Future biologics manufacturing

Future biologics manufacturing Process integration with single-use technology Dr. Günter Jagschies Senior Director, Strategic Customer Relations GE Healthcare Life Sciences Uppsala, Sweden

Mammalian Cell Culture Evolution Slightly re-written (hi)story of an otherwise fantastic development Product titre 5-50 mg/l barely justifiable 50-1,000 mg/l largely inefficient 1,000-5,000 mg/l acceptable to good efficiency > 5,000 mg/l questionable benefits matching need for Mabs 1982-1985 1985-2005 2005-2010 tpa If an alternative had existed (and with the current view on cost), mammalian cell culture would not have been chosen to produce glycosylated biopharmaceuticals mabs & Etanercept The low productivity of cell culture started the trend to build extremely costly, huge 6 to 12-pack bioreactor farms with economic issues until today Legacy mabs Technology is here to produce any realistic quantity of protein therapeutics. Inherited upstream inefficiencies now create barriers for improvement & change of process and facility > 2010 Future processes At 5 g/l a 4x 1,000 L facility can produce > 350 kg mab annually *). Good fit with available single-use reactors, purification steps, and market demand. More titer might be less *) 700 kg with 4x 2,000 L Page 2 / G Jagschies, GE Healthcare /

Purification Evolution Upstream technology Downstream technology USP Scale de-coupled from product mass DSP Scale proportional to product mass * Nxt gen production rate Current gen production rate 1 st gen production 1 st gen rate Various plant fit improvements 2 nd gen resins Future facility: 200 L 1,000 L bioreactors 3rd gen resins Cell level purification Harvest alternatives Depth filter area Decouple DSP Flow-through mode Multimodal resins Virus filtration Continuous processing Combined unit operations In-line buffer / adjustment Plant fit limits * Monoclonal Antibodies in 15,000 L bioreactors, 10% loss in harvesting Page 3 / G Jagschies, GE Healthcare /

Scale, how much is enough? The business framework for science (1) A number of factors has reversed the scale focused trends dominating the discussions of the last decade: increasing competition, not the least from biosimilars decreasing number of new blockbuster scale drugs technologies to increase drug potency accompanying diagnostics, targeted patient selection All of these aspects are likely to drive required annual production volumes down and make for good feasibility of a new, much smaller, generation of flexible facilities. Page 4 / G Jagschies, GE Healthcare /

The new challenges are instead The business framework for science (2) High throughput of projects through development and clinical manufacturing facilities Balance development time and efforts and costs at continued low success rates Avoid processing issues rather than solve them after the fact, with technology that is then ending up considered costly Flexible manufacturing of multiple (small) products in the same facility Flexible manufacturing of rapidly varying quantities of any given product Get things improved in an extremely short-term focused financial environment Page 5 / G Jagschies, GE Healthcare /

Change phase 1-2 scale practice Change phase 3 scale practice Reducing scale, phase 1-3 & small product Use the opportunity from bioreactor productivity and process understanding 12,000 L Batch sizes (75% yield): 12,000 L = 45 kg 2,000 L = 7.5 kg 1,000 L = 3.7 kg 250 L = 0.9 kg 100 L = 0.4 kg 600 L Protein A resin 2,000 L 2,000 L 100 L Protein A resin 1,000 L 1,000 L 50 L Protein A resin 100 L 5 L Protein A resin 5 g/l product titer 95 % harvest process yield, 75% overall yield 40 g/l dynamic binding capacity (~6 min residence time) 80% utilization of column capacity 3 cycles per batch Page 6 / G Jagschies, GE Healthcare /

Change phase 1-2 scale practice Change phase 3 scale practice Reducing scale, phase 1-3 & small product Use the opportunity from bioreactor productivity and process understanding 12,000 L 600 L Protein A resin reduce costs double cycling 300 L Protein A resin Batch sizes (75% yield): 12,000 L = 45 kg 2,000 L = 7.5 kg 1,000 L = 3.7 kg 250 L = 0.9 kg 100 L = 0.4 kg 2,000 L 2,000 L 100 L Protein A resin reduce costs double cycling 50 L Protein A resin 1,000 L 1,000 L 50 L Protein A resin 100 L 5 L Protein A resin reduce efforts no cycling 15 L Protein A resin 5 g/l product titer 95 % harvest process yield, 75% overall yield 40 g/l dynamic binding capacity (~6 min residence time) 80% utilization of column capacity 3 cycles per batch Page 7 / G Jagschies, GE Healthcare /

