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Turnkey Modular Disposable Vaccine Production Plants
Breakthroughs in Biomanufacturing…
IABS
New Cells for New Vaccines IIISeptember 30, 2008
Parrish M. Galliher
SLIDES 18-21 are XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745 and 12104]
“A” (approved for Public Release, Distribution Unlimited)
SLIDES 18-21 are XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745 and 12104]
“A” (approved for Public Release, Distribution Unlimited)
2
Outline
• Corporate Overview
• “Universal” single use vaccine manufacturing technology
• Representative mfg. data – mammalian and microbial
• Global consortium for distributed vaccine mfg. supply
• Summary
10/10/200810/10/2008
3
Xcellerex Overview
• Contract Services with next generation biomanufacturing platform:
• PDMax™ process optimization – maximize productivity
• FlexFactory ™ Single use GMP manufacturing – 2 INDs, 1 CTX filed, next IND 2009
• Next Generation Single Use Biomanufacturing Systems Sales (worldwide)
• XDR™, XDM™Single use Disposable Bioreactors/Mixers – 50L -2,000L working volume
• FlexFactory™ - entire turnkey modular single use production plants
- Global vaccine manufacturing consortium
• Drug Pipeline
• Developing an inactivated vaccine – IND 2009
• M/A: licensing in biotherapeutics, bio-similars and bio-betters
• Mfg. R/D: $19M DTRA contract for Accelerated Manufacturing of Pharmaceuticals
• Microbial production of subunit vaccines and monoclonal antibodies – Phase 1 complete
4
Xcellerex’s Technology Platform
• High Performance/Rapid Deployment PD and Mfg. Technologies
• Process Development - PDMax™
• Cell line development, cell banking, purification, formulation
• HTS robotic technology for upstream process optimization
• High throughput analytics development
• Manufacturing - FlexFactory™
• Flexible, portable modular systems
• Disposable mfg. equipment, XDM mixer, XDR bioreactor, purification
• Electronic controls - eFactory™
• Paperless, e-batch record, e-process control/doc. software
• On-Line quality assurance and environmental monitoring
5
XCELLEREX XCELLEREX Proprietary Proprietary
Vaccines/Vaccines/BiotherapeBiotherapeuticsutics
Xcellerex Business Model
Mfg. ProductsMfg. Products
XDR™ bioreactorXDR™ bioreactor
XDM™ mixer XDM™ mixer FlexFactoryFlexFactory™™FlexFactoryFlexFactory
Drug DevelopmentDrug Development
PDMaxPDMax™ process ™ process developmentdevelopment
GMP ManufacturingGMP Manufacturing
6
Chips CDU SNPGene/Target Identification
Drug(s) discovery
Lead drugIdentification
Drug TestingPreclinical
HumanClinical Trials
Commercial drug sales/ marketing
Xcellerex Focus
FlexFactory™- fast, flexible GMP
manufacturing
Xcellerex Uniquely Provides Complete BioManufacturing Platform
7
Chips CDU SNPDrug(s)
discoveryDrug TestingPreclinical
HumanClinical Trials
Faster, better, lower cost drug development and manufacturing
Xcellerex Focus
FlexFactory™- fast, flexible GMP
manufacturing
Xcellerex Uniquely Provides Complete BioManufacturing Platform
8
Chips CDU SNPGene/Target Identification
Drug(s) discovery
Lead drugIdentification
Drug TestingPreclinical
HumanClinical Trials
Commercial drug sales/ marketing
ChemistryCell Line
developmentProcess
DevelopmentPre-ClinicalTox. studies
Phase 3 clinical trials
Phase 3Clinical trials
FDA Approval
Market Launch
Phase 3 clinical trials
Phase 1, 2a, 2b clinical trials
FDA Approval Market launch
PDMax™ – fast, high yield process optimization
Faster, better, lower cost drug development and manufacturing
Xcellerex Focus
FlexFactory™ - fast, low cost, transferrable GMP
facilities
FlexFactory™- fast, flexible GMP
manufacturing
Xcellerex Uniquely Provides Complete BioManufacturing Platform
9
100% StainlessFixed Systems,Single Product
Revolution of BioManufacturing Technology
To 1990
100% StainlessFixed Systems,Multi-Product
Mid 90s
Fixed Systems,Disposables for Media, Buffers
1999-2000
Fixed Systems,Disposables
Process Components
2002
Integrated, Universal,Portable, Novel
Disposable Factories
TODAY
10
Xcellerex Single Use Mixers 100L, 200L, 500L, 1,000L (with cooling available)
11
XDR-200, 500, 1000, 2000L Single Use GMP Bioreactor
Disposable Bag Assembly (incl.
