Industry wisdom is that there is nothing new to learn about tablet making. Drugmakers have been doing it essentially the same way for more than 100 years. But that idiom was turned on its head this year when the FDA learned suspected carcinogens could be formed in “sartan” drugs from a specific sequence of manufacturing steps and chemical reactions—and that the U.S. drug supply had been riddled with them for years.
The initial discovery of one of the impurities, N-nitrosodimethylamine (NDMA), came this summer at a U.S. drug manufacturer that had used valsartan API from China’s Zhejiang Huahai Pharmaceutical. Since then, the FDA made a discovery: NDMA and a similar agent, N-nitrosodiethylamine (NDEA), can be created in certain manufacturing situations, a fact the agency had been completely unaware of before.
The surprise findings set off global recalls of hundreds of lots of valsartan, irbesartan and losartan—ubiquitous drugs used to lower blood pressure—and an intensive FDA investigation into how it could have happened and the dangers it posed to U.S. consumers.
The agency banned the valsartan APIs produced by Huahai and savaged the Chinese company in a warning letter for changing its manufacturing processes without thoroughly evaluating the risks. The FDA said that when Huahai altered its manufacturing process in 2011 to include a solvent suspected of producing the impurity, it didn’t even consider that the changes might lead to the formation of mutagenic impurities in its valsartan APIs.
But the FDA has since learned that the impurities were found in the APIs of other drugmakers, including Aurobindo and Mylan, and in finished products from Sandoz, Teva and others.
The levels of those substances found in some drugs exceeded those scientists say are safe, and the findings have pushed the FDA to dive deep into their cancer risks. While the risk is low, the agency has said, it is still a risk. Among patients who have taken the highest valsartan dose (320 mg) containing NDMA from the recalled batches daily for four years, there may be one additional case of cancer in 8,000 people.
The FDA updated testing methods just last week to detect NDMA and NDEA impurities in both APIs and finished products. Meanwhile, the investigations continue into something about which everyone, including the FDA, figured they knew pretty much all there was to know.