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Art. 5(3) Referral on Nitrosamines

Last September EMA opened an Art.5(3) Referral to request the risk assessment of the presence of impurities (nitrosamines) in drugs for human use containing chemically synthesised Active Pharmaceutical Ingredients (APIs).

The request originated from the detection – back in 2018 – of nitrosamine impurities in some classes of drugs. The impurities found included N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).

As these impurities are considered as possible human carcinogen substances, Competent Authorities provided for a review of all classes of drugs to investigate their presence and establish the relevant threshold values.

EMA, National Authorities, EDQM etc. showed full cooperation, and trade associations also made themselves available, coordinating their members and circulating information, needs and requests as much as possible.

This review of all registrations involved all companies and all European Authorities, generating a huge amount of information and data to be necessarily managed.

In details, EMA asked MA holders to implement “precautionary measures to mitigate the risk nitrosamine formation” during the API and finished product manufacturing, or in the immediate packaging of their medicinal products.

The referral refers to all medicinal products containing chemically synthesised active substances and provides for subsequent 3 steps; its closure is scheduled in 3 years.

The first step provides for that MA holders inform Competent Authorities that they have carried out a specific Risk Evaluation of their own products. MA Holders, in strict cooperation with manufacturers of medicines and active substances, drafted and/or are drafting specific Risk Assessments on the presence of nitrosamines for all their medicinal products affected by the referral, indicating to the Authorities the conclusions of these assessments (also toxicological, if required).

In case a non negligible risk of nitrosamine presence is identified in the finished product, MA Holders shall inform the Authorities also including the timetable for the finalisation of (non optional) confirmatory studies, and providing a toxicological assessment in parallel.

The submission of the documentation produced with the assessments is not required. These documents shall be available at the company, should the Authorities require to consult them.


Trade associations officially requested to Competent Authorities for a time extension for the closure of the first step.

The deadline of 26 March, already considered rather limitative when the referral was published in (September 2019), has in fact become critical following the COVID-19 emergency that invested the whole Europe.

Following this request, EMA granted to postpone the closure of the first step until 1 October 2020.

The referral steps are summarised below:

  • Step 1: Risk Evaluation: a risk evaluation is requested to identify products at risk of N-nitrosamine formation or (cross-)contamination. The report should be finalised by 1 October 2020 at the latest.
  • Step 2: Confirmatory testing: further confirmatory testing should be performed on the products identified to be at risk of N-nitrosamine formation or (cross-) contamination. Report confirming the presence of nitrosamines should be available as soon as possible.
  • Step 3: Changes: any necessary changes to the manufacturing process resulting from this review should be applied using the established regulatory procedures.

Written by: Valeria Cardinale