Module 3 - Strategic case studies in practice

2.2.4. Discussion on root causes and strategies to mitigate the presence of N- nitrosamines in human medicinal products NDMA and other N- nitrosamines from water are unlikely to represent a realistic source for contamination of APIs.. In summary, NDMA and other N-nitrosamines from water are unlikely to represent a realistic source for contamination of APIs. However, drug substance degradation processes caused by the use of disinfected water cannot be excluded as a contributing factor. So far, neither N-nitrosamines from water nor N-nitrosamines from API degradation processes linked with impurities in water have been identified as contributing factors. In addition, secondary/tertiary alkylamines and quaternary alkyl ammonium salts were found to be contaminated with N- nitrosamines, having detected levels in the low ppm range. The relevance of these results, discovered 40 years ago in secondary and tertiary amines of unknown quality, is currently considered unknown. The ICH Q3C (R7) solvent dimethylacetamide represents –in addition to DMF and NMP- an additional source of secondary amines susceptible to NDMA formation in combination with nitrosating agents. The ICH Q3C (R7) solvent nitromethane cannot be excluded to act as nitrosating agent in combination with certain oxidants/catalyst and to form N- nitrosamines in combination with secondary and tertiary amines. N- nitrosamine impurities e.g. in sartans could be linked directly to the simultaneous presence of the reagent NaNO 2 and of solvents, reagents and catalysts as sources of secondary and tertiary amines. These compound combinations are considered critical and present a high risk of N- nitrosamine formation and should be avoided or strictly monitored if it is justified adequately to be unavoidable in the entire API manufacturing processes. In addition, the potential formation of Cohort of Concern Compounds (CoC compounds) such as N- nitrosamines should be evaluated by the MAHs/Applicants during manufacturing process development. MAHs/Applicants are reminded that all materials used in the manufacturing process should be included in the dossier, irrespective of their intended use. From the pioglitazone case, it was concluded that NDMA formation / contamination of this API manufactured in line with good manufacturing practice is considered principally avoidable by eliminating DMF as nitrosatable solvent from synthetic route I and by replacing it with a non- nitrosatable solvent as part of a variation procedure. In addition, selecting synthetic route II for production of pioglitazone HCl under good manufacturing practice offers the possibility to exclude N- nitrosamine formation in general. The option, to choose between two different manufacturing processes, demonstrates the need for thorough justification of the entire synthetic route during manufacturing process development. Also, the aminophenazone case showed that the option to choose between two different manufacturing processes, demonstrates the need for thorough justification of the entire synthetic route during manufacturing process development. According to Brambilla et al. (2007), 173 APIs have been found to form N-nitroso compounds such as N- nitrosamines upon reaction with nitrite under in vitro conditions. Therefore, it is recommended that the WHO NAP test be conducted on starting materials, intermediates and APIs during manufacturing process development. In case of positive findings, further investigations such as AMES testing etc. may be required in accordance with the ICH M7 Guideline. In view of finished product manufacturing, it is concluded that N- nitrosamine formation in and contamination of finished products during primary packaging, performed in line with good

EMA/369136/2020

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