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Speed to GMP: Moving from Rapid Process Development to High Throughput Tech Transfer
This document discusses strategies for rapidly transferring biologics manufacturing processes from development to commercial production. It provides examples of how KBI Biopharma employs standardized platform processes and integrated development approaches to minimize changes between scales. For antibody processes, extensive use of platform cell lines, media, and unit operations allows seamless transfer. Non-antibody processes require more customization but subsequent products can still leverage a base platform. Tech transfer timelines are established early and deliverables like batch records are reviewed. This enables timely preparation for cGMP manufacturing and regulatory filings.
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Speed to GMP: Moving from Rapid Process Development to High Throughput Tech Transfer
- 1. Confidential Speed to GMP: Movingfrom Rapid Process Development to High Throughput Tech Transfer Niket Bubna Presented at 257th ACS National Meeting 2019 Orlando, FL
- 2. 2 Confidential Who We Are Background Howwe Tech Transfer? Tech Transfer Case Studies Conclusions Outline
- 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. 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. 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. Confidential 7 Rapid process developmentand 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. 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. Confidential 9 KBI-NC has beensupporting ~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. 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. Confidential 11 • Key goalis 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. Confidential 12 • Tech transfermilestones 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. Confidential 13 Case Study: SKITech 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. Confidential 14 SKI Tech Transfer 02 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. Confidential 15 • Difficult todevelop 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. Confidential 16 Examples for non-standardprocess 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. Confidential 17 • Commercial processdevelopment 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. Confidential 18 Tech Transfer forCommercial 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. Confidential 19 • Platform-based processdevelopment 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. Confidential Questions? Visit us athttp://www.kbibiopharma.com