Convergence: FDA official reviews common BLA deficiencies, offers advice on avoiding CRLs

LONG BEACH, CA – The number of complete response letters (CRLs) issued to sponsors of biologics license applications (BLAs) by the US Food and Drug Administration (FDA) has been increasing over the past decade, with facility deficiencies being the most frequent issue cited, said Leslie Rivera Rosado, a supervisory interdisciplinary scientist for the Office of Pharmaceutical Quality within the agency’s Center for Drug Evaluation and Research (CDER).

Rivera Rosado made these comments during a panel at the RAPS Convergence 2024 conference on Wednesday, which she joined remotely, that focused on quality reviews for biologics and biosimilars. She was joined by industry experts from Visterra, a clinical-stage biotech firm.

“Looking at the numbers, it is clear that there has been a rise in total number of CRLs along with the total number if BLA submissions,” said Rivera Rosado. Facility deficiencies were cited as the most common reason for CRL and span a variety of topics, with insufficient quality oversight a “recurring theme.”

This data was from a survey FDA conducted analyzing over 100 CRLs for CDER BLAs submitted from 2014 to 2024, which included all CRs causes, including chemistry, manufacturing and control issues. The survey did not include BLA supplements and included multiple CRLs issued for a single BLA. Most of the CRLs cited more than one deficiency. Biological products reviewed by CDER include monoclonal antibodies (mAb) and “antibody like” therapeutic proteins, such as cytokines, enzymes, immunomodulators, growth factors, insulins, and peptides with over 40 amino acids.

She noted that more foreign manufacturing sites are associated with CRLs than domestic ones, and approximately half of all facility deficiencies are for contract manufacturing organizations (CMOs). In addition, approximately 75% of applicant-site CRLs are for biosimilars.

Common facility-related deficiencies include environmental/personnel monitoring, data integrity, aseptic control and validation, and equipment cleaning, and cross contamination.

To ensure smooth BLA reviews, Rivera Rosado advised companies to plan their pre-BLA interactions with FDA at least six months before the BLA filing to allow enough time for feedback. Companies should also be ready for facility inspections once the BLA is filed, especially if the company has bever been inspected before. It is also important to identify all critical/non-critical in-process controls and implement an adequate in-process control strategy.

She also recommended validating analytical methods with numerical acceptance criteria at the time of BLA filing and to develop and validate sensitive anti-drug antibody (ADA) and neutralizing antibody (NAb) assays with the appropriate controls. She added that formatting is also an important part of the labeling and to “take this seriously.”

Tulay Kilicdagi, associate director of regulatory affairs for Visterra, discussed the results of a recent study that evaluated what FDA looks for in BLA submissions. The study evaluated 63 BLAs that were approved by FDA to discern some shared areas of concern of questions raised by the agency in reviewing these applications.

Some of the findings include that FDA expects firms to submit a complete filing at the time of submission, including documentation of the cell bank stability protocol, compatibility and in-use stability data, and extractable and leachable assessments.

Convergence: FDA official reviews common BLA deficiencies, offers advice on avoiding CRLs

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