BLAs Not Submitted Concurrently May Result in Refuse-to-File Actions

The FDA is recommending that producers of biological drug products engaged in shared manufacturing agreements submit biologic license applications (BLAs) and supplements concurrently or risk a refuse-to-file action, according to a recent draft guidance.

“We recommend that all license applications/supplements that pertain to a particular product to be manufactured under a shared manufacturing arrangement be submitted concurrently,” the FDA writes. “Lack of one or more related applications may be a basis for a refusal-to-file action.”

Share manufacturing agreements are defined as contracts where two or more firms are licensed and responsible for specific aspects of the production of a product, but none are responsible for the entire process, the FDA says.

Under common shared manufacturing agreements, where one firm produces an intermediate biologic product while the other produces the final product, the FDA says that the company responsible for the final form of the biologic is expected to assume responsibility for providing data to the agency that demonstrates safety, purity and potency of the product.

In addition, “we … expect the licensed finished product manufacturer to be primarily responsible for any postapproval obligations, such as postmarketing clinical trials, additional product stability studies, complaint handling, recalls, postmarket reporting of the dissemination of advertising and promotional labeling materials … and adverse event reporting,” the FDA says.

Applications or supplements from companies that produce intermediate products must include criteria used to determine lot-by-lot acceptability, including sterility, stability, product characterization, potency and purity specifications, the FDA says.

The draft guidance, “Cooperative Manufacturing Arrangements for Licensed Biologics,” can be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/99d-2013-gdl0002.pdf.