Nitrosamines alert: Potential for endogenous formation of NDSRIs (nitrosamine drug substance-related impurities)

Recently, FDA is pushing to investigate the presence of certain types of nitrosamine impurities – formed in several drug products. These nitrosamine drug substance-related impurities (NDSRIs) are a class of nitrosamines sharing structural similarity to the API that can be generated during manufacturing or during the shelf-life storage period of the drug product, and, in some cases, by the nitrite impurities present in excipients in ppm amounts. Furthermore, it is well-known that nitroso compounds can be formed by reaction of ingested secondary and tertiary amines and nitrite in the gastro-intestinal tract.

So, the formation of endogenous nitrosamines is an area where more information could be required by the Competent Authorities in the future, pushing MAHs to explore different approaches to mitigate or prevent formation of NDSRIs. Examples of possible mitigation strategies related to formulation design are described below:

• assess the risk of NDSRIs forming in the gastrointestinal tract;
• importance of carrying out studies (e.g. stress tests, in vitro tests) to check the potential formation of endogenous NDSRIs;
• focus on risk factors as use of less basic amines usage, elevated processing temperatures, low pH conditions in combination with high nitrite levels.

How Mérieux NutriSciences pharma division can fast investigate the presence of NDSRIs in your products?

Thanks to the long-standing experience of different labs in Mérieux NutriSciences, our scientists have been developing various strategies and approaches for the nitrosamines detection in order to investigate the potential endogenous formation of NDSRIs in drugs according to FDA requests:

• Stress tests of drug products
• NAP test
• Gastro-intestinal digestion simulation with in vitro models mimicking in vivo condition (link a brochure)
• Nitrite determination
• development and validation of high sensitivity method for the determination of NDSRIs, as for example:

4-Nitroso Hydrochlorothiazide
N-Nitroso Ambroxol
N-Nitroso Benazepril
N-Nitroso Betahistin
N-Nitroso Clonidine
N-Nitroso Dorzolamide
N-Nitroso Duloxetin
N-Nitroso Naphazoline
N-Nitroso Nevibolol
N-Nitroso Phenylephrine
N-Nitroso Pramipexole
N-Nitroso Propranolol
N-Nitroso Rasagiline
N-Nitroso Tamsulosin
N-Nitroso Desmethyl Tripelennamine
N-Nitroso Varenicline N-Nitroso Zolmitriptan