State of the Biosimilar Industry and Implications for Technology. Presented at DCAT Week 2014 March 10 14, 2014 New York, NY

Transcription

1 State of the Biosimilar Industry and Implications for Technology Presented at DCAT Week 2014 March 10 14, 2014 New York, NY

2 Growing and Changing Pharmaceutical Market A Few Issues Shaping the Pharma Industry 1 Prescription pharmaceuticals forecasted to cost >$500B by 2017 Currently, biologics drug expenditure already accounts for ~25% of pharmaceutical spend and are >33% of all drugs in development MAbs are largest and fastest growing segment 2 Continuous financial pressure on healthcare systems to make significant and sustained cost reductions US healthcare spending by 2021 forecast to be ~20% GDP 3Major products are losing patent protection coupled with new regulatory approval pathways 2 Global Pharma Market (USD bn) Source: Evaluate Pharma May 2012 Enable emergence of a biosimilar industry 2

3 Demand for Biosimilars As of Sep 2011 Source: Decision Resources APPROVED Many monoclonal antibodies will be off patent in the next few years Biosimilar monoclonal antibodies approved in Europe and Korea, as well as India and China All major markets now have biosimilar legislation in place Large players are increasingly entering this segment Biosimilar versions of first generation biopharmaceuticals already approved in many markets In Development As of Sep 2011 Source: Decision Resources 3

4 How Will Changes in the Industry Impact Development and Manufacturing Technology? Cell Lines Cell Culture Purification Analytics Capacity Facilities 4

5 29% 7% Conventional Expression Systems 3% 5% E. coli S. cerevisiae (yeast) Mammalian (primarily CHO) Transgenic Other Advantages CHO high expression; easily cultured Microbial fast growing; economical Disadvantages Prone to HCP contamination and 56% adventious agents Ref: Fritz T. Manufacturing strategies for biosimilars. For biosimilar developers, these cell lines provide less opportunity for innovation, fewer intellectual property advantages, and minimal patent protection. Can alternative expression systems be successfully used for biosimilar development and commercialization?? 5

6 Increased Cell Line Productivity Productivity has doubled every 1.5 years Following Moore s Law Date Cell lines Expression systems: glutamine synthetase (GS; Lonza), Ubiquitous Chromatin Opening Elements (UCOE; Millipore/Cobra), Selexis Genetic Elements (SGE; Selexis), Gene Product Expression Platform (GPEx; Catalent) etc. Cells: High viable cell density, suspension and medium adapted Process Media: Animal component free, defined medium Culture conditions: Feed strategies, catabolite control, gas exchange Courtesy of P Ball of Actavis. Adapted from BPTC W. Noe, Biomanufacturing Summit,

7 GS System expression vectors include the gene encoding the selectable marker Glutamine Synthetase (GS) Selexis discovered and developed a unique class of genetic elements which they have termed Selexis Genetic Elements (SGEs) that control the dynamic organization of chromatin within all mammalian cells and enable certain genes to be maintained in an open chromatin configuration Catalent s Gene Product Expression Platform (GPEx) technology is based on the utilization of a modified, non replicating retrovirus that can be used to infect production cell line hosts and introduce the recombinant gene into the genome UCOE expression technology is similar in concept to Selexis SGE;mBy including UCOE elements in an expression vector, nearby genes are maintained in an open configuration that is accessible to the cellular transcriptional machinery

8 Purification Development Increased scale Improvements / new methods Increased dynamic binding capacity Negative, multi modal and membrane chromatography Simulated moving bed (SMB) chromatography Courtesy of Tarpon Biosystems Courtesy of Lonza Biologics 8

9 Cell Line and Process Development for Biosimilars Cell line 1 st = Similarity, 2 nd = Titer Orthogonal analysis of CQAs Use caution with novel systems Process Yield, COG, time Refine process to retain target CQA Transferrable processes Ref. product Refined process 1 st iteration process Courtesy of P Ball of Actavis. 9

10 Biosimilars Demand Increased Control Challenge Biologics are complex molecules Complexity increased by glycosylation, etc. Structural motifs related to function Not a single molecule but a mixed population Old New Solution Highly sensitive analytical techniques Biophysical and structural analysis Biological characterization In process analysis (PAT) Process Product Courtesy of P Ball of Actavis. 10

