Interim Risk Assessment Report

1. National Institute for Pharmaceutical Technology and Education (NIPTE) Interim Risk Assessment Report

2. Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Identification Risk Analysis Risk Analysis Risk Evaluation Risk Evaluation unacceptable Risk Control Risk Communication Risk Management Tools Risk Reduction Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Process Risk Review Review Events Quality Risk Management • Brainstorming • Elementary Cause and Effect Assignments • Fishbone (Ishikawa) diagram • Failure mode/effect table • Fault tree analysis • Process map • Flow charts • FMEA • FMECA • Risk ranking • Process sensors • SOP • Data flow optimization From ICH Q9

3. Formulation Gabapentin 600 mg Poloxamer 407, NF 11 mg Crospovidone NF 22 mg Pregelatinized corn starch, NF 60 mg Mg Stearate, NF 7 mg MCC NF (Avicel PH102) 100 mg Talc USP Extra-fine 9 mg Hydroxypropyl cellulose 40 mg Hydroxypropyl cellulose 40 mg(Binder ) 3

4. Critical quality attributes Content uniformity Assay Disintegration Physical form of API Physical stability of API Purity Chemical stability Microbiology Appearance Unit operations Binder solution preparation Granulation Drying Granulate shipping Blending Compression Preliminary Risk Assessment 4

5. Example of Failure Mode Table

6. Histogram of all Failure Modes Assessed (RPN values) Medium High High: > 60 Medium: = 60

7. Preliminary RPN Results:Risks sorted by Unit Operation • Binder solution preparation • Number of risks assessed: 11 • No high or medium risk failure modes • Granulation • Number of risks assessed: 75 • High risk failure modes: 13 /75 • Medium risk failure modes: 20 /75 • Fluid bed drying • Number of risks assessed: 30 • High risk failure modes: 3 /30 • Medium risk failure modes: 16 /30

8. QbD Approach to Formulation Optimization • The original HPC grade (Klucel EXF, fine PSD) was sensitive to small changes in water content (lacking robustness) • A second HPC grade (Klucel EF, larger PSD) was more robust. • Similar PSDs were achieved using Klucel EF at 5.5% water as with Klucel EXF at 2.5%.

9. Comparing Granule PSD Produced from Different HPC Grades Granules formed with EF and 5.5% water were similar to granules formed with EXF and 2.5% water • Particle size distribution

10. Drying of Wet Granulations with 2 Different Grades of HPC

11. Klucel EXF Klucel EF Klucel EXF vs. Klucel EF

12. FBD Stability Concerns (Example Process Models and Design Space)

13. Summary of Drying Stability Specs • Residual moisture stabilizes granules and blends from lactam formation • Some residual moisture is good to decrease lactam formation, but too much residual moisture has flow and hardness consequences, which could result in content uniformity and disintegration problems. • High temperature drying results in higher lactam formation. • There was no improvement in efficiency by drying at higher temperatures due to increased cooling times, so low temperature drying is optimum.

14. Lab Scale Compression Data (Rotary Press) • By changing the extragranular HPC from Klucel EF (larger PS), to Klucel EXF (Fine PS), the crushing strength threshold of 6 kp was achieved.

15. Additional Assessment Efforts • Evaluate all stability data • Update design space models at each scale • Develop design space model across scales • Identify and document • Risks to product quality • Advantages of current methods for reducing risk • Modeling • Process monitoring/control