More metformin recalled for NDMA; 6 firms now affected

Regulatory NewsRegulatory News | 08 July 2020 |  By 

Two manufacturers have announced voluntary recalls of metformin formulations containing elevated levels of a potential carcinogen.
Granules Pharmaceuticals, based in Virginia, has issued a recall for its extended-release metformin, although just one of 12 batches tested exceeded acceptable levels of N-nitrosodimethylamine (NDMA) in the firm’s testing. The recall includes 100- and 500-count bottles of 750 mg metformin tablets.
Separately, India-based Lupin Pharmaceuticals recalled all US batches of both 500 mg and 1,000 mg versions of extended-release metformin. The product was available in 60-, 90-, and 100-count bottles.
The new recalls come after an earlier round of voluntary extended-release metformin recalls involving five pharmaceutical companies, one of which was Lupin, which had just one lot recalled at the time. (RELATED: FDA names five companies recalling NDMA-contaminated metformin, Regulatory Focus 12 June 2020)
The potential carcinogen in question, NDMA, is ingested in very small quantities in the diet but cancer risk may occur with long-term exposure to greater quantities. No immediate-release metformin has yet been found to contain elevated NDMA levels, but the histamine-2 receptor blocker ranitidine and angiotensin II receptor blockers (ARBs) have also been found to have elevated NDMA levels. (RELATED: FDA clarifies impurity risks from ARB recalls, Regulatory Focus 29 August 2019).
The question of NDMA contamination in metformin had been clouded because of earlier discrepancies between FDA testing and testing reported by a private laboratory, which had filed a Citizen Petition reporting elevated NDMA levels in 16 of 38 metformin products tested. However, FDA testing had only yielded elevated NDMA levels in 8 products from the same batch using orthogonal methods, and FDA tests had “generally observed lower values than reported by the private testing laboratory,” according to a recent paper authored by FDA staff.
After investigation, the cause of the discrepancy was the presence of another chemical, N,N-dimethylformamide (DMF), that interfered with NDMA mass spectrometry measurements. “Overall, care should be taken to assure the necessary specificity in analytical procedures for adequate assessment of the nitrosamine level in drug products that also contain DMF or other potential interfering substances,” wrote first author Jingyue Yang, PhD, and her coauthors, writing in the AAPS Journal.
Yang, a staff fellow at FDA, and her coauthors called the investigation’s findings a “cautionary tale” that highlights the importance of having measurement resolution that can reach to the parts-per-billion level in analyzing small molecules such as nitrosamines.


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