Apotex Inc. Canada is recalling one lot of APO-Amitriptyline due to presence of nitrosamine impurity, N-nitrosodimethylamine (NDMA) above the acceptable limit at the 48-month stability testing timepoint



For reference:

SMILES: c3cc2c(/C(c1c(cccc1)CC2)=C\CCN(C)C)cc3


As Amitriptyline is tertiary amine, it should be concerned with not only N-nitrosonortriptyline(AI = 8ng/day) but also NDMA. It’s reasonable but challenging for us.

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Amitryptylene, where ever the process involves usage of dimethyl amine in final step, will convert to NDMA during stability . We should consider the case similar to Metformin.


Thank you for sharing the information, @siva. I confirmed the synthetic scheme of amitriptyline with DMA.

I was concerned that some APIs with dimethylamino structure might risk NDMA contamination through direct nitrosation of the tertiary amine. But if they contain DMA as an impurity, NDMA contamination is reasonable!!


N-nitrosonortriptyline AI = 8ng/day which is published in EMA Q&A and there is no any reference in FDA guidance.
As per FDA guidance default limit for any nitrosamine AI = 26.5 ng/day.

Kindly looking for your valuable thoughts about which AI limit for N-nitrosonortriptyline shall be considered for USA submission.

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Hi, @Yuvraj.

Thank you for asking me. I’m sorry that I have no experience consulting the AI of unknown nitrosamines with the FDA.

The FDA allows us to use read-across in the guidance. If you suggest the different values from 8ng/day as the AI of N-nitrosonortriptyline, the reason why it is more appropriate than 8ng/ day may be required. I think the default values are applicable for nitrosamines free from read-across and you can suggest 8ng/day to the FDA in this case.

And I’m not sure how the FDA will respond. Does anyone have any additions?

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Thanks for valuable input and guidance.

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