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There is no harmonized guidance on pre-use integrity testing of sterilizing filters, prompting discussion among users as to whether such testing is necessary.
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 test.
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.
For gamma presterilised single-use systems, where the filter manufacturer has already validated that gamma irradiation does not compromise filter integrity, the risk of filter damage during sterilisation appears even more remote. The primary risk of product loss due to integrity failure of gamma-sterilised filters in a single-use filtration system would most probably be from filter damage incurred after sterilisation, for instance, during shipping, handling, and system installation. The lower risk of filter damage and product loss in this case may be further ameliorated if the process is a bulk filtration and, in the event of post-use filter integrity failure, refiltration is qualified and documented in the SOP.
Alternatively, a redundant filtration scheme may be used to minimise risk of product loss in the event of a filter integrity failure discovered only postuse. Finally, the cost of the drug product or process fluid may be sufficiently low that an infrequent disposal is considered inconsequential (e.g., buffers and inexpensive small-molecule drug products).
Although the potential for product loss due to filter nonintegrity may be very low, the effect can be great if the product is expensive and cannot be refiltered, such as with biopharmaceuticals and vaccines. Avoiding catastrophic batch loss, as well as possible product shortages, is a justifiable reason to perform pre-use, poststerilisation filter-integrity testing on single-use filtration systems.
Another advantage of single-use systems compared with stainless steel is that versatile system designs can readily accommodate the necessary flushing to prewet filters before the pre-use integrity test. Stainless-steel tanks for the supply and collection of wetting liquid, which must be cleaned and steam sterilised in place, or autoclaved and aseptically connected, can be easily replaced with preassembled flush supply and collection bags that are gamma sterilised in place. Sterilisation validation is provided by the supplier. Where product is used to prewet the filter for integrity testing, even the side-flush collection bag can be eliminated in some cases. Additional schemes are also available to enable flushing the filter to reduce leachables and any particles that may be present on the downstream side of the filter, along with wetting them for pre-use integrity testing. Filters can be flushed with product to wet the filter, reducing filter leachables and potential particles while recovering the product to maximise yield.
Jerold Martin is senior vice-president of Global Scientific Affairs at Pall Life Sciences, Port Washington, NY (US), and chairman of the Board and Technology Committee at Bio-Process Systems Alliance. Tel. +1 516.801.9086 firstname.lastname@example.org.
1. FDA, Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice (Rockville, MD, Sept. 2004).
2. EC, Guide to GMP, Annex I — Manufacture of Sterile Medicinal Products (Brussels, Belgium, revised Feb. 2008, effective Mar. 2009).
3. J. Wood, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012).
4. J. Martin, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012).
5. E. Mahajan et al., Pharmaceutical Engineering, 32 (3), 54–56 (2012).
6. K. Lear, presentation at the IBC Single-Use Conference (San Francisco, CA, Jun. 4–6, 2012).