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FUNDAMENTALS OF STERILE FILTRATION
Selection
and Implementation
Millipore Corporation
Randy Wilkins
Technical Consulting Manager
Agenda
Selection criteria and techniques
• Vmax test
– Principles
– Practical application
– Benefits and limitations
Filter system sterilization
• Considerations for successful SIP
Integrity testing
• Current regulatory perspectives
• Practical solutions
Four Step Sterile Filter Selection
1. Materials Compatibility– Chemical compatibility
– Sterilization compatibility
– Adsorption considerations
2. Retention
– “Sterilizing-grade” – Confirmed with specific process fluid and
operating parameters
• Generally 0.2 or 0.1 um rated
3. Flow Rate
– Can be estimated from vendor flow/dP data
4. Capacity
– Understanding how flow/dP changes during processing
Cake formation Complete pore Gradual pore
plugging plugging
Capacity – Plugging Mechanisms
Factors Controlling Plugging
Concentration
Particle
to Pore
Size Ratio
HighLowLow
High
1
The filtration mechanism depends on:
– Particle to Pore Size Ratio
– Particle Concentration
Gradual Pore Plugging
Complete
Pore
Blocking
Cake Filtration
Monolayer
Adsorption
Complete
Pore
Blocking
Caking
Filtration
Gradual
Pore
Plugging
Plugging Models
<<1 <1 ~1 >1
Particle/Pore size Ratio
• For particle & pore size distributions– One mechanism may dominate hydraulics-apply simple model
– Mechanism may change over filtration-apply simple model to section of data
– Mixed mechanism hydraulics-apply more complex plugging models
• For identical particles & uniform pores– Different models depending on where particles are deposited
Plugging Model Behavior
• Resistance or permeability
changes
– Adsorption - no change
– Gradual - delayed change
– Complete - slight delay, then
rapid change
– Cake - steady change
Plugging Models
1.02.03.04.05.06.07.08.09.0
10.0
0 200 400 600 800 1000
L/m2
R/R
o Adsorption
Gradual
Complete
Cake
Plugging Models
Cake Formation
– Particles accumulate on filter
surface
– Hard, non deformable particles
Complete Pore Blocking
– Particles completely block pore
– Soft deformable particles
Gradual Pore Blocking
– Predominant in biologics
– Particles block a portion of a pore
– Both particle types
Mathematical Models
Cake Formation
– t/V = CV + D
Complete Pore Blocking
– V=E(1 - e-kt)
Gradual Pore Blocking
– t/V = At + B
A,B,C,D,E & k are constants
t = time, V = cumulative volume
Filter Plugging Models - Vmax
Mechanism of filter plugging:
d2t/dV2 = k(dt/dV)n
where:
t = filtration time
V= cumulative volume at time t
k = constant whose dimensions are dependent on n
H.P. Grace, "Structure and Performance of Filter Media,"
AICHE Journal 2(3), 307-336 (1956)
In practical terms:t/v = t/Vmax + 1/Qiwhere: Vmax = maximum volume that can be filtered at time infinity
Qi = instantaneous initial flow
Vmax: test procedure
Test Operation:– Select test filter type for
application
– Select test system & scaledown device
– Wet/vent test filter with buffer or product
– Gently add representative feed solution to reservoir
– Filter at constant pressure
– Record cumulative filtrate weight or volume vs time
– Stop after either set time, set L/m2 throughput, or set %flow decay
Air SupplyScaledown
filter
BalanceFeed Reservoir
Collection
Reservoir
Vmax analysis
0.000
0.005
0.010
0.015
0.020
0.025
0.030
0 10 20 30 40 50 60
minutes T
min
/mL T
/V
CGW1 media 13.8 cm2
SHF buffer 13.8 cm2
Vmax: data analysis
• Plot data as t/V vs t
– Gradual pore plugging model gives t/V=t/AVmax+1/AQi
• Use linear least squares to generate a best fit line
• If poor fit (r2 < 0.99) or negative slope
– Eliminate suspect points (initial wetting or buffer flush out transients, scale jumps,…)
– Re-run, run longer (higher % flow decay)
– Try fitting another plugging model
• If good fit (r2 > 0.99), i.e. CGW1
– t/V=0.000209t+0.00979 min/ml
– Extract model parameters:
• Vmax= 1/slope/area= 0.000209 ml-1/13.8 cm2
= 3470 L/m2
• Note Vmax -> as slope->0
• Qi= 1/intercept/area=1/0.00979 ml/min/13.8 cm2 = 4440 LMH
Application of Vmax
• Ideal for rapid screening of membrane and membrane combinations
• Useful for initial system sizing estimates
– Three process scenarios or cases are usually relevant:
• Case 1: Batch Volume to be filtered
• Case 2: Batch Volume to be filtered at a maximum allowable process
time
• Case 3: Batch Volume to be filtered in a process time with a specified
minimum allowable flow rate
– Largest surface area that fulfills all process requirements is selected
– Compare area, Amin, to available filter configurations & select smallest
configuration that meets/exceeds Amin this is Aconfiguration
– Suggested minimum safety factor ~ 20%
Vmax: Sizing Equations
)/( max
min
test
B
AV
VA
Case 1. Only VB (Batch Volume is given; No batch time, minimum flow)
Btesti
B
test
B
tAQ
V
AV
VA
)/()/( max
min
Case 2. VB (Batch Volume) and tB (Batch time) are given
Case 3. VB (Batch Volume), tB (Batch time) & Qmin (minimum flow rate) are given
minmaxmin
min
)/()/(1
AAV
V
AAQ
Q
test
B
testi
• Eq. gives the minimum area required; No safety factor is included
• Ensure that Amin leads to respectable batch times
• Using Trial & Error, Solve Eq. For ‘Amin’
• Select the largest ‘Amin’ from 1., 2., & 3.
