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Speed to GMP: Moving from Rapid Process Development to High Throughput Tech Transfer

Authored and Presented by: Niket Bubna, Ph.D

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Speed to GMP: Moving from Rapid Process Development to High Throughput Tech Transfer

  1. 1. Confidential Speed to GMP: Moving from Rapid Process Development to High Throughput Tech Transfer Niket Bubna Presented at 257th ACS National Meeting 2019 Orlando, FL
  2. 2. 2 Confidential Who We Are Background How we Tech Transfer? Tech Transfer Case Studies Conclusions Outline
  3. 3. Confidential 4 Who We Are • Analytical & Formulation Services, Microbial, Mammalian & Cell Therapy CDMO • CDMO services first offered in 2004 • Acquired by JSR Corp in 2015 • Highly experienced Executive & Management Teams • Excellent Track Record & Client Satisfaction KBI Biopharma’s mission is to accelerate the development of innovative discoveries into life- changing biological products & expand global access of medicines to patients in need
  4. 4. Confidential 5 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 KBI’s North America Locations March 2018 Louisville, CO (2018) Elion Labs • Analytical Technologies • Leading Biophysical Chara
  5. 5. Confidential 6 SelexisKBI Selexis – Geneva, Switzerland (2017) Affiliate of KBI Best in class cell line development & candidate selection technologies KBI Leuven, Belgium (2018) Analytical, Formulation and QC services for GMP & non-GMP product testing European Locations
  6. 6. Confidential 7 Rapid process development and manufacturing approach for faster IND submission is often being used for biologics • What role does KBI play in enabling faster delivery of products to the clinic? • What strategies are employed for rapid process development? • Can manufacturing readiness be accelerated? Speed to GMP/IND
  7. 7. Confidential 8 Biologics CMC & Rapid Process Development FIH CMC Speed to GMP/IND using SKI • Platform cell line • Platform cell culture and downstream processes • Standard scale-up manufacturing operations Selexis KBI Integrated Development Approach
  8. 8. Confidential 9 KBI-NC has been supporting ~10 IND/IMPD filings per year since 2015 What is needed to accelerate manufacturing of biologics? Types of Mammalian Manufacturing Projects mAb, 45.1% Fc-fusion, Fusion, 9.8% Bispecific, 21.6% Recombinant Protein, 5.9% Glycoprotein vaccine, 13.7% Enzyme, 3.9%
  9. 9. Confidential 10 Questions to Consider • How is tech transfer performed within a CDMO? • Multi-product facilities • Phase I to Phase III projects • Are there standard approaches that ensure 100% success?
  10. 10. Confidential 11 • Key goal is to ensure seamless transfer of process parameters, raw materials and process knowledge for cGMP manufacturing • Initiate process transfer while process development is on-going; 4-5 months prior to manufacturing start • Need to reduce gaps in equipment and raw material grades between development and manufacturing • Use of platform upstream and downstream processes minimizes changes in manufacturing operations • Templated documents for process transfer and manufacturing ops Tech Transfer Business Process: Considerations
  11. 11. Confidential 12 • Tech transfer milestones defined with T=0 as cell culture vial thaw or harvest • Process descriptions, batch record review and floor support are key deliverables from process development Tech Transfer Business Process
