To be Continuous or Discontinuous, that is the Question

Transcription

1 E2E Integrated Continuous Manufacture of Therapeutic Proteins: Key Technologies Needed and Lessons Learned To be Continuous or Discontinuous, that is the Question Charles L. Cooney Robert T. Haslam (1911) Professor of Chemical and Biochemical Engineering, Emeritus MIT, Cambridge, MA Repligen Bioprocessing Seminar Cambridge, MA June 21, 2018

2 Opening Questions in the soliloquy To be continuous or not to be? that is the question Followed by :

3 Integrated Continuous Bioprocessing a starting point We may be here as believers but we need to understand why we should invest in change We all have similar and different reasons to pursue ICB We all bring a disability to the table our prior experience The number of symposia attests to expanding interest, BUT how will that translate to action? I will try to place ICB into context with the issues in the industry and the needs of the firms

4 State of the Industry Health Care Pricing Pressures Patent Expiration BIOTECHNOLOGY & PHARMACEUTICAL INDUSTRY Low R&D Productivity Rx Dynamics & Precision Medicine 4

5 State of the Industry Health Care Pricing Pressures Patent Expiration We need: How can Integrated Lower COGS BIOTECHNOLOGY & Speed to Market PHARMACEUTICAL Flexibility INDUSTRY Quality Bioprocessing address these issues? Low R&D Productivity Rx Dynamics & Precision Medicine 5

6 Speed, Quality, Cost & Flexibility Health Care Pricing Pressures Patent Expiration We need: Speed to Market BIOTECHNOLOGY & Lower COGS PHARMACEUTICAL Flexibility INDUSTRY Quality Low R&D Productivity Rx Dynamics & Precision Medicine 6

7 What is your Goal? Retain market leadership volume, sales, margin, Fill the gap created by patent expiration and price pressure Deliver Precision Medicine in competitive markets Improve your Supply Flexibility for clinical or commercial markets Expand to New Markets and geographies You need: Reduced CapX & OpX, Speed to Market, Flexibility and Assured Quality

8 A journey into uncertainty is embracing risk We begin with an ASPIRATION Ama Dablam, 7,000 m, 8 Khumbu Region, Nepal

9 Clarity in your goals as you embrace & manage risk along each step of the journey Approaching Ama Dablam Summit at 7,000 m

10 The GOAL of pharmaceutical manufacturing is the sustained delivery of a quality product (safe and efficacious) to the patient Technology provides the tools that can tactically be deployed to help us get there (cost, productivity, quality, etc.)

11 Historical Perspective to Meet Product Demand Industrial Evolution Industrial Intensification Steel Chemicals Food Pharmaceuticals Driven by need to Reduce cost Meet market demand Decentralize manufacturing Assure robust quality Create flexibility Batch Continuous or Integrated

12 Continuous Biomanufacturing is Not New Continuous brewing from the 1890 s Continuous culture 1950 s Continuous extraction of penicillin 1950 s Continuous chromatography s Fed-batch & repeated withdrawal for penicillin production (aka Perfusion) 1960 s Tangential flow filtration 1960 s Continuous crystallization for AA s 1960 s BUT our interest in RENEWED

13 Batch Manufacturing is by Choice S-101 Inoculum Prep S-103 Primary Recovery S-158 S-157 S-159 S-102 S-150 S-151 S-153 P-1 / TFR-101 T-Flask (225 ml) S-107 P-2 / RBR-101 S-104 Roller Bottle (2.2 L) S-108 S-110 P-30 / V-101 Surge Tank P-31 / DS-101 Centrifugation S-152 P-32 / DE-108 Polishing Fitler S-154 P-33 / V-103 Storage S-155 P-34 / UF-101 Concentration S-156 S-160 P-35 / V-105 P-36 / DE-104 Virus Inactivation Polishing FIlter S-161 S-162 S-105 P-3 / BBS-101 Bag Bioreactor (20 L) S-106 P-4 / BBS-102 Bag Bioreactor (100 L) S-109 S-164 S-165 PrA-Eluat PrA-Wash PrA-Equil Protein-A S-111 S-120 S-163 S-180 S-182 S-112 S-113 P-6 / V-102 P-7 / DE-101 Media Prep Sterile Filtration S-116 S-114 S-115 S-118 P-5 / SBR1 First Seed Bioreactor (1000 L) S-119 P-37 / V-107 Storage S-169 P-38 / DF-102 Diafiltration S-168 P-39 / MX-101 Mixing S-166 PrA-Reg S-167 P-40 / C-101 Prot-A Chromatography S-181 P-41 / DE-105 Polishing FIlter S-183 P-42 / V-108 Prot-A Pool Tank S-184 P-8 / G-101 Gas Compression S-117 P-9 / AF-101 Air Filtration S-148 IEX-Equil S-194 HIC-Equil S-121 S-130 IEX-WFI IEX-Wash IEX Chrom HIC-Eluat HIC-Wash HIC Chrom S-124 S-122 S-126 S-123 P-12 / DE-102 P-11 / V-104 Sterile Filtration Media Prep S-127 P-14 / AF-102 P-13 / G-102 Air Filtration Gas Compression S-140 S-125 S-128 P-10 / SBR2 Second Seed Bioreactor (5000 L) S-129 IEX-Eluat IEX-Strip IEX-Rinse S-190 P-52 / V-109 S-191 IEX Pool Tank P-50 / C-102 IEX Chromatography S-192 P-51 / MX-102 S-193 Mixing S-195 HIC-Reg S-200 P-60 / C-103 S-201 HIC Chromatography P-61 / MX-103 S-203 Mixing P-62 / DE-106 Dead-End Filtration S-205 S-202 S-204 Bioreaction S-149 S-141 S-142 S-143 S-211 S-212 Final Filtration S-145 P-21 / V-106 Media Prep P-22 / DE-103 Sterile Filtration S-144 P-20 / PBR1 S-147 Production Bioreactor (20000 L) S-216 S-210 Final Product P-70 / V-110 P-72 / DE-107 P-73 / DCS-101 HIC Pool Tank P-71 / DF-103 S-215 Final Polishing Filtration Freeze in Plastic Bags Saarland S-214 University June Diafiltration P-23 / G-103 Gas Compression S-146 P-24 / AF-103 Air Filtration S-213 S-217

