FDA Warns China’s Zhejiang Huahai Over Failures to Detect Impurities in Valsartan API Batches

China-based Zhejiang Huahai Pharmaceuticals drew a US Food and Drug Administration (FDA) warning letter over failures to conduct investigations into impurities classified as probable human carcinogens.

The warning letter is FDA’s latest move in its ongoing review of the potential impact of two impurities on batches of valsartan active pharmaceutical ingredients (API). Zhejiang Huahai has been at the center of the international drug safety issue since certain valsartan-containing products were recalled from the EU market in July over the presence of the first detected impurity, N-nitrosodimethylamine (NDMA).

FDA flagged significant violations of good manufacturing practices (GMP) during a site inspection at the Zhejiang Huahai API manufacturing facility in Linhai, Taizhou Zhejiang as well as inadequacies in the firm’s response letter from August to the subsequently issued FDA Form 483.

The firm’s response “states that NDMA was difficult to detect,” FDA said. “However, if you had investigated further, you may have found indicators in your residual solvent chromatograms alerting you to the presence of NDMA.” This GMP violation relates to inadequate customer complaint handling as NDMA was identified as an “unknown peak” in a complaint the firm received from a customer in June.

The second GMP violation involves inadequate procedures for managing changes to manufacturing processes to ensure that unanticipated impurities are appropriately detected and controlled. FDA said it has “grave concerns about the potential presence of mutagenic impurities in all intermediates and API manufactured at your facility, both because of the data indicating the presence of impurities in API manufactured by multiple processes, and because of the significant inadequacies in your investigation.”

FDA called on the firm to respond with certain measures to resolve to the violations. These include a revised complaint handling procedure and test results for all investigations into the presence of NDMA, the second probable human carcinogen to be tied to the drug safety issue—known as N-Nitrosodiethylamine (NDEA)—and other “potentially mutagenic impurities,” among other measures.

Zhejiang Huahai Pharmaceutical 11/29/18