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

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

3. Basic Processing Sequence 3 RA Results

4. CPPs

5. Design Space Definition 5 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 6 courtesy: Dr. Steef. Boerrighter, Purdue University

7. Preliminary Design Space 7 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 8 Compression Force Bulk density 0.52 kg/m 3 Bulk density 0.46 kg/m 3 Median PS

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

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

11. Preliminary Tabletting Design Space 11

12. 12 Blending 12 Significant increase in STS at extreme conditions

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

14. L 0, D 0 ~ Drying CPP 14 D 0, crystal damage L 0, in-process lactam X – Wet Massing Time Y – Water Content

15. Preliminary Drying Design Space 15

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

17. Preliminary Granulation Design Space 17

18. Preliminary Design Space 18 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 19 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