Biopharma's Flexible Imperative. Robert Dream Principal, HDR COMPANY LLC April 24, 2013

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1 Biopharma's Flexible Imperative Robert Dream Principal, HDR COMPANY LLC April 24, 2013

2 Biopharma's Flexible Imperative Introduction Can history help us see the future Comparing 1918 and today Pandemic influenza as an example Public health and healthcare delivery Current preparedness challenges Where do we go from here Case Studies 2

3 The Backdrop Recently, a number of different trends have converged to demand a new type of biopharmaceutical delivery facility one that emphasizes flexibility and agility. 3

4 An Overview Drawing this new blueprint are: Business needs to minimize timelines and financial risks Biotech on Demand, and the ability to shore up local manufacturing capacity, quickly, to meet market needs National security needs for systems that can easily and rapidly respond to biological attacks Urgent national health needs to protect the public from large-scale, fast moving epidemics and pandemics 4

5 Understanding Pandemic Pandemic An epidemic that becomes very widespread and affects a whole region, a continent or the Globe. Influenza pandemics; o 10 pandemics recorded in the last 300 years o 10 to 49 years between pandemics (50,000, ,000,000 deaths worldwide)

6 1918 Source: Center for Infectious Disease Research and Policy 6

7 16 different Hemagglutinin antigens (HA) 9 different Neuraminidase antigens (NA) HANA, e.g.: : H1N1, Spanish Flu : H2N2, Asian Flu : H3N2, Hong Kong Flu 7

8 Antigenic shift and drift (Virology, Epidemiology) Influenza virus undergoes two kinds of changes. Drift: One is a series of mutations that occurs over time and causes a gradual evolution of the virus. This is called antigenic drift Shift: The other kind of change is an abrupt change in the hemagglutinin and/or the neuraminidase proteins. This is called antigenic shift In this case, a new subtype of the virus suddenly emerges. Influenza type A virus undergoes both kinds of changes and could cause a pandemics Influenza type B virus changes by the more gradual process of antigenic drift only and does not cause any pandemics Influenza type C is less common than types A & B and usually only causes mild disease in children 8

9 Facilities of the Future, Today : issues and technologies driving new Biopharmaceutical manufacturing facility design and construction, both in the US, EU, and in growing markets. Among the questions; US/EU: Where are the facilities being built and how will that affect industry employment trends, and drug supply to the patients? How are they being designed? In newer markets: the issues are many, including: Imperfect harmonization among FDA, SFDA, EU, Japan, and WHO. What should companies expect and how can they prepare? How should they plan to handle data, to ensure IP security (e.g.: INDIA patent nullification will it spread)? Energy conservation in design Layout and systems: how to facilitate collaboration when the culture emphasizes the opposite How to work with local and global suppliers?

10 Do a risk assessment and analyze - Why we need a facility - Why it has to be: Modular, Flexible, and/or Rigid Cost, capital investment Time to market Preclinical and/or Clinical operation that goes through multiple product changes in a very short time We don t know what we are planning to manufacture it is pandemic response facility Regions of the world where crafts is not available to build a regulatory compliant and safe clean room The life of the product is very short and change over requires flexibility within a short time And so on

11 How to build and sustain a quality culture so your organization can: Improve process Minimize risk Decrease cost Increase productivity Remain compliant

12 Agency: Department of Health and Human Services (DHHS) Biomedical Advanced Research and Development Authority (BARDA) Agency: Department of Defense (DoD) Defense Advanced Research Projects Agency (DARPA) 12

13 The BARDA Strategic Plan emphasizes five goals for BARDA will use to accomplish its mission: An advanced development pipeline replete with medical countermeasures and platforms to address unmet public health needs, emphasizing innovation, flexibility, multi-purpose and broad spectrum application, and long-term sustainability. A capability base to provide enabling core services to medical countermeasure innovators. Agile, robust and sustainable U.S. manufacturing infrastructure capable of rapidly producing vaccines and other biologics against pandemic influenza and other emerging threats Responsive and nimble programs and capabilities to address novel and emerging threats A ready capability to develop, manufacture and facilitate distribution of medical countermeasures during public health emergencies 13

