An Integrated Approach to Ensure Viral Vector and Gene Therapy Commercial Readiness
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Come learn more about our integrated approach to ensure viral vector and gene therapy commercial readiness. We will discuss topics relating to process development for viral vector manufacturing, biosafety testing and commercial readiness. Significant progress has been made for the use of viral vectors for gene therapy. Promising clinical trial results as well as recent FDA approval for CAR-T cell therapy to treat certain children and young adults with B-cell lymphoblastic leukemia have signaled advancements in the field. This marks a historic action, providing opportunities for new viral vector technologies to transform medicine and the way patients are treated and even cured. The need for process development for viral vector manufacturing to improve yield to meet patient demand, biosafety testing for product characterization, potency and safety and commercial readiness to accelerate therapy to-market are critically important. Here, we emphasis an integrated approach that allows our customers solutions to ensure viral vector and gene therapy commercial readiness to meet the growing market need. In this webinar, you will learn: ● Process development advances for production scale-up of viral vectors for gene therapy ● Methods specific for viral gene therapy product characterization, purity, potency, safety and release testing ● Commercial readiness through our US and UK Centers of Excellence for viral product manufacturing
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An Integrated Approach to Ensure Viral Vector and Gene Therapy Commercial Readiness
- 1. Elie Hanania, Ph.D. Marian L. McKee, Ph.D. Dave Backer October 19, 2017 An Integrated Approach to Ensure Viral Vector and Gene Therapy Commercial Readiness
- 2. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. 2
- 3. Agenda 1 2 3 4 Viral Vector Current State and Future Perspectives Viral Vector Scalability and Reproducibility Testing and Quality Regulatory Approval and Commercial Readiness 5 Concluding Remarks 3
- 4. Viral Vector current State and future perspectives
- 5. Demand for Clinical and Commercial Doses are Increasing Viral Vector Current State Phase 1 184 Phase III 34 Phase II 286 Gene Therapy and Gene-Modified Cell Therapy 2017 Worldwide Clinical Trial Landscape: 504 Alliance for Regenerative Medicine: 2017 Q2 Report In vivo and ex vivo gene therapy targeting: • Cancer • Infectious Diseases • Monogenic Diseases • Cardiovascular Diseases • Ocular Diseases • and more 5
- 6. Demand for Clinical and Commercial Doses are Increasing Viral Vector Current State Phase 1 184 Phase III 34 Phase II 286 Gene Therapy and Gene-Modified Cell Therapy 2017 Worldwide Clinical Trial Landscape: 504 Alliance for Regenerative Medicine: 2017 Q2 Report Roots Analysis and Research and Markets, both predict the gene therapy market as a whole to reach $10-11 billion by 2025. FDA approves first ever gene modified cell therapy, CAR-T, for children and young adults with B-cell ALL August 2017 In vivo and ex vivo gene therapy targeting: • Cancer • Infectious Diseases • Monogenic Diseases • Cardiovascular Diseases • Ocular Diseases • and more 6
- 7. Path to Commercialization – Critical Factors Viral Vectors Manufacturing cGMP Compatible • Raw Materials and Reagents • Equipment • Consumable Sets Reproducible • Product Quality • Product Yield • Titer • Purity Scalable • Equipment • Units of Operation Robust • Mode of Operation • Stability • Tolerance • Feasible Range • Process Time 7
- 8. Orphan and Other designations have sped up the clinical trial process Kite: Rolling BLA submission announced (Dec, 2016) Breakthrough Therapy Designation Priority Review of BLA PRIME Regulatory support for EU Novartis: FDA Approval (Sep, 2017) Breakthrough Designation, Priority Review, PRIME support Spark: Submission planned for late 2017 Orphan Drug, Breakthrough, PRIME… Non-industrialized processes are still the norm Plasmids rather than viral banking Limited downstream processing or ultra-centrifugation Using materials and equipment designed largely for MoAb market Continued complexity: 4 Major ways to manufacture AAV Path to Commercialization Viral Vectors: Promise, Money, Passion and Issues 8
