To FIT or Not to FIT, That is the Question - A risk-based approach for real-world situations. - BioPharm International

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To FIT or Not to FIT, That is the Question
A risk-based approach for real-world situations.


BioPharm International
Volume 22, Issue 11

ABSTRACT

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.


Millipore Corp.
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.

USING FMEA TO ASSESS RISK

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.


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