturing Changes for Specified Biological 
Products To Be Documented in Annual Reports 
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 provides recommendations to holders of biologics license applications (BLAs) for 
specified biological products regarding the types of changes to an approved BLA to be 
documented in an annual report under 21 CFR 601.12. Specifically, the guidance describes 
chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that FDA 
generally considers to have a minimal potential to have an adverse effect on product quality.2 
Under FDA regulations, postapproval changes in the product, production process, quality 
controls, equipment, facilities, or responsible personnel that have a minimal potential to have an 
adverse effect on product quality must be documented by applicants in an annual report.3 
 
This guidance applies to biological products, as defined in 21 CFR 600.3(h), that fall under one 
of the following categories specified in 21 CFR 601.2(a): therapeutic DNA plasmid products, 
therapeutic synthetic peptide products of 40 or fewer amino acids, monoclonal antibody products 
for in vivo use, and therapeutic recombinant DNA-derived products.4 It also applies to 
combination products licensed under a BLA, where the biological product constituent part falls 
under one of these categories specified in 21 CFR 601.2(a). The guidance does not apply to 
blood or blood components, blood-derived products, in vitro diagnostics, cellular and gene 
therapy products, or vaccines and related products5; however, a BLA holder for any other 
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research at the Food and Drug Administration.  
2 In this guidance, the term product quality refers to the identity, strength, quality, purity, or potency of the product 
as [these factors] may relate to the safety or effectiveness of the biological product (21 CFR 601.12(d)(1)). 
3 See 21 CFR 601.12(d). 
4 Only a product that meets the definition of biological product can fall within the specified categories of biological 
products described in 21 CFR 601.2(a). 
5 For recommendations related to these products, see guidances for industry Changes to an Approved Application: 
Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture 
(December 2014) and Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain 
Biological Products (June 2021). 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 
 
naturally derived biological product should discuss with FDA whether the recommendations in 
this guidance apply to his or her BLA.  
 
This guidance focuses on reporting mechanisms. For information about change management 
within the pharmaceutical quality system, see International Council for Harmonisation (ICH) 
guidances for industry Q9 Quality Risk Management (June 2006), Q10 Pharmaceutical Quality 
System (April 2009), and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical 
Ingredients (September 2016). 
 
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 Agency 
guidance means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
An applicant must notify FDA of a change to an approved BLA in accordance with all statutory 
and regulatory requirementsincluding section 506A of the Federal Food, Drug, and Cosmetic 
Act (FD&C Act) (21 U.S.C. 356a) and 21 CFR 601.12.6 Section 506A of the FD&C Act 
provides requirements for making and reporting manufacturing changes to an approved 
application or license and for distributing a drug made with such changes. Under 21 CFR 601.12, 
each postapproval change in the product, production process, quality controls, equipment, 
facilities, or responsible personnel established in the approved BLA must be reported using the 
submission type associated with one of three reporting categories: major, moderate, or minor.7  
 
If a change is considered to be major, an applicant must submit and receive FDA approval of a 
supplement to the BLA before the product produced with the manufacturing change is 
distributed (also known as a prior approval supplement (PAS)).8 If a change is considered to be 
 
6 Applicants must also comply with other applicable laws and regulations, including current good manufacturing 
practice (CGMP) regulations in 21 CFR parts 210 and 211, as well as the applicable requirements in 21 CFR parts 
600 through 680. CGMP regulations cover activities such as establishing and following appropriate written 
procedures reviewed and approved by the quality control unit, qualifying equipment as suitable for its intended use, 
using validated test methods, and ensuring the manufacturing processs ongoing state of control (which may include 
additional stability studies depending on the nature of the change). 
7 The ICH guidance for industry Q12 Technical and Regulatory Considerations for Pharmaceutical Product 
Lifecycle Management (May 2021) outlines terminologies and concepts, including established conditions, that may 
impact how an applicant reports postapproval CMC changes. FDA considers established conditions to include the 
description of the product, manufacturing process, facilities and equipment, and elements of the associated control 
strategy, as defined in an application, that assure process performance and quality of an approved product, and that 
can be specifically identified and proposed by the sponsor and approved as part of a BLA. Changes to the 
established conditions must be reported to FDA (21 CFR 601.12). CMC information in an application that is not 
considered an established condition may be changed postapproval without the submission of a supplement or 
documentation in an annual report.  
8 21 CFR 601.12(b). 
  2  Contains Nonbinding Recommendations 
 
