Chemistry, Manufacturing, and 
Controls Changes to an Approved 
Application:  Certain Biological 
Products 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
For questions on the content of this guidance, contact the Center for Biologics Evaluation and 
Research (CBER), Office of Communication, Outreach, and Development (OCOD) at 240-
402-8010 or 1-800-835-4709, or email ocod@fda.hhs.gov; or the Center for Drug Evaluation 
and Research (CDER), Office of Communications, Division of Drug Information, phone 1-
855-543-3784 or 301-796-3400, or email druginfo@fda.hhs.gov. 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
Center for Drugs Evaluation and Research 
June 2021 Chemistry, Manufacturing, and 
Controls Changes to an Approved 
Application:  Certain Biological 
Products 
 
 
Guidance for Industry 
 
 
Additional copies of this guidance are available from: 
 
Office of Communication, Outreach and Development 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Avenue, WO71, Room 3128  
Silver Spring, MD 20993 
Phone:  1-800-835-4709 or 240-402-8010 
E-mail:  ocod@fda.hhs.gov  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances 
 
or 
 
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 
Phone:  301-796-3400 or 1-855-543-3784; Fax:  301-431-6353  
E-mail:  druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION ................................................................................................................. 1 
II.  BACKGROUND ................................................................................................................... 1 
III.  SCOPE ................................................................................................................................... 3 
IV.  REPORTING CHANGES .................................................................................................... 5 
A.  Reporting Categories ................................................................................................ 5 
1.  Prior Approval Supplement (PAS) ................................................................. 5 
2.  Changes Being Effected in 30 Days/Changes Being Effected Supplements 
(CBE30/CBE) ................................................................................................. 5 
3.  Annual Report (AR) ........................................................................................ 6 
B.  Assessing and Implementing Manufacturing Changes ......................................... 6 
1.  Applicant Assessment and Implementation of Change  ................................. 6 
2.  FDA Assessment of Change ...........................................................................7 
C.  Submission of Changes to FDA ............................................................................... 8 
D.  Comparability Protocols .......................................................................................... 9 
E.  Recommendations for Reporting Categories ....................................................... 10 
V.  SPECIAL CONSIDERATIONS ........................................................................................ 11 
A.  Change in Process Parameters .............................................................................. 11 
B.  Change in a Supplier of Raw Materials ................................................................ 11 
C.  Miscellaneous changes not specified in Appendix ............................................... 12 
VI.  GLOSSARY ......................................................................................................................... 12 
VII.  REFERENCES .................................................................................................................... 17 
APPENDIX ...................................................................................................................................... 19 
 
 
   
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Chemistry, Manufacturing, and Controls Changes to an Approved 
Application:  Certain Biological Products 
 
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 
responsible for this guidance as listed on the title page. 
 
 
I.  INTRODUCTION 
 
We (FDA or Agency) are providing guidance intended to assist applicants and manufacturers of 
certain licensed biological products in determining which reporting category is appropriate for a 
change in chemistry, manufacturing, and controls (CMC) information to an approved biologics 
license application (BLA) as specified in Title 21 of the Code of Federal Regulations 601.12 (21 
CFR 601.12) (i.e., post-approval changes) (Refs. 1 and 2).  The guidance describes general and 
administrative information on evaluating and reporting changes and recommendations for 
reporting categories based on a tiered-reporting system for specific changes under 21 CFR 
601.12.  This guidance finalizes the draft guidance, Chemistry, Manufacturing, and Controls 
Changes to an Approved Application:  Certain Biological Products dated December 2017, and 
supersedes the guidance entitled Guidance for Industry:  Changes to an Approved Application: 
Biological Products dated 1997 (July 1997 guidance). 
 
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 
 
Applicants and manufacturers (applicants), for a variety of reasons, often implement changes 
to the product, production process, quality controls, equipment, facilities, or responsible 
personnel, or labeling approved in an application for licensed biological products (for purposes 
of this document, manufacturing changes).  An applicant must notify the Agency about each 
manufacturing change to an approved BLA under 21 CFR 601.12.  If the applicant makes a 
manufacturing change to an approved BLA, the applicant must also conform to other applicable 
laws and regulations, including the current good manufacturing practice (CGMP) requirements 
of section 501 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
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351(a)(2)(B)) and the regulations in 21 CFR Parts 210, 211, as well as the applicable 
requirements in 21 CFR Parts 600 through 680 and 820.  In addition, section 506A of the FD&C 
Act (21 U.S.C. 356a) provides requirements for making and reporting manufacturing changes to 
an approved BLA and for distributing a licensed product made with such a change.  Prior to 
distribution of the product made with a change, an applicant must assess the effects of the change 
and demonstrate, through appropriate validation and/or other clinical and/or non-clinical 
laboratory studies, the lack of an adverse effect of the change on the identity, strength, quality, 
purity, or potency of the product (for purposes of this guidance, product quality) as they may 
relate to safety or effectiveness of the product.1   In accordance with 21 CFR Parts 210, 211, 600 
through 680, and 820, manufacturers must comply with the CGMPs and other applicable 
requirements and with recordkeeping requirements to ensure that relevant records are readily 
available for examination by authorized FDA personnel during an inspection. 
 
FDA issued the July 1997 guidance to assist applicants in determining which reporting 
mechanism is appropriate for reporting a change to an approved application to reduce the burden 
on applicants when reporting changes and to facilitate the approval process of the change being 
made.  FDA is updating the July 1997 guidance to accommodate advances in manufacturing  and 
testing technology and to clarify the FDAs current thinking on assessing reportable changes. 
 
On August 21, 2002, FDA launched the initiative, Pharmaceutical Current Good Manufacturing 
Practices (cGMPs) for the 21st Century - A Risk-Based Approach2 (FDA initiative) to stay abreast 
of new technological advances and enable the Agency to regulate pharmaceutical manufacturing 
and allocate regulatory resources more effectively.  As part of this FDA initiative, the Agency 
determined that, to provide the most effective public health protection, the CMC regulatory 
review should be based on an understanding of product risk and how best to manage this risk. 
 
We have conducted a review and evaluation of manufacturing changes reported across licensed 
biological products that are within the scope of this guidance.  To determine the appropriate 
reporting category based on a tiered-reporting system for a specific change, we applied principles 
of quality risk assessment and risk management consistent with the FDA initiative and the 
general recommendations outlined in the Guidance for Industry:  Q9 Quality Risk Management 
(Ref. 3).   Based on this evaluation and our overall experience from inspections and review of 
manufacturing changes, we have revised the recommendations contained in the July 1997 
guidance for reporting categories by reclassifying the risks associated with specific changes.  
Moreover, we have provided additional examples of manufacturing changes to provide further 
guidance to applicants and manufacturers and assist with making more informed decisions when 
reporting and implementing post-approval changes.  In some instances, these updated 
recommendations will result in a less burdensome approach for reporting changes, thereby 
accelerating distribution of the product made with the change.  These updated recommendations 
are expected to promote continual improvement and innovation over the product lifecycle and 
minimize the risks for product shortages.  These revisions are consistent with the risk-based 
regulatory review approach applied by the FDA to the regulation of biological product 
manufacturing. 
 
 
1 21 CFR 601.12(a)(2). 
2 The final report on the FDA initiative can be found at https://www.fda.gov/media/77391/download. 
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III.  SCOPE 
 
This guidance applies to certain biological products licensed under section 351(a) of the Public 
Health Service Act (PHS Act).  This guidance applies to all manufacturing locations, including 
contract locations.  Licensed biological products that are within the scope of this guidance 
include: 
 
  Vaccines; 
  Allergenic products; 
  Plasma-derived products e.g., albumin, immunoglobulins, clotting factors, fibrin 
sealants, proteinase inhibitors, etc.); and their recombinant analogs;   
  Antitoxins, antivenins, and venoms; 
  Naturally-derived (i.e., not recombinant) protein products (e.g., naturally-derived 
enzymes and certain toxins); 
  Cellular and gene therapy products;3 
  In vitro diagnostics (IVDs) regulated under the PHS Act (e.g., blood donor screening 
assays, etc.); and 
  Other biological products licensed under the PHS Act subject to exceptions listed 
below. 
 
This guidance also applies to combination products licensed under a BLA, unless the biological 
product constituent part is a specified biological product described in 21 CFR 601.2(a) or is 
otherwise outside the scope of this guidance, as described below.  Biological products that are not 
within the scope of this guidance include: 
 
  Whole Blood, blood components (including Source Plasma) and Source Leukocytes 
(Ref. 4); 
  Specified biological products described in 21 CFR 601.2(a);4 and 
  Biosimilar and interchangeable products subject to licensure under section 351(k) of 
the PHS Act (42 U.S.C. 262(k)).  
 