CAUTION!!: DO NOT use with Non-
Plugging Streams (Vmax >1000).Assume a
batch time and use equation under 2 below
Vmax Magnitudes
Vmax Range
• >1,000 l/m2
• 200 l/m2 to 1,000 l/m2
• <200 l/m2
• Low Plugging
– Primarily flux based sizing
– Buffers, simple media
• Moderate Plugging
– Vmax critical range
– Protein solutions, some
media
• High Plugging
– Cell harvest
– Serum, hydrolysates
Vmax - Summary
• Ideal for rapid screening of multiple membrane candidates
– Minimum of time and feed required
• Ideal for determining effectiveness of prefilter candidates
• Good tool for initial filter system sizing
– Attention to dP, filter area, and feedstream consistency helps
minimize scaling error
• Does not tell you anything about filtrate quality
– Indirectly Vmax, with a tighter filter, on the filtrate is a measure
of filtrate quality
• Only applies to gradual pore plugging model
Pmax & Tmax: test procedure
• Application:– High permeability filters (depth,
open prefilters)
– Filter plugging or filtrate quality limits performance
• Test Operation:– Select test filter type for
application
– Select test system & scaledown device
– Wet/vent test filter with buffer or product
– Gently add representative feed solution to reservoir
– Filter at constant flow
– Record volume, pressure drop & filtrate quality (e.g. NTU, 0.2 um Vmax) vs time
– Stop after test end-point (time, L/m2 throughput, psid pressure drop, filtrate quality)
Pump
Scaledown filter
BalanceFeed Reservoir
Collection
Reservoir
Quality measure
Pressure
Centrate Clarification
0.027m2, 110 LMH
0
5
10
15
20
25
30
0 50 100 150 200 250
minutes time
psid
0
5
10
15
20
25
30
35
40
45
50
NT
U
A1HC psid
A1HC NTU
Scaling up
Rapid
scaledown
testing
• Batch testing
• Vmax, Pmax, Tmax
• Filter screening
• Extrapolate process &
rough sizing
• to time, throughput
• to variable
flows/pressures
• to series operation
• Sensitivity and
variability testing
• Include scaling &
safety factors
Simulation
scaledown
testing
Simulation
pilot testing
Engineering
runs at scale
• Full filtration process
• Time, throughput
• Variable
flows/pressures
• Single/series
• Monitor ∆P for each
filter, flow rate,
throughput (turbidity
for depth filters)
• Validate batch
testing
• Update process &
sizing
• Flow & capacity
• Pilot test: area,
feed volume
• Full Filtration process
• Prepare to replace
filters that plug
• Attention to all steps
(flush, SIP, integrity)
• Monitor ∆P for each
filter, flow rate,
throughput (turbidity for
depth filters)
• Validate scaledown
• Updated process &
sizing
• Flow & capacity
• Area
Vmax References
System Design Considerations
Sterilization and Integrity Testing
Sterilization Options
Autoclave Steam-in-place Gamma
Post sterilization
assembly
Likely None Can vary from
multiple steps to
none
Operation Automated Can vary from
fully manual to
fully automated
Vendor
Validation Extensive Extensive Vendor
Filter damage Extremely
remote
Design/operation
dependent
Materials
dependent
Options for Process Operation
Sequence
Set up &
Install Cartridges
Flush/WetTest Integrity
Air Blow Down
P < 5 psi
SIP
ProcessFlush/Wet
Test Integrity
Operation Sequence Options
• SIP > Wet > IT
– Advantages
• Identify filters damaged during SIP before operation
– Constraints
• Filter must wet easily after SIP
• Wet > IT > SIP
– Advantages
• Perform IT under non-sterile conditions
– Constraints
• Must be able to SIP wet filter
Successful SIP Considerations
• Steam pressure and differential pressure must be
controlled to assure sterility and prevent damage to filter
– Filters must be resistant to hydraulic and thermal stress
– Integrity failures equal:
• Lost time – 2 to 4 hours for re-installation and re-SIP
• Potential contamination resolution – varies widely from
thousands to potentially millions of dollars