14 Flexible, multi-product, multi-technology capability within a biomanufacturing ecosystem; commercial operator(s) Flexible multi-product, multi-technology pilot plant with robust process development capabilities & commercial / SNS (Strategic National Stockpile) facility Commercial / SNS Facility 8-10 modular process trains for surge of pandemic flu and/or ongoing MCM production for SNS Full surge capability to 10X baseline within 24 hours Stockpile pods with complete processes for major biothreats Life cycle management program with scheduled rotation through production Consideration of adjacent facility for integration/validation of clinic-ready emerging technology platforms (DARPA AMP and others) Highly integrated intermediate development cluster Animal model development and validation, biomarker evaluation, imaging, GLP pre-clinical studies and animal rule efficacy, and human Phase 1 clinical trials. 14

Mimic System Transitioning AMP: Accelerated Manufacture of Pharmaceuticals Program AMP Ongoing DTRA:

15 Operational Goal From pathogen emergence to millions of doses of definitive therapy in 16 weeks Deployed as Strategic and Tactical Assets Transitioned to DTRA and JPEO- CBD for Advanced Development Mimic System Transitioning AMP: Accelerated Manufacture of Pharmaceuticals Program AMP Ongoing DTRA: Defense Threat Reduction Agency JPEO-CBD: Joint Program Executive Office for Chemical and Biological Defense 15

16 Case Studies (Two): Flexible Manufacturing Viral Vector by Mammalian Cell Culture Vaccines (Influenza) Monoclonal Antibody (mab) Sub-Unit Protein Vaccines Autologous Cancer Vaccines Virus Vector Manufacturing by Plant Culture 16

17 National Center for Therapeutics Manufacturing 17

18 Scope Flexible-by-design architecture and platforms Accommodates multiple production technology platforms and products: allows utilization of best of breed flexible bioprocess technologies Completely reconfigurable clean rooms required for campaigns and surge, without interruption of ongoing operations. Personalized therapeutics to moderate scale bioreactors (2000 L) Focus on Phase I, Phase II, and Phase III run in Shared core services; medium throughput fill and finish Educational programs to train U.S. workforce in commercial cgmp-compliant production and related R&D 18

19 Operating Platform Modular, scalable, mobile clean rooms rated at ISO 8, 7 & 5 Operational design (42 Long x 18 Wide x 13 High) and can accommodate up to 2000 liter bioreactor Dual redundant systems including 2 AHUs, SCADA, bag in / bag out HEPA filtration for supply and exhaust Remote quality control, security, and maintenance via wireless communications PODs will allow significant increase in the tooth-to-tail ratio for bio-manufacturing facilities Predicted reduction in operational costs and energy utilization of at least 50%. 19

20 Therapeutics Manufacturing Facility Academic Wing: ~48,000 ft 2 GMP Bioprocess Wing: ~104,000 ft 2 20

21 Manufacturing Space 21

22 Single Use Technologies 22

23 MBF Interior Standard: 42 Long x 18 Wide x 13 High 23

24 Exterior Utility Connection 24

25 HVAC System - Supply & Exhaust 25

26 Non-Viral Manufacturing Pressure Scheme MBF Mechanical Space MBF Mechanical Space P~+36 Pascal's P~+24 Pascal's + 0 Ambient P~12 Pascal's - P~-12 Pascal's ISO 7 Space ISO 8 Space Material Pass Through Processing Suite Gray Space Service Corridor Processing Suite Gowning De-Gowning Gowning Clean - + Corridor Gray Space + + Material Pass Through De-Gowning 26

27 Viral Manufacturing Pressure Scheme MBF Mechanical Space MBF Mechanical Space P~-36 Pascal's P~-24 Pascal's - 0 Ambient + ++ P~-12 Pascal's P~+12 Pascal's P~+24 Pascal's ISO 7 Space ISO 8 Space Material Airlock Processing Suite Gray Space Clean Corridor Service Corridor Processing Suite Gowning Gowning De-Gowning Gray Space + + Material Airlock De-Gowning 27

28 Personnel Flow MBF Specific Controlled Personnel Flows for USP With Limited DSP Access MBF Mechanical Space MBF Mechanical Space Processing Suite USP Processing Suite DSP ISO 7 Space ISO 8 Space Material Pass Through Gowning Material Pass Through De-Gowning Gowning De-Gowning Clean Corridor Service Corridor 28

