FDA 483 - Kyowa Hakko Bio Co., Ltd. - April 15, 2022

During an FDA inspection conducted from April 11-15, 2022, at Kyowa Hakko Bio Co., Ltd., an active pharmaceutical ingredient manufacturer in Japan, several significant observations were noted regarding their quality, laboratory, and production systems. The inspection highlighted deficiencies in adhering to established procedures and regulatory expectations for manufacturing quality.

Key issues included a quality control unit that did not consistently follow its own procedures, evidenced by a lack of proper root cause investigations and corrective actions for recurring laboratory incidents like poor endotoxin calibration curves. Additionally, risk assessments were often absent for deviations with potential product quality impact, and numerous deviations, change controls, and complaint investigations remained open for unusually long durations, some exceeding hundreds of days, without adequate progress tracking.

The firm also failed to properly evaluate the potential impact of proposed changes on product quality, such as assessing microbial growth risks after system shutdowns or ensuring correct storage conditions for shipped products. Furthermore, there was no documented evidence to confirm the suitability of water used in manufacturing due to a lack of specifications for objectionable microorganisms. Laboratory controls were found wanting, with improper sample disposition, unlogged samples, and a lack of audit trail review proficiency among staff. Finally, production procedures did not classify critical process alarms, hindering operators' ability to identify and address significant events.

These observations indicate a need for Kyowa Hakko Bio Co., Ltd. to implement comprehensive corrective and preventive actions, strengthen its quality management system, and ensure full compliance with manufacturing standards to safeguard product quality and patient safety.