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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”