Introduction

The integrity test is the End User’s method  to  confirm  the  structural  integrity of  a  membrane  filter  before  and  after use. It is a non-destructive test that has been correlated to bacteria retention and validates the performance of the filter cartridge. An “in specification” result confirms the porosity of filter membrane  and  that  the  cartridge  is  structurally integral.

Compressed gas and tank vent filters are typically sterilized in-place as part of the production process system to ensure the equipment has maintained sterility after in-situ sterilization and that the equipment is ready to receive sterile product. Compressed gas and tank vent filters are non-product contact filters and are usually used over an extended period of time as compared to liquid filters that are typically discarded after a single product batch has been filtered. Hydrophobic compressed gas and tank vent filters are typically subjected to multiple  sterilizations  and  therefore  integrity  tested multiple times as compared to filters used in liquid filtration applications.

 

 

Filter integrity can be determined by any of the following four test methods :

1.Forward Flow Integrity Test (FFIT) 2.Bubble Point Test (BPT)  3.Pressure Hold Test (PHT)

4.Water Intrusion Test (WIT)

Unlike  the  typical  hydrophilic  filter  medium  used  for  liquid  filtration  applications,  compressed   gas  and   tank vent filters are fabricated with hydrophobic filter medium. Hydrophobic  filter  medium  prevents  the  bulk  flow  of aqueous based product through  the  filter  at  differential  pressures  below the  intrusion  pressure  of the  medium,  while permitting the free passage of gas through the filter. Integrity testing of  hydrophobic  filters  by  three  of  the  four conventional integrity test methods listed previously (FFIT, BPT and PHT) require the use of  wetting agents, such  as alcohol or an alcohol and water mixture, to thoroughly wet the filter membrane prior to integrity testing. All three of these tests must be performed off-line to prevent the wetting fluid from contaminating the sterile downstream side of the filter membrane.

The fourth integrity test (WIT) can be performed in-situ using water. This eliminates the use of wetting agents and does not

require the penetration of the filter membrane by the wetting fluid.

All four tests can be conducted either manually or with an Automatic Integrity Tester.

The following procedures provide the instructions for integrity testing 10”cartridges. Contact SERENE Technical Service for details on how to integrity test other cartridge and capsule configurations.

 

Forward flow integrity test

1. Definition

According to Fick’s Law of Diffusion, when a differential gas pressure exists across a wetted membrane, the gas molecules will “diffuse” through the wetting fluid filling the pores of the membrane. The rate of passage  is  proportional  to  the solubility of the gas in the wetting fluid, the surface tension of the wetting fluid, the differential pressure, the thickness of the membrane, and the surface area of the membrane. The diffusion rate is  measured  at  the  minimum  completely retentive membrane bubble point pressure. The Forward Flow Integrity Test (FFIT) may  be  employed  with  multi- cartridge housings.

The Forward Flow Integrity Test is the preferred test method to determine if the membrane and cartridge are structurally integral. The diffusion rate is typically measured at a test pressure at or near the minimum completely retentive bubble point pressure. The Forward  Flow Integrity Test has been shown  to be both a quantitative measurement  and to correlate  to bacteria retention. The bubble point of the membrane can be a subjective determination and does not always correlate to

 

 

Figure 1 - Forward Flow Integrity Test (Manual Method)

 

Pressure Gauge       Pressure                 V3                                V4 Regulator               V1                                                                                                    V6   V2       Drain Graduated Cylinder

The bubble point of a membrane containing small defects will not correlate to bacteria retention due to the limited sensitivity of the bubble point test method to detect these small defects. Only the bubble point of a completely defect-free membrane will correlate to bacteria retention.

 

Selecting a test pressure for the Forward Flow Integrity Test at the Industry Standard Practice  of 80% of the initial membrane bubble point does not ensure the integrity or the retention capability of the filter. This leaves a region between the test pressure and the membrane bubble point that is not tested and therefore the integrity of the membrane can not be ensured in this region. This is analogous to testing at 80% of the expected membrane bubble point.

Therefore, membrane filters should be tested at a more aggressive test pressure to ensure both the integrity and the correct pore size of the membrane. It is, therefore, recommended that the Forward Flow

Integrity Test be conducted at a test pressure at or near the minimum completely retentive membrane bubble point. Integrity testing can be performed manually or Automated Integrity Tester.