This guidance also does not apply to human cells, tissues, and cellular and tissue-based products 
(HCT/Ps) regulated solely under section 361 of the PHS Act (42 U.S.C. 264) and the regulations 
in 21 CFR Part 1271. 
 
This guidance does not apply to changes to an applicants name.  Such submissions are handled 
separately as product correspondence, in accordance with established procedures.  For example, 
see CBERs Standard Operating Policy and Procedure (SOPP) 8403:  Issuance and Reissuance 
of Licenses for Biological Products for further information on name changes.5 
 
 
3 For purposes of this guidance, the term gene therapy products includes cell-based gene therapies. Cellular 
therapy products include tissue-engineered products regulated under section 351 of the PHS Act.  
4 For additional information on changes to an approved application for specified biotechnology and specified 
synthetic biological products, see Ref. 5. 
5 Available at https://www.fda.gov/media/108918/download.  
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Some manufacturing changes discussed in this guidance may also require revision of the 
approved labeling (Ref. 6).  Such changes are outside the scope of this guidance.  In general, 
under 21 CFR 601.12(f): 
 
  Labeling changes requiring supplement submission and FDA approval before 
distribution of the product with the labeling change include any change in the 
package insert, package label, or container label, including information required 
under 21 CFR 201.57(a), or, if applicable a Medication Guide required under 21 CFR 
Part 208, except those described in 21 CFR 601.12(f)(2) and (3);6 
 
  Labeling changes that require supplement submission and FDA approval, but which 
do not require FDA approval of the supplement before the product with the labeling 
change may be distributed, include certain safety-related labeling changes to the 
package insert, package label, or container label to reflect newly acquired 
information, or any other labeling change that FDA specifically requests to be 
submitted in a changes being effected supplement under 21 CFR 601.12(f)(2)(i)(E);7 
and 
 
  Labeling changes requiring submission in an annual report include changes to any 
final printed package insert, package label, container label, or Medication Guide 
required under 21 CFR Part 208 include, among other things, editorial or similar 
minor changes and changes in the information on how the product is supplied that 
does not involve a change in the dosage strength or dosage form.8 
 
For manufacturing changes that impact labeling, reporting classification is generally 
commensurate with the risks of the manufacturing change.  If the reporting classification 
recommendations are unclear for submissions that include both manufacturing and labeling 
changes, license holders are advised to consult with the appropriate FDA Review Division. 
 
During the finalization of this FDA guidance, the International Council for Harmonization (ICH) 
published Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle 
Management (see also the associated Annex) (Ref. 7).  The ICH Q12 guidance describes certain  
   
 
6 21 CFR 601.12(f)(1).  See also FDA guidance on The Deemed To Be a License Provision of the BPCI Act:  
Questions and Answers (March 2020), available at https://www.fda.gov/media/119274/download (recommending 
submission of a prior approval supplement for BLA-specific labeling changes for deemed BLAs). 
7 21 CFR 601.12(f)(2). 
8 21 CFR 601.12(f)(3). 
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terminologies and concepts, including Established Conditions,9 that may impact how an 
applicant reports post-approval changes.  The ICH Q12 guidance, should be used by applicants 
in concert with any other applicable FDA guidance to report post-approval changes to the 
Agency when such reporting is required by the statute and regulation. 
 
 
IV.  REPORTING CHANGES 
 
A.  Reporting Categories 
 
Under 21 CFR 601.12, each post-approval change in the product, production process, 
quality controls, equipment, facilities, responsible personnel, or labeling established in 
the approved BLA must be reported using the submission type associated with one of the 
three tier-based reporting categories depending upon the potential (i.e., risk) of the 
change to have an adverse effect on the identity, strength, quality, purity, or potency of 
the product as they may relate to the safety or effectiveness of the product (i.e., a 
substantial potential, moderate potential, or minimal potential).  The reporting categories 
in this regulatory provision also specify when the product made using the change can be 
distributed.  The submission types and associated reporting categories are as follows: 
 
1.  Prior Approval Supplement (PAS) - Changes that have a substantial 
potential to have an adverse effect on product quality (i.e., major changes) 
require an applicant to report the change to the FDA in a supplement to the 
approved BLA.  A PAS must be approved by the FDA prior to distribution of 
the product manufactured using the change (21 CFR 601.12(b)). 
 
2.  Changes Being Effected in 30 Days/Changes Being Effected 
Supplements10 (CBE30/CBE) - Changes that have a moderate potential to 
have an adverse effect on product quality (i.e., moderate changes) require an 
applicant to report the change to the FDA in a supplement at least 30 days 
prior to distribution of the product made using the change (21 CFR 601.12(c)).  
In certain circumstances, the FDA may determine that, based on the Agencys 
experience with a particular type of moderate change, the supplement for such 
a change is complete and provides the proper information and particular 
assurances that the change has been appropriately submitted.  The product 
made using such a change may be distributed immediately upon receipt of the 
supplement by the FDA (21 CFR 601.12(c)(5)).  These circumstances may 
include substantial similarity with a type of change that ordinarily involves a 
CBE supplement or a situation in which the applicant presents evidence that 
the change has been validated in accordance with an approved comparability 
protocol (CP) under 21 CFR 601.12(c) and 21 CFR 601.12(e). 
 
9 Established Conditions are defined by the FDA as 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). 
10 This paragraph refers to CBE supplements submitted under 21 CFR 601.12(c), and does not refer to CBE 
supplements for certain types of labeling changes submitted under 21 CFR 601.12(f)(2). 
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3.  Annual Report (AR) - Changes that have a minimal potential to have an 
adverse effect on product quality (i.e., minor changes) shall be documented by 
the applicant in an annual report (21 CFR 601.12(d)). 
 
 
B.  Assessing and Implementing Manufacturing Changes 
 
1.  Applicant Assessment and Implementation of Change 
 
The potential for a change to impact product quality as it may relate to the safety 
or effectiveness of the product should be thoroughly assessed and documented.  
The information and data to demonstrate comparability of the product pre- and 
post- change can include a combination of testing, validation studies, and non-
clinical or clinical studies as necessary to evaluate potential effects of the change.  
Knowledge and experience accumulated during development and commercial 
manufacturing regarding how product performance relates to material attributes 
and process parameters is useful in assessing the impact of manufacturing 
changes (Ref. 8). 
 
When assessing the impact of a change on product quality, some or all of the 
following considerations should be taken into account by the applicant: 
 
  Prior knowledge (e.g., established chemical and biological engineering 
principles; published, peer-reviewed scientific and technical literature; and 
applied manufacturing experience) (Ref. 9); 
  Development and manufacturing of the drug substance and drug product11 
(Ref. 10); 
  Process validation activities and experience gained during commercial 
manufacture; 
  Quality risk management activities; 
  Studies conducted at less than commercial scale to gain an increased 
understanding of the effects of the change on product quality and process 
consistency; and 
  Cumulative impact of multiple related changes. 
 
An integral component in successfully implementing any manufacturing change is 
an effectively-designed and effectively-managed change management process 
(Ref. 8).  This requires an effective multidisciplinary team to implement the 
change and to evaluate the potential effects of the change on the product.  
Implementation of a change also requires oversight by the manufacturers Quality 
Control Unit and includes the studies and data that support the change approved 
by the applicant. 
 
The applicant may choose to take advantage of opportunities to reduce the 
 
11 For the purposes of this document, Drug Substance also refers to In vitro Substance. 
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potential risks associated with implementing a manufacturing change.  The 
development of robust manufacturing processes12 and process controls that utilize 
innovative approaches to process validation and analytical testing provides an 
important component for the manufacture of high-quality products and may 
mitigate the risks associated with manufacturing changes.  Product and process 
knowledge and understanding gained during development and commercial 
manufacturing provide a foundation for an informed change management process 
(Refs. 8 and 10).  Thoroughly characterized products, processes, and components 
can provide meaningful acceptance criteria and limits that assist in evaluating the 
potential impact of the change and reduce the risk of an unintended outcome 
occurring because of a manufacturing change. 
 
An effective quality risk management system can enable the applicant to make 
informed decisions regarding manufacturing changes and can permit the FDA to 
have greater confidence regarding the applicants ability to assure product quality 
and process consistency while continuously monitoring, verifying, and, as 
appropriate, acting upon identified risks (Ref. 3).  Conducting and submitting to 
the FDA formal or informal risk assessments in support of a post-approval 
manufacturing change can allow the FDA to conduct a more effective assessment 
of the impact of a change, thereby facilitating timely review and decision. 
 
2.  FDA Assessment of Change 
 
Based upon an initial assessment of the submission by the Agency, the applicant 
may be notified that the manufacturing change falls into a higher or lower 
reporting category than was proposed by the applicant.  In those cases, the 
applicant must comply with the distribution requirements associated with the new 
reporting category (21 CFR 601.12(a)(2)). 
 
