An FDA analysis addresses the risk of impurities from ARB for patients

A recent badysis of impurities in N-Nitrosodimethylamine (NDMA) has shown that the risk to patients appears to be low. The badysis, which was conducted by the FDA, was based on the maximum possible exposure.¹

The badysis followed a series of recalls of some generic versions of angiotensin II receptor antagonist drugs (ARAs) containing nitrosaminic impurities not meeting the FDA's safety standards. Used to treat high blood pressure and heart failure, the recalled ARBs include valsartan, irbesartan and losartan.¹

The impurities of nitrosamine, which include NDMA and N-Nitrosodiethylamine (NDEA), are probably carcinogenic to humans. These 2 substances are known environmental contaminants and are found in water and food, including meats, dairy products and vegetables. However, according to the FDA, the presence of NDMA and NDEA in drugs is not acceptable.¹

In a joint statement, Scott Gottlieb, MD of the FDA Commission, and Janet Woodbad, MD, director of the Center for Evaluation and Drug Research, said that the FDA's badysis results do not diminished neither the agency's concern nor its determination to discover occurred.¹

"We are committed to taking steps 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 pharmaceutical products or their components (including active pharmaceutical ingredients, or APIs), "said Gottlieb and Woodbad in their statement.¹

According to Gottlieb and Woodbad, although the FDA is continuing its research into the root causes of impurities, its investigative work has shown that these impurities can be generated when specific chemicals and reaction conditions are present in the manufacturing process. IPA. Impurities can also come from the reuse of materials, such as solvents.¹

The FDA first recognized a nitrosamine impurity problem in mid-2018 when it was informed that the IPA manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. a potential security problem.¹

The agency announced in December that a warning letter had been sent to ZHP. The letter described several manufacturing infractions at the company's Chuannan site, including control of changes, cross-contamination from one production line to another, and control of impurities. The FDA had previously put this facility on an import alert, which prevented any API products manufactured in that country and finished products manufactured using its API products to legally enter the United States. United.²

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

The FDA continues to collaborate with drug manufacturers containing ARB to recall products that pose risks to patients.¹

"Because of the way API is distributed in the supply chain, a source of contaminated API can affect multiple products," Gottlieb and Woodbad said in their prepared statement.¹

"As part of this ongoing process, last week we alerted patients and healthcare 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 subsidiary of Prinston Pharmaceutical Inc. The recall is due to unacceptable amounts of NDEA in irbesartan API manufactured by ZHP, "noted Gottlieb and Woodbad.

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

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References

1. Statement by FDA Commissioner Scott Gottlieb and Janet Woodbad, Director of the Center for Drug Evaluation and Research, on the FDA's ongoing investigation into the impurities of valsartan and ARB, and the actions taken by the agency to address root causes of security issues [news release]. Silver Spring, MD; January 25, 2019. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629796.htm. Accessed January 25, 2019.
2. The FDA warns the API maker involved in the recall of valsartan and provides information to 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.
3. Safety and availability of FDA drugs. FDA updates on recalls of angiotensin II receptor antagonists (ARAs), including valsartan, losartan, and irbesartan. FDA website. https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm. Updated January 23, 2019. Accessed January 25, 2019.