FDA CRL - MediWound Ltd

MediWound, Ltd., c/o Vericel Corporation, received a Complete Response Letter from the FDA for its Biologics License Application (BLA 761192) for a "concentrate of proteolytic enzymes enriched in bromelain" gel, submitted on June 29, 2020, under section 351(a) of the Public Health Service Act. The FDA determined the application cannot be approved in its present form due to significant product quality and manufacturing control deficiencies. Main issues include inadequate botanical raw material authentication, which currently relies solely on morphology and requires additional genetic, chemical, or biological methods. The microbial control strategy for Bromelain Special Production (BSP) and Drug Substance (DS) manufacturing is insufficient, lacking robust measures against adventitious agents and clear microbial limits for in-process intermediates. Deficiencies were also noted in endotoxin testing and bioburden method suitability. Furthermore, the company must provide complete facility information for a manufacturing site (Challenge Bioproducts Company Ltd.). For the drug product, the container closure integrity test validation failed, and critical in-process bioburden method validation data are missing. Chemistry, Manufacturing, and Controls (CMC) issues encompass outstanding process validation data, extractable/elemental analysis studies, and an in-use stability study. The BLA also requires detailed information on the BSP container closure system, clarification of BSP stability sampling/testing, and a post-approval stability protocol. MediWound must address these deficiencies and provide comprehensive data and revised protocols to support the application.