Change phase 1-2 scale practice Change phase 3 scale practice Reducing scale, phase 1-3 & small product Use the opportunity from bioreactor productivity and process understanding 12,000 L Batch sizes (75% yield): 12,000 L = 45 kg 2,000 L = 7.5 kg 1,000 L = 3.7 kg 250 L = 0.9 kg 100 L = 0.4 kg 600 L Protein A resin reduce costs double cycling 300 L Protein A resin Right sizing is the only truly powerful cost reduction approach, most other approaches are just cosmetics and may even hide weaknesses 2,000 L 2,000 L 100 L Protein A resin reduce costs double cycling 50 L Protein A resin Single-use feasibility! 1,000 L 1,000 L 100 L 50 L Protein A resin 5 L Protein A resin reduce efforts no cycling Continuous processing? 15 L Protein A resin 5 g/l product titer 95 % harvest process yield, 75% overall yield 40 g/l dynamic binding capacity (~6 min residence time) 80% utilization of column capacity 3 cycles per batch Page 8 / G Jagschies, GE Healthcare /

Cost [$/gram] Right sized, cost competitive Economic competitiveness from Enterprise Solutions For clinical batches or product launch COGS per gram are not lowest (anywhere), but nevertheless they are competitive Right sized (1,000 L reactors) Flexible (single-use design) Modern process (e.g., titer 2 g/l, resins) 500 L 2,000 L 20,000 L CMO costs at x L bioreactor scale (2.g/L) Batches per Year In regular production, the small biosimilar facility can reach COGS near state of the art large scale facility Page 9 / G Jagschies, GE Healthcare /

Annual capacity [kg] Current drug substance capacity: circa 30-90 kg/yr From one 1,000 L bioreactor 70 % overall process yield 3 weeks facility downtime Working hypothesis (1): CHO batch time can be reduced to yield 170 kg/yr from one 1,000 L reactor! Ref.: L. Hagel, G. Jagschies, G. Sofer Handbook of Process Chromatography Elsevier, 2007 My upstream hypothesis: Reducing time is more effective than increasing titer further (>5 g/l) 500 450 400 350 300 250 200 150 100 50 0 0 1 2 3 4 5 6 7 80 8 9 10 20 10 12 14 16 18 8 6 4 Working hypothesis (2): Titer beyond 5 g/l likely to cause DSP issues: e.g., biomass, aggregates, scale, cost 1 day turnaround for bioreactor station 1 product in facility [kg/yr] 450-500 400-450 350-400 300-350 250-300 200-250 150-200 100-150 50-100 0-50 Page 10 / G Jagschies, GE Healthcare /

Inoculum & seed to 2,000 L, alternatives 1 ml vial thawed Classic: 6 operations Perfusion: 4 operations 1 ml vial thawed 3 shakers 2 shakers 50 L WAVE bag 10 L perfusion WAVE bag 25 ml-2.5 L expansion 200 L Disposable bag 230 L Medium Filters and assemblies 110 L Medium 25 ml-250 ml expansion 17 days of expansion 16 days of expansion 24 hours working time 20 hours working time 25 L expansion 1-5 L perfusion expansion 250 L expansion Eliminate steps in the seed train High cell densities in n-1 step ( 100*E6 cells/ml) at high viability in less than 15 days Possibility to directly inoculate large-scale bioreactor 2,000 L cultivation Page 11 / G Jagschies, GE Healthcare /

Smart Flexibility Be alert for the next challenge, but do not build readiness in concrete and steel instead make things reconfigurable. Add and take away as needed, do not rebuild Keep things light and mobile, not just as they always were Facilitate change through standardization and modularization Keep non-value adding activities off-line, just-in-time Develop and use automation to eliminate hold time and manual activities Design for the norm, manage the exceptions Page 12 / G Jagschies, GE Healthcare /

Single-use technology strategy aspects With single-use technology becoming available, there are now some choices in a facility investment plan that did not exist previously. Cash outflows are not any more dictated by the rules of steel & concrete dinosaur plants and they are not automatically pulled to a time many years before the first cash inflow can be expected. Overall, management now has a number of ways to develop smarter cash flow strategies and improve the net present value quite significantly. Before this the only viable option had been the Contract Manufacturing route. These new degrees of financial freedom alone speak in favor of single-use technology and place it on the list of standard options to consider. Page 13 / G Jagschies, GE Healthcare /

High-level decisions and effects Facility design concept Right-sized and multi-product Consider the unexpected Make things re-configurable Spend when making product Process design concept Platform process / workflows Modern production tools Start purification at cell level Integrate all parts of process Quality design concept Product and process understanding High throughput process development High gain analytical development Facilitate change, stay robust Anticipate and simplify change, guarantee robustness Page 14 / G Jagschies, GE Healthcare /