Filters & Tubing)
Jacketed Stainless Steel
Support Tank
View Ports
Probe Ports
Shaftless, seal-less
Bottom Mag. Drive
Agitator
Temperature Control Unit
-cooling and heating – no
utilities needed
PLC or Delta V Controller:
pH, DO, agit., temp, gas
sparge, CO2 strip,
headspace gas, weight,
media feed
Integrated Acid/Base, Media
Feed Pumps
Bag pressure protection and •P weight control
Tank weight control
- • P or load cells
Exhaust filter heater
12
XDR GMP Single-Use Bioreactor Family
Fully integrated systems with modular process control2000 liter reactor (working volume) available now50 system available in Dec 2008 - 5000 liter working volume system pendingCharacterized and modeled – optimized performance on first runProcess know-how from Xcellerex Development and Process teamsOver 500 FTE-years of experience developing systems and c-GMP operations
XDR-200 XDR-500 XDR-2000Not shown: XDR-1000
13
Many Vaccine Types – need universal mfg. facility
Live,
attenuated
EmpiricalRecombi-
nant
Inactivated Subunit
Vector
PurifiedRecombi-
nant
DNA
Conjugate (protein
-polysaccharide)
Toxoid
(Bacterial)
Prime boost combinations
Killed,
metabolically
active
Virus- like
particle
14
Xcellerex Disposable Manufacturing Experience
• Mammalian cell
• Microcarrier systems, bead-to-bead transfer
• Vero, FRhL, MDCK, PerC6, 293, MRC-5, PDK
• Serum free, animal protein free media
• Downstream systems for both released and cell associated virus
• Insect cell, baculovirus
• Yeast
• Bacterial fermentation
• Fungi
• Plants
• Crustaceans
15
10L, 200L and 1,000L XDR Scalability Human Cell HEK 293 Perfusion Culture
XDR-1000 vs. XDR-200 vs. 10L744-02 &03 Perfusion Runs
Viable Cell Density
0.00
2.00
4.00
6.00
8.00
10.00
12.00
0 120 240 360 480 600 720
Time in Culture hours
Viab
le C
ells
/mL
(x10
e6)
XDR-1000
XDR-200XDR-1000 Total VC
10L BR
Vi-Cell Sample Undiluted
Vi-Cell Sample Diluted
Centritech Setting Issue
Viable Cell Density (Total)
16
Vero Growth on Beads in Disposable Bioreactor
10/10/200810/10/2008
17Confidential
West Nile Vaccine - Insect Cells S2
XDR-200 Growth Curves Vials #21
0.00E+00
5.00E+06
1.00E+07
1.50E+07
2.00E+07
2.50E+07
3.00E+07
3.50E+07
4.00E+07
4.50E+07
5.00E+07
0 48 96 144 192
Time in XDR-200 (h)
Cell
Dens
ity
80
100
#21-1A Viable cells/ml#21-1A Viability (%)
Induce with 0.2 M CuSO4
Added Glucose
Added Glucose
Added Antifoam and Glucose
Added Antifoam
Added Antifoam
Highest cell
density achieved
in stainless steel
bioreactors was
32 E6 cell/ml
XDR-200
reaches 25%
higher cell
density than SS
bioreactors
18
GMP Mfg. in FlexFactory – West Nile Vaccine Insect Cells S2
fed batch
80.0
100.0
0.0E+00
5.0E+06
1.0E+07
1.5E+07
2.0E+07
2.5E+07
3.0E+07
3.5E+07
4.0E+07
4.5E+07
5.0E+07
0 48 96 144 192
Cel
l Den
sity
Time in XDR-200 (h)
XDR-200 Growth Curves
VCD
200L GMP
Run in
FlexFactory
19
0.0010.0020.0030.0040.0050.0060.0070.0080.0090.00
100.00110.00120.00130.00140.00150.00
0 10 20 30 40 50 60
OD
600
Hours
XDR Bioreactor Runs Yeast (S. cerevisiae)
Culture Density
XDR-200#1
XDR-200#2
XDR-200#3
XDR-50
XDR-30 Turbo, 200 Yeast Fermentation Growth
Yeast in mammalian disposable bioreactor
