A Single-Use Strategy to Enable Manufacturing of Affordable Biologics

Transcription

1 A Single-Use Strategy to Enable Manufacturing of Affordable Biologics Renaud Jacquemart, PhD Principal Scien9st Director Vaccines Process Sciences Natrix Separa9ons Benjamin Damien, PhD Director Business Development Univercells James Stout, PhD Vice-President, Process Sciences Natrix Separa9ons January 9 th, 2017

2 What Enables Affordability? A holis?c approach an fully integrated strategy not just focusing on the high cost of Protein A Maximized produc?vity Smaller facili?es that drive down capital investment Greater flexibility streamlining infrastructure High Produc,vity Processes = Smaller Facili,es = Lower Costs 2 2

3 Holis?c Vision In Collabora?on With Univercells Con9nuous Automated Small Footprint Manufacturing Facility Combine USP and DSP opera?ons in one small-footprint system, employing robust process architecture Reduce Therapeu?c Manufacturing Cost CAPEX <$25M for 500 kg/year (10x less) CoG <$50-$85/gram (25-50% less) Improve access to biopharmaceu?cals Accommodate small and emerging markets Low CAPEX and total flexibility built-in by design Lower costs enable a sustainable economic model 3 3

4 Holis?c Vision In Collabora?on With Univercells Con9nuous Automated Small Footprint Manufacturing Facility Project Objec?ves For Natrix: Natrix advanced materials enable development of high produc,vity, fully single-use, DSP that enables small footprint, automated manufacturing à Process architecture compa?ble with most mab processes à High produc?vity to shrink manufacturing footprint à Process matching current and future (improved) USP à Simple to implement and operate 4 4

5 Build With High Produc?vity Technologies High Cell Density Bioreactor Engineered Cell Lines & Op?mized Feeding Strategies High Throughput Clarifica?on High Produc?vity Chromatography Membranes (Both B&E & FT opera?on) Small Footprint, High Yield Single-Use Upstream Manufacturing Right-Sized, Fully Single-Use Purifica?on Process Integrated Con?nuous Process Small footprint, low cost (OPEX and CAPEX) automated manufacturing 5

6 Build With High Produc?vity Technologies High Cell Density Bioreactor Engineered Cell Lines & Op?mized Feeding Strategies High Throughput Clarifica?on High Produc?vity Chromatography Membranes (Both B&E & FT opera?on) Small Footprint, High Yield Upstream Manufacturing Right-Sized, Fully Single-Use Purifica?on Process Integrated Con?nuous Process Small footprint, low cost (OPEX and CAPEX) automated manufacturing 6

7 Towards A Fully Single-Use DSP Protein A Membrane Capture Is The Key Seed Wave Bioreactor Bioreactor Clarification Protein A (HD-A) Viral Inactivation Polishing 1 (HD-Sb) UF/DF (Optional) Polishing 2 (HD-Q) Virus Filtration Protein A resin is gold standard, but with limita?ons: Large footprint, low produc?vity, not flexible, labor/quality-intensive High CAPEX & OPEX è Not economical unless media life is fully amor?zed There is no single-use, cost-efficient alterna?ve to Protein A resin that also matches upstream throughput Not yet 7

8 Towards A Fully Single-Use DSP Protein A Membrane Columns Natrix Protein A Membrane Robust manufacturing process delivers inter-lot reproducibility Caus?c stable, single-use per batch, plug and play High binding & high flow rate = high produc?vity capture Demonstrated 10% dbc range from 30 to 60 mg/ml at 1s Rt for 20+ mabs Fully scalable, GMP Bind & Elute columns will deliver op?mized opera?onal performance 8

9 Towards A Fully Single-Use DSP Protein A Experimental Set Up > All Protein A data presented was generated by Natrix s partners with a membrane screening holder ( Test Cell ) > Typical Protein A run condi?ons EQ : 20mM Sodium Phosphate, 150mM NaCl, ph 7.6 Elu?on: 50mM Sodium Acetate, ph 3.5 Strip: 0.1M ace?c acid CIP: 0.1M NaOH 9 9

10 Towards A Fully Single-Use DSP Protein A Membrane Is A PlaRormable Tool Protein A membrane clearance is comparable to reference Protein A resins 10

11 Towards A Fully Single-Use DSP Protein A Membrane Is High Produc9vity DBC at 10% BT (mg/ml-media) Residence Time (seconds) mab 1 mab 2 mab 3 mab 4 mab 11 mab 13 High produc,vity ProA membrane enables right sized columns that can match USP throughput in a small footprint truly flexible manufacturing facility 11

12 Towards A Fully Single-Use DSP Protein A Membrane Maintains Performance Over Cycling Cycling Study mab 8: g/l Load HCP LRV Recovery (%) Avg Leached ProA <2ppm Avg Delta Column Pressure <2psi Cycle Number

13 Towards A Fully Single-Use DSP Protein A Membrane Enables Rapid Mul9-Cycling mab 11 mab 21 mab cycles Load: 28 g/l Avg Yield: 81% Avg HCP Reduc?on: 2.6 LRV Avg DNA Reduc?on: 3.3 LRV Leached Pro A: <3 ppm Well within opera?ng condi?ons of chrom skid Studied with/without CIP 101 cycles Load: 21 g/l Analy?cs in process Avg Delta Pressure <12 psi across 1.2 sec RT 150 cycles Load 20 g/l Avg Yield: 84% Avg HCP Reduc?on: 2.5 LRV Well within opera?ng condi?ons of chrom skid Media life can be fully u,lized in a single batch to op,mize process economics 13 13

