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Rick Morris, PhD Interphex April 2019
Biosimilars Next Generation Biotech Processes and The Road To Bioprocess 4.0. Rick Morris, PhD Interphex April 2019
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New Era of Biomanufacturing
Cost pressure and competition Multiple mAbs against the same target Rise of biosimilars Blockbuster mAbs Large patient populations Source: IMS Health, IMS Institute for Healthcare Informatics, Jan 2016 How do you manage unpredictable demand and cost pressures?
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Biosimilars Global Activity
Biosimilars still not drug of choice in the U.S. The biosimilar market share continues to grow. Europe on board, and Asia is prepping for demand with capacity buildup. These two regions account for $2.4 billion in active capital projects. South America is on track with $1.5 million of activity In the US, even with a growing number of biosimilar drug approvals, the roadblocks make market entry of approved drugs questionable strong patent protection lack of price control (price difference is not comparable to generics) lack of patient trust that the drug will be equally as effective for treatment as the copied drug Pfizer dropped five preclinical biosimilar products. There is a growing opinion that big pharma might exit biosimilar business In the U.S. (BI, Merck, and Sandoz adjusted their focus areas in 2018) PF , a trastuzumab biosimilar referencing Herceptin PF , a rituximab biosimilar referencing Rituxan; PF , an adalimumab biosimilar referencing Humira PF , a bevacizumab biosimilar referencing Avastin PF , a pegfilgrastim biosimilar referencing Neulasta The EMA has already approved 51 biosimilars The FDA lags behind with 17 approvals but is catching up. These approvals mostly consist of recombinant proteins, the majority of which are monoclonal antibodies (mAbs) Source: Industrial Info Resources
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Waves of Biosimilar Opportunity by Patent Expiry of Innovator Biologics
Of the five biggest products set to lose exclusivity in the US this year, Roche owns three: Avastin, Herceptin and Tarceva Amgen is the lead contender for launching an Avastin biosimilar, though court cases are ongoing and hearings are scheduled for later this year and in 2020 Launch this year not widely expected Source: GlobalData, EvaluatePharma
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Pall’s Vision for a Platform for Continuous Bioprocessing
5/15/2019 Pall’s Vision for a Platform for Continuous Bioprocessing Leading provider of integrated platform technologies for continuous manufacturing of biologics Robust across multiple molecules (>75%) at multiple scales from PD > Clinical > Commercial Manufacturing Ability to complete process development within 4 weeks High overall yield (65%) Meets/exceeds purity requirements Post Chrom: HCP <10 ppm and Aggregates <1% Continuous
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Biopharmaceutical Industry Trends and Drivers
CAGR: Compound Annual Growth Rate CAGR 2017 - 2024 Vaccines Plasma rProteins mAbs and other Ab modalities Gene and Cell Therapy Growing the fastest: Monoclonal antibody (mAb) and other mAb modalities (ADCs, bispecific/trispecific, fragments, nanobodies …) Gene and cell therapy Pressure on manufacturing: Cost Speed to market Manufacturing flexibility Same or increased product quality
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Enabling Manufacturing Technologies Required
How To Deliver? Good Fast Inexpensive Safe Enabling Manufacturing Technologies Required
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The Advent of Single-Use Technologies in Bioprocessing
Single-use capsule filters 2000s Single-use TFF, depth filters, chromatography membrane adsorbers Capsule systems Sterile connectors Biocontainers and bioreactors 2010s Automated single-use systems
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Benefits from Adoption of Single-Use Technologies
No risk of cross contamination 58.9 No cleaning requirements 55.5 Reduce time to get facility up & running 35.4 Reduce capital investments in facility & equipment 33.0 Greater assurance of sterility 33.0 Reduce production cycle time 32.5 Easier QA/QC 30.1 % Source 4th Annual Report and Survey on Biopharmaceutical Manufacturing, Bioplan Associates, June 2006
