Nitrosamine Impurities

CHMP Article 5(3) Scientific Opinion

The assessment report of the Article 5(3) referral to CHMP, regarding nitrosamine impurities in human medicinal products, which commenced in September 2019 has now been finalised. This assessment report can be accessed from the EMA website and provides a comprehensive insight into the issue of nitrosamine impurities and outlines a number of conclusions and recommendations. As outlined in the assessment report, the recommendations are applicable to all human medicinal products. All MAHs/applicants of human medicinal products should continue to work with the manufacturers of their active pharmaceutical ingredients and finished products, to mitigate and control the presence of such impurities in their medicinal products. 

Furthermore, the EMA’s human medicines committee (CHMP) has requested as a matter of precaution that marketing authorisation holders (MAHs) for human medicines containing chemically synthesised and now also biologically derived active substances review their medicines for the possible presence of nitrosamines, test all products at risk, and submit variations to the marketing authorisation as required. This process is referred to as the ‘call for review’ and is an ongoing exercise that commenced in September 2019.

For medicinal products within the scope of the ‘call for review’, MAHs should engage with the defined process and relevant steps outlined by CMDh and EMA. Further practical guidance for MAHs involved in the ‘call for review’ has been published by CMDh, and is available on the HMA website. This includes information on the procedural aspects to be followed for non-centrally authorised products and the deadlines to be adhered to. The deadlines for completion of the various steps have recently been amended, and the deadlines differ between chemical and biological medicinal products. Please see the table below for information on deadlines. 

MAHs are required to review the process and guidance as published by CMDh, submit the required information and to note the following additional national procedural requirements.

  • The responses outlined should be submitted in the agreed CMDh template format to nitrosamines@hpra.ie including the required email headings and details. For step 1 responses, the inclusion of several products in one template where the outcome is the same, as outlined by CMDh can be accepted.

  • Where the risk of a nitrosamine impurity is identified as part of Step 1, or nitrosamines are detected as part of Step 2, the relevant excel files as published by CMDh must also be completed and provided as part of the response.

  • Where nitrosamines are detected as part of step 2, and the quantity detected exceeds the acceptable intake limit (AI) or exceeding the lifetime excess cancer risk of 1:100,000, the applicant should also copy qualitydefects@hpra.ie in the email when submitting the response. 

In all instances, the MAH is responsible for performing an independent review of the data prior to submission. In the event of further queries, please submit these to nitrosamines@hpra.ie.

Further information for companies in respect of centrally authorised medicines is available from the EMA website.

Deadlines for completion of steps

The deadlines for each step are outlined in the table below. 

Step Number

Chemical Medicinal Products

Biological Medicinal Products

Step 1 – Risk Evaluation

31 March 2021

01 July 2021

Step 2 – Confirmatory Testing

26 September 2022

01 July 2023

Step 3 – Submission of relevant changes

26 September 2022

01 July 2023


Submitting Step 1 risk evaluation responses 

Please submit Step 1 ‘risk identified’ or ‘no risk identified’ outcome templates to nitrosamines@hpra.ie by 31 March 2021 for chemical products by and by 1 July 2021 for biological products.

MAHs should follow closely the practical guidance available on the CMDh website under ‘Advice from CMDh /Nitrosamine impurities’ and submit only the requested declarations, using the required templates, under the appropriate email headings. No supplementation of the Step 1 declarations with unrequested information, or revision of previous declarations from ‘risk’ to ‘no risk’ may be undertaken.

The risk evaluation documents do not have to be submitted at this point but should be available on request. Where any risk has been identified, the MAH should progress immediately to Step 2 of the call for review, i.e. confirmatory testing, and establish whether nitrosamine is detected or not in the finished product using validated analytical methods.

Further information on the development of analytical methods is available in the EMA/CMDh Q&A for MAHs/applicants on the CHMP opinion for the Article 5(3) referral.