moderate, an applicant must submit a supplement at least 30 days before the product is 
distributed (CBE-30 supplement) or, in some cases, the product may be distributed immediately 
upon FDAs receipt of the supplement (CBE-0 supplement).9 If a change is considered to be 
minor, an applicant may proceed with the change but must notify FDA of the change in an 
annual report.10 For any change, applicants must assess the effects of the change on product 
quality through appropriate validation and/or other studies.11 For additional background 
information regarding the reporting categories for BLAs, see the guidance for industry Changes 
to an Approved Application for Specified Biotechnology and Specified Synthetic Biological 
Products (July 1997).  
 
The number of CMC manufacturing supplements for BLAs has increased over the last several 
years. In keeping with a risk-based approach to CMC review,12 FDA has evaluated the types of 
changes that have been submitted in postapproval manufacturing supplements and determined 
that certain changes being reported generally present minimal risk to the quality of the product 
(i.e., they generally have minimal potential to have an adverse effect on product quality).  
 
 
III.  RECOMMENDATIONS FOR REPORTING CERTAIN CHANGES IN AN 
ANNUAL REPORT 
 
Examples of changes that have minimal potential to have an adverse effect on product quality 
and therefore must be submitted in an annual report are found in 21 CFR 601.12(d). 
Additionally, FDA provides examples in the Appendix of changes that it generally considers to 
have a minimal potential to have an adverse effect on product quality, which are categorized 
according to the type of manufacturing change. BLA holders may, based on their specific 
circumstances, determine that a change described in the Appendix would appropriately be 
submitted as a supplement rather than in an annual report. If FDA disagrees with the 
categorization, FDA generally intends to notify the applicant of the correct category and may 
request additional information. 
 
The examples of changes in the Appendix include modified versions of relevant CMC changes 
included in the guidance for industry Changes to an Approved Application for Specified 
Biotechnology and Specified Synthetic Biological Products. Thus, before submitting a 
supplement based on the guidance for industry Changes to an Approved Application for 
Specified Biotechnology and Specified Synthetic Biological Products, an applicant should also 
refer to the examples listed in the Appendix of this guidance, which are intended to help clarify 
whether submission of a supplement or documentation of the change in an annual report may be 
appropriate. 
 
When considering the correct reporting category for a submission, the applicant should ensure 
that the highest risk change determines the reporting category that is chosen for the submission. 
 
9 21 CFR 601.12(c). CBE is changes being effected. 
10 21 CFR 601.12(d). 
11 21 CFR 601.12(a)(2). 
12 See FDAs Pharmaceutical CGMPs for the 21st CenturyA Risk-Based Approach (September 2004). 
  3  Contains Nonbinding Recommendations 
 
For example, there may be several minor-risk changes associated with one major-risk change, in 
which case the reporting category for the major-risk change should define the appropriate 
submission type (i.e., PAS). 
 
If unsure whether a change should be submitted to FDA in a supplement or documented in an 
annual report,13 applicants should contact the Office of Pharmaceutical Quality in CDER or the 
Office of Communication, Outreach and Development in CBER.  
 
 
IV.  CONTENTS OF ANNUAL REPORT NOTIFICATION 
 
To document changes in an annual report in accordance with 21 CFR 601.12(d), the applicant 
must include the following information for each change14:  
 
  A full description of the CMC change, including: 
 
  The manufacturing sites or areas involved. 
o
 
  The date the change was made. 
o
 
  A cross-reference to relevant validation protocols and/or standard operating 
o
procedures. 
 
  Relevant data from studies and tests performed to assess the effect of the change on 
o
product quality. 
 
  A list of all products involved. 
 
  A statement that the effects of the change have been assessed. 
 
The applicant should describe each change in an annual report in enough detail to allow FDA to 
evaluate the change and determine whether the appropriate reporting category has been used.15 If 
the submitted change is inappropriate for documentation in an annual report, FDA generally 
intends to notify the applicant of the correct category and may request additional information. 
However, applicants should only use this mechanism of reporting a change when they are 
confident that documentation in an annual report is appropriate.
 
