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Compressed Timelines for Breakthrough Therapies: Impact on Process Characterization & Validation

Authored and Presented by: Niket Bubna, Ph.D

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Compressed Timelines for Breakthrough Therapies: Impact on Process Characterization & Validation

  1. 1. Confidential Compressed Timelines for Breakthrough Therapies: Impact on Process Characterization & Validation Niket Bubna Presented at BPI West March 2019
  2. 2. 2 Confidential About KBI Biologics and Breakthrough Accelerating PC & SD-PPQ SDM Considerations PC & Timeline Conclusions KBI Biopharma
  3. 3. 4 Durham, NC (2004) Mammalian • Clinical & Commercial (pre-PAI) cGMP Manufacturing • Analytical, Formulation, Stability & QC • Mass Spec Core Facility • Cell Based Assays Boulder, CO (2014) Microbial • Strain Development • Process & Analytical Development • Clinical & Commercial (Approved) cGMP Manufacturing • QC, Analytical, Formulation, Stability • Particle Characterization Core RTP, NC (2013) Venture Center, NC (2018) Mammalian • Cell Line Development • Process & Analytical Development • Process Characterization • Small scale Process Validation The Woodlands, TX (2017) Cell Therapy • Process and Analytical Development • cGMP Manufacturing & Testing • Cell Based Assays San Diego, CA (2017) Alliance Protein Labs • Analytical Technologies • Leading AUC expertise KBI Sites North America Locations March 2018 Louisville, CO (2018) Elion Labs • Analytical Technologies • Leading Biophysical Chara
  4. 4. Confidential 5 SelexisKBI Selexis – Geneva, Switzerland (2017 – an affiliate of KBI) Best in class cell line development & candidate selection technologies Leuven, BE (2018) Analytical, Formulation and QC services for GMP & non-GMP product testing European Locations
  5. 5. Confidential 6 Large number of biologics under development and regulatory review Expedited drug development; rolling and priority review can be requested Biologics & Breakthrough Designation Ref: CDER Breakthrough Therapy Designation Requests Received by Fiscal Year (As of 31 December 2018) Ref: The Biopharmaceutical Pipeline: Innovative Therapies in Clinical Development (July 2017) 0 20 40 60 80 100 120 140 160 2012 2013 2014 2015 2016 2017 2018 Total Requests Received Granted Breakthrough Biopharmaceuticals
  6. 6. Confidential 7 Typically carrying out process development and scale-up manufacturing for >10 new biologics each year Several products from 2013-15 are now under commercialization Breakthrough and Fast Track designation products under commercialization New Biologics IND/IMPD 0 5 10 15 20 25 30 35 2013-14 2015 2016 2017 2018 New Products Mfg Batches KBI Mammalian Manufacturing Plant (Durham, NC)
  7. 7. Confidential 8 • Platform-based process development • Commercialization to focus on specific improvements like titer or yield Biologics CMC & Timelines FIH CMC Timeline
  8. 8. Confidential 9 • Single-use for entire cell culture manufacturing process • Bioreactor agitation and gassing scale-up is heavily dependent on preset factors like tip speed, P/V, kLa, volumetric gas flow KBI Mammalian Cell Culture Manufacturing Platform Parameter XDR-50 SUB XDR-200 SUB XDR-2000 SUB Impeller Diameter 0.2159 m 0.2159 m 0.4191 m Impeller Power Number 1.50 1.15 0.72 Pitched-blade Impeller 3 blades at 40° 3 blades at 40° 4 blades at 40° Turn-down Ratio 2.2:1 5:1 5:1 Aspect Ratio 1.5:1 1.5:1 1.5:1
  9. 9. Confidential 10 • Go small-scale and high throughput route for maximum steps • Single-use bioreactors for process development and manufacturing • Efforts for miniaturization, especially in bioreactor systems have resulted in several products in the market High Throughput & Single-use Technologies for Cell Culture PD & PC
  10. 10. Confidential 11 • Test SDM during Phase I/III process development • Carry out PC for different unit operations in parallel • Leverage Phase I experience and FMEA RA to design PC • Aim to complete main PC stages and key experiments for first submission • Consider using pilot-scale runs to qualify harvest SDM • Use high throughput tools for experiments • Deploy statistical analysis using JMP, Design Expert etc. where possible • Consider MVDA for large data sets like at-scale or SDM runs Accelerated PC & SD-PPQ Timelines: Our Approach
