Guidance on Nitrosamine Impurities in Medications
Updated: August 1, 2025.
Health Canada has released a major update to its Guidance on Nitrosamine Impurities in Medications that took effect on August 1, 2025. This updated version introduces stricter limits, more listed impurities, and clearer expectations for pharmaceutical companies. It’s a crucial step toward ensuring the safety of drug products across Canada.
At ResolveMass Laboratories, we help companies navigate these new requirements with ease. In this article, we break down the key updates and explain how your company can stay compliant under the revised framework.
🔍 Overview of the New Guidance on Nitrosamine Impurities in Medications
The August 2025 revision expands Health Canada’s regulations regarding nitrosamine contamination. A total of 17 new nitrosamine compounds have been added to the list, each with specific Acceptable Intake (AI) limits. Timelines for implementing corrective actions have also been updated, along with more detailed guidance on confirmatory testing and risk management.
These updates are designed to align with international standards and help improve patient safety.
Expanded List of Nitrosamines in the Guidance on Nitrosamine Impurities in Medications
17 New Nitrosamine Impurities and AI Limits
Health Canada’s latest update now includes 17 additional nitrosamine impurities. Each one is assigned a specific AI limit using the Compound-Specific Potency Category Approach (CPCA). This means manufacturers need to evaluate every product in their pipeline to see if these impurities are present or could form during manufacturing.
Failing to do so could result in non-compliance or product recalls, so early assessment is key.
Revised AI for N-Nitroso-N-desmethyl-doxylamine
| Compound | Previous AI (ng/day) | New AI (ng/day) |
|---|---|---|
| N-Nitroso-N-desmethyl-doxylamine | 18 | 100 |
The increased limit allows more flexibility in product formulation while still maintaining a safe threshold for patients. This change also aligns Canada’s standards more closely with international regulations.
Learn more about Risk-Based Assessment
CAPA Timelines and Risk Management
New Timelines for CAPA Implementation
| AI Limit Type | CAPA Deadline |
|---|---|
| Published before Aug 1, 2025 | Until August 1, 2028 |
| Published on/after Aug 1, 2025 | Three years from publication date |
These updated timelines give manufacturers more time to take necessary corrective and preventative actions (CAPA). However, companies should start immediately, especially for products with higher patient risk.
Lifetime AI Limits Only
The guidance now mandates the use of Lifetime AI limits for all products, regardless of how long the drug is used. Health Canada has officially removed Less-than-Lifetime (LTL) thresholds from its framework.
This means every risk assessment and safety review must now consider long-term exposure, not just short-term use.
Technical Requirements in the New Guidance on Nitrosamine Impurities in Medications
Confirmatory Testing Aligned with ICH Q3A/Q3B
Manufacturers must now follow ICH Q3A (for drug substances) and ICH Q3B (for drug products) guidelines when testing for nitrosamines. These international standards help ensure consistency and accuracy in impurity analysis.
Following these guidelines also supports faster approvals during audits or regulatory reviews.
Support for Confirmatory Testing
LOQ Validation and Sensitivity
All testing methods must now validate the Limit of Quantitation (LOQ). This confirms that the testing method is sensitive enough to detect even tiny amounts of nitrosamines.
LOQ validation is especially important when demonstrating your product’s safety and the reliability of your lab results.
Regulatory Flexibility and Reformulation
Handling Supplements and Post-DIN Changes
Minor product changes that don’t increase nitrosamine risk may no longer require a regulatory submission. This helps manufacturers manage product changes more efficiently without unnecessary delays.
Always maintain proper documentation to show that these changes are risk-free.
Using Alternative Risk Control Methods
If the formation pathway of nitrosamines is well understood, alternative control methods—like using antioxidants or pH modifiers—may be accepted. However, these alternatives must be backed by strong scientific data.
Reformulation and Bioequivalence Requirements (Appendix 5)
Appendix 5 outlines the new expectations for drug products reformulated to include nitrosamine-reducing agents such as:
- Antioxidants
- pH modifiers
- Chelating agents
Companies must prove that reformulated products remain therapeutically equivalent to the original versions. This includes conducting full bioequivalence studies.
How ResolveMass Supports Nitrosamine Compliance
ResolveMass Laboratories offers full-service support to pharmaceutical companies aiming to comply with Health Canada’s latest updates. Our specialized services include:
- Orphenadrine Nitrosamine Testing
- Nizatidine Nitrosamine Testing
- Metformin Nitrosamine Testing
- AI Risk Evaluation
We work closely with your team to ensure your products remain safe and compliant under the updated Guidance on Nitrosamine Impurities in Medications.
❓ Top 10 FAQs About the 2025 Guidance on Nitrosamine Impurities in Medications
The latest update includes 17 newly listed nitrosamines with established Acceptable Intake (AI) limits. It also revises timelines for implementing CAPAs and introduces stricter technical requirements, such as LOQ validation and expanded confirmatory testing based on international guidelines.
Yes. If any of the newly identified nitrosamines could be present or form in your drug product, confirmatory testing must be carried out. A fresh risk assessment is also required to comply with the new Health Canada guidance.
Products with AI limits published before August 1, 2025, must complete CAPAs by August 1, 2028. For AI limits published after that date, companies have three years from the specific publication date to complete the corrective and preventative actions.
No. Health Canada now mandates the use of Lifetime AI limits for all products, regardless of treatment duration. This shift is aimed at providing more conservative and long-term protection for patient safety.
Yes, alternative mitigation strategies such as antioxidants, pH modifiers, or chelating agents may be used—if the root cause of nitrosamine formation is understood and scientifically justified. Proper documentation is essential to support their use.
Not necessarily. If a detailed risk assessment shows that nitrosamine levels are within safe limits and manageable through existing controls, reformulation may not be required. However, any changes must still meet regulatory expectations.
You should prepare complete risk assessments, validated testing data, CAPA implementation plans, and scientific justifications for any alternative control strategies. All documentation must be clear, accurate, and aligned with the revised guidance.
Validation should involve matrix-matched samples, certified reference standards, and statistical analysis to ensure trace-level detection capability. This process confirms that your method is sensitive and reliable, especially for regulatory inspections.
Missing the deadline can result in serious regulatory consequences, including warning letters, product recalls, or suspension of your drug product’s market authorization. Companies are encouraged to act early and stay on schedule.
ResolveMass Laboratories offers end-to-end support including nitrosamine testing, LOQ validation, regulatory consulting, and CAPA strategy development. Our team helps ensure your drug products meet all requirements under the 2025 guidance.
📌 Final Thoughts on the 2025 Guidance on Nitrosamine Impurities in Medications
The 2025 update from Health Canada represents a big shift in how pharmaceutical companies must manage nitrosamine impurities. With more compounds listed and stricter compliance rules, it’s essential to take action early.
ResolveMass Laboratories is here to help you meet these new standards confidently—with expert testing, documentation, and regulatory support every step of the way.
