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