Considerations on Re-Use of Sterilizing-Grade Filters - Pharmaceutical Technology

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Considerations on Re-Use of Sterilizing-Grade Filters
The author examines re-use of hydrophilic- or hydrophobic-membrane sterilizing-grade filters in liquid sterilizing applications.

Pharmaceutical Technology

Definitions of re-use in liquid service

In general, one can consider re-use of sterilizing-grade filters as applying to filtration of multiple batches of product or other process fluid. This approach is consistent with applications of re-use of air, gas, and vent sterilizing filters in multiple batches or campaigns. However, in the case of liquid sterilizing filtration, there are many interpretations of re-use. Each interpretation has different implications on filter performance. Filters can be considered re-used when they are employed for multiple batches in the following instances:

  • Without removal, rinsing, cleaning, sanitization, or resterilization
  • With inter-batch rinsing only
  • With inter-batch rinsing and resterilization
  • With inter-batch rinsing, cleaning, and resterilization
  • Intermittent use with inter-batch drying.

Without cleaning or resterilization. In the first case of re-use, defined as "without removal, rinsing, cleaning, sanitization, or resterilization," the filters are initially sterilized and left in place with no interference as multiple batches of fluid pass through them. Although additional stress on the filter from re-use is minimal with this approach, a significant risk factor is that bacteria from the first batch and subsequent batches, may remain viable on the membrane during the re-use cycles. These bacteria could potentially produce smaller cells while dividing and migrating through the largest pores of the filter media until they contaminate the filtrate and compromise the sterility of later batches. This time-dependent bacterial penetration, sometimes referred to as "grow-through," has been reported for integral 0.2 μm-rated sterilizing-grade filters even for single batches that are run for extended periods of time (> 8 h). The results would be no different if a single batch were simply subdivided into multiple batches of product, each processed through the same installed filter in shorter consecutive periods of time. This risk becomes greater, however, when the filters are allowed to stand unused for additional time between processing of consecutive batches. Risk of time-dependent bacterial penetration cannot be assessed by filter-integrity testing because there is no additional stress on the filter.

With inter-batch rinsing. A second and similar process of sterilizing-grade filter re-use occurs when the filters are subjected to water or other solvent rinse between each use to minimize carryover of process fluid components from one product to the next, or one batch to the next. While this type of re-use benefits from reduced batch-to-batch cross-contamination of process fluid components and may slow the ability of retained bacteria to multiply by removing some process fluid-derived nutrients, the risk of time-dependent bacterial penetration remains. This risk remains because retained viable bioburden can continue to divide even under starvation conditions, forming biofilms comprised of cells and cell-derived adhesive secretions that are difficult to rinse away. If the bioburden load from the previous batch is significant, or a biofilm develops on the filter membrane, there is additional risk of downstream contamination with bacterial byproducts such as endotoxins, where the rinse fluid can stress the retained bacteria.

With inter-batch rinsing and resterilization. The third type of re-use (inter-batch rinsing and resterilization) can limit the risk of extended time-dependent bacterial penetration beyond a single batch processing time and control possible development of biofilm. If the filter is not sufficiently rinsed after each re-use cycle before resterilization and introduction of the next batch, however, the resterilization can degrade retained bacteria and leave increased levels of leachable bacterial endotoxins and other cellular byproducts that can contaminate the subsequent processed batch. This type of re-use also imposes additional physical stress on the filter during resterilization. Most sterilizing-grade filters are qualified by their supplier to withstand several steam autoclave or SIP cycles without compromise to integrity or bacterial retention capability. It should be noted, however, that filter-supplier qualifications are typically conducted on intact filters wet only with water, subjected to multiple laboratory steaming cycles, and then tested. Although indicative of filter robustness, these tests do not necessarily model the additional chemical degradative stresses on the filter that may occur when residual product or cleaning agent is insufficiently rinsed out before subjecting a filter to steaming conditions. The tests also do not take into account that a particular end-user sterilization cycle may be more stressful to the filter than the controlled laboratory sterilizations conducted by the filter manufacturer to support product claims.

With inter-batch rinsing, cleaning, and resterilization. The fourth type of re-use (incorporating inter-batch rinsing, cleaning, and resterilization) further reduces risk of cross-contamination or leaching of retained bacterial byproducts during rinsing and cleaning. Despite the reduced contamination risk, this type of re-use becomes more severe in terms of potential stress to the filter and risk of filter damage that may not be detectable by routine integrity testing. In addition to rinsing out the process fluid with a suitable solvent, this type of re-use subjects the filter to an aggressive cleaning fluid intended to dissolve or degrade retained contaminants. Compatibility of the filter membrane and other component materials must be determined beyond only the batch process fluid in this situation to also consider the cleaning fluids and regimens, cumulative contact time, and so forth. Residual products or cleaning agents retained within the filter due to inadequate rinsing after cleaning and before steam exposure for resterilization can be more aggressive at the elevated temperature conditions of the resterilization process. An example of the potential impact of such conditions is provided in the case study discussed later in this article.

Intermittent use. The fifth category of re-use entails a different form of stress incurred by drying the membrane between batches. Some membranes may be damaged by repeated drying cycles, particularly if dried in hot-air ovens. Residual contaminants, cleaning fluid, or residue can be concentrated within the filter during drying, exerting further chemical stresses on the membrane and compromising its functionality without being detected by routine integrity tests.

In each of these cases where an end user considers re-use to economize on filtration costs, it is incumbent that all process and re-use conditions be properly validated for filter performance and leachables. It is critically important that the filter's ability to retain bacteria and the filter integrity tests' ability to predict filter integrity not be compromised.


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