How to calculate the Limit of Nitrosamines from excipients?

Limits of Nitrosamines
1

Hello, good day community.

Performing the risk assessment of a certain product with two active ingredients, we found that an excipient (coating) could cause the possible formation of a nitrosamine, so we want to calculate its maximum concentration limit (specification). We know that for this we can use:

AI (ng/day) / DDM of the drug (mg/day) = maximum concentration limit of nitrosamines (ppm)

My question is, since it is a nitrosamine not coming from one of the two active ingredients of the product, which DDM should be used? Or in this case, how could the limit be established?

2

Hello Lucia

Maybe, if you transform the DDM of the drug into the corresponding quantity (in weight) of the final product to be consumed, it will be easier to assess compliance.

For instance, let’s say the AI for the nitrosamine is 100 ng/day, and the maximum daily dose of your pharmaceutical product is 500 mg (as a whole). In this case, you should not have more than 200 ppb of the said nitrosamine in the final drug product.

4 Likes
3

Dear Lucia,
i think that you should follow the ‘‘worst case’’ approach, which means that you should use the higher MDD between the two APIs for the calculation of the spec. limit.
best regards
Christos

2 Likes
4

dear Lucia,
although I trust that I would follow @chrischar approach too, on the other hand, @Yosukemino recently published an interesting paper included theoretical justification and detailed calculations, especially in case you have actual levels for nitrosamines or nitrites in your excipient. perhaps it would be helpful for your case Risk Assessment and Management Strategy of Two New Nitrosamine Drug Substance Related Impurities (NDSRIs) in a Pharmaceutical Drug Product for the Treatment of a Rare Disease- from Prediction to Control-Pub - Risk Assessment Strategy / Tools & Technology - Nitrosamines Exchange

BR

2 Likes
5

Dear Lucia, some thoughts on that. If the excipient is used in the tablet coating only, the weight of one tablet and the max number of tablets/per day (weight of final DP consumed/day) might be the more appropriate base to calculate the max concentration limit. You might face the situation that there are tablets of different strength of API, but with similar weight and patients taking different numbers of tablets per day.

3 Likes
6

Dear LUcia,

Since nitrosamine sources are not only active ingredients, but they should also be evaluated on the basis of the total mass of the maximum daily dose of the relevant drug form. What is important is the amount of N-nitrosamine that has entered the digestive system and the limitation is made within this scope.

1 Like