Guidance Note USD 2301

Integrity Testing a Filter in a

Pre-sterilized Single-use Bag System
 Introduction
Filter capsules are increasingly used in pre-sterilized single-
use systems that include bags and tubing for
biopharmaceutical applications. Integrity testing the filter
to meet regulatory requirements is an important
consideration for these systems.

As single use filter systems are predominantly customized

to meet process requirements and may be used in many
different applications, there is no single solution for
integrity testing the filter. This guidance note is intended
to provide guidance on the different options available.

Pre-use Test and Post-use Test or Post-use Test Only?

While regulatory guidelines strongly recommend pre-use filter integrity testing to enhance the safety of
filtration processes in critical applications, biopharmaceutical companies can also benefit economically
from this practice.

Pre-use integrity tests are performed to ensure that the effectiveness of sterilizing grade filters has not
been compromized during shipping, operator handling or sterilization prior to use. In applications where
high value fluid products are used, pre-use filter integrity testing can prevent the loss of costly product
batches by alerting operators to a failed filter prior to use.

A risk assessment should be performed to determine whether the filter must be tested prior to use. In
applications where the filter is used to sterilize product prior to filling, both EC and US GMP require
that the filter is integrity tested pre- and post-use(1), (2). In other applications where single use systems are
used, for example for preparing buffers for chromatography columns or media for fermenters, regulations
may not require a pre-use integrity test and the decision whether to perform a pre-use integrity test or
not should be based on economic considerations.

Where a pre-use filter integrity test is not required, the filter can be disconnected from the single use
system after processing is complete and simply integrity tested off-line.

(1)
The EC GMP guide for Aseptic Processing says that: “The Integrity of the sterilized filter should be verified before use and should be con-
firmed immediately after use by an appropriate method”
(2)
FDA Guidance – Sterile Drug Products Produced by Aseptic Processing
“Normally, integrity testing of the filter is performed prior to processing, after the filtration equipment has already been assembled and
2 sterilized.”
“It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the
filtration.”
 Figure 1 Palltronic® Flowstar unit testing a capsule off-line

REMOTE
VENT VALVE

Pre-use Test Required

Where a pre-use test is required, consideration should be given to:

• Selection of wetting liquid for the integrity test

• Procedure for wetting the filter and collection of the flush liquid

• Maintaining sterility of the system

• Installation for performing the integrity test

Selection of Test Liquid

Standard filter integrity test parameters are usually supplied for filters wet with water for injection for
hydrophilic filters used in liquid applications and typically 60% (v/v) isopropylalcohol (IPA)/40% (v/v)
water for hydrophobic filters used in air, nitrogen or vent applications. Integrity test parameters for other
wetting fluids including product can be provided by filter manufacturers.

Most single use system applications are for liquid filtration. Vent filters are not required for systems with
bags, since the bags are empty and do not require venting. Air, nitrogen or vent filters can be required
for disposable bioreactor applications and could be integrity tested, following procedures outlined below.

The benefits of product wet integrity test parameters include:

• No need to wet the filter with water before testing and may still need to flush the filter to
reduce extractables

• No need to remove the integrity test fluid before processing the product.

In addition, when product is used as the wetting fluid for a post-use test, there is no need to flush the
product-wetted filter with water before testing.
3
 When product wet integrity test values can be used, the system shown in Figure 2 could be employed
with the following protocol. For this example, the filter is attached to a disposable container (bag). The
process fluid is filtered and stored in the bag. The bag can be used for pre-use integrity test as well as for
storage of filtered fluid.

Pre-use Test Protocol for Pre-sterilized System

The following outline of pre-use filter integrity test steps, which corresponds to Figure 2 below, provides
a simple and efficient method of protecting critical or high value products.

1. Open clamp 1 to product bag.

2. Flush filter with sufficient product to wet the filter for the integrity test.

3. Attach an automated integrity test instrument to the upstream side of the filter. Perform an integrity
test using the test limits recommended by the filter manufacturer for that filter, fluid and test gas
combination. During the stabilization phase, fluid remaining on the upstream side of the filter will
be forced through the filter and collected in the product bag.

4. System is ready to process the remaining product.

Figure 2

PRODUCT
PRODUCT
CLAMP BAG

FILTER

4
Integrity Test Type
Filter integrity tests are performed using Forward Flow or Bubble Point tests. With either test, it is
important that steps be taken to evaluate the possible effects of filter failure because significant pressurization
of the product bag could result in a bag failure. A Forward Flow test is generally preferred because it
quantitatively measures the diffusive flow as well as flow through any open pores in a wetted membrane
filter and performs the test at a defined test pressure. For an intact filter, the gas flows are relatively small.
This enables the supplier to determine and design the test system for maximum system pressure and
downstream gas volumes.

If the filters are to be tested by Bubble Point test, the maximum system pressure will be unknown because
the test pressure will increase until the bubble point is detected. In addition, when the bubble point is
reached, very high gas flow passes through the filter which must be managed within the downstream sterile
environment.

Venting On the Downstream Side

If the filter fails a Forward Flow test or if a Bubble Point test is preferred, bulk flow of test gas passes into
the product bag on the downstream side. Pressurization of the bag can be observed by an operator and
the test stopped before the bag failure point is reached. Alternatively, a vent filter could be fitted to the
downstream side of the system as shown in Figure 3.

Vent filters typically used in pharmaceutical processes are made from PVDF membranes (for example
Pall® Emflon® II filters) or PTFE membranes (for example Pall Emflon PFR filters). We recommend the
use of a vent filter with a gamma tolerant membrane, for example Pall Emflon II filters as PTFE is not
stable to gamma irradiation and therefore not suitable for use in a gamma irradiated pre-sterilized
disposable system.

Figure 3

PRODUCT
PRODUCT
CLAMP BAG

FILTER

VENT
FILTER

5
 A Pre-Use Test Using Water or Solvent Wet Integrity Test Values
Where an integrity test is not performed using product as the wetting fluid, a flush bag on the downstream
side can be used to collect the fluid required to wet the filter for the integrity test.

The following outline of pre-use filter integrity test steps, which corresponds to Figure 4 below, provides
a simple solution to wetting the filter with fluid, which is not product, prior to processing.

1. Ensure that clamp 1 is fully closed. Open clamp 2 to the flush bag.

2. Flush filter with the wetting solution. The flush volume and wetting fluid may vary depending on
filter type and size. Collect used flush fluid in the flush bag.

3. Attach an automated integrity test instrument to the upstream side of the filter. Perform a Forward
Flow integrity test using the test limits recommended by the filter manufacturer. During stabilization
phase, fluid remaining on the upstream side of the filter will be forced through the filter and
collected in the flush bag.

4. Drain any residual wetting solution in “T” connector into the flush bag.

5. Close clamp 2 to the flush bag.

6. Open clamp 1 to process bag. System is ready to process product. (Note: If product dilution is a
concern, a small quantity of product can be directed to the flush bag before collecting product in
the product bag.)

Figure 4

CLAMP 1
“T”
PRODUCT
CONNECTOR
PROCESS
BAG

FILTER

FLUSH
BAG
CLAMP 2

6
Conclusion
The decision tree below provides a guide to choosing a simple method to integrity test a filter in a pre-
sterilized disposable system. As most systems are customized to meet individual process requirements,
there is no single method or solution for testing the filter. Further information and guidance can be given
by your local Pall office.

Figure 5

PRE-USE NO
INTEGRITY FIGURE 1
TEST

YES

WETTING PRODUCT FIGURE

FLUID 2 OR 3

NOT PRODUCT

FIGURE 4

7
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10.2004