A septically produced liquid pharmaceutical and biopharmaceutical products are usually sterilized by filtration. The filtration process must be validated to ensure that it is capable of removing all microorganisms from the product. Validation consists of challenging the filter with a suspension of Brevundimonas diminuta and analyzing the filtrate for microorganisms. The filtrate must be sterile.
Filters used in production should be equivalent to the filters used in the bacterial-challenge validation studies. Because actual production filters cannot undergo bacterial-challenge testing, integrity testing is performed to demonstrate bacterial-retention equivalence. If the integrity-test values obtained for the production filters are equivalent to those obtained for the filters successfully passing bacterial-challenge testing, then it is assumed that the filters have the same bacterial-retention properties and that the filtered pharmaceutical product is, therefore, sterile.
Integrity testing for the hydrophilic filters used in pharmaceutical production relies on the measurement of gas flow through wetted membranes. This flow can be classified as diffusive or bulk and is sometimes a combination of both. Fick's Law of Diffusion shows that diffusion of the test gas through the liquid-filled pores in the membrane is a function of the diffusion constant and the solubility of the test gas in the liquid at the test temperature, the pressure differential of the test gas across the membrane, the thickness of the liquid layer, and the area and porosity of the membrane (1). Diffusion is not directly related to pore size although, as will be shown later, there is an indirect correlation. Bulk flow occurs when the test gas flows through the nonwetted or empty pores of the membrane. Open pores occur because the filter membrane has been incompletely wetted or because the bubble point of the membrane has been exceeded. Bulk flow primarily is a function of the size and number of the open pores, the thickness of the membrane, and the pressure differential of the test gas across the membrane at the test temperature.Gas flow through wetted membranes
The knee area of the curve is where the influence of the bubble point is manifested. Here, the largest pores of the filter become unblocked as the applied pressure overcomes the capillary forces within those pores, and bulk flow begins to increase the slope of the curve. It is also in this region that diffusive flow begins to increase because the thickness of the liquid trapped in the largest pores begins to decrease as a result of the increasing pressure differential. Therefore, within the knee area of the curve a complex relationship exists between diffusive and bulk flow, both influenced by the pore structure and pore-size distribution.