FDA 483 - Shionogi Pharma Co. Ltd. - October 20, 2023

An FDA inspection of Shionogi Pharma Co., Ltd. in Tokushima, Japan, conducted from October 16 to October 20, 2023, revealed several critical deficiencies in their manufacturing of Active Pharmaceutical Ingredients and intermediates, as documented in an FDA 483 report. The primary violations centered on inadequate Out of Specification (OOS) investigations, often invalidating initial failing results without sufficient scientific justification and reporting re-test results as official records without proper corrective and preventive actions. Additionally, analytical methods lacked appropriate validation and transfer, with issues noted in method linearity for cleaning validation and establishing swab/rinse recovery, leading to failures in meeting residue carry-over limits.

Further observations highlighted weaknesses in laboratory controls, including a Coulometric Titrator lacking audit trail capability, posing a data integrity risk. The firm also used an unprotected spreadsheet for stability sample management, allowing unrestricted changes, and performed identification tests without concurrently analyzing standards and samples. Lastly, water sampling for quality control was not representative of actual manufacturing use, and no microbial speciation, including for Burkholderia Cepacia, was conducted for water used in API production. Shionogi Pharma is required to provide comprehensive corrective actions to address these significant deviations from regulatory expectations.