Guest Column | February 18, 2022

FDA Releases CMC Postapproval Manufacturing Changes For Specified Biological Products To Be Documented In Annual Reports

By Mark Durivage, Quality Systems Compliance LLC

Expert NetworkThe FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) released CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports on Dec. 9, 2021.

This guidance represents the current thinking of the FDA regarding the types of changes to an approved biologics license application (BLA) that BLA holders for specified biological products must document in an annual report. The products include therapeutic DNA plasmid products, therapeutic synthetic peptide products of 40 or fewer amino acids, monoclonal antibody products for in vivo use, and therapeutic recombinant DNA-derived products.

The guidance describes the chemistry, manufacturing, and controls (CMC) postapproval changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that FDA generally considers have minimal potential to have an adverse effect on product quality that must be documented by applicants in an annual report.

This guidance focuses on reporting mechanisms concerning changes within the pharmaceutical quality system. For additional information, please refer to the International Council for Harmonisation (ICH) guidances for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016), Q9 Quality Risk Management (June 2006), and Q10 Pharmaceutical Quality System (April 2009).

Applicants are required to notify the FDA of changes to an approved BLA in accordance with all statutory and regulatory requirements, including section 506A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Postapproval changes in the product, production process, quality controls, equipment, facilities, or responsible personnel established in the approved BLA must be reported using the submission type associated with one of three reporting categories: major, moderate, or minor.

Applicants must assess the effects of all changes on product quality through appropriate validation and/or other studies usually documenting the assessment through a formal change control system utilizing a cross functional team. 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.

If the change assessment determines the change to be minor, the applicant may proceed with the change but is required to notify the FDA of the change in the annual report.

If the change assessment determines the change to be moderate, the applicant must submit a CBE-30 (changes being effected in 30 days) supplement at least 30 days before the product is distributed or, in some cases, the product may be distributed immediately upon FDA’s receipt of a CBE-0 (changes being effected in 0 days) supplement.

If the change assessment determines the change to be major, the applicant must submit and receive FDA approval of a supplement to the BLA before the product produced with the manufacturing change is distributed (also known as a prior approval supplement (PAS)). The applicant may ask the FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked: “Prior Approval Supplement-Expedited Review Requested.”

The guidance provides a comprehensive appendix: Changes That FDA Generally Considers Having a Minimal Potential To Have An Adverse Effect On Product Quality. The appendix provides examples of CMC postapproval manufacturing changes that FDA generally considers have minimal potential to have an adverse effect on product quality, which can help the applicant determine if the change is considered a minor change and subject to documenting in the annual report.

Additional information regarding the reporting categories for BLAs, can be found in Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (July 1997). Additionally, 21 CFR 601.12 Changes to an Approved Application provides the regulatory requirements for reporting.

If you are unsure whether a change should be submitted to the FDA as a supplement or documented in the annual report, applicants are encouraged to contact the Office of Pharmaceutical Quality  in CDER or the Office of Communication, Outreach and Development in CBER.

Content Of Annual Report Notification

Applicants are required to include the following information for each change in the annual report:

  • A full description of the CMC change, including:
  • The manufacturing sites or areas involved.
  • The date the change was made.
  • A cross-reference to relevant validation protocols and/or standard operating procedures.
  • Relevant data from studies and tests performed to assess the effect of the change on product quality.
  • A list of all products involved.
  • A statement that the effects of the change have been assessed.

The applicant should describe each change in an annual report with sufficient detail to allow the FDA to evaluate and determine whether the appropriate reporting category was used. When the submitted change is not appropriate for the annual report (moderate or major), the FDA generally intends to notify the applicant of the correct category and may request additional information. However, applicants should only use this mechanism of reporting a change when they are confident that documentation in an annual report is appropriate.

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. 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, CSQP, 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. Durivage resides in Lambertville, Michigan. Please feel free to email him with any questions or comments.