  12. 12. Confidential 13 Case Study: SKI Tech Transfer Passage 4 (N-2) 50 L Wave Cellbag Passage 3 5 L Shake Flasks Passage 2 500 mL Shake Flasks Production bioreactor (XDR-2000) Passage 5 (N-1) (XDR-200) Vial thaw - Passage 1 125 mL Shake Flask Process Parameter Process Value Temperature Platform Temp Downshift Platform DO Platform pH Control Platform pH Shift Variable Agitation Fixed P/V Air Sparge Fixed VVM Air Overlay Fixed HVM Basal Medium Platform Target Seed Density Variable Base for pH Control Platform Feed Medium Platform Supplement Platform Harvest Criteria Variable • Inoculum train duration and parameters (temperature, agitation and CO2 %) are fixed for all SKI cell lines • Several production bioreactor parameters (for e.g. temperature set point, DO set point, seed density) are consistent among SKI processes • Nutrient medium and feed media are fixed for all SKI cell lines • Product-specific nutrient supplements or process parameters can be included • Process duration is generally 14 days – range of 12-16 days depending on desired QTPP
  13. 13. Confidential 14 SKI Tech Transfer 0 2 4 6 8 10 12 14 16 Viability VCC Days 200 L PD Run VCC 1000 L cGMP VCC 200 L PD Run Viability 1000 L cGMP Viability 0 2 4 6 8 10 12 14 16 pCO2 pH Days 200 L PD Run pH 1000 L cGMP pH 200 L PD Run pCO2 1000 L cGMP pCO2 ProATiter Days 200 L PD Run 1000 L cGMP 0 2 4 6 8 10 12 14 16 Lactate Glucose Days 200 L PD Run Glc 1000 L GMP Glc 200 L PD Run Lac 1000 L GMP Lac 0 2 4 6 8 10 12 14 16 Ammonia Glutamine Days 200 L PD Run Gln 1000 L GMP Gln 200 L PD Run Amm 1000 L GMP Amm Scale-up into a 2000 L SUB from the 200 L process development scale is seamless and provides reproducible cell culture performance
  14. 14. Confidential 15 • Difficult to develop a standard platform processes for manufacturing non antibody products • Changes to basal medium, feeds, chromatography resins, buffers can be frequently necessitated to achieve desired productivity and product quality • Final process tested in same scale bioreactors prior to start of cGMP manufacturing • Developed and manufactured a series of gp120 vaccine proteins in CHO cell lines where first molecule required changes to manufacturing operations, but subsequent molecules were transferred as a ‘platform’ process Case Study: Non-mAb Tech Transfer
  15. 15. Confidential 16 Examples for non-standard process steps • No seed bioreactor operations: no seed bioreactor (production bioreactor inoculation using shake flasks • Vendor liquid for all raw materials • No use of single-use BPC bags • Deed and supplement addition based on cell growth, • Harvest day dependent on cell growth and viability Non-mAb Tech Transfer Production Bioreactor (XDR-200 SUB) Harvest Clarification (Depth Filtration) Vial Thaw (Passage 1) InoculumExpansionProduction&Recovery 4 days 12-14 days Shake Flask Passages (Passage 2-5) 14 days Cell Culture & Harvest Process
  16. 16. Confidential 17 • Commercial process development and commercial launch manufacturing is often being expedited • Limited changes from FIH to commercial processes to reduce time required for BLA filing • Follow same approach as FIH process transfer, but provide NOR definition and FMEA RA to enable CPP and critical raw materials assessment • Important to develop qualified scale-down models to support PPQ readiness, commercial manufacturing and CPV • PPQ campaign performed using initial risk and criticality assignments; PAR updated post-PPQ using PC data package Case Study: Tech Transfer for Commercial Manufacturing
  17. 17. Confidential 18 Tech Transfer for Commercial Manufacturing PAR Equivalence testing between SDM & at-scale performance Post-PC Tech Transfer cGMP n=10 SDM n=5 Pre-PC Tech Transfer 0 2 4 6 8 10 12 14 16 Day ambr250 (n=3) 3 L Scale (n=9) 200 L PD (n=3) 2000 L cGMP (n=10) 6 8 10 12 14 16 Day ambr250 (n=3) 3 L Scale (n=9) 200 L PD (n=3) 2000 L cGMP (n=10)
  18. 18. Confidential 19 • Platform-based process development is an important starting point to streamline process transfer and manufacturing operations • Need to ensure process scalability at pilot-scale prior to GMP manufacturing • Equipment and raw materials must be aligned between process development and manufacturing • Minimize changes to standard practices, equipment platforms and document templates Does each new process require a ‘full’ tech transfer? Focus only on non-platform, non-standard process changes Key Takeaways
  19. 19. Confidential Questions? Visit us at