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Chapter 1 - Key achievements in 2019

Nitrosamine impurities: the network's response

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In June 2018, the European medicines regulatory network became aware of the presence of nitrosamine impurities (N-nitrosamines) in a class of medication used to control high blood pressure, known as ‘sartans’. Regulatory actions were instituted across the EU, including the recalls of some medicines from pharmacies and measures to prohibit the use of active pharmaceutical ingredients from certain manufacturers.

EMA’s CHMP subsequently conducted a review of sartans, which finished in January 2019. While the network was looking at the lessons to be learnt from dealing with the sartans, impurities in a small number of other medicines were detected. This chapter describes the regulatory actions and measures taken throughout the year to protect public health, and the causes and consequences of nitrosamine impurities.

Focus on nitrosamines

N-nitrosamines are substances that are formed in certain chemical reactions in the environment; most people are exposed to them in small amounts in some foods as well as in drinking water. They are classified as probable human carcinogens (i.e. substances that could cause cancer in humans), on the basis of animal studies. The current regulatory guidelines set very strict limits.



The CHMP found that the risk from the N-nitrosamine impurities was low. In the vast majority of sartan medicines, nitrosamine impurities were either not detected or were present at very low levels. Given the greater risk to patients from stopping their treatments, the Committee advised patients not to stop their sartan treatments without consulting their healthcare professionals.

The review concluded that the use of a certain solvent (dimethylformamide) together with sodium nitrite in the presence of an acid led to the formation of N-nitrosamines during the manufacture of sartan active pharmaceutical ingredients (APIs). There was also a potential for contamination from other sources, including solvents, reagents and manufacturing equipment already contaminated with N-nitrosamines.

Therefore, the review set out new requirements for MAHs of sartan medicines, including the requirement to test their products for N-nitrosamines and make the necessary changes to their API manufacturing processes.

The CHMP also set interim limits for two N-nitrosamine impurities (NDMAiN-Nitrosodimethylamine and N-Nitrosodiethylamine. and NDEA) in APIs valid for a two-year transitional period. After this period, all companies must have implemented the necessary changes to their manufacturing processes to minimise the risk of nitrosamines contamination, with the goal of having no quantifiable N-nitrosamines in sartans. 

Lessons learnt from the presence of nitrosamine impurities in sartans

The European medicines regulatory network and the European Directorate for the Quality of Medicines & HealthCare (EDQM) launched a ‘lessons learnt exercise’ in order to look at possible approaches to prevent unexpected impurities such as N-nitrosamines from being present in human medicines and to improve management of such incidents, should they occur in the future. The publication of a report, including recommendations and a technical analysis, is envisaged for mid-2020. 


Following the detection of low quantities of a nitrosamine impurity in a few batches of the diabetes medicine pioglitazone manufactured in India, EMA called on companies to test their products and check their processes to rule out contamination.


After tests showed nitrosamine impurities in some batches of ranitidine, the European Commission asked EMA to conduct a regulatory review of these medicinesiunder Article 31 of Directive 2001/83/EC.. Ranitidine-containing medicines are widely used to treat and prevent conditions caused by excess acid in the stomach, such as heartburn and stomach ulcers. The CHMP started reviewing all available data with the aim of issuing recommendations in early 2020. 


As nitrosamine impurities had been detected in a number of medicines by September 2019, EMA’s Executive Director asked the CHMPiunder Article 5(3) of Regulation (EC) No 726/2004. to provide guidance to MAHs on how to avoid the presence of nitrosamines impurities, on the basis of what was known about their origins.

As a matter of precaution, the CHMP requested that MAHs for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines, perform a risk evaluation and test all products that might be at risk.

The CHMP has given companies six months from the start of the review to complete the risk evaluation and three years to complete the testing. The European medicines regulatory network plans to complete this exercise by 26 September 2022. 


Coordinating international efforts

Since the presence of nitrosamines in medicines was first discovered, it was clear that this issue would have global ramifications. This is a consequence of the close integration of the pharmaceutical global supply chain, with the lion’s share of APIs being produced in China and India.

To provide an adequate response to this challenge, the European medicines regulatory network enhanced its cooperation with international partners. Beginning with the sartans, an international strategic group was set up to coordinate the activities of the different regulators and facilitate the rapid exchange of information.

The close cooperation is ongoing with international partners such as Health Canada, US Food and Drug Administration, Japan’s Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency, Australia’s Therapeutic Goods Administration, Singapore’s Health Science Authority, and Swissmedic.


How the EU network manages incidents

The EU medicines regulatory network has set up the Incident Management Plan to establish procedures on how to deal with emerging information related to medicines safety in the EU. One of the main objectives is to have a coordinated approach at the EU level to manage incidents affecting the safety, quality or supply of medicines.

Within the context of the nitrosamine incidents, the EU network has utilised several organisational structures:

  • the Quality Defect rapid Alert system, which was established to circulate information concerning the recall of medicinal products due to quality defects or which are falsified within the network and to international partners and organisations;
  • the Incident Review Network (IRN), a virtual advisory network that reviews incidents and advises the network on approaches to take. The composition of the IRN includes staff members from the EMA, the EC and NCAs.

This approach has been reinforced by measures agreed in December 2019 with the network and pending the outcome of the article 5(3) review being undertaken by CHMP.