A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

“…Besides nitrosation side reactions encountered with vulnerable amine reagents used in API synthesis, N -nitrosamines can also be generated , from the reaction of vulnerable amine-containing (a) parent APIs (e.g., varenicline → N -nitrosovarenicline in Scheme C), (b) impurities present in the API and degradation product(s) of the API, (c) counterions (e.g., dimethylamine, diethanolamine salts of the parent API) and/or (d) excipient(s) with nitrite sources in synthetic reactions, nitrocellulose in blister packs as well as in excipients (e.g., cellulose, lactose, sodium starch glycolate, hydroxypropyl cellulose, etc.) present in formulations; − even trace nitrite in water has come under scrutiny …”

Letter to the editor of Heliyon re: determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation Heliyon. 2021; 77: e06179

“…Methodology flaws have been raised as possible root-causes for the high values provided, which may constitute analytical artifacts: Sample preparation: A significant number of syringe filters contain levels of nitrite and therefore could have led to overestimation of the nitrite levels reported during analysis. This was experienced and confirmed by several companies that donated data to the Nitrites in Excipients Database [ [1] , [5] ]. The manuscript highlights that the samples were sonicated until they were dissolved.…”

“…A significant number of syringe filters contain levels of nitrite and therefore could have led to overestimation of the nitrite levels reported during analysis. This was experienced and confirmed by several companies that donated data to the Nitrites in Excipients Database [ [1] , [5] ].…”

“…The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. As such, 678 data points on 79 excipients, from different lots, and suppliers have been collected in the Nitrites in Excipients Database [ [1] , [5] ].…”

Regulatory Highlights

“…In this case this is provided by traces of nitrite in common excipients. A recent publication looked at the extent of nitrites within common excipients, 10 This showed presence at sublow ppm level of nitrite was ubiquitous. While this may seem low levels, when talking about processes such as wet granulation where water is of course present, such levels are sufficient in many instances to form ppb levels of Nitrosamine of the active itself.…”