National Institute for Pharmaceutical Technology and Education (NIPTE) Interim Risk Assessment NIPTE ‘=:Quality Risk Management Trine Quality Risk Management Process Risk Communication “7 Review Events Rik Asem Risk Identification Risk Analysis Rak Control Brainstorming Elementary Cause and Effect Assignments — Fishbone (Ishikawa) diagram — Failure mode/effect table Fault tree analysis Process map Flow charts Risk Acceptance “Output Result of the ity Risk Management Process soon apdateuene RT FMEA FMECA Risk ranking From ICH Q9 inepreving Gaal ad NIPTE i=: Process sensors SOP Data flow optimizationFormulation Gabapentin Poloxamer 407, NF Crospovidone NF Pregelatinized corn starch, NF Mg Stearate, NF MCC NF (Avicel PH102) Talc USP Extra-fine Hydroxypropy! cellulose Hydroxypropyl cellulose (Binder ) 600 mg 11mg 22mg 60 mg 7mg 100 mg 9mg 40 mg 40mgPreliminary Risk Assessment Critical quality attributes + Unit operations — Content uniformity - Binder solution preparation — Assay — Granulation — Disintegration - Drying — Physical form of API — Granulate shipping — Physical stability of API - Blending — Purity — Compression — Chemical stability — Microbiology — AppearanceExample of Failure Mode Table S | O | D | RPN Effect Cause Effect (CQA) —_| Mechanism of tablets effect | Scale-up | Unit op Cause 1 Homogeneity 4[2]|2| 6 Disintegration of HPC x Blending Inadequate blending Hydrate formation Physical form during s|{a|a] so API Processing x Granulation ‘Time as wet mass The (CQA) test is out of specification because (mechanism of effect). The source of the problem is in (Unit operation) and is caused by (Cause), caused by (Cause2), caused by (Cause3). NIPTE aEHistogram of all Failure Modes Assessed (RPN values) —= Cumulative %| | 80% 2 High: > 60 NIPTE 2222722225 stone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 NIPTE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%.Comparing Granule PSD Produced from Different HPC Grades Particle size distribution Granules formed with EF and 5.5% water were similar to granules formed with EXF and 2.5% water Mass % 225% 120; 16 mLiin;250 RPA; 2 Ml, Wot Mass: (HPC EXF {5.5% H20;24 mLmin; $00 RPM; 90 see. Wet Mass; (HPC ER ee ee ee ee 35 177 250 5k 500. 707 1000 1000 ‘Sie Fraction (um) <6) GL BR OE 17 250 SEL UE TOT > 125 177 260 354 5007071000 1000 ‘20 Fraction (um) NIPTE : racial entrant Leacaon ‘improving (ualty ani towering Coos of PharmaretiealeDrying of Wet Granulations with 2 Different Grades of HPC Water added 5.5% | 4% 38% | 2.5% | 2% BF fe | cnckees | une | Sve Growh | Size Grown | Size Growth E x e fuidestion fushosion fuidenton v vKlucel EXF vs. Klucel EF 4200p 5 S = (a0) Klucel EXF = § 600 oot a oot 5 ec 3 400 _- 5 a® S 200 “oe 3 (apa Klucel EF a 0 ° 5 10 1 2% 2 30 35 Water Addition (@) PS ——— — — — —FBD Stability Concerns (Example Process ani O68 boar baa boar foce ‘led Prstseed% Lact Prected pow 7200057 RSq-0 78 RUSE-0.0029 ‘Summary of Fit Asaian avn Sq A acon, Foctiean Siac Err omaas Ls a of Rosporeo ones Gnsenatone or Sum Wa) 2 p= Analysis of Variance _ er Source OF Squares Mean Square F Ratio he Moet 3 0.00014099, 0.00004? = 8.2022 E ror 8 000004067 5.0808 Prob>F es Gitta 11 oooraion fied . Parameter Estimates : Tm imate SWEror Palo Prot i reece owteso oness 1038 < 00st d eer “Gorases Ootse 240 Jom Eno Ml Tag “2008 a (ceross.aenuee Tapas oceans cose INAPIRE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. NIPTE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.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