Valsartan probe teaches FDA lesson about impurities in manufacturing

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The FDA says a combination of conditions, including certain chemicals, processing conditions and production steps, can lead to the formation of the NDMA impurity during manufacturing. (FDA)

It was a U.S. drugmaker that first alerted the FDA that the valsartan API it got from a Chinese ingredient maker contained a potentially dangerous impurity. And in the process of investigating, the FDA learned something it hadn’t known: that a combination of manufacturing conditions could lead to formation of the NDMA impurity in an API.

In an update on the global recall of the contaminated ingredient, the FDA says Prinston Pharmaceuticals contacted the FDA June 19 to report it had stopped making its blood pressure medicines after detecting N-nitrosodimethylamine (NDMA) in the API manufactured by Zhejiang Huahai Pharmaceutical (ZHP).

The agency has determined that NDMA, a probable cancer-causing agent, has contaminated certain valsartan APIs for up to four years. While the levels of NDMA  in ZHP’s valsartan API were trace amounts, they were considered unacceptable, the FDA reported Thursday.

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“Although the risk to patients taking the affected products is extremely low, we take matters of pharmaceutical quality very seriously,” the FDA said.

It turns out the FDA was not alone in investigating ZHP’s products. Another regulator also was looking into the situation. In July, the European Medicines Agency announced that some valsartan products made by the Chinese company were being recalled from Europe and Asia and shortly after the FDA announced the recall in the U.S.

Since then, the U.S. recall has expanded to include five manufacturers and other companies that repackage those products under a different name. More than half of all valsartan products on the market (PDF) are being recalled, but patients can still find untainted products (PDF) from other producers, the FDA noted.

The FDA says that based on its initial investigation, it believed, but didn’t have proof, that the impurity resulted from changes that ZHP made to the manufacturing process for its API. It has since figured out that “a combination of conditions, including certain chemicals, processing conditions and production steps, could lead to formation of the NDMA impurity,” something that it was totally unaware of before now.  

The FDA has inspected ZHP in response to the issue and may go back, it said, and may also inspect other valsartan producers in future.

It also is looking into the chemical class of “genotoxic impurities,” into which valsartan falls, and has given manufacturers guidance “that lays out risk assessments that manufacturers can use to evaluate the presence of genotoxic impurities.”