I would agree with Giovanni, the reactivity is the key in this case. If there is not very strong justification to prove significantly higher reactivity of the API, then you should consider also the risk of the impurity
thanks!!
Hello everyone.
Considering a scenario in which we have an API classified as a secondary amine (CPCA class 4), and the manufacturer reports the presence of two synthetic impurities that are also secondary amines — one class 1 and the other class 3. Would you consider it justifiable to perform testing only for nitroso-API? Or would you prioritize confirmatory testing only for the class 1 impurity? Or would you conduct confirmatory testing covering all three potential risks?
Do you believe it would be possible to justify carrying out only one assessment?
For example: evaluating only nitroso-API, due to its higher quantity, or only nitroso-impurity, as it is more prone to nitrosation?
Thank you in advance.
Based on the information provided, it would be required to test for the three nitrosamines. Due to the ratio of AIs of nitroso-imp class I, class III and nitroso-API class IV = 18/400/1500, the nitroso-imps cannot be neglected, even if the ratio of the quantities are considered 0.1/0.1/100. A well documented risk assessment should answer the question in more details, however. Nitrosamines may be generated in the API and drug product. The impurities may be process and degradation products at the same time.
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Hi Mariana,
Mariana, if I am not mistaken, you refer to DP assessment.
Are these amine-impurities (precursors) controlled in the final API specifications?
I can see the conservative approach described by Mircea. Based on previous experience with authorities, I have seen that some request such data.
However, if the risk is well ruled out in the API, and none of these amine-impurities are API degradants, then the risk of carry over of these amine-impurities in the DP is minimal.
In any case, if you consider to control all these potential nitrosamines in the final DP, and even if you find levels at <LOQ (10% acceptable intake), you may monitor the behavior during shelf life as well.
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Dear Mariana,
for sure confirmatory test for the nitrosamine of the API should be performed.
Regarding the other impurities, you can proceed with a theoritical calculation of the quantities of the nitrosamine of the impurities using the below tools
- calculation of total nitrite content (using the very useful tool of DFE pharma)
Entry the maximum nitrite levels for any excipient.
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paper of Moser (Moser J et all, J Pharm Sci. 2023;112(5):1255-1267), where is noticed that the conversion of impurities to nitrosamines is <10%
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The abundant of the API vs impurities, in a molar ratio. This one we use only if the impurities are API-structure related.
If the outcome of the theoritical calculation is a quantity of impurity nitrosamine <10% of its acceptance intake then we claim that no confirmatory test is needed. We have tried twice and in both cases has been accepted from the european authorities.
best regards
Christos
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