Integrating Continuous and Batch Operations for Efficient...
Transcript of Integrating Continuous and Batch Operations for Efficient...
Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals
Joseph McLaughlin Pfizer IncBioProduction Summit, 12-13 Dec, 2016
Pfizer’s BioProcess R&D is a Fully Integrated Organization Advancing Projects Across Four Sites
Andover, Massachusetts
Chesterfield, Missouri
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
Chapel Hill, NC
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Pfizer has a Large and Diverse Biologics Portfolio
Application of Continuous Processing to Early Clinical Supply Protein Manufacturing?
Even breaking rocks can be improved by application of continuous operation, process integration and method intensification
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Kleeman Continuous Gravel Crusher with Large Excavators and Hammers
Outline
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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
Biological Clinical Manufacturing Process Improvement Synopsis
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~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.
Biological Clinical Manufacturing Process Improvement Historical Synopsis
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~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
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
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Research Lead Development Reg MarketedPRECLINiCAL PH1 PH2a PH3PH2b
IDEA Clone
Selection
IND, First In Human
Proof Of Concept
NDA/BLA NME
Continuous Vision derived from an“ End to End” Drug Product Life Cycle perspective
Preclinical Clinical Commercial
Production Bioreactor ProA
Low pH Viral
InactivationAEX VRF UFDF FiltrationExpansion
Continuous Process Vision For Regulatory Toxicology and Phase 1 Clinical Manufacturing
Seed Vial
Drug Substance
Storage
Continuous Process Development Focus
Perfusion Production
CultureCapture pH
InactivationAEX
AEXFlow
Through
SinglePass UF
Platform Batch Process
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Formulation & Final Filtration
Store DS
Fed Batch Production Culture
Seed Vial
Wave Expansion
Shake Flask Expansion
N-1 Cell CultureHarvest
Hold
AEXLoad
pH Reduction pH Inactivation
pH Neutralization
AEXColumn
Detergent Viral Inactivation
Harvest Clarification
Capture Load
Capture Column
Capture Pool
Recovery Hold
Ultrafiltration Viral Filtration AEX Flow Through
Filtrate Concentrate
13 Batch Process Steps (6 with multiple cycles)10 Process Holds
Current Platform with Media and Solution Prep
First Economic Evaluation Perfusion Culture
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Perfusion culture higher cost due to increased use of downstream “single use” consumables and labor. Shift
focus to Integrated process
Total
Annual
TAC/Batch or
Perfusion TAC/Gram
$/year
$/batch or
perfusion
campaign
$/grambatches/
year
grams/
batch
Base Case
Production 500L,
Titer = 1.3 g/L, 2 cycles on capture,
1 harvest
100% 100% 100% 24 438
Improved
Batch
Process
8 cycles on capture column 83% 83% 83% 24 438
N-1 Perfusion, Production 500 L
Titer = 2.25 g/L
2 Harvests
136% 149% 75% 22 866
Perfusion Production 100L,
Titer = 0.36 g/L
17 harvests,
205% 290% 273% 17 465
Perfusion
Annual Throughput
Scenario
Capture column operation alternatives
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Perfusion Production Culture
Load 1
Load 2Elute
Capture 2 Column Operation
Perfusion Production Culture
Elute
Accumulate
Load
Surge Tank
Periodic 3 column chromatography also To increase the dynamic capacity
Simulated Moving bed chromatography to provideContinuous elution flow
Surge Tank:
2 Columns:
More Columns:
2nd Economic Evaluation: Capture column
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Total
Annual
TAC/Batch
or Perfusion TAC/Gram
$/year
$/batch or
perfusion
campaign
$/grambatches/
year
grams/
batch
Base CaseProduction 500L,
Titer = 7 g/L, 4 cycles on capture,
1 harvest
100% 100% 100% 23 1000
1 Capture Column +
Surge vessel
100 L perfusion culture,
5 days startup, 7.5 days harvest
at 1 g/L ,
62% 57% 57% 25 1000
2 Capture Columns100 L perfusion culture,
5 days startup, 7.5 days harvest
at 1 g/L, 2 x Capture columns
66% 60% 60% 25 1000
2 Capture Columns +
Improved
Production
100 L perfusion culture, 2 days
startup, 7.5 days harvest at 1 g/L,
2 x Capture columns
77% 55% 55% 32 1000
Annual Throughput
Scenario
Dual Periodic capture column operation selected as more compatible with work to increase upstream productivity
Multiple upstream processes Considered
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Upstream Process
modelsDescription
Bioreactor
Productivity
(g/L BRx/d)
Media
Usage
(L/g)
Fed Batch Fed batch to maximize productivity 0.3 0.5
Continuous Perfusioncell concentration control with stable
permeate & product flow 1.2 2.0
N-1 Perfusion +Continuous
Perfusion
High Density inoculum to reduce
startup time1.6 1.5
High-Intensity Low-Volume
Perfusion (HILVoP)
Multiple feeds to control growth and
maximize bioreactor productivity.
