FDA Analysis Addresses ARB Impurity Risk to Patients

A recent analysis of N-Nitrosodimethylamine (NDMA) impurities has found the risk to patients appears to be small. The analysis, which was conducted by the FDA, was based on the maximum possible exposure.¹

The analysis followed a series of recalls for some generic versions of angiotensin II receptor blocker (ARB) medicines containing nitrosamine impurities that do not meet the FDA's safety standards. Used to treat high blood pressure and heart failure, the recalled ARBs include valsartan, irbesartan, and losartan.¹

The nitrosamine impurities, which includes NDMA and N-Nitrosodiethylamine (NDEA), are probable human carcinogens. These 2 substances are known environmental contaminants and found in water and foods, including meats, dairy products and vegetables. However, according to the FDA, the presence of NDMA and NDEA in drug products is not acceptable.¹

In a joint statement, FDA Commission Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, said the finding of the FDA’s analysis does not diminish the agency’s concern nor its determination to find out how the impurities occurred.¹

“We’re committed to implementing measures to prevent these impurities from occurring in the manufacturing process in the future. Our ultimate goal is to ensure that these impurities are not present in finished drug products, or their components (including active pharmaceutical ingredients, or API),” said Gottlieb and Woodcock, in their prepared statement.¹

According to Gottlieb and Woodcock, while the FDA is continuing to investigate the root causes of the impurities, its investigative efforts have determined that these impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API. The impurities may also result from the reuse of materials, such as solvents.¹

The FDA first recognized an issue with nitrosamine impurities in mid-2018 when the agency was informed that API manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. (ZHP), in Linhai, Taizhou Zhejiang China for some generic valsartan-containing medicines contained NDMA, posing a potential safety concern.¹

The agency announced in December that a warning letter had been sent to ZHP. The letter outlined several manufacturing violations at the company’s Chuannan facility, including change control, cross contamination from 1 manufacturing process line to another, and impurity control. The FDA had previously put this facility on import alert, which stopped all API made there and finished drug products made using its API from legally entering the United States.²

Hetero Labs has also been identified by the FDA as a manufacturer of API containing an unacceptable level of valsartan. Hetero uses a manufacturing process similar to ZHP.³

The FDA is continuing to work with manufacturers of ARB medicines to recall products that pose risks to patients.¹

“Because of the way API is distributed in the supply chain, 1 source of contaminated API can impact multiple products,” said Gottlieb and Woodcock, in their prepared statement.¹

“As part of this continuing process, last week, we alerted patients and health care professionals to a voluntary recall of 1 lot of irbesartan and 7 lots of irbesartan and hydrochlorothiazide combination tablets distributed by Solco Healthcare LLC, a Prinston Pharmaceutical Inc. subsidiary. The recall is due to unacceptable amounts of NDEA in the irbesartan API manufactured by ZHP,” Gottlieb and Woodcock noted.

Since July 2018, a variety of products containing valsartan, irbesartan and losartan products have been recalled, due to nitrosamine impurities. These recalls have involved multiple pharmaceutical companies, including Teva, Aurobindo, Mylan, Camber, Prinston, ScieGen, Sandoz and Torrent.³

RELATED

• Six Additional Lots of Losartan Tablets Recalled
• Aurobindo Recalls 80 Lots of Valsartan Tablets
• FDA Announces Recall of Some Lots of Blood Pressure Medications

References

• Statement from FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research on the FDA’s ongoing investigation into valsartan and ARB class impurities and the agency’s steps to address the root causes of the safety issues [news release]. Silver Spring, MD; January 25, 2019. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629796.htm. Accessed January 25, 2019.
• FDA warns API manufacturer involved in valsartan recall, provides information for patients taking these medications [news release]. Silver Spring, MD; December 11, 2018: FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628189.htm. Accessed January 25, 2019.
• FDA Drug Safety and Availability. FDA updates on angiotensin II receptor blocker (ARB) recalls including valsartan, losartan and irbesartan. FDA website. https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm. Updated January 23, 2019. Accessed January 25, 2019.