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Design Space Integration

NIPTE-FDA Collaborative Case Study On Model-based Design Space Development Across Scales & with Stability Considerations. Design Space Integration. Design Space Integration. Considered Degradation NMT 0.4 mole % lactam Hardness NLT 3 kP Weight variation 90 % - 110% % RSD NMT 6%

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Design Space Integration

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  1. NIPTE-FDA Collaborative Case Study On Model-based Design Space Development Across Scales & with Stability Considerations Design Space Integration

  2. Design Space Integration • Considered • Degradation • NMT 0.4 mole % lactam • Hardness • NLT 3 kP • Weight variation • 90 % - 110% • % RSD NMT 6% • Dissolution • NLT 40% @ 5 min • Disintegration • NMT 10 min

  3. Shelf Life Design Space Probability of lactam < 0.4 mole % after 2 years @ 22°C Low Moisture max p=0.7 Medium Moisture max p=0.71

  4. Tabletting Design Space % dissolved @5 min =78.1 – 0.1 * hydrophobicity – 3.0 * hardness disintegration time =-4.54 + 0.86 * hydrophobicity + 0.06 * hardness Hydrophobicity Hardness

  5. Tabletting Design Space Hydrophobicity = -26 + 36 * Blend Time => # of rotations are limited Dissolution Disintegration

  6. Dissolution Data (provided by FDA)

  7. Dissolution % dissolved @5 min = 63.3 – 2.4 * disintegration time Disintegration is often limiting step for highly soluble drugs

  8. Single Unit Op

  9. Unit Op Interactions

  10. Single Unit Op Design Space

  11. Unit Op Interactions

  12. Design Space Integration • Tablet weight variation = f (spray rate, impeller speed) • within USP limit • In-process lactam is well below 0.4 mole % • a meaningful limit may be established only after accelerated stability studies

  13. Model Building In-process lactam ~ max. product temperature Lab scale

  14. Model Validation (Lab Scale)

  15. Model Prediction No need to run full factorial!!! Single experiment to calibrate model parameters Second experiment to verify model predictions

  16. Model Prediction (Intermediate Scale)

  17. Summary Design space for shelf life stability determined Unit op interactions determined Design space for each unit op can be determined by backward propagation Models help to predict process behavior at larger scale => save on experimental effort

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