Fl F tFl F tFlexFactory™
from XcellerexFlexFactory™
from Xcellerex
A Proven Biomanufacturing Platform Enabled by Disposables
Presented byParrish GalliherF d & Chi f T h i l OffiFounder & Chief Technical Officer
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Challenges Facing BiomanufacturingChallenges Facing Biomanufacturing
Industry Challenges
• $80+ billion biotherapeutics market$80+ billion biotherapeutics market
• Resurgent vaccine market
• Pandemic and bioterror threats
• Emerging follow-on / biosimilars market
• Personalized medicine = smaller k f bl kbmarkets, fewer blockbusters
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Challenges Facing BiomanufacturingChallenges Facing Biomanufacturing
Industry Challenges
• $80+ billion biotherapeutics market
Company Challenges
• Prohibitive cost to build new $80+ billion biotherapeutics market
• Resurgent vaccine market
• Pandemic and bioterror threats
Prohibitive cost to build new capacity… $2,000/sq ft
• 4 year timeline for new capacity
• Risk of committing capital during • Emerging follow-on / biosimilars market
• Personalized medicine = smaller k f bl kb
• Risk of committing capital during early high-risk stage
• Building a conventional single-drug plant limits long-term asset
markets, fewer blockbustersp gutilization
• Conventional plant is expensive to operate
• CMO option reduces long-term control
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Automotive Manufacturing RevolutionAutomotive Manufacturing Revolution
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Biomanufacturing RevolutionBiomanufacturing Revolution
1,000L Bioreactor1982
1,000L Bioreactor1994
Xcellerex 2000L Single Use Bioreactor
TODAY
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TODAY
Presenting FlexFactoryPresenting FlexFactory
E bli l ti i th bi h ti l d i Enabling a revolution in the way biopharmaceuticals and vaccines are developed, manufactured & commercialized
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What is FlexFactory?What is FlexFactory?
A modular biomanufacturing platform that provides unrivaled deployment speed, capital efficiency and flexibility through the novel combination of three technologies:the novel combination of three technologies:
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What is FlexFactory?What is FlexFactory?A modular biomanufacturing platform that provides unrivaled deployment speed, capital efficiency and flexibility through the novel combination of three technologies:
1. Disposables
• Used wherever feasible (everywhere but bind & elute chromatography)
• Eliminates need for hard piping CIP SIP most utilitiesEliminates need for hard piping, CIP, SIP, most utilities
2. Controlled Environment Modules
• “Shrinking the clean room down around the unit op”
• Decreases gowning increases operator mobility• Decreases gowning, increases operator mobility
• Protects product from greatest source of environmental contamination (the operator)
3. Process Automation & Electronic Batch Records
• Reduces operator hands-on operations
• Reduces chances for human error
• Provides mechanism for automated QA, data mining
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The Fully Disposable ProcessThe Fully Disposable Process
Seed reactor(Wave System20 shown)
N-1 reactor(Xcellerex XDR-200 shown)
Production reactor(Xcellerex XDR-2000 shown)
Perfusion centrifuge(Centritech Cell I shown)
Depth filtration(Millipore POD shown)
Chromatography 0.2u Filtration Virus Filtration Buffer/Media Prep Buffer/Process Storage
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(BioFlash 8cm shown) (Sartorius Sartopore shown) (Pall DV20 shown) (Xcellerex XDM-500 shown) (Hyclone Labtainer shown)
Advantages of Single Use SystemsAdvantages of Single Use Systems
Reductions in:Cl i• Cleaning
• Sterilization• Engineering cost• Equipment lead time• Utility requirements• ValidationValidation• Quality / Regulatory burden• Space• Labor• Waste generation
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Advantages of Single Use SystemsAdvantages of Single Use Systems
Reductions in:Cl i
Improvements in:• Cleaning• Sterilization• Engineering cost
• Manufacturing quality
• Capital investment
• Facility buildout time Lead to• Equipment lead time• Utility requirements• Validation
Facility buildout time
• Cycle time
• FlexibilityValidation
• Quality / Regulatory burden• Space
• Environmental impact
• COGS
• Labor• Waste generation
