Guidance

Nitrosamines impurities in medicines

Published 24 August 2023

Acceptable intakes for nitrosamines – balancing recognition and independent national review

The Medicines and Healthcare products Regulatory Agency (MHRA) look to align nitrosamine-related regulations with international authorities, whilst ensuring the appropriate application in the United Kingdom. We adopt a harmonised approach to establish acceptable intake levels (AIs) based on ICH M7 guidelines.

We review European Union (EU) decisions on nitrosamine AIs, either recognising EU assessments or conducting national reviews based on product specifics. If AIs are exceeded, we conduct a national assessment for necessary market actions.

Ensuring consistency in nitrosamine intakes for the UK market

MHRA look to maintain consistency with the EU, considering historical ties, while reviewing information. If our assessments differ from European Medicines Agency (EMA) / Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) Q&A publications, our UK conclusions are directly communicated to affected Market Authorisation Holders (MAHs).

Implementing CMDh Q&A on nitrosamines in the UK

MHRA align with regulatory authorities like EMA, referencing the Article 5(3) referral during EU membership. The Q&A guidance by EMA and CMDh applies mostly in the UK. Any deviations from this guidance are communicated to stakeholders. We regularly assess changes in EMA/CMDh documents for UK applicability.

Divergent MHRA assessment outcomes from EMA/CMDh Q&A are directly shared with affected MAHs.

Common mistakes in nitrosamine submissions

We frequently encounter the following issues:

• Lack of initial submission details (e.g. Ames test, method validation, batch data)
• Incorrect use of step 2 cover letter templates
• Inaccurate declaration of LTL concept use
• Unclear or missing step 3 proposals
• Timelines not adhered to for step 1 and 2 submissions
• Misinterpretation of Call for Review scope
• Improper calculation of limits based on SmPC’s MDD
• Inadequate sensitivity of analytical methods
• Incomplete risk evaluation and assessment
• Insufficient details in read-across proposals
• Omission of batch information, burn rate, market share, and test data

Releasing batches with nitrosamines below AI

Products with nitrosamines < AI are safe for patients and can be marketed, requiring step 2 submission.

Releasing batches with nitrosamines above AI

Products surpassing AI are evaluated for LTL concept applicability, assessment outcomes are shared with companies. Immediate step 2 submission is required upon nitrosamine detection > AI, and DMRC should be contacted.

Temporary use of less-than-lifetime concept

Under specific circumstances, LTL concept can be used if aligned with EMA/CMDh Q&A, with product supply criticality considered. Detailed clinical & safety data is essential for concept justification.

Batch details, burn rate, market share, expiry date, and nitrosamine data should be included. Note that these concepts are temporary, and a proper AI should be used long-term.

Testing during establishment of new nitrosamine AI

Pending new nitrosamine AI, routine batch monitoring is advised to detect mutagenic impurities. Testing/skipping testing for products <10%/<30% of the general AI (18 ng/d) can be justified with appropriate batch data.

Chloramine consideration in risk assessments

MHRA does not have a set chloramine limit in purified water. Risks tied to water use should follow general risk assessment guidelines based on local purification systems.

Assessing new nitrosamines for toxicology

ICH M7 principles and EMA’s Q&A document guide AI development. Expert assessment using a weight of evidence approach is required. Negative Ames test supports an AI of 1.5µg/day. In vivo mutagenicity study results determine non-mutagenic impurity control.

Meeting call for review timelines

MHRA don’t plan to extend Call for Review timelines. Unmarketed products are step 2 exempt without available test data. Step 3 may be delayed accordingly. Product marketing should follow completed step 2 and 3.

We remind Market Authorisation Holders (MAHs) of their obligations under HMR Part 5, Reg 75(2) and 75(4)

Public information

This guidance is to help medicine manufacturers adhere to safe nitrosamine impurity levels. Impurities are non-medicinal components of drugs. While no harm evidence exists, prolonged high-level exposure might elevate cancer risks. Nitrosamine presence can result from manufacturing, chemical structure, storage, or body processing.

MHRA act on impurity investigations, set safe limits, and collaborate globally for patient safety.