Nitrosamine Impurity Analysis including N-nitrosodimethylamine (NDMA) in Drugs by LC-MS or Headspace GC-MS Methods

N-nitrosodimethylamine (NDMA) impurity analysis by the FDA Liquid Chromatography and Headspace Gas Chromatography methods in drugs

Nitrosamine impurities in ranitidine or some angiotensin II receptor blocker (ARB) medicines have been highlighted by the US FDA as an area of concern.

Nitrosamine impurities such as N-nitrosodimethylamine (NDMA) became a focus for the FDA and EMA in July 2018, when the FDA announced a recall of some angiotensin II receptor blocker (ARB) medicines. This impurity is classified as a probable human carcinogen and is believed to have been introduced into the finished products as a result of the manufacturing process. Subsequently, additional impurities including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), and N-nitrosodibutylamine (NDBA), and N-nitrosomethyl-4-amino-butyric acid (NMBA) have also been flagged as potential nitrosamine impurities. The FDA has been working closely with industry to ensure products entering the market do not contain these impurities in the future, whilst establishing suitable analytical methods to determine levels of these impurities and establish interim limits for nitrosamine impurities. More recently some over-the-counter medicines used to prevent and relieve heartburn associated with acid ingestion, such as ranitidine, have been the subject of some recalls in association with suspected low levels of NDMA. 

 

GC/MS Headspace Chromatography Mass Spectrometry Approach 
The FDA Office of Testing and Research have developed a combined GC/MS headspace method for the simultaneous evaluation of four nitrosamine impurities in ARB drug substance and drug product. These impurities are; N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), and N-nitrosoethylisopropylamine (NEIPA). The method was developed and validated on valsartan drug substance and drug product. 

 

Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product
The FDA have observed that the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities is not suitable for testing ranitidine because heating the sample generates NDMA. A LC-HRMS method was subsequently developed by the FDA to measure the levels of NDMA in ranitidine drug substance and drug product following ICH Q2(R1). The limit of detection (LOD) is 0.011ppm, limit of quantitation (LOQ) is 0.033 and range of the method is 0.033 – 3.33ppm.

Intertek's Nitrosamine Impurity Analysis Services
Our GMP analytical team are experienced in providing analytical services according to these FDA GC/MS-HS and LC methods, including performing the required method validations where the data can be used to support regulatory submissions or quality assessment of the API or drug product. 

With scientists who are adept at method development and validation of suitable analytical procedures, we regularly help clients overcome the challenges of low detection levels, difficult matrices and identification of unknowns in the course of pharmaceutical impurities analysis. Additionally, we offer highly sensitive and specific method development and validation expertise to assess other carcinogenic or genotoxic impurities in drug products.

In addition to experienced pharmaceutical impurity analysis, we can support with toxicological risk assessments. Our experienced consultants conduct risk assessments to address the impact associated with exposure to residual solvents, process impurities, extractables & leachables, elemental impurities (ICH Q3D) and other substances that may find their way into a given pharmaceutical product.