  11. 11. Confidential 12 • LIVCA – Carry out with commercial launch process cGMP runs • Medium-Feed Stability Study – Define stability time points with practical use • Raw Material Qualification – Aim to test within PC and leverage PD results • Worst-Case Linkage (Production/Harvest with Downstream) Accelerated PC & SD-PPQ Studies: Our Approach
  12. 12. Confidential 13 Important to test proposed scale-down model during commercial process development to ensure success in SDMQ and PC. Cell bank and scale- dependent parameters like agitation and gassing should be tested. Focus on matching CPPs and cell culture process outcomes Establishing SDM
  13. 13. Confidential 14 • Equivalence testing on SDM; comparison with cGMP results • Need to establish acceptable difference between scale-down models and cGMP • Consider to establish ‘offset’ for known differences in factors like doubling time or a pCQA Establishing SDM
  14. 14. Confidential 15 • Scale-down models are established using scale-dependent parameters including agitation and gassing, which use P/V, kLa, tip speed, vvm, etc. • Scale-down approaches in ambr250 do not necessarily use equivalent P/V or kLa values Establishing SDM in ambr250
  15. 15. Confidential 16 Important to mimic at-scale cellular environment to obtain a robust scale-down model Establishing SDM in ambr250 Key parameters pH control DO control Temperature control Feed addition Titer (g/L)
  16. 16. Confidential 17 • Impact of sampling in ambr250 is larger when compared with at-scale runs • Adjust feeding strategy to provide nutrient levels similar to at-scale Establishing SDM in ambr250 Key parameters pH control DO control Temperature control Feed addition
  17. 17. Confidential 18 Matching cell growth, metabolite profiles is important to qualify SDMQ using pre- determined criteria including CPP and pCQAs Establishing SDM in ambr250 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 VCC(e^6cells/mL) Time (days) Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Lactate(g/L) Time (days) Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3)
  18. 18. Confidential 19 Predicting CPP and pCQA Performance DOE OFAT cGMP SDM Over feedingPlanned Excursion Extended Medium HoldTiter Response for a CPP over production PC test conditions SDM within cGMP range DOE to be analyzed for design space and prediction model OFAT conditions show impact of stress factors
  19. 19. Confidential 20 Response for a glycan peak from production PC study SDM within cGMP range cGMP results within BDS specification range Reduction in %peak area correlated with test conditions Predicting CPP and pCQA Performance cGMP SDM CP N-glycan peak (BDS Spec) DOE Hi Condition Planned Excursion Hi DO
  20. 20. Confidential 21 DOE models used to generate prediction profile across tested process range Process control strategy update – NOR and PAR Predicting CPP and pCQA Performance NOR PAR
  21. 21. Confidential 22 • Preceded by commercial process development and pilot-scale (200 L) runs • Upstream is rate-limiting • Downstream PC can be accelerated with equipment and resources • Draft CSD prepared based on historical development data • PPQ campaign performed in parallel with PC • Control Strategy is updated post-PC Accelerated PC and SD-PPQ Timelines
  22. 22. Confidential 23 • Process development approach and SDM establishment are important for PC success • Implement parallel PC execution of several unit operations • Deploy high throughput approach for maximum operations including analytical testing PC and SD-PPQ data package to support BLA submission can be achieved in 9 months Concluding Remarks Meaningful PC Factors Mix of DOE & OFAT DOE for Interactions only Separate Raw Material Experiments Use FMEA RA Predictable SDM Mimic at-scale environment: pH & DO Control Feed addition CPP & pCQA Equivalence Robustness Reproducibility Benefits of ambr250 SDM High throughput Accuracy Resource Efficiency Process monitoring Data collection Accelerating PC Timelines Parallel Experiments High Throughput Workflow Pre-PC Studies during PD Leverage Ph I/II Data Pilot-scale Runs  PC 2-3 FMEA RA
  23. 23. Confidential Thank You Visit us at