Nitrosamine Alert
December 10th, 2019
|   NEWS , ALERT
Nitrosamines alert

Nitrosamines analyses on pharmaceutical products is available at Mérieux NutriSciences GMP facility!

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. High-sensitive in-house validated methods for target nitrosamines detection (e.g. NDMA, NDEA) in high risk APIs (e.g. Sartans, Ranitidine, Metformin)
  3. Method development and validation of target methods for the determination of specific nitrosamines in APIs and pharmaceutical products at low limits (NMT 30ppb)
  4. GMP analysis for analytical batch release
  5. Multiresidual analysis (standard set): NDMA, NDEA, NMEA, NEIPA, NMBA, NDPHA, NDPA, NDIPA, NDBA, NMA, NDELA
  6. Multiresidual analysis (on demand): NPIP, NPYR, NMOR, MNPZ
  7. Targeted screening by HRMS and/or MS/HRMS (for detection of NAC without available reference standards)
  8. Risk Assessment with qualified partners

 

Nitrosamines are classified as probable human carcinogens, which means that long-term exposure above certain levels may increase the risk of cancer. They are present in some foods and drinking water supplies, and where they have been found in medicines the risk of developing cancer has been low but under authorities evaluation and control.

June 2018
US manufacturer Prinston Pharmaceuticals Inc. had contacted FDA’s Center for drug Evaluation and Research to inform the agency that it had stopped manufacturing valsartan products because it had detected trace amounts of a nitrosamines impurity called NDMA (N-nitrosodimethylamine) in valsartan API supplied by Chinese manufacturer Zhejiang Huahai.

July 2018
Authorities in Europe became aware of the presence of NDMA in valsartan manufactured at a facility based in China. Subsequently, another nitrosamine NDEA (N-nitrosodiethylamile) was detected and other sartans from more API manufacturers were implicated.

Late 2018 - early 2019
Companies that make sartan blood pressure medicines (also known as angiotensin II receptor blockers) are being required to review their manufacturing processes so that they do not produce nitrosamine impurities and many valsartan recalls continued both in EU and US.

September - November 2019
FDA has learned that some ranitinide medicines contain a nitrosamines impurity called NDMA (N-nitrosodimethylamine). FDA has detected that also some nizatidine (which is chemically similar to ranitidine) medicines, contain NDMA impurities.

December 2019
EMA and FDA are aware concerning the presence of low levels of NDMA in some metformin diabetes medicines outside the Europe and United States. At this point, there are no data indicating that US and EU metformin medicines are affected, but authorities are in the process of working with companies to test medicines and provide more information.

February 2020
Ranbaxy Pharmaceuticals Canada Inc. recalled six lots of its RAN-Metformin prescription drug from the Canadian market.

March 2020
After questioning about the suitability of the FDA LC-HRMS method reported in the guidance document FY20-058-DPA-S, Valisure detected high levels of NDMA in several metformin drugs.

The Article 31 review of sartans identified a number of root causes of nitrosamine formation and contamination:

  1. during API processing under certain processing conditions and in the presence of some types of raw materials, starting materials, and intermediates;
  2. the use of sodium nitrite (NaNO2), or other nitrites, in the presence of secondary or tertiary amines;
  3. the use of contaminated raw materials in the manufacturing process;
  4. the use of recovery of materials (e.g. solvents, reagents and catalysts);
  5. contaminated starting materials, including intermediates supplied by vendors that use processing methods or raw materials causing formation of nitrosamines.
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