Risks of N-Nitrosamine Impurities in Canadian Pharmaceuticals
Understanding the Threat
N-nitrosamine impurities, a class of potentially carcinogenic substances, have become a significant concern in the pharmaceutical industry. These compounds can form during the drug manufacturing process or due to degradation. In recent years, their presence in various medications has prompted regulatory bodies, including Health Canada, to take stringent measures to protect public health.
Health Canada’s Response
In response to the growing concern, Health Canada has issued comprehensive guidance for evaluating and managing the risks of N-nitrosamine impurities in human pharmaceutical, biological, and radiopharmaceutical products. The guidance outlines a stepwise approach for industry stakeholders, including:
- Risk Assessment: Companies must conduct thorough risk assessments to identify potential sources of N-nitrosamine contamination in their products. This involves evaluating raw materials, manufacturing processes, and storage conditions.
- Acceptable Intake Limits (AIs): Health Canada has established AI limits for specific N-nitrosamine impurities. These limits serve as benchmarks for determining acceptable levels of contamination.
- Confirmatory Testing: If the risk assessment indicates a potential for N-nitrosamine contamination, confirmatory testing is required to determine the actual levels of these impurities in the product.
- Mitigation Strategies: If N-nitrosamine impurities exceed acceptable limits, companies must implement effective mitigation strategies to reduce or eliminate contamination. This may involve changes to manufacturing processes, raw materials, or product formulation.
- Regulatory Reporting: Health Canada requires companies to report any findings of N-nitrosamine impurities above acceptable limits.
Recent Updates from Health Canada
Health Canada has recently updated the list of established Acceptable Intake (AI) limits (Appendix 1) posted online. The updates to Appendix 1 of the Health Canada Guidance on nitrosamine impurities in medications include:
- Nine (9) additional nitrosamine impurities and their corresponding CPCA-derived AI limits,
- Revised AI limits for three (3) nitrosamine impurities (N-nitroso-ciprofloxacin, N-nitroso-N-desmethyl-citalopram, and N-nitroso-sertraline (of note, the AI limit for N-nitroso-sertraline is reduced from 1,500 ng/day to 100 ng/day)), and
- A line listing for entacapone drug substance to indicate that NDEA (AI limit = 26.5 ng/day) is a structurally related impurity.
The list of established AI limits can be filtered by date to identify the most recent additions.
To access Health Canada’s updated Guidance on nitrosamine impurities in medications, please click on the following link: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html.
Key Considerations for Industry
- Proactive Risk Management: Companies should adopt a proactive approach to N-nitrosamine management by implementing robust quality control measures and conducting regular process reviews.
- Supply Chain Assessment: Careful evaluation of suppliers and raw materials is crucial to prevent N-nitrosamine contamination.
- Analytical Capabilities: Investment in advanced analytical techniques is essential for accurate detection and quantification of N-nitrosamine impurities.
- Regulatory Compliance: Staying updated on Health Canada’s guidance and regulations is vital to ensure compliance and protect public health.
The Road Ahead
While significant progress has been made in addressing N-nitrosamine impurities, the pharmaceutical industry continues to face challenges. Ongoing research and development are necessary to identify new sources of contamination and develop innovative mitigation strategies. Collaboration between industry, regulators, and academia is essential for ensuring the safety and efficacy of medications.
By adhering to Health Canada’s guidelines and implementing robust quality management systems, the pharmaceutical industry can effectively mitigate the risks associated with N-nitrosamine impurities and protect public health.
References
1- Health Canada’s updated Guidance on nitrosamine impurities in medications; https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html.
2- Google AI. Gemini (2024.07.25 Version) [Large Language Model]. https://gemini.google.com/app
About the author: Kossi Molley, PMP., LSSBB., Chemist