In some circumstances, the applicant may request an expedited review of a PAS 
for public health reasons or if a delay in making the described change would 
impose an extraordinary hardship on the applicant.13  This expedited approach is 
not intended to compensate for an ineffective change management process by the 
applicant, but should be requested in situations that warrant its use, such as 
unexpected circumstances or product shortage.14 
 
For most supplements, the CGMP status of the manufacturers applicable 
product(s) and establishment(s) must be determined before the Agency renders a 
final decision regarding the approvability of a supplement (21 CFR 601.20).  
Compliance with the CGMP regulations and statutory requirements are required 
 
12 Process robustness is defined as an ability of a process to tolerate variability of materials and changes of the 
process and equipment without a negative impact on quality (Ref. 10). 
13 21 CFR 601.12(b)(4). 
14 If the applicant is requesting an expedited review due to potential product shortage, for public health reasons, or 
for other extraordinary hardship reasons, the applicant should mark the supplement and cover letter with Prior 
Approval Supplement  Expedited Review Requested.  In the case of a potential drug shortage, the applicant 
should also notify the FDA Drug Shortage Staff or the CBER Product Shortage Coordinator. 
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regardless of how the change is reported to the Agency.  Moreover, it is 
incumbent upon the applicant to ensure that contract manufacturing and testing 
sites have a satisfactory CGMP status for the type of operation involved.  CGMP 
requirements include 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 process is under control.15  When deemed necessary, the Agency 
may conduct an inspection as part of the complete review of a submission 
supporting the change.16 
 
C.  Submission of Changes to FDA 
 
The applicant should prominently label each submission with the reporting category 
under which the change is being reported, provide a description of the change, as well as 
data to demonstrate comparability of pre-change and post-change intermediates, drug 
substance, and/or drug products, as appropriate, for the type of change and the reporting 
category.  Refer to the guidances for industry on chemistry, manufacturing and controls 
information for specific product class content information to consider in evaluating and 
submitting information (Refs. 11 through 14), where applicable/available. 
 
A submission describing the change(s) should contain all the required and expected 
information (i.e., descriptive narrative and appropriate data) to support the approval of 
the change(s) in the submission.  The submission should be well organized to facilitate 
timely review by the FDA (Ref. 15). 
 
An applicant is to include the following information in any supplement (PAS, CBE30, or 
CBE)17: 
 
  A detailed description of, including a rationale for, the change; 
  The product(s) involved18; 
  The manufacturing site(s) or area(s) affected; 
  A description of the method(s) used, and studies performed to evaluate the effects 
of the change on the product quality, and data derived from these studies; 
  Relevant validation protocols and data; and 
  A reference list of relevant standard operating procedures (SOPs). 
 
An applicant is to include the following information in an Annual Report19: 
 
15 21 CFR Parts 210 and 211. 
16 The authority for FDA to conduct establishment inspections is included in both the FD&C Act and the PHS Act. 
Under section 351(c) of the PHS Act (42 U.S.C. 262(c)) and section 704 of the FD&C Act (21 U.S.C. 374), the 
FDA has authority to inspect any establishment where biological products are manufactured. 
17 Itemized information must be provided in all supplements under 21 CFR 601.12(b) and (c).  This paragraph does 
not apply to CBE supplements for certain types of labeling changes submitted under 21 CFR 601.12(f)(2). 
18 Product(s) involved means the licensed product(s) affected by the change being described in the supplement.  
Information about product(s) that are not covered by the BLA in question should be provided in the submission only 
if introduction of a new product into the manufacturing facility may affect the quality of a licensed product. 
19 Itemized information must be provided in an annual report under 21 CFR 601.12(d). 
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  A list of all products involved in the change; 
  A full description of and rationale for the implemented changes including: 
  the manufacturing site(s) or area(s) involved; 
o
  the date the change was implemented; 
o
  a cross-reference to relevant validation protocols and/or SOPs; 
o
  relevant data from studies and tests performed to evaluate the effects of the 
o
change on product quality;20 and 
  A statement by the holder of the approved application or license that the 
o
effects of the change have been assessed. 
 
D.  Comparability Protocols 
 
A CP is a comprehensive, prospectively written plan for assessing the effect of a 
proposed CMC change(s) on product quality.  An applicant has the option to submit one 
or more CPs describing the specific tests, validation studies, and acceptance criteria to be 
achieved in order to demonstrate the lack of adverse effect(s) for specified types of 
manufacturing changes on product quality.  A CP shall be submitted as a PAS requiring 
approval from the FDA before distribution of a product made using the change outlined 
in the protocol.  If approved, the CP may justify a less burdensome reporting category for 
the particular change (Ref. 9).21  A less burdensome reporting category should be 
requested and approved by FDA as part of the CP.  
 
After a CP is approved, an applicant may introduce changes to the CP.  Under 21 CFR 
601.12(e), such changes shall be submitted as a PAS (major change).  Notwithstanding 
this requirement, as provided in 21 CFR 601.12(a)(3), to make CPs more useful and 
flexible, FDA may provide for a less burdensome notification of certain types of 
modifications to an approved CP.22 
 
A CP may be submitted for a single, or multiple related changes, and may cover a single 
or multiple BLAs (i.e., a trans-BLA).  Submission and approval of a CP may enable: 
 
(1) greater predictability regarding the timing of implementation of CMC changes; 
(2) placing the product into distribution sooner than without the use of a protocol; and 
(3) more effective planning of the product supply chain. 
 
   
 
20 For some minor changes, summary of data or risk assessment may be provided, with full data being available 
upon request. 
21 21 CFR 601.12 (e). 
22 21 CFR 601.12(a) and (e).  
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E.  Recommendations for Reporting Categories 
 
The FDA reviews manufacturing changes reported across licensed biological products 
within the scope of this guidance using the tiered reporting system23 described in section 
IV.A. of this guidance. 
 
In the Appendix of this guidance, a table of frequent manufacturing changes and 
recommended reporting categories is provided.  It is meant to serve as a guide to assist 
applicants and the FDA to identify reportable post-approval changes and determine 
appropriate reporting categories.  It is based, in part, upon our overall assessment of the 
potential risks to process performance and product quality caused by the change.  This 
assessment is supported by the Agencys accumulated experience resulting from 
inspections and reviews of post-approval manufacturing changes.  The recommendations 
for reporting categories provided in the Appendix should be read to determine the 
appropriate category for the specific manufacturing change(s) under consideration.  This 
table does not represent an exhaustive list of possible reportable manufacturing changes; 
a manufacturing change may still be considered reportable even if not listed in the table. 
 
Although the selection of a reporting category for a change generally should be made in 
accordance with the recommendations provided in this guidance, a different selection 
may in some instances be determined to be appropriate, provided it complies with 
applicable regulatory requirements.  Early consultation with the FDA is recommended to 
determine the appropriate reporting category for manufacturing change(s) not described 
in the table in the Appendix, or when considering an adjustment to the recommended 
reporting categories.  The Agency will make a decision regarding the reporting category 
based upon available information and the Agencys current thinking.   
 
Some manufacturing changes may be reported in multiple categories, depending upon the 
type and extent of the change and its potential effects.  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.  For example, 
there may be several moderate-risk changes associated with one major risk change, in 
which case the reporting category for the highest risk change may define the appropriate 
submission type (e.g., PAS). 
 
When multiple changes are made to a process, it may be appropriate to consider the 
cumulative impact of all changes, which may lead to a higher reporting category. 
 
We recommend, if an applicant includes multiple changes in one supplement, that all of 
the changes in the supplement be somehow related or pertain to a similar step in the 
manufacturing process (e.g., changes associated with an increase in a production scale, or 
multiple changes made to a purification process).  While the inclusion of multiple related 
changes in one supplement may result in a higher reporting category proportionate to the 
change with the highest risk as well as cumulative impact of all changes, this approach is 
expected to provide a comprehensive assessment of the combined effect of all changes on 
 
23 21 CFR 601.12. 
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process performance and product quality.  Inclusion of multiple unrelated changes in one 
submission, even those in the same reporting category, could result in a potential delay in 
implementing all of the changes (e.g., approvability of any single change may affect 
approvability of all the changes included in the supplement). 
 
 
V.  SPECIAL CONSIDERATIONS 
 
A.  Change in Process Parameters 
 
Process parameters (operating and performance) are frequently adjusted over a products 
lifecycle.  Additional knowledge and experience about material attributes, operating and 
performance parameters, and the way their interaction affects product quality and process 
performance typically enable a more informed risk assessment and risk ranking.  Any 
change to process parameters (operating or performance) outside of an approved 
validated range(s) should be evaluated with respect to criticality, impact on process 
performance and product quality, and effectiveness of the overall control strategy and 
must be reported to FDA.24  The reporting category selected should be commensurate 
with the risk of an unintended outcome resulting from changes involving these elements. 
 
