Conduct a risk evaluation to identify active substances and finished products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome by:
Proposed approach
Impurity risk
Nitrosamine impurities found in some angiotensin II receptor blocker and histamine II receptor blocker medicines, have been the driver for recent product recalls. Laboratory studies have concluded that these impurities are classified as probable human carcinogens. They are believed to have been introduced into the finished products during the manufacturing process, although they are not expected to cause harm when ingested in very low levels. In recent years unacceptable quantities of nitrosamine impurities have been detected in some medicines and have become the subject of focus for regulatory agencies. In 2018, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in a number of blood pressure medicines, such as valsartan,
leading to a recall of several products and an EU review, which set strict new manufacturing requirements for these medicines. In 2019, NDMA was detected in some batches of ranitidine, a H2 receptor blocker used to treat acid reflux, resulting in product recalls and initiating further regulatory review. Other nitrosamine impurities, N-nitrosodiisopropylamine (NDIPA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) are also considered impurity risks and robust analytical testing methods are required to ensure that drugs and drug products are safe for consumption now and in the future. In response to these impurity concerns the FDA Office for Testing and Research (OTR) has established suitable analytical methods to determine levels of these nitrosamine impurities and establish interim acceptance limits. The methods include
Our experts detect and quantify nitrosamine impurities in APIs and finished drug products. Data can be used to support regulatory submissions or quality assessments
• GC/MS Headspace Chromatography-mass spectrometry (GC-MS)
• Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS)
• Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
Intertek also offers an Ultra-Performance Liquid Chromatography Low Resolution Tandem Mass Spectrometry (UPLC – LR/ MS/MS) method for the rapid detection of several nitrosamine impurities. Additionally, 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.
Meeting your nitrosamine challenges
We can help you to meet the FDA and EMA requirements for product testing and risk evaluation through our tailored nitrosamine analysis services to detect and quantify nitrosamine impurities. Intertek has established the FDA methods within our GMP laboratory services to assist clients in performing the required method validations where the data can be used to support regulatory submissions or quality assessment of the API or drug product.
Our services include:
• Method Development & Validation
• Impurities Analysis – for nitrosamine and other carcinogenic or genotoxic impurities
• Toxicology Risk Assessments
NITROSAMINE IMPURITY ANALYSIS
(NDMA, NDEA, NDIPA AND NMBA) IN MEDICINES
GC-MS Headspace Method for Detection of NDMA in Valsartan Drug Substance and Drug Products
In 2018, the FDA announced a recall of Valsartan tablets (an angiotensin II receptor blocker used to treat high blood pressure) because of the potential for certain products to contain NDMA. A second impurity was subsequently reported, N-Nitrosodiethylamine (NDEA). The OTR developed a gas chromatography-mass spectrometry (GC/MS) headspace method to detect and quantify the presence of NDMA (Limit of Detection (LOD) 5ng/g, and Limit of Quantitation (LOQ) 100ng/g) or NDEA (LOD 20ng/g, LOQ 50ng/g) in drug substance samples (Figure 1).
Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product
As GC based methods had been observed to elevate NDMA levels in tested materials an alternative method was developed by the FDA which prevents the degradation of ranitidine and the subsequent formation of NDMA. In September 2019, a liquid chromatography method using high resolution mass spectrometry (LC-HRMS) to measure NDMA levels in ranitidine drug substance and drug product was published, 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 liquid chromatography FDA method is based on a triple-quadrupole mass spectrometry platform. It is an alternative or confirmatory method for the detection of NDMA in ranitidine drug substance and drug products. The triple quadrupole platform is more widely available than the LC-HRMS platform previously shared by the FDA. A Rapid Detection Approach Ultra-Performance Liquid Chromatography, Low Resolution Tandem Mass Spectrometry (UPLC- LRMS/MS) method for the determination of NDMA, NDEA, NMBA and NDIPA in valsartan drug substance. Intertek have also developed an alternative approach using UPLC-LRMS/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.
Toxicological risk assessment
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 pharmaceutical product.
Total Quality Assurance
Intertek’s network of GMP compliant laboratories provide compliant data to support regulatory requirements or product development activities of our global clients. Bringing quality and safety to life, we help you bring your product to market quickly, responsibly, and economically, ensuring Total Quality Assurance.
2021 News Update: Nitrosamine Impurity Testing and Analysis, including N-nitrosodimethylamine (NDMA), in API and final drug products by LC-MS/MS, GC-MS and GC-MS/MS Methods
In February 2021, the FDA have issued a guidance “Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry”.
Nitrosamine impurities such as N-nitrosodimethylamine (NDMA) have been highlighted by the US FDA and other regulatory authorities as an area for concern. In February 2021, the FDA have issued a guidance “Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry”. This document provides guidance on steps to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. This was published alongside a recommendation that pharmaceutical manufacturers should conclude risk assessments of approved / marketed products to mitigate nitrosamine impurities in their products within 6 months of publication date (March 31, 2021).
Nitrosamine 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 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.
Although nitrosamine impurities have been found in only some drug products, and batches of those products have been recalled when there were unacceptable levels of these impurities, nitrosamine impurities might exist in other APIs and drug products due to use of certain processes and materials that may produce nitrosamine impurities.
Additional impurities including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NIEPA), 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, in early 2020, the CHMP requested that marketing authorisation holders for human medicines conduct a risk evaluation in order to identify products at risk of N-nitrosamine formation or (cross-) contamination.
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.
At Intertek we also offer a GC-MS/MS approach which has allowed our experts to achieve excellent LOD and LOQ values. Overall, GC has proved extremely useful for some difficult projects, helping us to present an alternative and successful route to avoiding challenges associated with Liquid Chromatography co-elution of NDMA and DMF, as well as other potential interferences, where present. This flexibility in platform approaches means we can apply sample and nitrosamine-specific, tailored analytical solutions that are highly relevant for your nitrosamine testing needs.
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.
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), with LOD 10ng/g, lower LOQ 33ng/g and upper LOQ 3333ng/g.
Intertek's Nitrosamine Impurity Analysis Services
Our GMP analytical team are experienced in providing analytical services according to FDA GC-MS, GC-MS/MS, LC-MS/MS and LC-HRMS 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.
