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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

www.xcellerex.comwww.xcellerex.com

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


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


Automotive Manufacturing RevolutionAutomotive Manufacturing Revolution


Telecommunications RevolutionTelecommunications Revolution


Biomanufacturing RevolutionBiomanufacturing Revolution

1,000L Bioreactor1982

1,000L Bioreactor1994

Xcellerex 2000L Single Use Bioreactor

TODAY


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


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:


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


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


(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


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


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



Replacing Stainless w/ Disposables…Replacing Stainless w/ Disposables…

WFI CIP Buffer Storage


PW Clean SteamHVAC

Buffer / Media Prep

Cleaning Records


allwa

ys

allwa

ysall

ways

allwa

ysall

ways

allwa

ys


Records

Production SOPs

Lock

s & H

a

Lock

s & H

aLo

cks &

Ha

Lock

s & H

aLo

cks &

Ha

Lock

s & H

a


Air L


Air L

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Air L



Form / Fill

…Eliminates Utilities…Eliminates Utilities

Cleaning SterilizationHVAC

Cleaning Records


allwa

ys

allwa

ysall

ways

allwa

ysall

ways

allwa

ys


Records

Production SOPs

Lock

s & H

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Lock

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Lock

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Air L


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Adding Microenvironments…Adding Microenvironments…

Cleaning SterilizationHVAC Cleaning Records


allwa

ys

allwa

ysall

ways

allwa

ysall

ways

allwa

ys


Records

Production SOPs

Lock

s & H

a

Lock

s & H

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cks &

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Lock

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Lock

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Air L


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…Eliminates Clean Rooms & Complex HVAC…Eliminates Clean Rooms & Complex HVAC


ays

Cleaning Records


ks &

Hall

wa Validation & Maintenance

Records

Production SOPs

Air L

ock


Cell Culture Purification Form / FillSpecifications Manufacturing

Reports


Adding E-Batch Records & Automation…Adding E-Batch Records & Automation…

Cleaning SterilizationeFactory™

Cleaning Records


allwa

ys


Records

Production SOPs

Lock

s & H


Air L

Cell Culture Purification Form / FillSpecifications Manufacturing

Reports


…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 &

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eFactory™

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C ll C lt P ifi ti F / FillCell Culture Purification Form / Fill


FlexFactory Plantall

ways

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eFactory™

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eFactory


Operators work in “gray space” and can move easily from one unit op to another between upstream and downstream or between products


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




1. Xcellerex builds and operates FlexFactory for client at Xcellerex siteclient at Xcellerex site

2. Client builds facility at their own pace




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




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


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


(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


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

9/9/200411:16

9/9/200411:16

9/9/200411:17

9/9/200411:18

9/9/200411:18

9/9/200411:19

9/9/200411:20

9/9/200411:21

www.xcellerex.comwww.xcellerex.comContact Xcellerex for additional XDR performance data

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


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


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?


Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility(newly fabricated downstream modules, GMP manufacturing facility


Xcellerex GMP FlexFactory


Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility)(newly fabricated downstream modules, GMP manufacturing facility)


Xcellerex GMP FlexFactoryXcellerex GMP FlexFactory(newly fabricated downstream modules, GMP manufacturing facility(newly fabricated downstream modules, GMP manufacturing facility


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


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


Fusion protein

January 2007 In clinic

Client 158 P j t 2

mAb January 2009 Clinic to start ‘09Project 2


Vaccine Q2 2009 Clinic to start mid ‘09Project 1 09


Vaccine Q2 2009 Clinic to start ‘09


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!


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


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


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


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


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


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


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


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


THANK YOU!

170 Locke Drive, Marlborough, Massachusetts 01752

www.xcellerex.com

1.866.Xcellerex


If you have question forIf you have question for

Parrish Galliher send them to:Parrish Galliher send them to:

[email protected]

BPI Xcellerex Webcast - bioprocessintl.com F tFlexFactory ™ from Xcellerex A Proven...

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