Medicines Healthcare Products Regulatory Agency
Overview
In accordance with the CHMP opinion under Article 5 (3) of Regulation (EC) No. 726/2004 on the presence of nitrosamine impurities in human medicinal products, as a precaution, MAHs should review their manufacturing processes to identify and, if found, to mitigate the risk of nitrosamine impurities being present.
MAHs should work with manufacturers of API and finished products in order to review the API and finished product manufacturing processes in light of the arrangements for preventing nitrosamine formation as well as contamination or cross-contamination. This should take into account their knowledge of the manufacturing processes as well as the potential sources of nitrosamine impurities.
Update July 2023: Clarification regarding the recent CMDh Q&A update (version 16) is provided.
Deadline and inclusion of biological medicinal products
The scope of the review has been widened to cover all medicinal products for human use. For example, it includes medicinal products containing chemically synthesised active pharmaceutical ingredients, as well as biological medicinal products) authorised in the UK, Great Britain (England, Scotland and Wales) and Northern Ireland.
The following deadlines are applicable:
Step 1
- Chemical medicinal products: 31 March 2021
- Biological medicinal products: 1 July 2021
Step 2
- Chemical medicinal products: 26 September 2022
- Biological medicinal products: 1 July 2023
Step 3
- Chemical medicinal products: 1 October 2023
- Biological medicinal products: 1 July 2023
The deadline for the submission of Step 1 risk evaluation outcomes for medicines containing chemically synthesised API has now passed.
MAHs that have not submitted the Step 1 risk evaluation outcomes for these medicines are reminded to comply with the conclusions of the CHMP (EMA Committee for Medicinal Products for Human Use) Scientific Opinion and provide a Step 1 submission as a matter of priority.
Step 1 risk evaluation outcomes must be provided for all products within the scope of the review irrespective of their marketing status.
The Step 3 deadline has been extended to 1 October 2023 for chemical medicinal products to enable companies to perform a thorough investigation and to establish any required risk mitigating actions in light of new scientific developments since 2020, in particular those concerning active substance-derived nitrosamines. This extension does not affect the deadline for completing the Step 2 confirmatory testing for chemical medicines, which remains 26 September 2022. Marketing authorisation holders should submit complete Step 2 outcomes by this deadline.
Article 5(3) Submission of Nitrosamine risk evaluation
We confirm that, following review by the Commission of Human Medicines (CHM), the changes to Q10 of the CMDh Q&A document on nitrosamines that were introduced with version 16 of the document in July 2023 are also applicable in the UK.
Step 1 - Risk Evaluation
The following guidance is for all UK, Great Britain and Northern Ireland MAHs and should be followed to submit the outcomes of the Stage 1 nitrosamine risk evaluation, as detailed in the guidance CMDh practical guidance for MAHs of nationally authorised products in relation to the Art. 5(3) Referral on Nitrosamines.
Step 1 risk evaluation outcomes must be provided for all products within the scope of the review irrespective of their marketing status.
Please refer to Information on Nitrosamines for Marketing Authorisation Holders
For all products licensed in the UK, Great Britain and Northern Ireland (including UK National licences and EU licences where UK is RMS or CMS), MAH should submit one of two templates supplied by CMDh depending on the risk evaluation outcome:
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Step 1 no risk identified response template document
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Step 1 risk identified response template document and spreadsheet
Completed template file names should begin with the relevant UK number i.e. PL, PLGB or PLNI as appropriate for easy identification and no documents should be scanned or locked. It must still be possible for accurate, automated, text copying to occur from the completed document.
For efficient processing please also provide a table with all submissions using the MHRA excel template below, ensuring the minimal requirements requested are fully completed for each product on separate rows. There is no requirement for a separate cover letter to be sent with the templates and no other spreadsheets will be required by the MHRA at Step 1. Bulks of up to 20 completed risk assessment forms with the same outcome will be accepted only if supported by tabulated details of the bulk submission in the template provided. Each bulk should be submitted as a separate submission. Please note the specific format requirements for the PL/PLGB/PLNI number - further examples are provided in the tips and examples for successful submissions document below.
Step 1 MHRA Excel Table template
For further guidance, please read these tips and examples for successful submissions before submission.
eCTD format should not be used and the MAH should submit the completed forms as information updates via MHRA Submissions using the regulatory activity: Nitrosamine Step 1 and sub-category: Response.
For EU licences where Northern Ireland is CMS, the completed forms should be submitted as information updates via CESP using the regulatory activity ID: G0008 - Follow-Up Measure and sub activity ID: H005 - Closing Documents.
The submission of the risk evaluation template as the outcome of Step 1 can take place only once.
- If the Step 1 template is submitted with risk identified, it cannot be subsequently revised by a Step 1 re-submission. Confirmatory testing should commence immediately and a Step 2 submission should follow no later than the published deadline.
- If the template is submitted with no risk identified and a risk is subsequently identified, Step 1 should be resubmitted and confirmatory testing commenced immediately. Step 2 submission should follow no later than the published deadline.
Any changes to the risk classification must be handled in the product life cycle by submission of an appropriate procedure supported by a cover letter and all supporting data.
Please note that for MAs for which no risk is identified in Step 1, the detailed risk evaluation documents should be introduced into the CTD sequence (in section 3.2.P.5.5 or 3.2.P.5.6 with cross-references in the dossier as required) by including them at the next regulatory opportunity (i.e. quality variation). These documents are included in the CTD for information only and will not be routinely assessed.
Step 2 Risk assessment and confirmatory testing
Please refer to CMDh practical guidance for MAHs of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines. For all products licensed in the UK, Great Britain and Northern Ireland (including EU licences where Northern Ireland is CMS) the MAH should submit the templates supplied by CMDh depending on the outcome of the confirmatory testing: