Residual amines and risk assessment - how far do you go?

In the context of risk assessment for medicinal products, I find the topic of residual amines to be the most tricky one to handle. From a pure DS synthetic process, impurity profile (by- and degradation products + residual solvents), and DP manufacturing process we can indeed identify the main sources for amines that have the potential to react to form nitrosamines however to what extend do you consider these? The IPEC questionnaire for excipient Nitrosamine Risk Assessment considers the potential presence of secondary or tertiary amines but no indication on how deep this should be investigated is given. The EfPIA has recently issued a presentation where it is highlighted that experimental data from model studies suggests that amine impurities at ICH Q3A/B identification limits are not considered a risk for nitrosation with trace nitrite. What is your view on this? are you aware of addition efforts going in this direction?

It seems that generic residual amines methods are now becoming popular, is this something that you consider as relevant?



@Julien lot of good questions in there. Recently @ASrinivasan presented at FDA workshop similar proposal related to Nitrite content on Excipients. I believe we all agree that defaulting to testing on the content of nitrires/secondary amines without a full understanding of risk and impact is not the solution. @jakob.bonde @cfisher @hwood @nitrodude21 @schwemg your thought?

@Julien It’s good information. I’m not sure the EfPIA’s presentation and if it is clarified, it will be very helpful. As you may know, this paper may also be helpful. According to this, the amounts of nitrite, the amounts of amine, pKa of amine, pH, temperature are concerned with the nitrosamine formation. Of course, the limit of nitrosamine is also important.

In my opinion, to control or clarify the amounts of nitrite with purge factor may also be a key issue because there is less opportunity for nitrite to be installed in manufacturing processes. Anyway I perfectly agree with focusing on the reactivity of nitrite with amines to assess the risk of nitrosamine contamination. Does anyone have any remarks?

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