Methods for determination of nitrosamine drug substance-related impurities (NDSRIs) and intermediate-related contaminants

The German OMCL at the Landesamt für Gesundheit und Lebensmittelsicherheit (LGL) in Bavaria established the following analytical procedures:

The analytical procedures are validated for the determination of the declared N-nitrosamines in the defined medical products. For other dosage forms, they must be suitably validated.

The OMCL at Swissmedic established three LC-MS/MS analytical procedures for the determination of specific NDSRIs. The official valid analytical procedure is the German version, the English version is translated for ease of use.

The links to the German versions of the three analytical procedures are listed hereafter:

Please note that prior to use (APIs or finished products), in-situ validation with a focus on extraction, specificity and quantification is required.

The U.S. FDA has also published analytical procedures for determination of NDSRIs:

 

Methods for determination of nitrosamines in sartans

The Official Medicines Control Laboratories (OMCLs) of the General European OMCL Network (GEON) are involved in investigations and actions to address the issues related to the detection of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and other concerned nitrosamines (e.g. NMBA – N-Nitroso-N-methyl-4-aminobutyric acid) in valsartan and related sartans. The Network has developed methods for the specific testing of nitrosamines in sartans on the basis of different analytical principles.

The Irish OMCL in the Public Analyst’s Laboratory in Galway (PALG), the French OMCL at the ANSM site in Montpellier, the German OMCL at the “Chemisches und Veterinär-Untersuchungsamt (CVUA) Karlsruhe”, the OMCL at Swissmedic and the German OMCL at the “Landesamt für Gesundheit und Lebensmittelsicherheit (LGL)” in Bavaria established different methods on behalf of the Network.

These methods are publicly available and can be accessed below:

  • This LGL method is an LC-MS/MS (AB Sciex Qtrap) method for the quantitative determination of NMBA in losartan drug substances.
  • This Swissmedic limit test for the determination of Nitrosamines by GC-MS/MS is validated for the following sartan preparations (valsartan, losartan, irbesartan, olmesartan and candesartan). Please note that prior to use for other samples (APIs or finished products), in-situ validation with a focus on extraction, specificity and quantification is required. The German version is the official version. In order to access the official version, please use the following link.
  • This CVUA Karlsruhe method is based on UHPLC-APCI-MS/MS and allows determination of NDMA and NDEA in sartan drug substances and drug products.
  • This PALG method is based on Headspace GC-MS (single quad) and applicable to the determination of NDMA in drug substances and corresponding powdered tablets of the sartan group.
  • This ANSM method is based on HPLC-UV and applicable to the determination of NDMA and NDEA in sartan drug substances (valsartan, losartan, irbesartan, candesartan and olmesartan).
  • This ANSM method is based on HPLC-UV and applicable to the determination of NDMA in drug substance and corresponding powdered tablets of valsartan.

Please note that OMCLs of the General European Network are by their status and role only performing tests on behalf of competent authorities and for that reason are not in the position to accept contract work for private companies.

The U.S. FDA, Health Canada and Taiwan FDA have also published methods for determination of nitrosamines.

Methods for determination of nitrosamines in ranitidine

The German OMCL at the “Landesamt für Gesundheit und Lebensmittelsicherheit (LGL)” in Bavaria and the German OMCL at the “Chemisches und Veterinär-Untersuchungsamt (CVUA) Karlsruhe” established the following methods:

  • This LGL method is a GC-MS screening method for NDMA in ranitidine drug substances.
  • This CVUA Karlsruhe method is based on UHPLC-APCI-MS/MS and allows determination of NDMA in ranitidine drug substances and drug products.

The U.S. FDA and the Health Sciences Agency (HSA) of Singapore have also published methods for determination of nitrosamines in ranitidine:

Methods for determination of nitrosamines in metformin

The German OMCL at the “Landesamt für Gesundheit und Lebensmittelsicherheit (LGL)” in Bavaria and at the “Chemisches und Veterinär-Untersuchungsamt (CVUA) Karlsruhe” established the following methods:

  • This LGL method is a GC-MS method for the determination of NDMA in metformin drug substances and drug products.
  • This CVUA Karlsruhe method is a GC-MS/MS for the determination of NDMA in metformin drug substances and drug products.

The Swissmedic method « 31_PV_171_Nitrosamine by_GC_MS_MS_V01 EN » published above for Sartan preparations can be applied for Metformin APIs and Finished Products using the modifications as described in the following instructions released by the Swissmedic OMCL on 20/2/2020.

The Health Sciences Agency (HSA) of Singapore and the U.S. FDA have published methods for determination of nitrosamines in metformin:

Method for determination of genotoxic substances in sartans as AZBT (azidomethyl biphenyl tetrazole) or AZBC (azidomethyl biphenyl carbonitrile)

The German OMCL at the “Landesamt für Gesundheit und Lebensmittelsicherheit (LGL)” in Bavaria, the Swissmedic OMCL and the Taiwan FDA established the following methods:

  • This LGL method is an LC-MS/MS method for the determination of AZBT in valsartan, irbesartan, candesartan and losartan drug substances.
  • This Swissmedic method is an LC-MS/MS method for the determination of AZBT and AZBC in sartans. The German version is the official version. In order to access the official version, please use the following link.
  • Taiwan FDA method (AZBT in sartan drug substances including candesartan, irbesartan, losartan, olmesartan, and valsartan).