FDA CRL - Kashiv BioSciences, LLC

The FDA has issued a Complete Response Letter (CRL) to Kashiv BioSciences, LLC regarding its Biologics License Application (BLA) for Theragrastim, a proposed biosimilar product. The application, submitted under section 351(k) of the Public Health Service Act, cannot be approved in its current form.A primary issue is the unfulfilled requirement for an inspection of Kashiv BioSciences' drug substance manufacturing facility in Chicago, Illinois. This inspection, necessary to assess compliance with Current Good Manufacturing Practices (CGMP), was not conducted due to travel restrictions and remains a prerequisite for approval.Several product quality deficiencies were also identified. These include concerns regarding the completeness and traceability of quality data from a third-party audit, particularly for older clinical manufacturing lots where some raw data (HPLC, UV, SDS-PAGE) were untraceable or unavailable. The FDA requires untraceable data to be removed from the comparative analytical assessment, which may necessitate further studies. Additionally, the company must explain the etiology and impact of detected sequence variants on the product's similarity to the reference product, Neupogen.Further issues pertain to stability protocols, which lack acceptance criteria for EC50 values in reference standards and need updates for drug product stability specifications, including syringe performance and container closure integrity testing. Shipping validation protocols also require revisions to justify worst-case scenarios for filling volumes and to include post-shipment packaging integrity assessments. Kashiv BioSciences must address these deficiencies for the BLA to be reconsidered for approval.