Alerts | Contaminants | Pharmaceuticals | Services

Nitrosamine alerts: EMA never stops updating Q&A documents on nitrosamine impurities

EMA continues updating the document “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”.

5th December 2022
Q&A document rev.13 introduces specific AI limits for 3 NO-APIs/NDSRIs (N-nitroso-fluoxetine, N-nitroso-paroxetine, N-nitroso-mefenamic acid) and other 3 nitrosamines (N-nitroso-diphenylamine, N-nitroso-pyrrolidine and N-nitroso-diethanolamine).
The introduction of specific AI limits, higher than that based on the class specific TTC for nitrosamines of 18 ng/day, could help MAH to solve analytical sensitivity issues during the development of very high sensitivity methods suitable for waiving/skipping approach during quality control of drug products/APIs with high MDI/MDD.

21st December 2022
Q&A document rev.14 introduces:

  • Q&A 22 on approach to control presence of N-nitrosamine exceeding the AI while CAPAs are being implemented
  • Update of Q&A 20 to consider the possibility of an interim limit based on the LTL approach during CAPA implementation
  • Update of Q&A 21 for increased clarity on the application of the temporary universal limit.

Our capabilities

Thanks to the long-standing experience in nitrosamines analyses, Mérieux NutriSciences’ Pharmaceutical and R&D Divisions have developed and validated suitable high sensitive LC-MS/MS methods for a wide range of nitrosamines limit determination – and for specific NO-APIs/NDSRIs – in pharmaceutical products. In order to respond quickly to our customers, dedicated lines have been implemented to offer rapid and targeted analytical services for nitrosamine analysis.

Target methods available for specific API related nitrosamines (not exhaustive list)

  • N-Nitroso-Ambroxol
  • N-Nitroso-Benazepril
  • N-Nitroso-Betahistin
  • N-Nitroso-Biotine
  • N-Nitroso-Clonidine
  • N-Nitroso-Diclofenac
  • N-Nitroso-Dorzolamide
  • N-Nitroso-Duloxetine
  • N-Nitroso-Enalapril
  • N-Nitroso-Flumazemil
  • N-Nitroso-Fluoxetine
  • N-Nitroso-Furosemide
  • 4-Nitroso-Hydrochlorothiazide (4-Nitroso HCT)
  • N-Nitroso-Naphazoline
  • N-Nitroso-Nevibolol
  • N-Nitroso-Nimodipine
  • N-Nitroso-Phenylephrine
  • N-Nitroso-Pramipexole
  • N-Nitroso-Propranolol
  • N-Nitroso-Pseudoephedrine
  • N-Nitroso-Quinapril
  • N-Nitroso-Rasagiline
  • N-Nitroso-Ropivacaine
  • N-Nitroso-Salbutamol
  • N-Nitroso-Tamsulosin
  • N-Nitroso-Zolmitriptan

The latest update

10th October 2022 – Q&A rev.12

  • added AI limit for N-Nitroso-duloxetine
  • introduction of an approach to control presence of nitrosamine while the AI is being established proposing a temporary AI (t-AI) of 178 ng/day

Please refer to the Questions & Answers document for complete information.

Discover more