Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals

Transcription

1 Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals Joseph McLaughlin Pfizer Inc BioProduction Summit, Dec, 2016

2 Pfizer s BioProcess R&D is a Fully Integrated Organization Advancing Projects Across Four Sites Chesterfield, Missouri Andover, Massachusetts Chapel Hill, NC Pearl River, New York Scope of Responsibilities Cell Line Dev, Cell Culture Dev, Purification Dev, Conjugation Dev, Gene Medicines, Pilot Scale Production Deliver large molecule drug substance Provide support from molecular assessment and candidate selection through launch Close partnerships with Research Units and Manufacturing organizations

3 Pfizer has a Large and Diverse Biologics Portfolio Application of Continuous Processing to Early Clinical Supply Protein Manufacturing? 3

4 Even breaking rocks can be improved by application of continuous operation, process integration and method intensification 4

5 Kleeman Continuous Gravel Crusher with Large Excavators and Hammers 5

6 Outline 1. Process Improvement synopsis 2. Continuous Process Development Collaborators 3. Continuous Vision & Platform process 4. Economic Evaluations 5. Innovation Design 6. Laboratory/Pilot Model 7. Prototype Design 8. Continuous Process Metrics 9. Development Challenges 10. Preliminary Scale-up Strategy 6

7 Biological Clinical Manufacturing Process Improvement Synopsis ~1980 s Plan for Success Clinical manufacturing, regulatory acceptable (safe, effective and pure) Process development for impurity identification and control. Capital expenditures and CMO partnerships to assure material availability for completion of clinical studies and product launch. ~1990 s Titer and Yield Process development focus on upstream Titer and downstream Yield. Excess Capacity as products fail in clinical trials and processes are improved. First facilities designed and built with Single Use Application consideration (Solution Storage) to reduce capital. 7

8 Biological Clinical Manufacturing Process Improvement Historical Synopsis ~2000 s Fast to First in Human Elimination of Clinicial manufacturing as a constraint to new product development. High throughput process development, platform processes, accelerated cell line selection and screening. Single Use equipment Single use facilities and CMO Partnership form to reduce capital and new facility startup time. ~2010 s - Continuous Vision or Integrated and Intensified Clinical manufacturing of numerous diverse products. Process development for some focused on regulatory acceptable safe, effective and pure products. Others are expedited using platform process development guided by process cost models to balance fixed and variable cost, Construction of flexible development and clinical manufacturing facilities for application of diverse operating modes 8

9 Continuous Process Development Collaborators Boeheringer Ingleheim(BI): Contract Manufacturer for Batch Single Use Clinical Material Supply Partner in development of iskid: Integrated continuous single use process and equipment CRB, Clark Richardson and Biskup Consulting Engineers, Inc: Economic Evaluations and Initial Design Bend Research Contract Research Organization Various Academic Consultants Pfizer Pharmaceutical Sciences Analytical R&D, Cell Line Development, Cell Process Development, Purification Process Development, Clinical Manufacturing 9

10 Continuous Vision derived from an End to End Drug Product Life Cycle perspective Preclinical Clinical Commercial IDEA Clone Selection IND, First In Human Proof Of Concept NDA/BLA NME Research Lead Development PRECLINiCAL PH1 PH2a PH2b PH3 Reg Marketed Continuous Process Vision For Regulatory Toxicology and Phase 1 Clinical Manufacturing Seed Vial Expansion Production Bioreactor ProA Low ph Viral Inactivation AEX VRF UFDF Filtration Drug Substance Storage Continuous Process Development Focus Perfusion Production Culture Capture ph Inactivation AEX Single Pass UF AEX Flow Through

11 Platform Batch Process Seed Vial Shake Flask Expansion Wave Expansion N-1 Cell Culture Fed Batch Production Culture Harvest Hold Harvest Clarification Recovery Hold Detergent Viral Inactivation Capture Load Capture Column Capture Pool ph Reduction ph Inactivation ph Neutralization AEX Load AEX Column AEX Flow Through Viral Filtration Filtrate Ultrafiltration Concentrate Formulation & Final Filtration Store DS 13 Batch Process Steps (6 with multiple cycles) 10 Process Holds 11

