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Conducting a FMEA analysis is a good first step in a risk-based approach for determining the need for a filter integrity test.
Throughout the industry, there are questions regarding when to integrity test filters in the purification and buffer preparation areas. This includes liquid filters as well as vent and air filters. The requirement to warrant a filter integrity test (FIT) is based on compliance with the validated claim of microbial retention and criticality of the filter performance. Filters with no validated retention claim must be evaluated for integrity testing based on the level of risk to product quality and business risk. An approach for determining risk based on filter criticality and location was developed and adopted in a high-volume biopharmaceutical manufacturing plant. The results showed that certain filters might present a high risk to product quality after failure and warranted integrity testing.
Membrane filters are used to remove particulates from liquids or gases to maintain a high-quality product. Removed particulates can include debris from processing as well as microbial or viral particles. Filter integrity testing is a means by which the integrity of a used filter or filter assembly is confirmed, providing a high degree of assurance of proper filtration.
Filter integrity tests (FITs) measure flow or pressure drop across a wetted filter. The acceptance criteria provided by the vendor is based on a correlation between the measured parameter and bacterial retention. For a sterilizing grade filter, passing the integrity test ensures that the filtered product can be claimed sterile, provided the following two conditions are met: (1) the bacterial load was less than 107 per cm2 of the filter area and (2) a validation study was successfully completed to demonstrate retention in the representative feed stream.1 For the cases where such validation was not performed, passing a FIT result gives a high degree of assurance that the filter performed as expected (bioburden reduction), but the pool cannot be claimed as sterile. Therefore, the requirement to warrant a FIT must be based on: (1) compliance with the validated claim of microbial retention and (2) criticality of the filter performance.
In an ideal world, we would like to integrity test all membrane filters after use, and thereby ensure that each product pool has met proper sanitary standards. But, is this practical or necessary? FIT requires valuable time and resources. If all filters are integrity tested, costs can add up quickly. On average, integrity testing of one filter housing takes two operators approximately two hours. Assuming $75 per hour for an operator's time and about 40 housings for testing (liquid and vent), an average batch costs $6,000 for FIT. A process running once per week would incur $312,000 for resources or the equivalent of two full-time employees for integrity testing alone (cost information is for illustration only). Filters that have been validated for viral or microbial retention require an integrity test. However, those with no validated retention claim may or may not need integrity testing based on the business risk associated with the processing step.
A risk-based approach to determine when a filter must be integrity tested can be performed by conducting a failure mode and effects analysis (FMEA). An FMEA may include application categories such as tank-vent filtration, buffer filtration, pre-drug substance (DS) filtration, and DS filtration. Each category is assigned a risk number based on severity, frequency (occurrence), and detectability of filter failure. The combined score from the analysis for each system can be used to determine the relative priority level for performing a FIT.
The FMEA approach to determine the risk level associated with the integrity testing of filters was used with the ultimate goal of optimizing cost and resources for FITs in a high run-rate routine manufacturing scenario. The FMEA session comprised a cross-functional team including members from manufacturing, process development, and quality departments.
Each filter used throughout the purification and buffer preparation areas (liquid and vent filters) were evaluated based on the following criteria:
Occurrence is based on the number of failed integrity tests historically observed (based on filters previously integrity tested). Steaming in place (SIP) of filters increases the probability of a breach because of potential issues with the SIP process. If SIP is conducted for filters, the occurrence scores must be higher in comparison to filters for which SIP is not done. Installation practices also could play a role. If more than one procedure is used for installation or if the training is not adequate, FIT failure occurrence could be higher.
The primary way to detect a nonintegral filter is through a FIT. A large gross failure may be detected by monitoring differential pressure across the filter, but any small breach is unlikely to be detected without an actual FIT being performed on the filter. Therefore, filters that are not tested are likely to have low detectability scores.
The filters used in the FMEA case study presented here were routinely sterilized by SIP. The filters were installed using procedures that are very similar to each other and the personnel involved in the installation were uniformly trained. This resulted in the same occurrence rating across all of the filters evaluated in the case study. Similarly, it was assumed that none are currently integrity tested and there are no other means to detect a filter breach. Therefore, the detectability of a filter failure because of integrity breach is low and the same rating was applied across all filters evaluated. In a different scenario, the occurrence and detection scores may not be the same if differences exist in SIP practices, installation procedures, personnel training, or if alternate means for detecting a breach in associated filters exist.
