Novel Pathways To Robust And Cost Effective Vaccine Manufacturing

Transcription

1 Novel Pathways To Robust And Cost Effective Vaccine Manufacturing Merging High Productivity Technologies Into A New Concept For Integrated Manufacturing Renaud Jacquemart, Ph.D. Principal Scientist, Process Sciences Natrix Separations March 31, 2016

2 Outline Introduction Objective line of sight to cost efficient manufacturing processes Platform transferable to multiple vaccines Engineering concept Continuous automated low footprint manufacturing facility Technologies selected Proventus Bio engineered Vero cell line Univercells integrated vaccine manufacturing Natrix Separations high productivity affinity membranes Status Current proofs of concept, economic modelling Conclusions Benefits and perspectives 2

3 Build With High Productivity Technologies This concept merges four technologies to establish an integrated manufacturing platform, broadly applicable to multiple vaccines Engineered Vero Cell Lines Target: >30 fold increase in viral titres High Cell Density Bioreactor Target: >10 fold increase in cell density Affinity Purification Membranes Target 2 fold increase in recovery in single step purification Integrated Continuous Process Small footprint, low cost (OPEX and CAPEX) automated manufacturing 3

4 4 Vision Of The Integrated Vaccine Platform Continuous Automated Low Footprint Manufacturing Facility Proventus Bio Cell line development >30X productivity Natrix Separations Affinity Membrane 2X recovery IN Cells & Virus 10M Capital OUT Purified bulk 40M Dose/Year Univercells Integrated manufacturing system, including bioreactor >10X productivity 4

5 High Productivity Engineered Vero Cell Lines Augmented Intrinsic Productivity To Reduce Costs Cell lines genetically engineered to support increased virus production Specifically knocked out for certain genes involved in endogenous control of virus replication Stable Genetic Modifications Virus infection Viral Replication & Assembly >80-fold 5

6 Proven Technology For Sabin Polio Virus Production Gene Silencing To Increase Virus Titers Data for 3 cell lines for production of Polio Sabin virus strains Demonstrated fold increase in virus yields van der Sanden, Sabine MG, et al. "Engin eering Enhanced Vaccine Cell Lines to Er adicate Vaccine-Preventable Diseases: Th e Polio End Game. "Journal of Virology (2 015): JVI

7 High Efficiency Single Use Bioreactors Simpler System & Smaller Footprint Reduce Costs icellis Univercells Stainless Steel Bioreactor + Micro Carriers Microcarriers replaced by microfibers to reduce bioreactor size Cell density up to 100M cells/ml (compared to 1 5M cells/ml Cytodex) Biological contactor reduces media usage Reduced size allows less complex and costly design 7

8 Single Step Affinity Purification High Binding & Short Residence Time For Optimized Productivity Natrix HD Membranes Reinforced, porous polymer hydrogels containing a high density of binding groups Interconnected pore structure provides large surface area for protein binding and high membrane permeability Reactive membrane libraries with 100 s of candidates have been developed Proven IEX columns introduced in 2013, accepted for GMP manufacturing Affilin libraries (Scil Proteins) Derived from human ubiquitin Engineered to generate de novo binding affinity towards desired target Randomization of different sets of surface residues Libraries with high complexity of variants 8

9 Single Step Affinity Purification Capture >99.9% Pure Product Superior selectivity even at 6 seconds residence time Increased productivity and multi cycling operation drive column size and costs down Optimized process architecture improves overall process yield Molecule Affinity Membrane Binding Capacity (mg/ml) Feed HCP (ppm) Eluate HCP (ppm) HCP (LRV) % Purity mab1 Biosimilar Engineered Protein A , mab2 Collaborator EGFR (HEK 293) EGFR (Yeast lysate) Engineered Protein A 35 84, Affilin , Affilin 8 2,050, >99.9% Residence time: 6 to 12 seconds One layer of prototype affinity membrane in unoptimized 25 mm SS holder 9

10 Projected Process For Case Study Simplified process architecture SUB enabled by efficient DSP Optimized Single-use clarification Affinity-based capture Ion exchange polishing Defining flexible and multi-use facilities Alain Pralong & Renaud Jacquemart BDP week, 02 April 2015

11 Case Study Results USP Highlights DSP Highlights Incremental Improvement Plan 1 3x1600L SSB + 3 clarification trains 2 UC multi-cycle + multi columns chrom Optimized New Process Architecture 2x500L SUB + continuous SU clarification No UC + affinity membrane chrom KEY OUTCOMES Throughput per year (MSD) Cycle time (days) Cost/dose ( )* CAPEX investment (M- ) Scale-up flexibility Limited Yes, add more SUB to increase further.(dsp capacity not limiting) Case Study illustrates opportunities with an membrane affinity-based approach: NPV of Optimized Process Architecture: 400M Eliminate intrinsic compliance issues, 6σ ops yield few enforcement actions Build facilities inmarket; regain/retain market share lost to low cost producers Viability to profitably expand markets, serve developing countries Defining flexible and multi-use facilities Alain Pralong & Renaud Jacquemart, BDP week, 02 April 2015 (*) CoGs to bulk, does not include fill/finish MSD= Million Sellable Doses; SSB= Stainless Steel Bioreactor; 11 SUB= Single Use Bioreactor; UC= UltraCentrifuge

12 Summary Of Platform And Concept Step Change Reduction In Physical Scale, Cost/Dose, Investment Conceptual platform combines four high productivity technologies Three process components (cell line, bioreactor, affinity membranes) deliver game changing increases in vaccine yields Fourth component (integration cabinet) packages process in small footprint, low capital cost, easy to establish and operate manufacturing environment Platform Concept: Industrial production at lab scale Plug & Play system - can be deployed for in-country/for-country manufacture Factory operational in few months Applicable for any viral vaccine Goals: 40M vaccine doses per year from $10M facility Cost of goods at <$0.10/dose drug substance 12

13 Acknowledgements Natrix Process Sciences Jim Stout (VP Process Sciences) Annabel Shang Navneet Sidhu Melissa Vandersluis Mochao Zhao Natrix R&D Gary Skarja (Dir. R&D) Elena Komkova Amro Ragheb John Grande Collaborators & Scientific Advisors Univercells (J. Castillo, S. Dubois) Batavia Biosciences (C. Yallop, A. Luitjens) Proventus Bio (J. Karpilow) Scil Proteins (U. Haupts, A. Katzschmann) Merck & Co. (D. Pollard, M. Brower, Y. Hou, A. Gospodarek) Sanofi (B. Mothes) GSK Vaccines (M. Sanders, A. Pralong) Natrix CEO John Chickosky 13