- The Food and Drug Administration has sent a warning letter to Zhejiang Huahai Pharmaceutical in China, citing "significant deviations from current good manufacturing practice (cGMP) for active pharmaceutical ingredients," observed during an inspection in late July and early August.
- The letter calls out the company's failure to fully investigate a customer complaint in June, right at the beginning of the valsartan contamination saga. Other complaints over API batches dated as far back as September 2016.
- Regulators also noted that Zhejiang Huahai put in place a change in manufacturing in November 2011 without evaluating the potential effect it could have on API quality. The FDA deemed Zhejiang Huahai's responses to its letter to be inadequate and recommended getting a cGMP consultant on board to help to resolve the issues.
Zhejiang Huahai has been at the core of the valsartan investigation since its beginning mid-2018, when the FDA and the European Medicines Agency backed a voluntary recall of tablets made using active pharmaceutical ingredient (API) from the Chinese manufacturer.
The API was contaminated with the potential carcinogen N-nitrosodimethylamine (NDMA). That compound and another impurity, N-nitrosodiethylamine (NDEA), appeared to arise as part of the manufacturing process.
Zhejiang Huahai defended itself by claiming NMDA was difficult to detect and that it wasn't the only company to find NMDA in valsartan API. Yet FDA officials have fired back, with their strongly worded warning letter being the latest example.
"[Y]our investigation was inadequate and failed to resolve the control and presence of NDMA in valsartan API distributed to customers," they wrote.
The November 2011 manufacturing changes were intended to improve the plants processes, increase product yield and lower costs. So far, however, they seem to have caused more problems than solutions as the company doesn't appear to have taken into account any potential for the formation of toxic impurities. It argued that "predicting NDMA formation during the valsartan manufacturing process required an extra dimension over current industry practice."
Regulators disagreed, reminding Zhejiang Huahai in the letter that common industry practice was not always consistent with cGMP requirements and companies are responsible for the quality of the drugs they produce.
While the FDA is continuing to look into the root cause of the valsartan contamination, it's clearly not happy with Zhejiang Huahai: Commissioner Scott Gottlieb described the manufacturer as having a concerning lack of oversight.
"FDA 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," regulators wrote in their letter.