B.  Change in a Supplier of Raw Materials 
 
We recommend the following manufacturing changes be reported in a PAS: 
 
  A change in a supplier of raw materials that have a substantial potential to 
affect product quality, including inactivation, detoxification, immunization in 
the production of hyperimmune plasma, or conjugation (e.g., PEG, acridinium 
ester, biotin, beads); and 
  A change in a supplier of raw materials that have a substantial potential to 
affect product quality, including an ability to maintain specified pH or ionic 
strength in the manufacture of plasma-derived fractionated products (e.g., 
phosphate, tris, ethanol). 
 
We recommend the following manufacturing changes be reported in a CBE30: 
 
  A change in a supplier of raw materials used to aid in filtration (e.g., celite, 
diatomaceous earth, activated carbon); or 
  A change in a supplier of trypsin or serum used in the manufacture of viral 
vaccine products. 
 
   
 
24 21 CFR 601.12. 
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We recommend the following manufacturing change be reported in an AR: 
 
  A change in a supplier of raw materials that have a minimal potential to affect 
product quality, provided that the materials specific use, physicochemical 
properties, impurity content, and acceptance criteria remain unchanged. 
 
C.  Miscellaneous changes not specified in Appendix 
 
The Appendix contains examples for the types of manufacturing changes most commonly 
seen by FDA and is not intended to be comprehensive.  If you plan to implement a 
manufacturing change that is not covered in the Appendix, it is your responsibility to 
perform a risk assessment to determine the appropriate reporting category and to contact 
the appropriate FDA Review Division if you have questions. 
 
 
VI.  GLOSSARY 
 
Acceptance Criteria - Numerical limits, ranges, or other suitable measures for acceptance of the 
results of analytical procedures which the Drug Substance or Drug Product or materials at other 
stages of their manufacture should meet (Ref. 16). 
 
Adventitious Agent - A microorganism (including bacterium, fungus, mycoplasma/spiroplasma, 
mycobacterium, rickettsia, virus, protozoa, parasite, Transmissible Spongiform Encephalopathy 
(TSE) agent) that is inadvertently introduced into the production of a biological product (Ref. 
17). 
 
Analytical Procedure - Refers to the way of performing the analysis.  It should describe in 
detail the steps necessary to perform each analytical test.  This may include, but is not limited to:  
the sample, the reference standard and the reagents preparations, use of the apparatus, generation 
of the calibration curve, and use of the formulae for the calculation (Ref. 18). 
 
Analytical Technique/Methodology - Refers to a general principle/mechanism of operation 
upon which an analytical procedure is based (e.g., Reverse Phase High Performance Liquid 
Chromatography, Near Infrared Spectroscopy, Sodium Dodecyl Sulfate Polyacrylamide Gel 
Electrophoresis, Analytical Ultracentrifugation). 
 
Analytical Test - A measure of a specific attribute (e.g., identity, purity, potency, strength). 
 
Comparability Protocol (CP) - A comprehensive, prospectively written plan for assessing the 
effect of a proposed CMC change(s) on the identity, strength, quality, purity, and potency of a 
drug product or a biological product (including an IVD), as these factors may relate to the safety 
or effectiveness of the product.  The CP describes the specific tests and studies to be performed 
and the acceptance criteria to be achieved to demonstrate the lack of adverse effect(s) of one or 
more proposed CMC changes on product quality (Ref. 9). 
 
   
12 
  Contains Nonbinding Recommendations 
 
Container Closure System (CCS) - The sum of packaging components that together contain 
and protect the dosage form (Drug Product).25  The CCS includes primary packaging 
components that are or may be in direct contact with product; it can also include secondary 
packaging components, that are not and will not be in direct contact with the product, if these are 
intended to provide additional protection to the Drug Product.  A packaging system is equivalent 
to a CCS (Ref. 19). 
 
Control Strategy - A planned set of controls derived from current product and process 
understanding that assures process performance and product quality.  The controls can include 
parameters and attributes related to drug substance and drug product materials and components, 
facility and equipment operating conditions, in-process controls, finished product specifications, 
and the associated methods and frequency of monitoring and control (Ref. 8). 
 
Device Quality System Regulation (QSR) - Means the organizational structure, responsibilities, 
procedures, processes, and resources for implementing quality management 
(see 21 CFR Part 820). 
 
Establishment - A place of business under one management at one general physical location. 
The term includes, among others, independent laboratories that engage in control activities for 
a registered drug establishment (e.g., consulting laboratories), blood donor centers, and animal 
facilities used for the production or control testing of licensed biologicals (see 21 CFR 207.1). 
 
Excipient (an inactive ingredient) - An ingredient added intentionally to the drug substance 
which should not have pharmacological properties in the quantity used (Ref. 16). 
 
In-house Primary Reference Material - An appropriately characterized material prepared by 
the manufacturer from a representative lot(s) for the purpose of biological assay and 
physicochemical testing of subsequent lots, and against which an in-house working reference 
material is calibrated (Ref. 16). 
 
In-house Working Reference Material - A material prepared similarly to the in-house 
primary reference material that is established solely to assess and control subsequent lots for 
the individual attribute in question.  It is calibrated against the in-house primary reference 
material (Ref. 16). 
 
Intermediate - For biotechnological/biological products, a material produced during a 
manufacturing process which is not the drug substance or the drug product but whose 
manufacture is critical to the successful production of the drug substance or the drug product.  
Generally, an intermediate will be quantifiable and specifications will be established to 
determine the successful completion of the manufacturing step prior to continuation of the 
manufacturing process.  This includes material which may undergo further molecular 
modification or be held for an extended period of time prior to further processing. 
 
   
 
25 For the purpose of discussion of CCS in this guidance, dosage form (Drug Product) also includes Drug 
Substance and stored intermediates.  
13 
  Contains Nonbinding Recommendations 
 
In vitro Product - The licensed product in its final form and all assembled supporting 
components (Ref. 12). 
 
In vitro Substance - Any and all raw materials and intermediates used in the manufacture of the 
final in vitro product as defined in 21 CFR 820.3(c) (Ref. 12). 
 
Location - All buildings, appurtenances, equipment and animals used, and personnel engaged 
by a manufacturer within a particular area designated by an address adequate for identification 
(see 21 CFR 600.3(v)). 
 
Master Cell Bank (MCB)26 - An aliquot of a single pool of cells which generally has been 
prepared from the selected cell clone under defined conditions, dispensed into multiple 
containers and stored under defined conditions.  The MCB is used to derive all working cell 
banks (Ref. 20). 
 
Master Virus Seed - A viral seed from which all future production will be derived, either 
directly or via Working Virus Seeds (Ref. 17). 
 
Manufacture - Each step in the manufacture, preparation, propagation, compounding, or 
processing of a drug.  Manufacture includes the making by chemical, physical, biological, or 
other procedures or manipulations of a drug, including control procedures applied to the final 
product or to any part of the process.  Manufacture includes manipulation, sampling, testing, or 
control procedures applied to the final product or to any part of the process, including, for 
example, analytical testing of drugs for another registered establishments drug (see 21 CFR 
207.1). 
 
Method Performance - The ability of a procedure to fulfill the type and level of characteristics 
appropriate for its intended use (e.g., accuracy, specificity, precision). 
 
Packaging - A packaging component means any single part of a CCS.  Typical components are 
containers (e.g., ampules, vials, bottles), container liners (e.g., tube liners), closures (e.g., screw 
caps, stoppers), closure liners, stopper over seals, container inner seals, administration ports (e.g., 
on large-volume parenterals (LVPs)), overwraps, administration accessories, and container 
labels.  A primary packaging component means a packaging component that is or may be in 
direct contact with the dosage form.  A secondary packaging component means a packaging 
component that is not and will not be in direct contact with the dosage form (Ref. 19). 
 
Pharmaceutical Quality System (PQS) - A management system to direct and control a 
pharmaceutical company with regard to quality.  The PQS includes the organizational structure, 
responsibilities, procedures, processes, and resources for implementing quality management to 
ensure continual improvement (Refs. 8 and 21). 
 
Process Step (Unit Operation) - A discrete manufacturing activity or manipulation that 
achieves a specific process objective (e.g., cell culture/fermentation, filtration, centrifugation, 
 
26 Master Cell Bank (MCB) and Working Cell Bank (WCB) definitions are not applicable to some cellular and gene 
therapy products, where cell bank uses and characteristics vary considerably.   
14 
  Contains Nonbinding Recommendations 
 
inactivation, holding, specific chromatography steps, packaging, labeling, chemical 
modification). 
 
