FDA 483 - Alexion Pharmaceuticals, Inc. - August 06, 2012

An FDA inspection of Alexion Pharmaceuticals, Inc.'s therapeutic drug substance manufacturing facility in Smithfield, RI, conducted from July to August 2012, revealed significant concerns regarding manufacturing controls and quality systems. The inspection documented observations primarily centered on inadequate investigations into multiple microbiological contamination events impacting their Soliris drug substance. Specifically, the FDA noted that investigations into microbial contamination, including instances of "too numerous to count" organisms and identified pathogens like Bacillus thuringiensis, were insufficient. The company failed to adequately quantify potential impurities, verify their removal, or file required biological product deviation reports for out-of-specification lots. There were seven contamination events within 15 months, and the firm did not effectively investigate their links or prevent reoccurrence. Furthermore, the effectiveness of routine cleaning cycles was not adequately evaluated, especially after high bioburden or decontamination, with visual residues noted post-cleaning despite initial "passing" inspections. The need for increased sporicidal agent use in clean rooms was also not assessed. Additional observations included an inadequate investigation into a leak and mold event, lacking assessment of impact on active batches and sufficient environmental monitoring. The firm's procedures for selecting environmental isolates for media quality control were incomplete, and deviations were not consistently initiated for all visual inspection failures, such as pooling after cleaning cycles. Lastly, raw material sampling practices were found deficient, occurring in an uncontrolled room with insufficient cleaning procedures. Alexion Pharmaceuticals is required to address these observations with comprehensive corrective and preventive actions to ensure compliance with good manufacturing practices.