12 Current Platform with Media and Solution Prep

13 First Economic Evaluation Perfusion Culture Base Case Improved Batch Process Perfusion Scenario Production 500L, Titer = 1.3 g/l, 2 cycles on capture, 1 harvest Total Annual $/year TAC/Batch or Perfusion $/batch or perfusion campaign TAC/Gram $/gram batches/ year grams/ batch 100% 100% 100% cycles on capture column 83% 83% 83% N-1 Perfusion, Production 500 L Titer = 2.25 g/l 2 Harvests Perfusion Production 100L, Titer = 0.36 g/l 17 harvests, Annual Throughput 136% 149% 75% % 290% 273% Perfusion culture higher cost due to increased use of downstream single use consumables and labor. Shift focus to Integrated process 13

14 Capture column operation alternatives Surge Tank Accumulate Surge Tank: Perfusion Production Culture Load Elute 2 Columns: Perfusion Production Culture Capture 2 Column Operation Load 1 Elute Load 2 More Columns: Periodic 3 column chromatography also To increase the dynamic capacity Simulated Moving bed chromatography to provide Continuous elution flow 14

15 Base Case 2 nd Economic Evaluation: Capture column 1 Capture Column + Surge vessel 2 Capture Columns 2 Capture Columns + Improved Production Scenario Production 500L, Titer = 7 g/l, 4 cycles on capture, 1 harvest 100 L perfusion culture, 5 days startup, 7.5 days harvest at 1 g/l, 100 L perfusion culture, 5 days startup, 7.5 days harvest at 1 g/l, 2 x Capture columns 100 L perfusion culture, 2 days startup, 7.5 days harvest at 1 g/l, 2 x Capture columns Total Annual $/year TAC/Batch or Perfusion TAC/Gram $/batch or perfusion $/gram campaign Annual Throughput batches/ year grams/ batch 100% 100% 100% % 57% 57% % 60% 60% % 55% 55% Dual Periodic capture column operation selected as more compatible with work to increase upstream productivity 15

16 Multiple upstream processes Considered Upstream Process models Description Bioreactor Productivity (g/l BRx/d) Media Usage (L/g) Fed Batch Fed batch to maximize productivity Continuous Perfusion cell concentration control with stable permeate & product flow N-1 Perfusion +Continuous Perfusion High Density inoculum to reduce startup time High-Intensity Low-Volume Perfusion (HILVoP) Multiple feeds to control growth and maximize bioreactor productivity. Variable permeate and product flow

17 3 rd Economic Evaluation Upstream Fed Batch Continuous Perfusion Continuous Perfusion Fast Start High Intensity Low Volume Perfusion Initial development on multiple upstream options 17

18 Current Process Development Focus Seed Vial Shake Flask Expansion Wave Expansion N-1 Cell Culture Perfusion Production Culture Capture ph Inactivation AEX Single Pass UF AEX Flow Through Viral Filtration Filtrate Ultrafiltration Concentrate Formulation & Final Filtration Store DS 6 Batch Process Steps 1 Periodic Step 4 Process Holds 18

19 Laboratory/Pilot Model Schematic 100 L Perfusion Single Use Bioreactor Single Use Perfusion Bioreactor Dual Capture Columns ProA Continuous ph Inactivation Acid cvi Base Single Pass Tangential Flow Filtration Polishing Step SPTFF Stable Intermediate Hold SPTFF pool Media/Feed 19

20 Laboratory/Pilot Model 100 L Perfusion Single Use Bioreactor, Continuous perfusion or High Intensity Low Volume Perfusion 20

21 Laboratory/Pilot Model (Continued) Dual Capture Columns Elution Stream Chamber ph Inactivation Reactor Elution Stream Chamber added to de-couple AEX Flow-through 21