Process Parameters: 
  Operating Parameter - A condition of the manufacturing process that can be 
directly controlled.  Typically, these parameters are physical or chemical (e.g., 
temperature, process time, column flow rate, column wash volume, reagent 
concentration, or buffer pH) (Ref. 21). 
 
  Performance Parameter - A characteristic of the process that provides assurance of 
consistency and quality. 
 
Raw Material - A general term used to denote starting materials, reagents, and solvents intended  
for use in the production of intermediates or Active Pharmaceutical Ingredients (APIs) (Ref. 22).  
For the purpose of this document the term raw material also is used to denote culture media, 
buffers, and ancillary materials used in the production of biological product.  
  Biological Raw Material - Raw material from a biological source (e.g., animal, 
human, microbial, or plant). 
 
Reference Material - See In-house Primary Reference Material and In-house Working 
Reference Material. 
 
Reference Standard - An international or national standard used to calculate the units of activity 
in a biological assay and to calibrate the in-house reference material (Ref. 16). 
 
Reference Panel - A group of reference materials or reference standards established to 
collectively aid the evaluation of assays or diagnostic tests (Ref. 23).  
 
Reprocessing - Subjecting an in-process material, Drug Substance or Drug Product, including 
one that does not conform to predetermined specifications to a previous step in the validated 
manufacturing process in order to obtain acceptable quality in-process material, Drug Substance 
or Drug Product (Modified from Ref. 22). 
 
Reworking - Subjecting an in-process material, Drug Substance or Drug Product that does not 
conform to predetermined specification to one or more processing steps that are different from 
the established manufacturing process in order to obtain acceptable quality in-process material, 
Drug Substance or Drug Product.  In general, reworking operations are developed post-
approval, and the application is updated through submission of a PAS (Modified from Ref. 22). 
 
Specification - The quality standards (i.e., tests, analytical procedures and acceptance criteria) 
provided in an approved application to confirm the quality of products, intermediates, raw 
materials, reagents, components, in-process materials, container closure systems, and other 
materials used in the production of a product (see 21 CFR 600.3(kk)).  The term test is defined 
as Analytical Test in alphabetical order above; the terms Analytical Procedure and 
Acceptance Criteria are likewise defined in alphabetical order above. 
 
15 
  Contains Nonbinding Recommendations 
 
Starting Material (or Source Material) - For  purposes of this document, material from a 
biological source which is intended to be used in the manufacture of a biological product and 
from which the active ingredient is derived either directly (e.g., plasma derivatives, ascetic fluid, 
bovine lung,) or indirectly (e.g., cell substrate, host/vector production cells, eggs, viral strains) 
(Modified from Ref. 24). 
 
Viral Clearance - Elimination of target virus by removal of viral particles or inactivation of 
viral infectivity (Ref. 25). 
 
Working Cell Bank/Working Virus Seed27 - Cell/virus bank prepared from aliquots of a 
homogenous suspension of cells/viruses derived from culturing the Master Cell Bank/Master 
Virus Seed under defined culture conditions (Ref. 20). 
 
 
   
 
27 See footnote 26. 
16 
  Contains Nonbinding Recommendations 
 
VII.  REFERENCES 
 
1.  Changes to an Approved Application; Final rule (62 FR 39890, July 24, 1997).  Available 
at https://www.gpo.gov/fdsys/pkg/FR-1997-07-24/pdf/97-19427.pdf. 
2.  Supplements and Other Changes to an Approved Application; Final rule (69 FR 18728, 
April 8, 2004).  Available at https://www.gpo.gov/fdsys/pkg/FR-2004-04-08/pdf/04-
7532.pdf. 
3.  Guidance for Industry:  Q9 Quality Risk Management, June 2006.  Available at 
https://www.fda.gov/media/71543/download. 
4.  Guidance for Industry:  Changes to an Approved Application:  Biological Products: 
Human Blood and Blood Components Intended for Transfusion or for Further 
Manufacture, December 2014.  Available at 
https://www.fda.gov/media/86137/download. 
5.  Guidance for Industry:  Changes to an Approved Application for Specified 
Biotechnology and Specified Synthetic Biological Products, July 1997.  Available at 
https://www.fda.gov/media/75318/download.   
6.  Guidance for Industry:  Labeling for Human Prescription Drug and Biological Products - 
Implementing the PLR Content and Format Requirements, February 2013.  Available at 
https://www.fda.gov/media/71836/download. 
7.  ICH Q12:  Technical and Regulatory Considerations for Pharmaceutical Product 
Lifecycle Management; and Annex, May 2021.    
Available at) 
https://www.fda.gov/media/148476/download and 
https://www.fda.gov/media/148477/download, respectively.  
8.  Guidance for Industry:  Q10 Pharmaceutical Quality System, April 2009.  Available at 
https://www.fda.gov/media/71553/download. 
9.  Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and 
Controls Information; Draft Guidance for Industry, April 2016.*  Available at  
https://www.fda.gov/media/97148/download. 
10.  Guidance for Industry:  Q11 Development and Manufacture of Drug Substances, 
November 2012.  Available at  https://www.fda.gov/media/80909/download. 
11.  Guidance for Industry:  For the Submission of Chemistry, Manufacturing and Controls 
and Establishment Description Information for Human Plasma-Derived Biological 
Products, Animal Plasma or Serum-Derived Products, February 1999.  Available at  
https://www.fda.gov/media/124397/download. 
12.  Guidance for Industry:  Content and Format of Chemistry, Manufacturing and Controls 
Information and Establishment Description Information for Biological In Vitro 
Diagnostic Product, March 1999.  Available at 
https://www.fda.gov/media/124394/download. 
13.  Guidance for Industry:  Content and Format of Chemistry, Manufacturing and Controls 
Information and Establishment Description Information for Vaccine or Related Product, 
January 1999.  Available at https://www.fda.gov/media/73614/download. 
14.  Guidance for Industry:  On the Content and Format of Chemistry, Manufacturing, and 
Controls Information and Establishment Description Information for an Allergenic 
Extract or Allergen Patch Test, April 1999. Available at 
https://www.fda.gov/media/124400/download. 
17 
  Contains Nonbinding Recommendations 
 
 
15.  Good Review Management Principles and Practices for New Drug Applications and 
Biologics License Applications; Draft Guidance for Review Staff and Industry, 
September 2018.*  Available at https://www.fda.gov/media/72259/download. 
16.  Guidance for Industry:  Q6B Specifications:  Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products, April 1999.  Available at 
https://www.fda.gov/media/71510/download. 
17.  Guidance for Industry:  Characterization and Qualification of Cell Substrates and Other 
Biological Materials Used in the Production of Viral Vaccines for Infectious Disease 
Indications, February 2010.  Available at https://www.fda.gov/media/78428/download. 
18.  ICH Harmonised Tripartite Guideline:  Validation of Analytical Procedures:  Text and 
Methodology:  Q2(R1), November 2005.  Available at 
https://database.ich.org/sites/default/files/Q2_R1__Guideline.pdf. 
19.  Guidance for Industry:  Container Closure Systems for Packaging Human Drugs and 
Biologics:  Chemistry, Manufacturing, and Controls Documentation, May 1999.  
Available at https://www.fda.gov/media/70788/download. 
20.  Q5D Quality of Biotechnological/Biological Products:  Derivation and Characterization 
of Cell Substrates Used for Production of Biotechnological/Biological Products, 
September 1998.  Available at https://www.fda.gov/media/71463/download. 
21.  Guidance for Industry:  Quality Systems Approach to Pharmaceutical CGMP 
Regulations, September 2006.  Available at  
https://www.fda.gov/media/71023/download. 
22.  Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; 
Guidance for Industry, September 2016.  Available at 
https://www.fda.gov/media/71518/download. 
23.  Standards Development and the Use of Standards in Regulatory Submissions Reviewed 
in the Center for Biologics Evaluation and Research; Guidance for Industry, March 2019.  
Available at https://www.fda.gov/media/124694/download. 
24.  Guidance Document:  Post  Notice of Compliance (NOC) Changes:  Quality Document, 
Government of Canada, September 2009.  Available at  
https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-  
products/applications-submissions/guidance-documents/post-notice-compliance-  
changes/quality-document.html. 
25.  Guidance for Industry:  Q5A Viral Safety Evaluation of Biotechnology Products Derived 
From Cell Lines of Human or Animal Origin, September 1998.  Available at 
https://www.fda.gov/media/71394/download.   
26.  ICH Harmonised Tripartite Guideline:  The Common Technical Document for the 
Registration of Pharmaceuticals for Human Use:  Quality  M4Q(R1), September 2002.  
Available at https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf 
 
 
* When finalized, this guidance will represent the Agencys current thinking on this topic. 
18 
  Contains Nonbinding Recommendations 
 
 
 
APPENDIX 
 
Examples of Post-Approval Manufacturing Changes and Recommended Reporting Categories  
 
3.2.S. DRUG SUBSTANCE28 (Ref. 26) 
3.2.S.2. Manufacture 
3.2.S.2.2 Description of Manufacturing Process and Process Controls 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition, deletion, or substitution of unit     
operation(s) (process step(s) or change in 
their sequence). 
 
