Nitrosamine Impurities in Excipients

Limits of Nitrosamines
1

Hello, I’m seeking your advice on the following question:

If a nitrosamine impurity is detected in an excipient, how should the specification limit for that nitrosamine in the drug product be calculated? Specifically, which maximum daily dose (MDD) should be considered when establishing the acceptable limit of that nitrosamine impurity in the finished drug product?

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hi. you mean you detect a nitrosamine at >LOQ in an excipient used for the DP formulation?

if yes, then you should check if this nitrosamine is present in the final product with the MDD of final product as described in the SmPC.

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3

@vishu Specification limit of concern impurity will be based on MDD of product only as excipient is part of product. Though during AMD, test calculation should be as per composition of that excipient in product.

4

Similar issue we have gone through. There is a remote change to have nitrosamines in the excipients but it is possible in few cases.

If the excipient contains the nitrosamines, let it be. The limit will be based on the MDD of the product as DP will be consumed by the patients.

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5

That means the MDD is the total amount of the drug product consumed per day?

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This is how I work it.

If your limit is 100ng per day then your limit per dose is 100ng/number of doses, so 1 tablet a day would mean a limit of 100ng/tablet, where as 2 tablets taken 5 times a day would be 100/10 = 10ng/tablet.

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7

Hi, If in particular drug product, suppose excipients quantity is higher that the API quantity as per the batch formula and Nitrosamine impurity is originating from the excitement only, then amount of the Nitrosamine impurity going to form in the drug product shall be depends on the amount of excipient used. In that case MDD in terms of API to be used for the calculation of the limit or quantity of the excipient associated with the MDD of the API to be used for the limit calculation, since it will be higher that the actual MDD?

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8

Hi Vivek, in any of the case, only API MDD is to be considered for the limit calculations. API MDD will cover the excipients contribution too.

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9

i agree with Dileep, only the MDD of the API which is contained in the final product defines the specification limit along with the acceptance intake of the specific nitrosamine.

This is clear, at least in EMA and FDA guideline.

thank you

Christos

10

Thanks a lot for clarification

11

Thank you all for clarification

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12

Just in case you did not capture, I just published a new application note in the Analytical Hub for testing nitrites in Crospovidone…

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