66 TWENTYFOURSEVENBIOPHARMA Issue 1 / March 2026 DIPHARMA N-nitrosamines, commonly referred to as nitrosamines, are carcinogenic substances belonging to the broader family of N-nitroso compounds. Trace amounts of nitrosamines are present in everything from air and water to tobacco and cosmetics, and in sufficient quantities can have potent mutagenic and carcinogenic effects on any individuals exposed to them. While the existence of nitrosamines has been known for decades, scrutiny in the pharmaceutical industry dramatically increased in 2018 after the EMA discovered N-nitrosodimethylamine (NDMA) in valsartan, a commonly prescribed hypertensive drug. This event, along with the subsequent discovery of nitrosamines in various other drugs, led to a concerted effort from the global pharmaceutical industry to understand how and why these potent carcinogens were ending up in drug products. While the scientific community now has a much more comprehensive understanding of how and why nitrosamines end up in pharmaceuticals, nitrosamine-related recalls nonetheless continue occurring. To unpack this problem and the proactive approaches needed to comprehensively address it, 24/7 BIOPHARMA spoke with Dr. Roberto Fanelli, Catalogue APIs Business Unit Leader at Dipharma, a global CDMO and API manufacturer. A brief history of regulatory guidance for nitrosamines Core to an understanding of nitrosamines is understanding the differences between the two structural classes of nitrosamines: small-molecule nitrosamine impurities and nitrosamine drug substance-related impurities (NDSRIs). Smallmolecule impurities do not share structural similarity to the API, but NDSRIs do and, as such, are generally unique to each API. According to Dr. Fanelli, the emergence of NDSRIs highlighted that many APIs containing amine functionalities may form nitrosamines under specific conditions, prompting broader concern that a substantial share of marketed drugs could require risk evaluation. In light of the potential extent of the nitrosamine problem, regulators moved quickly to establish core expectations for
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