Thermo Fisher Scientific SingleUse Systems – S.U.B. and
S.U.M.
16 June 2011
Spencer Parkinson
Overview
• Single-Use: Market Drivers and Trends
• Single-Use Bioreactor
• Scalability
• Single-Use Mixer
2
Industry Trends
• Increasing productivity/yields
• Fewer blockbuster drugs
(more personalized medicine)
• Smaller bioreactor capacity
and working volume
+
• Scalable single-use
Dave Wolton, CMC, BioProduction 2009
• Increased impetus for SingleUse Bioreactors
3
Strong Demand
What’s the Ultimate Scale of Single-Use?
• As volume increases above 500–1000 L
• Increase in engineering challenges
• Increase in expectation of customization
• Decrease in potential number of units sold
• Packaging challenges
• End-user handling challenges
• Decreased customer acceptance
• 10,000 L mixing system was available over
10 years ago
• Realistic maximum scale 2000–3000 L
4
Single-Use Bioreactor (S.U.B.)
• Launched in April 2006
• Originally intended as a retrofit product to
replace the stainless steel bioreactor
vessel in existing bioreactor systems
• Outer support container on mobile skid
• S.U.B. BioProcess Container (BPC)
provides fully functional bioreactor
chamber with single-use contact surfaces
5
Advantages
• Low investment cost
• Short lead-times / Faster to market
• No CIP or SIP so setup time between runs is
only hours rather than days
• Reduced validation requirements
• Reduced risk of cross-contamination
• Allows flexible modular approach
• Choice in control systems
• Economic advantages
6
Proven Scalability from 25 to 2,000 L
7
S.U.B. Offering
• Units with maximum working volumes of 50 L to 2000 L
• Three approaches to control:
• Open architecture retrofit
• Open architecture turnkey through integration partner
• Open architecture turnkey through Thermo Fisher
Scientific
• Customer-led product development program
• Installed base of over 550 hardware units
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Collaborations with Integrators
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Scalable Mixing Approach
• Angled shaft to avoid need for baffles
• Integrated single-use seal/bearing assembly
allowing impeller rotation and maintaining bag
integrity
• 2:1 turndown ratio chosen for high mixing
performance
• Pitched blade (45°) impeller scaled for
working volume
• 1.9:1 overall reactor geometry
• Power input and energy dissipation suitable
for culture of shear sensitive cells
10
S.U.B. Hardware Components: 1000L
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Water Jacket S.U.B. Options
• Water jacket versions for all (6)
S.U.B. sizes
• Temperature Control Unit (TCU) is
not included
• Quick Connects allow easy
connection to stand alone TCU or Inhouse temperature control systems
• Temperature mapping data available
12
Original Membrane sparge
• Sparge system a disk of Tyvek sealed into
base of the S.U.B. BPC
• Sparge results acceptable in most cases
• Requests for different sparge design to
improve CO2 stripping
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Dual Sparge
•
Porous frit (PVDF material) with 25
micron pore size for sparging
•
Open pipe (standards from 0.125” /
3.18mm to 0.25” / 6.36mm) for CO2
stripping (to improve pH control)
•
Supporting data included in Validation
Guide
•
No hardware changes required
Frit
Open
Pipe
Flange
Sealed into
BPC
Gas In
Gas In
14
Overview of Dual Sparge S.U.B. BPCs
Main Differences:

Dual sparge

Extended vent filter tubing
15
Advantages of Dual Sparge S.U.B. BPCs
• Improved oxygen transfer
• Excellent CO2 stripping capability
• Independent control over O2 transfer and CO2 stripping
• Decreased foam generation
• Ability to raise flow rates beyond membrane sparge recommendations
• Elevated exhaust filters to reduce risk of vent filter fouling
• More consistent performance over extended time period than disk
sparge
16
Scalability (Mixing): Power Input
• PIV curves using standard
impeller: vessel diameter ratio
• RPM for nominal 0.1 hp/1000 gal
1000L : 98 RPM
500L : 105 RPM
250L: 140 RPM
100L: 152 RPM
50L: 190 RPM
• PIV curves using higher impeller:
vessel diameter ratio
• RPM for nominal 0.1 hp/1000 gal
1000L : 62 RPM
500L : 70 RPM
250L: 78 RPM
100L: 85 RPM
50L: 120 RPM
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Scalability (Gas Mass Transfer): kLa Data
50 L Range (air only)=2-10
Frit
