Common nitrosamine impurity limit calculation when it is contributing from both API as well as excipients

When common nitrosamine like NDMA, NDEA, etc… in Finish product are contributing from API and excipients both, then in this case how to set the limit? In this case do we still need to calculate based on the maximum daily dose of API only??
Do we need to calculate limit based on maximum total weight of formulation consumed daily?
What should be the calculation formula for calculating nitrosamine impurity in finish product in both the above cases?

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Just to confirm, when you say Nitrosamines from API and excipients that means for example:

Two different Nitrosamines, NDMA for API & “Nitroso-excipient” from excipient? In that case, the limit in ppm I think could will be still limited by the API as lets say MDD of the DP is 3 tablets, that would mean 3 times the excipient quantity as MDD of the “Nitroso-excipient” so AI (ng/day)/ MDD of “Nitroso-excipient”.

Or you mean same NDMA coming from both the API and excipient? In that case I would continue to take the API as the MDD.

I can be mistaken, but times ago, I asked myself the same question with azo-colorants for example as excipient.

@Diego_HM : I am talking about the same NDMA coming from both the API and excipient, in this case whatever the results of NDEA obtained in finish product is contributed by both API and excipient, then why we are calculating limit based on API only? should we not consider MDD of total weight of formulation while calculating the limit?

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If common nitrosamines are contributing from both DS and its excipients, in this case you have to consider API as well as excipients MDD. Current guideline does not allow the maximum total weight of formulation to calculation.

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The total weight of the sample powder taken for analysis is to be considered for the calculation of General Nitrosamines. This will be the worst-case scenario and the best approach.

Perhaps bit out of the scope of the discussion, but have you identified nitrosamine-contaminated excipient? Can you share any reference to that? Or are we taking strictly hypothetical?

In my understanding, what is relevant is how much NAs contains the maximum daily dose.

  • MDD is always about the API, irrespective of how much excipients are included in dosage forms, that’s why NAs are reported to MDD .
  • When analyzing a DP, one cannot differentiate the source of the Nas.
  • It is not plausible to have significant amount of NAs in excipients.
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Hi Naiffer,
There are many excipient declarations available stating that they have tested NDMA or NDEA and found below 0.1 ppb or 0.2 ppb, in some excipient declarations particularly the name of the nitrosamine tested are not mentioned and they simply mention that nitrosamines are tested and found below 0.1 ppb or 0.2 ppb.

now my API vendor tested suppose to say NDMA and found below 10% of the limit hence they are not keeping the control strategy in the specification.

when it comes to finish product and just to ensure the absence of NDMA, i am going to perform confirmatory testing of NDMA at this time NDMA can be contributed by any means API or excipients. in this case should i consider MDD of API only or MDD of whole formulation powder intake?
mostly people are taking MDD of API only.

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When it comes to General Nitrosamines, I believe it is like testing residual solvents. The total weight of the drug product to be part of calculation. For NDSRI, It is same as that of general impurities where weight of API alone is considered.

IMO where the nitrosamines come from is secondary. Just make sure that the daily ng/day limit is not exceeded, and whether it will be converted into API or the entire mass of the product is in fact irrelevant. It is just a way to show this value to make it easier for analysts and officials to work.