Dears,
we mostly receive nitrosmaine test results laying much below the theoretical calculated ones due to the very conservative approach to use maximum nitrite values from LHASA database. We are searching now for an alternative approach to use conversion factors, derived from literature such as from Moser et. al:
Has anybody used also suc an approach and how was the point of view from HA?
Many thanks for sharing your experience and opinion!
I have been using the conversion factor approach proposed by Moser et al. in my nitrosamine risk assessments. In practice, I apply the conversion percentages reported in Table 7 and select the worst-case conversion scenario that best matches the specific product characteristics, such as wet granulation versus direct compression, secondary versus tertiary amines, hydrochloride salts versus free bases, etc. The paper demonstrated that nitrosamine formation in solid dosage forms is significantly lower than the theoretical 100% conversion typically assumed in worst-case assessments, with a maximum observed conversion of approximately 38% under the most critical conditions
From my experience, this approach has been accepted by ANVISA in Brazil when supported by a sound scientific justification. I have successfully used both the conversion-factor approach from Moser et al. and more refined kinetic models as alternatives to the very conservative assumption of complete nitrite conversion.
However, I would highlight an important caveat. For some higher-risk APIs, ANVISA has not always accepted nitrite values derived solely from databases or even from IPEC supplier questionnaires. In several cases, the agency has requested either:
Analytical results for the specific nitrosamine of concern; or
Experimental nitrite data for each excipient used in the theoretical calculation.
Therefore, my experience is that theoretical calculations are generally accepted, including more realistic approaches based on conversion factors or kinetic models. However, this acceptance comes with important reservations, and for critical cases the agency may still require experimental data to support the assessment.
Overall, I have found the Moser conversion-factor approach to be a useful and scientifically justified refinement of the initial theoretical calculations, provided that it is applied conservatively and with appropriate product-specific justification.
Dear @tassiloh. Just to highlight, if you intend to leverage the publication by Moser et al., your scenario must be demonstrably more conservative than the one described in the paper. This means that key parameters should be equal to or more stringent than those reported in the publication, such as an equal or higher pKa of the susceptible amine, equal or lower levels of the vulnerable amine, equal or lower nitrite content per tablet, and comparable or less favorable conditions for nitrosamine formation. Otherwise, the comparison cannot be considered sufficiently conservative to support your case. Finally, but that is a risk to be evaluated, the matrix used in the publication would not be equal to yours, and the stability study was performed for 1 month, not the full shelf life of common pharmaceutical products. In any case, it could work but should this considerations be taken into account.
I completely agree with the previous comments.
I believe the best approach is to find a balance between these conversion factors which I also use (especially the one published by Moser et al.) and the experience observed in previous products with similar structures, excipients, and behavior.
Considering the high variability in nitrite content among batches of excipients from different suppliers and, even from the same supplier, the best approach would be to analyze the nitrites in all excipient batches. Another option to save time and resources would be to use theoretical values based on your previous analyses from your supplier, but in this case, it would be advisable to be somewhat more conservative (using slightly higher values) to avoid surprises arising from a batch with higher-than-expected nitrite levels and to repeat the analyses periodically.
These theoretical approaches are very useful for nitrosamines derived from impurities; however, based on experience, when the nitrosamine comes from the API itself, I would always recommend performing confirmatory analyses, as it is difficult to predict its behavior given that many factors may cause variability and there is a risk of exceeding the corresponding limit. Therefore, unless the product has a very high limit that is easy to justify theoretically, when the API forms the nitrosamine, it is best to perform confirmatory analyses.
Very well put, Diego, the agencies are hestitant to accept this kind of comparison, because, as you said, the bigger nitrosamines behave very differently from each other in different matrices. I have tried for clients with little success to use this justification and I understand why. When I was in the FDA, I would have possibly not accepted it as a standard argument.
