European regulator finds at least 20 medicines with significant nitrosamine contamination

Exclusive: The European Medicines Agency has said products identified as containing nitrosamine above acceptable levels will likely require a variation in their marketing authorisation.
Ranitidine 150mg tablets on blister pack

The European medicines regulator has said it is “carefully considering” taking regulatory action after a review found that a significant number of medicines may contain contaminants linked with an increased risk of cancer.

Data provided to The Pharmaceutical Journal by the European Medicines Agency (EMA) reveal that 17% of centrally authorised chemical drug products have been identified as being at risk of nitrosamine contamination.

A spokesperson for the EMA said that the process of collecting data on all its products was continuing, but that so far only 15% of the identified products contained nitrosamines levels above the “acceptable intake” and will likely require a variation in their marketing authorisation.

This would equate to around 20 or more chemical products, according to previous figures seen by The Pharmaceutical Journal.

Limits have been established for some specific N-nitrosamines that refer to the “acceptable intake” of a specific substance, which is defined as an amount that carries a negligible risk to the individual; a theoretical excess cancer risk of <1 in 100,000 over a lifetime of exposure.

In the UK, several precautionary recalls have been carried out over the past year on specific batches of medicines to avoid further exposure to impurity levels above the set limit, including Accuretic 10/12.5mg film-coated tablets (quinapril hydrochloride; Pfizer), Accupro (quinapril hydrochloride; Pfizer) 5mg, 10mg, 20mg, 40mg film-coated tablets and Stemetil (prochlorperazine; Aventis Pharmacy Ltd [t/a Sanofi]) 5mg/5mL syrup.

In 2020, all licences for ranitidine medicines were suspended by the European Commission and the Medicines and Healthcare products Regulatory Agency (MHRA) after N-nitrosodimethylamine (NDMA) — a probable human carcinogen — was found to be present in unacceptable concentrations in batches of the drug.

In 2019, the EMA, and other medicines regulators around the world, asked marketing authorisation holders to carry out a comprehensive review of all chemical and biological human medicines for the possible presence of nitrosamines, with an initial risk evaluation due by 1 July 2021 and full confirmatory testing by 26 September 2022.

According to a spokesperson for the EMA, for centrally authorised products, the global response rate from marketing authorisation holders exceeded 95% and EU regulatory authorities were “carefully considering” the need to take regulatory action to protect public health, while ensuring availability of critical medicines and considering the risk of shortages.

“Concerning chemical products, a risk was identified for 17% of products and for these confirmatory testing has to be performed, in accordance with existing guidance,” they said.

“For biological products, a risk of nitrosamines was identified for only 1% of products.”

They added that, of the 17% of chemical products where a risk had been identified, 15% had been identified as containing nitrosamines above the acceptable intake and will therefore require a variation in marketing authorisation.

According to previous figures — presented on 8 December 2021 at the second meeting of the ‘Nitrosamine Implementation Oversight Group’, which was set up in 2021 — 136 centrally authorised products (16%) had a risk identified, compared to 704 (84%) with no risk identified.

The Pharmaceutical Journal contacted the MHRA about the review, but it was unable to provide final data; however, it did confirm that the majority of companies who had completed the two steps of the review had found there to be no risk. 

A spokesperson for the European Federation of Pharmaceutical Industries and Associations said: “Investigations so far have confirmed that the great majority of products are free from nitrosamine impurities, but companies continue to work closely with regulators to do further testing and compile more scientific evidence in this area.

“We have confidence in the robust international regulatory process underway. All action is being taken to introduce controls on nitrosamine impurities where necessary, while securing supply of essential medicines where possible.”

Last updated
The Pharmaceutical Journal, PJ, April 2023, Vol 310, No 7972;310(7972)::DOI:10.1211/PJ.2023.1.180953

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