29 Material Flow MBF Mechanical Space MBF Mechanical Space Processing Suite Processing Suite ISO 7 Space ISO 8 Space Material Pass Through Gowning Material Pass Through De-Gowning Gowning De-Gowning Clean Corridor Service Corridor 29

30 Waste Flow MBF Mechanical Space MBF Mechanical Space Solid Waste & Small Volume Liquid Carboy Pass Through & Transport Enclosure Cart Processing Suite Processing Suite ISO 7 Space ISO 8 Space Material Airlock Gowning Material Airlock De-Gowning Gowning De-Gowning Clean Corridor Service Corridor 30

31 Isolator Technology small and flexible Production lines tend to become smaller and more flexible multiple product lines require short change over times down time has to be reduced Short decontamination cycles Short cleaning and filter change over time Short glove testing time Modular isolator system

32 Short Glove Testing Time Wireless Glove Tester

33 Short Cleaning and Filter Change over Time Filter cartridge

34 Short Decontamination Cycles H2O2 Decontamination isolator carrier gas nozzle H 2 O 2 vapor closed vaporizer H 2 O 2 solution

35 Short Decontamination Cycles Cycle Time to <1ppm 2 hours down to 0,5ppm Genentech

36 Short Decontamination Cycles Cycle Time to <100ppb 0,1ppm 5 hours

37 Manufacturing Profile 1. A Modular Bioprocessing Unit (MBU), is a portable, self contained environment that allows for drug development in multiple locations. The key to the design of these MBUs is that they are self-contained with inherent air handling and other critical equipment and controls components. 2. Each MBU is used for a single, biologically distinct technology (bacteria, mammalian cells, plants, etc.), thereby eliminating any cross contamination issues with regulatory agencies. 3. When MBUs are not in use, they are moved to cleaning/refurbishing areas and ready MBUs are plugged in for manufacturing. 37

38 A Unit Being Moved in a Manufacturing POD 38

39 Necessary Connections Being Made 39

40 Single Use Reactor and Support Equipment/Controls 40

42 Case Study: GreenVAX Plant Based Vaccine Manufacturing 42

Project Objective and Metrics Objective: Perform the R&D required to deliver recombinant H1N1 subunit vaccine, expressed in hydroponic tobacco plants, at a scale of one kilogram of purified vaccine

43 Project Objective and Metrics Objective: Perform the R&D required to deliver recombinant H1N1 subunit vaccine, expressed in hydroponic tobacco plants, at a scale of one kilogram of purified vaccine protein per month, that meets all regulatory requirements for purity, quality, and current cgmp Total project timeline: 12 months from initial funding to first 10 million dose test run Technology Investment Agreement (TIA) between DARPA & Texas Plant-Expressed Vaccine Consortium Consortium contribution: $21,144,223 Federal contribution: $39,998,063 Facility expandable to 100MM doses per month; or dual product capabilities, for ~$18M additional 43

44 Plant Based Vaccine Manufacturing Timeline Tobacco based vaccine system (Fraunhofer) optimized through DARPA AMP Program Yield of H1N1 recombinant protein now mg/kg of plant biomass at pilot scale facility in Delaware Preliminary subunit vaccine highly protective in ferret challenge model Clinical development plan for Phase 1 under DARPA management GreenVax Consortia will continue clinical development upon completion of current DARPA project 44

45 Plant Under Construction Precast Tilt-up Concrete Panels Double-T Roof Panels 45

46 Plant Based Vaccine Manufacturing 46

48 Pre and Post Infiltration Racks Post Infiltration Pre Infiltration 48

49 Infiltrator 49

50 Overall Schedule D e c 0 9 F e b 1 0 J u n e 1 0 S e p t 1 0 D e c 1 0 Proposal submitted Contract Signed Program Kickoff Engineering and Process Design and Specification Process Control Design Installation of Process Equipment Production of 1kg Purified Antigen 50

51 A platform that has been successfully used for the development and manufacture of a wide range of vaccines and therapeutics: Low-cost, rapid production of proteins Correctly folded and biologically active cgmp-qualified master virus banks and cell line Extensive clinical use and regulatory history Scalable to large volumes and high cell densities FDA-qualified cell line and virus bank cgmp clinical materials at an affordable price Manufacturing and treatment facilities on a moment notice 51

52 Biopharma s Flexible Imperative Q&A Robert F Dream HDR COMPANY LLC Robert.f.dream@gmail.com (513) (513)

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