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On 04/07/2024, the European Medicines Agency (EMA) released an update to Appendix 1 (EMA/154403/2024 /Rev. 5) of the Nitrosamines Guideline. In this Appendix the different nitrosamines that have an established Acceptable Intake (AI) are listed.
What’s new?
In this update, the Acceptable Intake (AI) values for nitrosamines related to the use of DIPEA (NDIPA and NEIPA) and NMP (NMBA) have been re-evaluated according to CPCA standards, resulting in a notable increase. Additionally, new nitrosamine drug substance-related impurities (NDSRIs) associated with the manufacturing processes of several active substances (Cinnarizine, Benzydamine, Bilastine, Caspofungin, Riociguat, Clarithromycin, Tramadol, Valsartan, Dimenhydrinate/Diphenhydramine, Tigecycline, and Trandolapril) have been published.
Updates of the AI values have also been made to other NDSRIs, such as Nitroso-STG-19 from Sitagliptin and N-nitroso-desmethyl-citalopram. Furthermore, the nitrosamine 1-(2,3-dichlorophenyl)-4-nitrosopiperazine, previously incorrectly linked to Eculizumab, is now correctly associated with Aripiprazole. The CPCA category of N-nitroso-N-desmethyl-dextromethorphan has also been corrected.
What does this mean to you?
This update significantly impacts the assessment of nitrosamines related to certain solvents (NDIPA, NEIPA, and NMBA). With their AI values notably increased, the acceptable limits of these impurities have also risen. This change means that some assessments could shift from a risk to no risk conclusion. Moreover, the specification limits for these nitrosamines are now higher.
If you market medicines containing any of the active substances listed above, you should review whether you have assessed the potential presence of these new NDSRIs. If not, it’s crucial to promptly update your NRA to consider these new risks.
For those who have already assessed these NDSRIs and identified a risk, the next step is to verify whether the AI values used in your calculations have changed with this update. The limits may have changed significantly, potentially altering the conclusions of your confirmatory analysis results.
How can the QbD Group assist you?
Our expert team toxicologist is here to guide you through regulatory changes and ensure your Nitrosamine Risk Assessments are up-to-date and compliant.