Disposable equipment What is available? Shorter set-up time Shorter change-over time Reduced cleaning burden Reduced cleaning validation Less ss CIP piping High impact time savings Bioreactors (wide range, various technical principles) Centrifuges (limited availability and feasibility) Filtration cartridges (wide range) Tanks for buffers and intermediate product (wide range) Chromatography (system with single-use flow path) Membrane adsorbers (flow-through mode use) Virus filtration (default single-use) UF/DF (system with single use flow path, HF cartridges) Mixing systems for culture media and buffer preparation (wide range) Page 15 / G Jagschies, GE Healthcare /

Disposable equipment What are the limitations? While the flexibility aspect is widely accepted in pilot facilities and small to mid scale production, many open issues remain Different risk profile, partly immature technology Cost for frequent use, can be very high for functional devices Bioreactors, mixers, columns, flow paths, certain filters Value gains need to be verified carefully Physical integrity issues, leaks, lost bags or even batches Liquid transfer to / from bags, 1 is largest available connection Limited availability of sensors in disposable format Supply chain capacity and lead times are being questioned Transparency / predictability of the supply chain still not satisfactory Experienced production engineers still need to be convinced Rather widespread skepticism versus large bioreactors Page 16 / G Jagschies, GE Healthcare /

Cost reduction below reference Economics, what is it you can do? Your reference cost Modern strategies allow $ 30-40 per g COGS levels for DS* Fixed cost: facility utilization Variable cost, Working capital * DS = Drug substance Page 17 / G Jagschies, GE Healthcare /

Cost reduction below reference Economics, what is it you can do? Your reference cost Fixed cost: facility utilization Modern strategies allow $ 30-40 per g COGS levels for DS* Right-size for clinical trials!!! Have cheap extra space Avoid dedicated and customized solutions Enable expansion on demand Spend only when making Shorter project times Value generation Versatility: multiple use, no extra CAPEX $ 100K - $ 10M Time translates to money, if more product can be made Variable cost, Working capital Use current process tools and designs LEAN your process, maximize robustness Simplify batch record, analytical efforts * DS = Drug substance Page 18 / G Jagschies, GE Healthcare /

Cost reduction below reference Economics, what is it you can do? Your reference cost Fixed cost: facility utilization Modern strategies allow $ 30-40 per g COGS levels for DS* Right-size for clinical trials!!! Have cheap extra space Avoid dedicated and customized solutions Enable expansion on demand Spend only when making Shorter project times Value generation Versatility: multiple use, no extra CAPEX Time translates to money, if more product can be made Fewer, smaller batches $ 100K - $ 10M Variable cost, Working capital Use current process tools and designs LEAN your process, maximize robustness Simplify batch record, analytical efforts Higher yields Value generation Disposable cost * DS = Drug substance Page 19 / G Jagschies, GE Healthcare /

Cost reduction below reference Economics, what is it you can do? Your reference cost Fixed cost: facility utilization Variable cost, Working capital Modern strategies allow $ 30-40 per g COGS levels for DS* Right-size for clinical trials!!! Have cheap extra space Avoid dedicated and customized solutions Enable expansion on demand Spend only when making Use current process tools and designs LEAN your process, maximize robustness Simplify batch record, analytical efforts Shorter project times Value generation Higher yields Versatility: multiple use, no extra CAPEX Value generation $ 100K - $ 10M Time translates to money, if more product can be made Fewer, smaller batches Disposable cost Unlock bottlenecks Enable fresh revenue from existing facility Modern strategies allow to unlock $ 10-100 M fresh revenue Revenue gains: $ 100s M from earlier revenue start $ 10s M from additional batches $ 10s M per % additional process yield * DS = Drug substance Page 20 / G Jagschies, GE Healthcare /

Finally, what are the challenges? Some single-use devices are cost efficient or even cheap, others are (yet) more the opposite. An individual economics scenario analysis is absolutely necessary. Beyond 500 to 1,000 L scale handling of single-use devices is no longer truly convenient, the flexibility begins to fade. The supply chain and parts of QA need to be re-defined to fit single-use strategies in manufacturing. Some of this is not too well understood or established. Single-use is one of many tools in efficiency improvement. Its true advantage lies in improving facility utilization and in the cash management options (spend when making product) The greatest technically driven efficiency gain would come from shortening the production bioreactor batch time. Page 21 / G Jagschies, GE Healthcare /

Acknowledgments Gail Sofer Lars Hagel Karol Łącki Howard Levine and BPTC team Brian Kelley Greg Blank Wolfgang Berthold Joachim K Walter Page 22 / G Jagschies, GE Healthcare /

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