Technologies of the Future:
Disposables at Genentech
Chris Lorenz, Process Development Engineering
February 28, 2008
Agenda
• Introduction to Disposables & Implementation
• Examples of Disposables Implementation at Genentech
• Case Study: Disposable vs. Stainless Steel Bioreactors
• Conclusions
Introduction
Why consider disposables?
•
Lower Fixed / Capital Costs
•
Faster Procurement & Installation
•
Increased Flexibility
•
Quick Turnaround Times
•
No CIP / SIP Required
•
Reduced Cleaning Validation
•
Decreased Utility Requirements
•
Low / No Cross-Contamination
Introduction
What are disposables?
Single-Use Bioreactors
Mixing & suspension accomplished
with rocking motion
Mixing & suspension accomplished
with an impeller
Bottom-mounted
Top-mounted
Courtesy of Sartorius-Stedim Biotech
Courtesy of GE Healthcare
Mixing & suspension accomplished
via other mechanisms
Courtesy of Xcellerex, Inc.
Courtesy of ThermoFisher Scientific
Many other examples exist
Courtesy of Cellexus Biosystems
Introduction
What are disposables?
Single-Use Bioreactors
Capabilities / Uses:
•
•
•
•
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Seed train
Inoculum train
Production (including perfusion)
Volume ranges from 1-1,000 liters
kLa values comparable to stainless steel or glass vessels
On the horizon:
• Greater than 1,000 liters
• Fermentation (inoculum and production)
Introduction
What are disposables?
Single-Use Mixers
Courtesy of Xcellerex, Inc.
Courtesy of LevTech, Inc.
Courtesy of Millipore
Courtesy of ThermoFisher Scientific
Courtesy of ATMI Life Sciences
Courtesy of Sartorius-Stedim Biotech
Courtesy of LevTech, Inc.
Courtesy of GE Healthcare
Introduction
What are disposables?
Single-Use Mixers
Capabilities / Uses:
•
•
•
•
•
•
•
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Liquid-liquid mixing
Solid-liquid mixing
High concentration solutions (5 M NaCl)
Primarily in the 50-1,000 liter range
Media prep
Buffer prep
Pool suspension
Hold tanks
Introduction
What are disposables?
Harvest Systems
Filtration Systems
Courtesy of Millipore
Courtesy of Pall Life Sciences
Connector Technologies
Disposable to Stainless
Tubing to Tubing
Disposable to Disposable
Courtesy of Millipore
Courtesy of GE Healthcare
Courtesy of Pall Life Sciences
Introduction
What are disposables?
Bioprocess Containers:
•
•
•
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Buffer storage
Media storage
Sampling
Additions
Courtesy of Sartorius-Stedim Biotech
Introduction
Where might you want to implement disposables?
Limited
Large Scale •
•
Facility
•
Buffer concentrates
Sampling
Filtration
Ideal
Small Scale •
•
Facility
•
•
Limited
Bioreactors
Mixing (buffer, media)
Harvest & Filtration
Sampling & Storage
New Facility
•
•
•
Buffer concentrates
Sampling
Filtration
Possible
•
•
•
•
Bioreactors
Mixing (buffer, media)
Harvest & Filtration
Sampling & Storage
Existing Facility
Introduction
Where might you want to implement disposables?
Possible
High Run •
•
Rate
•
Low capital investment
High flexibility
High variable cost
Ideal
Low Run •
•
Rate •
Low variable cost
Low capital investment
High flexibility
New Facility
Limited
•
•
•
Existing equipment
High variable cost
Can create flexibility
Possible
•
•
•
Low variable cost
Can create flexibility
Existing equipment
Existing Facility
Introduction
Other factors to consider
Leachables & Extractables Testing
R&D vs. GMP, Buffers vs. Bulk
Vendor vs. Internal
Hardware & Bag Customization
Does an “off the shelf” version even make sense for bags?
Hardware design requirements often coupled to bag design
Pricing & Lead Time
Tiered pricing vs. Huge inventory
Service & Support
Heavier reliance on vendors
Scale-up
Consistency between: small & large scale, glass/steel & plastic
Disposal of Disposables
Introduction
Current limitations
Connector Technologies
Tubing sizes >1” ID, of various tubing types
Bag to bag connections (for ports ≥3”)
Truly sterile connections for disposable to disposable
Integration of ports into bags
Storage & Transport
Freezing bags to -80°C (and not giving up other properties)
Larger volume freezing
Rigid handling systems for shipping & transport
Other
Cost of consumables
Scale
• Current limit on bioreactors ~1,000 liters
• Large column chromatography not practical
Introduction
Ideal State for a “Factory of the Future”:
•
•
•
•
Utilize “dirty” warehouse (non-classified air environment)
No need for clean room or complex HVAC system
No need for steam
“Plug n’ Play” modular mode of operation, from media
prep to bulk storage
• All product-contacting surfaces are (economically)
single-use
Examples at Genentech
Buffer Bags for In-Line Dilution, Large Scale GMP
Large Scale, Low Throughput, New Facility
Needs / Drivers:
• Large volumes of buffer needed to
feed new chromatography columns
(1.8 m diameter)
• Minimize floor space requirements
• Small equipment footprint
desired
• Reduce capital costs
• Leverage bags over stainless
steel tanks
Examples at Genentech
Buffer Bags for In-Line Dilution, Large Scale GMP
Large Scale, Low Throughput, New Facility
Outcome:
• Coupled with in-line dilution to