11 Thorough Characterization with State of the Art Analytics Biological characteristics Antigen binding Effector function Compliment interactions Fc receptor interactions Physiochemical characteristics N terminal heterogeneity Amino acid modifications Deamidation, oxidation, glycation, isomerization Fragmentation Cleavage in hinge region, Asp Pro Oligosaccharides Fucosylation, sialylation, galactosylation Disulfide bonds Free thiols, disulfide shuffling, thioether C terminal heterogeneity Lysine processing, proline amidation From Kozlowski and Swann 11

12 Better Yield, Lower COG, Excess Capacity Increasing expression levels Multiple large scale facilities Increased yield Decreasing cost of goods Smaller batch volumes Excess capacity 12

13 Global Distribution of Cell Culture Capacity North America 1,821 1,963 UK/Ireland Europe Korea Japan China <1 125 India Singapore/ Malaysia Australia < Note: Perfusion capacity adjusted to equivalent fed batch capacity where appropriate Russia 0 7 South America 0 4 Volume in 000s L

14 Today s Biopharmaceutical Facility Most facilities today were built for low titer (<1 g/l) processes Multiple 20,000 L bioreactors each with inoculum bioreactors up to 4,000 L Current facilities struggle to match downstream capacity with bioreactor output due to large process volumes Technologies that enable higher bioreactor titers will exasperate the DSP bottleneck 14

15 Biopharmaceutical Facilities of the Future Designed for modern, state of the art processes Cell culture titers >5 g/l Smaller bioreactors will produce similar quantities similar to today s six pack facilities Expanded use of new technologies, including disposables, to reduce capital investment, increase flexibility, and compress timelines Reduced capital requirements may enable smaller companies to construct their own facilities rather than outsource Enable facilities to be built in emerging markets Continuous processing, PAT and other modern manufacturing methods will be incorporated into bioprocessing Incorporate greater DSP space and capabilities Ratio of USP to DSP space will decrease 15

16 Disposable Options for All Manufacturing Operations Cell Culture Recovery/ Downstream Processing Formulation/ Fill Media Prep/ Storage Buffer Prep/ Storage Photo courtesy of Pall Life Sciences 16

17 Single Use Bioreactors Xcellerex XDR TM Bioreactor Sartorius Stedim Biostat Culti bag Thermo Fisher (Hyclone) Single use Bioreactor GE Healthcare Wave Bioreactor ATMI Nucleo TM Bioreactor 17

18 Downstream Disposable / Single Use Options 18

19 Formulation/Fill/Storage Options Millipore Opticap Filters Sartorius Stediem FlexAct System Pall Kleenpak Connectors Pall Allegro 3D Biocontainers Sartorius Stedium Celsius FFT Pall Allegro 2D Biocontainers 19

20 Biomanufacturing Capacity Adequate but Tightening Increase in number of products and expanding markets will increase demand by ~1 million liters by 2016 Current and anticipated supply of capacity is sufficient to meet the market needs for the foreseeable future Existing capacity may not be available at the time needed or under the appropriate conditions Product companies control >70% of total capacity Utilization rates for the majority of the industry will reach almost 75% by 2016 Companies without manufacturing capacity or ability to secure manufacturing contracts may experience difficulties in accessing capacity in the coming years 20

21 Partnerships and Alliances to Develop Biosimilars Development and Regulatory State of the art analytical and clinical capabilities to speed up development and ensure regulatory compliance Market Access Optimize time to market and ensure key stakeholders (KOL, payers) are onboard and supportive to drive advocacy and acceptance Manufacturing Scale and know how to manufacture at reasonable COGs Biogen and Samsung Biocon and Mylan Merck BioVentures and Parexcel Baxter and Momenta Amgen and Actavis Hospira and Celltrion Teva and Lonza Sales and Marketing In country capabilities and understanding of local dynamics 21

22 Thank You! Patti Seymour BioProcess Technology Consultants, Inc. 12 Gill Street, Suite 5450 Woburn, MA 01801