NOTE:  This change applies both to 
upstream steps of Drug Substance 
manufacture through harvesting and 
downstream purification steps. 
Changes to the Upstream Steps of Drug Substance Manufacture through Harvesting 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the growth culture conditions     
(e.g., time, temperature, pH) and/or media 
composition outside of the parameters 
specified in the approved BLA. 
 
 
28 For the purposes of this document, Drug Substance also refers to In vitro Substance. 
19 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in a batch size (increase or decrease),    Change in fermentation step batch 
using different equipment or involving change  size (e.g., minor adjustments in 
in process parameters, controls and  volume) using the same equipment 
specifications.  with no change in process 
parameters, controls and 
specifications. 
Change in the production capacity for  Addition of a duplicated cell culture  Change in the production scale 
concurrent manufacturing processes by  process train with no change in process  (increase or decrease) of ancillary 
addition of identical unit processes (an  parameters specified in the approved  equipment (e.g., media tanks, 
increase in throughput).  BLA.  buffer tanks) with no direct 
    product contact and no change in 
NOTE:  This applies only to cellular and  NOTE:  This does not apply to cellular  process parameters specified in the 
gene therapy products.  and gene therapy products.  approved BLA. 
    Change in the harvesting and/or 
pooling procedures that does not 
affect the method of manufacture, 
recovery, storage conditions, 
production scale or sensitivity of 
detection of adventitious agents. 
 
NOTE:  This does not apply to 
cellular and gene therapy 
products. 
20 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change from a stainless steel to disposable     
(e.g., bag) bioreactor or vice versa. 
 
NOTE:  This information may be provided in 
3.2.S.2.2 and/or 3.2.A.1 
Change in the Drug Substance Purification Process 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in a batch size (increase or decrease)  Addition of duplicated process train or   
by changing the size of  process step(s) (e.g., 
purification/inactivation equipment.  bioreactor/fermenter, 
  purification/inactivation) with no 
NOTE:  This information may be provided in  change in the process parameters 
3.2.S.2.2 and/or 3.2.A.1  specified in the approved license. 
Increase in the number of cycles of resin and  Change in the filter or resin supplier  Increase in the number of cycles of 
membrane re-use without an approved  with no change in the resin material,  resin and membrane re-use 
protocol.29  operating or performance parameters.  according to an approved protocol. 
  Addition of a bioburden reduction or   
clarifying filter. 
A change in the composition or formulation     
(e.g., pH, ionic strength, molarity) of 
solutions (e.g., buffers, reagents) used in 
processing. 
 
29 In this guidance approved protocol refers to protocol reviewed and approved by the FDA as part of original BLA or post-approval regulatory 
submission. In approved protocol, the FDA may approve reporting category for specific change, which is different from this guidance.   
21 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
New or revised purification process (e.g.,    Minor changes to purification 
change in the resin or filter material, loading  process parameters (e.g., volume of 
scale, column size, or elution rate of a  buffer for column equilibration) 
chromatographic column). 
Change in the method(s) for virus or    Sanitization/cleaning procedure 
adventitious agent removal or inactivation.  changes. 
 
NOTE:  This information may be provided in 
3.2.S.2.2 and/or 3.2.S.2.3 
Reprocessing in the manufacture of a Drug    Reprocessing in the manufacture 
Substance without an approved protocol.  of a Drug Substance with an 
approved protocol. 
Reworking in the manufacture of a Drug     
Substance. 
22 
  Contains Nonbinding Recommendations 
 
3.2.S.2.3 Control of Materials 
Changes to the source of starting materials and raw materials 
 
   
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in a source of starting material.     
 
NOTE:  This type of change may in some 
instances (e.g., from tissue or plasma-derived 
to recombinant, from animal to plant) result 
in a separate BLA.  Applicants should 
discuss with the appropriate FDA Review 
Division to determine the appropriate 
reporting category. 
Change in a source of a biological raw     
material (e.g., animal, human, or plant). 
Adding a new source of pancreatic tissue    Adding a new source of pancreatic 
outside of the approved region.  tissue within the approved region. 
 
NOTE:  This does not apply to cellular 
therapy products isolated from pancreatic 
tissue. 
 
   
23 
  Contains Nonbinding Recommendations 
 
Changes to the cell banks/cell seeds  
 
Generation of a new master cell bank or     
master virus seed from a source material or 
cell line using the same expression 
construct. 
 
NOTE:  The use of a different expression 
construct may require a new BLA. 
Generation of a working cell bank or  For cellular and gene therapy products,  Generation of a working cell bank 
working virus seed from an approved master  generation of a cell bank from cells/tissues  or virus seed from an approved 
cell bank or master virus seed without an  of a new human donor according to an  master cell bank or master virus 
approved protocol.  approved protocol.  seed according to an approved 
protocol. 
 
Change in an approved protocol for     
 
qualification of master/working cell bank or 
master/working seed. 
Extension of the shelf life of cell banks or    Extension of the shelf life of cell 
cell seeds used in the manufacture of cellular  banks or cell seeds used in the 
therapy, viral and bacterial vaccine products.  manufacture of cellular therapy, viral 
and bacterial vaccine products 
provided the change is made 
according to an approved protocol. 
   
24 
  Contains Nonbinding Recommendations 
 
 
3.2.S.2.4 Controls of Critical Steps and Intermediates 
 
 
PRIOR APPROVAL (PAS)  CHANGES BEING EFFECTED in 30 
ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the critical process parameters (if     
defined in the BLA) or change in the process 
parameter(s) monitored at critical steps of the 
manufacturing process identified in 3.2.S.2.2 
outside of the range validated in the approved 
BLA. 
 
NOTE:  For additional guidance on how to 
determine (critical) process parameters see 
section V.A. of this guidance. 
Deletion/replacement of an in-process test.    Addition of an in-process control. 
 
NOTE:  For cellular and gene 
therapy products Applicants should 
discuss with the appropriate FDA 
Review Division to determine the 
reporting category for this change.  
Widening of acceptance criteria for in-   Tightening of acceptance criteria for 
process control.  in-process control. 
Change in the parameters of an approved     
holding step or addition of a new holding 
step. 
Change in the procedure used for conjugation     
reaction (e.g., incubation time, temperature, 
concentration of the starting materials). 
25 
  Contains Nonbinding Recommendations 
 
 
PRIOR APPROVAL (PAS)  CHANGES BEING EFFECTED in 30 
ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the procedure used for inactivation     
or detoxification (e.g., incubation time, 
temperature, type and amount of materials 
used). 
 
NOTE: Applies only to vaccine products for 
changes to Drug Substance manufacture and 
purification. 
 
3.2.S.4. CONTROL OF DRUG SUBSTANCE 
(also applies to 3.2.P.5 CONTROL OF DRUG PRODUCT) 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the Container Closure System    Change in the CCS used for 
(CCS) used for storage and/or shipping of a  storage and/or shipping of a stored 
stored intermediate that includes a change in  intermediate with no change in the 
the product-contact material, or dimensions  product-contact material, or 
(size and shape).  dimensions (size and shape). 
 
 
 
26 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the Drug Substance, Drug  Relaxation of acceptance criteria to  Tightening of an approved 
Product or Intermediate release  comply with a compendial test approved  acceptance criterion due to 
specifications including:  in the BLA that is consistent with FDA  improved process or assay 
  Adding, deleting, or replacing a test(s).  statutory and regulatory authority  performance. 
  Adding, deleting, broadening or shifting  (21 CFR 601.12(c)(2)(iv)).   
the approved acceptance criteria.  NOTE:  If tightening is in 
  Replacing or modifying an approved  response to mitigating safety risks, 
or if the product is unable to meet 
analytical procedure resulting in a change 
the new limits possibly leading to 
in analytical technique/methodology, 
drug shortage, the applicant should 
acceptance criteria or method 
consult appropriate FDA Review 
performance. 
Division. 
    Minor modifications to an 
approved analytical procedure 
with no change in the analytical 
technique/methodology, 
acceptance criteria, and method 
performance. 
Replacing critical test control(s) or reagents    Replacing critical test control(s) or 
(e.g., positive controls, capture antibodies)  reagents (e.g., positive controls, 
without an approved protocol.  capture antibodies) according to 
an approved protocol. 
27 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
    Any change made to a compendial 
method to comply with a change 
to an official compendium, except 
for relaxation of acceptance 
criteria or deletion of a test, that is 
consistent with FDA statutory and 
regulatory requirements. 
      
