Hello everyone,
I would like to ask that in case of potential drugs, MDD is very low and NDSRI limit (in case of higher AI i.e. 1500ng/day) is very high while any other impurity limit 0.10%. What should be the appropriate limit the NDSRI for method development.
For example: MDD of Arformoterol Inhalation solution is 0.03mg/day, based on it limit will be 50000ppm whereas any other impurity limit for product is 0.10% (1000ppm). In this case, NDSRI limit is justifiable or not. Need expert opinion on this.
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For the other impurities: when an ICH Q3A/B identification threshold is used also as specification, this is because it is possible (levels low) and no other data can be/was used to justify higher limits. So the 0.10% is an application of the ALARP principle, cf. decision tree in ICH Q3A/B guidance.
For analytical method development of nitrosamines development around a LOQ of 1000-5000 ppm should be reasonable, ideally 1000 ppm probably to protect against regulatory evolutions. Absence of detection >5000 ppm should confirm no risk. It can be worthwile reviewing the risk that the true AI is lower than the CPCA AI (based on structure and analogue/compound data if any) and the influence of the exposure route (inhalation) on the mutagenicity risk assessment and take that into account for method development.
Complexity for nitrosamine-guidance based limit higher than standard ICH Q3A/B limit (point of departure limit) would start if the specific impurity goes to “NMI” later on:
See also:
Limit for NDSRI - Limits of Nitrosamines - Nitrosamines Exchange (usp.org)
Then you might again need the rationale that the nitrosamine-guidance based limit and later NMI was based on compound specific consideration and specific safety science, thus allowing overruling of the ICH Q3A/B thresholds if needed (though ICH Q3A/B still offers exclusion from the call for review under NMI in some territories, regulatory review/discussions might not be ending if the (registered) limit was higher though regulatory revision should in principle not be needed). (Idea that NMI status continues to support at least 1500 ng/day - high MDD as part of justification.)
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