From risk assessment to control: Integrated nitrosamine management in APIs
Juliette Martin of Seqens looks at the challenges brought by a major class of impurities
Nnitrosamine impurities have emerged as a major global regulatory concern because of their severe toxicological profile and their widespread occurrence across pharmaceutical products. These compounds can contaminate APIs and finished drug products, posing significant risks due to their carcinogenic, mutagenic and toxic properties. 1 They also occur in food, water, air pollution, tobacco smoke and consumer products.
Several major drug recalls, beginning with valsartan in 2018 and followed by losartan, irbesartan, metformin, ranitidine and varenicline, after nitrosamine contamination was detected. In response, regulators have implemented structured, lifecyclebased risk management approaches, supported by updated guidance, analytical controls and new scientific tools to prevent and control nitrosamine impurities across pharmaceutical development and manufacture.
Sources of nitrosamines
Nitrosamines are nitroso compounds characterised by an N – N = O functional group that is formed through nitrosation reactions between amines and nitrosating agents under specific conditions of pH, temperature and reagent availability. Their formation requires nitrosable nitrogen-containing substrates, such as secondary and tertiary amines, and nitrosating agents, including nitrites or nitrous acid.
Such conditions can arise unintentionally during synthesis steps, wet processing or even product storage, due to heat, humidity or oxygen exposure. These precursors
Figure 1- Risk factors for presence of simple & NDSRI compounds
Dea / kylat / ve mechanism:
Figure 2- Mechanistic pathway with tertiary amines
may be present at trace levels and can originate from raw materials, solvents, water, excipients, degradation products or environmental sources, making nitrosamine risk pervasive across the entire drug lifecycle.
Much of the chemistry of nitrosamines has only been studied in solution. However, they can also form later, during the production of finished products or during storage. These reactions may occur either in the solid state or at interfaces between solids and liquids, such as surfaces.
Impurities commonly found in excipients, such as nitrites, peroxides and formaldehyde, can contribute individually or together to nitrosamine formation during formulation and storage. Additionally, during packaging
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, ________, operations, gaseous nitrosating agents may form and react with amines, further promoting the formation of nitrosamines.
Figure 1 shows the mechanistic pathway with tertiary amines. Nitrosamine carcinogenicity is linked to metabolic α-hydroxylation, which generates a DNA-reactive diazonium species.
Nitrosamines lacking α-hydrogen atoms cannot undergo this activation and are generally not considered part of the ICH M7 Cohort of Concern( CoC). Likewise, a tertiary amine can only form a potentially potent nitrosamine if it possesses at least two α-carbon atoms bearing C – H bonds, enabling both dealkylation to a secondary amine and subsequent metabolic activation( Figure 2). 2
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