 

1. Procedure (Manual Testing - Figure 1)
   1. Configure the system as shown in Figure 1.
   2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v) @20°C, 60% / 40% IPA - Isopropyl alcohol / water (v/v) @25°C, or 70% / 30% IPA - Isopropyl alcohol / water (v/v) @25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes. Valid integrity test limits will be obtained when  the wetting fluid temperature is maintained within ± 2°C and concentration within

± 2% v/v.

1. 1. Close inlet V1 and outlet valve V6 to isolate the housing. Drain all the wetting fluid from the upstream side of the filter by positioning V5 to direct flow to drain. Adjust the pressure regulator to deliver 200 – 300 mbar  of air  or nitrogen (DO NOT USE CO2). Slowly open V3. Close V3 when wetting fluid discharge is no longer evident.
   2. Connect one end of a flexible tube to the outlet port V5 and submerge the other end in a container  of water*. Position V5 to direct flow to the container of water.
   3. Open V3 and slowly adjust the pressure regulator to pressurise the system to the specified FFIT pressure value and allow the system to equilibrate for a maximum of 2 minutes, or until steady bubbling is seen from the submerged end of the tube.
   4. Place the opening of the tube under an inverted graduated cylinder or burette (calibrated in millilitres or cubic centimetres) of an appropriate size filled with and submerged under sterile water.
   5. Measure the air flow for 3 minutes. Calculate the diffusion rate in ml/min.
   6. When the test is complete, compare the result to the cartridge FFIT specification.
   7. After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the water from the housing or adjust the pressure regulator  to  deliver  200 – 300 mbar  of air  or  nitrogen. Slowly open V3. Close V3 when  wetting  fluid discharge  is no longer  evident. Dry the cartridge before  placing the cartridge  in service.

 

 

 

 

 

* It is important  to make  an aseptic connection and to close the outlet port immediately  after the system  has been

integrity tested to prevent contamination.

 

 

2

 

J.     If the diffusion rate is higher than the specification, consider the following questions and re-test if necessary : Was the filter completely wet out ?

Was the correct pore size filter installed ?

Was the temperature of the wetting and filter ambient ? Was the stabilisation time adequate ? Was the test time adequate ?

Was the filter seated correctly in the housing and were the O-rings undamaged ?

 

1. Procedure (Automated Testing - Figure 2)

 

1. 1. Figure 2 - Forward Flow Integrity Test (Automated Method)

      Pressure Gauge

      Pressure Regulator

      Shut-off Valve

      Vent

      V3

      V4   Filter Housing

      Automatic Tester Tester

      V1

      V6

      V2

      V5

      Drain

      Configure the system as shown in Figure 2.
   2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v) @ 20°C, 60% / 40% IPA - Isopropyl alcohol / water  (v/v)

@ 25°C, or 70% / 30%  IPA  -  Isopropyl alcohol / water (v/v) @ 25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes.

1. 1. Close  inlet  V1  and   outlet   valve  V6  to

isolate the housing.

Drain all  the  wetting  fluid  from  the upstream side of the  filter  by positioning V5 to direct flow to drain. Adjust the pressure   regulator    to   deliver   200   –

300 mbar of air or nitrogen (DO NOT USE CO2). Slowly open V3. Close V3 when  wetting fluid discharge is no longer evident.

D.Close the housing inlet valve V1 and connect the Automated Integrity Tester at V3 and initiate the automated forward flow integrity test protocol. When prompted, program a stabilisation time of 2 minutes and a test time of 3 minutes.

E.When the test is complete, compare the measured Forward Flow Integrity value against the acceptable limit for the filter cartridge under test.

F.After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the wetting fluid from the housing or adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen. Slowly open V3. Close V3 when wetting fluid discharge is no longer evident. Dry  the  cartridge  before  placing  the  cartridge  in service.

G.Automated Integrity Tester from the housing.

 

Seraflon                                                 FFIT Pressure - bar                  FFIT Specification (ml/min) per 10"equivalent
Part Number	1.11	£ 8.7 (25%/75% TBA/Water) @ 20°C
		£ 35.5 (60%/40% IPA/Water) @ 25°C
		£ 54.0 (70%/30% IPA/Water) @ 25°C

 

 

NOTE : Valid integrity test limits will be obtained when the wetting fluid temperature is maintained  within  ± 2°C and concentration is maintained within ± 2% v/v.