3.2.S.5. REFERENCE STANDARDS OR MATERIALS USED TO RELEASE DRUG SUBSTANCE 
(also applies to 3.2.P.6. REFERENCE STANDARDS OR MATERIALS USED TO RELEASE DRUG PRODUCT) 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
 Changing to a new lot of, new source for, or    Changing to a new lot of, new 
different, in-house reference material or  source for, or different, in-house 
reference panel (panel member) without an  reference material or reference 
approved protocol.  panel (panel member) according to 
an approved protocol. 
Changing from a national or international     
reference standard to an in-house reference 
material and vice versa. 
Changing from a national to an international     
reference standard and vice versa. 
 
28 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Changing an approved protocol to qualify    Tightening of the acceptance 
an in-house reference material.  criteria of an in-house reference 
material. 
Extension of the shelf-life of an in-house    Extension of the shelf-life30 of an 
reference material without an approved  in-house reference material 
protocol.  according to an approved protocol. 
 
   
 
30 Changes to approved protocol, including changes in testing intervals (re-test date),) should be approved by the FDA under PAS.  
29 
  Contains Nonbinding Recommendations 
 
3.2.S.6. CONTAINER CLOSURE SYSTEM FOR DRUG SUBSTANCE 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Adding or replacing a primary CCS for    Change in a supplier of a primary 
storage and/or shipping of Drug Substance  CCS (other than disposable bag) 
including a change in the product-contact  with no change in the product- 
material, or dimensions (size and shape).  contact material, or dimensions 
(size and shape). 
Adding or replacing a primary CCS for    Change in a primary CCS for 
storage and/or shipping of lyophilized Drug  storage and shipping of a 
Substance.  bioburden-controlled Drug 
Substance with no change in the 
product-contact material and 
dimensions (size and shape). 
Change in the container closure integrity test,     
or an analytical procedure to demonstrate 
container closure integrity, of a primary CCS 
for storage and shipping of sterile Drug 
Substance. 
Change in the shipping conditions (e.g.,    Change in the shipping conditions 
temperature, duration, packaging)  (e.g., temperature, duration, 
without an approved shipping  packaging) based on an approved 
validation protocol.  shipping validation protocol. 
 
   
30 
  Contains Nonbinding Recommendations 
 
3.2.S.7. STABILITY 
(also applies to 3.2.P.8. DRUG PRODUCT STABILITY) 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Extension of a shelf life without an approved    Extension of a shelf life based 
protocol, or a change in the storage  upon full shelf life data on 
conditions (e.g., temperature, humidity,  commercial batches and a protocol 
orientation) for Drug Substance, Drug  that is approved for this specific 
Product or a stored intermediate.  purpose. 
Change in the post-approval stability    Change in the stability protocol to 
protocol or stability commitment (3.2.S.7.2  include more stringent parameters 
and 3.2.P.8.2) including:  (e.g., tightened acceptance criteria 
  deletion, replacement or change in  or additional time points). 
stability specifications.   
  change in storage conditions (e.g.,  NOTE:  If tightening is in response 
to mitigating safety risks, or if the 
temperature, humidity, orientation). 
product is unable to meet the new 
  deletion of time point(s) within the 
limits, which could possibly lead 
approved shelf life. 
to drug shortage, the applicant 
should consult the appropriate 
FDA Review Division. 
 
   
31 
  Contains Nonbinding Recommendations 
 
3.2.P. DRUG PRODUCT31 
3.2.P.1. Description and Composition of the Drug Product 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition or replacement of a dosage     
form (e.g., liquid to lyophilized). 
  Change in the target fill volume.   
Addition of a strength.     
Change in the diluent co-packaged with the     
product (e.g., new manufacturer, new 
location, new filling line, change in 
sterilization method/cycle). 
 
NOTE:  This does not apply to convenience 
kits or commercially available diluents. 
Change in a type or concentration of     
preservative. 
Addition of a new presentation (e.g., addition     
of prefilled syringe to vial). 
 
 
 
 
31 For the purposes of this document, Drug Product also refers to In vitro Product. 
32 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Deletion or reduction of an ingredient    Deletion or reduction of an 
intended only to affect the color of Blood  ingredient intended only to affect 
Grouping Reagents  the color of the product. 
(21 CFR 601.12(d)(2)(ii)).   
NOTE:  If a change is intended 
only to affect the color of Blood 
Grouping Reagents, the applicant 
must submit a PAS, and FDA 
approval of the change is required 
prior to distribution of the product 
made using the change 
(21 CFR 601.12(d)(2)(ii)). 
 
3.2.P.3. MANUFACTURE 
3.2.P.3.3 Description of Manufacturing Process and Process Controls 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition, deletion, or substitution of unit  Change from manual to automated visual  Addition of an in-process control 
operation(s) or change in their sequence.  inspection.  (IPC). 
 
NOTE: For cellular and gene therapy 
products Applicants should discuss 
with the appropriate FDA Review 
Division to determine the reporting 
category for this change 
33 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in scale of the manufacturing  Introduction of new computer system or  Tightening of IPC acceptance 
process.   automation of a process step without a  criteria. 
change in the manufacturing process. 
Reprocessing in the manufacture of Drug     
Product without an approved reprocessing 
protocol. 
Reworking in the manufacture of Drug     
Product. 
 
3.2.P.3.4  Controls of Critical Steps and Intermediates 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the critical process parameters (if     
defined in the BLA) or change in the process 
parameter(s) monitored at critical steps of the 
manufacturing process identified in 3.2.P.3.3 
outside of the validated range in the approved 
BLA. 
 
NOTE:  For additional guidance on how to 
determine (critical) process parameters see 
section V.A. of this guidance. 
34 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the CCS used for storage and/or    Change in the CCS used for 
shipping of a stored intermediate that  storage and/or shipping of a stored 
includes a change in the product-contact  intermediate with no change in the 
material or dimensions (size and shape).  product-contact material and 
dimensions (size and shape). 
 
3.2.P.4. CONTROL OF EXCIPIENTS 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in the composition or concentration  Relaxation of acceptance criteria for   
of excipients.  compendial excipients to comply with 
changes to compendia. 
Change in the source of an excipient to one  Change in the source of an excipient   
that carries risk for Transmissible  that eliminates the risk for TSE (i.e., 
Spongiform Encephalopathy (TSE) (i.e.,  animal to plant or synthetic). 
plant or synthetic to animal). 
    Change in the supplier of an 
excipient with no change in the 
source  
35 
  Contains Nonbinding Recommendations 
 
3.2.P.5. CONTROL OF DRUG PRODUCT 
(See also Section 3.2.S.4. CONTROL OF DRUG SUBSTANCE) 
 
Change in the Testing Location 
NOTE:  It is incumbent upon the Applicant to ensure that contract testing locations meet CGMP requirements.  
 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition or replacement of a testing  Addition or replacement of a testing  Addition or replacement of a 
laboratory that performs release or stability  laboratory for release or stability testing  testing location for in-process 
testing with a testing laboratory at a new  by moving within an existing  controls. 
location.   location.32 
  Change in the cell/seed bank testing   
location with no change in the 
specifications used for the release of the 
cell/seed bank. 
 
32 For minor changes in laboratory configuration or equipment location please contact the appropriate FDA Review Division. 
36 
  Contains Nonbinding Recommendations 
 
 
3.2.P.6. REFERENCE STANDARDS OR MATERIALS USED TO RELEASE DRUG PRODUCT 
(See section 3.2.S.5. REFERENCE STANDARDS OR MATERIALS USED TO RELEASE DRUG SUBSTANCE) 
 
