One of the most frequent technical questions I encounter during Nitrosamine Risk Assessment discussions is: Should nitrosamine testing be performed on a single unit dose or on the Maximum Daily Dose (MDD)?
This question is important because regulatory limits for nitrosamines are defined as ng/day, not per tablet or capsule.
Regulatory Principle
EMA, FDA, WHO and other agencies assess patient exposure based on Maximum Daily Intake. Therefore, the final comparison must always be made at the MDD level.
However, this does not automatically mean that laboratories must physically test the full MDD quantity in all cases.
Accepted and Widely Used Approach
For simple, uniform solid oral dosage forms (such as immediate-release tablets and capsules), the following approach is considered scientifically and regulatorily acceptable:
- Analyze nitrosamine content in a single unit (tablet/capsule)
- Calculate nitrosamine per unit (ng/unit)
- Multiply by the number of units constituting the Maximum Daily Dose
- Compare the calculated ng/day value with the applicable Acceptable Intake (AI) limit
This approach is acceptable when:
- The formulation is homogeneous
- The manufacturing process does not create localized nitrosamine formation
- Unit-to-unit variability is not expected
- The analytical method is validated and suitable
This is the most common industry practice for IR tablets and capsules.
When Single-Unit Scaling Is NOT Appropriate
Testing only a single unit and scaling to MDD is not recommended for complex or non-uniform systems, such as:
- Coated tablets where coating materials may contribute to nitrosamine risk
- Bilayer or multilayer tablets
- Multiparticulate systems (pellets, MUPS)
- Disproportionate formulations across strengths
- Products with known process-related nitrosamine variability
In these cases, direct testing of the actual MDD quantity is scientifically justified and preferred.
Key Regulatory Takeaway
Regulators are concerned with total daily exposure (ng/day), not the specific sampling strategy, provided the approach is scientifically justified, risk-based, and well documented in the Nitrosamine Risk Assessment (CTD 3.2.P.5.6).
Final Conclusion
- Maximum Daily Dose is the regulatory exposure reference
- Single-unit testing with mathematical scaling to MDD is acceptable for uniform formulations
- Full MDD testing is required for complex or heterogeneous dosage forms
- Scientific justification and documentation are critical
A clear, risk-based rationale not only satisfies regulatory expectations but also avoids unnecessary testing and delays.
Read also:
- Nitrosamine Risk Assessment for Human Drug Products
- How Are Nitrosamine Impurities Generated in Pharmaceuticals?
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