Considerations in Using "Bubble Point"

Type Tests as Filter Integrity Tests, Part

I.(Brief
Article)(Bibliography)(Technical)
Effect of Test Methodology on Cartridge "Bubble Point" Measurements and
Implications for the Use of "Bubble Point" Type Test as Correlated Tests

The term "bubble point" test refers to a collection of many different test methods. in
this Part 1 of a two-part article, the authors report on the effect of test methodology on
"bubble point" measurements, including those using automated instruments. Results
indicate that "bubble points" measured for the same filter cartridge can vary by ~5-6
psi, depending on the exact "bubble point" type test used and that all tests detected
"bubble points" for the filter cartridges at pressures well above the intrinsic transition
point marking the onset of bulk flow. These results clearly show that the use of
"bubble point" specification as a correlated (critical) test on a process filter is most
valid when the test is performed using the same specific protocol, equipment, and
filter area used to establish the primary correlation in the first place.

Microporous membrane filters have been used successfully for many years to remove
bacteria and particulates from fluid streams (1). Sterilizing filtration has been defined
as the process of removing all microorganisms, excluding viruses, from a fluid stream
using microporous filters (2). Integrity testing of sterilizing-grade filters before and
after use is a fundamental element of sterility assurance (3). The most stringent
integrity test for a sterilizing-grade membrane filter is a bacterial retention test.
Unfortunately, this is a destructive test; the filter cannot be used afterward in a
production process. Intentionally introducing bacteria in a production environment to
perform a bacterial challenge test on a production process filter after use would not be
prudent either. As a result, an important aspect of the use of sterilizing-grade filters is
having a nondestructive physical integrity test that is correlated to the production of
sterile effluent in a bacterial challenge test.

For a nondestructive physical integrity test to be useful, the results of the test must be
able to predict the ability of the filter to remove bacteria. Such a test should also be
easy to perform in a reproducible manner. The physical integrity test primarily
establishes that the process (test) filter is undamaged and is similar to the filters that
have been validated to retain a bacterial challenge under the specific conditions used
by the filter manufacturer when establishing integrity test specifications for that given
filter type. The objective of such a nondestructive physical integrity test has also been
defined sometimes as determining "the presence of oversized pores or defects which
compromise a given filter's retention capability without destroying the filter" (2).

Establishing a filter's microbial retentivity under process- and product-specific

conditions that are different from those used by the filter manufacturer requires
additional validation testing under these user-specific conditions. If such a process-
and product-specific validation has been performed, then the integrity test also
establishes the similarity of the process filter to those filters that haven't been
validated to retain a bacterial challenge under user-specific conditions and in the
user's product.

Contrary to popular belief, the integrity test is not an intrinsic indication of the
retentivity of the filter, nor an accurate measure of the largest pore(s) of the filter. A
set of correlation (validation) data also must exist, documenting that filters that meet
specific criteria when a specific integrity test is performed will produce sterile
effluent. In addition, the characteristics of the membrane filters tested to obtain this
prediction must be used to establish quality control (QC) specifications, which are
consistently maintained in filter manufacturing. The combination of these three
factors -- the bacterial challenge test, the correlated nondestructive integrity test, and
filter manufacturing QC -- allows membrane filters to be used reliably for sterilizing
filtration of pharmaceutical products.

Three major tests are used to determine the integrity of a membrane filter: the forward
flow test, the pressure hold test, and the "bubble point" test (3-5). The basics of these
tests have been reviewed many times in the literature and will not be discussed here
(6-11). These tests are all based on the same physics: the flow of a gas through a
liquid-wetted membrane at different pressures. They differ in the portion of the flow-
pressure spectrum they examine. A fourth test, the water-intrusion test, is used to
determine the integrity of hydrophobic membrane filters and is discussed elsewhere in
the literature (12-14).

Although these integrity tests have been in widespread use in the pharmaceutical
industry, they have been the subjects of renewed interest as a result of the publication
of Parenteral Drug Association's (PDA's) Technical Report No. 26, "Sterilizing
Filtration of Liquids" (2). This report is an educational monograph about sterilizing
filtration technology published by the PDA International Association for
Pharmaceutical Science and Technology. It presents a comprehensive view of the
factors influencing the sterilizing filtration of liquids, including the validation of
sterilizing filtration processes. The document includes sections on filter validation and
integrity testing, which provide guidance on correlating integrity test results to
bacterial retention as well as setting integrity test limits for production-scale filter
cartridges. Although this document was meant to provide recommendations from an
expert industry task force and "not intended to establish any mandatory or implied
standard," its recommendations have been cited by regulators when issuing
insufficiency letters as well as FDA-483s.

PDA Technical Report No. 26 recommends that to ensure that a process membrane
filter cartridge is capable of sterilizing a drug product, the "membranes used for
fabricating process filters must meet or exceed the integrity value established during
product-specific bacterial retention testing" and that the "filter user should be able to
supply such evidence" (2). In other words, the worst-case integrity test value
determined on a membrane disk (usually a 47-mm disk) during validation must be
related to the integrity test value of the process filter with a typically much larger area
(even a single 10-in. cartridge contains 300- to 500-fold more area than a 47-mm
disk). The forward or diffusive flow test cannot be performed on a small-area disk
because the gas flow is too low to measure accurately with current instrumentation.
This has led some to suggest that only a "bubble point" type test, which can be
performed both on small-area disks and larger-area filter assemblies, can be used for
integrity testing of sterilizing-grade filters in a manner consistent with the
recommendations of PDA Technical Report No. 26. In this interpretation, the lowest
"bubble point" tested in product-specific bacterial retention validation on one 47-mm
disk essentially becomes the integrity test specification for the process filters. In other
words, a single "bubble point" determination is being interpreted as an absolute value
without regard to the effects of test methodology and filter area on "bubble point"
determinations.

However, one must note that the term "bubble point" test actually refers to a
collection of many different test methods. This document uses the term "bubble point"
type tests to more accurately reflect the fact that "bubble points" can vary with the test
methodology (i.e., the definition of the end point of such a test, the actual test method
used, the equipment used, or the operator performing the test) and the filter area being
tested (6).

Only very limited information has been published on the effects of test methodology
and filter area on "bubble point" determinations, and these have exclusively focused
on manual determinations (15,19,21). This study is the first comprehensive attempt to
determine the effect of test methodology on "bubble point" measurements, including
those using automated instruments, and to determine the effect of filter area on the
"bubble points" measured by different methods. This study presents the results of
different "bubble point" type tests on several kinds of filters containing various types
of membranes in both high- and low-area configurations. As a result, the data
illuminate several issues that must be considered when using a "bubble point" type
test as a physical integrity test.

In this study, the high-area configuration used was the 10-in. cartridge format with
effective filtration areas ranging from 5 to 7.5 [ft.sup.2] (4650-7000[cm.sup.2]),
depending upon the filter type. The low-area configurations used were typically 47-
mm membrane disks (some larger-area disks were tested for one filter type), which
were carefully removed from the cartridges and installed in disk holders to provide an
effective filtration area of 0.015 [ft.sup.2] (13.9 [cm.sup.2]). For each of these
formats, "bubble points" were determined using four automated instruments and two
manual methods, each of which was performed by two different operators. This Part I
compares the results of the various "bubble point" type tests for each filter type, as
well as with the results of the multi-point flow versus pressure curve (forward flow
spectrum) on these filters