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AUTOMATIC INTEGRITY TESTING OF

AUTOCLAVES INLET FILTERS

M.W.Jornitz

The Water Intrusion Test, based on the use of water as the testing medium, can be integrated to
autoclave processes by using an external pressure sensor. This article discusses the IQ/OQ
instructions and the SOP to conduct the WIT with an external pressure sensor linked with the PLC of
the autoclave, on hydrophobic membrane filters used for the sterile venting of autoclaves.

Principle of the Water Intrusion Test


The Water Intrusion Test (WIT), is a completely non-invasive integrity test for sterilising
grade hydrophobic filters. The principle of the test relys on the fact that membrane filters
designed for air sterilisation duties are constructed from highly hydrophobic materials such as
the ePTFE membrane found in commercially available filters. In this case Sartofluor filter
cartridges were used. The test method involves filling the upstream of the filter housing
including the filter with water, till the airvolume above the water column reaches 2.5 bar. This
pressure of 2.5 bar is also the test pressure, which is applied during stabilization and the test
period. After 10 min. stabilisation, during 10 min. test time, the pressure drop in the air
volume is measured and compared to the max. allowable pressure drop installed into the
PLC of the autoclave. Each 0,2 µm sterilising grade filter cartridge is characterised by a max.
allowable pressure drop value established by correlation to the HIMA Bacteria Challenge
Test (1,2,3,4,5). In this case the pressure drop measured is compared to a max. allowable
pressure drop established by the max. allowable intrusion and the upstream air volume
according to the formula bellow :

max. ∆P = max. WIT x Vm Equation 1

P0 x t

where WIT is the intrusion rate in ml/min,


∆P the pressure drop in mbar, Po the atmospheric pressure,
Vm the upstream gas volume in ml, and t the test time in min.

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The pressure drop is caused by the intrusion of water into the pores of the PTFE
membrane can be accurately measured by a sensitive pressure sensor fitted on the top part
of the filter housing. The upstream volume (Vm) imposed by the compacting of the cartridge
at 2,5 bar (standard test pressure) depends on the cartridge size, the pipework configuration
on the top part of the housing and the filling conditions of the filter assembly. That means that
a filtration system filled with a reproducible process, will produce a constant air volume. The
upstream volume determination and its reproducibility are the key points of the validation
procedure proposed in this article.
Qualification of an equipment designed for automatic integrity testing

Many autocalves vent filters are positioned such that access for integrity testing is
extremely difficult and manual WIT procedures under these circumstances are not so
practical. This is the main reason why such equipment requires a fully automatic method
which only involves the measurement of the pressure drop during the test. In order to
calculate the maximum pressure drop allowed in a filter system, the airspace volume above
the water must be determined by mean of an integrity test device measuring the upstream
volume, in this case a Sartocheck 3. The qualification of a new plant designed for an
automatic Water Intrusion Test will therefore focus on the following objectives :

Determination of the upstream volume : The upstream volume (VM) measured by


Sartocheck 3 also takes into account the inlet volume of Sartocheck and the outlet pressure
tubing fitted to the housing (Vmo). The real upstream volume (Vm) when using a pressure
sensor is then calculated by substracting Vmo from VM ( see table A).

Determination of the maximum allowable pressure drop : The maximum allowable


pressure drop for a filter assembly is calculated by using the equation 2 resulting from the
equation 1 :

∆Pmax = ( WITmax x Po x t ) / Vm Equation 2

where WIT max is the Intrusion rate limit value established in correlation
with the HIMA bacteria challenge test, and Vm the upstream volume in ml ( VM - Vmo.).

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IQ/OQ instruction and establishment of the validation certificate : The tests required for
the validation of the filter system shown in figure 1 are conducted 3 times on 3 cartridges
from different batches according to the following procedure :
• Determination of Vmo
• Waterfill of the filter housing: open V1, V2, and V3
• Vent the compressed air volume produced during the filling operation : close V1
and V2, open V4
• Connect Sartocheck 3
• Start a WIT program ( printing of the VM, pressure drop and WIT values )
• Calculate Vm = VM - Vmo
• Calculate the maximum allowed pressure decay (equation 2)
• Compare the pressure drop measured by sartochek 3 and the pressure sensor
• Disconnect Sartocheck 3
• Drain the housing : open V2 and V7
• Dry the cartridge : close V2 and V7. Open V3, V5 and V6 during 10 minutes.

Table A shows the results obtained for the test set up illustrated in figure 1. This document is
supplied as a qualification document for the individual filter assembly.

cartridge N° 5181507T9 A 5181507T9 B 5181507T9 C MEAN


parameters test 1 test 2 test 3 test 1 test 2 test 3 test 1 test 2 test 3 VALUE
Vmo at 2.5b
sartocheck 3 33 33 33 33 33 33 33 33 33 33
in ml
VM at 2.5b
sartocheck 3 57 59 59 60 56 60 62 58 58 59
in ml
Vm in ml
Vm = VM - Vmo 24 26 26 27 23 27 29 25 25 26
DPmax in mbar
equation 2 167 154 154 148 174 148 138 160 160 156

Table A : Determination of the maximum allowable pressure drop. This data is installed in
the software of the machine as the limite value for an integer filter.

