Nitrosamine impurity analysis including NDMA and NDEA impurities according to the FDA headspace gas chromatography-mass spectrometry (GC/MS) methods
N-Nitroso impurities 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, such as valsartan, due to the potential for certain products to contain an impurity, N-nitrosodimethylamine (NDMA). 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 NNitrosodibutylamine (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.
NDMA and NDEA Impurities
The FDA Office of Testing and Research have developed a combined N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) impurity assay by GC/MS-Headspace chromatography-mass spectrometry (GC/MS-HS) method to detect and quantify the presence of NDMA (LOD 0.005ppm, LOQ 0.1ppm) or NDEA (LOD 0.02ppm, LOQ 0.05ppm) in drug substance samples of valsartan.
Nitrosamine Impurity Analysis Services
Intertek are experienced in providing analytical services according to the FDA GC/MS-HS method from our GMP laboratory, 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.