 

Bubble point test

1.Definition

The bubble point is the minimum gas pressure required to overcome the surface tension holding a wetting fluid in  a membrane filter’s largest pore.

The bubble point pressure measurement is only recommended for single 10-inch cartridge filters or smaller.

When more filter area is on line, it becomes difficult to distinguish diffusional flow from the true bulk flow which occurs at the bubble point  pressure. For assemblies with 2 or  more 10-inch equivalent cartridges, diffusion flow or pressure hold measurements are recommended.

The Automated Integrity Tester can be used to perform a bubble point test. When using the Automated Integrity Tester, follow the installation instructions for connecting the unit to the upstream valve as shown in Figure 4. Consult the appropriate literature for the filter cartridge bubble point value for the filter to be used and program this value into the Tester when requested during the test set-up.

 

 

1. Procedure (Manual Testing - Figure 3)

   1. Figure 3 - Bubble Point (Manual Method)

      Pressure Gauge       Pressure                      V3 Regulator                                                              V4             V1                                                                            V6   V2     V5 Drain

      Configure the system as shown in Figure 3.
   2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v) @ 20°C, 60% / 40% IPA - Isopropyl alcohol / water  (v/v)

@ 25°C, or 70% /  30%  IPA  -  Isopropyl alcohol / water (v/v) @ 25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes.

1. 1. Close inlet V1 and outlet valve V6 to isolate the housing. Drain all the wetting fluid from the upstream side of the filter by positioning V5 to direct  flow to drain. Adjust  the  pressure  regulator   to  deliver

200 – 300 mbar of air or nitrogen  (DO NOT  USE  CO2 ).  Slowly   open   V3. Close V3 when wetting fluid  discharge  is no longer evident.

1. 1. Connect a tube from the outlet port V5 to a container of sterile water*.
   2. Open V3. Using the pressure regulator, slowly pressurize the system with air or nitrogen (DO NOT USE CO2 ), raising the pressure 300 mbar per minute. When within 300 mbar of the expected bubble point pressure, make only very gradual 50 mbar increases allowing 5 - 10 seconds between pressure increases to observe evidence of bubbling.
   3. Observe any air flow from the tube connected to the downstream port. A modest flow of small bubbles is diffusion flow

only. When a continuous flow of large bubbles appears, the filter’s bubble point has been reached.

1. 1. When the test is complete, compare the measured Bubble Point value against the acceptable Bubble Point value for the filter cartridge under test.
   2. After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the water from the housing or adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen. Slowly open V3. Close V3 when wetting fluid discharge is no longer evident. Dry the cartridge before placing the cartridge in service.

I.     If the bubble point is less than the recommended value, consider the following questions and re-test if necessary : Was the filter completely wet out ?

Was the correct pore size filter installed ?

Was the temperature of the wetting fluid and filter ambient ?

Was the filter seated correctly in the housing and were the O-rings undamaged ?

 

* It is important  to make  an aseptic connection and to close the outlet port immediately  after the system  has

been integrity tested to prevent contamination.

 

1. Procedure (Automated Testing - Figure 4)

   1. Figure 4 - Bubble Point Test (Automated Method)

      Pressure Gauge       Pressure           Shut-off                                                  V3 Regulator             Valve                                                                                         V4 Filter Housing Automatic       V1                                                                              V6   V2 Drain V5

      Configure the system as shown in Figure 4.
   2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v) @ 20°C, 60% / 40% IPA

-  Isopropyl alcohol /  water  (v/v)  @ 25°C, or 70%

/  30%  IPA -  Isopropyl  alcohol  /  water (v/v)

@ 25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes.

1. 1. Close inlet V1 and outlet valve V6 to isolate the housing. Drain all the wetting fluid from the upstream side of the filter by positioning V5 to direct flow to drain. Adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen (DO NOT USE CO2). Slowly open V3. Close V3 when wetting fluid discharge is no longer evident.
   2. Disconnect the wetting fluid  supply line and allow the wetting fluid to drain from the housing. Leave V5 or V6 open to atmosphere.
   3. Close V1 and connect the  Automated Integrity Tester at V3 and initiate the automated bubble point test protocol.
   4. When the  test  is complete, compare  the  measured  Bubble  Point  value  against  the  acceptable  limit  for  the  filter cartridge under test.
   5. After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the water from the housing or adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen. Slowly open V3. Close V3 when wetting fluid discharge is no longer evident. Dry the cartridge before placing the cartridge in service.
   6. Disconnect the Automated Integrity Tester from the housing.

