Assessment of Manufacturing Related Deficiencies for Modified Release Tablet in Abbreviated New Drug Applications.

Abstract

Generic drugs play an important role in public health. However, the first review cycle approval rate for Abbreviated New Drug Applications (ANDAs) is generally low. To identify if the drug product (DP) manufacturing related deficiencies are the potential root causes of low first review cycle approval of the modified release (MR) tablet ANDAs, we collected and analyzed the review recommendations from each review discipline and the DP manufacturing (process and facility) related deficiencies for original MR tablet ANDAs submitted between FY17 and FY19. We identified 193 original MR tablet ANDAs. The analysis showed that 12% of the applications were approved in first review cycle, while 88% received complete responses (CR). Of the 169 CR applications, 91% were found inadequate for multiple review disciplines. A total of 1345 DP manufacturing process-related deficiencies were issued to 184 ANDAs during the first review cycle. We have identified common deficiencies across ANDAs based on DP manufacturing process categories. The top deficiencies cited reasons include facilities are out of compliance/not ready to commercialize/not ready for inspection; critical process parameter (CPP) ranges are not proposed/proposed CPP ranges are too wide and/or not supported by studied range and no in-process controls (IPCs) are proposed/proposed IPCs acceptance criteria (limits) are too wide and/or not supported by observed data etc. Avoiding the common DP manufacturing deficiencies may reduce the need for issuing DP manufacturing related deficiencies in information requests (IRs), discipline review letters (DRLs), and CRs for MR tablet ANDAs.