“TECHNOLOGY OF THE FUTURE”
Using Disposables to Build a Flexible
Manufacturing Capacity
San Francisco / Bay Area ISPE Vendor Night
28 February, 2008
Geoffrey Hodge, VP Process Development & Technology, Xcellerex
Outline
• Introduction
• Case Study: 1000L perfusion culture in a
disposable bioreactor
• Concept: A new platform approach to fast,
flexible, turnkey manufacturing
• Case Study: Flexible mAb facility
• Strategic manufacturing options
• Conclusions and Q&A
INTRODUCTION
The need for speed (and flexibility)
Strategic Outlook
Industry Growth
New Technology
Smaller Markets
Cost Pressures
• 15% annual avg.
• Better process yields
• Fewer blockbusters
• Health care reform
• >20 approved mAbs
• Potent compounds
• Personalized medicine
• Biogenerics
• >150 mAbs in clinic
• Drug delivery
• Genetic diagnostics
• Follow-on drugs
• Genomics impact
Capacity shortage
(captive capacity)
Smaller batch
sizes
Smaller R&D
budgets
.
Need for more efficient PD &
fast, flexible and inexpensive manufacturing capacity
Advantages of Single Use Systems
Reductions in:
• Cleaning
• Sterilization
• Engineering cost
• Equipment lead time
Lead to
• Utility requirements
• Validation
• Quality / Regulatory burden
• Space
• Labor
• Waste generation
Improvements in:
• Manufacturing quality
• Capital investment
• Facility buildout time
• Cycle time
• Flexibility
• Environmental impact
• COGS
CASE STUDY
1000L perfusion in a disposable bioreactor
Project Overview
Goal: reproduce client bench scale process in XDR
disposable bioreactor first at 200L then at 1000L scale
SCALE
LOCATION
DAYS
HARVESTS
10L
Client
27
22
200L
Xcellerex
28
22
1000L
Xcellerex
19
12
XDR-200 Disposable Bioreactor System
Disposable Bag Assembly
(incl. Filters & Tubing)
Jacketed Stainless
Steel Support Tank
View Ports
PLC or Delta V
Controller
Integrated
Acid/Base, Feed
Pumps
Probe Port
Eccentric Bottom
Mag. Drive Agitator
Temperature
Control Unit
XDR Disposable Bioreactor Overview
Disposable Assembly
• All product contact surfaces single-use except sensors
• No assembly required within sterile barrier
• USP Class VI films & components, low endotoxin, low
particulate, non-cytotoxic materials
Bioreactor Hardware and Controls
• Turnkey, fully integrated with DeltaV or PLC process
controller
• Stirred tank design — bottom magnetic drive agitation,
integrated sparger
• Jacketed tank — 30-45 minute heat-up
• 5:1 turndown ratio (operates at 20% volume)
Confidential
®
CentriTech LAB Disposable Centrifuge
Perfusion Schematic
Harvest
Perfusion out
Perfusion in
pump
pump
CentriTech
XDR
Cell concentrate return
®
XDR 200 Disposable Bioreactor & CentriTech LAB
™
XDR™200
CentriTech® LAB
Challenges for 1000L Scale
• Medium supply
• Made in XDM™1000
• New filter welded daily
• Filtered into 1 of 3 1000L holding bags
• Connectivity
• Aseptic components welded
• “Daisy-chained” holding bags – FIFO drain &
fill
• Process control
• Tuning feed pump & load cell
1000L Scale Perfusion Layout
Centritech Cell I® disposable
continuous centrifuge
Harvest hold bag and
chilled tank
XDR™-1000 disposable bioreactor
(1000L working volume)
Load cell controlling
medium feed pump
Daisy-chained 1000L media
hold bags & holders
1,000L disposable media mixing
system (XDM-1000)
Viable Cell Density
10.00
6
x 10 cells/mL
Viable cell density,
12.00
8.00
6.00
4.00
10 L glass
XDR-200 disposable
XDR-1000 disposable
2.00
0.00
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Days in Production, Days
Viable cell density in XDR at 200 and 1000L scale comparable
to client 10L benchtop
Cell Viability
100.0
Viability, %
90.0
80.0
70.0
10 L glass
60.0
XDR-200 disposable
XDR-1000 disposable
50.0
-10.0
-5.0
0.0
5.0
10.0
15.0
20.0
25.0
Days in Production, Days
Cell viability in XDR at 200 and 1000L scale comparable to
client 10L benchtop
Cumulative enzyme production per liter
bioreactor working volume
Enzyme Productivity
0.0
5.0
10.0
15.0
Cumulative enzyme production
Cumulative Productivity
10 L glass
XDR-200 disposable
XDR-1000 disposable
20.0
Specific
Productivity
25.0
Days in Production, Days
Volumetric and specific
productivity in XDR at 200
and 1000L scale comparable
to client 10L benchtop data
10 L glass
XDR-200 disposable
XDR-1000 disposable
0
From Yin, BioProcessing Challenges for Large Scale Disposable
Bioreactors, IBC BioPharm Production Week, Boston, Oct. 2007
20
40
60
80
100
120
140
160
Integrated viable cell density, million cells/mL * day
180