- 9. Testing and Quality • Viral vectors must be efficacious without concern for recombination • Methods specific for viral gene therapy product characterization, purity, potency, safety and release testing are vital Scalability and Reproducibility • Both upstream and downstream manufacturing processes must be predictable and well controlled • Process development for production scale-up is critical Regulatory Approval • Processes must be capable of producing high quality viral vectors to achieve regulatory approval • Prepare well in-advance for regulatory agencies Path to Commercialization Pillars for Success 2 3 1 Commercial Readiness 9
- 11. General Outline for Viral Vectors Production / Purification Upstream Production Midstream Processing Downstream Purification Cell Thaw & Expansion Infection / Transfection Harvest (Cell Lysis) Benzonase® Treatment Clarification (Concentration and Buffer Exchange ) Chromatography (Single or Multi-Step) Concentration and Final Formulation Final Filtration and Fill Abundant Sampling Limited Sampling Restricted Sampling 1 11
- 12. Scale OUT 3 T-Flasks Layered Flasks Large Number of Layered Flasks T-Flask Shaker Flasks Expanded Shaker Flasks 1 Shake Flask Images: Corning Life Sciences 12
- 13. Scale UP T-Flasks 10-Layered Flasks 36-Layered Flasks T-Flask Shaker Flasks Small Disposable Bioreactor Rocking-Bed Bioreactor Stir Tank Bioreactor 1 Shake Flask and HyperStack Images: Corning Life Sciences; Rocking-Bed Bioreactor: GE Life Sciences 13
- 14. More Scale UP – Beyond Traditional Approaches T-Flasks 10-Layered Flasks Stacked Trays Fixed Bed Bioreactor Microcarriers T-Flask Shaker Flasks Intermediate Stir Tank Bioreactor Large Stir Tank Bioreactor 1 Shake Flask Images: Corning Life Sciences; Stacked Trays and Fixed-Bed Bioreactors: Pall Corporation 14
- 15. Midstream and Downstream Scale-Up Thaw and Expand Cells Seed Expansion Vessel Vector Production – Infection/ Transfection Filter Clarification Concentration and Diafiltration 1st Chromatography Step Concentration and Final Formulation Sterile Filtration Fill and Finish 1 • Volume • Surface Area • Pore Size • Flow Rate • Pressure / Shear • Volume • Media • Virus Size & Properties • Purification Mode • Nature of Contaminants • Pressure / Shear • Final Filtration • Aggregation 2nd Chromatography Step 15
- 16. Manufacturing processes must meet the high demand Process parameters require optimization to increase yield Bioreactors can help overcome scale limitations Fixed-bed bioreactors like iCELLis® can be used for adherent cell processes Stirred tank bioreactors like Mobius® can be used for adherent cell processes using microcarriers Midstream processing and downstream purification parameters require optimization and scale-up to handle increased upstream yield Improvements in gene delivery and targeting may reduce the need for large batch sizes Process improvements can help reduce dependence on adherent culture and serum containing media The bottom line … 1 16
- 18. Basic Product Safety and Characterization Identity Purity Potency Residuals Product 18
- 19. Vector and Cell Safety and Characterization Plasmid/Virus Master Cell Bank (MCB) Working Cell Bank (WCB) Process Development (Growth/Production/Modification) Master/Working Virus Bank (MVB/WVB) Drug Substance Drug Product Cell Identity Safety Purity Identity Safety Stability Lot Release Testing Container Closure Shipping QA/QC In- Process Testing In- Process Testing In- Process Testing 19
- 20. Master/Working Cell Bank for Vector Production Cell Bank Characterization Purity Identity (cf ICH Q5D) Bacteria, fungi- sterility Mycoplasma Virus (cf ICH Q5A) Broad specificity - in vitro/in vivo assays Species specific – human/bovine/porcine Retroviruses – PCR/EM/PERT New technology – Next Generation Sequencing (NGS) 20