vastly reduce equipment footprint
• 12 x 2,500-L bags vs. 12 x
25,000-L tanks
• Bag lift-assist system designed to
aid in bag installation
• Buffer blending & bag performance
passed internal testing
• Capital savings of 10% of overall
facility cost
Examples at Genentech
Storage Systems for Bulk Drug Substance, Clinical GMP
Small Scale, Low Throughput, Existing Facility
Needs / Drivers:
• Issues with current metal alloy
container:
• Long lead times for new
containers
• Extensive inventory
management
• High costs
• Cleaning validation difficult
• Supply chain becoming more
complex
Examples at Genentech
Storage Systems for Bulk Drug, Clinical GMP
Small Scale, Low Throughput, Existing Facility
Outcome:
•
•
•
•
Greatly reduced capital costs
Acceptable L&E data
Cleaning validation removed
Much more flexible to dynamic
clinical needs
Examples at Genentech
Single-Use Bioreactors, R&D
Small Scale, High Throughput, Existing Facility
Needs / Drivers:
• Fast turnaround times
• Multi-product facility
• Limited floor space or expansion
capability
• Non-GMP status
• Good arena for testing new
technologies
Examples at Genentech
Single-Use Bioreactors, R&D
Small Scale, High Throughput, Existing Facility
Outcome:
• Comparable performance to SS
bioreactors
• Cell growth, viability, product quality
• Used extensively to produce material for
Research
• Modular design allows for easy storage,
relocation
Courtesy of GE Healthcare
Additional Work:
• Integration of disposable sensors
• Eliminate use of glass / steel probes,
autoclave
• Create fully disposable solution
Courtesy of PreSens GmbH
Courtesy of ThermoFisher
Case Study
Aging Stainless Steel Bioreactors in Pilot Plant
Set of two 100-L bioreactors were vastly outdated
“Leftovers” from first GMP plant built in SSF
Three options:
1. Upgrade existing vessels
2. Replace existing vessels with new stainless bioreactors
3. Replace existing vessels with disposable bioreactors
Case Study
Aging Stainless Steel Bioreactors: Assumptions
Evaluation Items
Stainless Steel Bioreactor
Disposable Bioreactor
12 months (accelerated)
4-6 months
Installation (After Delivery)
1 month (accelerated)
1 week
Start-up / Commissioning
3 months (accelerated)
1 week
Start-up / Commissioning
Resources
3 FTE full time, 2 part time
for 3 months
1-2 people for 1 wk
Clean / Turnaround Time
1-2 days
1 hour
1 day
3 hours
Maintenance/Annual PM
4-5 days
1 day
Contamination Potential
Low / Medium
Low
3-5 days
3 hours
Utility / Facility Requirements
High
Low
Leak / Puncture Risk
Low
High
Highly Automated
Automated
GNE Standard
Not GNE Standard
Yes
In Progress
Complete
Incomplete
System Robustness
High
Medium
Cost (Complete Installation)
High
Low
PO to Delivery
Prep Time
Contamination Turnaround Time
Automation
Hardware / Software
Representative of Large Scale
cGMP Validation Documentation
Case Study
Aging Stainless Steel Bioreactors
Utilities Required for Stainless Steel Bioreactor:
Plant Steam
Clean Steam
Process Gases
Instrument Air
CIP Chemicals
Refrigerated Glycol / Water
De-ionized Water
480V 3-phase Electrical Power
120V 1-phase UPS Electrical Power
120V 1-phase Non-UPS Electrical Power
Case Study
Aging Stainless Steel Bioreactors
Estimated Schedule:
• URS & Design: 5 months
• Construction/Fabrication/Installation: 10 months
• Commissioning: 3 months
Estimated Resources & Costs:
• Full Time Employees: 6 (both internal & contractors)
• Total Cost: $4 million capitalized
Operations Test Fits not Ideal
• Limited floor space for two new stainless bioreactors
Case Study
Aging Stainless Steel Bioreactors
Utilities Required for Disposable Bioreactor:
Plant Steam
Clean Steam
Process Gases
Instrument Air
CIP Chemicals
Refrigerated Glycol / Water
De-ionized Water
480V 3-phase Electrical Power
120V 1-phase UPS Electrical Power
120V 1-phase Non-UPS Electrical Power
Case Study
Aging Stainless Steel Bioreactors
Estimated Schedule:
• Design: 1 month
• Construction/Fabrication/Installation: 4 months
• Commissioning: 1 month
Estimated Resources & Costs:
• Full Time Employees: 2 (internal only)
• Total Cost: $700 thousand capitalized
Operations Test Fits Worked Better
• Smaller footprint allowed easier access to bioreactors
9 Decision Made to Pursue Disposable Bioreactor Option
Conclusions
Disposable technologies can offer excellent alternatives to
traditional methods
• Bioreactors, mixers, storage systems are just a few examples
Disposable technologies are not ideal for every application
• Scale, throughput, facility size must be considered
The “Factory of the Future” will most certainly leverage many
disposable technologies to make processes cheaper, faster,
and more flexible
• Competition will force companies to watch their ‘$ spent/g produced’
much more closely
• The trend is away from 1000+ kg products in favor of multiple 100+ kg
products
Acknowledgements
Process Development
Engineering
Brad Wolk
Tim Matthews
Concentrated Buffer
Storage
Bryan Bean
Stan Forman
Disposable Bioreactors
Jim Varley
Jim Long
Donna Giandomenico
Large Scale Pilot Plant Staff
BDS Storage Systems
Kellen Mazzarella
Adam Goldstein
Ugochi Umelo
Stephen Hohwald