EMA Nitrosamine Q&A Rev15 published

If you follow closely EMA’s “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products” an important regulatory update was added to Q&A 22

Amendment of Q&A 22 to indicate that no variation should be submitted to implement temporary above AI limits in specifications

@Yosukemino already reported (Dec’22) the addition of Q&A 22


The updated part is as follows;

MAHs are expected to ensure that the implementation of adequate controls for the detected nitrosamines is done as a matter of priority. During the use of the interim limit, monitoring measures may be evaluated by the lead authority as required. However, it is not the expectation that MAHs include these interim limits in specifications via variation.(updated)


Doesn’t it give you a feeling that the regulatory agencies are now understanding what they have unleashed and trying to put back the toothpaste in the tube. I think the recommendation of not including any limits in the drug specification is a way to wait till the TD50 of several of these nitrosamines are published and then slowly let this problem go away, as, may be in many cases with NDSRIs, a limit of 1.5 mcg/day may be adequate.


May be you are correct. I see, as these are interim limits derived from already available AI by LTL approach, they may have indicated that - let the interim limits not part of specifications.

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No new TD50’s are going to be published because nobody is running new carcinogenicity studies for nitrosamines.


I wonder why this update was not considered revision 15. It is still revision 14 even though revision 14 was already published on 21 December 2022.

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Dear @conudel,

“Rev.14” is just a typo. The revision history shows the latest version as rev.15.

To help your understanding of the updates, I add the slide by NIOG.

If it is applied, we may set an interim limit of up to four years to avoid a shortage of drugs. But I’m not sure whether the period is enough or not. I’m not sure about the limit, either.

And we don’t have to include these interim limits in specifications via variation, however, monitoring measures may be evaluated by the lead authority as required. Then we should set the in-house specification for releasing tests by ourselves.


Yes, anyway the AIs for most of the NDSRIs were not based on TD50 studies but surrogate studies. Example, N-nitrosamine of Varenecline. Surrogate selection based on read across is an approximation and can vary from scientist to scientist. So, it may be better that unless real work is done to find the TD50s (may take 2 years per molecule or may be 6 months if an alternative is allowed), it may be better that the agencies hold back on published these values. FDA has refrained. I was told that Health Canada will not publish beyond the 24 they have published. I think EMA has been too open with this :smile: and may have to decide if they want to publish information unless the nitrosamine justifies a limit of 1.5 mcg/day or is very carcinogenic (some larger nitrosamines are)


I do agree with you that it feels like EMA seems to have realized that they went too far on the restrictive side, and that with NDSRIs especially, things are getting out of control. The interim limits are shy steps backwards, but I don’t expect either anytime soon getting new AI based on experimental data.

There has been a strange radio silence since December

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I think we all should appreciate EMA for coming up with regular updates - which is lacking with other agencies, irrespective of which step it is (forward or shy step backward).

This gives sense, agency is also continuously learning things with time and understanding industry problems. Soon we may have solution!

Coming to the business of TD50’s - As a toxicologist, i feel this may not be long-term viable value for establishing compound specific safe levels. For nitrosamines- most of them still unstudied, the relative potency categorization and classification might be useful approach.

Having said above- Testing for mutagenicity driven carcinogenicity will remain essential to understand the real risk with more new approach methodologies but not by 2-year rodent study.


Good to know this. It would be great if any of the agencies provide a pathway related to the studies needed to establish that their nitrosamine may not be carcinogenic, so that sponsors could control it at 1.5 mcg/day. I am seeing the plight of the unapproved drugs that are secondary and tertiary amines. Basically, as you said, radio silence from at least FDA and Health Canada, while people are going crazy wondering what they should do.