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sizing
Vmax and Pmax method
Presentation Overview
Pmax/Tmax Method
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How a Filter
Works
Microporous Membranes
Virus Membranes
Ultrafiltration Membranes
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Particle Retention Mechanisms
Adsorption
• Attraction forces between particles
and filter material
• Molecular and/or electrical
• Not size-dependent
Depends on
• Particle type
• Solution properties
• Filter material and structure
Key Membrane and
Depth Filter
Characteristics
What do Membrane Filters look like?
Mainly made by casting membrane
Can be either hydrophilic or hydrophobic
Rated on the size of the smallest particle it
retains
Very thin (100 - 260 um)
Adsorption depends on materials
• Not the primary retention mechanism
Examples
• Cellulose ester
• Regenerated cellulose
• Nylon
• Polysulfones
• PVDF
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Key Membrane Filter Characteristics
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What do Surface (Pre-) Filters look like?
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What do Depth Filters look like?
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Depth filter composition
• Refined grade
• Large surface area
• Entrapment sites
Resin binder
• Positive charge & hydrophobicity
for adsorption
An introduction to filter
sizing
Types of Particles in Biological Fluids
Non-deformable types
• Resin beads or fines
• Drug crystals
• Carbon fines
• Diatomaceous Earth (D.E.)
• Form porous permeable
cakes.
Deformable types
Proteins
Lipids
Sugar/protein complexes
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Complete Pore Blocking
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Gradual Pore Plugging
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Impact on Filter Behavior
Gradual blockage most common
Constant flow
filtration –
∆p increases as
filter fouls
Gradual and complete blocking do
not have a linear relationship
between ΔP and capacity
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Filter Performance Characterization
Capacity
• Volume that can be process per filter area (L/m2)
• How much?
Flowrate
• Volume processed per time per area (L/m2/hr = LMH)
• How fast?
Performance depends on:
• Filter selection- the correct filter for the application
• Process parameters
• Optimizing pressure, flowrate, time, area
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Small-Scale Test Methodologies
Constant Pressure (Vmax) Constant Flow Rate
Fluid is held at constant (Pmax/Tmax)
pressure and forced through Fluid is pumped at a constant
filter media flow rate through the filter
Filter plugging is observed by media
the decrease in flow rate over Filter plugging is observed by
time an increase in differential
Classically, based on pressure over time
gradual pore plugging OR
model Filter plugging is observed by
an increase in filtrate turbidity
over time
Based on a small-scale
process simulation with
15/5/2017 empirical data fitting
Choosing a Filter Sizing Technique:
Fouling Mechanism Basis
Constant
Sizing Method Name:
Mode of Testing
Pressure Vmax
Volume Endpoint Vmax
Tmax
Vmax
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Gradual Pore
Plugging
and Vmax
Method
Available Test Methodologies for Sizing Filters
pressure
turbidity
flow rate
throughput throughput
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Filter Plugging Models
• d2t/dV2 = k(dt/dV)n
where:
t = filtration time
V= cumulative volume at time t
k = constant whose dimensions are dependent on n
n = 1.5 for gradual plugging
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The Vmax (Constant Pressure) Test
• Accelerated screening technique to estimate scaled-up filter size requirements
• Helps to optimize filtration train rapidly
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Vmax: Result Analysis
Typical Curve
• Highly linear region r2 > 0.99
− r2 > 0.99 1/Qi
t/V 1/Vmax
What happens when r2 < 0.99?
• Prediction of Capacity (Vmax) based on
10 min test becomes less reliable
• Remove earlier points to see if fit is
t
improved,
− Need at least 6 points in the
straight line for reliable correlation r2 < 0.99
t
Vmax: Approaches to Filter Sizing
Largest surface area that fulfills all process requirements is selected, Amin
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Vmax: Sizing Equations
Qmin VB
1− =
Qi × Amin Vmax × Amin
• Using an Iterative Method, Solve Eq. For ‘Amin’
•‘Case 2’ can give a reasonable initial guess
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Vmax: Advantages/Benefits
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Vmax: Limitations
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Pmax/Tmax
method
Large scale Small scale
Golden rule:
Process parameters
Fluid characteristics
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Challenges to Clarification
Process Optimization
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First Process Challenge: Understanding Fluid Complexity
• Others – Buffers
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Second Process Challenge: Optimal Technology Selection
Separation Application
Benefits Limitations
Technology Scope
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Third Process Challenge: Optimizing Technology Integration
Cell Density
TFF or centrifuge
High TFF
+ 1-stage charged
TFF or centrifuge depth filter
+ 2-stage charged
depth filter
Med Depth filter
1 or 2-stage
charged
Low TFF or centrifuge depth filter
+ 1-stage charged Surface filter
depth filter
Cell Viability
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Capacity
Goal:
• Maximize the amount of fluid that can be processed through a filter.
Capacity
The volume filtered up to the point when the maximum pressure or
turbidity is achieved
• defined in volume/area (L/m2)
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The Pmax/Tmax (Constant Flow) Test
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Methodology: Pmax
constant flow, P limitation
Maximal pressure
Pressure
(psi)
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Methodology : Pmax
Define throughput as
volume per area (L/m2)
Throughput (L/m2)
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Analyzing Test Results
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Applying the Pmax Sizing Algorithm
Resistance (psi/LMH)
and Capacity = VB/A 0.50
Permeate NTU
0.8
0.40
0.30 0.6
3. Calculate Resistance, Rcalc. = 0.20
∆P/Javg.
0.4
0.10
0.2
0.00
0 50 100 150 200 250 300 350 400 450
4. Determine Actual Resistance -0.10
Capacity (L/m²)
0
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How Accurate is the Pmax
Sizing Method?
resistance (LMH/psi)
between large and
small-scale are
carefully controlled
Example at right
shows a 130X scale-
up/scale-down
filter loading (l/m2)
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Safety Factors
Considerations
Safety Factors:
Introduction
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Safety factors
Depending on your unit operation and information on typical variability, this safety factor should be
smaller or larger.
- i.e. control over cell culture consistency, centrifuge operation can reduce required safety factor
and make secondary clarification very economical, lack of control might lead to large installations.
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Safety Factors:
Using a cost benefit analysis
$/batch
labor
$5,000
total buffer
Higher membrane area $4,000
capital
$3,000
increases overall cost but $2,000
consumable
4" Opti
MPAK20
MPAK40
MPAK60
MPAK100
MPAK200
1
2
3
4
5
6
7
8
9
12
15
18
21
38
# 10" elements
• Existence of a minimum value for a failed batch vs. overall cost is the base case
for determining a safety factor
Safety factor:
Choosing a robust safety factor
1000.00
Cost Ratio
2
10.00 2.2
Similarly, each unit 2.4
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Safety Factors for Depth Filtration
• Depth filtration has a relatively high cost ratio due to a relatively high variable
cost ($/g)
• The cost-benefit analysis suggests that safety factors of 1.5-2.3 are justified
• Historically, safety factors as high as 3.0 have been employed in depth filtration
operations (depends on control over feed variability)
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Wrap-Up
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