FDA currently published "Updates on possible mitigation strategies to reduce the risk of nitrosamine..."

It is a very forward-looking post and has addressed some of the topics discussed in GDUFA Complex Generic Meeting by the generic industry. It talks about controlling the nitrosamines based on process and product understnading and prevention. While prevention is the better than cure in my opinion, there may be some challenges with controlling nitrosamines at the FDA proposed levels based on process control and reformulation with nitrite scavengers. Many efficient nitrite scavengers are not in IID. So, the question remains as to how FDA will treat them. If a battery of non-clinical testing is needed to qualify these scavengers, the purpose of doing the reformulation may be lost. Also, without control for nitrite/nitrate in every excipient, ruling out the possibility of formation of NDSRI is impossible. As pharma is possibly only 10% of the market for excipients. Will the manufacturers be ready to do this? How will it impact the price of drugs if say the price of MCC triples based on the additional controls needed for nitrites? Just by looking just at drugs with USP monographs, about 35-40% of drugs approved will have the possibility of forming NDSRIs. So, we should also understand how best to test these impurities to find out the actual levels of Acceptable Intake, maybe look at Ames test, transgenic animal assays, and available literature for read-across. The limit of 26.5 ng/day for multiple nitrosamines is leading to “ppt” levels in some cases. We don’t have analytical methods to detect these impractical levels if present. Lots of food for thought, for industry and Agencies. DR. LOEPPKY, I MISS YOU.

FDA Post: Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products | FDA

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I found articles introducing it.


Was information was based on a public comment in FDA’s GDUFA Complex Generic workshop in June 2021, way before the article was published. Please see this presentation. I was the presentator on prevention of ntirosation. Additionally the SVPs from Apotex and TEva discussed this. FDA took the gist of the presentations and put it in the website.

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