FDA Draft Guidance on CMC Postapproval Manufacturing Changes for Specified Biological Products

Recommendation

7/8 May 2024

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Regulatory Requirements and Practical Implementation

In some cases it will be necessary to have some changes of chemistry, manufacturing or control (CMC) of a biologics license application (BLA).  Postapproval changes in the product, production process, quality controls, equipment, in facilities or by responsible personnel have the potential to influence the quality of the pharmaceutical product. And the number of CMC manufacturing supplements for BLAs has continued to increase during the last years. But the FDA recognized that certain changes being reported generally present minimal risks to the quality of the product. Therefore the FDA published a new guidance on "CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports".

The aim of this new guideline document is to support holders of biologics license applications (BLAs) for specified products and give recommendations regarding the types of changes to an approved BLA to be documented in an annual report under 21 CFR 601.12. It is intended for such changes that the FDA generally considers to have a minimal potential to have an adverse effect on product .quality. With regard to the effected products, the FDA defines:

"This guidance applies to all of the specified categories of biological products in 21 CFR 26 601.2(a). The guidance does not apply to blood-derived products, in vitro diagnostics, cellular and gene therapy products, and vaccines and related products; however, a BLA holder for any other naturally derived biological product should discuss with FDA whether the recommendations in this guidance apply to his or her BLA."

Generally, the FDA differentiates changes in major, moderate and minor and defined different procedures for the holders of biologics license applications (BLAs) in these cases as follows:

"If a change is considered to be major, an applicant must submit and receive FDA approval of a supplement to the BLA before the product produced with the manufacturing change is distributed (also known as a prior approval supplement (PAS)). If a change is considered to be moderate, an applicant must submit a supplement at least 30 days before the product is distributed (CBE-30 supplement) or, in some cases, the product may be distributed immediately upon FDA’s receipt of the supplement (CBE-0 supplement). If a change is considered to be minor, an applicant may proceed with the change but must notify FDA of the change in an annual report.

Therefore, the reporting categories for BLAs are described in detail in the guidance for industry "Changes to an Approved 61 Application for Specified Biotechnology and Specified Synthetic Biological Products"