Updated: FDA, Health Canada and EMA Spot Second Impurity in Valsartan

Regulatory NewsRegulatory News | 14 September 2018 |  By 

Following the identification of an impurity known as N‑nitrosodimethylamine (NDMA) in the blood pressure-lowering medicine valsartan, FDA, EMA and Health Canada announced Thursday that a second impurity, called N-nitrosodiethylamine (NDEA), has been found in valsartan manufactured by Zhejiang Huahai Pharmaceuticals in China.

FDA also said Thursday that its latest testing of products shows an additional unexpected impurity in three lots of Torrent Pharmaceuticals’ recalled valsartan drug products. These Torrent products were included in the company’s recall on 23 August 2018.

Both NDEA and NDMA are classified as probable human carcinogens, meaning long-term exposure could cause cancer.

FDA and the European Medicines Agency have learned that Zhejiang Huahai Pharmaceuticals (ZHP) found NDEA in several batches of its valsartan API. The FDA immediately began retesting all valsartan API and products, including both recalled products and those currently marketed in the United States, for NDEA. Based on FDA testing to date, the agency discovered NDEA in some of ZHP’s valsartan API. This impurity was also found in Torrent’s valsartan 160mg (lot BV47D001) and 320mg (lots BV48D001 and BV48D002) tablets, which were made using API from ZHP and were part of the earlier recall.

“The new information regarding NDEA is very limited at this time,” Health Canada said, noting that it is “assessing the issue and will update Canadians as more information becomes available, including whether the presence of NDEA impacts Health Canada's health risk assessment related to valsartan products containing NDMA.”

All drugs containing valsartan manufactured by Zhejiang Huahai Pharmaceuticals have been recalled in Canada after the first impurity was identified earlier this summer. Similarly in the US, where manufacturing issues were spotted two years before the recall, FDA has updated its list of valsartan products under recall and the list of valsartan products not under recall to incorporate recalls of valsartan-containing products manufactured by Hetero Labs Limited, in India, labeled as Camber Pharmaceuticals Inc.

Danish Study

A Danish registry study, meanwhile, has examined if the cancer incidence rate is higher among people treated with valsartan, though it concluded that “no increased cancer incidence can be seen at present.”

The Danish Medicines Agency in July halted all sales of specific valsartan products from Danish pharmacies.

EMA Update

The European Medicines Agency (EMA) on Thursday announced that, in line with a previous assessment, the lifetime risk of cancer is considered low and is estimated to be on the order of 1 in 5,000 for an adult patient who had taken an affected valsartan medicine at the highest dose (320 mg) every day from July 2012 to July 2018.

EMA last month also said that low levels of NDMA have been detected in the valsartan active substance manufactured by a second company, Zhejiang Tianyu.

“Patients who have taken treatments with lower doses or for shorter lengths of time will be at a lower risk. The risk will also be lower for patients who have taken valsartan produced by Zhejiang Tianyu, which had smaller amounts of NDMA than valsartan produced by Zhejiang Huahai,” EMA said.

Article updated on 9/14/2018 with more information on the second impurity.


© 2023 Regulatory Affairs Professionals Society.

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