Medicines: Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing
Source: gov.uk (2025-09-03)

Marketing Authorisation Holders should review their manufacturing processes to identify and, if found, to mitigate the risk of nitrosamine impurities being present.

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 (https://www.ema.europa.eu/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf), as a precaution, marketing authorisation holders (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 October 2025: Clarification on step 2 submissions where multiple nitrosamines affect a product.

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
Step 1 risk evaluation outcomes must be provided for all products within the scope of the review irrespective of their marketing status.

The deadlines of the call for review (steps 1, 2 and 3) for medicines containing chemically synthesised and biological active substances have passed. Any MAH that has not notified the MHRA about identified nitrosamine impurities should report them as a matter of priority in line with the CHMP’s Article 5(3) opinion as well as any updates to previous notifications, using the response templates and available reporting mechanisms previously established.

MAHs are reminded of their responsibilities to ensure the quality, safety and efficacy of their medicines and to adhere to the nitrosamines guidance outlined by the MHRA. MAHs and Manufacturers should work together and take precautionary measures to mitigate the risk of presence of nitrosamines during the manufacturing and storage of all authorised medicinal products.

The MHRA will continue to take all necessary measures to protect patients and ensure that medicines in the UK meet the required quality standards.

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 (https://www.hma.eu/human-medicines/cmdh/nitrosamine-impurities.html)

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:

Step 1 no risk identified response template document (https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_406_2019_Rev1_2021_01-_Step_1_no_risk_identified_response_template.docx)

Step 1 risk identified response template document and spreadsheet (https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_407_2019_Rev.1_2021_01_-_Step_1_risk_identified_response_template.docx)

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 (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/872089/MHRA_Nitrosamine_Submission_-_Step_1.xlsx)

For further guidance, please read these tips and examples for successful submissions (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/884081/Tips_and_examples_for_successful_submissions.pdf) before submission.

eCTD format should not be used and the MAH should submit the completed forms as information updates via MHRA Submissions (https://www.gov.uk/guidance/registering-to-make-submissions-to-the-mhra-from-1-january-2021) 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 (https://www.hma.eu/human-medicines/cmdh/nitrosamine-impurities.html) 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:

Step 2 no nitrosamine detected response template document (https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_411_2019__Rev.2_08_2022_-_Step_2_no_nitrosamine_detected_template_for_response_01.docx)

Step 2 nitrosamine detected response template document (https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_409_2019_Rev.6_2023_07_clean_-_Step_2_outcome_notification_template_-_nitrosamine_detected.docx)

Step 2 nitrosamines detected above acceptable intake or new nitrosamine detected response template (https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_410_2019_Rev.1_2021_01-Step_2_-_Nitrosamine_detected_above_acceptable_intake_or_new_nitrosamine_detected_response_template.xlsx)

Submission Step 2 may be delayed beyond the deadline, for medicines that are not marketed on the due date, if no finished product batches are available for confirmatory testing. In such circumstances a Step 2, and if necessary, Step 3 submission must be submitted and approved before the product is placed on the market.

For national Marketing Authorisations where nitrosamines have been detected above the acceptable intake or where new nitrosamines have been detected, for efficient processing please also provide the following summary document which provides some additional guidance, a checklist of documents to be included in the submission and summary tables.

For nitrosamine impurities that are classified as non-mutagenic based on in-vivo mutagenicity studies, the submission of step 2 confirmatory testing is not required, and these impurities should be controlled according to ICH Q3A and ICH Q3B guidelines. To allow nitrosamine outcomes to be correctly recorded for each Marketing Authorisation, we ask Marketing Authorisation Holders to continue making step 2 submissions for these products. The cover letter should indicate that the identified nitrosamine is non-mutagenic and that therefore no test data are provided.

Summary document (https://assets.publishing.service.gov.uk/media/6152e38ee90e077a2db2e80b/Step_2_summary_document_template_Clean_23-09-2021.docx) (MS Word Document, 37 KB)

eCTD format should not be used and the MAH should submit the completed documents:

Existing MHRA Portal users should use the General Product Licensing Submission form

via MHRA Submissions (https://www.gov.uk/guidance/registering-to-make-submissions-to-the-mhra-from-1-january-2021) using the regulatory activity: Nitrosamine Step 2 – and sub-category: Original Submission.

For EU licences where Northern Ireland is CMS, the completed documents should be submitted as information updates via CESP using the regulatory activity ID: G0008 - Follow-Up Measure –and sub activity ID: H005 - Closing Documents.

Where multiple nitrosamines affect the same product, information relating to all relevant nitrosamines should be included in one submission.

Submissions may be bulked across different strengths of the same pharmaceutical form, provided their risk assessment outcome is identical.

Step 3 - Changes to the marketing authorization

Please refer to CMDh practical guidance for MAHs of nationally authorised products in relation to the Art. 5(3) Referral on Nitrosamines.

The necessary variation should be submitted through the usual channels by the above deadlines. It should be clearly identified in the reason comment that the change is the outcome of the Step 2 risk assessment and confirmatory testing.

Lifecycle management

MAHs are reminded of their responsibilities to ensure the quality, safety and efficacy of their medicines. MAHs are expected to continue to review and re-visit the outcome of the risk evaluation and risk assessment as and when new information becomes available. This includes:
- Changes to known root causes which may also affect the product in question, including when a new Acceptable Intake (AI) limit is published for the product in question.
- Changes in the product lifecycle that may require a revision of the risk evaluation and may change the outcome of the risk evaluation (e.g. changes to formulations, processes or supply chains).
Appropriate timelines for reviewing the previous risk evaluation and for conducting confirmatory testing (if needed), should be followed depending on the risk identified. 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.

The risk evaluation should be maintained throughout the lifecycle of the product. It should be provided as part of the updated CTD documentation whenever required for a variation submission. This would include, but is not limited to, changes to the active substance source or manufacturing process, changes to the finished product manufacturing process, composition or packaging.

MAH compliance with these obligations for nitrosamines will be subject to market surveillance through regular controls by competent authorities including during inspections.

CAPA Implementation

In case levels of N-nitrosamines are detected exceeding the AI, MAHs are expected to establish and implement corrective and preventive actions (CAPAs) without any delays in

order to ensure patients safety and product quality. The implementation of CAPAs and submission of step 3 responses should be done at the earliest opportunity, but within 3 years from the establishment and publication of the AI. If companies become aware that they will not be able to bring their product into compliance within this 3-year period, these companies should inform MHRA with detailed justification and timelines for completion of CAPAs.

Further guidance on acceptable intakes

The MHRA has provided further guidance related to acceptable intake limits (https://www.gov.uk/government/publications/nitrosamines-impurities-in-medicines).