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Stainless Steel vs Single-Use mAb Downstream Process Cost Modeling – Process Overview
Clarification Capture Polishing Final Formulation Protein A Capture 62% mAb yield 150 g/L Variable feed Disk Stack Centrifuge Virus Filter Depth Sterile Protein A Low pH Virus Inact. Depth Sterile AEX FT MM B/E UF/DF/UF Sterile No centrifuge (up to 2000 L) Filter capsules instead of cartridges in stainless steel housing Biocontainers in tote instead of stainless steel tanks (up to 2000 L) Skids adapted for single-use flow path Pre-packed columns Membrane adsorber for flow through purification Single-use TFF
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Stainless Steel vs Single-Use mAb Downstream Process Cost Modeling – Process Overview
Scale of Manufacturing Clinical (0.1 – 19 kg/year) Commercial (17 – 1600 kg/year) Volume (L) 200 – 1000 – 2000 2000 – 6000 – 12000 Titer (g/L) 1 – 3 – 5 1 – 5 – 9 Batches/year 1 – 2 – 3 15 – 20 – 25
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Cost Saving with Single-Use
Stainless Steel Single-Use Clinical Manufacturing (2 batches / year)* Commercial Manufacturing (20 batches / year)* *Trends are insensitive to batches / year
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Enabling Manufacturing Technologies Required
How To Deliver? Good Fast Inexpensive Safe Enabling Manufacturing Technologies Required
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Options Available from Process Intensification
Examples Process Intensification from Chemical Engineering Perspective Process Intensification Methods Multifunctional Reactors Heat integrated reactors Reactive separators Reactive comminution Reactive extrusion Fuel cells Hybrid Separations Membrane adsorption Membrane distillation Adsorptive distillation Alternative Energy Sources Centrifugal fields Ultrasounds Solar energy Microwaves Electric fields Plasma technology Other Methods Supercritical fluids Dynamic (periodic) Reactor operation Equipment Reactors Spinning disk reactor Static mixer reactor Monolithic reactor Microreactor Equipment for Non-Reactive Operations Static mixer Compact heat exchanger Centrifugal adsorber
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Options Available from Process Intensification
Examples Process Intensification from Chemical Engineering Perspective Process Intensification Methods Multifunctional Reactors Heat integrated reactors Reactive separators Reactive comminution Reactive extrusion Fuel cells Hybrid Separations Membrane adsorption Membrane distillation Adsorptive distillation Alternative Energy Sources Centrifugal fields Ultrasounds Solar energy Microwaves Electric fields Plasma technology Other Methods Supercritical fluids Dynamic (periodic) Reactor operation Equipment Reactors Spinning disk reactor Static mixer reactor Monolithic reactor Microreactor Equipment for Non-Reactive Operations Static mixer Compact heat exchanger Centrifugal adsorber Use of Equipment and Methods for Process Improvement
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Benefits From Process Intensification
Economics Improved capital utilization Reduced OPEX Reduced plant footprint Reduced time to market Process and product Process and Product Improved selectivity/purity Improved throughput and yield Improved safety Improved product quality Reduced idle time Environment Reduced energy usage Reduced water/solvent usage Reduced waste
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Benefits From Process Intensification
Economics Improved capital utilization Reduced OPEX Reduced plant footprint Reduced time to market Process and product Good Inexpensive Safe Fast Process and Product Improved selectivity/purity Improved throughput and yield Improved safety Improved product quality Reduced idle time Environment Reduced energy usage Reduced water/solvent usage Reduced waste
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Lean Thinking: From Batch to Continuous Bioprocessing
Higher quality & productivity in a smaller foot-print with shorter lead times “One-piece flow” Extra processing Defects Motion Over-production Inventory Non-utilized talent Transportation Waiting 8 Wastes in Production Lean Batch