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Traditional Manufacturing PlantTraditional Manufacturing Plant
WFI CIP Buffer Storage
Cleaning Sterilization
PW Clean SteamHVAC
Buffer / Media Prep
Cleaning Records
Sterilization Records
allwa
ys
allwa
ysall
ways
allwa
ysall
ways
allwa
ys
Validation & Maintenance
Records
Production SOPs
ocks
& H
a
ocks
& H
aoc
ks &
Ha
ocks
& H
aoc
ks &
Ha
ocks
& H
a
Batch Records Deviations, CAPAs
Air L
Cell Culture Purification Form / Fill
Air L
Air L
Air L
Air L
Air L
Specifications Manufacturing Reports
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Cell Culture Purification Form / Fill
Replacing Stainless w/ Disposables…Replacing Stainless w/ Disposables…
WFI CIP Buffer Storage
Cleaning Sterilization
PW Clean SteamHVAC
Buffer / Media Prep
Cleaning Records
Sterilization Records
allwa
ys
allwa
ysall
ways
allwa
ysall
ways
allwa
ys
Validation & Maintenance
Records
Production SOPs
Lock
s & H
a
Lock
s & H
aLo
cks &
Ha
Lock
s & H
aLo
cks &
Ha
Lock
s & H
a
Batch Records Deviations, CAPAs
Air L
Cell Culture Purification Form / Fill
Air L
Air L
Air L
Air L
Air L
Specifications Manufacturing Reports
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Form / Fill
…Eliminates Utilities…Eliminates Utilities
Cleaning SterilizationHVAC
Cleaning Records
Sterilization Records
allwa
ys
allwa
ysall
ways
allwa
ysall
ways
allwa
ys
Validation & Maintenance
Records
Production SOPs
Lock
s & H
a
Lock
s & H
aLo
cks &
Ha
Lock
s & H
aLo
cks &
Ha
Lock
s & H
a
Batch Records Deviations, CAPAs
Air L
Cell Culture Purification Form / Fill
Air L
Air L
Air L
Air L
Air L
Specifications Manufacturing Reports
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Cell Culture Purification Form / Fill
Adding Microenvironments…Adding Microenvironments…
Cleaning SterilizationHVAC Cleaning Records
Sterilization Records
allwa
ys
allwa
ysall
ways
allwa
ysall
ways
allwa
ys
Validation & Maintenance
Records
Production SOPs
Lock
s & H
a
Lock
s & H
aLo
cks &
Ha
Lock
s & H
aLo
cks &
Ha
Lock
s & H
a
Batch Records Deviations, CAPAs
Air L
Cell Culture Purification Form / Fill
Air L
Air L
Air L
Air L
Air L
Specifications Manufacturing Reports
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…Eliminates Clean Rooms & Complex HVAC…Eliminates Clean Rooms & Complex HVAC
Cleaning Sterilization
ays
Cleaning Records
Sterilization Records
ks &
Hall
wa Validation & Maintenance
Records
Production SOPs
Air L
ock
Batch Records Deviations, CAPAs
Cell Culture Purification Form / FillSpecifications Manufacturing
Reports
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Adding E-Batch Records & Automation…Adding E-Batch Records & Automation…
Cleaning SterilizationeFactory™
Cleaning Records
Sterilization Records
allwa
ys
Validation & Maintenance
Records
Production SOPs
Lock
s & H
Batch Records Deviations, CAPAs
Air L
Cell Culture Purification Form / FillSpecifications Manufacturing
Reports
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…Eliminates Paper, Provides Electronic Data & Web Access Through Secure Portal…Eliminates Paper, Provides Electronic Data & Web Access Through Secure Portala a & e ccess oug Secu e o aa a & e ccess oug Secu e o a
llway
soc
ks &
Hal
eFactory™
Air L
o
C ll C lt P ifi ti F / FillCell Culture Purification Form / Fill
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FlexFactory Plantall
ways
Lock
s & H
a
eFactory™
Air L
Cell Culture Purification Form / Fill
eFactory
Cell Culture Purification Form / Fill
Operators work in “gray space” and can move easily from one unit op to another between upstream and downstream or between products
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another between upstream and downstream or between products
Another dimension of FlexFactory:The FlexFactory TransPlant
Another dimension of FlexFactory:The FlexFactory TransPlantThe FlexFactory TransPlantThe FlexFactory TransPlant
1. Xcellerex builds and operates FlexFactory for client at Xcellerex siteclient at Xcellerex site
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Another dimension of FlexFactory:The FlexFactory TransPlant
Another dimension of FlexFactory:The FlexFactory TransPlantThe FlexFactory TransPlantThe FlexFactory TransPlant
1. Xcellerex builds and operates FlexFactory for client at Xcellerex siteclient at Xcellerex site
2. Client builds facility at their own pace
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Another dimension of FlexFactory:The FlexFactory TransPlant
