FDA 483 - Novartis Singapore Pharmaceutical Manufacturing Pte. - February 15, 2020

During an inspection conducted by the U.S. Food and Drug Administration (FDA) from February 10-15, 2020, Novartis Singapore Pharmaceutical Manufacturing Pte Ltd. received a Form FDA 483 outlining significant observations related to its drug substance manufacturing operations. The inspection revealed several concerns indicating potential non-compliance with Good Manufacturing Practices. A primary issue was the inadequate identification of root causes and ineffective corrective and preventive actions (CAPAs) for recurring bioburden and endotoxin excursions within the manufacturing system. Despite numerous deviations, investigations frequently failed to pinpoint the underlying causes, and implemented CAPAs did not prevent recurrence, with biofilm still observed. Further observations included the scientifically unjustified transfer of analytical methods, where a potency method was approved despite demonstrating differing performance. The company's procedures for investigating Out-of-Specification (OOS) results were also found to be inadequate, permitting the invalidation of original test results based on retesting without establishing a specific assignable cause. Deficiencies were also noted in the management of critical materials and reference standards, with SOPs lacking details on storage and inventory checks for key standards. Lastly, the firm failed to adhere to its own production and process control procedures, specifically regarding the required full testing of materials from certified raw material suppliers for certain cell banks. Novartis is required to thoroughly address these observations by conducting comprehensive investigations, identifying definitive root causes, and implementing robust and effective corrective actions to ensure full compliance and prevent future recurrences.