Lotte Biologics USA, LLC – FDA EIR, Jun 5, 2019

An FDA inspection was conducted at Bristol-Myers Squibb Co., Pharmaceutical Research Institute's East Syracuse, NY facility from May 28 to June 5, 2019. The inspection focused on the commercial drug manufacture of licensed biological drug substances, including Belatacept, Ipilimumab, Nivolumab, and Elotuzumab. The regulatory oversight adhered to Current Good Manufacturing Practices (CGMP) as outlined in CPGM 7356.002M for Biological Therapeutic Drug Products and ICH Q7 for Active Pharmaceutical Ingredients, examining Quality, Production, Laboratory Control, and Facilities & Equipment systems. The inspection identified significant deficiencies, leading to the issuance of an FDA-483 form. The primary violation concerned a failure to thoroughly investigate unexplained discrepancies and out-of-specification (OOS) results. Specifically, the firm repeatedly invalidated initial OOS results based on passing retests without scientifically sound and justifiable root causes. These OOS results were often attributed to 'undetermined laboratory error' without adequate supporting evidence. Examples included issues with release testing for Belatacept drug substance involving various assays and stability tests, and specific gravity testing for raw materials. Additionally, a verbally discussed deficiency highlighted repeated occurrences of foreign microbial growth leading to batch terminations during manufacturing, with root causes not consistently identified, indicating insufficient control over microbial contamination. In response, the facility's General Manager, Mr. Michael E. Furlong, acknowledged the observations and committed to providing a written response to the FDA within 15 business days. The agency emphasized that OOS results can only be invalidated with scientifically proven root causes, and retest results alone do not confirm laboratory error, implying corrective actions must align with these principles.