Hello everyone, when conducting a nitrosamine risk assessment, is the risk of nitrosamines produced by the reaction between amides and nitrites considered? How is the control limit for nitrosamines generated by the reaction between amides and nitrites established?
These impurities are classified as N-nitroso-structures, which are different from normal N-nitrosamines. EMA has established some AI values for these impurities. For a specified one, case by case evaluation is neceesary.
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If there are no reference compounds for nitrosamide compounds, is there a unified control limit, or can TTC 1.5 micrograms be used?
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N‑nitroso structures are classified as the ‘cohort of concern’ in ICH M7, so the standard TTC cannot be applied. If the EAT assay for the impurity is negative, a limit of 1.5 µg/day may be acceptable.
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If there are no reference compounds available, is it necessary to conduct an Ames test? Can QSAR assessment be used to confirm whether the result is negative? If the result is negative, can it be controlled according to the TTC? If the result is positive, can it be controlled according to the minimum acceptable intake of nitrosamines, which is 18 ng/day?
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If the total nitrosamine level is below 26.5 ng/day (EMA: 18 ng/day), no additional safety data are required—this level is considered acceptable regardless of impurity classification. However, given the negative QSAR result for this compound, it remains unclear whether the authority will accept the TTC approach. Therefore, if the analytical method is sufficiently sensitive to detect the impurity at a very low level and the impurity is confirmed to be absent, an Ames test is not required.
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first of all you should clarify if the nitrosamide you are considering as a risky compound is feasible to be synthesized. If not, all of the above discussion has no meaning.
So, first of all secure that you have a solid and valid reference standard of this nitrosamide and them proceed with any other action.
Till now, we have never been asked about any nitrosamide neither from EU athorites neither from a client.
thanks
Christos
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As per my openion no CPCA rules will be applicable for such compound so better to do AMES test back up study for further submission purpose.