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MHRA Guidance: MAH Submission of Nitrosamine Risk Evaluation, Risk Assessment and Confirmatory Testing

Nitrosamines have become a significant concern in the pharmaceutical industry due to their potential carcinogenicity. In response to this issue, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has released an updated guidance (17 January, 2023) for "Marketing Authorisation Holders (MAHs) on the submission of Nitrosamine risk evaluations, risk assessments, and confirmatory testing" as part of the marketing authorisation application process.

Nitrosamines are a group of chemical compounds that are known to have carcinogenic properties. They can be formed during the manufacture of certain medicines, particularly those containing certain chemically active functional groups. Nitrosamines are a concern because even at low levels, they can pose a risk to patient safety over the long term.

This guidance provides detailed instructions where the Marketing Authorisation Holders should review their manufacturing processes to identify and, if found, to mitigate the risk of nitrosamine impurities being present. The recent update was the addition of guidance about lifecycle management in the existing guidance and details about the submission of Steps 1/2/3 (as applicable) as all deadlines have now passed.

  • Step 1: Risk Evaluation

  • Step 2: Risk assessment and confirmatory testing

  • Step 3: Changes to the marketing authorization

In the review, all medicinal products for human use have been included, including products containing chemically synthesized active pharmaceutical ingredients and biologically derived medicines, all of which are authorised in the United Kingdom, Great Britain (England, Scotland, and Northern Ireland) and Northern Ireland.

It is expected that MAHs will re-evaluate the risk evaluation results as 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.


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