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Turnkey Modular Disposable Vaccine Production Plants

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1 Turnkey Modular Disposable Vaccine Production Plants Breakthroughs in Biomanufacturing… IABS New Cells for New Vaccines III September 30, 2008 Parrish M. Galliher [email protected] SLIDES 18-21 are XCELLEREX DARPA AMP PROJECT SUMMARY, [DISTAR case 11745 and 12104] “A” (approved for Public Release, Distribution Unlimited)
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Page 1: Turnkey Modular Disposable Vaccine Production Plants

1

Turnkey Modular Disposable Vaccine Production Plants

Breakthroughs in Biomanufacturing…

IABS

New Cells for New Vaccines IIISeptember 30, 2008

Parrish M. Galliher

[email protected]

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)

Page 2: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 3: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 4: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 5: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 6: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 7: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 8: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 9: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 10: Turnkey Modular Disposable Vaccine Production Plants

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Xcellerex Single Use Mixers 100L, 200L, 500L, 1,000L (with cooling available)

Page 11: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 12: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 13: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 14: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 15: Turnkey Modular Disposable Vaccine Production Plants

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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)

Page 16: Turnkey Modular Disposable Vaccine Production Plants

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Vero Growth on Beads in Disposable Bioreactor

10/10/200810/10/2008

Page 17: Turnkey Modular Disposable Vaccine Production Plants

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

Page 18: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 19: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 20: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 21: Turnkey Modular Disposable Vaccine Production Plants

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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)

Page 22: Turnkey Modular Disposable Vaccine Production Plants

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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)

Page 23: Turnkey Modular Disposable Vaccine Production Plants

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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)

Page 24: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 25: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 26: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 27: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 28: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 29: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 30: Turnkey Modular Disposable Vaccine Production Plants

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Xcellerex BioFacilities Revolution 1980-2006

1,000L Bioreactor 1982 1,000L Bioreactor 1994 Xcellerex XDR-1,000L Bioreactor, present day

Page 31: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 32: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 33: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 34: Turnkey Modular Disposable Vaccine Production Plants

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FlexFactory Facility – Portable Vaccine Manufacturing

Page 35: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 36: Turnkey Modular Disposable Vaccine Production Plants

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

Page 37: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 38: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 39: Turnkey Modular Disposable Vaccine Production Plants

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

Page 40: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 41: Turnkey Modular Disposable Vaccine Production Plants

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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

Page 42: Turnkey Modular Disposable Vaccine Production Plants

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

Page 43: Turnkey Modular Disposable Vaccine Production Plants

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

Page 44: Turnkey Modular Disposable Vaccine Production Plants

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

Page 45: Turnkey Modular Disposable Vaccine Production Plants

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


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