Based on EMA/409815/2020 Rev.21 for nitrosamine impurities “If quantitative testing is performed to justify omission of specification, the LOQ of the analytical method employed should be ≤ 10% of the acceptable limit based on the AI”. what are the exceptions for the above? there is a case, based on the supplier the LOQ is 10% of the acceptable limit of NDMA (NMT 0.096 ppm) and the results of 28 batches are below the LOQ. the supplier proceeded with skip testing as a control strategy, and it is mentioned in the CEP with the limit NMT 0.096 ppm.
why the test not omitted? and what could be the reason for mentioning the NDMA limit in the CEP? knowing that it is the only nitrosamine controlled in this API. and the MDD is considered 1000mg
Dear Heba,
according to the guidelines, the test should be omitted, you are right.
I think that they follow the ‘‘over safe’’ approach
regards
Christos
Dear Christos,
thank you, maybe from the supplier side they follow ‘‘over safe’’ approach, but from the EDQM/CEP side?
to be honest i cannot answer to your question,
thank you
Without any details is hard to say, but it may be the case that the results are below 10% at release, but the nitrosamine increases overtime? It may be that the nitrosamine content is above 10% during the API shelf-life
Did you look at the LOD of the method? I think that piece of data will give you peace of mind in relying on the ‘skip testing’ decision.
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Based on your earlier message, it was stated that “the supplier proceeded with skip testing as a control strategy.” Could you confirm if the supplier included skip testing as a control strategy in their CEP dossier before the CEP was granted?
Generally, EDQM does not take position on skip testing unless if specifically foreseen in guidelines e.g. ICH Q3D for elemental impurities, ICH M7 for mutagenic impurities and EMA/425645/2020 for nitrosamine impurities.
However, based on the results (less than 10% of AI) and suitable LOD/LOQ of the methods, test can be omitted.
dear Javier,
I also agree that this might be the case, but I trust that this is a grey area (if I may say), in the guidelines.
Actually guidelines recommend confirmatory testing to be conducted in newly produced batches but also retained samples of batches still within expiry date.
Additionally, it is supported that “If quantitative testing is performed as a routine control, the LoQ should be ≤ of the acceptable limit based on the relevant acceptable intake (AI) for the respective nitrosamine impurity”.
And finally it is recommended “MAHs should give consideration to the stability of the finished product and should ensure that the AI of any N-nitrosamine impurity is not exceeded until the end of shelf life of the FP”.
So although I clearly see your point on cautiousness, at the same time I realize that this is a bit grey in the available Guidelines.
I would highly appreciate your feedback.
BR
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