Limits more than one Nitrosamine?

Good evening Community!

If my compound has NDMA and NDEA both impurities.

AI limit for NDMA is 96ng/day and for NDEA is 26.5ng/day.

So for the calculation of ppm in my product, can I go with an individual limit or with 26.5ng/day for both?

Ex. A.
NDMA= 96/300=0.32 ppm and
NDEA = 26.3/300=0.088ppm

Ex B

NDMA= 26.5/300=0.088 ppm and
NDEA = 26.3/300=0.088ppm

Which one is the right answer?

Thanking in advance

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Hello Buddy ,

As per my understanding and support of guidence ,
the limit of impurity is as per Exp-B.

Means you have to consider 26.5 for more than one COC impurities


If you refer to EMA '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’,

Question 10: Which limits apply for nitrosamines in medicinal products?

For determining limits in the case of the presence of more than one nitrosamine, two approaches are considered acceptable in order not to exceed the acceptable risk level of 1:100,000 as outlined in ICH M7(R1) guideline:

  1. The total daily intake of all identified N-nitrosamines not to exceed the AI of the most potent Nnitrosamine identified, or
  2. Total risk level calculated for all identified N-nitrosamines not to exceed 1 in 100,000.

If you refer to FDA’s Control of Nitrosamine Impurities in Human Drugs Guidance for Industry Rev 1

For drug products with an MDD of less than 880 mg/day, a recommended limit for total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug products with an MDD above 880 mg/day, the limit for total nitrosamines should be adjusted so as not to exceed the recommended limit of 26.5 ng/day

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As per my understating, B is correct answer.

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I am just sharing my thoughts & understandings. Anyone can correct me.

I think Calculation of PPM should be done with individual AI Limit. Ex A. Based on the evaluation of results one has to decide, how to keep the specification limit.
If results are not detected with less than 10% of respective AI, then no action required, and if the results are more than 10% of respective AI, then you have consider cumulative of both of these NDEA and NDMA should be less than 26.5ng per day.
And instead of giving individual limit, a total limit as per most potent one plays an important role

As per EMA guidance:

It is considered that the presence of one or more N -nitrosamines at <10% of their respective AI constitutes a negligible toxicological risk, and as such, they do not need to be specified. N- Nitrosamines present below 10% of their respective AI do not need to be factored into the calculation of limits for individual or total N -nitrosamine(s).
If the results are at or above 10% of their respective AI, you can consider the multiple approach given in the EMA guidance,

Either of Option 1 / Option 2 (Fixed) / Option 2 (flexible)

Or if you you refer FDA guidance,
If more than one of the nitrosamine impurities identified and the total quantity of nitrosamine impurities exceeds 26.5 ng/day (the AI for the most potent nitrosamines) based on the maximum daily dose (MDD), the manufacturer should contact the Agency for evaluation.
For drug products with an MDD of less than 880 mg/day, a recommended limit for total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable.
In your case the MDD is 300mg, so considering 26.5ng/day = 0.08 ppm is the total limit you have to consider.
So, either EMA or US FDA approach you may consider, first you have to analyze as per their respective AI. Based on the evaluation of results you have to decide further approach for finished product specification.


I would like to add @Diego_HM @DAB @Frabaneda to our limits discussion.

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Thanks Naiffer @Naiffer_Host .
FDA today made available draft addendum to ICH M7(R2) for comments.
Would like to go through it b4 commenting on this case study

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I will go for B as well. We should always consider the less risky option.

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There are multiple scenarios possible as per EMA guidance.

  1. As per guidance, either you can limit your total impurity with 26.5ng/day. In this case, we need not to apply individual limits to each impurity.

  2. If you want to apply individual limit then you can but the total impurity limit should not exceed 26.5ng/day.

  3. You can opt out flexible approach and assign % to each impurity based on the batch analysis data. In this case, the total impurity limit is not needed.

  4. As per FDA, the total impurity limit should not exceed 0.03ppm for a dose of less than 880mg/day. This case is similar to point no. 2 with stringent total impurity limit.


Example A is correct

Hi All, see the Rev 8 of EMA. They have provided several ways of looking at how to control multiple nitrosamines.

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I agree with @Naiffer_Host, @Sarada.jena, @sumitkumarjain, and @ASrinivasan.

Ex. C.
NDMA= x/300 (ppm)
NDEA = (26.5-x) /300 (ppm)

0 < x < 26.5 (ng)

Ex. D.
NDMA= 96y/300 (ppm)
NDEA = 26.5(1-y) /300 (ppm)

0< y < 1

Ex. C. is acceptable for both EMA and FDA.
Ex. D. is acceptable for only EMA.
As @Sarada.jena pointed out, the nitrosamine whose amount is less than 10% of the original AI is negligible in the calculation of the total limit. Does it make sense?


While I agree that FDA does not consider Ex D, in my opinion it is quite logical and possiby one issue that industry needs to push on. We need convergence in how we control multiple nitrosamines in a product or the industry will not be able to move forward.


Both should be OK, but you should control total NSA content should not be more than 26.5 ng/day.

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i think B ans is correct.

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Hi Naiffer Romero Sir

As per Health Canada guidance AI limit for 1-methyl-4-nitrosopiperazine (MNP) is 96.0 ng/day, However as per EMA guidance is 26.5 ng/day.
Which AI limit we should consider during product Risk assessment? How this has been derived?


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@Nilesh the guidance comes directly from the Agency where the product will be registered.

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@Nilesh the limit will depend on in which market you are filing the product. If you keep the stringent limit i.e. 26ng/day, it can work for both the markets.
This logic is same as for other impurities which we follow, while filing the product in multiple markets.

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Thanks Jaideep Sir & Naiffer Romero Sir for your instant response,

As per my understanding, AI limit for all Nitrosoamine’s should be harmonized globally, as they are “Cohort of Concern” more carcinogenic/ mutagenic than Genotoxic Impurities.

Hi Naiffer Romero Sir,

At the time of Confirmatory test (in terms of Analytical method), we need reference standard of the relevant nitrosamine impurity.
However, now a days many new nitrosamines are detecting specially NDSRI’s & other impurities which are noted in “EMA/409815/2020 Rev.9” EMA guideline.
For these Nitrosamines only (NDBA, NDEA, NDIPA, NDMA, NEIPA, NMBA, NDPA), Ph. Eur. Refence Standard is available.

What could be the approach for confirmatory test, for those nitrosamine impurity (specially NDSRI’s & others) for which relevant reference standard are not available? How will we do confirmatory test?


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