Another dimension of FlexFactory:The FlexFactory TransPlantThe FlexFactory TransPlantThe FlexFactory TransPlant
1. Xcellerex builds and operates FlexFactory for client at Xcellerex site
3. Xcellerex trains client to operate
FlexFactoryclient at Xcellerex site FlexFactory
2. Client builds facility at their own pace
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Another dimension of FlexFactory:The FlexFactory TransPlant
Another dimension of FlexFactory:The FlexFactory TransPlantThe FlexFactory TransPlantThe FlexFactory TransPlant
1. Xcellerex builds and operates FlexFactory for client at Xcellerex site
3. Xcellerex trains client to operate
FlexFactory
4. Xcellerex TransPlants theFlexFactory to the clientfacility
client at Xcellerex site FlexFactory
5 Client 2. Client builds facility at their own pace
5. Client restarts
FlexFactory
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The Engine of the FlexFactoryXDR Single Use GMP Bioreactors
The Engine of the FlexFactoryXDR Single Use GMP BioreactorsXDR Single Use GMP BioreactorsXDR Single Use GMP Bioreactors
Bag pressure protection and ∆P weight controlExhaust filter heater
Disposable Bag Assembly (incl. Filters & Tubing)
Jacketed StainlessSteel Support Tank
PLC or Delta V Controller: pH, DO, agit., temp, gas sparge, CO2 strip, headspace gas weightSteel Support Tank
View Ports
headspace gas, weight, media feed
Integrated Acid/BaseProbe Ports
Temperature Control
Integrated Acid/Base, Media Feed Pumps
Tank weight control- ∆ P or load cells
Shaftless, Seal-less Bottom Magnetic
Drive Agitator
Temperature Control Unit -cooling and heating – no utilities needed
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(50L, 200L, 500L, 1000L & 2000L working volumes — XDR-2000 Shown)
Advantages of XDR Stirred Tank Bioreactor SystemAdvantages of XDR Stirred Tank Bioreactor System
• Stirred tank configuration simplifies scale up
• Turnkey, fully integrated and tested with DeltaV or PLC process controller
• Agitation – powerful bottom magnetic drive impeller; proven mixing effectiveness
• No rotating shaft to insert
• No rotating seals to leak
• Multiple sparger options
• Jacketed tank 30 45 minute heatup fast temp shifts with cooling• Jacketed tank – 30-45 minute heatup, fast temp shifts with cooling
• 5:1 turndown ratio (operates at 20% volume) saves tanks
• 2 independent bag film suppliers
• GMP grade, full validation package
• Full technical process support – tested at Xcellerex with real drug processes
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XDR-1000 Mixing Time: 1000L 40 rpm – 60 seconds
XDR-1000 Mixing Time: 1000L 40 rpm – 60 seconds
Each timepoint
1000L, 40 rpm – 60 seconds1000L, 40 rpm – 60 seconds
10.2
10.3
10.4
Lower pH probe
Each timepoint is 10 seconds
pH
9 8
9.9
10
10.1
pHSpare
p p
Upper pH probe
9.5
9.6
9.7
9.8 probe
Real time, minutes
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9/9/200411:18
9/9/200411:19
9/9/200411:20
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Even normally very complex processes are now possible: 10L, 200L, 1,000L XDR Scalability
H C ll P f i C lt
Even normally very complex processes are now possible: 10L, 200L, 1,000L XDR Scalability
H C ll P f i C ltHuman Cell Perfusion CultureHuman Cell Perfusion Culture
XDR-1000 vs. XDR-200 vs. 10L744-02 &03 Perfusion Runs
Viable Cell Density12 00 Viable Cell Density
10.00
12.00
e6)
XDR-1000
XDR-200
XDR-1000 Total VCVi-Cell Sample Diluted
Centritech Setting Issue
Viable Cell Density (Total)
6.00
8.00
e C
ells
/mL
(x10
e
10L BR
2.00
4.00
Viab
le
Vi-Cell Sample Undiluted
0.000 120 240 360 480 600 720
Time in Culture hours
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ory
oryApplication Servers:
Data Historian S
Web Report Server
Domain Controller
#1
Domain Controller
#2
acto
actoServer Server #1 #2
Network Switches:
Cisco Cisco
WonderwareClients:
e-F
e-FRedundant Wonderware Servers:
AOS/DI dB t h
AOS/DI dB t h
3750 3750 InTouchandBatch
Client
InTouch
erex
er
ex
Network Switches:
andBatch Server #1
andBatch Server #2 andBatch
Client
celle
celle
Redundant PLC:
Cisco 2955
Cisco 2955
Xc
Xc
Flex Factory Modules:
Contr Logix Processor #1
Contr Logix Processor #2
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Flex Factory Modules:
Harvest Clarificatn
Capture Affinity Chrom
UF/DF Conc/BuffeXc
hngIEC Chrom/HIC
Virus Filtration Bulk
FillBioReactor(s)
FlexFactory ProductionVision or Reality?
