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

2. Define Target Product Profile (TPP) Derive Quality Attributes from TPP Propose Manufacturing Process RiskAnalysis (FMEA) Risk Evaluation (Risk-based Classification) Propose Parameters to Investigate (e.g., by DOE) PROCESS DESIGN SPACE QbD process

3. RA Results Basic Processing Sequence

4. CPPs

5. Design Space Definition • For each unit op establish functional relationships of CPP and CQA of input materials with CQA of output materials • e.g. disintegration time ~ compression force and hydrophobicity • Establish interactions between unit ops • e.g. hardness ~ PSD and compression force • Establish design space boundaries by propagating backwards limits imposed on final product CQAs

6. Design Space Definition courtesy: Dr. Steef. Boerrighter, Purdue University

7. Preliminary Design Space • Considered • Degradation • NMT 0.4 mole % lactam • Hardness • NLT 3 kP • Weight variation • 90 % - 110% • % RSD NMT 6% • DS definition for 15 CPPs • Interactions were established for some CPPs • one or more slides included to describe those interactions • There were no significant interactions for few CPPs • ranges for those are shown in slide 18

8. Tablet Hardness ~ Intermediate CQA Compression Force Median PS Median PS Bulk density 0.46 kg/m3 • Bulk density 0.52 kg/m3

9. Tablet Hardness ~ Intermediate CQA • PAT application: • Real time measurement of bulk density and particle size

10. Tablet Hardness ~ Tabletting CPP Min Punch Gap Comp. Height Comp. Height Press speed 21120 tab/hr • Press speed 63360 tab/hr

11. Preliminary Tabletting Design Space

12. Blending Significant increase in STS at extreme conditions 12

13. Tablet Hardness ~ Drying CPP EEF Comp. Force End Moisture Target = 0.5% End Moisture Target = 1% Comp. Force

14. L0, D0 ~ Drying CPP L0, in-process lactam D0, crystal damage X – Wet Massing Time Y – Water Content

15. Preliminary Drying Design Space

16. Tablet Hardness ~ Granulation CPP Water Content Comp. Force Comp. Force WMT=0s WMT=60s

17. Preliminary Granulation Design Space

18. Preliminary Design Space • Granulation • Impeller speed • 500 RPM • Fr 1.20 • Critical Fr determined for 4 L Gral at 250 RPM = 0.30 • Drying • End Product Target Temperature • 25°C – 30°C • Blending • 15 – 25 RPM • 60% – 80% fill ratio • # of rotations: 42-125

19. Summary • Risk Assessment helps to identify CPP • Preliminary Design Space is defined by backward propagation • Some PPs identified by RA are not critical in the explored experimental domain • Preliminary Design Space is constructed for: • Wet granulation • Fluidized bed drying • Blending • Tabletting • Some interactions between unit ops were considered • Tabletting and intermediate CQA • Fluidized bed drying and tabletting • Wet granulation and tabletting