14 Transition from traditional to CB Media Bioreactor Harvest Hold Clarification Clarified Harvest Protein A Capture Viral Inact Intermediate Purification Polish Unform DS Reduce Reduce X X X Reduce Reduce Reduce X Reduce Current technology: fed-batch or perfusion X Efficiency Simplicity Flexibility Quality Cost Facility Mobility Standardization New platform Media Continuous Small footprint Source: Konstantin Konstantinov Purified Product Small, flexible, portable multi-product facility International Symposium on Continuous Manufacturing of Pharmaceuticals MIT, May 20-21, 2014

15 Benefits from Continuous Biologicals Manufacturing Feature Flexibility in scaling by time and parallelization Smaller equipment and process footprint Short process residence time Flexibility in scheduling Continuous Improvement Benefit Fast process development and flexible production Reduction in capital expense Reduction in degradation; improved yield and quality Rapid response to demand Driving cost from >$100 <$10/gm Robust Quality Flexibility Cost/Profit

16 Through an Upstream Process Lens Upstream Process What I am hearing Robust product quality thru tighter control of chemistry and time in perfusion culture High cell density and productivity N-1, Cell retention, improved cell lines, conc d media, Process modeling for design and control Single-use technology Low cost media Perfusion Culture Scaling by parallel operation

17 What I am hearing Through a Downstream Process Lens Downstream Process Cell retention for perfusion & clarification - Interface Retain DSP architecture for flow through without pooling Multicolumn chromatography (SMB) SPTFF for concentration and diafiltration Continuous viral inactivation Integrated & closed systems Pre-packed columns Single-use technology In- & at-line analytics with control and RTR

18 What I am hearing Through a business lens Flexibility/Agility to meet uncertain demand New products (managing clinical trial and launch) New markets (Precision Medicine in competitive markets) Cost effective ability to meet future needs Improving Speed to Clinic and Market Real time assurance of Product Quality Dominant design & standards in the ICB toolkit provided by technology suppliers

19 What I am hearing Through a Regulatory Lens First approval of product by continuous manufacturing ICB as an evolution not a revolution 15 years of Initiatives to improve & clarify approval QbD and PAT enable and support transition to ICB Goal to align field operations with the Center (FDA) Seek international collaboration on harmonization Recognition of enabling new technology FDA Emerging Technology Team Encouragement of precompetitive collaboration Challenges to traditional regulation by RTR, QMS, automation, scaling in time, etc. Acceptance of analytical comparability

20 What I am hearing Barriers & Challenges Regulatory uncertainty Little experience with innovative technologies Perception of regulatory constraints (e.g. self inflicted wounds by industry) Market uncertainty for new products New modalities with complex product portfolios Geographically diverse markets Lack of experience with new technologies Design, operation, scaling up, down and between Managing breakthrough and orphan designation Organization Mindset overcoming development, operation and quality in silos

21 Alternative Process Configurations: Multiple tactics to capture value Source: Konstantinov and Cooney, JPS 2014

22 Why is ICB emerging now? Evolution in Technology Single-Use Technology Closed systems Cell retention Cellular productivity Media development MAB platform Multicolumn Chrom. Pre-packed columns SPTFF Analytical methods & Automation Machine learning & AI Emerging Business Case Speed to market Enabling technologies Precision Medicine (low volume) Competitive markets (accelerated commoditization) Value Pricing Desired COGS reduction Flexibility in supply Improve productivity Assure quality

23 How are we doing?

24 Risk = Probability X Impact 6,000 m on the Yellow Tower of Ama Dablam

25 Implications of ICB Are we ready to manage risk? Operating in a new ecosystem New dependencies on materials, suppliers and collaborators Closer relationship with regulators Flexibility to address uncertainty in markets, products, technology are the physical and human assets in place? Is your QMS appropriate and enabled? Do you have a culture receptive to innovation and change with an appetite for risk? Utilization of legacy assets?

26 Call to Action! The goal is about Supply and Quality Central to dispersed supply chains Analytical support of quality Process intensification is a strategy and technologies are the tactics Improve current (incremental), develop new (radical) and employ hybrid processes Collaboration & Open Innovation to stimulate innovation Remove USP and DSP from vocabulary - it is ICB Break down traditional interfaces: physical, organizational, disciplinary

27 How are we doing? Excited by what is being accomplished Fearful that it won t work Saddened that it is taking so long

28 If you reach the summit you are 25% towards your goal 20 March