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Simplified, efficient sizing of sterilizing-grade normal flow
filters for buffer solutions
Yanglin Mok , Lise Besnard , Priyabrata Pattnaik , Bala Raghunath
1
2
1
1
1 Biomanufacturing Sciences and Training Centre, Merck Millipore, Merck Pte Ltd., Singapore 2 Merck Millipore, Millipore SAS | 39 Route Industrielle de la Hardt, 67120 Molsheim France
Theoretical Background
Amin
#10” cartridge =
area of 1 x 10” cartridge
Q'median =350 LMH/ps
0.0035
Qg' with 1.3x safety factor =
260 LMH/psi
0.003
n = 49
0.0015
Where:
Using extensive data from Vmax™ trials with non-plugging fluids
on Optiscale® 25 disposable capsules, data points exhibiting
Vmax™ values greater than 3000 L/m2 were compiled to generate
a normal curve for each sterilizing grade filter (Figure 1). The
generic permeability (Qg’) taken at 1.3 x (safety factor1) from the
median of each curve represents the typical filter permeability.
Corresponding Author: [email protected]
EMD Millipore, the M mark and Vmax are trademarks of Merck KGaA, Darmstadt, Germany.
Durapore, Millipore Express and Optiscale are registered trademarks of Merck KGaA, Darmstadt, Germany.
Copyright 2014 EMD Millipore Corporation, Billerica, MA USA. All rights reserved.
1
KBuf =
Q’g x (Area of one 10” cartridge)
0.0005
0
0
Amin (m2)
10
1
350
1.93
3.12
5 x 10”
3.45
1.8
5000
5
1
1060
0.93
1.45
3 x 10”
1.64
10000
21.8
1
671
0.72
1.15
3 x 10”
1.47
Case
Study
Filter
Type
Area of
1x10”
(m2)
1
CVGL
0.69
NaHS
5000
2
SHF
0.54
1M Sodium
Acetate
3
SHC
0.49
100mM
Glycin
Buffer
VB (L)
∆P (psi)
Conf.
Filtration
Area (m2)
Overall
SF
KBuf Area/
Vmax™
Area
3.5
4 x 10”
2.76
1.4
0.8
1.8
2.8
3 x 10”
1.62
1.7
1.0
2.0
2.2
3 x 10”
1.47
2.0
1.0
Conf.
Final
Filtration
area (m2)
Overall
SF
# 10”
required
100
200
300
400
500
600
700
Figure 2. Reference charts for sizing sterilizing-grade filters
for buffer solutions.
a) Durapore® CVGL b) Millipore Express® SHF
c) Millipore Express® SHC
Filtration area sized with KBuf sizing tool was compared against
sizing results from Vmax™ sizing method with the same scaling
constant and safety factor applied. KBuf results were within 20%
of Vmax™ sizing method as shown in Table 2.
A
Conclusion
Q', Permeabilty LMH/psi
To account for device format differences between flat sheet cut
disc membrane used during trials (Optiscale® 25) and cartridges
used for production, scaling constants and in-line housing
pressure loss2 of 7% was included into KBuf constant to arrive at
KBuf final constant. KBuf final constant can be applied directly into
Equation 3 for the approximation of filtration area. A reference
chart, Figure 2, was developed based on KBuf final constants and
filtration time of 1 hour at selected applied pressures. The sizing
constant and reference charts are only applicable for water-like
buffers up to 1M in concentration with viscosity similar to water
(1cP) at room temperature.
Millipore Express® SHF, 0.2µm
Q'median = 1060 LMH/psi
0.0014
n = 192
Qg' with 1.3x safety factor = 800
0.0012
LMH/psi
0.001
0.0008
0.0006
0.0004
0.0002
Durapore® CVGL Reference Chart
16
KBuf final= 0.0069
Filtraon me = 1 hour
14
12
# of 10" cartridge
B
10
8
6
4
2
0
0
1000
2000
3000
5 psi
0
250
500
750
1000
1250
1500
1750
2000
4000
5000
6000
7000
8000
9000
10000
Batch Volume, L
0
10 psi
15 psi
B
Table 1. Sizing constants and formula for sizing
sterilizing-grade filters
20 psi
References
Millipore Express® SHC Reference Chart
10
1. Lutz H., Rationally defined safety factors for filter sizing, Journal of Membrane Science,
2009, 341 268-278
KBuf final= 0.0047
Filtraon me = 1 hour
9
2. Giglia S., Rautio K., Kazan G., Backes K., Blanchard M., Caulmare J., Improving the accuracy
of scaling from discs to cartridges for dead end microfiltration of biological fluids, Journal of
Membrane Science, 2010, 365 347-355
8
C
®
Millipore Express SHC, (0.5/0.2µm)
Q'median = 700 LMH/psi
0.0018
Qg' with 1.3x safety factor =
0.0016
530 LMH/psi
KBuf sizing results were within 20% of the laborious Vmax™
sizing method and provided adequate safety factors of 1.4 to 2.
