Information and Guidance for Applicants on the Call for Review on Nitrosamine Impurities

The CHMP Article 5(3) Scientific Opinion on nitrosamine impurities and the call for review

In September 2019 the CHMP Article 5(3) referral opinion on nitrosamine impurities in human medicinal products was commenced. The resultant assessment report, published in June 2020, provides comprehensive insight and outlines several conclusions and recommendations on the issue of nitrosamine impurities.

As outlined in the assessment report, the recommendations are applicable to all human medicinal products. Recently, CMDh has clarified that the recommendations also apply to new applications/registrations for (traditional) herbal medicinal products (THMPs). All marketing authorisation holders (MAHs) and applicants of human medicinal products or new THMPs should continue to work with the manufacturers of their active pharmaceutical ingredients or herbal substances/preparations and finished products, to mitigate and control the presence of such impurities in their medicinal products.

Furthermore, 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. Though commenced in September 2019, the process is currently being finalised and is referred to as the ‘call for review’.

What are the required steps for completion by MAHs in the Call for Review?

The call for review requires MAHs to review their manufacturing processes to identify and mitigate, where necessary, any risk of nitrosamine impurities present in their medicines. This review is then reported back to authorities. The process consists of three steps as follows:

• 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. 
• Step 2 If a risk is identified in step 1, MAHs are required to perform confirmatory testing to confirm whether nitrosamines are present or not. MAHs should report these outcomes as soon as possible.
• 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.

What are the deadlines for completion of steps by MAHs in the Call for Review?

The deadlines for each step have now passed. Any outstanding submissions should be submitted by MAHs in the required format to the HPRA as soon as possible.

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.

Important additional national procedural requirements

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 known nitrosamines & are detected as part of Step 2, and the quantity detected exceeds the acceptable intake (AI) limit or exceeds the lifetime excess cancer risk of 1:100,000, the applicant should submit a Step 2 nitrosamine detected response template, required supporting documentation and do the following

• Copy qualitydefects@hpra.ie in the email when submitting the response
• Complete a Quality Defect report following the HPRA’s Guide to reporting and investigation of quality defects in human and veterinary medicinal products using the Quality defect reporting form for MAHs, manufacturers and wholesalers.
• Ensure the Excel file submitted specifically highlights the results where nitrosamine levels above the AI limit are detected.

Where unknown nitrosamines are detected in Step 2, the applicant should submit a Step 2 nitrosamine detected template, required supporting documentation and do the following:

• Calculate or propose an AI according to the EMA/CMDh Q&A on nitrosamines (Question 10). This limit will be reviewed at EU level and published in the Appendix 1 of the Q&A when finalised for MAHs to use.
• Copy qualitydefects@hpra.ie in the email when submitting the response if the level detected exceeds the proposed AI, to discuss the required action for affected batches intended for Ireland.
• Ensure the Excel file submitted specifically highlights the results where unknown nitrosamine levels above the proposed AI limit are detected.

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

What guidance is available on the issue of nitrosamine impurities for MAHs?

• Detailed guidance on the expectations around nitrosamines control from the CHMP opinion for the Article 5(3) referral is available in the EMA/CMDh Q&A for MAHs/applicants.
• 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’ e.g. further details on supporting documentation required. MAHs should engage with the defined process and relevant steps and required documentation as outlined by CMDh and EMA.

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

Queries:

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