Nitrosamines and bioequivalence studies

Dear Nitrosamines investigators,

What is your experience and knowledge regarding conducting a BE study for your generic products when your Drug substance of study is one of the known-to-contain nitrosamines?

Is it sufficient to submit IMPs with nitrosamines results lower than the AI either for the brand batch or the test batch?

Is it mandatory to submit your risk assessment and root-cause analysis to the drug authority where the BE study will be conducted?

Are there any guidelines or authority circulars that discuss this issue?

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When you look at Control of Nitrosamine Impurities in Human Drugs Guidance for Industry from the FDA, the responsibility lies with the manufacturer.

The test vs reference would be meaningless other than giving you a sense of security.

The requirement is seen at registration. You would need the full risk assessment at that point.

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To my mind there is no logic for the authorities to ask for a nitrosamine risk assessment. Firstly the product may fail and never be approved and secondly - its still not an approved product and there is no life time use. However, forget about the authorities. You should have done the risk assessment much earlier on. You would look pretty silly if you passed the biostudy and then, as required for your Market Authorisation, found that you have a nitrosamine risk product!!!
I would suggest remediation before you make an application:)


Very true. There should be some preliminary assessment before formulation begins. This should be a living document through development. Then, before registration, the formal risk assessment should be completed.


This a very important presentation related to this topic.