FlexFactory ProductionVision or Reality?Vision or Reality?Vision or Reality?
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Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility(newly fabricated downstream modules, GMP manufacturing facility
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Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility)(newly fabricated downstream modules, GMP manufacturing facility)
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Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility(newly fabricated downstream modules, GMP manufacturing facility
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FlexFactory Biologics Experience (major campaigns at Xcellerex)
FlexFactory Biologics Experience (major campaigns at Xcellerex)
Product Cell Line Scale Status
mAb – anti CCR7 CHO cells 100L Non-GMP FlexFactory
mAb – anti-IL-2-fusion Hybridoma cell 200L GMP FlexFactory, IND 2006
IL-2 – fusion CHO cells 200L, 500L GMP FlexFactory, IND 2006
mAb anti tissue factor CHO cells 200L GMP FlexFactory, IND 2009
HGH – fusion CHO cells 200L, 500L, 2000L Pilot Plant, FlexFactory
Therapeutic enzyme Human HEK 293 200L, 1,000L perfusion
Pilot Plant, FlexFactory
Th ti H 200L f i Fl F tTherapeutic enzyme Human sarcoma 200L perfusion FlexFactory
Beta 1,3 Glucan Yeast 250L (SS) GMP FlexFactory, IND 2005
West Nile subunit vaccine Insect cells 200L GMP FlexFactory, IND 2008
HIV Nef subunit vaccine bacteria 30L Pilot Plant
Anti-Fluorescein mAb bacteria 30L Pilot Plant
Tropical Disease Inactivated vaccine Vero cells 50L (on beads) Pilot Plant, GMP FlexFactory, IND 2009
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p ( ) , y,(planned)
Regulatory Submissions:Products in FlexFactory (at Xcellerex)
Regulatory Submissions:Products in FlexFactory (at Xcellerex)
SponsorProduct Type
IND Filing Date Status
Client 521 Project 1
mAb December 2002(filed in UK)
Phase 1 complete, asset sold
Client 158 Project 1
Fusion protein
January 2007 In clinic
Client 158 P j t 2
mAb January 2009 Clinic to start ‘09Project 2
Client 424 Project 1
Vaccine Q2 2009 Clinic to start mid ‘09Project 1 09
Client 424 Project 2
Vaccine Q2 2009 Clinic to start ‘09
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Project 2
Regulatory Acceptance of FlexFactoryRegulatory Acceptance of FlexFactory
• 1 CTX on file in UK
3 IND fil d i US• 3 INDs filed in US
• Commercial plant awarded with multiple 2000L reactors
f• FDA Type C manufacturing: very strong support
• FDA inspectors asked to send trainees to Xcellerex!