Yeast in mammalian disposable bioreactor
Yeast in microbial disposable bioreactorcomparable to stainless steel fermentors 120-150 OD
Yeast in microbial disposable bioreactorcomparable to stainless steel fermentors 120-150 OD
20
XDR-30 Disposable Bioreactor - Bacterial Growth
XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 12104]“A” (approved for Public Release, Distribution Unlimited)XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 12104]“A” (approved for Public Release, Distribution Unlimited)
Stainless steel 20L
conventional
bioreactor
XDR disposable
bioreactor
21
Subunit Vaccine Mfg. using Pseudomonas in Disposable Bioreactors33,000 doses/L/wk purified from disposable bioreactor
33,000 doses/L/wk purified from disposable bioreactor
XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 12104)“A” (approved for Public Release, Distribution Unlimited)XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 12104)“A” (approved for Public Release, Distribution Unlimited)
22
0
1020
3040
50
1 2 3 4
Cell Mass % Solids
Bioreactor Harvest Cell Mass % Solids
XDR-30 DC608
Dow DC608 20L
-5
5
15
25
35
45
1 2 3
Cell Mass % Solids
Bioreactor Harvest Cell Mass % Solids
XDR-30 DC606
Dow DC606 20L
% Solids in disposable
bioreactor is comparable to
that in Dow conventional
bioreactors
XDR-30 Disposable Bioreactormax cell mass - % solids
XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745]“A” (approved for Public Release, Distribution Unlimited)XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745]“A” (approved for Public Release, Distribution Unlimited)
23
05
101520253035404550
0 20 40 60 80 100 120
Dry
Cel
l W
eigh
t [m
g/m
L]
Hour of Culture
Continuous Fungi 10L Glass Bioreactor Runs vs & XDR-30 Continuous
Disposable
XDR-30
Bioreactor
10L Glass
Bioreactor
XDR-30 Disposable Bioreactor
Fungal Fermentation - Growth
XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745]“A” (approved for Public Release, Distribution Unlimited)XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745]“A” (approved for Public Release, Distribution Unlimited)
24
FlexFactory™ Total Solution Integration
Lg. Scale Bioreaction Depth/TFF filtration
Media/buffer mixing Product mixing
Centrifugation
E-Factory - Fully Integrated
GMP Process Control
API FiltrationCartridge ChromPD Optimization
25
Traditional Manufacturing Plant
Water Systems: USP & WFI Complex HVACClean In Place Clean Steam
Paper-based QA
Customer
On-Site Offices
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysCell Culture Purification Form / Fill
QC
Air L
ocks
& H
allwa
ys
26
Traditional Manufacturing Plant
Complex HVAC
Paper-based QA
Customer
On-Site Offices
FlexFactory™
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysCell Culture Purification Form / Fill
- Disposable Equipment
QC
Air L
ocks
& H
allwa
ys
27
Traditional Manufacturing Plant
Complex HVAC
Paper-based QA
Customer
On-Site Offices
FlexFactory™
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysAi
r Loc
ks &
Hall
ways
Air L
ocks
& H
allwa
ysCell Culture Purification Form / Fill
- Disposable Equipment- Environmental Enclosures
QC
Air L
ocks
& H
allwa
ys
28
