FDA Acceptable intake limit for multiple nitrosamines in one drug product -Calculation

Limits of Nitrosamines
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I am posting this question on behalf of a community member:

About APPENDIX C: EXAMPLE OF CONTROL AND SPECIFICATION FOR THE RECOMMENDED ACCEPTABLE INTAKE LIMIT FOR MULTIPLE NITROSAMINES IN ONE DRUG PRODUCT from FDA recent update.

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“We have questions regarding the calculations in Table C of the new nitrosamine impurity guidance released by the FDA on September 4, 2024. If a risk assessment has already demonstrated that a particular nitrosamine impurity is of low risk and confirmed that the detected amount of this impurity, both initially and during stability testing, is less than 10% of the AI limit, can it be disregarded in the calculation of the total nitrosamine amount as per the formula in the table below?”

Similar to question above, if we have 2 or 3 nitrosamines in one product, does the 10% principle apply for every nitrosamine or 10% is for the sum of all the nitrosamines?

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dear Naiffer,
in the Europe, the guideline is clear
EMA/409815/2020 Rev.21
In Q10 (Which limits apply for nitrosamines in medicinal products?) it is written:
‘‘It is considered that the presence of one or more N-nitrosamines at <10% of their respective AI constitutes a negligible toxicological risk, and as such, they do not need to be specified. N-Nitrosamines present below 10% of their respective AI do not need to be factored into the calculation of limits for individual or total N-nitrosamine(s).’’
So, the 10% of the AI limit is applied for every nitrosamine.
This means that if you have for example two nitrosamines and the one is constantly <10% of the limit, then in the ‘‘total nitrosamine’’ you present only the one of them.
thank you
Christos

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