How to Comply with the Nitrosamine Regulations for Your New Drug Product Marketing Applications

September 14, 2022


  • Are you in the development phase for your medicinal product?
  • Have you assessed your manufacturing processes with respect to the requirements for investigating the potential presence of nitrosamine impurities prior to your submission of the marketing application?
  • Are you Interested in learning more?
  • Do you need a Subject Matter Expert to guide you?

Nitrosamines are a family of carcinogens which are formed by the reaction of secondary and tertiary amines, amides, carbamates, derivatives of urea with nitrite or other nitrogenous agents.

Our experts will support the Marketing Authorization Holder (MAH) to perform the nitrosamine risk assessment in collaboration with the drug substance and excipient suppliers and will also define how to document and discuss the potential presence of these impurities for regulatory submissions.

ProPharma Group is a unique partner with comprehensive knowledge of the latest regulatory guidelines for nitrosamines to support your drug product marketing applications, including:


The presence of nitrosamine impurities should be mitigated as much as possible and controlled at or below a limit defined based on ICH M7(R1) principles for substances of the “cohort of concern”.


EMA finalized a scientific review under Article 5(3) of Regulation (EC) No 726/2004 in June 2020 and agreed on an implementation plan in February 2021. It provides the initial guidance to MAH’s on how to avoid the presence of nitrosamine impurities in human medicines. The Q&A document is a living document and has undergone several updates during 2022.


The FDA Guidance for Industry Control of Nitrosamine Impurities in Human Drugs provides detailed instructions. The agency updated this guidance in February 2021 to specify timeframes for completion of nitrosamine mitigation activities by drug manufacturers.

In the updated guidance manufacturers are asked to evaluate the presence of nitrosamine drug substance-related impurities (NDSRIs), that may be produced if nitrite impurities are present in excipients (at parts-per-million amounts) or may be generated during manufacturing or storage.


At its 168th session in November 2020, the Ph. Eur. Commission adopted a new general chapter on the analysis of N-nitrosamine impurities in active substances (2.5.42, previously listed as 2.4.36).

USP General Chapter (<1469>) is aligned with the current FDA guidance and has been developed to ensure the appropriate control of nitrosamine impurities in drug products and is intended to provide a science-based approach for eliminating or reducing their presence in pharmaceuticals.

Based on the nitrosamine regulations, the expectations of the MAH are:

  • A scientific understanding of the generation, speciation, and stability of potential nitrosamine impurities is needed.
  • Knowledge of drug-excipient incompatibilities.
    Excipient impurities along with understanding of drug stability and dosage form characteristics are essential for building product robustness and reducing the risk of forming nitrosamines.
  • Understanding of the analytical methods to be use if necessary.

ProPharma Group can:

  • Provide reports of the risk evaluations of your medicinal products needed for inclusion in regulatory submissions/dossiers.
  • Provide a full assessment of both your drug substance manufacturing process and its possible impact on your drug product in combination with your formulation process. This assessment will include:
    • The evaluation of any pathway (including degradation) that might introduce nitrosamines during manufacturing or storage
    • The impurities are listed with their sources of generation
    • Stability upon storage and processing, and the potential reactions with drug candidates are also reviewed
  • Based on possible risks, recommend mitigation strategies for avoiding or preventing the formation and presence of nitrosamines, such as:
    • modified Active Pharmaceutical Ingredient (API) properties
    • formulation and manufacturing process
    • use of protective materials
    • established controls of raw materials
  • Set up of general analytical methods of nitrosamines
  • Assess and evaluate your line extension or variation applications.

Interested in learning more? Contact us today to find out how we can help with your risk assessment for nitrosamines.


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