Nitrosamine impurities in drug product specification

1.Based on development data it is determined that nitrosamine in drug product is process impurity (does not rise during stability) and not degradant, is it sufficient to include in release specification and exclude in stability specification wrt regulatory acceptance?

  1. In case of multiple strength bracketing and matrixing approach or worst case still valid for Nitrosamine ?

Hi Sameer, answering your first question: in case it is not a degradation impurity this is correct, you should not need to test this during stability.

Thanks. For Metformin ER tablets we have observed that NDMA level after 6Months stability for long term (25/60) , intermediate (30/65) and accelerated condition (40/75) is more or less at same level indicating no further degradation

If you have adequate data to establish this, controlling the nitrosamine in question only in release may be acceptable.

In Metformin, the main source of NDMA is chiefly the dimethylamine used in the API manufacturing procwess. However, based on the structure of Metformin, NDMA could be a degradant. While the conditions that favor the formation of NDMA in Metformin may not be present in your formulation, the Agency may want a control of NDMA in Metformin, due to intrinsic nature of the API and the fact that excipient quality may differ from batch to batch in content of nitrite/nitrate.

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Thanks . Totally agree.
Metformin API long term data by vendor showed no increasing trend upto 5 years shelf life. So may be in presence of some excipients with nitrite and nitrate and with traces of Dimethylamine in metformin API generate NMDA formation. But reaction is very slow. Any way to extrapolate data or predict level in formulation based on level of Dimethylamine in API and nitrite and nitrate in excipients

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Need to very careful in drawing conclusions applicable to all forms of Metformin based formulations - there is clear evidence for example of formation within the formulation on stability within extended release formulations. This complex but likely related to DMA residual within the API, possible degradation to yield DMA and nitrite within excipients. Also important is the pH within the formulation


Agree. Water content in formulation also contributing to some extent to accelerate rate of reaction

Hi @sameer, as you may solve your questions, I add some comments. For the second question, EMA Q&A 8 and 14 are available.

If a product is available in multiple strengths of the same dosage form with the same risk factors
applicable to each, then testing could be rationalised by testing only the worst-case scenario strength.
The worst-case approach should be justified by the MAH on a case by case basis. The justification
should be documented in the risk assessment in the MAH’s pharmaceutical quality system.

And the following NIOG slides may be helpful. I think it will be justified on a case-by-case basis.

Dear Srinivasan,
Do you have any supporting information for this statement. Mainly the pathways?. Is the possible degradant is NDMA or Dimethyl amine?

@fernandaw @David @MichaelBurns do you have any experience or case study for this case? Thx in advance.

As we have all been taking, if there is possibility of nitrites in the formulation and the pH is conducive to nitrosation, there is a possibility that NDMA may be a degradant of Metformin. However, it will have to be a situation where everything falls in place for the NDMA formation.