Nitrosamine Impurity Testing and Analysis, Including N-nitrosodimethylamine (NDMA)

Nitrosamine impurities such as N-nitrosodimethylamine (NDMA) have been highlighted by the US FDA and other regulatory authorities as an area for concern. Accurate and sensitive testing is crucial to detect and quantify these impurities in pharmaceutical products, ensuring patient safety and compliance with regulatory standards. The precision of such testing is vital for identifying trace levels of nitrosamines and implementing appropriate measures to mitigate their presence and maintain the integrity of pharmaceutical products.

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. 

 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.

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.