14 Towards A Fully Single-Use DSP Protein A Membrane Enhances Con9nuous Processing mab 13 on Pall Cadence TM BioSMB with five Natrix test cells à 50 g/l*h produc?vity achieved (5x increase over reference column), using nonop?mized test cells. One of first demonstra?ons of con?nuous mul?-membrane chromatography 91 cycles Load: 30 g/l Avg Yield: 87% Avg HCP Reduc?on: 4.1 LRV DNA in Eluate: <1 ppm Leached Pro A: 15 ppm Pall Life Sciences Avg Delta Pressure < 2 psi across 4 sec RT) Next genera,on con,nuous purifica,on pla@orms further op,mize produc,vity Source: High Capacity Protein A Membranes for mab Capture: An Alternative to Column Chromatography, Gospodarek et al., 2016 AIChE Annual Meeting 14 14

15 Towards A Fully Single-Use DSP Flow Through Clearance Of Aggregates Using HD-Sb, MM CEX ProA purified mab 8: IgG1, 142 kda, pi 8.2 prone to aggregation at low ph (HMW>10%) UV1_280nm Cond mau 2500 Flowthrough ms/cm 0.3 Flowthrough Feed Strip A280 (AU) min 20.0 HD-Sb Chromatogram Minutes SEC Chromatogram HMW reduc,on from 10.4% to 0.5% and monomer yield of 90% in FT mode, at 300 g/l load in <30 minutes (ph 5.5 & 10 ms/cm) 15

16 Towards A Fully Single-Use DSP Load Independent HCP, DNA & Virus Clearance Using HD-Q AEX HD-Sb purified mab 8 submitted to HCP and MVM clearance study HCP Clearance (ppm) HCP Clearance MVM Clearance Loading Capacity (kg/l media, ph 7.5, 10 ms/cm) MVM Clearance (LRV) Full Natrix DSP delivers HCP <10ppm, no detectable DNA, and 7 LRV MVM 16

17 Right-Sizing, Rapid Mul?cycling Concept Enabling Small Footprint DSP Matching High Produc9vity USP 4.5kg mab sent to Protein A over 10 days 100L Depth filtration 2.2 m 2 /day 17 h/day Productivity of Protein A membrane capture is 400 g/h L-media 30X better than Pro A resin productivity: 13.5 g/h L-media Daily production Day1: 450g Day2: 450g Day10: 450g 120kg mab purified annually in approx. 20 b 2 of GMP suite Daily purification train MV: 0.5L Load 45g/L 20 cycles 2.5 hours 95% yield MV: 0.5L Load 300g/L 3 cycles 1.5 hour 90% yield MV: 0.03L Load:12.5kg/L 1 cycle 3.5 hours 98% yield HD-A Capture HD-Sb Polish HD-Q Polish Adapted from: A Single-use Strategy to Enable Manufacturing of Affordable Biologics, Jacquemart et al., PepTalk 2016 proceedings in CSBJ, 06/

18 18 Vision Of The Integrated Plavorm Con9nuous Automated Low Footprint Manufacturing Facility Univercells Single-use perfusion bioreactor Natrix Separations Chromatography membranes IN Cells OUT Purified bulk Univercells Integrated manufacturing system 120kg/Year per production unit Source: Univercells 18

19 Vision Of The Integrated Plavorm Cost Savings Are Confirmed Even For Large Scale Manufacturing Merck s BioSolve model supports Univercells conclusions Source: Standardized Economic Cost Modeling for Next-Generation MAb Production, Pollard et al., BioProcess International Journal, 09/

20 Summary Of Plavorm And Concept Step Change Reduc9on In Physical Plant Scale, Invested Capital & COGs Natrix HD membranes enable a new manufacturing paradigm Quality / purity comparable to reference resin processes DSP match productivity of USP Higher productivity enables smaller columns and facilities Fully single-use, flexible, low cost facilities Industrial production at lab scale Plug & Play system - can be deployed for in-country/for-country manufacture Factory operational in few months Demonstrated for mabs, but applicable for any biologic drug or vaccine Pay-off mab COGs savings up to 50% Fully flexible facilities become reality (USP/DSP) Enable affordable biologics and enhance competitive advantage 20 20

21 Acknowledgements Natrix CEO John Chickosky Natrix Process Sciences Jim Stout (VP Process Sciences) Navneet Sidhu Karan Sukhija Melissa Vandersluis Mochao Zhao Natrix R&D Gary Skarja (Director R&D) Elena Komkova Amro Ragheb John Grande Collaborators & Scien,fic Advisors Univercells (J. Cas?llo, B. Damien, S. Dubois, M. Duyck) Merck & Co. (D. Pollard, M. Brower, Y. Hou, A. Gospodarek) Sanofi (S. Schleper, O. Klingel, S. Krause, J. Chow, B. Mothes) Charles River Labs (T. Jaber & H. Ruppach) And more 21