FDA 483 - Takeda Pharmaceutical Company Limited - November 26, 2019

The FDA Form 483 details seven observations from an inspection, highlighting significant deficiencies in the facility's quality control, aseptic processing, and equipment maintenance.

**Observation 1** notes the Quality Unit's failure to adequately oversee production, aseptic controls, and equipment maintenance. It also cites unauthorized and undocumented full-size trial runs on filling lines, lacking proper reconciliation, line clearance, and destruction procedures.

**Observation 2** indicates that investigations into batch failures, specifically involving black metal particles, were not extended to other potentially affected batches.

**Observation 3** identifies inadequate validation of aseptic and sterilization processes. This includes the absence of aseptic process simulations (media fills) after HVAC re-qualification and system maintenance, contrary to SOP H-SOP-PRD-0010. Furthermore, the design of the aseptic process simulation for the sterile line did not represent actual production operations, and a failed sterility test was attributed to operator error without requiring operators to conduct media fills of this specific process.

**Observation 4** points to inadequate controls for in-house sterilization and replacement of gowns for classified areas, with observed discrepancies in sterilization dates and lack of access control.

**Observation 5** reveals that two batches of drug product (lots [redacted]) that failed sterility testing were released based on re-test passing results, despite an investigation lacking evidence to support the invalidated initial tests.

**Observation 6** details issues with equipment maintenance, specifically an equipment