The US Food and Drug Administration (FDA) has provided an update on its investigation into an impurity found in certain samples of valsartan, which is used to treat high blood pressure and heart failure. The investigation began in June 2018 after a manufacturer detected a probable carcinogen in its active pharmaceutical ingredient, which followed with other companies recalling products.

In June 2018, Prinston Pharmaceuticals, a US manufacturer of valsartan products, informed the FDA’s Center for Drug Evaluation and Research (CDER) that they had stopped making valsartan products manufactured by Zhejiang Huahai Pharmaceutical Co. (ZHP), a Linhai, China-based pharmaceutical company, after ZHP detected N-nitrosodimethylamine (NDMA) in the API. NDMA is classified as a probable human carcinogen based on results from laboratory tests. NDMA is found in trace amounts in water and some foods. However, the trace amounts of NDMA in ZHP’s valsartan API were unacceptable, according to the FDA.

“We recently found that some generic versions of one medication, valsartan, contain an impurity that doesn’t meet FDA’s safety standards,” the FDA said in an August 30, 2018 agency statement. “The FDA currently has a major operation underway to investigate and address this troubling finding. This investigation is led by a dedicated task force of experts focused solely on this important work.”

In July 2018, the FDA announced a voluntary recall of several drug products containing the API. The recall was due to NDMA, which was found in the recalled products. The presence of NDMA was unexpected and is thought to be related to changes in the way the active substance was manufactured, according to information from the FDA. Specifically, a combination of conditions, which include certain chemicals, processing conditions and production steps, could lead to formation of the NDMA impurity. Not all products containing valsartan are being recalled, however.

The agency says it has shared information about its investigation with other regulatory bodies, including the European Medicines Agency, and learned about its findings as well. The FDA is investigating how many US valsartan products are affected, where the impurity came from, and what the potential health consequences are.

The FDA identified four manufacturers using the valsartan API from ZHP for the US market and recommended recalls to each one. By July, the FDA stated that three companies had products containing NDMA and were voluntarily recalling them, including Teva Pharmaceutical Industries, Major Pharmaceuticals, a Livonia, Michigan-based generic pharmaceutical provider, and Solco Healthcare, a Cranbury, New Jersey-based generic pharmaceutical provider. In August, Torrent Pharmaceuticals, Novo Nordisk’s Ahmedabad, India-headquartered manufacturing partner, also voluntarily recalled its products. In addition to ZHP, the FDA identified 13 other API manufacturers that supply more than 20 drug companies that make valsartan for the US market and plans to check if their products could contain NDMA.

“CDER toxicologists and chemists evaluated the risk to the public,” the FDA said in its statement. “On July 27, we shared what our scientists were able to estimate was the theoretical risk that the impurity could pose to patients. We estimated that if 8,000 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 8,000 people beyond the average cancer rate among Americans.”

In March 2018, the FDA issued a guidance for manufacturers that lays out risk assessments that manufacturers can use to evaluate the presence of genotoxic impurities, such as NDMA. This is an internationally harmonized guidance that both regulators and industry have agreed to. To implement the risk assessment for any genotoxic impurity, there has to be recognition that it can occur in the manufacture of the product. The guidance lays out the conditions under which these risks can occur, and the steps that manufacturers should take to test for these potential impurities.

The FDA has inspected ZHP in response to this problem, and the agency says it may re-inspect ZHP and inspect other manufacturers of valsartan API in the future. The initial recall has expanded to now include five manufacturers and other companies who repackage those products under a different name. Currently, more than half of all valsartan products on the market are being recalled, according to information from the FDA. The agency says it is also working to help make certain that patients have access to the treatment that they need.

Source: FDA