Potential sources for Nitrosamine Impurities

The EMA has recently published a Q&A document entitled Questions and answers on "Information on nitrosamines for marketing authorisation holders" EMA/CHMP/428592/2019 Rev. 1 which has now been updated. A new chapter entitled "What are the currently identified root causes for presence of nitrosamines?" has been added. It includes eight subsections about already identified root causes for nitrosamine contamination. These are briefly summarized below:

  • Sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts within the same or different synthesis step in which these compounds are carried over due to incomplete depletion.
  • Sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, from which secondary or tertiary amines are generated by degradation reactions.
  • Contaminated raw materials (solvents, reagents, catalysts) in the API production process.
  • Recovered materials (solvents, reagents, catalysts), in particular when reprocessed by third parties using equipment not dedicated for this purpose.
  • Contaminated starting materials and intermediates from suppliers whose manufacturing processes or the starting materials used may allow nitrosamine formation.
  • Cross-contamination between different manufacturing processes on the same production line that are not clearly allocated and operator-related errors.
  • Degradation processes of starting materials, intermediates and finished products, including those induced by inherent reactivity in combination with carry-over of sodium nitrite, which could occur also during finished product formulation or storage.
  • Primary packaging materials such as blisters in which the nitrocellulosic lidding foil reacts with amines in the pinting primer used to form nitrosamines, which would then be transferred to the product during the packaging process.

Marketing authorisation holders of medicinal products with synthetic chemical APIs are obliged to assess the risk of contamination with nitrosamines in their products within six months (see our News "Nitrosamine contamination: EMA requests risk evaluation for drug products containing chemically synthesised APIs"). The updated Q&A document is intended to support these risk assessments.

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