 

Seraflon                                                                                Minimum Bubble Point Pressure - bar
Part Numbar	1.11

 

Pressure hold test

1. Definition

A variation of the FFIT is the Pressure Hold Test (PHT). Instead of measuring the diffusion  rate  of  gas  across  the membrane, the PHT uses a sensitive pressure gauge to measure the decay of pressure in a closed volume on the upstream side of the membrane as the gas diffuses through the membrane. PHT values are dependent on the volume of the specific filter housing employed, less the volume of the installed cartridges. Therefore, they must be determined on a case by case basis. Please contact SERENE Technical Service for assistance, if necessary.

The Automated Integrity Tester can be used to perform a pressure hold test. When using the Automated Integrity tester, follow the installation instructions for connecting the unit to the upstream valve as shown in Figure 6.

Consult  the  appropriate  Automated Integrity tester literature  for  the  test  pressure  and  PHT  value  for  the  filter  cartridge  to  be  used  or calculate the maximum allowable value using the following equation. Program these values into the Tester when

 

requested during the test set-up.

 

DP      D x Pa

 

The following equation can be used to calculate the PHT value :                =

T         Vhsg

D         = Manufacturer’s maximum allowable diffusion rate for all the installed filters in ml/min (see FFIT specifications) T

= Time (typically 3 minutes) Pa       = Atmospheric pressure

Vhsg = Upstream housing volume (ml) less the volume occupied by the cartridge(s)

DP       = Allowable pressure loss

 

1. Procedure (Manual Testing - Figure 5)

   1. Figure 5 - Pressure Hold Test (Manual Method)

      Pressure Gauge         Pressure                         V3 Regulator                                                                  V4                       V1                                                                                        V6   V2 Drain V5

      Configure the system as shown in Figure 5.
   2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v)

@ 20°C, 60% / 40% IPA - Isopropyl alcohol /  water (v/v) @ 25°C, or 70% / 30% IPA - Isopropyl alcohol / water (v/v) @ 25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes.

1. 1. Close inlet V1 and outlet valve V6 to isolate the housing. Drain all the wetting fluid from the upstream side of the filter by positioning V5 to direct flow  to drain.  Adjust  the  pressure  regulator  to  deliver 200

–  300  mbar  of  air  or  nitrogen  (DO  NOT  USE CO2

).   Slowly open   V3.   Close V3   when   wetting   fluid discharge is no longer evident.

1. 1. Disconnect the wetting fluid supply line and allow the

wetting fluid to drain from the housing. Leave V5 or V6 open to atmosphere.

E.Open V3 and slowly adjust the pressure regulator to pressurise the system to the specified PHT pressure value and

allow the system to equilibrate for a maximum of two minutes.

F.Using a stopwatch, measure the pressure decay for 3 minutes. Calculate the pressure decay over the 3 minute period in mbar/min.

G.When the test is complete, compare the measured Pressure Hold value against the acceptable pressure hold value for the filter cartridge under test.

H.After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the wetting fluid from the housing or adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen. Slowly open V3. Close V3 when wetting fluid discharge is no longer evident. Dry the  cartridge  before  placing  the  cartridge  in service.

I.               If the pressure decay is higher than the specification, consider the following questions and re-test if necessary

: Was the filter completely wet out ?

Was the correct pore size filter installed ?

Was the temperature of the wetting fluid and filter ambient ? Was the stabilisation time adequate ?

Was the test time adequate ?

Was the filter seated correctly in the housing and were the O-rings undamaged ? Are there any leaks on the upstream side of the filter ?

 

1. Procedure (Automated Test - Figure 6)

1. Configure the system as shown in Figure 6.
2. Install the filter in the housing and flow wetting fluid (25% / 75% TBA - Tertiary butyl alcohol / water (v/v) @20°C, 60% / 40% IPA - Isopropyl alcohol / water (v/v) @25°C, or 70% / 30% IPA - Isopropyl alcohol / water (v/v) @25°C) through the filter at a rate of approximately 4 lpm/10” cartridge for a minimum of 2 minutes.

