Guest Column | July 14, 2021

FDA Releases Guidance On CMC Changes To An Approved Application: Certain Biological Products

By Mark Durivage, Quality Systems Compliance LLC

On June 21, 2021, the FDA released a new guidance, Chemistry, Manufacturing, and Controls Changes (CMCs) to an Approved Application: Certain Biological Products, 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 21 CFR 601.12 Changes to an approved application. This guidance finalizes the draft guidance, Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products, dated December 2017, and supersedes the guidance titled Guidance for Industry: Changes to an Approved Application: Biological Products, dated July 1997. 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.

Applicants and manufacturers implement changes to the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling approved in an application for licensed biological products, otherwise known as “manufacturing changes.” Applicants and manufacturers must notify the FDA about each manufacturing change to an approved BLA under 21 CFR 601.12 and 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. 351(a)(2)(B)), 506A of the FD&C Act (21 U.S.C. 356a), and the regulations in 21 CFR Parts 210 and 211, as well as the applicable requirements in 21 CFR Parts 600 through 680 and 820.

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
  • Antitoxins, antivenins, and venoms
  • Naturally derived protein products
  • Cellular and gene therapy products
  • In vitro diagnostics (IVDs) regulated under the PHS Act
  • Other biological products licensed under the PHS Act
  • Combination products licensed under a BLA.

Products that are out of scope for this guidance include:

  • Biological product constituent parts that are described in 21 CFR 601.2(a)
  • Whole blood, blood components (including source plasma), and source leukocytes
  • Specified biological products described in 21 CFR 601.2(a)
  • Biosimilar and interchangeable products subject to licensure under section 351(k) of the PHS Act (42 U.S.C. 262(k))
  • 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
  • The guidance also does not apply to changes in an applicant’s name or labeling changes.

Evaluating Changes

Evaluating changes to a manufacturing process should include a risk-based change control process with participation from a cross-functional team with representation from appropriate functions and oversight by quality.  The change control process should thoroughly assess product safety or effectiveness and document the information and data to demonstrate comparability of the product pre-change and post-change and include a combination of testing, validation studies, and non-clinical and clinical studies to evaluate potential effects of the change. Collective tribal knowledge and experience can also provide useful information when assessing the impact of manufacturing changes. An effective risk management system that utilizes production and post-production data can be useful to provide justification and allow the FDA to conduct a more effective assessment of the impact of a change.

Once applicants and manufacturers submit notifications, the FDA may move the change into a lower or higher class, requiring the applicant or manufacturer to comply with the distribution requirements of the associated class. The applicant or manufacturer may request an expedited review of a prior approval supplement (PAS) for public health reasons or if a delay in making the described change would impose an extraordinary hardship on the applicant causing unexpected circumstances or product shortages. The FDA may conduct an inspection as part of the complete review of a submission supporting the change.

For most supplements, the CGMP status of the manufacturer’s applicable product(s) and establishment(s) must be determined before the FDA renders a final decision regarding the supplement (21 CFR 601.20). Compliance with the CGMP regulations and statutory requirements is required for the manufacturer as well as any contract manufacturer. CGMP requirements include establishing and following appropriate written procedures reviewed and approved by quality, qualifying equipment as suitable for its intended use, using validated test methods, and ensuring the manufacturing process is under control.

Reporting Changes

21 CFR 601.12 requires each post-approval change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved BLA to be reported using the submission type associated with one of the three tier-based reporting categories depending upon the potential 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:

  • Annual report (AR)
  • Changes Being Effected in 30 Days/Changes Being Effected supplements (CBE30/CBE)
  • Prior approval supplement (PAS)

An AR is used for minor changes that have a minimal potential to have an adverse effect on product quality (21 CFR 601.12(d)).

Changes Being Effected in 30 Days/Changes Being Effected supplements are used for changes that have a moderate potential to have an adverse effect on product quality. These require a reporting of 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 agency’s 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 under 21 CFR 601.12(c) and 21 CFR 601.12(e).

Prior approval supplements are major changes that have a substantial potential to have an adverse effect on product quality; they require an applicant to report the change to the FDA in a supplement to the approved BLA. The PAS must be approved by the FDA prior to distribution of the product manufactured implementing the change (21 CFR 601.12(b)).

The applicants and manufacturers 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.

When submitting a PAS, applicants and manufacturers are required to submit a comparability protocol (CP). A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC change(s) on product quality that describes the specific tests, validation studies, and acceptance criteria to be achieved to demonstrate the lack of adverse effect(s) for specified types of manufacturing changes on product quality.

An applicant or manufacturer is to include the following information in any supplement (PAS, CBE30, or CBE):

  • A detailed description of, including a rationale for, the change
  • The product(s) involved
  • 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
  • A reference list of relevant standard operating procedures (SOPs).

An applicant or manufacturer is to include the following information in an AR:

  • 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
  • the date the change was implemented
  • a cross-reference to relevant validation protocols and/or SOPs
  • relevant data from studies and tests performed to evaluate the effects of the change on product quality
  • a statement by the holder of the approved application or license that the effects of the change have been assessed.


Recent changes in the organization, structure, and philosophy at the FDA are a positive sign for the pharmaceutical industry. The guidance contains a comprehensive Appendix that provides several practical examples to help classify the change type, which will be useful for reference and as a training tool when implementing the change assessment and notification process.

About The Author:

Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow and SRE Fellow. Durivage primarily works with companies in the FDA regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals), focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at with any questions or comments.