The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

Drawing a Line: Where Might the Cohort of Concern End?

“…In the context of pharmaceutical drug products, it is not currently expected that aflatoxin-like or alkyl azoxy compounds will be present as impurities, and thus, they should not make a significant contribution to regulatory assessments. Instead, given the recent issues regarding the identification of nitrosamines in drug products, − it is relevant to consider the assessment of N -nitroso compounds in the context of carcinogenic potency. The following sections will discuss the carcinogenic potency of N -nitroso compounds, highlighting specific subclasses that may be considered outside the CoC due to lower or negligible carcinogenic potency.…”

“…Furthermore, the electron-withdrawing nature of the oxygen (or equivalent atom) decreases the potential reactivity of the nitrogen toward nitrosation, meaning that the formation of these is less likely than for other vulnerable amines. 14 ■ IMPLICATIONS FOR TOXICITY TESTING Those compounds that require metabolic activation, such as the dialkyl N-nitrosamines, are currently a particular challenge for the elucidation of safe limits since the reliability of the bacterial reverse mutation assay (Ames test) has been challenged for nitrosamines. In particular, there is some doubt, based primarily on older papers 58 that do not follow the current OECD guidance, 56,57 that the sensitivity may not be adequate, especially in relation to the metabolic activation (whether due to the species from which the rodent liver S9 is sourced or the choice of solvent, as DMSO may interfere with CYP 2E1-mediated metabolism 73 ).…”

“…Up to 40% of all marketed drugs contain the potential to form a nitrosamine, 14 most commonly via acid-catalyzed reaction of nitrite impurity with a free secondary or activated tertiary amine, 84 and there is no practical bioisosteric replacement for the secondary amine functionality. As a result, the avoidance of amines in the API�even before other sources, such as solvents, bases, and excipients are considered�is impractical.…”

Regulatory Highlights

“…You may reflect and then askso how big is a scale of the problem? A recent article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities. This has looked to identify nitrosatable structures, assessing their potential to form nitrosamines.…”

Quantum-Mechanical Approach to Predicting the Carcinogenic Potency of N-Nitroso Impurities in Pharmaceuticals

“…The potential hazard posed by N -nitrosamines and other N -nitroso compounds (NOCs) has long been recognized by the scientific community, notably in 2018, when NDMA ( N -nitrosodimethylamine), a potent carcinogen in rodents, was found in Valsartan. , Subsequently, these compounds have been detected at low levels in other pharmaceuticals, where a reaction of a secondary or tertiary amine with a nitrosating agent (e.g., sodium nitrite) generates these compounds during the manufacturing of an active pharmaceutical ingredient (API) . Currently, US and EU regulations require N -nitrosamine risk assessments to be carried out on all commercial medical products by deriving acceptable intake (AI) limits from rodent TD 50 values, where TD 50 refers to the median toxic dose of a substance at which toxicity occurs in 50% of a species.…”