- 21. Viral Vector Testing Characterization of AAV batches Identity PCR for vector and transgene AAV serotype Sequencing of vector (NGS) Titer Infectivity assay - TCID50 Genomic titer - DNase resistant AAV particles by PCR Purity Aggregation of virus Sterility Mycoplasma and spiroplasma In vitro assay for adventitious viruses Replication competent AAV (rcAAV) Empty vector particles Residuals Helper virus or transfected plasmids (PCR) Host cell DNA, Host cell proteins, residual Benzonase®, residual BSA, residual AAV affinity ligand Potency of r-AAV expressed protein 21
- 22. Viral Vector Testing Characterization of Retrovirus Batches Identity PCR identity assay or Immunochemical method or Restriction enzyme analysis Titer Infectious virus Titer of nuclease resistant retrovirus particles by PCR Purity Sterility, Mycoplasma and spiroplasma In vitro assay for adventitious viruses Replication competent viruses Host cell DNA, Host cell proteins, residual Benzonase®, residual BSA Transfected plasmids Absence of process related contaminants Potency of r-retrovirus expressed protein 22
- 23. Gene Therapies Testing is a Continuous Process M/WCB Stability TestingVSS or plasmids Final Product PD Drug Substance 23
- 25. Quality System Audits 2004 through 2017 Client Type Total Audits Academic 6 Biotech 117 Pharmaceutical 16 Government 13 California DHS, Food and Drug Branch 3 FDA, EMA 2 Total 157 Phase III @ SAFC 20 European QP 36 *Highlight: total number of audits for Carlsbad, CA site 25
- 26. Three clients have, or are expected to announce, BLA submission in 2016-2017 Carlsbad, CA facility underwent 3 internal GMP audits in 2016/early 2017, including an outside consultant audit. 6 work streams identified and executed over 12 month program Focus on specific client processes and overall Quality Systems FDA visit: June, 2017 EMA visit: September, 2017 Future visits expected for clients with upcoming BLA submissions Commercial Readiness 26
- 27. Regulatory agencies are very interested in cell and gene therapy space Expect a thorough inspection and plan at least 12 months in advance Fast Track/Orphan Drug/PRIME Status have accelerated timelines across the board, including for commercial readiness and inspections Manufacturing expertise of viral vectors for gene therapy, immunotherapy, and gene-modified cell therapy is valued Learnings from Commercial Inspections 27
- 29. Current state (Planar / Adherent Desired state (Suspension/ Perfusion) Vial thaw P1 1 1 2 3 5 Vial thaw Vial thaw Path to Commercialization Scaling Up Rather than Scaling Out P2 P3 P4 P5 P6 P1 P2 P3 P4 P5 P1 P2 P3 P4 Improved alternative to fixed bed could include suspension bioreactors employing microcarriers for cell adherence The “Holy Grail” LV & AAV upstream process using a producer cell line Shake Flask Images: Corning Life Sciences; Fixed-Bed Bioreactors: Pall Corporation, Rocking-Bed Bioreactor: GE Life Sciences 29
- 30. Testing and Quality • Methods specific for viral gene therapy product characterization, purity, potency, safety and release testing are vital • BioReliance® Testing Services has a proven track record in the industry and is the leader for testing services worldwide Scalability and Reproducibility • Process development and optimization is critical to ensure predictable and well controlled manufacturing • Our cGMP raw materials, single- use assemblies and equipment allow for scalable, reproducible and robust manufacturing Regulatory Approval • Prepare well in-advance for regulatory agencies • BioReliance® Manufacturing Services supports the development and manufacture of viral vectors and gene therapies to meet client’s regulatory and scientific needs Partnering for a Path to Commercialization Pillars for Success 2 3 1 Commercial Readiness 30
- 31. Head of Commercial Development Gene Editing and Novel Modalities dave.backer@sial.com Dave Backer Sr. Director, Head Global Operational Development Services marian.mckee@sial.com Marian L. McKee, Ph.D. Head of Process Development elie.hanania@sial.com Elie Hanania, Ph.D. Thank You