200
™
FLEXFACTORY :
A Novel Platform for Biomanufacturing
The Requirements
Design a biomanufacturing capability to:
•
•
•
•
•
•
Minimize capital cost
Be rapidly constructed
Handle a wide range of processes
Be flexible and quickly reconfigurable
Assure a high level of product quality
Minimize labor and operating cost
The Concept
An integration of emerging technologies
•
•
•
•
Disposable bioprocess components
Microenvironments (modular clean spaces)
Process automation
Electronic batch records
Advantages of Disposables
• Heavy use of disposables allows the
FlexFactory manufacturing platform to
operate without utilities
• Additional advantages:
•
•
•
•
Cleaning
Sterilization
Engineering
Equipment lead time
•
•
•
•
Validation
Quality / Regulatory
Space
Labor
Advantages of Microenvironments
•
•
•
•
Save space
Decrease HVAC complexity
Portable and reconfigurable
Greater protection of product from human
contamination
Advantages of Process Automation and
Electronic Batch Records
• Reduce manual operations
• Reduce labor
• Reduce chance for human error
• Increase opportunity for data collection and
process control
• Enable on-line tools
Traditional Manufacturing Plant
WFI
CIP
Buffer Storage
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
HVAC
Clean Steam
Purification
Air Locks & Hallways
Air Locks & Hallways
Cell Culture
Air Locks & Hallways
Air Locks & Hallways
Buffer / Media Prep
Air Locks & Hallways
Air Locks & Hallways
PW
Form / Fill
Specifications Manufacturing
Reports
Replacing Stainless w/ Disposables…
WFI
CIP
Buffer Storage
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
HVAC
Clean Steam
Purification
Air Locks & Hallways
Air Locks & Hallways
Cell Culture
Air Locks & Hallways
Air Locks & Hallways
Buffer / Media Prep
Air Locks & Hallways
Air Locks & Hallways
PW
Form / Fill
Specifications Manufacturing
Reports
…Eliminates Utilities
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
Cell Culture
Purification
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
HVAC
Form / Fill
Specifications Manufacturing
Reports
Adding Microenvironments…
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
Cell Culture
Purification
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
Air Locks & Hallways
HVAC
Form / Fill
Specifications Manufacturing
Reports
Air Locks & Hallways
…Eliminates Cleanrooms & Complex HVAC
Cell Culture
Purification
Form / Fill
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
Specifications Manufacturing
Reports
Adding E-Batch Records & Automation…
Cleaning
Records
Sterilization
Records
Validation &
Maintenance
Records
Production
SOPs
Batch
Records
Deviations,
CAPAs
Air Locks & Hallways
eFactory™
Cell Culture
Purification
Form / Fill
Specifications Manufacturing
Reports
Air Locks & Hallways
…Eliminates Paper, Provides Electronic
Data & Web Access Through Secure Portal
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
FlexFactory Plant
Air Locks & Hallways
™
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
Technology Assessment
• Economics of operation
• Commissioned model from BioPharm Services
• Cost of disposables more than offset by capital
savings, decreased utilities / water
• Engineering study
• Commissioned study w/ PFI to examine cost
and timing of facility construction
• Capital cost < 50% of traditional design
• Construction timeline of 1 year
CASE STUDY
Construction cGMP mAb Facility
Proof of Concept: Fully Disposable Process
• 10 L Wave disposable bioreactor scale
• Typical mAb process
• All product components disposable
• All media & buffers provided / made in
bioprocess bags
• All process intermediates stored in bioprocess
bags
• All product contact components, including
sensors, fully disposable
Technology Feasibility
Prototypes
•
•
•
•
Built prototype units for 100L scale
Operated with typical mAb process
Worked out design and operability issues
Collected EM data
The Challenge
January 2002: Need cGMP mAb by year end
Facility construction
Design & fabrication
Validation
Manufacturing campaign
Drug substance release testing
Fill
Drug product release testing
Drug product release
Distribute to clinic
Start clinical trial
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
The challenge: Design, build & validate a facility
in less than 6 months
Dec
The Project
• Two parallel tracks – facility and
modules
• Facility
• Identified CMO with expansion space
• Unused portion of warehouse
• 600 sq. ft.
