How to justify the absence of NDSRIs in finished product if the custom synthesis of the same NDSRIs is not possible?

Due to the presence of secondary and Tertiary amines in the impurity profile of either API or FP, many times Health Agencies request for adding either testing results of possible NDSRIs or to justify the absence of the same impurities.

  1. If the custom synthesis of the NDSRIs is not possible, Impurity vendors provide justification for non-formation of Nitrosamine impurities. Will it be accepted by Health Agency?

  2. Additionally, how can we justify the absence of the same Nitrosamine impurity in formulation?

  3. Through which method it is possible to show the absence of the NDSRIs in formulation can be justified?

4)Is it acceptable to justify the absence of Nitrosamine impurity through screening method, in which absence of specific mass of possible nitroso impurity through MRM mode of LCMS by injection spiked sample of finished product along with all impurities as per related substance method?

5)which method can be adopted further for justification of absence of possible nitrosamine impurity in formulation?

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generally, a combined theoretical assessment and experimental evidence is required. The justification should be first of all theoretical, included in the risk assessment. For the experimental part a starting point can be the Guidance 6 (1 & 2) (Can the N nitrosamine be formed?) and Guidance Note 7 for EFPIA DP Workflow, in ‘Workflows for Quality risk management of nitrosamine risks in medicines’. Version 2.0. Aug 2022.
A detailed declaration of a reputabled impurity vendor may be also accepted.

Current EMA Q&A 14:
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