Given the toxicological profile of N-nitrosamines, their presence in the drug directly impacts on its quality and safety. In order to avoid the presence of this type of impurities, health agencies have requested marketing holders of innovative, generic or OTC medicines to assess the risk of nitrosamines formation in all chemically synthesised medicines for human use.

According to the guidelines proposed by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and the Coordination Group for Decentralised Procedures and Mutual Recognition of Medicinal Products for Human Use (CMD) (EMA/189634/2019 and EMA/428592/2019), the risk analysis of nitrosamines shall be carried out by assessing the potential formation of nitrosamines at different points in the manufacture of the medicinal product. In particular, the potential formation of nitrosamines in the synthesis of the active substance, in the manufacture of the medicinal product and also in the processes of reuse of solvents, degradation of the active substance, packaging of the finished product or in potential cross-contamination processes shall be reviewed.

 1. Prioritisation of products based on the criteria in EMA/189634/2019 and EMA/428592/2019

 2. Risk analysis of nitrosamines:

  • Risk of nitrosamines formation in active ingredient synthesis
  • Risk of formation of nitrosamines in the manufacture of the finished product
  • Risk of nitrosamines formation due to cross-contamination
  • Risk of formation of nitrosamines by reuse of solvents
  • Risk of formation of nitrosamines by degradation of active ingredient
  • Risk of formation of nitrosamines from primary packaging material

In case their presence is indeed confirmed, it will be necessary to implement changes in the synthesis route of the medicinal product in order to avoid the formation of these impurities and to guarantee the quality of the product.

At Dalia Global we have an extensive and up-to-date database of excipients that allows us to perform accurate and time-saving evaluations.

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1. Risk analysis of nitrosamines based on available information on:

  • Synthesis of active principle
  • Drug product manufacturing process
  • Cross-contamination processes
  • Reuse of homogeneous solvents and catalysts
  • Active ingredient degradation processes
  • Primary packaging material

In case the risk analysis for nitrosamines suggests the presence of nitrosamines:


2. Purging or mitigation study (estimation of the elimination of impurity through the manufacturing process of the drug)


3. Calculation of toxicological limits for nitrosamine These limits are specific to the route of administration and are the starting point for confirmatory tests in the analytical laboratory.

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