Post on 14-Jul-2015
BPI Conference & ExhibitionLong Beach, 2 Nov 2011
Practical, Robust Single-Use Scale-up, From Benchtop to Production
Outline
• Introduction
• XDR-10 Product Highlights
• XDR Design Space
• Comparative Process Data
• Questions & Discussion• Questions & Discussion
FlexFactory® Biomanufacturing Facility
Equipment Platform
Services Platform
Integration & Process Know-How
FlexFactory
Proven Technology – FlexFactory/XDR
• Representative application data and history
Product Definition
XDR-10™ is…a small scale version of the XDR-2000 allowing “linear scalability” up to 2000L in the same single-use platform while maintaining constant power and shear from bench top to production.
(Patent Pending)
Major Uses
1. Process Development 2. GMP Production
• Seed train for larger scale
• Satellite bioreactor – scale down model
• Larger scale trouble-shooting
• GMP standard
• IQ/OQ validation
• Process scale up & scale down
• Tech transfer
• Process optimization
• Inoculum scale-up• IQ/OQ validation
• Easy to handle
• Consistent automation platform
• Toxicity test
• Toxicity test
• Consistent materials
XDR 10 - Vessel
Tubing Manager
Light Source Blocked
Vessel
Heating Blanket
Exhaust Filter Heater
Viewing Window
Probe Support
Heating Blanket
Probe ports
Agitator Motor
Heating Blanket
XDR 10 - Controller
Touch Screen (17”)
Industrial
pH/DO Transmitter
E-stop/ Reset
Process Pumps
Process Pumps
[Front Panel]
Shown with optional 4th pump (WM313);
standard option includes two (2) WM114 and one (1) WM313 pumps
E-stop/ Reset
XDR GMP Single-Use Bioreactors
50 L
200 L
500 L
1000 L
2000 L
10 L
XDR Single-Use BioreactorDesign Rational
• Scalable and turn-key, intended for GMP manufacturing
• KLA to support 100x106 cells/mL & maintain CO2 <100mm Hg
• Lowest shear configuration
•• Mixing, or blend times < 1 minute
• Simple design – low mass impeller, robust configuration
• Optimized sparge position – below the impeller in the shear field
• Flexibility in sparger configuration
System Characterization
XDR: Unique Impeller Design
• Optimal impeller-to-sparger orientation
• Tank bottom tank location for uniformity gas distribution – analogous to conventional
• Impeller profile optimized to achieve scalable mixing times
• No seals - reduced contamination risk.•
• Low profile for ease of installation and small storage needs
Type Detail Np
Power #
Rushton 90o turbine
(4 or 6 blade)
4.2 - 5.2
EE 45o pbt (2 or 3 blade) 1.15 – 2.00
XDR: Impeller – Design Comparison
EE 45 pbt (2 or 3 blade)
(abec, app, BB)
1.15 – 2.00
XDR M40E 40o pitched blade
(3 or 4 blade)
0.72 – 1.50
A315 34-38o hydrofoil
(3 or 4 blade)
0.30 – 0.75
Common bioreactor “degrees of freedom” process control tools
Agitation
Sparge slpm
Sparge Composition
Headspace Overlay
Normalized Performance
Target
1.5
CO2
Interfacial Shear
Hydrodynamic Shear
CO2
Interfacial Shear
Hydrodynamic Shear
Scale-Up/Tech Transfer Obstacles
1.0
0.5
XDRs include 2 additional process control tools for better performance = “6 degrees of freedom”
Normalized Performance
Target
1.5
CO2 Stripping Sparger
Multiple Sparge Elements
Agitation
Sparge slpm
CO2
Interfacial Shear
Hydrodynamic Shear
CO2
Interfacial Shear
Hydrodynamic Shear
Scale-Up/Tech Transfer Obstacles
1.0
0.5
Sparge slpm
Sparge Composition
Headspace Overlay
XDR GMP Single-Use Bioreactorside-by-side performance assessment
Tit
er
0 2 4 6 8 10 12 14
Batch Age (day)
Tit
er
Solid= 500L Stainless Dashed= XDR500
XDR GMP Single-Use Bioreactorside-by-side performance assessment
8%
10%
12%
14%
dC
O2 (
%)
0%
2%
4%
6%
8%
0 2 4 6 8 10 12 14
Batch Age (day)
dC
O2 (
%)
Solid= 500L Stainless Dashed= XDR500
The XDR Mass transfer predictability
Sintered Sparger
35
40
The XDR Mass transfer predictability
drilled hole sparger
35
40
KLaPredicted and measured to confirm scale-up performance
Data show the model is a good predictor of performance across scales
0
5
10
15
20
25
30
35
0 10 20 30 40
Predicted KLA, (1/h)
Ob
serv
ed
KL
A,
(1/h
)
KLA Predicted
XDR200
XDR500
XDR1000
XDR2000
0
5
10
15
20
25
30
35
0 10 20 30 40
Predicted KLA, (1/h)
Ob
serv
ed
KL
A,
(1/h
)
XDR200
XDR2000
XDR50
Impact of XDR Sparger Selection on KLA
15
20
25
KL
A (
1/h
)
SS Type-2 (EE)
SS Type-3 (Hydrofoil)
SS Type-1 (Rushton/pb)
Improved KLa using XDR Sparge FlexibilityXDR Paradigm Shift – Multiple Spargers Increase Process Options
0
5
10
15
0 20 40 60 80 100 120
