FDA 483 - Regeneron Ireland Designated Activity Company - May 07, 2021

During an FDA inspection conducted from May 4-7, 2021, at Regeneron Ireland Unlimited Company, a drug substance manufacturer located in Raheen Business Park, Limerick, Ireland, several significant observations were noted, indicating deficiencies in their operational controls and adherence to Good Manufacturing Practices. A primary concern was the failure to establish adequate engineering controls for electronic data acquisition systems, leaving data vulnerable to unauthorized manipulation. Specifically, a "go to wavelength" function on a Shimadzu UV-1800 instrument allowed for repeat data collection, a vulnerability identified but not fully addressed in a timely manner. Furthermore, the inspection revealed inadequate personnel training and insufficient detail in written procedures for manufacturing operations. Multiple deviations highlighted this, including issues with equipment setup, incorrect sampling, inaccurate result reporting, and material loss, all attributed to training gaps or unclear procedural instructions. The facility also exhibited a lack of adequate control over microbial ingress risks, evidenced by 168 recurring in-process leaks since 2017, including instances with microbial recovery from breached drug substance bags. Finally, the company's investigations into 130 HEPA filter failures since 2017 were deemed insufficient, as corrective and preventive actions lacked effective procedural controls and proper checks to prevent recurrence. Regeneron Ireland Unlimited Company is expected to respond to these FDA 483 observations by developing and implementing comprehensive corrective and preventive actions to address the identified systemic issues.