• Process system SIP is a time-consuming operation
– Being able to SIP multiple system components together
saves time
• Minimizes potential for sterility breaches
• Save labor time
SIP Options
Filter + tank - separate sterilization
•Sterilize filter and tank
separately or consecutively
•Sterile boundary
•Long
•More equipment
•Complex
P1
T1
Transfer
line
V1
V2
V3
P3
P4
T3
Air/N2
P2
Vent
filter
Steam
Steam
Multi-Round Experiments –
Forward or Reverse SIP
Dry Forward SIP
Express SHC CHGE73TS3 Multi-Round 3 x 30"
Filter Wetting, Integrity Test, Blow Down, and
"Dry" Forward SIP at 121 oC, 20 minute Exposure Time
0
20
40
60
80
100
120
140
0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 315
Time (Min)
Tem
pe
ratu
re (
oC
)
0
10
20
30
40
50
60
70
80
90
100
Diffe
ren
tia
l P
ress
ure
(p
sid
)
TC- A 01 TC- A 02 TC- A 03 TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08
TC- A 09 TC- A 10 Delta P
Wetting
Integrity
Test
Blow Down SIPSpore
InstallationExposure
Wet Forward SIP
Express SHR with Prefilter CHVE73TS3 Multi-Round 3 x 30"
Filter Wetting, Integrity Test, and "Wet" Forward SIP at 121 oC, 20 minute Exposure Time
0
20
40
60
80
100
120
140
0 15 30 45 60 75 90 105 120 135 150
Time (Min)
Tem
pe
ratu
re (
oC
)
0
10
20
30
40
50
60
70
80
90
100
Diffe
ren
tia
l P
ress
ure
(p
sid
)
TC- A 01 TC- A 02 TC- A 03 TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08
TC- A 09 TC- A 10 Delta P
Integrity
Test
Wetting SIPSpore
Installation
Exposure
SIP OptionsFilter + tank - Reverse steaming
P1
T1
P3
P2
Vent
filter
Liquid
filter•Easy, maximum simplicity
•Reduced number of drain & valves
•Clean steam required
Requires a robust
filter
Dry Reverse SIP
Express SHC CHGE73TS3 Multi-Round 3 x 30"
Filter Wetting, Integrity Test, Blow Down,
and "Dry" Reverse SIP at 121 oC, 20 minute Exposure Time
0
20
40
60
80
100
120
140
0 15 30 45 60 75 90 105 120 135 150 165 180
Time (Min)
Tem
pe
ratu
re (
oC
)
0
10
20
30
40
50
60
70
80
90
100
Diffe
ren
tia
l P
ress
ure
(p
sid
)
TC- A 01 TC- A 02 TC- A 03 TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08
TC- A 09 TC- A 10 Delta P
Wetting Integrity Test Blow Down Spore
Installation
SIP Exposure
Wet Reverse SIP
Express SHC CHGE73TS3 Multi-Round 3 x 30"
Filter Wetting, Integrity Test, and "Wet" Reverse SIP at 121 oC, 20 minute Exposure Time
0
20
40
60
80
100
120
140
0 15 30 45 60 75 90 105 120 135 150 165 180
Time (Min)
Tem
pe
ratu
re (
oC
)
0
10
20
30
40
50
60
70
80
90
100
Diffe
ren
tia
l P
ress
ure
(p
sid
)
TC- A 01 TC- A 02 TC- A 03 TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08
TC- A 09 TC- A 10 Delta P
Wetting Integrity
Test
Spore
InstallationSIP
Exposure
SIP Cycle Summary
Forward, Dry
– Best option for minimum filter stress
Reverse, Dry
– Best option for simultaneous SIP of filters and tanks
Forward, Wet
– OK if steam introduction is carefully controlled
Reverse, Wet
– Not recommended
Post Sterilization/Pre-use
Integrity Testing
• Regulatory references
– FDA Aseptic Process Guidelines, 2004
– EMEA Annex 1, 2008
• Practical Challenge
• Sterile Barrier Options
– Process equipment
– Catch Can
– Millidisk Barrier Filter
• Redundant filter system testing
• Cost/Benefit Considerations
Regulatory Guidance - FDA
• FDA
– 2004 Aseptic Processing
Guidelines
Regulatory Guidance - FDA
Regulatory Guidance - FDA
Regulatory Guidance - EMEA
• EMEA
– Annex 1
– 2008
Regulatory Guidance - EMEA
Regulatory Guidance - EMEA
Regulatory Guidance Summary
• Documents & Guidance provide general, not practical guidance
– Vendors and PDA Technical Report 26, ‘Sterilizing Filtration of Liquids” are good sources of practical guidance
• EU / EMEA says less but appears far more skeptical than FDA
• White Paper – for each company on qualification and validation of aseptic processes is very prudent.
