Secondary amine Risk Assessment

Guidance, Documents, Resources
1

Dear Team,
I have to provide safe limit of Dimethyl amine, a secondary amine. Is there any article or reference indicating that it doesn’t need to be stringent controlled because of its potential to generate NDMA in presence of Nitrite and low pH? Thanking you in anticipation. Regards. Monaz

2

If your are not testing for NDMA and showing compliance (and if dimethylamine is present in a drug product, you should test for NDMA) and you want to base your control strategy dimethylamine, you may be required to prove that dimethylamine is low enough to form <10% of the AI of NDMA.

In metformin, for example, the specification of DMA is still set at <0.05% in Europe, but it may not be low enough.

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3

Thank you very much.

4

Is the topic related in the API? If it is, indeed is possible to dismiss the risk, for example doing a purge factor calculation of the DMA, nitrite and/or the possible formed nitrosamine if there is a probability for forming as per ICH M7 Option 3 (As Option 4 is still a bit reluctant from authorities to accept).

5

I have to assess safety of DMA as Leachable in parenteral drug product. While determining PDE, I need to look for applying uncertainty factors. In anticipation that it will form NDMA in appropriate microenvironment does DMA needs to be controlled at conservative levels? Being Leachable, option 4 of ICH M7 will not be applicable. Thanking you in anticipation. Regards.

6

@MonazBmysorewala I’m really interesting on how different is the risk assessment that you performed when it’s a parental VS solid dosage form.

7

Dear Sir,
There is no route specific difference particularly for DMA. The principle to assess risk applies same while safety evaluation for any chemical of interest. With respect to Nitrosamine impurities as our understanding become clear (thanks to this forum! ), wanted to clarify my understanding with respect to secondary amine anticipate to leach in parenteral drug product. Thanking you in anticipation.
Regards.
Monaz

8

Can you give more details on DMF as a leachable? Are talking here about a common container closure system or any other part of the product closure?

9

Yes, it is leaching from container closure system into parenteral drug product. Thanking you in anticipation. Regards.
Monaz

10

Thank you for the feedback, maybe this thread is also supporting you

There is also an interesting paper from BettineBoltres

All the best

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