Nitrosamine impurities – call for review

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 was finalised in June 2020. This assessment report 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 marketing authorisation holders (MAHs) and applicants of human medicinal products should continue to work with the manufacturers of their actives 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 MAHs for human medicines containing chemically synthesised and 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.

Guidance for MAHs

Detailed guidance on the expectations around nitrosamines control is available in the EMA/CMDh Q&A for MAHs/applicants on the CHMP opinion for the Article 5(3) referral.

For medicinal products within the scope of the ‘call for review’, the CMDh published further information and practical guidance for MAHs involved in the ‘call for review’. MAHs should engage with the defined process and relevant steps outlined by CMDh and EMA.

Steps for completion by MAHs

The call for review requires MAHs to review their manufacturing processes in order to identify and, if necessary, mitigate the risk of nitrosamine impurities being present in their medicines and report back to authorities. The exercise consists of three steps described below.

• In Step 1, MAHs are required to perform a risk evaluation to determine if APIs and/or finished products could be at risk of containing nitrosamines.  The deadline for the submission of step 1 responses has now passed. Any MAHs with outstanding step 1 submissions should submit these in the required format to the HPRA as soon as possible.
• In Step 2, if a risk was identified in step 1, MAHs are required to proceed with confirmatory testing in order to confirm whether nitrosamines are present or not. MAHs should report outcomes as soon as possible. Step 2 should be completed by 26 September 2022 for medicines with chemically synthesised APIs and by 1 July 2023 for medicines with biological APIs.
• In Step 3, if the presence of nitrosamines was confirmed at relevant levels, MAHs are requested to implement effective risk mitigating measures through submission of variation applications. Step 3 has been extended to 1 October 2023 for products containing chemically synthesised APIs to allow companies to conduct thorough investigation and establish any required risk mitigating actions.

Deadline for completion of steps

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

Whilst the risk from nitrosamines in medicines remains low, MAHs are reminded of their responsibility to ensure the quality, safety and efficacy of their medicines and are requested to implement the required testing and risk mitigating activities as a matter of priority and in accordance with the recommendations from the Article 5(3) procedure. EU and national authorities will continue to monitor the situation with respect to nitrosamines and take any actions necessary to uphold quality standards of medicines in the EU.

Additional national requirements for MAHs

MAHs are required to review the process and guidance as published by EMA and 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, the relevant excel file as published by CMDh must also be completed and provided as part of the response. For Step 2 nitrosamine responses the relevant excel file is only required in the situations described by CMDh published guidance.
• Where nitrosamines are detected as part of step 2, and the quantity detected exceeds the acceptable intake (AI) limitor exceeds 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 the above circumstance (i.e. limits exceeded) the applicant should also complete a Quality Defect report following the HPRA’s Guide to Reporting and Initial Investigation of Quality Defects in Medicinal Products for Human and Veterinary Use using the Quality Defect Report form.
• The excel file submitted as part of the response should specifically highlight the results where nitrosamine levels above the acceptable daily intake are detected.

In all instances, the MAH is responsible for performing an independent review of the data prior to submission.

Queries

In the event of further queries, please submit these to nitrosamines@hpra.ie.

Please also see the EMA's information for companies in respect of centrally authorised medicines.