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Journey to Continuous Bioprocessing: Enabling Unit Operation Platforms
Capture – Cadence BioSMB System Polish – Cadence BioSMB System Virus Inactivation + Depth + 0.2 µm Multicolumn Chromatography Purification Cadence BioSMB System Chromatography Cell Clarification and Perfusion Cadence® Acoustic Separator Depth + Clarification Acoustic Wave Separation (AWS) Cadence Inline Concentrator Pegasus™ Prime + Protect Single-Pass TFF for Concentration and Diafiltration Filtration Cadence Single-Pass TFF (SPTFF) Cadence Inline Diafiltration
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Cadence Acoustic Separator*
Continuous Clarification Acoustophoretic separation for continuous removal of cells and cell debris > 85% clarification efficiency Reduces depth filtration area by 4X Greatly reduces buffer volume and increased yield Robust clarification platform process Continuous process with minimal temperature rise and no impact on protein quality Flow Direction * On June 15, 2015, Pall announced the exclusive licensing agreement with FloDesign Sonics (FDS) for acoustic wave separation (AWS) in Bioprocessing
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Perfusion Harvest Using Acoustics
Harvest Flow Direction Transducer Reflector Recirculation Stream (Tangential Flow) Acoustic Boundary Effect Residence time less than 1 minute out of bioreactor No measurable impact on cell health and protein quality 60 days continuous use, including maintenance of sterility Retention of >99% cells at x 106 cells/mL No loss of protein passage or fouling during process
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AWS Perfusion System Performance
5/15/2019 AWS Perfusion System Performance Reliable retention of cells (> 90%) at up to 87 x 106 cells/mL 3 entirely different sieving coefficients set the systems apart Constant product transmission using the AWS perfusion system Hollow fiber-based TFF and ATF clarification systems resulted in significant product losses
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Cadence BioSMB Technology*
System for continuous chromatography Cassette** can handle up to 16 column/capsule positions Single-use with simple flow path * Pall Announced the acquisition the Cadence BioSMB technology platform from Tarpon Biosystems on March 31, 2015. ** = Cassette: US Patent: US B2 As mAb titer increases productivity can be maintained by increasing column number
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Platform for Continuous Final Formulation
5/15/2019 Platform for Continuous Final Formulation ILC ILDF ILC/SPTFF 0.2 µm Continuous Viral Clearance with Pegasus™ Prime Filters Continuous Final Formulation with Cadence SPTFF mAb in Buffer B mAb in Buffer A Buffer B Bullet point page on white background Utilizes SPTFF design principles ≥ 99.9% buffer exchange in single pass continuous mode No recirculation
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Pall’s Continuous Bioprocessing Laboratory
Integrated Continuous Bioprocessing: g mAb produced in 24 hours
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Clarification Purification Filtration
Integrated Continuous Downstream mAb Process Run Benchtop Scale (200 L Bioreactor) Cadence Acoustic Separator Cadence ILC Depth + 0.2 µm Clarification Polish – Cadence BioSMB System VI + Depth + 0.2 µm Capture – Cadence BioSMB System Purification Pegasus Prime + Protect 0.2 µm Cadence Inline Concentrator Cadence Inline Diafiltration Filtration Unit Operation Sizing 200 L/day Cadence AWS / Depth / 0.2 µm 50 L/h / 0.25 m2 / m2 Cadence ILC 0.7 m2 Cadence BioSMB Capture 8x50 mL KANEKA KanCapA Columns VI + Depth / 0.2 µm 0.05 m2 / m2 Cadence BioSMB Polishing Mustang Q (FT) / CMM (B&E) 3x5 mL XT Capsules / 6x50 mL Columns Virus m2 Pegasus Prime Virus Removal Filter m2 Pegasus Protect Virus Prefilter Cadence ILC / ILDF / 0.2 µm 0.065 m2 / 0.22 m2 / m2
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100 g/day Integrated Continuous Process CQA Trends
5/15/2019 100 g/day Integrated Continuous Process CQA Trends Allegro™ STR 200 Bioreactor 50 4 g/L g/L mAb IN 54 L, ~190 g 200 L, ~187.4 g mAb OUT 1.79 L, ~107.2 g 3.2 L, ~115.9 g Process Total 20.67 hours 21.5 hours Productivity ~124 g/day ~129 g/day Overall Yield ~56% ~62%
