creating the biologic manufacturing facility of the future
TRANSCRIPT
8/2/2019 Creating the Biologic Manufacturing Facility of the Future
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Presentation Overview
Biopharmaceutical Development Process Biopharmaceutical Market Trends Introduction to the typical Biologic manufacturing process
Production Technologies Comparison of Various Protein Expression Platforms Project Lifecycle Program Process Design(Conceptual, preliminary & Detail Design) Worked Example for USP of Cell Culture(Preliminary &
Detail design Phase) Current Design Trends in Industry Challenges in Biopharmaceuticals Future Trends
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Biopharmaceutical Development
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Biopharmaceutical ProductSales
2009 US sales for 130 biologic productsexceeded $95 billion
11% of total pharmaceutical market.
16% annual growth rate
In 2009, 27 biopharmaceutical products
with worldwide sales in excess of $1Billion
1 fewer “blockbuster” product than in 2008
10 manufactured by microbialfermentation
17 manufactured by mammalian cell
culture9 antibody‐based products
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Demand for all Biopharmaceutical productscurrently on the market or
in development
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Typical Biopharmaceutical ProcessMicrobial Fermentation
Working Cell Bank
Seed Preparation
Production Fermentor
Harvest & Centrifugation Cell Disruption
(Intracellular Proteins)
Ultrafiltration
Chromatography Sterile Filtration/or
Formulation
Final Bulk Storage
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Typical Biopharmaceutical ProcessMammalian Cell Culture
Media Preparation &Hold
Working CellBank/InoculumPreparation
Cell Culture Harvest &
Clarification Intermediate Bulk
Storage Buffer Preparation/Buffer
Hold Viral Inactivation
Ultrafiltration &Diafiltration Chromatography Column Bulk Filtration/ or
Formulation
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Production Technologies
E.coli Protein Expression System:
Inclusion Body process. Yeast & Filamentous Fungi Expression Systems
Saccharomyces, Pichia & Schizosaccharomyce:
Soluble Intracellular Product
Mammalian Cell Culture Process
Chinese Hamster Ovary(CHO) Cell LinesMouse Myeloma Cell Lines(NS0)Human Embryonic Kidney(HEK293)
Production Technology Selection Systems Process Type
Bacterial Protein ExpressionSystem
E.coli Inclusion BodyProcessLactobacillus
Yeast and Filamentous Fungi
Protein Expression System
Pichia Pastoris Soluble Intracellular
ProductSaccharomycesSchizosaccharomyces
Mammalian Cell Culture CHO Cell Lines Cell Culture
PER.C6 Cell Lines
NS0 Cell Lines
HEK 293
Insect Cells Sf9 or Sf21 cells fromSpodoptera Frugiperda
Cell Culture
Automated Peptide Synthesis Solid Phase PeptideSynthesis
Synthetic Process
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Comparison of Various ProteinExpression Platforms
System Advantages Disadvantages
E.coli Well Defined genetically, cheap &easy to grow, high yields, widerchoice of cloning vectors
No Secondary modificationcapability, High endotoxin content
Lactobacillus No inclusion bodies, tightpromotors,numerous membraneproteins expressed
Chaperones and other foldingproteins may be lacking; expressionlevels mgs/ml
Yeast GRAS Organism, High yield, Lackdetectable Endotoxin, Posttranslational modification possible
Gene expression less easilycontrolled, proteolysis byendogenous proteins
Mammalian Cells Proper Secondary modification &folding, strong regulatoryacceptance, expression vectors
available, yields in gms/L
High Media Cost, bioreactors &facilities, easily contaminated
Insect cells Post translational modificationspossible, expression up to 500mg/L
Product not always immunogenic,lack of information on glycosylation.