13 For example, the change is not listed in the Appendix, or multiple related changes being implemented 
simultaneously increases the potential to have an adverse effect on product quality. 
14 21 CFR 601.12(d)(3) describes the information for each change that must be contained in the annual report. 
15 Under 21 CFR part 211, manufacturers are required to retain certain records, including records related to batch 
production and control, and to make those records readily available for inspection during the retention period. Other 
documentation and data that support reporting the change in an annual report should also be retained and made 
available to FDA on request (e.g., during an inspection or in responding to a request for information in advance or in 
lieu of an inspection, in accordance with section 704(a)(4) of the FD&C Act). 
  4  Contains Nonbinding Recommendations 
 
APPENDIX: CHANGES THAT FDA GENERALLY CONSIDERS HAVING A 
MINIMAL POTENTIAL TO HAVE AN ADVERSE EFFECT ON PRODUCT QUALITY 
 
This appendix provides examples of chemistry, manufacturing, and controls postapproval 
manufacturing changes that FDA generally considers having a minimal potential to have an 
adverse effect on product quality. Changes that have a minimal potential to have an adverse 
effect on product quality must be submitted in an annual report in accordance with 21 CFR 
601.12(d).  
 
1.  Components and Composition 
 
1.1.  Elimination or reduction of an overage from the drug product manufacturing batch 
formula that was previously used to compensate for manufacturing losses. Note that 
this does not apply to loss of potency during storage. 
 
2.  Manufacturing Sites1 
 
2.1.  Site change for testing. This includes: 
 
  Testing of process-related impurities whose risk has been mitigated (e.g., residual 
solvents) when the method has been successfully validated at the new site. 
 
  Compendial methods that are of low complexity (e.g., pH, osmolality). 
 
This does not include: 
 
  Testing for conformance to quality control specifications, including potency and 
impurities (except those whose risk has been mitigated, such as residual solvents).  
 
  Testing for quality attributes for which the robustness of the analytical method may 
be critical (e.g., sterility and virus testing) unless the new site is registered with and 
has been inspected by FDA for the type of testing being transferred and the methods 
and specifications for testing quality attributes are the same as for the original 
testing site. 
 
2.2.  Site change for labeling or secondary packaging. 
 
2.3.  Change in the location of manufacturing steps within a manufacturing area that is 
already listed in an approved biologics license application (BLA) where those steps are 
 
1 Manufacturing site changes that are submitted in annual reports should only be effected in facilities that meet 
current good manufacturing practice (CGMP) requirements. Where FDAs current classification is official action 
indicated, the facility is considered to be in an unacceptable state of compliance with regard to CGMP 
requirements. FDA posts inspection classification decisions in a publicly available database updated every 30 days; 
see Inspection Classification Database at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/inspection-classification-database. Applicants should consider the status in the database and request 
and use information from the proposed new manufacturing site if more current than that posted by FDA. 
  5  Contains Nonbinding Recommendations 
 
part of a nonsterile drug substance production process and the new location will have 
no impact or will lower the risk of contamination or cross-contamination (e.g., 
improved air classification, better process flow, enhanced segregation of pre- and post-
viral inactivation steps). 
 
2.4.  Modification of a manufacturing facility listed in an approved BLA that does not 
increase the risk of contamination (e.g., affect sterility assurance) or otherwise present a 
meaningful risk of affecting product quality. 
 
2.5.  Introduction of an additional drug product in a multiple-product area, or a multiple-
product contract manufacturing site, that is listed in an approved BLA and producing 
other products, if: 
 
  Specific identity tests exist to prevent cross-contamination and other errors;2 and 
 
  Changeover procedure between manufacturing processes does not require new 
changes in cleaning procedures; and 
 
  The products do not represent an additional level of risk. Additional levels of risk 
might include, but are not limited to, the manufacture of highly toxic or potent 
products (e.g., botulinum toxin), highly immunogenic or allergenic products (e.g., 
penicillin), products that can accelerate degradation of another product (e.g., 
proteases), products that represent a new or added risk for adventitious agents, or a 
product for adults added to a line manufacturing pediatric products.  
 