Dual Sparge
System
Open
Pipe
Flange
Sealed into
BPC
Gas In
Gas In
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2000 L Range (air only)=4-18
Scalability (Performance): Cell Growth and Viability
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2000L SUB
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Foaming and Pressure
• Single-Use Bioreactors not pressure rated
so vent filters critical
• Heated vent filters ok with smaller sizes
• 2 x10” vent filters added to 2000 L
• Single-use condenser system
• Reduces vent filter fouling
21
Process Control: Conventional Sensors
• Conventional pH and dO2 sensor probes
presently industry standard
• Traditional probe integration
• Assembled probe autoclaved in probe kit
• Connection to the bioreactor bag is performed via
aseptic connectors
• Probe kit collapses for insertion of the probe into
the bioreactor
• Open architecture approach
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Hanging Probe Clips
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Process Control: Single-Use Sensors
• Open architecture approach and
close collaboration with sensor
suppliers on development and
integration of sensors
• Sensor integrated at time of
manufacture and sterilized with the
S.U.B. bag
• Standard options offered for pH,
dO2, and pressure; evaluating other
sensors for biomass, glucose, etc.
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TruFluor Sheath
with reader
attached
Drain and Sparge Lines
Use the circular plate for the drain and open pipe sparge lines
and the pivoting access cover for the frit sparge lines.
25
Differences in Operating Parameters (in User
Guide)
Original
Disk
Sparge
New
Dual
Sparge
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Example of Oxygen Transfer Data (50 L)
• Shows effect of both spargers
• Potential results higher than with disk sparger
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Cell Platforms Supported in the S.U.B.
• Mammalian cell lines
• CHO
• NS0 (Cholesterol supplementation may be required for
cholesterol-auxotrophs)
•
•
•
•
•
•
PER.C6™ (a trademark of Crucell N.V.)
Various hybridoma (SP2/0)
HEK 293
Vero
MDCK
BHK-21
• Insect cell lines
• SF9
• SF21
• Yeast
• Saccharomyces sp.
• Pichia sp.
• Bacteria
• E. coli
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cGMP Manufacturing Implementation Case Study
• Includes scale-up from 50–1000 L
• Hydrodynamic testing and cell runs
• cGMP implementation with Finesse
control system
29
Economic Justification: Actual Customer Experience
• Most customer presentations
concerned with technical
results showing equivalence to
conventional systems
• Some included reports on
cost/time savings with 50–
1000 L units
• Example shown also
highlighting reduced project
time
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Economic Justification: Customer Predictions
• Estimate from 2007
• Based on work done
on smaller units
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S.U.M. – Single Use Mixer
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Applications of the S.U.M
•Hydration of powdered media & buffers.
•Preparations of solutions from liquid concentrations.
•Preparations or re-suspending of particulate emulsions.
•Pooling and mixing of intermediates
33
Features to Meet Market Applications
34
Features to Meet Market Applications
35
Advantages of the S.U.M.
• Same contact surface as other BPCs
• Powerful and efficient mixing based on
tried and tested stirred tank principles
• A range of options: jacket, open or
closed bags, probe access, load cells,
docking station, Powdertainer arms,
liquid or powder mixing, customization of
bag and hardware)
• Applications support from our Technical
Services Team
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2009 S.U.M. Portfolio Expansion
1. 50L S.U.M. with stainless steel jacketed
and non-jacketed hardware
2. 2000L S.U.M. with stainless steel jacketed
and non-jacketed hardware
3. S.U.M. Docking Station with 200, 500 and
1000L stainless steel jacketed and nonjacketed tanks
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S.U.M Stainless Steel Hardware
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S.U.M. Stainless Steel Jacketed Hardware
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S.U.M. 2000 L Jacketed Hardware
1.
2.
3.
