🇺🇸 FDA NDSRI Limits update -Mar 2024

Glad to share the update posted on FDA NDSRI Webpage (revision 4). The update is in following:

  • N-nitroso-varenicline is deleted from table 2 and added in table 1. Now the AI is 400 ng/day while previously it was 37 ng/day. Indeed a good news to industry.



Why is this limit revised? and in that case, we need to perform partial method validation for higher limit w.r.t analytical testing.

At first, the FDA decided the interim limit of varenicline as 185ng/day aside from 37ng/day. Then the interim limit was lifted because US manufacturers could adequately supply the market with varenicline at or below the acceptable intake limit of 37 ng per day. The 400ng/day is from CPCA and is the same as the limit by EMA. It looks more appropriate than read-across from NTHP(37ng/day).

The MDD of Chantix is 2mg. The range of test methods that the FDA recommended is 1-200 ppm. It covers 400ng/day.



N-nitroso-varenicline-FDA was already working on the acceptable limit for this NDSRI. Please see this link

FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix) | FDA where In July 2021, FDA announced it would not object to certain manufacturers distributing varenicline tablets containing N-nitroso-varenicline above FDA’s acceptable intake limit, but below the interim acceptable intake limit of 185 ng per day.

Now as a continuous effort, the AI 400 ng/day is published by FDA as per the CPCA category.

See FDA NDSRI Webpage: Updated Information | Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) | FDA

Regarding the method please follow the link (https://www.fda.gov/media/175552/download?attachment) wherein range of test methods that the FDA recommended is 1-200 ppm as shared by Yosukemino. It covers 400ng/day.

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FDA updated the Interim AI limit of N-nitroso-ciprofloxacin to 12,000 ng/day, @lucas10mauriz taught me. The AI of N-nitroso-ciprofloxacin is 1500 ng/day(CPCA Cat.4) simultaneously.