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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 l.jpg

NIPTE-FDA Collaborative Case Study

On Model-based Design Space Development Across Scales & with Stability Considerations

Design Space Integration


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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


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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


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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


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Tabletting Design Space

Hydrophobicity = -26

+ 36 * Blend Time

=>

# of rotations are limited

Dissolution

Disintegration



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Dissolution

% dissolved @5 min = 63.3 – 2.4 * disintegration time

Disintegration is often limiting step for highly soluble drugs




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Single Unit Op

Design Space



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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


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Model Building

In-process lactam ~ max. product temperature

Lab scale



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Model Prediction

No need to run full factorial!!!

Single experiment to calibrate model parameters

Second experiment to verify model predictions



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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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