The severity score of a filter failure is based on the criticality and risk associated with the particular filtration step. In this case study, severity of failure varied widely across the filters evaluated. Filters validated for bacterial and viral removal scored very high on the severity scale, whereas those used as guard filters stationed between unit operations scored lower. Because the occurrence and detection scores were the same between filters, severity became the determining factor for differentiation in risk. In a different scenario, all three parameters may vary from filter to filter. The risk level is then determined by the product of the individual scores. This product is referred to as a risk prioritization number (RPN).
In this case study, additional rigor was placed on assigning the severity score. A rating system for severity was developed to assess each filter based on criticality of filter performance. The criticality was dependent on two factors: (1) filter location (or the location where the filter is being vented if the filter physically is located away from where it is vented) and (2) the processing step where the filter is being used. For this case study, to evaluate all filters from an equal starting point, it was assumed that no filters currently are being integrity tested.
The filter location is important because filters serve as barriers against microorganisms entering tanks. The risk of contamination from a breached filter varies depending on the particulate counts in the room in which the equipment is vented or exposed. Buffer and product filters are typically housed and vented in a class 100,000 or 10,000 area while vent filters may or may not be vented to classified areas.
Virus filtration is a validated filtration process that requires integrity testing of all associated filters. A failure closer to the final DS or drug product poses a higher risk of affecting the product compared to a failure occurring further upstream in the purification process where there are additional filtration or removal steps.
A risk rating system (scale of 1–5) addressing the two critical factors associated with severity (filter location and filtration processing step) can be developed as shown in the example in Table 1. A rating of five is considered highest risk, while a rating of one is considered lowest risk.
Table 1. Examples of critical factors with associated ratings
Table 2 shows an example of how the rating system is used to assess filters used in the buffer preparation and purification areas in a manufacturing facility.
Table 2. Filtration step severity ratings for each critical factor (overall rating = location of filter x processing step)
A confirmation of filter integrity in the form of passing a FIT result is required for any filtration process that has been validated for either sterility or virus removal. The virus filters and drug substance final filters, both validated for retention, received overall severity ratings of 15 and 10, respectively. These filters typically are validated for virus or microbial retention and require post-use integrity testing as a confirmation of either viral reduction or sterility. Therefore, in this case study, an overall severity rating of 10 was chosen to be an appropriate cut-off to determine when a FIT must be performed. This severity rating cut-off can vary depending on the level of risk a manufacturing facility is willing to take.
The decision to perform a pre-use integrity test on filters is based on risk associated with the processing step. This is a business risk rather than a compliance risk. There currently are no regulatory requirements for pre-use integrity testing. In some cases, however, it is recommended to perform a pre-use integrity test to reduce risk and build quality into the process. A pre-use test that identifies a filter breach or an installation issue may help avoid costly re-processing or discard of a valuable drug substance intermediate after post-use integrity failure (e.g., in the case of virus filtration). Pre-use integrity test recommendations must be evaluated on a case-by-case basis to determine if the business risks are high enough to adopt them. If there are resource constraints with performing a pre-use test and the risk is evaluated to be low, a pre-use test may safely be omitted.
Vent filters are one class of filters where a pre-use test may be valuable. Performing a pre-use integrity test will confirm proper installation of the filter. When the filter is left in place and confirmed integral, vendor data (e.g., steam hours) can be used to justify multiple uses if business risk is assessed to be low. Significant cost savings from resource and filter costs could be realized.
Figure 1 shows a decision tree for determining whether or not a FIT is warranted. It can be used to assess the necessity of pre- and post-use FIT based on regulatory and quality risk as well as business risk.
Figure 1. A decision tree for determining whether or not a filter integrity test (FIT) is warranted
A post-use integrity test is required for filters that are validated for microbial or viral retention. However, filters with no validated claim of retention must be evaluated for integrity testing based on risk. Conducting an FMEA is a good first step toward a risk-based approach for determining the need for a FIT. If needed, filters can be further evaluated based on filtration criticality, filter (or vent) location, and the processing step where the filter is being used. If FITs are limited to only those steps, which are validated and those potentially posing high risk to product quality or high business risk, time and resource needs can be dramatically reduced. With the biopharmaceutical manufacturing industry focusing on operational excellence and cost optimization, decreasing nonvalue-added activities such as low-risk filter integrity testing is highly desirable.
Katherine Chaloupka is a senior engineer, Naveen Pathak is a principal engineer, and Sourav Kundu is the director of process engineering, all in the process development department at Amgen, Inc., West Greenwich, RI, 401.392.4391, firstname.lastname@example.org
1. US Food and Drug Administration. Department of Health and Human Services. Guidance for Industry. Pharmaceutical cGMPs. Sterile drug products produced by aseptic processing—current good manufacturing practice. Rockville, MD; 2004 Sept.
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