3.2.P.7. CONTAINER CLOSURE SYSTEM FOR DRUG PRODUCT 
 
CHANGES BEING EFFECTED in 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
30 DAYS (CBE30)* 
Adding or replacing a primary CCS for    Deleting a CCS when multiple 
storage of Drug Product including a  CCS have been approved. 
change in the product-contact material or   
dimensions (size and shape), or  NOTE:  If the change also impacts the 
ports/tubing.  labeling, inquire with an appropriate 
FDA Review Division regarding the 
reporting classification. 
37 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
30 DAYS (CBE30)* 
Adding or replacing a supplier for  Adding or replacing location that  Adding or replacing a supplier of a 
components of the CCS that are supplied  performs depyrogenation or  primary CCS with no change in the 
as ready-to-use or ready-to-sterilize with  sterilization for components of the  product-contact material, or 
or without a change in the product- CCS that are supplied as ready-to-use  dimensions (size and shape). 
contact material or dimensions (size and  or ready-to-sterilize without a change   
shape).  in supplier, product-contact material,  NOTE:  When changing or adding 
or dimensions (size and shape).  a new supplier of CCS including 
the container closure material 
(e.g., glass vial), biologic 
manufacturers are advised to 
examine the quality management 
program of CCS manufacturers to 
assure appropriate selection and 
qualification of the incoming 
materials.  The current good 
manufacturing practice regulations 
require that all final containers and 
closures shall be clean and free of 
surface solids, leachable 
contaminants and other materials 
that will hasten the deterioration 
of the product or otherwise render 
it less suitable for the intended 
use per 21 CFR 600.11(h). 
38 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
30 DAYS (CBE30)* 
Change in the container closure integrity,    Change within the CCS for a 
or an analytical procedure to demonstrate  nonsterile product, based upon a 
container closure integrity of a primary  showing of equivalency to the 
CCS for storage and shipping of Drug  approved system under a protocol 
Product.  approved in the application or 
published in an official 
compendium 
(21 CFR 601.12(d)(2)(iv)). 
    Change in dimensions (size and 
  shape) of a container containing the 
same number of dosage units 
for a nonsterile solid dosage form 
product, without a change from 
one CCS to another 
 (21 CFR 601.12(d)(2)(v)). 
    Change in functional secondary 
packaging of Drug Product. 
Change in the shipping conditions (e.g.,    Change in the shipping conditions 
temperature, duration, packaging)  (e.g., temperature, duration, 
without an approved shipping validation  packaging) based on an approved 
protocol.  shipping validation protocol. 
    Addition by embossing, debossing, or 
engraving of a code imprint to a solid 
dosage form biological product other 
than a modified release dosage form, or 
a minor change in an existing code 
imprint. 
               
       
39 
             
 
           
       
         
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
30 DAYS (CBE30)* 
    Changes to a crimp cap (ferrule and flip 
cap/overseal), provided that there are no 
changes to the color and that the 
container and closure integrity have been 
demonstrated using a validated test 
method. 
      
40 
  Contains Nonbinding Recommendations 
 
3.2.P.8. DRUG PRODUCT STABILITY 
 
(See section 3.2.S.7. DRUG SUBSTANCE STABILITY) 
FACILITIES AND EQUIPMENT 
 
NOTE:  Examples of changes described in this section may be provided in the sections 3.2.S.2, 3.2.P.3 and 3.2.A.1 (Ref. 26) 
 
EQUIPMENT 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition of new equipment (e.g.,  Addition of duplicated process train or  Addition or replacement of 
bioreactor/fermenter,  process step(s) (e.g.,  equipment of the same size and 
purification/inactivation) that results in a  bioreactor/fermenter,  material of construction used in 
change in a batch size (increase or decrease)  purification/inactivation) with no  harvesting and pooling with no 
or operating parameters.  change in the process parameters  change in the process parameters 
specified in the approved BLA.  specified in the approved BLA. 
  Replacement of equipment with that of   
similar, but not identical, design and 
operating principle that does not affect 
the process methodology, process 
operating parameters or aseptic 
processing. 
 
41 
  Contains Nonbinding Recommendations 
 
FACILITIES 
Change in the Manufacturing Location 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition or replacement of a manufacturing    Addition of new areas used for the 
facility for production of Drug Substance,  preparation of sterile 
Drug Product or intermediates.  materials/equipment for sterile 
product manufacture. 
    Addition of packaging and/or 
labeling lines to an approved 
facility. 
Addition or replacement of an existing  Addition or replacement of a primary  Change to or addition of a secondary 
labeling and/or packaging location(s) that  packaging site with acceptable CGMP  packaging site.  
does not have a CGMP status (i.e., no  compliance status.  
inspectional history). 
42 
  Contains Nonbinding Recommendations 
 
Changes within a location 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Addition or replacement of an existing  Addition or replacement of an existing  Relocation of manufacturing 
building for production of Drug Substance,  suite/room that does not affect sterility  equipment within an approved 
Drug Product or intermediates within an  assurance or contamination/cross-  manufacturing location to improve 
approved manufacturing location.  contamination within an approved  product/personnel/raw material 
manufacturing building.  flow and segregation of materials. 
Addition, expansion or replacement of a    Change in a location or 
suite/room that may affect contamination or  modification to areas used in 
cross-contamination within an approved  support operations (e.g., 
manufacturing building.  preparation of buffers, media, 
gowning, temperature-controlled 
areas, upstream processing such as 
egg incubation and inoculation, 
plasma thawing and pooling). 
    Installation of a new, or 
modification of an existing, 
Water for Injection (WFI) system 
in an approved facility.  (NOTE: 
This information should be 
provided as part of a complete 
submission for a new facility.) 
    Change in the Environmental 
Quality Classification to a lower 
(less stringent) classification 
except for aseptic processing 
areas. 
43 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
    Establishing new environmental 
monitoring levels for aseptic 
processing areas such as decrease 
in sampling points and frequency 
based on historical data. 
    Installation of a new HVAC 
system or modification to an 
existing system to environmentally 
controlled areas used for process 
steps (e.g., cell culture, 
purification) except for aseptic 
processing areas. 
 
Multiproduct Manufacturing 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Introduction of intermediate, drug substance,  Introduction of intermediate, drug  Introduction of intermediate, drug 
or drug product(s) that represent an additional  substance, or drug product(s) into a  substance, or drug product(s) into 
level of risk (e.g., toxic, highly potent,  manufacturing area using shared product  a manufacturing area using 
sensitizing, proteolytic, that represent added  contact equipment that requires  dedicated or shared product 
risks for adventitious agents or a new product  change(s) to the approved and validated  contact equipment with no 
class) into a manufacturing area that has not  cleaning and changeover procedure(s)  changes to the approved and 
been approved for this type of manufacturing  with no additional containment  validated cleaning and changeover 
operation(s).  requirements (not described under  procedure(s) (not described under 
Multiproduct Manufacturing PAS).  Multiproduct Manufacturing PAS 
or CBE30). 
 
44 
  Contains Nonbinding Recommendations 
 
Aseptic Processing/Sterilization 
 
NOTE:  Information pertaining to the product quality microbiology data, description and validation of the sterilization 
process, and aseptic processing should be submitted in accordance with ICH M4Q(R1) (Ref. 26). 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Transfer of manufacturing of an aseptically  Use of an alternate filling line approved  Addition or replacement of 
processed sterile Drug Substance or Drug  for aseptic manufacture of other  equipment used in the 
Product into a new or renovated aseptic  products with no change in the validated  sterilization/depyrogenation of 
processing area within the currently licensed  aseptic process and product contact  equipment used for processing of 
building.  equipment.  sterile intermediates and drug 
product (e.g., autoclave, new 
steam-in-place equipment, 
depyrogenation oven or tunnel) 
where operating parameters have 
not been changed. 
Addition or modification to an approved  Change to a final sterilization filter   
filling line that affects sterility assurance.  supplier with no change in material, 
dimensions or sterilization method. 
Changes that may affect product sterility  Addition or replacement of equipment  Addition or replacement of an 
assurance, such as changes in product or  (e.g., autoclave, new steam-in-place  autoclave for sterilization of 
component sterilization method(s), or an  equipment, depyrogenation oven or  materials used for 
addition, deletion or substitution of steps in  tunnel) used in the  microbiologically controlled Drug 
an aseptic processing operation  sterilization/depyrogenation of product-  Substance or Drug Product. 
(21 CFR 601.12(b)(2)(vi)).  contact materials (e.g., vials, stoppers) 
and/or equipment (e.g., tanks, filling 
lines) used for sterile intermediates and 
Drug Product where operating 
parameters have been changed. 
45 
  Contains Nonbinding Recommendations 
 
CHANGES BEING EFFECTED in 30 
PRIOR APPROVAL (PAS)  ANNUAL REPORT (AR) 
DAYS (CBE30)* 
Change in a membrane material or  Changes to sterilization cycles for sterile   
dimensions of the final sterilization filter.  product contact equipment. 
*FDA recommends that the following manufacturing changes be submitted in a CBE supplement under 21 CFR 
601.12(c)(5).  As explained in this provision, products made using such changes may be distributed immediately upon 
receipt of the supplement by FDA: 
  Adding limits for production intermediates without a change in the process (applicable both to sections Changes 
to the Upstream Steps and Drug Substance Purification). 
  Change in the system suitability criteria without a change in an approved analytical procedure. 
  Change in a supplier of a disposable primary container (i.e., bag) with no change in the construction material. 
  Reduction in Drug Substance or Drug Product shelf life where acceptance criteria become tightened or remain 
unchanged (NOTE:  This change may result in a higher reporting category for cellular and gene therapy products with a 
very short shelf life.  Applicants should discuss with the appropriate FDA Review Division to determine the reporting 
category). 
  Addition or replacement of an existing labeling and/or packaging location that has a CGMP status (i.e., inspectional 
history). 
 
 
 
46