FDA 483 - Kyowa Kirin Co., Ltd. - December 14, 2022

An FDA inspection conducted from November 30 to December 14, 2022, at Kyowa Kirin Co., Ltd.'s Takasaki, Japan, manufacturing facility identified significant deviations from Good Manufacturing Practices. The Form FDA 483 report detailed multiple observations, indicating systemic issues in the production of sterile drug products.Primary concerns included inadequate validation of sterilization processes, specifically neglecting critical components in validation studies and failing to validate decontamination cycles. Sampling procedures for in-process materials, such as bioburden and water quality, were deemed non-representative, potentially compromising product quality assessments. Deficiencies were also noted in equipment cleaning validation and maintenance, with out-of-specification results not receiving proper root cause investigations.The inspection highlighted critical data integrity issues, including electronic signatures that lacked individual uniqueness and electronic records with insufficient retention or audit trail capabilities, failing to meet requirements like 21 CFR Part 11. Environmental monitoring in aseptic processing areas was found inadequate, with media fill studies not collecting all necessary samples and insufficient monitoring of personnel gowning and critical surfaces.Furthermore, the company did not consistently investigate unexplained discrepancies, evident in a substantial increase in "Lack of Efficacy" product complaints and unaddressed cleaning procedure deviations. Equipment was not always maintained to repeatedly produce valid results, leading to microbial contamination incidents. Inadequate laboratory controls for visual inspection personnel and aseptic gowning proficiency were also cited. Finally, records for dedicated equipment use were missing from batch records, material identification statuses were inconsistent, and manufacturing personnel were observed wearing inappropriate clothing in production areas.Kyowa Kirin Co., Ltd. is expected to promptly address these observations by implementing comprehensive corrective and preventive actions to ensure full compliance with regulatory requirements and maintain drug product quality and patient safety.