Automated PeptideSynthesis
Very fast & efficient for smallpeptides required in limitedquantities
Prohibitively expensive for largeproteins; folding issues; secondarymodifications not performed
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Process Design
ConceptualPhase
PreliminaryPhase
DetailPhase
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Conceptual Phase:Process Design Basis
PlantCapacity
Plantoperating
Philosophy
PreparingPFDs
PreliminaryURS
ProcessDescriptions
Utility LoadRequirements
Scope ofServices
Scope ofFacilities
Capitalequipment list
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Conceptual Phase: Define PlantCapacity /Objectives
Market Projection to define capacity
Success Rate
Step Yield
Plant Operation Schedule
Up & down times
Changeover Time (Multiproduct Facility)
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Determining Plant Capacity
Facility Capability forvarious products
Equipmentflexibility &Adaptability
FacilityExpandability
Final Build-outof the facility
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Define OperationalBasis(Fermentation Based) Development of Reasonable Plant Operating Schedule :
Input: Define Plant Operation PhilosophyDefine Batch Cycle Times
Define Yearly Batch Successful RateDefine Appropriate Titer Concentration
Output: Tank Requirements for media & buffer Preparation.No. of Bioreactors Required to achieve desired capacity
CIP Capacity RequirementsUtilities ConsumptionDesign of transfer panels or valve manifolds
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Preliminary Phase
PreliminaryPhase
Development ofURS/P&ID
Development ofProcess EquipmentSpecs/calculations/
Layouts
Request for
QuotationPackages
ProcessSimulations to
validateequipment size
Conduct SLIA
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Detail Design Phase
Review & Approval of:
Final Equipment Packages
Final Drawings( Piping Isometrics,equipment layouts)
Equipment Data Sheets
Validation Requirements
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Worked Example for USP of CellCulture Preliminary & Detail Design
Phase Considerations for Bioreactor System
Design Bioreactor Train
Scale up RatioOperation Mode(fed-batch)
Moving of media & inoculumCIP/SIP strategiesSlopes/dead legs/condensatetrapping
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Worked Example for USP of CellCulture Preliminary & Detail Design
Phase Bioreactor Design
Controlled Monoaseptic Environment
Good Mass & Heat Transfer
Good Mix & Blend Time
A Reliable Foam Control
A simple, rapid and thorough CleaningMethod
H/D Ratio (Aspect Ratio)
1.1:1 to 1.2:1 (for small Bioreactors)
1.5:1 to 2.0:1 (for large Bioreactors)
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W k d E l f USP f C ll
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Worked Example for USP of CellCulture Preliminary & Detail Design
PhaseNo. of Impellers
1 Impeller for an Aspect Ratio of 1.0 to 1.5
2 Impellers for an Aspect Ration of 1.6 to 2.0
Calculate Headspace required for foam and gas overlay
Agitator Design base on Calculation of Cell Culture Aeration
Calculate Shear rate
Sparger Design to avoid cell damage
Agitator Mounting & Mechanical Seal Considerations
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W k d E l f USP f C ll
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Worked Example for USP of CellCulture Preliminary & Detail Design
Phase Considerations for Harvest (Semi-continuous Process)
Centrifugation(extracellular product)
Consideration for cell density
Variation of solid load in feed
Flow and pressure fluctuations
Consider surge tank as air break toabsorb any shock to the system
Ensure Low shear type pumps
Operating Water Considerations
Steaming Considerations(fullSIP/Bio-burden Control)
CleaningConsiderations(manual/RunningCondition)
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Worked Example for USP of CellCulture Preliminary & Detail Design
Phase ClarificationConsideration to Turbidity of the filtrateDepth Filter size and space allocationSafety factor to compensate the variability in process fluidIn-situ Decontamination (for pathogenic organism)
UF/DFProtein Conc. required at the end of process stepMaximum operating timeCalculate Required Permeate Flow rate & operatingTMPFlux through membrane; required area & flow ratethrough skid.
Allowable Pipe velocity and Max. desirable line size todecide whether one or more skids are required.
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Process Support System Design
Cleaning In Place Skid
Skid allocation to maximize plantoperation efficiency
Segregation between USP & DSPoperations
Segregation between pre viral & postviral operations
Location with respect to facility layout& equipment arrangement
Spray pattern & location of spray balls
in tanks to be cleaned Available utilities
CIP Circuit designs
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Process Support System Design
Sterilization In Place
Design of steam distribution header
Piping Layout
Pipe slope
Dead Legs
Position of RTD for temperature monitoring
Considerations to steam seals within sterileboundaries.
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Current Design Trends
Modular design &construction
DriversFlexible Solutions
Quality of CraftsmanshipDocument Control
Time To Market
Building Module
○ Each Module contains
Building Structure Architecture finish
Process Equipment
HVAC System
Electrical Component
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10 Steps to Clean Room Design
Step 1:
Evaluate Layout for People/Material Flow
Must Consider
People flow
Process flow
Contamination proximity to sensitive areas
Facility limitations
Step 2:
Determine Cleanliness Classification
Sensitive the process better the classification
No more than a one order of magnitude differencebetween two adjoining spaces that have access to eachother.
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10 Steps to Clean Room DesignStep 3:Determine Pressurization
Prevents contaminants from entering the clean roomthrough infiltration.
Minimum Pressure difference of
10-15 Pa recommended between the clean rooms of
Different Grades
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10 Steps to Clean Room Design
Step 4:Determine Supply Air Flow
Based on level of cleanliness
Consider Process
Consider the Activity in the area
Step 5:Determine Air Ex-filtration Flow
Based on Pressure Differentials
Process Exhaust
Architectural Construction
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10 Steps to Clean Room Design
Step 6:Determine Area Air Balance
Based upon the Supply Air + Air Infiltration – Ex-filtration, Exhaustand Return airTrack where the Ex-filtration air goes to and where the infiltration aircomes from.
Step 7:Which variables need to be evaluated
TemperatureHumiditySpace PressurizationClean room Classification
LaminarityElectrostatic DischargeNoise LevelVibration
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10 Steps to Clean Room Design
Step 8:Main variable affecting mechanical system selection iscleanliness classification.Other factors affecting mechanical system selectioninclude:
Space AvailabilityAvailable fundingProcess RequirementsSpace OrientationSystem Air Flow
Required ReliabilityEnergy CostLocal Climate
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10 Steps to Clean Room DesignStep 9:
Perform Heating/CoolingCalculationsUse the most conservative climateconditions
Include infiltration into yourcalculations.