Traditional Manufacturing Plant
Complex HVAC
Paper-based QA
Customer
On-Site Offices
Simplified HVAC
FlexFactory™
Cell Culture Purification Form / Fill
- Disposable Equipment- Environmental Enclosures
QC
Air L
ocks
& H
allwa
ys
29
Traditional Manufacturing Plant
Complex HVAC
Paper-based QA
Customer
On-Site Offices
Electronic QA
Web Access
Simplified HVAC
FlexFactory™
Cell Culture Purification Form / Fill
- Disposable Equipment- Environmental Enclosures
QC
Air L
ocks
& H
allwa
ys— Paperless Operation
30
Xcellerex BioFacilities Revolution 1980-2006
1,000L Bioreactor 1982 1,000L Bioreactor 1994 Xcellerex XDR-1,000L Bioreactor, present day
31
Portable, modular, disposable, lower cost biomanufacturing facility
• Focus on simplicity• requires air, water, electricity only
• Multi-product manufacturing
• Novel disposable systems
• Modularity enables speed
• Major time and $ savings versus conventional facilities
• Portable to partner’s site
Xcellerex GMP FlexFactory™
Enabling GMP Manufacturing technology
32
FlexFactory™ Simplicity
What’s Not Required:
• No clean in place (CIP) skid systems, no detergents, acids or bases
• No clean steam generator or condensate return systems
• No water based heating or cooling systems for modules
• Less liquid waste and utilities consumption
• 70% less water consumption
• 70% less waste water generation
• 20% less electrical utility consumption
• 47% less facility footprint area required
• 2 vs 10-14 air handlers, vastly simplified HVAC
• 1 vs 4-5 clean rooms, 1 vs 4-5 gowning rooms
• Significantly reduced gowning requirements
33
Advantages of FlexFactory™ Mfg.
• 50% reduction in capital cost
• 70% reduction in time to build and start GMP mfg.
• 25% reduced operating costs
• 70% reduction in water consumption
• 70% reduction in waste water generation
• 20% reduction in utility consumption
• Flexible, modular, transferable
34
FlexFactory Facility – Portable Vaccine Manufacturing
35
Xcellerex Vaccine Development Programs
• GMP vaccine mfg. of vaccines:
• West Nile vaccine manufacturing underway
• Pending Flu vaccine manufacturing in 2009
• Inactivated vaccine program (vero cell) – IND 1H 2009
• Microbial vaccine programs pending
• US Gov’t DARPA pandemic/biodefense vaccine mfg. technology contracts:
• Fungi production of subunit vaccine
• Bacterial production of subunit vaccine
• Demonstrate mfg. of 3M vaccine doses in 12 weeks for pandemic flu or bioterrorism
• Phase 1 completed June 2008
• Phase 2 contract notification July 2008
36
Xcellerex Vaccine Expert Advisory Panel• Dr. Tom Monath, member of XLRX BOD, 35 yrs
• Acambis, Center for Disease Control, USAMRIID• Small pox, yellow fever, Japanese encephalitis, dengue, west nile
• Past President of American Society of Tropical Medicine• Past US National Vaccine Advisory Committee
• Dr. Cynthia Lee, VP Vaccine Drug Development, Acambis, OraVax, Mass BioLabs
• Dr. Keith Wells, consultant, 20 yrs• Merck, OraVax, Salk Institute• Hep A, Japanese encephalitis, ChimeriVax vaccine
• Dr. ShouSun Zou: 20 yrs NIH vaccine research, consultant • Typhoid conjugate vaccine
37
Global Vaccine Mfg. Consortium – What does it take?
