New FDA Draft Guidance on Manufacturing Changes for Biologics Issued

Guidance covers post-approval manufacturing changes that should be documented in annual reports.

Significant changes to drug manufacturing processes that can affect product quality or the properties of active pharmaceutical ingredients require regulatory approvals. There are many changes, however, that will have minimal impact on product quality. While approval is not required, these changes must be documented.

FDA recently issued a draft guidance regarding the types of manufacturing changes for approved biologics license applications (BLAs) that it recommends drug companies record in their annual reports. The draft guidance is entitled CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports.

The post-approval changes covered in the guidance are considered by FDA to have minimal likelihood of negatively impacting product quality. Under FDA regulations, post-approval changes that have a minimal potential to have an adverse effect on product quality must be documented by applicants in an annual report. The guidance specifically addresses chemistry, manufacturing and controls (CMC)-related changes, such as changes in product components and composition, manufacturing sites, batch sizes, manufacturing equipment, specifications and container-closure systems.

A driver for the issuance of the guidance was a steady increase in the number of CMC manufacturing supplements for BLAs being submitted to FDA that include changes that are likely to have little impact on product quality. The agency made this determination after evaluating the different types of post-approval changes included in the supplements in accordance with its risk-based approach to CMC review, which is in line with its Pharmaceutical Product Quality Initiative. The guidance was thus developed to provide recommendations for changes that can be documented in annual reports and do not require CMC manufacturing supplements. A list of these recommended types of changes is provided in the appendix to the draft guidance. 

While in general these changes should be fine to include only in an annual report, FDA does caution that each BLA holder planning to make a proposed change that is included the appendix of the draft guidance consider the specific change in the context of its manufacturing process and situation, in order to confirm that the change can indeed be expected to have a minimal impact on product quality. If a BLA holder determines that any of the types of changes included in the appendix to the draft guidance may have an impact on product quality, the company should submit the change as a CMC supplement. If FDA disagrees, the agency may notify the BLA holder of the proper categorization.


Guy Tiene

Guy supports the success of life science organizations by identifying synergies across research, content, marketing and communications resources to drive value for clients. With over 30 years of education and marketing experience and 18 years in the life sciences alone, Guy leads our editorial standards for client content, Pharma’s Almanac and Nice Insight research-based industry content as well as external communications for clients. Having served as head of global marketing and communications for a CMO, he also brings critical insight and guidance to all communications. Guy holds a Masters degree from Columbia University.