Design space under ICH Q8(R2) is powerful, but in modified-release products it is often treated as statistics instead of science. Here is a practical, regulator-aligned method.
1. Define the objective linked to QTPP.
- Set a clear goal such as establishing a polymer operating range that delivers consistent dissolution across the lifecycle.
2. Define dissolution as time-specific CQAs.
- Use multiple time points (early, middle, final) such as percent release at 1 to 2 hours, 6 to 8 hours, and 12 to 24 hours.
3.Define polymer variables as CMAs.
- Include polymer level, viscosity grade, and blend ratio because they control gel strength, diffusion path length, and erosion.
4. Perform risk assessment.
- Use Ishikawa and FMEA to justify polymer concentration and viscosity as high-risk drivers of dissolution.
5. Select the DOE.
- Use factorial, Box–Behnken, or Central Composite Design and ensure it can detect interactions and curvature.
6. Execute DOE batches with controls.
- Fix non-critical parameters and vary DOE factors only, then test dissolution at predefined time points.
7. Build the model and interpret scientifically.
- Use regression and ANOVA, but focus on meaning of main effects and interactions, not only p-values.
8. Generate response surfaces and contour plots.
- Show how polymer level and viscosity shift dissolution and where control is robust.
9. Set dissolution acceptance limits.
- Define upper and lower boundaries at each time point based on RLD behavior and regulatory expectations.
10. Create overlay plots to define design space.
- The common region meeting all dissolution limits simultaneously is the design space.
11. Verify the design space.
- Make confirmation batches at low edge, high edge, and center and confirm dissolution robustness.
12. State regulatory significance.
- Per ICH Q8(R2), movement within an approved design space is not a regulatory change if quality is maintained.
- Design space is not a statistical exercise. It is a scientific commitment to true product understanding.
Read also:
Resource Person: Moinuddin Syed. Ph.D, PMP®
