Monday, July 23, 2018

N-nitrosodimethylamine detected in generic valsartan

A tough situation if you're Teva (emphasis mine, via The New York Times): 
The Food and Drug Administration has announced a voluntary recall of a widely prescribed blood pressure medication made in China, reviving fears about the safety of imported drugs. 
Three companies that sell the generic drug, valsartan, in the United States agreed to recall it after the F.D.A. said it might be tainted by N-nitrosodimethylamine (NDMA), considered a probable human carcinogen. The agency is still investigating, but said the contamination was believed to be related to changes in the way that valsartan was manufactured. 
All of the valsartan that is being recalled was made in China by the same company, Zhejiang Huahai Pharmaceutical Co. Ltd. It is distributed in the United States by three companies: Major Pharmaceuticals; Teva Pharmaceutical Industries, Ltd.; and Solco Healthcare. Solco, which is owned by Huahai Pharmaceutical, had about 45 percent of the market in 2017, according to John Brito, of Fore Pharma, the market research firm.
How much do you want to be that Zhejiang Huahai has a change control with a Teva signature on it? (probably not.)  


  1. Real signature or forged e-signature?

  2. Not surprising, considering what's in those Warning Letters of the Week.

  3. That's the problem with generics - PGI control is probably not on the manufacturer's QC group's to-do list if all they care about is demonstrating bioequivalence.

  4. My guess is the valsartan contamination comes from the last two steps, and those have to involve use of nitrite + acid in the presence of a source of dimethylamine, such as DMF. My best guess is that the manufacturer chose the route that installs the aryl tetrazole moiety in the final step, and they balked at using sodium azide on large scale under reflux with ZnCl2, and opted for "safer" two step procedure of adding hydrazine to aryl nitrile, and treating the obtained amidhydrazone (=aminoamidine) with NaNO2+acid, to close the tetrazole ring. If there was any carryover of DMF traces into the final steps, this would produce dimethylnitrosamine.
    Dimethylnitrosamine is quite insidious, because it has a weak odor and it is a potent and cumulative hepatotoxin


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