 

 

 

 

 

6

 

1. Figure 6 - Pressure Hold Test (Automated Method)

   Pressure Gauge       Pressure    Shut-off                       Vent              V3 Regulator             Valve                                                                                    V4 Filter Housing Automatic       V1                                                                         V6 V2 Drain V5

   Close inlet V1 and outlet valve V6 to isolate the housing. Drain all the wetting fluid from the upstream side of the filter by positioning V5 to direct flow to drain. Adjust the pressure regulator to deliver  200  –  300  mbar  of  air or nitrogen (DO NOT USE CO2). Slowly open V3. Close V3 when wetting fluid discharge is no longer evident.
2. Disconnect the wetting fluid supply line and allow the wetting fluid to drain from the housing. Leave V5 or V6 open to atmosphere.
3. Close V1 and connect the Automated Integrity Tester at V3  and  initiate the pressure hold test protocol. Close the housing inlet valve V1 and connect the Automated Integrity Tester at V3 and  initiate  the  automated   forward   flow

integrity test protocol. When prompted, program a stabilisation time of 2 minutes and a test time of 3 minutes.

F.When the test is complete, compare the measured  Pressure Hold value against the acceptable limit for the filter cartridge under test.

G.After the test is complete, flush the wetting fluid from the assembly with clean, filtered water and drain the water from the housing or adjust the pressure regulator to deliver 200 – 300 mbar of air or nitrogen. Slowly open V3. Close V3 when wetting fluid discharge is no longer evident. Dry the cartridge before placing the cartridge in service.

H.Disconnect the  Automated Integrity Tester from the housing.

 

 

Water intrusion test

1.Definition

The WIT is only used with hydrophobic filters. The pores of a hydrophobic filter will resist the passage of water up to a certain  pressure.  The  pressure  at  which  water  will  pass  through  the  pores  of  a  hydrophobic  filter  is inversely proportional to the size of the pore.

The WIT offers several advantages over the previously described conventional integrity tests that are usually conducted with an alcohol or alcohol water mixture.

Safety – no flammability issues

Contamination – no wetting fluid or alcohol contamination of product Time – no drying of the filter required before placing back into service

The Automated  Integrity  Tester  must  be  used  to  perform  a  water  intrusion   test.  When   using the Tester, follow the installation instructions for connecting  the  unit  to  the  upstream  valve  as shown  in Figure 7. Consult the appropriate Tester literature for the test pressure and WIT value for the filter cartridge to be used and program these values into the  Tester when requested during the test set-up.

 

 

2.Procedure (Automated Testing - Figure 7)

1. Configure the system as shown in Figure 7.
2. Install the filter(s) in the housing and close all valves.
3. Open V4. Fill the upstream side of the system with water through either V1 or V2. When water emerges from V4, stop the water flow and close whichever valve (V1 or V2) was used to introduce the water to the system.
4. When water stops flowing from V4 close V4.

 

 

7

 

1. Connect the Automated Integrity Tester to the pressurised gas source, open the  shut-off valve, and, using the regulator, adjust the pressure to the Tester to the necessary level for the test being conducted.
2. Close the housing inlet valve V1 and connect

 

 

Figure 7 - Water Intrusion Test (Automated Method)

 

 

 

 

Pressure Gauge

 

The Automated Integrity Tester at V3 and initiate the automated water intrusion test protocol. When prompted, program a stabilisation time of 10 minutes, a test time of 10 minutes and set the volume calculation to type "3".

1. When the test is complete, compare the test result to the WIT specification for the filter being tested.
2. After  the test is complete, drain the water from the housing and place the cartridge in service.

 

Pressure Regulator

 

Shut-off Valve

Vent          V3

MicroCheck 2

V1

V2

V4

Filter Housing

 

V5

V6

Drain

 

1. Disconnect the Automated Integrity Tester from the housing.

1. If the WIT value is higher than the specification, consider the following questions and re-test if necessary : Was the filter dry and free of solvents or surfactants prior to starting the test ?

Was the correct pore size filter installed ?

Was the temperature of the water and filter ambient ? Was the temperature stable during the test period ?

Was the water free of solvents and/or surfactants ? Was the stabilisation time adequate ?

Was the filter seated correctly in the housing and were the O-rings undamaged ? Are there any leaks on the upstream side of the filter ?

 

SERAFLON	WIT Pressure - bar	WIT Specification (ml/min) per 10"equivalent
Part Number	2.76	0.59

 

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