There are three procedures available to carry out filter integrity testing: the bubble point test (BP) and the Forward Flow test (FF), when gas flow is measured indirectly by pressure changes, the pressure hold test or pressure decay test.
How Is Filter Integrity Testing Conducted?
There are three procedures available to carry out filter integrity testing and these are primarily chosen based on the filter membrane material. Commonly used test procedures for filters with hydrophilic membranes are the bubble point test (BP) and the Forward Flow test (FF), also known as the diffusive flow test or, when gas flow is measured indirectly by pressure changes, the pressure hold test or pressure decay test. The basic condition for the tests is complete wetting of the filter membrane pores utilizing a wetting fluid such as water, buffer, or the product for filtration. For hydrophobic membranes that will not wet with water, a low surface tension liquid such as a mixture of alcohol and water, is required. An alternative test method, that can be used for filters with hydrophobic membranes, avoiding use of organic solvent in the process, is the Water Intrusion test (WIT), also known as the water flow test.
A bubble point test is traditionally used to test small filter assemblies such as filters installed in a disc holder, cartridge filter housing or capsule. When air or nitrogen pressure is applied to the wetted membrane incrementally, the gas flow across the membrane at each pressure stage is measured. As the pressure increases it will reach a point at which it exceeds the capillary forces of the largest pores in the filter membrane. The automated test equipment will measure the increase in air flow as the wetting liquid is expelled and bulk gas flow occurs. This value is the bubble point and will define a pass or fail when compared to literature values for the filter/membrane. The strength of the bubble point test is its ability to identify pore sized related defects on membranes with a small surface area.
In comparison, the Forward Flow test is a measure of diffusive gas flow across a wetted filter membrane at constant air or nitrogen pressure. The gas flows across the wetted filter membrane by diffusion due to the difference in pressure across the membrane. A pass or fail is easily measured with automated test equipment, with defects being recognized by an increase in flow values beyond a validated maximum.
The Water Intrusion test is used for filters with hydrophobic membranes that cannot be wetted by water but are instead completely covered with water. When placed under pressure using air or nitrogen the penetration and passage of water is repelled by the membrane. However, a very small quantity of water will evaporate and pass through the membrane as water vapor. This low flow is measured by the automated test equipment with increased water flow beyond a validated maximum being an indicator of a non-integral filter.
These three simple, non-destructive tests can be effectively determined with the same automated test equipment, giving opportunity to ascertain filter integrity for a wide scope that can encompass not only a specific manufacturing process, but provide value within a whole manufacturing facility.
When Does Filter Integrity Testing Become a Consideration?
Clearly the progression to commercialization brings with it a necessity to conduct filter integrity testing based on compliance with Good Manufacturing Practice. Despite this necessity, the simple reality is that filter integrity testing mitigates risk, preventing product loss and protecting the financial investment when manufacturing high valued biopharmaceuticals. Most importantly however, is the knowledge that post-use filter integrity testing confirms the performance of the sterile filter to produce a sterile final drug product, giving assurance for patient safety. It is true to say that biological processes account for a very high number of new pharmaceutical products. Although terminal heat sterilization of injectable and other sterile drug products within their final container is the preferred choice, in most cases, this is not possible due to the heat sensitivity of biological products. As such, for many biopharmaceuticals, regulatory authorities accept cold sterilization as a method of choice with confirmation of filter integrity becoming a pivotal point in batch release. Integrity testing of a sterilizing grade filter utilized within a biopharmaceutical process is essentially a necessity to ensure that a filter can fulfill its task or has fulfilled it. With the known sensitivity limitations of compendial sterility tests, filter integrity is a critical control point contributing to the confirmation and release of a drug product as sterile.
The good news is that with modern automated equipment filter integrity testing has become fast, accurate, reproducible, traceable, and auditable. A key tool within the scope of successful manufacture of biopharmaceutical drug substances.