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As it investigates the root cause of an impurity discovered in valsartan, FDA extends its studies to APIs with similar synthesis processes.
FDA has identified a potential source of a probable cancer-causing chemical found in a commonly used blood pressure medicine and extended its testing to all products in the angiotensin II receptor blocker (ARB) class.
In a statement released on Aug. 30, 2018, the agency updated the public about its response to the discovery of trace amounts of N-nitrosodimethylamine (NDMA) in valsartan, as well as recommendations for patients concerned about the medical implications of taking the drug.
NDMA is a known environmental contaminant found in water and foods including meats, dairy products, and vegetables. FDA scientists estimated that “if 8000 people took the highest valsartan dose (320 mg) from NDMA-affected medicines daily for four years (the amount of time we believed the affected products had been on the U.S. market), there may be one additional case of cancer over the lifetimes of these 8000 people beyond the average cancer rate among Americans.” The estimate is a worst-case scenario, FDA noted; most patients who were exposed to the impurity by taking valsartan received less exposure.
On June 19, 2018, Prinston Pharmaceuticals notified FDA’s Center for Drug Evaluation and Research (CDER) that the company stopped making products containing the active ingredient valsartan that was manufactured by Zhejiang Huahai Pharmaceutical Co. (ZHP) after the API supplier reported that it detected NDMA in its valsartan API. During its initial investigation, FDA learned that a foreign regulator was also reviewing drugs containing ZHP’s valsartan; FDA reports it has shared information with agencies in Europe, Canada, and Japan. As of Aug. 30, 2018, five manufacturers of valsartan and other companies that market products under a different name issued recalls.
In the ongoing investigation, FDA has identified 13 other API manufacturers that are supplying the valsartan API to 20 drug manufacturers in the United States. As part of the investigation, CDER’s scientists have developed a gas chromatography-mass spectrometry (GC-MS) testing method to detect NDMA in valsartan API and tablets and have shared the method with drug manufacturers.
In the statement, FDA noted that the agency suspected that the impurity resulted from changes that ZHP made to the API manufacturing process. “We believe that these risks are introduced through a specific sequence of steps in the manufacturing process, where certain chemical reactions are needed to form the active ingredient. Before we undertook this analysis, neither regulators nor industry fully understood how NDMA could form during this process. We are still not 100 percent sure that this is the root cause of the problem,” FDA wrote in the statement.
The agency reported that “full understanding will require correlation of multiple test results from valsartan APIs made by different processes with the various process steps used by different manufacturers or at different times. We need to determine how NDMA can be formed and why it is not separated from the API during purification.”
Due to similarities in the synthesis processes of valsartan to other APIs in the ARB class, FDA announced that it would extend its testing program to determine if other ARB products contain NDMA.
FDA also emphasized that patients taking valsartan should not stop taking medications and should check with healthcare providers to get prescriptions for products that have not been recalled. The agency said it has received more than 6000 inquiries since the first recall and has established phone (855-543-3784) and email (email@example.com) access to answer questions from patients and medical professionals.