In a warning letter, issued on November 29, 2018, the US Food and Drug Administration (FDA) noted that Zhejiang Huahai Pharmaceuticals (ZHP)’s quality unit failed to investigate quality-related complaints, and failed to evaluate the effects of changing its manufacturing process.
In July, the first report of contamination of valsartan produced by ZHP led to global recalls. N-Nitrosodimethylamine (NDMA) was discovered by regulators within the ZHP-produced active pharmaceutical ingredient (API) – this contaminant is listed by the International Agency for Research on Cancer as a probable carcinogen.
The warning letter outlines two specific opportunities for the firm to take action on customer complaints to discover the issue, which ZHP received in September 2016 and June 2018.
The complaint issued two years prior saw a customer identify high levels of contamination within API batches, but the company dismissed the concerns as they conflicted with its own test results. As a result, ZHP reprocessed the API and released it to customers in non-US markets.
The FDA concluded that the company’s investigation into the more recent complaint was “inadequate and failed to resolve the control and presence of NDMA in valsartan API distributed to customers.”
According to the FDA’s warning letter, ZHP defended itself by stating that “NDMA was difficult to detect” and that “[it] was not the only firm to identify NDMA in valsartan API.”
In addition to ZHP, Zhejiang Tianyu was found to produce contaminated APIs, and several other companies, including Mylan, have also been found to manufacture valsartan containing another contaminant, N-nitrosodiethylamine (NDEA).
However, the FDA stated: “Analyses of samples identified amounts of NDMA in valsartan API manufactured at [ZHP] that were significantly higher than the NDMA levels in valsartan API manufactured by other firms.”
FDA commissioner, Scott Gottlieb concluded, “The issues cited in the warning letter are associated with the nitrosamine impurities found in these drugs, and these violations reveal a disturbing lack of oversight at this API manufacturer that puts patients at risk.”
The agency placed ZHP on import alert in September, which stops all API and finished drug products using API produced by the company from entering the US.