APRIL 2019: DETECTION OF N-NITROSAMINES IN PIOGLITAZONE
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.
SEPTEMBER 2019: CHMP STARTS REVIEW OF NITROSAMINE IMPURITIES IN RANITIDINE MEDICINES
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.
SEPTEMBER 2019: GUIDANCE TO MAHS ON HOW TO AVOID THE PRESENCE OF NITROSAMINES
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.