FDA EIR - Zhejiang Huahai Pharmaceutical - August 03, 2018

The U.S. Food and Drug Administration (FDA) conducted a comprehensive inspection of Zhejiang Huahai Pharmaceutical Co., Ltd., an Active Pharmaceutical Ingredient (API) manufacturer in China, from July 23 to August 3, 2018. This inspection, conducted under established Good Manufacturing Practice (GMP) guidelines for APIs, uncovered numerous critical deficiencies. The most significant finding was the presence of N-Nitrosodimethylamine (NDMA), a genotoxic impurity, in the company's Valsartan API, an issue that led to a recall prior to the inspection. The firm's investigation into the NDMA's root cause was deemed inadequate. The FDA issued an 11-item Form FDA 483, detailing widespread violations. These included an inadequate change control system, insufficient validation of manufacturing processes, cleaning procedures, and analytical methods, and a failure of the quality unit to consistently perform its duties. Additional issues involved poorly defined cleaning procedures, unsuitable equipment design, inadequate preventive maintenance, the use of non-food grade coolants, scientifically unsound sampling plans, and insufficient stability studies. Management initially disputed the observations and did not commit to immediate corrective actions, though they pledged to submit a formal written response. The FDA cautioned that unaddressed deficiencies could result in severe regulatory measures, including a warning letter or import detention. The company is now working to validate an optimized manufacturing process aimed at eliminating the NDMA impurity.