Nitrosamine Impurity Testing and Analysis, including N-nitrosodimethylamine (NDMA), in drugs by LC-MS and GC-MS Methods
N-nitrosodimethylamine (NDMA) impurity testing and analysis in drugs including FDA Liquid Chromatography and Gas Chromatography methods.
Nitrosamine impurities such as N-nitrosodimethylamine (NDMA) have been highlighted by the US FDA and other regulatory authorities as an area for concern. These impurities, classified as a probable human carcinogen, became a focus in July 2018, when the FDA announced a recall of some angiotensin II receptor blocker (ARB) medicines. In 2019, some over-the-counter medicines used to prevent and relieve heartburn such as ranitidine, were also the the subject of some recalls with the HSA in Singapore and Swissmedic laboratory (OMCL) also detecting levels of contamination with NDMA in certain metformin preparations, used in the treatment of type 2 diabetes. More recently the FDA has issued an alert following the recall of some nizatidine products in association with suspected low levels of NDMA.
Additional impurities including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), 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 acceptable levels of these nitrosamine impurities and establish interim limits. In September 2019, the EMA began a review under Article 5(3) of Regulation (EC) No 726/2004 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines. As part of this review, the CHMP has requested marketing authorisation holders for human medicines to conduct a risk evaluation to identify products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome by 26 March 2020.
The FDA has released the following methods for the determination of NDMA impurities in drugs.
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.
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), with LOD 10ng/g, lower LOQ 33ng/g and upper LOQ 3333ng/g.
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Determination of NDMA in Ranitidine Drug Substance and Solid Dosage Drug Product
This method is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of NDMA in ranitidine drug substance and drug product. This LC-MS method based on a triple-quad platform may be used as an alternative or confirmatory method for the liquid chromatography high resolution mass spectrometry (LC-HRMS) method. The triple-quad platform is more widely available than the LC-HRMS platform.
A Rapid Detection Approach
Ultra-Performance Liquid Chromatography, Low Resolution Tandem Mass Spectrometry (UPLC- LR/MS/MS) method for the determination of NDMA, NDEA, NMBA and NDIPA in valsartan drug substance.
Intertek have also developed an alternative approach using UPLC-LR/MS/MS. This method allows for the rapid detection and quantitation of several nitrosamine impurities, NDMA, NDEA, NMBA and NDIPA, with LOD 5ng/g, lower LOQ 15ng/g and upper LOQ 75ng/g. This is an ideal approach for a rapid initial screen for the common nitrosamine impurities to aid and accelerate your risk assessment. Once optimized for your APIs or drug products, we can validate the method if required.
Intertek's Nitrosamine Impurity Analysis Services
Our GMP analytical team are experienced in providing analytical services according to FDA GC-MS and LC-MS 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
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.
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