Collaborative Efforts in Nitrosamine Testing: How Canada and the US Are Working Together to Ensure Drug Safety

The presence of nitrosamine impurities in pharmaceuticals has raised global concerns regarding drug safety and regulatory compliance. Nitrosamines are classified as probable human carcinogens, and their detection in common medications has prompted urgent regulatory actions by agencies such as the U.S. Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) (FDA, 2023). This blog explores the collaborative efforts between Canada and the United States in nitrosamine impurities testing and analysis, highlighting regulatory advancements, analytical methodologies, and best practices for pharmaceutical manufacturers.

Understanding Nitrosamine Impurities Testing in Canada and US

Nitrosamines are a class of chemical compounds formed from nitrites and secondary amines under specific conditions, such as in drug synthesis. These impurities were first identified in medications such as valsartan, leading to widespread recalls and increased scrutiny (EMA, 2021).

Sources of Nitrosamine Contamination

1. API (Active Pharmaceutical Ingredient) Synthesis: Chemical reactions involving nitrites can introduce nitrosamines.
2. Excipients and Raw Materials: Contaminants in solvents, catalysts, or starting materials.
3. Manufacturing Processes: High-temperature reactions and improper pH control can lead to nitrosamine formation.
4. Packaging and Storage: Migration of nitrosamine residues from plastic or rubber containers.
5. Cross-Contamination: Nitrosamine precursors interacting with residual substances in production lines.

Regulatory Landscape in Canada and the US

United States: FDA’s Approach

The FDA has issued multiple guidance documents outlining acceptable limits, testing protocols, and risk mitigation strategies for nitrosamines. Key regulatory actions include:

• Guidance for Industry (2020): Limits nitrosamine levels to 26.5 ng/day based on acceptable daily intake (ADI) thresholds (FDA, 2020).
• Testing and Reporting Requirements: Manufacturers must test for N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and other nitrosamines in APIs and finished products.
• Risk-Based Approach: Implementation of advanced analytical techniques like LC-MS/MS and GC-MS.

Canada: Health Canada’s Response

Health Canada aligns with international regulatory bodies to maintain drug safety standards. Its approach includes:

• Screening and Testing Requirements: Manufacturers must conduct nitrosamine risk assessments for all drugs.
• Recalls and Market Withdrawals: Immediate recall of high-risk medications with unacceptable nitrosamine levels.
• Analytical Method Development: Adoption of high-resolution mass spectrometry (HRMS) for enhanced detection.

Analytical Techniques for Nitrosamine Impurities Testing in Canada and US

High-Performance Liquid Chromatography (HPLC)

• Detects trace levels of nitrosamines in drug formulations.
• Commonly coupled with mass spectrometry (HPLC-MS/MS) for enhanced specificity.

Gas Chromatography-Mass Spectrometry (GC-MS)

• Ideal for detecting volatile nitrosamines.
• Used in regulatory testing labs to confirm contamination levels (ICH Q3D, 2019).

Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS)

• Provides high sensitivity for complex drug formulations.
• Detects low ppm levels of nitrosamines.

Fourier Transform Infrared Spectroscopy (FTIR)

• Identifies structural signatures of nitrosamines.
• Rapid screening tool for quality control labs.

Collaborative Efforts: Nitrosamine Impurities Testing in Canada and US

Regulatory Harmonization

Both FDA and Health Canada have aligned their regulatory frameworks to ensure consistency in nitrosamine impurity limits, analytical methods, and risk assessments.

Joint Research Initiatives

• North American Pharmacopoeial Collaboration: Sharing of validated analytical methods.
• Cross-border Workshops and Seminars: Training industry professionals on nitrosamine risk management.

Pharmaceutical Industry Partnerships

• ResolveMass Laboratories Inc. collaborates with leading drug manufacturers to develop customized nitrosamine testing protocols.
• Innovative Risk Mitigation Strategies: Reformulation of APIs to minimize nitrosamine formation.

Best Practices for Manufacturers

Proactive Risk Assessments

• Conduct thorough raw material screening.
• Implement good manufacturing practices (GMP) to control impurities.
• Regular batch testing for nitrosamine levels.

Advanced Testing Capabilities

• Invest in state-of-the-art analytical instruments for accurate detection.
• Leverage third-party testing labs for independent verification.

Compliance with Regulatory Requirements

• Stay updated with Health Canada and FDA guidelines.
• Maintain comprehensive documentation for regulatory audits.

Conclusion

The collaboration between Canada and the US is strengthening nitrosamine impurity testing and analysis, ensuring a higher standard of drug safety. With evolving regulations and advanced analytical technologies, pharmaceutical manufacturers must prioritize impurity testing to remain compliant and safeguard public health.

REFERENCES

1. Shabangu PP, Kuwana RJ, Dube A. Collaborative reliance in medicine safety and quality regulation: Investigation of experiences in handling N-nitrosamine impurities among ZaZiBoNa participating countries. Frontiers in medicine. 2022 Sep 9;9:975032.
2. Elder DP, Johnson GE, Snodin DJ. Tolerability of risk: A commentary on the nitrosamine contamination issue. Journal of Pharmaceutical Sciences. 2021 Jun 1;110(6):2311-28.
4. Nudelman R, Kocks G, Mouton B, Ponting DJ, Schlingemann J, Simon S, Smith GF, Teasdale A, Werner AL. The nitrosamine “saga”: lessons learned from five years of scrutiny. Organic Process Research & Development. 2023 Jul 26;27(10):1719-35.