If a manufacturing change is made to an approved BLA, the manufacturer must classify that change based on a three-tiered reporting system and submit a report to FDA.
On June 21, 2021, the U.S. Food and Drug Administration (FDA) issued a final guidance to assist manufacturers in determining the appropriate category for reporting a change in chemistry, manufacturing and controls made to certain approved biologics license applications (BLA).
This newly issued guidance (1) updates FDA’s July 1997 guidance to accommodate advances in manufacturing and testing technology and to clarify FDA’s current thinking on assessing reportable changes and (2) finalizes the December 2017 draft guidance titled, “Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products.” The final guidance is applicable to biological products licensed under section 351(a) of the Public Health Service Act (PHS Act), such as vaccines, allergenic products and plasma-derived products, as well as combination products licensed under a BLA. However, the final guidance expressly does not apply to certain enumerated biologics, including whole blood products, biosimilars, exclusions under 21 C.F.R. § 601.2(a) or human cells, tissues, and cellular- and tissue-based products regulated under section 361 of the PHS Act.
If a manufacturing change is made to an approved BLA (including to the product, production process, quality controls, equipment, facilities or responsible personnel), the manufacturer must classify that change based on a three-tiered reporting system and submit a report to FDA. The appropriate reporting category depends on the risk that the manufacturing change could have an adverse effect on the safety or effectiveness of the product, i.e., product quality. Based on that risk, each of the three reporting categories specifies what type of report the manufacturer must submit and when the manufacturer can distribute the product made using the reported change. For example, major changes that have the highest potential to have an adverse effect on product quality are classified as prior approval supplement, which require the applicant to submit a supplement that FDA must approve before the manufacturer can distribute any product made using that change. The final guidance defines the three categories and details the contents of each report for those categories, including the supporting data necessary to demonstrate the effect on product quality; explains considerations that manufacturers should take into account to assess a change’s impact to product quality; and provides advice regarding successful implementation and reporting of manufacturing changes.
If FDA disagrees with the classification assigned by a manufacturer to the manner of reporting a post-approval BLA change, FDA can advise the manufacturer that a different classification is required—which ultimately may delay approval of the change and distribution of the product. To avoid this, the final guidance provides a table of frequent manufacturing changes and recommended reporting categories. However, for changes not described in the table or if a manufacturer is considering an adjustment to the recommended reporting categories, the guidance recommends early consultation with FDA to determine the appropriate reporting category.
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