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