“We have completed the risk assessment according to EFPIA guidelines, but the FDA still requires us to develop and validate analytical methodologies. How can we resolve this situation?”
Dear Yixuan Zhou,
Synthesis of N-nitroso-Amlodipine is not possible. Synthesis failure report may required to submit FDA. You may refer below justification mentioned in EMA guideline,
EMA has clarify that, despite extensive efforts, it becomes apparent that the
relevant nitrosamine impurity cannot be synthesized, then this could be an indication
that the nitrosamine either does not exist or that there is no risk of it being formed. In
such cases, it may not be necessary to conduct corifirmatory testing. This should be
justified thoroughly on a case by case basis according to appropriate scientific
principles. The justification could include relevant literature, information on
structural/stereo-electronic features and reactivity of the parent amine, stability of the
nitrosamine and experimental data to illustrate the efforts made to synthesize and to
analyse the impurity."
Thanks and Regards,
Yuvraj
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Refer above link for more details
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is this question recently? if it is, then this is very disappointing fact from FDA.
As Yuvraj said, the non-possible formation of N-nitroso amlodipine have been proved years ago.
Did you share with them justification letters from impurity vendors for this nitrosamine?
If not, then it could be a solution to your case and maybe the assessor accept this.
It is better to have at least two justification letters.
best regards
Christos
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