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Accessing FlexFactoryAccessing FlexFactory
• Global sales/service organization and start-up support, with customers in Japan, Korea, India, Europe, US, Canadap , , , p , ,
• TransPlant training program
• Flexible access
• Lease line
• Creative deal structuresCreative deal structures
• Utilize Xcellerex “CMO” service until the time is right
• Unique Xcellerex business model supports advancement and adoptionUnique Xcellerex business model supports advancement and adoption of FlexFactory and other Xcellerex technologies
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Xcellerex SnapshotXcellerex Snapshot
Products
XDR bioreactorXDM mixer
Contract ServicesContract Services
PDMax™ process PDMax™ process developmentdevelopment
FlexFactorypp
GMP ManufacturingGMP ManufacturingFlexFactoryFlexFactory
XCELLEREXXCELLEREXProprietary DrugsProprietary Drugsp y gp y g
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Unique blend of resources supports successful low-risk adoption of technology
Unique blend of resources supports successful low-risk adoption of technology successful, low-risk adoption of technology successful, low-risk adoption of technology
Next Generation Single Use Biomanufacturing Systems
• XDR, Single use Disposable Bioreactors/XDM Mixers – 50L -2,000L working volume
• FlexFactory complete turnkey modular single-use production plants; Global vaccine manufacturing consortium
Cont act Se ices ith ne t gene ation bioman fact ing platfo m Contract Services with next generation biomanufacturing platform:
• PDMax™ process optimization – maximize productivity
• FlexFactory Single use GMP manufacturing – 3 INDs, 1 CTX filed, next IND 2009
Drug Pipeline
• Developing an inactivated tropical disease vaccine – IND 2009
• M/A: licensing in vaccines biotherapeutics biosimilars and bio-betters• M/A: licensing in vaccines, biotherapeutics, biosimilars and bio-betters
Mfg. R/D: $19M US Defense contract for Accelerated Manufacturing of Pharmaceuticals
• Microbial production of subunit vaccines and monoclonal antibodies
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Microbial production of subunit vaccines and monoclonal antibodies
Summary: Core Advantages of FlexFactorySummary: Core Advantages of FlexFactory
•60%++ reduction in capital investment
•40% less space needed
•85% reduction in water and waste
•32% reduction in COGS
•Faster deployment: 12 18 months vs 4+ years•Faster deployment: 12-18 months vs. 4+ years
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Plant FootprintConventional vs. Xcellerex FlexFactory
Plant FootprintConventional vs. Xcellerex FlexFactory
for 4 x 2000L lines, cell vial to purified API bulk
MEDIA BUFFER
LABSU.S.P.U.S.P.LOCKERS/GOWNING
EQUIP.PREP
LOCKERS/GOWNING LABS
FlexFactory™
D.S.P.D.S.P. WAREHOUSEOFFICES
C.I.P./S.I.P.
WASH OFFICES WAREHOUSE
yPROCESSING
SUITE
PLANT UTILITIES
CLEAN UTILITIES
PLANT UTILITIES
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Environmental Advantages of FlexFactoryEnvironmental Advantages of FlexFactory
• The fabrication cost of stainless and plastic are roughly equivalent per batchq p
• Energy usage for purified water accounts for most of the carbon in stainless and disposable operations, but is much higher in stainlesshigher in stainless
• The added carbon generation from plastic incineration is more than offset by energy savings from purified water
SOURCE: After Leveen & Monge, ISPE Tampa Conference, 02 March 2009
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Additional Strategic AdvantagesAdditional Strategic Advantages
• Delay decision to build
• Design facility based on better process & market data• Design facility based on better process & market data
• Defer cost of capital; Reduce risk
• Transport to new locationsTransport to new locations
• Rapidly expand capacity
• Make use of tax havens / favorable regulatory climatesMake use of tax havens / favorable regulatory climates
• Opportunity to lease / resell facility
• Utilize Xcellerex GMP manufacturing as bridge, or to supplement capacity
• Reduction in environmental impact
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ConclusionsConclusions
• Disposables enable novel FlexFactory biomanufacturing platformp
• 70% reduction on time to build/validate to GMP ready
• 67% reduction in capital, 47% plant footprint, 87% water use
• 55% reduction in carbon footprint
• 32% reduction in COGS
• TransPlant: portable manufacturing capacity enables quick • TransPlant: portable manufacturing capacity enables quick start-up and GMP ready
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THANK YOU!
170 Locke Drive, Marlborough, Massachusetts 01752
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1.866.Xcellerex
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If you have question forIf you have question for
Parrish Galliher send them to:Parrish Galliher send them to: