Dissolution profile comparison is a key aspect of formulation development and regulatory submissions. However, when %RSD at the 5-minute time point exceeds 20%, direct f2 calculations may not be reliable, making it crucial to adopt alternative, agency-accepted methodologies.
Real-World Scenarios & Solutions
Scenario 1: Immediate-Release (IR) Tablets with High Variability at 5 min
- Challenge: In an IR tablet dissolution study, the first time point showed %RSD > 25% due to variability in disintegration.
- Solution: A Bootstrap f2 approach was used, where multiple resampling iterations provided a robust f2 value, ensuring regulatory acceptance.
Scenario 2: Poorly Soluble API with Inconsistent Initial Release
- Challenge: A BCS Class II drug showed significant variability at early time points due to API agglomeration.
- Solution: Multivariate Statistical Distance (MSD) and Chow & Ki’s method were applied to compare profiles, which was accepted by regulatory agencies.
- Challenge: A modified-release bead formulation had high %RSD at early time points due to non-uniform coating.
- Solution: The Mahalanobis Distance approach was used to assess overall dissolution similarity, successfully supporting a post-approval change.
Regulatory Perspective
Regulatory agencies, including FDA, EMA, and ICH, acknowledge that high variability at early time points can limit f2 applicability. Justifications with resampling methods like Bootstrap f2, alternative statistical techniques, and mechanistic understanding are often required for acceptance.
Read also:
- Comparative Dissolution Profile Guideline
- Global Regulatory Requirements for Multimedia Dissolution Testing
