CHMP's Assessment Report on Nitrosamines published

On 9 July 2020, the final report on nitrosamine contamination was published on the EMA website. This final statement of the CHMP entitled "Assessment report - Nitrosamine impurities in human medicinal products" EMA/369136/2020 represents the end of the procedure under Article 5(3) of Regulation 726/2004, which started on 10 September 2019. The 90-page document contains the current state of science and knowledge regarding nitrosamine impurities in human medicinal products and provides recommendations for manufacturers of medicinal products based on chemically defined APIs and biological medicinal products.

These recommendations are listed in the last section of the report (5. "Recommendations") and constitute an orientation framework for the manufacturers or marketing authorisation holders of the above-mentioned medicinal products. Below is a brief summary of the central points covered by these recommendations:

  • The content of nitrosamines in medicinal products for human use must be kept to a minimum and must not exceed the limits laid down in the ICH M7(R1) guideline. The daily exposure over a lifetime must be taken into account. 
  • Risk assessments shall be carried out to evaluate the risk for the presence of nitrosamines. If risks are identified, confirmatory tests must be carried out on the finished medicinal product. The potential sources of this type of contamination known so far shall be taken into account. 
  • If nitrosamines are present, limit values according to ICH M7(R1) must be established taking lifetime exposure into account. 
  • If contamination with several distinct nitrosamines is present, the total risk must not exceed 1:100,000 of lifetime risk. An alternative approach may be to limit the overall risk below the level of the highest risk nitrosamine species.

The list of recommendations contains some more detailed guidance on how to proceed in special cases, e.g. when substance-specific lifetime exposure cannot be calculated due to insufficient data or for preparations with genotoxic APIs.
One of the central statements in this section states that marketing authorisation holders must have implemented a control strategy that is suitable for minimising or completely preventing the risk of contamination with nitrosamines.

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