Agitation rate, P/V (W/m^3)
KL
A (
1/h
) SS Type-1 (Rushton/pb)
XDR 1.0 mm dh
XDR 2 µ
XDR 20 µ
XDR 0.5 mm dh
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
Design Space applicationsReview DS goals and applications
Design Space Goals:
1. Establish equipment operating conditions
(Find the acceptable range)
2. Make specific RPM & Aeration recommendations
(S-U equivalence)
P/V vs. KLa:
1. Shear Limit:ACKUP-S12)
Most commonly used – Eddy scaleShear Limit
Process O2 limit
CO2 limit
Interfacial/foam limit
Bounded
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
Vs=0.00008 m/s (0.13slpm) Vs=0.0005 m/s (1.0slpm)
Most commonly used – Eddy scale
2. Minimum Mixing Limit: (see BACKUP-S13/14)
Assures uniform gas/solids dispersion
3. O2 Limit:
Minimum KLa to sustain Process OUR
4 CO2 Limit:
Process dCO2 boundary (Typ. 100 mmHg)
5 Interfacial Foam Limit: (BACKUP-S15-17)
for drilled hole; exit velocity < 40 m/s
for sintered disk; SLPM/disk ≤ 3 SLPM
DESIGN SPACE
Minimum Mixing Limit
kLa=A(P/V)α * (Vs)β
KLa
Bounded
design
space
XDR GMP Single-Use BioreactorFlexibility- working volume range
• Performance equivalence demonstrated on an equal P/V basis for:
• XDR200
• XDR500
XDR Min Volume (L)
Max Volume (L)
10 4.5* 10
50 10 50
The XDR 5/1 volume range
• XDR500
• XDR2000
50 10 50
200 40 200
500 100 500
1,000 200 1,000
2,000 400 2,000
* XDR-10 has min working volume of 4.5L (2.2:1 turn down)
XDR-10 Design Space Agitation and aeration requirements: 20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
200
300
400
500
P/V
(W
/m^
3)
XDR10 at 4L Vw, 2 Micron sparge
200
300
400
500
P/V
(W
/m^
3)
0
100
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
100
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Vs=0.0005 m/s (1.0slpm)
Vs=0.00003 m/s (0.06slpm)
Equal P/V TT (82rpm,0.015vvm,100%O2, 100mmHg)
10L basic brx XDR10 (10L) XDR10 (4L)
P/V (W/m^3) 48 48 48
Impeller shear (1/s) 13.5 10.7 7.8
Bulk shear (1/s) 23.6 10.6 7.7
Kla (1/h) Kla (1/h)
Design Space XDR10 to XDR50 SU20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
XDR50 at 50L Vw, 2 Micron sparge
200
250
300
P/V
(W
/m^
3)
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
50
100
150
0 10 20 30 40 50
KLA (1/h)
P/V
(W
/m^
3)
Vs=0.0013 m/s (8 slpm)
Vs=0.00012 m/s (0.7 slpm)
XDR50 =P/V:(90 rpm, 0.024vvm, 74%O2, 100mmHg)
XDR10 P/V=48 (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Kla (1/h) Kla (1/h)
Design Space XDR10 to XDR200 SU20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
XDR200 at 200L, 2 Micron sparger
60
80
100
P/V
(W
/m^
3)
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
20
40
0 10 20 30 40 50 60
KLA (1/h)P
/V (
W/m
^3)
Vs=0.0013 m/s (20 slpm)
Vs=0.000259 m/s (3.9 slpm)
XDR200=P/V (157 rpm, 0.011vvm, 53%O2, 100 mmHg)
XDR10 P/V=48 (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Kla (1/h) Kla (1/h)
Design Space XDR10 to XDR500 20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
XDR500, 2 micron sparge
60
80
100
P/V
(W
/m^
3)
32
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
20
40
0 10 20 30 40 50
KLA (1/h)P
/V (
W/m
^3)
XDR10 P/V=48 (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Equal P/V (150rpm, 0,011 vvm, 35%O2, 100mmHg)
Vs=0.0002 m/s (5.7slpm)
Vs=0.00073 m/s (20.0slpm)
Kla (1/h) Kla (1/h)
Design Space XDR10 to XDR1000 SU20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
XDR1000, 2 micron sparge
60
80
100
P/V
(W
/m^
3)
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
20
40
0 10 20 30
KLA (1/h)P
/V (
W/m
^3)
XDR10 P/V=48 (112rpm, 0,015 vvm, 61%O2, 100mmHg))Equal P/V (140rpm, 0,007 vvm, 44%O2, 100mmHg)Vs=0.0002 m/s (5.7slpm)Vs=0.00055 m/s (24.0slpm)XDR1000 drive limitEqual MAX XDR2000 P/V (120rpm, 0,007 vvm, 46%O2, 100mmHg)
Kla (1/h) Kla (1/h)
Design Space XDR10 to XDR2000 SU20x106 cells/mL
XDR10 at 10L Vw, 2 micron sparge
300
400
500
P/V
(W
/m^
3)
XDR2000, 20 micron sparge
30
40
50
P/V
(W
/m^
3)
0
100
200
0 10 20 30 40 50 60 70 80 90 100
KLA (1/h)
P/V
(W
/m^
3)
10L bb (2) pbt (250rpm, 0.0095vvm, 67%O2, 100mmHg)
Equal P/V (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Vs=0.00008 m/s (0.13slpm)
Vs=0.0005 m/s (1.0slpm)
0
10
20
0 5 10 15
KLA (1/h)P
/V (
W/m
^3)
XDR10 P/V=48 (112rpm, 0,015 vvm, 61%O2, 100mmHg))
Max P/V=33 (112rpm, 0,011 vvm, 47%O2, 100mmHg)
Vs=0.0003 m/s (22.0slpm)
Vs=0.0005 m/s (36.0slpm)
XDR2000 drive limit
Kla (1/h) Kla (1/h)
Confidential
Thank you
DISCUSSION