The Vmax™ method accounts for viscosity variability whereas
KBuf method does not. Changes in viscosity, membrane and
process may result in larger differences in filtration area sizing
between the Vmax™ and KBuf method. The in-line housing
pressure loss (7%) may increase exponentially with increasing
flow rate and may differ for different membranes. Other process
considerations such as piping and system effects are not
included in the study.
2250
Q', Permeabilities, LMH/psi
Probability Density
The minimum filter area, Amin, required to process a batch
of buffer solution can be calculated with all the available
parameters. Process condition parameters (e.g.: tB, VB and ∆P) are
generally known. Q’ is generally unknown and obtained through
Vmax™ trials with Optiscale® 25 disposable capsules.
tb (h)
Permeability
(LMH/psi)
Area with
SF, ScF and
7% housing
loss (m2)
[Equation 3]
0.002
0.001
[Equation 2]
Note: Amin = minimum area; VB = batch volume; Ji = flux across filter; tB
= batch time; Q’ = specific fluid permeability with a particular membrane;
∆P = pressure drop across filter
VB x KBuf
=
tB x ΔP
KBuf constant sizing
Vmax™ sizing
0.0025
[Equation 1]
Combining with a simplified form of Darcy’s law expressed in
membrane permeability (Q’ = Ji / ∆P) gives:
Amin = VB/(Q’ x tB x ∆P)
Durapore® 0.22µm, CVGL
0.004
The Vmax™ model (based on the gradual pore plugging model) is
commonly used to size filtration area requirements. Considering
the non plugging behavior of buffers the model was simplified to
give:
Amin = VB/(Ji x tB)
The generic permeability, Qg’, was included into equation 2 and
the minimum area or number of cartridges can be estimated by:
Process conditions
n = 38
0.0014
Filter Type
0.0012
KBuf
Scaling
factor
KBuf Final
(incl. scaling
factor and
7% housing
pressure loss)
# of 10" cartridge
The KBuf sizing method uses a simple sizing tool developed
based on well characterized membrane permeability values for
sterilizing grade filters, Durapore® 0.22 μm, Millipore Express®
SHF and Millipore Express® SHC, taking into account safety
and scaling factors. This tool has shown to closely approximate
(within 20%) to the more laborious Vmax™ filter sizing model for
non plugging buffers with water-like viscosity and permeability
greater than 10,000 L/m2. The KBuf sizing method is a rational
approach for approximating filtration area requirement required
especially for Greenfield or Brownfield projects.
Table 2. Comparison of Vmax™ and KBuf method filter sizing recommendations
Formula for KBuf
Sizing Method
(based on KBuf
final constants)
7
6
5
4
3
2
Durapore® 0.22 µm,
CVGL
0.001
0.0008
0.0056
0.86
0.0069
#10” cartridge =
VB x 0.0069
1
tB x ΔP
0
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
0.0006
Millipore Express®
SHF, 0.2 µm
0.0004
0.0002
0.0023
0.89
0.0028
#10” cartridge =
Batch Volume, L
VB x 0.0028
tB x ΔP
5 psi
10 psi
15 psi
0
100
200
300
400
500
600
700
Q', Permeabilities, LMH/psi
800
900
1000
1100
Millipore Express®
SHC, 0.5/0.2 µm
0.0039
0.87
0.0047
#10” cartridge =
VB x 0.0047
tB x ΔP
C
20 psi
Millipore Express® SHF Reference Chart
6
KBuf final= 0.0028
Filtraon me = 1 hour
5
Note: VB is batch volume in liters, tB is time in hours and ∆P is differential
pressure in psi. The scaling factor for each filter type was measured by
EMD Millipore.
4
3
2
1
0
0
1000
2000
3000
4000
5000
6000
7000
8000
Batch Volume, L
5 psi
10 psi
15 psi
20 psi
Summary
KBuf sizing tool provides a close approximation of
filtration area required for buffer filtration applications.
It is a convenient, quick and effective tool for buffer
filter sizing for non plugging buffers with waterlike viscosity (1cP±20%) and permeability greater
than 10,000 L/m2. The KBuf sizing method is limited
to Durapore® 0.22 μm, Millipore Express® SHF and
Millipore Express® SHC sterilizing-grade filters. In
determining the final filter sizing recommendations,
the user should consider any additional process
impacts from the fluid characteristics (purity, viscosity,
temperature, etc.) and system design.
0
# of 10" cartridge
Filter sizing is commonly done using the laborious Vmax™ sizing
method or water flux data provided by filter vendors which may
not represent actual process conditions. An alternate method
based on extensive knowledge of buffer filtration was developed
to provide filter sizing.
A
Probability Density
Sterilizing grade filters are commonly used to control bioburden
and remove physical contaminant for a wide array of bioprocess
feed streams where the majority of the array consists of buffers.
As buffer filtration is considered a relatively “simple” application
in comparison to other unit processes, little time is dedicated to
provide filter sizing recommendations, leading to situations of
undersized or oversized filtration systems.
Developing a Sizing Constant (KBuf)
for Sizing Tool
Figure 1. Normal curve for sterile grade filters.
a) Durapore® 0.22 μm b) Millipore Express® SHF 0.2 μm
c) Millipore Express® SHC 0.5/0.2 μm.
Probability Density
Abstract
9000
10000

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