Practical Challenges
Remove
– Condensate
– Wetting Liquid
– Test Gas
Maintain
downstream
– Sterility
– Atmospheric
pressure (test)
Class BClass C
Filling Line
SterilisingProductFilter
A
Steam WaterGasCondensate
Current Practice
• Fluids are sent to downstream equipment
– Vented process tank or filling manifold
– Good option when product wet filter
testing is used
• Catch can with a sterile vent filter
– Not easy to handle
– Separate autoclaving
– No filter blow-down
– One vent filter to integrity test
– Limited wetting volume
to filling
An Alternate Solution
• Millidisk Barrier Filter technology facilitates
– Integrity testing of product filters
• in-situ
• post sterilization
• before use
– Sterile equipment
• Draining (residual condensate)
• Cooling
• Drying
• Venting (maintain atmospheric pressure on the sterile side…)
…Without breaching sterility
Millidisk Barrier Filter Design
One disk pair
3 Hydrophilic membranes
1 Hydrophobic membrane
Gas
Liquid
Condensate
Using the Millidisk Barrier Filter
After SIP, cool downwith compressed airEliminate condensate, steam & air through barrier filter
1
Open
Closed
SIP
Steam
Once cool, wet the sterilizing-grade filter and direct the effluent to drain through the Barrier Filter.
2 Wetting
Water
1 bar max
Integrity test of liquid filter
3
Vent test gasthrough Barrier Filter
Testing
Atmospheric Pressure
Using the Millidisk Barrier Filter
Dry the liquid filter prior to processing. Vent gas through the Barrier Filter.
After integrity of Barrier Filter is confirmed, start processing.
Product
Integrity test Barrier Filter off-line,IPA 70/30 bubble point test.
5 a4 Blowdown
5 b
Process
Compressed air
Redundant Sterile Filtration
P3
P2
P1
T
MilliBarrier
Aervent
Post Sterilization/Pre-use IT Options
Advantages Disadvantages
Process
Tanks
• No additional equipment • Product IT specs needed
• Entire system requires cleaning and re-prep in
case of filter failure
• Lost product
• No post-SIP extractables flush
Catch-Can • Use water test specs
• Extractables flush
• Flush volume limited
• Additional equipment to assemble and sterilize
• Likely no allowance for re-test
• Vent filter must be tested
Barrier Filter • Water test specs
• Extractables flush
• No limit to flush volume
facilitates re-test if necessary
• Easy Filter blow-down
• Additional equipment to assemble and sterilize
• Additional filter to test
• Limited flow rate (limit is 30-inch filters)
Many Examples
Barrier Filter technology currently in
use in a wide range of processes
Post SIP/Pre-use Integrity Testing
Cost/Benefit Considerations
Costs –
• Additional Capital Costs
– Hardware
– Hardware validation
• Processing costs
– Product to drain
– More filters to buy, prep and test
– More time for filter testing
– More cost associated with false IT failure
• Added Risks
– Sterility compromised by additional
manipulations around the sterilized
system
• Frequency unknown although
expected to be low in a well
designed and operated system
Benefits –
• Simple EU regulation compliance
• Avoid processing with SIP damaged filter
– Value of lost product
– Cost of re-work (if allowed)
• GCC analysis suggests SIP related
filter damage occurs about 1/15000
batches
–For all processes worldwide
–Actual for site would be predicted from
site specific history
• Redundant filtration essentially
eliminates this risk assuming one
filter is validated for sterilization
Conclusion
• Designing successful sterilizing filtration systems requires
– Knowledge of filter/fluid interactions
• Retention and plugging mechanisms
• Sizing techniques and applicability
– Sterilization methods
• Selection based on materials and facility
• Understand limitations for successful SIP implementation
– Integrity testing
• Understand risk/benefits of various options
– Including regulatory requirements
• Vendor experience is critical for efficient implementation
Acknowledgements
• Herb Lutz
• Kerry Roche-Lentine
• Richard Morin
• Maurice Phelan