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Pall Continuous Bioprocessing Solution from PD to Manufacturing
Cadence Acoustic Separator PD to Manufacturing Cell Culture Bioreactors Clarification Cadence Acoustic Separator Depth + 0.2 µm Cadence Inline Concentrator (ILC) Purification Formulation Capture – Cadence BioSMB + Cadence Virus Inactivation Polish – Cadence BioSMB Virus Filtration Cadence ILC Cadence Inline Diafiltration (ILDF)
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Enabling Manufacturing Technologies Required
How To Deliver? Good Fast Inexpensive Safe ? Enabling Manufacturing Technologies Required
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Cost Saving with Single-Use Continuous Bioprocessing
Stainless Steel Single-Use Single-Use Continuous Clinical Manufacturing (2 batches / year)* Commercial Manufacturing (20 batches / year)*
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Cost Savings with Continuous Bioprocessing
-$4.0 M/yr -$7.0 M/yr -$2.2 M/yr -$0.8 M/yr -$0.9 M/yr -$0.5 M/yr % Savings with Single-Use Continuous vs Batch Commercial Manufacturing
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Cost Savings with Continuous Bioprocessing
-$4.0 M/yr -$7.0 M/yr -$2.2 M/yr -$0.8 M/yr -$0.9 M/yr -$0.5 M/yr % Savings with Single-Use Continuous vs Batch Commercial Manufacturing Breakdown Analysis: 20 batches / year; 6000 L at 5 g/L - $2.2 M/yr
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Enabling Manufacturing Technologies Required
How To Deliver? Good Fast Inexpensive Safe ? Enabling Manufacturing Technologies Required
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Engagement with Regulatory Authorities Objective: Educate, learn, and gain consensus
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Feedback from the Regulators (FDA and PEI*)
High levels of engagement and enthusiasm Openness and willingness to learn about new technologies Sense of comfort with batch! Regulatory questions Bioburden management Lot definition and deviation management Design space Virus clearance strategy Source: Modernizing Pharmaceutical Manufacturing: from Batch to Continuous. Thomas O’Connor, Ph.D., Science Staff US FDA CDER, Presentation ISPE, Singapore, August 2016 * PEI is the Paul-Ehrlich-Institut is an Agency of the German Federal Ministry of Health. Its research and control activities promote the quality, efficacy and safety of biological medicinal products.
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Quality by Design for Continuous Bioprocessing
AWS DFF ILC PrA VI AIX MM VRF ILDF + ILC CQA CQA CQA CQA CQA CQA CQA CQA CQA CPP CPP CPP CPP CPP CPP CPP CPP CPP Design Space Design Space Design Space Design Space Design Space Design Space Design Space Design Space Design Space Process Integration & Perturbation Analysis Control Strategy
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PAT for Continuous Bioprocessing
CQA CQA CQA CQA CQA CQA CQA CQA CQA Biologic PQA Assessments SEC CEX CE-SDC HILIC ELISA Deamidation Glycation High Mannose Methionine Oxidation Signal Peptide Glycosylation CDR Tryptophan Degradation C-terminal Lysine Misincorporations C-terminal Amidation Fucosylation Residual Protein A Host Cell Protein Aggregate
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Advanced PAT for Continuous Bioprocessing
CQA CQA CQA CQA CQA CQA CQA CQA CQA Biologic PQA Assessments SEC CEX CE-SDC HILIC ELISA LC-MS MAM Workflow Deamidation Glycation High Mannose Methionine Oxidation Signal Peptide Glycosylation CDR Tryptophan Degradation C-terminal Lysine Misincorporations C-terminal Amidation Fucosylation Residual Protein A Host Cell Protein Aggregate LC-MS MAM Liquid Chromatography Mass Spectrometry Multi-Attribute Method
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Automated Continuous Process Monitoring and Control
Central Server MVDA Trending Predictive Models Product Stream Data Stream Data Historian MAM Automated Analytics
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Enabling Manufacturing Technologies Required
How To Deliver? Good Fast Inexpensive Safe Enabling Manufacturing Technologies Required
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Bioprocessing 4.0 at Your Finger
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Thank you! Questions?
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