• Constructed open 10K cleanroom
• HVAC, electrical only
• No pipes or other utilities
The Project
• Modules
• Designed and fabricated off-site
• Process equipment purchased
• Partial integration of equipment and
modules done off-site
• Commissioning done off-site
• Final integration, IQ/OQ done on-site
The Results
• Facility and modules completed and
validated in <6 months
• GMP production started June 10th
• Six batches of bulk drug substance
manufactured at 100% success rate
• Produced in campaigns—upstream
batches completed, modules swapped,
purification completed
• Clinical trial started in December, 2002
Xcellerex FlexFactory™ Today
- 200, 1,000L working volume
disposable stirred tank bioreactors
- Disposable downstream
processing (except columns)
- Modular clean environments
- Rapid deployment portability to
customer site
- Simple clean room facility
- No CIP or SIP systems
- 50% reduction in capital cost
- 70% reduction in time to build
- 25% lower operating costs
STRATEGIC IMPACT
Eliminating the Buy vs. Make Decision
Capital Investment Risk
Product Development Life Cycle
Phase I
(12 months)
• Safety
Clinical Development Timeline
(6-7 years)
Phase II
(24 months)
Phase III
(24 months)
• Dose Finding
• First Efficacy
• Pivotal Trials
Plant investment
decisions must be
made long before
product approval
Product
Launch
Filing & Review
(18 months)
Lead-Time for Building a Commercial Plant
(~4 years)
Design
(12 months)
Construction
(24 months)
Validation
(12 months)
Can organization support “Make” strategy if product fails?
Current Buy vs. Make Dilemma
Buy (CMO)
Make (Build)
• No capital expense
• Fast access to
Pro capacity
• No cost between
projects
•
•
•
•
Builds capability
Strategic asset
Control of projects
Flexibility
• Loss of control
• Does not build
Con internal capability
•
•
•
•
Capital expense
Long lead time
Risk
Maintenance cost
when idle
New Possibilities
• Problem: Buying CMO capacity is a fast,
low capital option, but money spent does
not build company assets
• Ideal Solution:
• Buy CMO capacity when risk / uncertainty is
high, cash is low
• Quickly establish in-house capacity when risk is
low, high product / pipeline demands certain
“Buy and Take” Manufacturing
Portable turnkey manufacturing platform enables a
new solution to the buy vs. make dilemma
Xcellerex / CMO
Customer Facility
design, build validate
FlexFactory™ modules
design, build, validate
Xcellerex / CMO
Customer contract
mfg., training
™
Customer
FlexFactory
The Ultimate
Tech Transfer
Re-qualify / cal, start GMP mfg.
CONCLUSIONS
Conclusions
• Competition and market pressures will
increase pressure on drug cost
• Manufacturing will increasingly be viewed as
a strategic asset
• Disposables offer opportunities for flexibility
and cost savings in manufacturing capacity
Conclusions
FlexFactory uses disposables for a platform
approach with several advantages over traditional
facility designs:
™
Facility
• >50% less capital cost
• Short lead time: 1 yr
(vs. 3-4
for traditional)
• Rapid capacity expansion
• Delays capital spend
• Portable, flexible
• Space savings, no utilities
Operations
• Reduced labor
• No SIP / CIP
• Mobility between unit ops
• Process automation & EBR
• Improved quality
• No chance of cross-contamination
• On-line control & QA
• Rapid turnaround
• Enables “buy & take” option for moving from outsourced
manufacturing to in-house capacity
Thank You
170 Locke Drive, Marlborough, MA 01752
www.xcellerex.com