FDA 483 - J.:)o,,a Hakko Bio Co., Ltd. - April 15, 2022

This FDA Form 483 details multiple observations regarding the facility's quality control, change management, materials, laboratory, and production systems.

**Observation 1** highlights failures within the quality control unit to follow established procedures. This includes: * Not establishing root causes or issuing CAPAs for poor endotoxin test calibration curves (LE2022-HB-002, LE2022-HB-004, LE2022-HB-018). * Lacking risk assessments for major deviations (DV-21-007:2) and proper investigations for deviations with potential product impact (DV-1596). * SOP YIS-QA-0039-02 lacking criteria for extending deviations, leading to several deviations remaining open for extended periods (e.g., DV-21-0591 for 275 days). * A backlog of over 300 open change controls, CAPAs, and complaint investigations, with many exceeding 100 days, and insufficient documentation of their progress despite SOP requirements.

**Observation 2** addresses inadequate evaluation of proposed changes: * Change Control CC-21-0292 for DIW water system holding tanks did not assess microbial growth risk during system shutdown or justify not increasing monitoring post-service. * Change Control CC21-0