FDA EIR - Merck Sharp and Dohme Corp. - August 16, 2013

An FDA inspection of Merck Sharp and Dohme's Summit, NJ facility took place from August 12 to 16, 2013. The inspection, conducted under Compliance Program 7348.001 for In Vivo Bioequivalence, focused on the analytical portion of study P06558 supporting New Drug Application #204886. The inspection revealed significant issues concerning the firm's analytical methods. Specifically, a Form FDA-483 was issued for two primary observations. Firstly, Merck failed to employ quality control (QC) sample concentrations that accurately represented the observed levels of SCH 530348 in study subjects' plasma. Over 90% of plasma sample concentrations fell within the lower range of the calibration curve, yet the QC concentrations used were not adequately low to ensure precision and accuracy across this critical range. Secondly, similar deficiencies were noted for SCH 2046273, where both calibration standards and QC sample concentrations failed to represent the actual range of metabolite concentrations found in subject plasma. The calibration curve required extension to its lower end to appropriately cover the majority of observed sample concentrations. In response, Dr. Gregory Szpunar, Senior VP of Pharmaceutical Science and Clinical Supply, accepted the FDA-483 and stated the firm would submit a written response within 15 working days. Additionally, discussions with management emphasized the necessity of improving documentation practices, ensuring thorough details in analytical checklists, and establishing a formal SOP for chromatographic integration. These actions are critical to uphold the integrity and reliability of bioequivalence study data.