In BCS Class II drug development, particle size distribution (PSD) is a critical attribute because it directly impacts dissolution and bioavailability. A common assumption is that the API manufacturer must test PSD using the same method as the finished product site. In reality, this is not required by regulatory authorities.
API suppliers and formulation sites can use different validated PSD methods as long as there is a scientifically justified correlation between them.
Why Methods Can Differ
Different PSD methods (dry vs wet dispersion, laser diffraction settings, dispersants, etc.) often produce slightly different numerical results. Regulators allow method differences as long as they provide equivalent control over the material.
What Correlation Should Demonstrate
A method correlation or bridging study is used to ensure that the supplier’s PSD results reliably predict the results obtained by the applicant’s method. A strong correlation generally demonstrates:
1. A consistent mathematical relationship between the two methods (linear, proportional, or constant bias).
2. Acceptable goodness of fit, typically with R² ≥ 0.9.
3. A predictable shift or ratio between supplier values and applicant values.
4. Low variability and no random scatter across multiple batches.
5. The ability to translate supplier PSD limits into equivalent in-house PSD limits.
This allows both parties to maintain independent specifications that control the same critical quality attribute.
How Suppliers Meet Applicant PSD Specifications
The supplier does not need to match the applicant’s numerical PSD limits. Instead, the supplier meets their own PSD specification, which has been shown through correlation to ensure the applicant’s PSD specification will also be met. This creates an equivalent control strategy aligned with ICH Q6A expectations.
Conclusion
For BCS Class II APIs, PSD controls are essential, but identical analytical methods are not. What matters is a well-defined correlation that links the supplier’s method and the applicant’s method, ensuring consistent dissolution performance and product quality.
