A broad issue for single-use filter users and suppliers across Europe and North America is the pre-use integrity testing of
sterilising filters in single-use systems. The subject has received considerable discussion lately, with differences in regulatory
requirements and risk assessments being considered. The properties and suitability of gamma-radiation sterilised single-use
filtration systems, and the flexibility of these designs, were not considered when regulatory guidelines were written, but
now provide additional options for manufacturers. At the moment, there is no harmonised guidance on the pre-use integrity
testing of sterilising filters. FDA does not formally require it, stating in its aseptic processing guidance that "Integrity
testing of the filter(s) can be performed prior to processing..." (1).
In contrast, the EMA states in EU GMP, Annex 1 that, "The integrity of the sterilised filter should be verified before use..."
(2). So, while integrity testing after use is a common requirement, pre-use testing, whether before or after sterilisation,
is not a universal requirement. This situation is further complicated in Europe where different national authorities apply
EU GMP differently. Some European inspectors demand that pre-use, poststerilisation integrity testing be conducted because
it is specifically required in EU GMP, while others are more flexible and do not require it.
The topic was discussed during a workshop at the May 2012 PDA–PIC/S conference in Geneva. Arguments were expressed both for
and against testing, but insufficient time was allotted to fully explore the technical issues and no resolution could be drawn.
This situation leaves manufacturers with inconsistent international regulatory expectations, and more work is needed to ensure
that inspectors have a common understanding.
The issue is relevant to single-use disposable technology because EMA's published rationale for requiring pre-use, poststerilisation
in integrity testing is based on the risks of filter damage or other loss of integrity during high-temperature sterilisation
processes, such as steam-in-place or autoclaving.
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EMA states, "The filter sterilisation process may be physically stressful for the filter. For example, high temperatures during
the process may cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater
than 0.2 μm in size. The performance of a filter can improve with use, as particles begin to block individual pathways and
remove larger pathways that smaller particles could successfully navigate" (3).
Although such filter distortions have been reported for some prototype membranes, commercialised sterilising-grade filters
are validated to maintain integrity and not undergo fluid path distortions (enlargement) during steam sterilisation that might
enable initial bacterial penetration. Furthermore, sterilisation by gamma irradiation, which is typically applied to single-use
filtration systems, can be considered a less stressful process (low heat, low pressure), and has not been implicated in the
distortion of fluid pathways or loss of filter integrity so long as the membrane material is compatible with gamma radiation
and that gamma dosage does not exceed specified maxima. These parameters are typically certified with every filter or single-use
system lot. Many users question whether the possible risk of introducing contamination by performing a pre-use, poststerilisation
integrity test on a sterile filter in a gamma-sterilised single-use filtration system is higher than the risk of not performing
The decision on whether or not to perform pre-use integrity testing should be made on a risk-assessment basis. Many users
consider the filter manufacturer's integrity test prior to release to be sufficient confirmation that the filter is integral
as made and is ready to use upon installation and sterilisation. It is rare for users to experience filter-integrity failures
post use, so any user pre-use testing, before or after sterilisation, seems unnecessary. Experience with steam-sterilised
filters, however, suggests that most instances of post-use filter-integrity failures, when they do occur, are due to gross
filter damage incurred during poorly controlled steam-in-place or occasionally autoclave cycles. Where steaming processes
are not well characterised and controlled to avoid filter damage, damage (if it occurs) can be recognised prior to product
filtration if a pre-use/poststerilisation integrity test is performed.