Professional Documents
Culture Documents
Agenda
Selection criteria and techniques
Vmax test
Principles Practical application Benefits and limitations
Integrity testing
Current regulatory perspectives Practical solutions
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 Understanding how flow/dP changes during processing
4. Capacity
Low
Low
Concentration
High
The filtration mechanism depends on: Particle to Pore Size Ratio Particle Concentration
Plugging Models
For identical particles & uniform pores
Different models depending on where particles are deposited
Monolayer Adsorption
Caking Filtration
<<1
>1
10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 200 400 L/m2 600
R/Ro
800
1000
Plugging Models
Mathematical Models Cake Formation
t/V = CV + D
Cake Formation
Particles accumulate on filter surface Hard, non deformable particles
In practical terms:
t/v = t/Vmax + 1/Qi
where: Vmax = maximum volume that can be filtered at time infinity Qi = instantaneous initial flow
Scaledown filter
Collection Reservoir
Feed Reservoir
Balance
Plot data as t/V vs t 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
min/mL T/V
0.030 CGW1 media 13.8 cm2 0.025 SHF buffer 13.8 cm2 0.020 0.015 0.010 0.005 0.000 0 10 20 30 minutes T 40 50 60
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
Amin
VB (Vmax / Atest )
CAUTION!!: DO NOT use with NonPlugging Streams (Vmax >1000).Assume a batch time and use equation under 2 below
Eq. gives the minimum area required; No safety factor is included Ensure that Amin leads to respectable batch times
Case 2. VB (Batch Volume) and tB (Batch time) are given
Amin
VB (Vmax / Atest )
VB (Qi / Atest ) t B
Case 3. VB (Batch Volume), tB (Batch time) & Qmin (minimum flow rate) are given
(Vmax
VB / Atest ) Amin
Using Trial & Error, Solve Eq. For Amin Select the largest Amin from 1., 2., & 3.
Vmax Magnitudes
Vmax Range >1,000 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
<200 l/m2
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
Pressure
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)
50 45 40
10 5 0 250
NTU
35 30 25 20 15
Scaling up
Vmax References
Sterilization Options
Autoclave Steam-in-place Gamma
Likely
None
Operation
Automated
Vendor
Validation
Extensive
Vendor
Filter damage
Extremely remote
SIP
Flush/Wet
Process
Test Integrity
Flush/Wet
Test Integrity
Steam
P2
Vent filter
P3
Steam
V2
T3 T1
100 90 80
Differential Pressure (psid)
120
Wetting
100
Temperature (oC)
70 60 50
80
60
40 30 20
40
20 10 0 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 Time (Min) TC- A 01 TC- A 09 TC- A 02 TC- A 10 TC- A 03 Delta P TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08 0 315
100 90 80
Differential Pressure (psid)
120
100
Temperature (oC)
70 60 50
80
60
40 30 20
40
20 10 0 0 15 30 45 60 75 Time (Min) TC- A 01 TC- A 09 TC- A 02 TC- A 10 TC- A 03 Delta P TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08 90 105 120 135 0 150
SIP Options
Filter + tank - Reverse steaming
P3
Easy, maximum simplicity Reduced number of drain & valves Clean steam required
Liquid
filter
P1
P2
Vent filter
100 90 80
Differential Pressure (psid)
120
100
Temperature (oC)
70 60 50
80
60
40 30 20
40
20 10 0 0 15 30 45 60 75 90 Time (Min) TC- A 01 TC- A 09 TC- A 02 TC- A 10 TC- A 03 Delta P TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08 105 120 135 150 165 0 180
100 90 80
Differential Pressure (psid)
120
100
Temperature (oC)
70 60 50
80
60
40 30 20
40
20 10 0 0 15 30 45 60 75 90 Time (Min) TC- A 01 TC- A 09 TC- A 02 TC- A 10 TC- A 03 Delta P TC- A 04 TC- A 05 TC- A 06 TC- A 07 TC- A 08 105 120 135 150 165 0 180
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
Condensate
Steam
Water
Gas
Class C Class B
Remove
Condensate Wetting Liquid Test Gas
Maintain downstream
Sterility Atmospheric pressure (test)
Filling Line A
Current Practice
Fluids are sent to downstream equipment
Vented process tank or filling manifold Good option when product wet filter testing is used
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)
Liquid Condensate
3 Hydrophilic membranes
1 Hydrophobic membrane
Gas
1 SIP
Wetting
3 Testing
Integrity test of liquid filter
Atmospheric Pressure
Steam
Water
1 bar max
After SIP, cool down with compressed air Eliminate condensate, steam & air through barrier filter
Open Closed
Once cool, wet the sterilizinggrade filter and direct the effluent to drain through the Barrier Filter.
Blowdown
5 a Process
Compressed air
Product
Dry the liquid filter prior to processing. Vent gas through the Barrier Filter.
5b
Integrity test Barrier Filter off-line, IPA 70/30 bubble point test.
Aervent
P1 P2
P3
MilliBarrier
T
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 Flush volume limited Additional equipment to assemble and sterilize Likely no allowance for re-test Vent filter must be tested Additional equipment to assemble and sterilize Additional filter to test Limited flow rate (limit is 30-inch filters)
Catch-Can
Barrier Filter
Water test specs Extractables flush No limit to flush volume facilitates re-test if necessary Easy Filter blow-down
Many Examples
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
Acknowledgements
Herb Lutz Kerry Roche-Lentine Richard Morin Maurice Phelan