Jacketed vessel
Tank front access hatch
Probe window with probe shelf and clips
attached
4. Electric panel
5. Tool mount bracket
6. Spanner, torque, combination wrench
7. ID plate
8. Drive motor assembly
9. Drive shaft assembly
10. Powder arm assembly
Differences to smaller S.U.M.s
•
No wheels – static use only
•
Electric panel mounting
•
BPC positioning system
•
Probe mounting
•
Open top setup
•
Powdertainer hanger item code
40
Docking Station Hardware
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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Platform with large diameter wheels
Mixer motor
Motor adjustment mechanism
Drive shafts
Control panel
Tool kit
Docking lock lever
Docking lock mechanism (grapple)
Step
ID plate
Docking Station Tank (Jacketed version shown)
1.
2.
3.
4.
5.
6.
7.
8.
Platform with large diameter wheels
(available with feet)
One of two hatches for BPC loading and
monitoring probe insertion
Bottom cut outs for BPC alignment
Sight window
Inlet/outlet for temperature control fluid
(jacketed version only)
Grapple receiver
Support are for Powdertainer (optional)
Handle to assist with tank mobility
200, 500 and 1000 L
All available with feet and casters
42
Docking Station System Operation
The mixer motor mounting is adjustable
vertically and horizontally as shown right.
In addition, the motor angle is adjustable.
The adjustments are simple to make with
indicators showing the correct setting for
each size of tank and secure licking
mechanism. Adjustments are made before
the S.U.M. BPC is loaded to the tank.
43
Powdertainer Hanger
• Optional accessory
• Preset locations for the 3 standard
sizes of Powdertainer (1, 5 and 25kg)
• Not interchangeable with previous
version on installed units but suitable
for ongoing original hardware
• Docking Station – has an extra bag
support collar to support seal bearing
assembly when BPC is disconnected
from Docking Station
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Open-Top Design
• Uses tank liners (new design)
• Reusable mixing hub locates in
motor
• Separate impeller sleeve not
connected to the liner
• Connects to motor sleeve using
CPC quick connects or triclamp in
2000 L S.U.M.
• Shaft goes through the connected
hub and sleeve
Impeller
Sleeve
Female
Quick
connect
Liner
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Mixing Evaluations – Single-Use Mixer
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Mixing Evaluations – High Viscosity
• Dissolution in High Viscosity Materials
• High fructose corn syrup (HFCS) was
used as a model
• 1200 cP at 21.1°C
• Specific gravity of 1.376
• Sodium hydroxide or hydrochloric acid
was added at time 0
• pH was measured on-line every 5
seconds
47
Mixing Evaluations – High Viscosity
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Mixing Evaluations – Yeast Resuspension
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Supporting Information
•
Data Sheets
• Technical and ordering information
•
User’s Guide
• Operation and maintenance
•
Validation Guide
• BPC and hardware testing
• Includes mixing studies
•
Equipment Turnover Package
• Supplied with product
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Thermo Scientific HyClone Mixtainer
Single-Use Containers
• BioProcess Containers are completely disposable
• Minimize the risk of cross contamination
• Ready to use, sterile via gamma irradiation
• Eliminate cleaning & reduce turnaround time
Medical-Grade, Animal Derived Component Free
• Medical-grade containers manufactured using animal
derived component free film
• Highly compatible with a wide range of media, process
liquids, and buffers
• Passes USP Class VI testing specifications
BioProcessing Flexibility
• BioProcess Containers are available
in 50, 100, and 200 L sizes
• Can be customized with a variety of
end connectors and sterile fluid paths including sterile filters
Self-Contained Mixing
• Mixtainers replace conventional mixing technology in
bioprocess containers using a recirculation loop or
shaking/rocking platforms
Tube Welder/Sealer Ready
• Containers have C-Flex® tubing and
are tube welder/sealer ready
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Thermo Scientific HyClone Mixtainer
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Summary
• Single-use bioreactors employed in cGMP biopharmaceutical
manufacturing
• Scalability to 2000 L
• Single-use mixing options increasingly penetrating bioprocessing
applications as well
• Single-use products will dominate in this sector over the next several
years
• Developments in technology will continue!
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Results Matter
Connecting all of science for one answer –YOURS
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