Variable permeate and product flow
1.5 0.5
3rd Economic Evaluation Upstream
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Initial development on multiple upstream options
High Intensity Low Volume Perfusion
Continuous PerfusionFast Start
Continuous Perfusion
Fed Batch
Current Process Development Focus
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Perfusion Production
CultureCapture
pH Inactivation
AEXAEXFlow
Through
SinglePass UF
Seed Vial
Wave Expansion
Shake Flask Expansion
N-1 Cell Culture
Formulation & Final Filtration
Store DS
Ultrafiltration Viral Filtration Filtrate Concentrate
6 Batch Process Steps 1 Periodic Step4 Process Holds
Laboratory/Pilot Model Schematic
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Polishin
g
Step
SPTFFSing
le Use
Perfu
sion
Biorea
ctor
ProA
cVI
Media/Feed
Acid Base
SPTFF pool
100 L PerfusionSingle UseBioreactor
Dual Capture Columns Continuous
pHInactivation
Single Pass
Tangential Flow
Filtration
StableIntermediate
Hold
Laboratory/Pilot Model
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100 L Perfusion Single Use Bioreactor, Continuous perfusion or “High
Intensity Low Volume Perfusion”
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Dual Capture Columns
Elution Stream Chamber
pHInactivation
Reactor
Elution Stream Chamber added to de-couple AEX Flow-through
Laboratory/Pilot Model (Continued)
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Laboratory/Pilot Model (Continued)
Single Path Tangential Flow Filtration
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Assembly and operation
Process Flow Diagrams, Process & Instrument Diagrams, Sequence & Valve Device Matrix
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Design a Prototype
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First Prototypes in fabrication
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Apply Metrics
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Batch Next Gen Change
mAb cost(%/batch)
100% ~50% - 2X
Buffer use(L/g)
23 3 - 8X
Bioreactor Productivity(g/L/day)
0.3 1.5 + 5X
Consumables(%/batch)
100% ~40% - 2X
Assay time ~ 1 week 5 min
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
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Development Challenges
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• 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 GMPmanufacturing “real time release”
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
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CRB
• Phil Lyman
• Eric Unra
• Kory Kaplan
• Tracy Wonnel
• Alejandro Kaiser
Backup Slides
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Plasmid DNA application of Continuous operation
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Pressure Swing Adsorption: Some Processes move from continuous to Periodic
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Pressure swing adsorption has many applications at times replacing Processes such as continuous cryogenic distillation for air and hydrocarbon gas separations
AB
SequenceStartup Pressurization of A with Feed
1.) Pressurization of B with FeedDepressurization of A reverse flow collect Product 1
2.) Purge A collect Product 23.) Pressurization of A with Feed
Depressurization of B reverse flow collect Product 14.) Purge B collect product 2
Feed
Product1
Product 2Similar to Dual Capture Columns
Reference: Adsorption and its Applications in Industry and Environmental ProtectionStudies in Surface Science and Catalysis, Vol. 120A. Dabrowski (Editor) 1998 Elsevier Science B.V.
Other Industries
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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?
Reference: ELEMENTARY PRINCIPLES OF THE THEORY OF RECYCLE PROCESSES,Author(s): M. F. Nagiev and P. V. Danckwerts1964
Thermal Cracking
Abstract
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Conference: 16th Annual Bioproduction Summit 12-13 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, high-volumetric 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.