Filter Integrity Testing

Troubleshooting Guidelines

Application
Note
Wayne Garafola Background: Troubleshooting Points to review for each
Senior Applications Specialist filter issue:
Filtration Technologies Integrity Testing is a non-destructive phys-
ical test to determine the presence of over- 1. First Check - Incomplete assembly, in-
Sartorius Stedim North America, Inc. complete wetting of the filter.
sized pores or other defects that may com-
promise a given filter’s retention capability. 2. Always use reinforced tubing that can
Performing filter integrity tests is a re- withstand high pressure (~90-100psi).
quirement by Regulatory Agencies (FDA, 3. Have a written documented filter fail-
EU) when a product is labeled ‘sterile’. ure investigation and retest procedure
documented.
During the integrity test, whether manually 4. Next step
or using an integrity test instrument like a. Ensure the correct program number
the Sartocheck 4 Plus, potential false filter was selected for the filter tested
integrity test failures can occur. This guide b. Check filter manufacturer’s filter test
should be used as a reference to trouble- parameters for actual values
shoot the integrity of the filter. c. Confirm which wetting fluid is being
used; Water, Product, other solvent
The Parenteral Drug Association (PDA), i. Always use the manufacturer’s
Journal of Pharmaceutical Science and recommended wetting procedure.
Technology - Technical Report No. 26 Example:
(Sterilizing Filtration of Liquids) specifically Rinse the filters in the direction of
addresses steps to take in troubleshooting flow for 5minutes with a differen-
filter integrity test failures. tial pressure of 4psid in order to
assure that the filters have been
PDA TR 26: Section 7.7 states: wetted completely. The higher the
Following these recommendation details a differential pressure, the better
3 strike rule. If the filter fails, repeat by re the wetting of the filter polymer.
-wetting with the same wetting agent, Generally, hydrophilic filters are
checking all connections, program type, wetted with water.
etc. If the 2nd test fails, wet the filter with d. Leaks (in vents, tubing). See Leak
a lower surface tension reference fluid to Testing recommendation step.
assess the filters wettability. If the filter e. temperature (room temperature me-
fails this 3rd test, the filter fails the test. If dium),
this case happens, industry recommends ii. high temperature increases solu-
contacting the filter manufacturer for fur- bility coefficient (higher diffusion)
ther assistance in resolving the integrity and decreaes surface tension
failure. (lower BP) causing false failures
f. calibration (review calibration stick-
er),
g. test setup (follow manufacturer’s
recommendation)
5. If the integrity test failed with a value
just above the test limit (diffusion test/
Intrusion test); re-wet filter (see Point
8); check connections and confirm wa-
ter temperature is room temperature.
Repeat test.
6. Minimize the time span between filter
use and filter integrity tests to mini-
mize the risk of drying product
(residue) on the filter membrane. If
filters are not tested right away, ensure
the inlet and outlets are capped until
testing time.
7. Ensure that the filter is adequately Leak Testing:
flushed in accordance with the Manu-
facturers Directions for Use to mini- Integrity Test Instrument – check connections for potential leaks. Use a cap on the end of
mize the amount of residual product the Outlet tubing set and run the following program. Perform a Leak test using the follow-
remaining in the filter. ing parameters:
a. If residual product is a concern; de-
termine Product Wet Specific Integ- Pressure Drop Test
rity Test value.
8. Following a water integrity test failure, Test Pressure ....................................................................... 45psi
increase the differential pressure (20-
Stabilization Time: .................................................. 3 minutes
30psid) and or flush time (5-
10minutes ) to minimize the amount of Test Time: ................................................................... 5 minutes
residual product remaining in the filter.
9. If water bubble point integrity tests Limit: ............................................................................... 0.05psi
continue to fail, perform an integrity
testing using Isopropyl Alcohol (IPA)/RO
Water. If the test result is greater than 0.05psi, check for leaks in the fittings by placing the Outlet
a. 60% IPA minimum bubble point with tubing set (with cap on end) in a bucket of water and repeat test. Look for bubbles and
a Sartobran P 0.2μm filter is 17 psi. tighten fitting.
b. 70% IPA minimum bubble point with
Recommended Integrity Filter Test Set-up:
a Sartobran P 0.2μm filter is 16 psi. The Sartocheck Outlet Tubing set to a test filter capsule (or housing) should be orientated
c. 60% IPA minimum bubble point with so that the Water trap filter assembly is higher than the test filter (see diagram). This ori-
a Sartopore 2 0.2μm filter is 19 psi. entation prevents fluid going back into the unit.
d. 70% IPA minimum bubble point with
a Sartopore 2 0.2μm filter is 17 psi.
10. Integrity tests with IPA alleviate most
false integrity test failures; however,
false failures can still occur and may
require cleaning of residual product
from the membrane. Contact filter
manufacturer for further options.

Repeating an integrity test on a filter that

has not been flushed prior to the integrity
test is not recommended. It has the poten-
tial of drying the filter on repeated tries by
an operator.