3.  Manufacturing Process, Batch Size, and Equipment3 
 
3.1.  Manufacturing batch size or scale change caused by minor changes in the size of pooled 
or separated batches to perform the next step in the manufacturing process if all batches 
meet the approved in-process control limits and the critical process parameter ranges for 
the next step remain unaffected. 
 
3.2.  Changes to batch sizes that do not involve use of different equipment (e.g., minor 
changes in roller bottle number, fermenter volume, or load volumes for chromatography 
columns). 
 
3.3.  Addition of an identical duplicate process chain or unit process in the drug substance 
and drug product manufacturing process with no change to equipment, process 
methodology, in-process control limits, process parameter ranges, or product 
 
2 In multiple-product contract manufacturing sites, if the identity tests are qualitative in nature, they should be 
specific to the additional product in its designated labeling and packaging configuration and should distinguish that 
product from others being processed at the same site (e.g., labeling and packaging configuration may be part of the 
identity testing of the product but should not be the standalone identity test). 
3 FDA generally considers these changes to have a minimal potential to have an adverse effect on product quality 
only when they are implemented in licensed areas for the same type of operation or testing and/or dosage form.  
  6  Contains Nonbinding Recommendations 
 
specifications, with the exception of addition of major equipment used in aseptic 
processing (e.g., new aseptic filling line, new lyophilizer). 
 
3.4.  Reduction of open-handling steps if there is a reduction in product exposure that 
represents improvement in the assurance of product protection (e.g., implementation of 
sterilize-in-place connections to replace aseptic connections, automated weight checks, 
installation of a barrier to protect product, replacement of a manual stopper recharging 
step with an automated recharging step). 
 
3.5.  For sterile drug products, change from a qualified sterilization chamber (e.g., ethylene 
oxide, autoclave) to another of the same design and operating principle for preparation 
of the container closure system when the new chamber and load configurations are 
validated to operate within the previously validated parameters. 
 
3.6.  For sterile drug products, changes to the ranges of filtration process parameters (such as 
flow rate, pressure, time, or volume, but not filter pore size) that are within previously 
validated parameters. 
 
4.  Specifications 
 
4.1.  Addition of tests and acceptance criteria to specification for approved excipients.  
 
4.2.  Change to a drug substance or drug product to comply with an official compendial test, 
except for changes described in 21 CFR 601.12(c)(2)(iv). 
 
4.3.  Change in the analytical procedure described in the approved application if the 
acceptance criteria remain unchanged and the revised method maintains basic test 
methodology (e.g., change in the flow rate or change in the sample preparation for an 
HPLC4 method) and provides equivalent or increased assurance that the drug substance 
or drug product will have the characteristics of identity, strength, quality, purity, or 
potency that it claims to have or is represented to possess.5  
 
4.4.  Replacement of a nonspecific identity test with a discriminating identity test that 
includes a change in acceptance criteria (e.g., replacing SDS-PAGE6 with peptide 
mapping). 
 
4.5.  Addition of an in-process test. 
 
4.6.  Addition of a test for packaging material to provide increased quality assurance. 
 
4.7.  Tightening of an existing acceptance criterion. 
 
 
4 HPLC stands for high-performance liquid chromatography. 
5 See 21 CFR 601.12(d)(2)(vii). 
6 SDS-PAGE stands for sodium dodecyl sulphate polyacrylamide gel electrophoresis. 
  7  Contains Nonbinding Recommendations 
 
4.8.  Extension of the drug substance retest dating period or drug product expiration dating 
period based on full shelf-life stability data following an approved stability protocol. 
 
5.  Container Closure System  
 
5.1.  Change in the container closure system for the storage of a nonsterile drug substance 
when the proposed container closure system has no increased risk of leachable 
substances (based on the extractables and/or leachables profile and whether stability 
data are consistent with historical trends), and the new container offers equivalent or 
greater protection properties (e.g., from air, moisture, and light (for light-sensitive 
products)). 
 
5.2.  Use of a contract manufacturing organization to wash the drug products container 
closure system in accordance with the original acceptance criteria for the washing 
process.  
 
5.3.  Changes to a crimp cap (ferrule and cap/overseal), provided that there are no changes to 
the labeling or the color and that container closure integrity has been demonstrated 
using a validated test method. 
  8