FDA Hits Valsartan Manufacturer with Warning Letter

The China-based API manufacturer at the center of the valsartan recalls failed to adequately investigate customer complaints, identify the contaminant and its source, and evaluate the potential effects that changes in a manufacturing process could have on API quality, FDA reports.

In a Nov. 29, 2018 warning letter to Zhejiang Huahai Pharmaceutical (ZHP), FDA noted that the agency “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.”

The Chuannan facility also was cited for cross-contamination from one manufacturing process line to another. The facility was placed on import alert in September 2018. The agency cited the company for failing to ensure that quality-related complaints were investigated and resolved.

“We’re continuing to investigate and take action to protect patient health and safety from products in this angiotensin II receptor blocker class that have been found to have dangerous impurities. As part of that investigation, we’ve uncovered serious manufacturing violations at ZHP, which is one of the manufacturing facilities that has been linked to these products. 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,” said FDA Commissioner Scott Gottlieb, in a press statement announcing the warning letter.

FDA’s investigation in the valsartan contamination issue began in June 2018, when a customer reported an unknown peak-identified as probable human carcinogen N-nitrosodimethylamine (NDMA)-was detected during analysis of residual solvents from valsartan API manufactured by ZHP. The company concluded the presence of NDMA was due to three process-related factors, including a solvent, and only one valsartan manufacturing process was affected. Subsequent FDA analysis of API and finished drug product using the Zhejiang API from multiple batches also reveal the presence of NDMA, including manufacturing processes that did not use the solvent.

Zhejiang approved a process change in the manufacture of valsartan API in November 2011, but “failed to adequately assess the potential formation of mutagenic impurities when you implemented the new process,” FDA noted in the letter. The company also failed to evaluate the need for additional analytical methods to detect impurities prior to making the process change.

In addition to requesting details on revised procedures to assess and control all impurities, FDA required “A retrospective analysis of other API and intermediates manufactured at your firm to determine if they were adequately evaluated for anticipated and unanticipated impurities, including potentially mutagenic impurities.”

The FDA announced recalls of valsartan in July 2018 due to the presence of NDMA in API supplied by ZHP. Since the initial recall, international investigations have expanded to include all manufacturers of API and finished drugs in the angiotensin II receptor blocker (ARB) class. Additional recalls were issued for valsartan, irbesartan, and losartan-containing products found to contain NDMA and N-Nitrosodiethylamine (NDEA), both known animal and suspected human carcinogens.  

Sources: FDA Warning Letter and Press Release