Downstream Without a Paddle
Speakers:
Aaron Allen – Jacobs Engineering Group
Larry James – CRB Consulting Engineers Inc.
Mark Trotter – Sartorius Stedim Biotech
Michael Rohr – Westfalia Separator Inc.
3/6/2008
ISPE Carolina South-Atlantic
Chapter
1
Introduction to TFF
Aaron Allen – Jacobs Engineering Group
3/6/2008
ISPE Carolina South-Atlantic
Chapter
2
Safety First
Safety Concerns for TFF
• Typical cleaning regime for TFF membranes is
hot sodium hydroxide. Contact with the
solution can result in serious chemical burns. It
is critical to therefore wear personnel protective
equipment as directed by procedures.
3
What is TFF?
Tangential Flow Filtration (TFF) may also be referred to as
Crossflow Filtration
Tangential Flow – Feed Flow Parallel to Membrane
Surface
Cross Flow – Feed Flow Perpendicular to Filtrate Flow
TFF is performed such that there is a constant sweeping of
the filtration membrane.
TFF has continuous flow across the surface of the
membrane.
Membrane
Tangential Flow Filtration
4
TFF comparison to Direct Flow
In Direct Flow Filtration particulates are retained
at the surface of the filter.
In TFF particulates are retained in the retentate
stream.
Feed
Retentate
Feed
Membrane
Filtrate
Direct Flow Filtration
Membrane
Filtrate or Permeate
Flux usually given in LMH
Tangential Flow Filtration
5
Why TFF vs Normal Filtration?
Comparison of Flux Decay
Normal Filtration Flux Decay
Flux Rate (L/m 2 /hr)
Flux Rate (L/m 2/hr)
Tangential Flow Filtration Flux Decay
Volume Processed (liters)
Volume Processed (liters)
6
TFF Diagram - Concentration
Retentate
Gel Layer
Membrane
Retentate
Tank
P
Supply Pump
Permeate
Feed
7
Transmembrane Pressure (TMP)
Transmembrane Pressure
Flux Rate (L/m2/hr)
Driving force for filtration. Defined as;
[Inlet Pressure + Retentate Pressure]/2 – Permeate Pressure
Optimum TMP
Transmembrane Pressure (psid)
8
Transmembrane Pressure
The filtrate flux or flux rate is defined as follows;
J (Flux) = A * TMP
•
•
•
•
A = Mass Transfer Coefficient
A = 1/[Rg + Rm]
Rg = hydraulic resistance of gel layer
Rm = hydraulic resistance of membrane
Rm is constant for the installed membranes. May
vary slightly from one lot to another.
Rg changes as the gel layer changes. Thus the
asymptotic nature of the previous graph.
9
TMP
Retentate
Gel Layer
Membrane
Retentate
Tank
P
Supply Pump
Permeate
Feed
10
TFF Design
Rejection Coefficient (σ)
• A rejection coefficient of 1 is complete retention of a
particle.
• A rejection coefficient of 0 is complete passage of a
particle.
Volumetric Concentration Ratio (VCR)
• VCR = Initial Volume (V0) ÷ Retentate Final Volume (VR)
Solute Concentration Ratio (SCR)
• SCR = Final Concentration (CR) ÷ Initial Concentration (CR0)
11
TFF Design
Design Formula: SCR = (VCR)σ
Solute Concentration Ratio
50
40
σ = 0.99
30
20
σ = 0.90
σ = 0.75
10
0
0
10
20
30
40
50
Volumetric Concentration Ratio
12
Theoretical Yield
Yield: Yield = (VCR)σ-1 x 100%
100%
σ = 0.99
90%
80%
Yield
70%
σ = 0.90
60%
50%
σ = 0.75
40%
30%
20%
10%
0%
0
10
20
30
40
50
Volumetric Concentration Ratio
13
Flux Characteristics
Flux Rate (L/m2/hr)
Filtrate Flux as a function of VCR
Volumetric Concentration Ratio
14
Flux Characteristics
Flux Rate (L/m2/hr)
Filtrate Flux as a function of SCR
σ = 0.99
σ = 0.75
σ = 0.90
Solute Concentration Ratio
15
Flux Characteristics
Filtrate Flux
2
Flux Rate (L/m /hr)
• Flux is affected by the concentration of the gel layer. Gel layer
concentration is determined by plotting Flux versus Log of VCR. Gel
layer concentration is where flux = 0.
Log VCR
CG = 50 VCR
16
Flux Characteristics
Filtrate Flux
• The ideal maximum bulk concentration is
determined by the following equation,
• CB=CG/e
• In this example,
• CB=50 / 2.718
•
= 18.4 VCR
• What does 18.4 VCR mean,
• If Initial Volume = 1000 liters, 18.4 VCR results in a final
volume of 54 liters.
• This results in the minimum processing time.
17
TFF Diagram - Diafiltration
Diafiltration Buffer
Retentate
Membrane
Retentate
Tank
P
Supply Pump
Permeate
Feed
18
Diafiltration Flux
Flux Rate (L/m2/hr)
Filtrate Flux as a function of VCR
Initial Concentration
Diafiltration
Volumetric Concentration Ratio
19
Final Concentration
Flux Rate (L/m2/hr)
Filtrate Flux as a function of VCR
Initial Concentration
Diafiltration
Final Concentration
Volumetric Concentration Ratio
20
TFF Scale-Up
What is needed from Development
• Flux Rate vs Volumetric Concentration Ratio
• Rejection Coefficient
Scale up is typically based on desired
processing time (perform in 1 shift).
• Depending on facility shift schedule this could
be 8 or 12 hours.
• With setup and cleaning, total process time may
be less than 4 hours.
21
TFF Scale-Up, Input Data
Input Data
•
•
•
•
•
Minimum Process Time
Initial Product Mass
Initial Product Volume
Final Concentration
Crossflow Rate
Development Data
• Rejection Coefficient
• Flux vs VCR
22
Equipment Considerations
Pump Selection
• Chosen to minimize shear
• Shear can lead to protein degradation and
cell disruption
Pipe Diameter
• Selection must be made to ensure
turbulent flow for cleaning purposes
23