Calculation of limit when more than one nitrosamine is identified

Hello, I am struggling to understand the 2nd option for calculating the analytical limit when more than 1 NA are expected to be found in the finished product. The EMA assessment report of the CHMP’s article 5 (3) Assessment report states the following:

Exceptionally, the presence of more than one nitrosamine may be identified in a given finished product.
For such cases, the ad-hoc expert group suggested the following approach, i.e. to limit the sum of N-nitrosamines to the limit of the most potent one found. Feasibility of such a concept may depend on the capability of effective control.

The SWP advised on an alternative approach that, in case more than one N-nitrosamine is present in a medicinal product, the total risk should be considered. Limits for individual nitrosamines could in principle be acceptable as long as the total risk does not exceed the 10-5 tumour risk level. SWP
favoured setting a specific limit for each nitrosamine which represents a fraction of the acceptable
1:100,000 tumour risk level. The sum of all nitrosamine specific risk levels should not exceed a total risk level of 1 in 100,000. This also means that controlling the sum of all nitrosamines to the limit of the most potent one, as suggested by the ad-hoc expert group, will automatically keep the total
nitrosamine specific risk level to ≤1:100,000, and both options are therefore equally acceptable for CHMP

Can you please provide insights/clarification on how the calculation should be done in the alternate approach? Does that mean we can take the 30% limit for each NA instead of having the 30% of the most portent one / MDD?

thank you

@Rawaa If you take the 30% limit for NA 1st, you can take up to 70% limit for NA 2nd. If 50% for NA 1st, 50% for NA 2nd is available. The total risk level is considered as 1 in 100,000.

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@AmandaGuiraldelli @giorgio @timothy_curran Any feedback for @Rawaa ?

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EMA and FDA recommends to establish a limit based on the sum of all nitrosamines found. This sum should not exceed the acceptable limit of the most potent one (26.5ng/day).
:white_check_mark: Based on Risk Assessment, NMPA and NDEA were identified as potential Nitrosamines to be formed in Valsartan Tablets (MDD: 320mg/day).

:white_check_mark: After confirmatory testing, NMPA and NDEA were detected above LOQ

:white_check_mark: Specification could be: Sum of NMPA and NDEA can not exceed 26.5ng/day (0.083ppm)

:white_check_mark: Here it is necessary to work high higher sensitivity. Why? Because the acceptable limit (AL) for each of these nitrosamines in this case is lower than the AL if a single nitrosamine was present.

:white_check_mark: This implies the control of the level for these 2 nitrosamines at a lower level

@Rawaa does that address your question?

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Thank you Amanda, that is helpful and appreciated. This is a straight forward approach, as I am dealing with large volume products that have a very high MDD value, I was wondering if the option 2 stated in EMA guidance is accepted by FDA and how would you apply it?

Hi Amanda Thank You very much for the update.
I just have another doubt if there are three impurities suppose NDMA, NMPA & NDEA. Then how to proceed.
Because, NDMA have a limit of 96 ng/day ( 0.3 ppm). & NMPA & NDEA have a lit of 26.5 ng/day ( 0.083ppm).
So, in this case the sum of NDMA,NMPA & NDEA cannot be exceed 26.5ng/day (0.083 ppm).

Hi @sarada.prasad

Based on the existing guidances the sum of detected Nitrosaminas should not exceed 26.5ng/day (independently if the accep. intake for the single nitrosamines is higher than 26.5ng/day). I guess that if you have a scientific justification for establishing a different limit it may be worthy to discuss with the local regulatory anyway…

I guess that the guide issued by Anvisa might shed some light on that topic. It brings an example about how establishing limit for nitrosamines when more than 1 can be present (see the example in english attached)

Note.: the only valid and official guideline issued by Anvisa is the one in portuguese which can be found here:

Amanda Guiraldelli

Thank you very much for the response.

Also fda guidance currently not providing calculation for combination drug product. In case of combination drug product for calculating nitrosamine level in ppm Maximum daily dose of which drug need to be considered??