22 Laboratory/Pilot Model (Continued) Single Path Tangential Flow Filtration 22

23 Assembly and operation 23

24 Process Flow Diagrams, Process & Instrument Diagrams, Sequence & Valve Device Matrix 24

25 Design a Prototype 25

26 First Prototypes in fabrication 26

27 Apply Metrics Batch Next Gen Change mab cost (%/batch) Buffer use (L/g) Bioreactor Productivity (g/l/day) Consumables (%/batch) 100% ~50% - 2X X X 100% ~40% - 2X Assay time ~ 1 week 5 min 27

28 Proposed Scale Up strategy for Single Cycle Development ~0.5 Kg/wk Clinical Design 100 L Bioreactor, ¼ inch downstream 25 Kg/yr Operate 50 wks/year 100 Kg/yr 4 bioreactors & 4 X¼ inch downstream 500 Kg/yr Scale upstream to 4X500 L Bioreactor 4X¼ inch downstream 2000 Kg/yr Scale upstream to 2000 L Bioreactor Scale downstream to ½ inch 28

29 Development Challenges Integration, automation and labor savings Perfusion filter fouling Bio-burden control Qualification of reduced residence time for continuous ph virus inactivation Data aggregation and analysis for GMP manufacturing real time release 29

30 Acknowledgements Pfizer Jeff Salm Marcus Fiadeiro Jill Kublbeck Min Zhang Mark Chipley Will Wellborn Greg Hiller Matt Gagnon Bob Kottmeier Advait Badkar Rob Fahrner Jason Starkey Dave Brunner Dave Sullivan Robert Kottmeier Boehringer Ingelheim Raquel Orozco Scott Godfrey Eike Zimmermann Jon Coffman Henry Lin Avneesh Saini Brendan Edwards Diana Koulechova Anoushka Durve Jeff Goby CRB Phil Lyman Eric Unra Kory Kaplan Tracy Wonnel Alejandro Kaiser 30

31 Backup Slides 31

32 Plasmid DNA application of Continuous operation 32

33 Pressure Swing Adsorption: Some Processes move from continuous to Periodic Pressure swing adsorption has many applications at times replacing Processes such as continuous cryogenic distillation for air and hydrocarbon gas separations Product 2 Similar to Dual Capture Columns Sequence Startup Pressurization of A with Feed Product 1 B A 1.) Pressurization of B with Feed Depressurization of A reverse flow collect Product 1 2.) Purge A collect Product 2 3.) Pressurization of A with Feed Depressurization of B reverse flow collect Product 1 4.) Purge B collect product 2 Feed Reference: Adsorption and its Applications in Industry and Environmental Protection Studies in Surface Science and Catalysis, Vol. 120 A. Dabrowski (Editor) 1998 Elsevier Science B.V. 33

34 Other Industries Petroleum processes use continuous operations to drive equilibrium controlled reactions with separation, material recycle, and energy recovery When will Bioprocessing Start using continuous with recycle? Water? Thermal Cracking Reference: ELEMENTARY PRINCIPLES OF THE THEORY OF RECYCLE PROCESSES, Author(s): M. F. Nagiev and P. V. Danckwerts

35 Abstract Conference: 16 th Annual Bioproduction Summit Dec 2016 San Diego, Ca Title: Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals Abstract: Biopharmaceutical manufacturers envision that, as in other industries, continuous processing will provide significant improvement to operations and enable increased global access to medicine. One definition of fully continuous operation is that all inputs, outputs and parameters are at steady state. Konstantinov & Cooney in, White Paper on Continuous Bioprocessing May 20 21, 2014 Continuous Manufacturing Symposium identified some of the advantages of continuous manufacturing as reduced equipment size, highvolumetric productivity, streamlined process flow, low-process cycle times, and reduced capital and operating cost. To realize these advantages in an initial clinical manufacturing platform, analysis of individual Unit operations was done in collaboration with contract manufacturer and engineering design partners to define integrated and intensified process options. The mode of operation of each step from vial thaw, through expansions, production culture and purification to product packaging was considered for continuous, transition, periodic or batch operation. This Presentation describes the use of deterministic process modeling to guide process definition, prototype assembly and operational testing. 35