Module 3 - Strategic case studies in practice

Figure 2.2.2.5.2-1 Chemical structures of APIs reported in literature to contain NDMA [Parr et al. (2019)]. In 1978, the WHO Expert Group suggested the nitrosation assay procedure (NAP test) as a general in vitro test system under standard conditions (10 mmol/l drug, 40 mmol/l nitrite, 37ºC, pH 3-4, with reaction times 1-4h) to study the nitrosation ability of drug substances, [IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Some pharmaceutical Drugs, (1980)]. At that time, aminophenazone was found to show the highest relative N- nitrosation of selected APIs. The authors stated that “Since the endogenous formation of N-nitroso compounds from nitrosatable amine precursors and nitrosating agents, such as nitrite or nitrous gases, is not usually taken into account in carcinogenicity tests of the parent compound, additional investigations are necessary to evaluate this possible hazard.” In 2007, Brambilla et al. (2007) summarized the genotoxic and carcinogenic risk to humans caused by drug-nitrite interactions in a review article. By referring to the IARC conclusion from 1980 mentioned above, these authors stated that “ in spite of this recommendation, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of performing adequate tests in order to assess whether a nitrosatable drug may undergo endogenous nitrosation to a genotoxic NOC ” (i.e. N- nitroso compound). As outlined above, NDMA formation in aminophenazone has been linked to nitrosative degradation of the API in response to sodium nitrite carry over during drug substance synthesis [Eisenbrand et al. (1979)]. 2.2.3. Confirmed root-causes for the formation of N- nitrosamines in medicinal products with regard to excipients and as contaminants from primary packaging Nitrates and nitrites can be found in many excipients at parts per million levels. Sodium starch glycolate, croscarmellose sodium, pre-gelatinized starch, polyvinylpyrrolidone (PVP), cross polyvinylpyrrolidone (cPVP), and lactose are excipients that might carry trace levels of nitrate or nitrite

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