If an operator / technician observes liquid coming out of the vent port on the right side of
the Sartocheck following any integrity test; Sartorius recommends the Sartocheck be
cleaned as soon as possible. Contact the Service Center at 1.866.208.3484, ext. 7247.
Vent Filters
If performing an Intrusion Test (WIT/WFT), ensure filter has sufficient room temperature water above the cartridge. During pressurization,
the water is pushed into the pleats and the level decreases from the initial start point.

Blow down of a Vent filter

If a vent filter fails the Water Intrusion Test (WIT) after long-term use, it may be attributed to the filter membrane being wetted out
(saturated with water) from the condensation that's occurred over the usage period. Even though the filter has passed the Pre-Use WIT, the
initial post-use WIT value exceeds the manufacturer's test limit.

Sartorius’ recommendation for vent filters that exceed the WIT test limit is to blow down the filter prior to repeat testing:

Forward Air Direction (Upstream side Downstream side)

Using a pressure regulator, provide a dry air source (Nitrogen (N2) or Compressed Air (CA)) @ ~15-20psi to the Inlet (top) of the filter hous-
ing for 25-30minutes. Slightly open the base vent drain on the housing (if applicable). This step allows excess moisture within the housing/
membrane to be dispersed out the base of the housing during the blow down period. Repeat the WIT test.

Reverse Air Direction (Inner Core Outer Core)

Using a pressure regulator, provide a dry air source (N2 or CA) @ ~15-20psi to downstream side (Outlet) of the filter housing for 25-30
minutes. Slightly open the base vent drain on the housing. This step allows excess moisture within the housing/membrane to be dispersed
out the base of the housing during blow down. Repeat the WIT.

Note: During the WIT, ensure the filter is immersed in water by adding a spool piece to the top of the filter housing. During the pressure
increase step, the air pressure forces the water level to decrease in the test housing. The spool piece allows extra volume of water so the
amount of decrease is not lower than the cartridge height.
Integrity Testing Crossflow Cassettes

1. Install the cassettes at 60 or 80Nm torque (use manufacture’s recommendation).

2. Wet the filter cassettes with water at 20-22°C with valve 2 and 3 closed. The wetting fluid will exit through valve 4 and 5 to drain. You
can install several filter cassettes (be aware of that low diffusion cassettes can mask high diffusion cassettes). The cassette holding
device and Sartocheck should be at the above-mentioned temperature.

2. Keep Valve 2 & 3 on the Sartocon test holding device closed during the integrity test. Afterwards, close the isolating valves. In addition,
water is forced through the permeate outlet during the stabilization phase of Sartocheck (make sure you have you low pint drain on
the permeate side open to drain the liquid).

3. If you are testing more than 10 cassettes at a time with an upstream volume less than 4L you have to use a reference tank connected to
the Sartocheck unit and a buffer tank of approx. 20L. If just a few cassettes, you can by-pass the buffer tank.

4. Test Program

Diffusion Test
Test Pressure ........................................................................................................................................................................... 15psi
Stabilization Time: ......................................................................................................................................................3 minutes
Test Time: .......................................................................................................................................................................5 minutes
Maximum air diffusion: ......................................................... Check manufacturer’s recommendation for specific cassette

5. Once the self-test has been run, the integrity measurement will automatically start. Following a successful measurement, the Sar-
tocheck automatically generates a printout.
Definitions:
1. Bubble Point Test - the pressure at which a given liquid in the wetted pores of a membrane is forcibly removed. The removal of the
liquid allows free flow of air through the membrane.
2. Diffusion Test is the flow of compressed gas (e.g. air or nitrogen) per time through the wetting liquid within the pore system of a mem-
brane at a defined test pressure (70–80 % of Bubble Point)
3. Diffusion & Bubble Point Test – Combination of Diffusion and Bubble Point test.
4. Intrusion Test is an in-situ integrity test for hydrophobic filters. The WIT measures the decay rate of a pressure level imposed upon a
hydrophobic membrane enveloped in water. Two Options:
a. Water Intrusion Test – performed on Sartorius filters
i. The WIT test option reports test results as a downstream flow measurement.
a. Water Flow Test – performed on non-Sartorius filters
i. The WF test option measures flow on the upstream side with the values expressed in terms of water flow measurement.
5. Pressure Drop Test is the pressure decay on the upstream side of a membrane filter system on the basis of diffusion of gas molecules
out of the constant volume of the upstream side

Reference:
1. PDA Technical Report No. 26 – (Rev 2008), Volume 62 – No. S-5 2008
2. FDA – Aseptic Guideline (page 33)
3. EC Guide to GMP, Revision to Annex 1, Feb 2008 (Annex 1 – Number 113)
4. Filtration in the Biopharmaceutical Industry (Theodore H. Meltzer, Maik W. Jornitz)
 Specifications subject to change without notice. Printed and copyrighted by Sartorius Stedim North America, Inc.

Sartorius Stedim North America

5 Orville Drive
Bohemia, NY 11716
Phone 800.368.7176
Fax 631.254.4264
www.sartorius.us