Vaccine drug discovery and
preclinical research
Vaccine drug discovery and
preclinical research
Vaccine process/mfg./formulation development
(PDMax)
Vaccine process/mfg./formulation development
(PDMax)
Low cost, disposable
vaccine mfg. facilities
(FlexFactory)
Low cost, disposable
vaccine mfg. facilities
(FlexFactory)
Vaccine clinical/regulatory
development
Vaccine clinical/regulatory
development
Vaccine commercialization
and supply
Vaccine commercialization
and supply
Forging Partnerships for global supply
38
Xcellerex TransPlant™ - Facility Transfer
Customer Facilitydesign, build validate
Customer FlexFactory™
Xcellerex / CMO
FlexFactory™ modules design, build, validate
Xcellerex / CMO
Customer contract mfg., training
Portable turnkey manufacturing platform enables a new solution to the buy vs. make dilemma
39
Xcellerex TransPlant™ - Facility Transfer
Customer Facilitydesign, build validate
Customer FlexFactory™
Re-qualify / cal, start GMP mfg.
Xcellerex / CMO
FlexFactory™ modules design, build, validate
Xcellerex / CMO
Customer contract mfg., training
Portable turnkey manufacturing platform enables a new solution to the buy vs. make dilemma
The Ultimate Tech Transfer
40
Forging Vaccine Partnerships: Partnerships in the works
• Vaccine Platform Partnerships:
• Live/inactivated vaccines
• Subunit vaccine technology
• VLP vaccine technology
• Viral vector vaccine technology
• Adjuvant fusion vaccine technology
•lVaccine Expression/Production Partnerships:
• Insect cell expression systems – S2, SF9
• Microbial expression systems
• E. coli, Pseudomonas
• Mammalian - Hybrid., HEK 293, Vero
• Fungal expression systems – Neurospora
Global Service and Technology Support
41
2003 2003
2002GMP
City to City startup
Building to building startup
State to State
startup
6 months
1 month2 weeks
State to State,
greenfield startup
International, greenfield
startup
12 months15 months
Existing Shell Facility siteActual FlexFactory installation timelines
Greenfield siteProjected by Engineering firms
2006GMP
4 months
On-site GMP
startup
FlexFactory™ Build and TransPlant™ Data (time to start mfg.)
2003
2002GMP2002GMP
4210/10/200810/10/2008
FlexFactory Project Locations
• US - Boston area – project started
• EU - Ireland, Luxembourg, Denmark
• China - Shanghai region
• Africa - Nigeria
• South America - Brazil
• Latin America - Mexico
• Canada - Vancouver
43
FlexFactory™ Mfg./Regulatory History
2003 2004 20062005 2007 20082001 2002
GMP mfg., file IND
FDA Training, WHO, EMEA, NAFDAC mtg.
FF GMP built, validated
GMPmab mfg., file CTX in UK
Conversion to 1,000L disposable tank XDRs
Prototype built
Toxicology mAb produced
FDA Type C mtg
2009
Subunit Flu vaccine
PreviousCompany Xcellerex
FDA Advisory panel
West Nile vaccine
2,000L GMP Mfg. file DMF
BLA PAI track
4410/10/200810/10/2008
Summary - Next Generation Biologics Manufacturing
• Large scale (2,000L), low cost disposable manufacturing is a reality
• Disposable bioreactor installations in US, EU, India, Japan, Korea
• “Universal” disposable Vaccine Mfg. achieved – microbial and mammalian
• 33,000 doses/L/week of vaccine have been purified from disposable XDR fermentors
• “Transplant” process reduces risk and speeds time to GMP manufacturing
• Regulatory support for portable disposable plants is strong – INDs and CTX filed
• BLA/commercial applications for FlexFactories are planned by Customers
• Global vaccine partnerships for local vaccine supply are taking shape
• Strong interest from many nations to establish their own vaccine capacity
4510/10/200810/10/2008
Acknowledgements
Dow Pharma
deltaDOT
BioPharm Services
Neugenesis
DARPA
DTRA
Geoff Hodge, Patrick Guertin
John Chickosky, Michael Fisher
Cynthia Lee, Ed Hayman