Development from Bench to Clinic

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1 Accelerating Novel Vaccine Development from Bench to Clinic Roger Lias. Ph.D. President Eden Biodesign, Inc

2 Questions Questions are encouraged and can be asked by sending an to:

3 The challenges Manufacturing design for novel vaccines offers significant and different challenges to traditional mab like products mabs are becoming small molecule-like No standard d platform for most novel vaccine products Vaccines remain anchored to process = product paradigm The need to combine good design with knowledge management for regulatory led vaccine development Global vaccine supply Speed, process transferability and scale-up Availability of expert support

4 Eden Biodesign Designing and developing valuable biopharmaceutical medicines by the application of good science from day one Consultancy Process Design & Development cgmp Manufacture Global CMC Support Regulatory Training Strategic t Issues Clinical Logistics Cell Line Development Process Development Analytical Development Cell Banking Mammalian Cell Culture Microbial Viral

5 Eden Biodesign Maintains a Globally Integrated Biopharmaceutical Network Research Triangle Park, NC North American HQ Liverpool, UK Global HQ & cgmp Operations Clients on all five continents San Diego, CA Business Development Office Client Assignments Eden Biodesign Presence Strategic Partners

6 Eden Biodesign

7 Novel Vaccine Market Dynamics Robust Biopharmaceutical Market mab market growth outstripping small molecules Equally dynamic vaccine market Deep product pipeline Biosimilars, follow-on on biologics Novel Vaccine Market Drivers Breakthroughs with new products to address unmet medical needs Contingency planning for pandemic infections Growing income in the developing world markets Threat from bioterrorism Price flexibility linked to demonstrable health economic benefits Potential for therapeutic vaccines Continued interest and investment from major pharma players

8 Dramatic Vaccine Developments in Diverse Product Types Live Attenuated Inactivated Purified Antigen Conjugates Recombinant Whole cell Microbial Viral Virus Like Particles Polysaccharides

9 ..Requiring an Equally Wide Range of Production Technologies Traditional plus. Modern Biopharmaceutical aceu ca Production o Techniques Mammalian cell culture Diverse cell types adherent and suspension culture Bioreactors (steel/disposable), cell factories, roller bottles, hollow fibers etc. Microbial fermentation Bacterial, yeast Chromatographic purification techniques..with associated analytical challenges

10 Meanwhile, mabs are becoming small molecule-like... l lik acetaminophen Immunoglobulin Commercial Trends Mainstream product class Biotech s mixed portfolio of small molecules and mabs Manufacturing Largely platform manufacturing design Easily outsourced Expanding international range of commercial facilities Availability of experienced scientists and engineers Regulatory Comparability protocols supporting flexibility scale-up options Application of PAT, QbD initiatives. CDER rather than CBER oversight

11 ..but Vaccine Process Developers Face More Difficult Challenges The need for speed, robustness and transferability pandemics, bioterrorism Cost-of-Goods pressures Limited available production expertise Few supporting service providers with necessary expertise vaccine development/regulatory l t experience process development expertise available cgmp facilities & equipment and, importantly. Vaccines are still anchored in the Process = Product paradigm

12 Vaccines remain anchored to process = product paradigm Novel vaccines are difficult to characterize a validated and reproducible PROCESS a characterised and consistent PRODUCT pre-determined acceptance criteria and specifications Inability to characterize and immunogenicity issues make process changes difficult Need to begin with the end in mind

13 The Impact No dominant production platform(s) Constraints on process change Processes difficult to scale-up and transfer Limited transferability of skills and knowledge between products Dedicated facilities High capital requirements Increased risk

14 Meeting the challenges New approaches are required... Adoption of innovative facility design permitting multitechnology vaccine production. Evaluation and application of new analytical l tools to create a data rich platform for process optimisation comparable to mab development More platform like approaches Knowledge management focusing on the quality of the end product: clinical i l vaccine and good paper

15 Meeting the challenges Multi-technology vaccine facility Contained Facility Design Revision of the Requirements for Live Vaccine Processing. [FDA 21 CFR Part 600] Disposable technologies Upstream Downstream Skid Mounted Unit Operations configurable for most classes of vaccine All major types of process technology Microbial Mammalian Viral VLPs

16 Towards a Platform Approach Pandemics, bioterrorism, third world markets etc. require a more platform like vaccine production approach that: Is robust Fewer unit operations, ambient processing, hold steps, etc. Is easily transferred Rapid global production Must have a realistic supply chain Is reproducible Is scalable Is economically viable Negates classical stepwise development and reduces timelines Can be applied as part of tech. transfer using generic parameters

17 Towards standard platforms VLPs Pichia pastoris Harvest Lysis Clarification Viral HEK293 DNA reduction Filtration Primary capture Polishing Formulation Purified Bulk Antigen

18 Standard Platform Considerations for Viral Vaccines Well characterized cell types with good provenance e.g. HEK293 Suspension culture Serum-free culture Safety and improved COGs at scale Low cell densities and low MOI generate max. titres Reduced inoculum build decreases suite occupancy time Smaller scale for MVSS production and easier processing Courtesy Thermo Fisher Courtesy GE Healthcare

19 Standard Platform Considerations for Viral Vaccines Disposable processing systems Reduced d contamination ti risk; rapid turnaround; less validation Stirred tank bioreactors where possible Reduced failure vs. static/roller bottle systems Facilitate online (PAT) analytics (e.g. NIRS) for real time monitoring High recovery chromatographic methods for purification Including disposable columns Established supply chain for global production Courtesy Thermo Fisher Courtesy GE Healthcare

20 Meeting the challenges Improved analytical methods which are rapid and robust are required to support process development, in-process monitoring and product characterization for novel vaccine products for example: Novel anion exchange HPLC methods Novel anion exchange HPLC methods that dramatically reduce time and increase sensitivity for analysis of adenoviral products

21 Development of HPLC AEX methods using monolith columns Strong Anion Exchanger Column size = 76 µl Max pressure = 150 bar Column temperature = 22ºC Injection volume = 25 µl Flow rate = 1mL/min Developed step gradient method provides very rapid (<10 min) sensitive and high resolution quantification of live adenovirus

22 Meeting the challenges Adoption of new analytical tools Harvest Lysis Clarification DNA reduction Filtration Primary capture Polishing Formulation Analytical CIM AEX HPLC

23 Meeting the challenges Live viral quantitation and purity determination ti in 10 mins compared with plaque assay > 3 days Harvest Imp Ad5 Imp Filtered harvest Lysis Clarification DNA reduction Imp = Impurity Filtration Ad5 Primary capture Primary capture Polishing Imp Imp Formulation

24 Knowledge Management Quality y( (CMC) Information in Common Technical Document Format Quality of Manufacturing throughout product life cycle Reference Standards Qualified Assays Structure conceptual process design

25 In conclusion Vaccine manufacturing development still faces challenges that have been largely overcome for mabs and other recombinant products Opportunities: Multi-technology facilities based on design, containment, disposables and new regulatory flexibility Utilisation of new analytical l methods to provide data to challenge the process = product orthodoxy Development and acceptance of more platform like production schemes for novel vaccine types Global vaccine development enhanced through focused knowledge management using technical summary reports as building blocks of value

26 Questions Questions are encouraged and can be asked by sending an to:

27 Thank You Follow-up webcasts will provide detailed technical insight into facility design, analytical methods and platform method developments that may dramatically improve the development of production processes for novel vaccines