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PLC Vmo sartocheck

air VENT V4
4 bar PI

V3
V6

CHAMBER
V1 V7 V2 V5

pressure
regulator DI
2,5 bar WATER
20 °C

Figure 1 : Test set up for the IQ / OQ operation of an automatic WIT.


5 ’ stainless steel housing ( 332019P15TT112A )
Sartofluor mini cartridge - 2000 cm2 - 0.2 µm ( 5181507T9B )

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WIT on autoclaves inlet filters.

In the case of a standard sterilizer, the WIT has to be performed after the steam
sterilisation of the filter and prior to the autoclaving cycle as described in the following
sequence :

∗ Sterilisation of the filter during the sterilisation cycle


∗ Drying of the filter
∗ Integrity testing by the Water Intrusion Test

SOP on a standard autoclave


Steam sterilizers used for the sterilisation of for example drug products or equipment, are
equiped with 0,2 µm air filters to allow an aseptic vacuum break at the end of the process.
The hydrophobic filters used for this purpose are steam sterilised in line. The WIT is a
suitable procedure to assess the integrity of the filter immediately after the steaming
operation. After the SIP, the system is cooled down to ambient temperature. Once the filter
assembly has reached a constant temperature, the process control system can start the
filling and the testing procedures ; the different steps of the process are presented on Figures
2 and Table B.

Steam sterilisation of the filter : the filter is steam sterilised during the autoclaving cycle. The filter
housing is designed with a condensate chamber base to allow the upstream condensate to be
collected. The critical sterilisation temperature is controlled on the downstream side of the filter and
the pressure regulation is achieved by the steam supply pressure regulator at 1,5 bar for 121 °C.
Cooling procedure : Before starting the WIT, the filter assembly must be cooled down and dried
which can be done by an air flow through the cartridge or a vacuum pump. The filter is then prepared
to be tested, the upstream side of the housing can be filled with water and the WIT is performed
during 20 minutes.
Water Intrusion Test : During the 10 minutes stabilisation period the head pressure is maintained at
2,5 bar through via a pressure regulator. The pressure decay in the housing is measured by the
pressure sensor and transduced to the process control system. After testing, the water is drained out
and the filter is dried again, if applicable.

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Steam
PI

V9 V1
Vent
Vm

V7 V4

Cham ber

com pressed V11


air
4 bar V8
V6 V5
V10 V3

Pressure W ater
R egulator
2.5 bar
Vacuum
pum p V2

Condensate C ondensate

Figure 2 : Automatic WIT on autoclaves inlet filters.

WIT
PHASE Chamber Sterilisation Drying Draining Drying
cooling vacuum
VALVES evacuation Cycle of the filter break Filling Test of filter of the filter

V1 Closed OPEN Closed Closed Closed Closed Closed Closed

V2 Closed OPEN Closed Closed Closed Closed Closed Closed

V3 OPEN Closed OPEN Closed Closed Closed Closed OPEN

V4 OPEN OPEN OPEN OPEN OPEN Closed Closed OPEN

V5 Closed OPEN Closed Closed Closed Closed Closed Closed

V6 Closed OPEN Closed Closed Closed Closed OPEN Closed

V7 Closed Closed Closed OPEN Closed Closed OPEN OPEN

V8 Closed Closed Closed Closed OPEN Closed Closed Closed

V9 OPEN OPEN OPEN Closed OPEN OPEN OPEN Closed

V10 Closed Closed Closed Closed OPEN Closed Closed Closed

V11 Closed Closed Closed Closed Closed Closed OPEN Closed

PUMP ON OFF ON OFF OFF OFF OFF ON

Table B : Standard Operating Procedure.

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CONCLUSION

It can be concluded that the use of a sensitive external pressure sensor enables fully
automatic in-situ testing of hydrophobic membrane filters. Being installed on top of the
housing, temperature influences are minimized. Furthermore the use of the sensor technique
enables the direct link to the PLC of the specific systems and therefore makes the test fully
automatic. This fact makes the filter test highly accurate and reproducible, additionally it is
practical and easy to perform. Collected experience with different installation verified these
factors. Moreover filter vendors technical services can support equipment manufacturers in
setting up the right filter assembly, in selecting adapted pressure regulators and pressure
sensors required for the reability of the automatic testing and will provide IQ/OQ instructive
guidelines together with qualification documentation. The W.I.T., conducted automatically, in-
situ, after the sterilisation, without putting the integrity of the plant at risk, meets all the
requirements of the biopharmaceutical industry.

References
1. Health Industry Manufacturers Association Document Nr 3, Version 4 (April 1982)
2. T.H. Meltzer et al, « The Hydrophobic Air Filter and the Water Intrusion Test », Pharm. tech. Sept. 94
P.76 - 84.
3. Michael Dosmar et al, « The Water Pressure Integrity Test for Hydrophobic Membrane Filters » J.
Paren. Sci. Tech 46(4), 102-106 (1992).
4. P. Waibel, « Integrity Testing Hydrophobic Membrane Filter Cartridges with the Water Intrusion
Test », Parenteral Drug Association Meeting, Chicago, March 1994.
5. Validation guide of SARTOFLUOR GA.
6. S.R. Parks et al, « A system for testing the effectiveness of microbiological air filters»European J.
Paren. Sci. Vol. 1 N°. 3 1996
.