Aurobindo Pharma USA, Inc., the US-based operations of Aurobindo Pharma, a Hyderabad, India-headquartered generics and active pharmaceutical ingredient manufacturer, is conducting a voluntary recall of 80 lots of amlodipine valsartan tablets USP, valsartan HCTZ tablets USP, and valsartan tablets USP in the US to the consumer level due to the detection of trace amounts of an unexpected impurity found in the finished drug product. It is the latest company to recall or have products evaluated due to possible impurities in products containing “sartan”-based active pharmaceutical ingredients (APIs).

The impurity detected in the finished drug product is N-nitrosodiethylamine (NDEA), which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, and has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC) classification. To date, Aurobindo Pharma USA, Inc. has not received any reports of adverse events related to this recall, according to information from the US Food and Drug Administration.

Amlodipine valsartan tablets USP, Valsartan HCTZ Tablets, USP and valsartan tablets USP are indicated to control high blood pressure and for the treatment of heart failure. This recall follows a series of recalls of “sartan” products in the US and the European Union.

In December 2018, Mylan Pharmaceuticals expanded its consumer-level voluntary US recall of valsartan-containing products to include all lots of valsartan-containing products within expiry. The company had earlier issued (November 2018) a voluntary recall to the consumer level of select lots of valsartan-containing products due to detected trace amounts of NDEA contained in valsartan. The valsartan API used in the recalled products was manufactured at one of Mylan’s plants in India. Teva Pharmaceutical Industries also announced a recall in November 2018 when it detected NDEA in the valsartan supply it received from Mylan’s plant in India.

In November 2018, Sandoz, the generics arm of Novartis, voluntarily recalled in the US one lot of losartan potassium hydrochlorothiazide tablets (USP 100 mg/25 mg) due to a trace amount of NDEA found in the API. The API was manufactured by Zhejiang Huahai Pharmaceuticals (ZHP), a Linhai, China-based pharmaceutical company. The US Food and Drug Administration (FDA) issued a Warning Letter issued to ZHP on December 11, 2018 that outlined several manufacturing violations at ZHP’s Chuannan, China facility, including those relating to impurity control, change control, and cross contamination from one manufacturing process line to another. The agency is still looking into the root cause of the impurity.

In July 2018, the FDA and the European Medicines Agency (EMA) began their initial investigations into the “sartans” after the EMA learned that ZHP had detected N-nitrosodimethylamine (NDMA) and NDEA, two probable human carcinogens, in several batches of its valsartan API. The FDA’s investigation began when a manufacturer of valsartan products detected NDMA in its API supplied from ZHP, which followed with other companies recalling valsartan products, including Teva. The EU’s detection of the two impurities led to an EU-wide review of all valsartan medicines marketed in the EU. The review was subsequently extended to other “sartan” medicines when very low levels of NDEA were found in losartan made by Hetero Labs, a Hyderabad, India-headquartered API producer and part of the pharmaceutical parent company Hetero Drugs. In October 2018, the EMA updated that it was evaluating the APIs, candesartan, irbesartan, losartan, and olmesartan, marketed in the EU in addition to its investigation into valsartan products. After low levels of NDEA were found in irbesartan, supplied to a US pharmaceutical company by Aurobindo Pharma, the FDA expanded its investigation to include both valsartan and irbesartan. An investigation of losartan followed in November.

Source: US Food and Drug Administration