Now updated APIC nitrosamine risk assessment template is available. The questionnaire is almost the same as Q4 of EMA/409815/2020 rev12 and CMDh/439/2022. It’s very practical. And the vulnerability or non-vulnerability of amine, hydrazine, hydrazide or hydrazone function can be written in the amine space.
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I worry about the oversimplification of all these checklists (yes/no). We in the community know that risk assessment goes WAY beyond a simple yes/no answer. While I agree they are great tools for discovery and a preliminary assessment, they cannot become the sole risk assessment document.
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Thank you for your good comments, @Naiffer_Host. I agree with you. I think justification is the most important in this kind of document. We used a similar questionnaire as a cover page and added other documents with the synthesis scheme and the information on used reagents to report details.
I think the most advantageous point of the questionnaire is that reviewers can understand the outline of the assessment at a glance. And if reviewers want to know details, they can read the additional reports. The questionnaire itself is not a perfect one for a risk assessment report.
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This is a great help for those looking for a starting point. Thanks for sharing
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On the topic of oversimplification in checklists:
The original yes/no from CMDh/439/2022 checklist is linked to the question “has this been evaluated?”, as a checklist to confirm that potential risk factors have been assessed. This is the template that is used in Europe to confirm to regulators that the risk evaluation has been performed based on the current scientific knowledge and the latest version of the Q&A, it does not replace the actual risk assessment.
It is indeed not appropriate to simplify the risk assessment itself in a yes/no checklist based on CMDh/439/2022. If the structure is used, it should be with an open text for evaluation and risk classification conclusion. CMDh/439/2022 inspires how to structure and template a risk assessment but it does not replace it. So I hope the focus of using the APIC template is mainly the “justification” boxes (but putting that in a box instead of a full document can already limit information transfer?) and that the recommendation from APIC to add detailed process information is applied, otherwise this doesn’t serve improvement of API risk assessment quality.
I have also concerns on the redefinition of vulnerable in some parts but not all of the document: it seems this is not always defined as theoretically vulnerable for nitrosation towards a stable nitrosamine (which is how guidance defines it I believe), but vulnerable in the sense of the metabolisation risks of the formed nitrosamine. A diphenylamine would not be considered a vulnerable amine, nonetheless its nitrosated form would be in scope of the call for review still and thus applicants would expect risk assessment. While this could involve mechanistic regards, it should not be simplified to not vulnerable no risk.
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Thank you for your comment, @ccdw. The checklist can be used for root cause analysis. If the root cause is found, further justification will be required. So I think it works as a communication tool between the manufacturer and MAH.
And I agree with you that the redefinition of vulnerable amine is misleading.
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