Nitrosamines Impurities

Nitrosamines analyses on pharmaceutical products is available at Mérieux NutriSciences GMP facilities.

​The FDA and EMA request pharma industries to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesised active ingredients.
Thanks to the long-standing experience, Mérieux NutriSciences has been developing various strategies and approaches for the determination of nitrosamines residues in different matrices through sophisticated mass spectrometry combined with a pool of experts.

HIGH LEVEL OF CAPABILITIES

1. Dedicated Team & Lab for analytical testing of NAC by: LC-HRMS or GC-HRMS with Orbitrap and/or TOF Technology; LC-MS/MS or GC-MS/MS (Triple Quadrupole Technology).

2. Confirmatory testing: method development and validation, and GMP quantitative tests with validated methods on medium and high risk nitrosamine impurities (NI) on representative drug products (DPs):
– Multiresidual analysis (standard set): NDMA, NDEA, NMEA, NEIPA, NMBA, NDPHA, NDPA, NDIPA, NDBA, NMA, NDELA, NPIP, NPYR, NMOR and MeNP.
– Targeted development method with standard and/or targeted screening without standard.

• N-Nitroso Ambroxol
• N-Nitroso Benazepril
• N-Nitroso Betahistin
• N-Nitroso Clonidine
• N-nitroso Diphenhydramine
• N-Nitroso Diclofenac
• N-Nitroso Dorzolamide
• N-Nitroso Duloxetine
• N-Nitroso Enalapril
• N-Nitroso Fluoxetine
• 4-Nitroso Hydrochlorothiazide (4-Nitroso HCT)
• N-Nitroso Ketamine
• N-Nitroso Naphazoline
• N-Nitroso Nevibolol
• N-Nitroso Phenylephrine
• N-Nitroso Pramipexole
• N-Nitroso Propranolol
• N-Nitroso Pseudoephedrine
• N-Nitroso Quinapril
• N-Nitroso Rasagiline
• N-Nitroso Tamsulosin
• N-Nitroso Zolmitriptan

– Targeted screening by HRMS and/or MS/HRMS (for detection of NI without available reference standards).

3. Risk evaluation. GMP or non-GMP screening limit or quantitative tests on raw materials of drug products supporting the Risk Assessment process in case of missing information: multiresidual NI analysis or single NI analysis (with or without reference standard).

4. New marketing authorisation and batch release.
– GMP multiresidual quantitative tests to demonstrate absence of NI before applying for new marketing authorisation
– GMP QC tests for analytical batch release

5. Alerts management.
– Target method development & validation (rush service)
– GMP QC tests on APIs and DPs on the market

6. Risk Assessment with qualified partners.

The Risk Evaluation process

STEP 1 RISK EVALUATION (31^st March 2021 and 1^st July 2021) 
MAHs should perform risk evaluation of their medicinal products containing chemically synthesised and biological APIs using quality risk management principles, as per ICH Q9 guideline and principles described in ICH M7 guideline related to toxicology assessment and control strategy. Prioritization of products is prescribed and risk evaluation of high risk / high priority products should be done immediately (e.g. higher daily exposure and chronic use). Risk evaluation documents should be made available upon request.
It should be avoided to submit premature risk evaluation outcomes mentioning a potential risk because of missing data since if the template is completed with a potential risk identified than the confirmatory testing has to be started immediately (CMDh/412/2019 Rev.6, 2020/09)

STEP 2 CONFIRMATORY TESTING (ASAP after risk evaluation in case of identified risk)
If a risk of presence of nitrosamines is identified, then confirmatory testing are required by the use validated and sensitive methods (GMP). MAHs should inform the competent authorities immediately if tests confirm the presence of a nitrosamine impurity irrespective of the amount detected.

STEP 3 CHANGES TO THE MARKETING AUTHORISATION
MAHs should apply for a variation in a timely manner to introduce any required changes, such as amendment of the manufacturing process or changes to product specifications.

According to EMA requirements, confirmatory testing should be concluded at the latest by 26 September 2022 for chemical medicines and 1 July 2023 for biological medicines whereas submission of Variations to the Marketing Authorization is expected within 1 October 2023.