Nitrosamine Impurity Testing For Health Canada: What You Need To Know

Nitrosamine impurities have become a major concern in pharmaceutical manufacturing due to their potential carcinogenicity. Regulatory bodies including Health Canada, EMA, and US FDA now enforce strict controls on nitrosamine levels in drug products. For Canadian submissions—such as New Drug Submissions (NDS) and Abbreviated New Drug Submissions (ANDS)—compliance with Health Canada’s specific requirements is essential for approval and continued market access.

Understanding Nitrosamines

Nitrosamines can form unintentionally during drug production, particularly when secondary or tertiary amines react with nitrites. Compounds such as NDMA and NDEA are probable human carcinogens. Their detection in several medications has led to widespread recalls and renewed regulatory scrutiny.

Health Canada’s Regulatory Approach

Health Canada follows a science- and risk-based framework consistent with ICH M7(R2). Key regulatory expectations include:

• Comprehensive risk assessments (covering APIs, excipients, packaging, and dosage forms)
• Validated analytical testing using sensitive methods like LC-MS/MS or GC-MS
• Implementation of risk mitigation when nitrosamine presence is possible
• Scientific justification in regulatory submissions
• Continuous monitoring and prompt reporting of levels exceeding acceptable limits

Acceptable Intake (AI) Limits for Select Nitrosamines

Key Elements for Compliance

1. Risk Assessment

Manufacturers must evaluate all materials and processes for potential nitrosamine formation, including:

• API synthesis routes
• Use of nitrites, amines, and other reactive agents
• Packaging and storage considerations

2. Analytical Testing

When risks are identified, testing must be performed using validated, sensitive methods such as:

• LC-MS/MS – Ideal for detecting non-volatile nitrosamines
• GC-MS – Best suited for volatile compounds like NDMA
• HRMS/NMR – Used in identifying unknown nitrosamines

3. Risk Mitigation Strategies

Mitigation may involve:

• Modifying API synthesis
• Reformulating products
• Sourcing alternative raw materials
• Adjusting process or storage conditions

4. Regulatory Documentation

Submissions must include:

• Detailed risk assessments
• Confirmatory testing results
• Justification for mitigation approaches
• Updates via NDS, ANDS, or Annual Drug Notifications (ADN)

5. Reporting Obligations

Exceeding AI limits requires immediate reporting to Health Canada and may result in:

• Product recalls
• Additional inspections
• Reassessment of benefit-risk profiles

Lifecycle and Ongoing Compliance

Nitrosamine control is a continuous process. Health Canada expects regular reassessments, especially following changes in formulation, suppliers, or manufacturing methods. Predictive tools like QSAR may be used to evaluate novel nitrosamines.

How Maven Scientific Laboratories Can Help

Maven provides comprehensive support for regulatory and analytical compliance, including:

• Risk Assessments – Evaluation across APIs, excipients, and packaging
• Toxicology Support – AI limit derivation per ICH and Health Canada guidance
• Analytical Testing – LC-MS/MS, GC-MS method development and validation
• Regulatory Services – NDS, ANDS, and DIN documentation
• Ongoing Monitoring – Batch testing and impurity profiling
• Sample Logistics – Global coordination of samples and data

When Is Nitrosamine Testing Required?

Testing and assessments may be needed during:

• NDS and ANDS submissions
• DIN renewals
• Regulatory responses
• Routine QC and post-market surveillance

Conclusion

Health Canada requires a proactive, scientifically sound approach to managing nitrosamine risks. By partnering with Maven Scientific Laboratories, companies can ensure their products meet stringent regulatory standards while maintaining patient safety and product integrity in Canada and international markets.