Include humidifier manifold heat intocalculations.
Include process loads into calculations.
Don t forget to include recirculation fanheat into calculations.
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10 Steps to Clean Room Design
Step 10:
Fight for Mechanical Room Space
If you have a 1,000 square feet clean room, the
approximate total facility square footage rangeneeded for each clean room classification is as
follows:
Class 100,000 (ISO8) 1,250 SF to 1,500 SF
Class 10,000 (ISO7) 1,250 SF to 1,750 SF
Class 100 (ISO5) 1,750 SF to 2,500 SF
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Current Design Trends
Process Module or SuperSkid (shop fabricatedmodule)○ Structural Framework○ Process Vessels○ Equipment, piping,
electrical/instrumentationwiring and components
Equipment Module orStandalone System○ Design standardization
and controlled innovation○ Pre-testing can be
accomplished in FAT○ Documentation
Consistency○ Flexibility of the facility
operation
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Current Design Trends
Single Use/Disposable Systems Bioreactors Membrane Filtration Chromatography Systems
Process Simulations
Computer Program to model, design, analyze &optimize the system Capability to manipulate and process data in
virtual environment & predicts the outcomes andchanges.
Develops Process Alternatives Estimates equipment sizing and cycle time
Enhances throughput analysis and bottlenecking Aids in equipment utilization optimization Quicker assessment of environmental impact
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Challenges inBiopharmaceuticals
Overall
Goal
Specific
Challenge
Risk Cost Implication
Area
Example
MitigationStrategy
Quality High PatientSafety
Contaminants such asadventious viruses
Raw Materialpreparation &Testing
SF/PF/APF/ACFmedia
ProcessReproducibility
Variable ProductYields & ProcessCycle Times leads toinconsistent processsteps
Analytical testing &Comparability;facility success rate& efficiency
PAT: Identificationof CPP & SettingSpecs. Lean/SixSigma approach
Cost High Clinical
batchproductivity andconsistentsupply
Intermittent Material
for Clinical Trials,Probability of success
Research &
Development
Earlier Process
Development
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Challenges in BiopharmaceuticalsOverallGoal
SpecificChallenge
Risk Cost ImplicationArea
ExampleMitigationStrategy
Cost High CommercialBatch Productivity& Consistentsupply
Unknown & Difficultto predict marketdemand
Development &Facilityinvestment
Use ofDisposables;process yieldtarget set beyondcurrent needs
Robust Scale-up New Technologiesand Facilities withless experience andsmaller knowledgebase
Product InventoryCost
LeverageOutsourcing; jointeffort with moreexperiencedpartners
Minimize ProcessChanges
Determining timingfor locking in theprocess
Additional ClinicalTrials
Analyticalcomparability; wellcharacterizedproduct
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Challenges in Biopharmaceuticals
OverallGoal
SpecificChallenge
Risk Cost ImplicationArea
ExampleMitigationStrategy
Speed Capture MarketShare &
maintain/raisestock price
Productsupply to clinic
& for sale
Facility/outsourcinginvestment;
licensing & royaltiesfor processreagents
Licensing andoutsourcing to
supplementinternal resources
Fast pace forprocessdevelopment
ProcessEfficiency
Product inventoryCost
Automation toincreasedevelopmentthroughput; use ofplatformtechnology
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Future Biopharmaceutical Facility
Multiple factors andbalance among thesefactors is required to meetproductivity & performance
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The Biopharmaceutical Facility ofFuture
Facility Design will incorporate high titer process >10g/L.
Greater DSP space and capabilities to handle high titerbioreactor output.
Ratio of Bioreactor space to DSP space will decrease.
Increase use of Single use technology will further reducethe operating cost/capital investment.
Smaller bioreactors will produce similar quantities totoday's large bioreactors.
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The Biopharmaceutical Facility ofFuture
Disposables will potentiallyalter the manufacturingfacilityIncreased facility utilizationby reducing changeover
timesReduced cleaning &cleaning validation cost in amultiproduct facilityIncreased speed to proof ofconcept and commercial
launchReduced Fixed PipingImproved process portability
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MAb Worked Example Future
Biopharmaceutical Expected yields Plant has 6 x 2,000 L
bioreactors (possibly singleuse bioreactors)
12 day fed‐batch CHO culturefor MAb Production 2,000 Lvolume,
10 g/L = 20 Kg MAb inharvest 80% purification yield = 16 Kg
per batch Harvest every 4 days 85 harvests/year (340 days) =
1,360 Kg/year
Capital investment < $100M Overall COGS < $70 per
gram One Purification train serving
single bioreactor
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“An optimist will tell you the glass is half‐full; thepessimist, half‐empty; and the engineer will tell you
the glass is twice the size it needs to be”