A common objective in pharmaceutical processing is the removal of solids from fluid suspensions through filtration. The usual purpose is the removal of the solid particles to a specified extent, within a given time interval, at the largest possible throughput. Attainment of those goals is managed by proper selection of filtration conditions: principally an adequate effective filtration area (EFA) as defined by filter porosity and a proper rate of flow as regulated by applied differential pressure (ΔP) over the period of filtration. Were the fluid “clean,” by definition free of particles whether of microbial or of other origin, the task would be amenable to mathematical analysis. Flow rate would be directly related to ΔP over time and also to the EFA's porosity in terms of pore numbers, dimensions, and so on. Time required could be calculated from the batch size processed over the duration.

PRODUCT FOCUS: BIOLOGICS

PROCESS FOCUS: DOWNSTREAM PROCESSING

WHO SHOULD READ: MANUFACTURING, ANALYTICAL, AND PROCESS DEVELOPMENT

KEYWORDS: MEMBRANE FILTRATION, MEMBRANE CHROMATOGRAPHY, FLOW RATE, ADSORPTIVE CAPTURE, PREFILTRATION

LEVEL: INTERMEDIATE

But when commonly processed liquids—those bearing suspended particles—are involved, the blocking and clogging of filter pores by retained particles change the equation. The pore size rating of a filter should be selected to retain the objectionable particles by sieving, and the aptitude of its polymeric composition for adsorptive sequestration of those particulates also needs to be known. The quantity and nature of retained particles requires accommodation in filtrative removal if the outcome is to be considered successful. Too extensive a particle load will prematurely block a filter's delivery of sufficient throughput to meet the filtration's goal. This equates with enough drug product to provide a adequate monetary return. Drug processing thus represents a technoeconomic challenge.

Particle load

As filtration of a liquid progresses, suspended particles (whether organisms or otherwise) are arrested by sieving at the filter pores or adsorption to the membrane or nonwoven structure of the filter. Contrary to earlier teachings, membranes are not limited to surface retention because of their thinness (~120–150 µm). Two outcomes await particles small enough to enter the pores or fiber matrix: They may be conveyed by the suspending liquid close enough to the matrix wall and become adsorptively fixed to it, or they may escape such capture to emerge in the filtrate.

When particles are arrested because of their size or shape, leading to near complete pore blockage, the effect on fluid flow is immediate. When particles gather at the walls (eventually to clog the passageway), the flow is diminished more slowly. Either way, it is particle capture that interferes with and ultimately terminates a filter's service life and defines its throughput. The term filter cake is usually reserved for a particle mass located on the filter surface. Plotting the rate of flow diminution over time can help ascertain mathematically a filter's particle retention mechanism (1,2).

A complete cessation of flow is not sought. When the initial flow rate has decreased by about 80%, a point of diminishing return is usually considered to have been reached. It is considered impractical in terms of labor and costs to go beyond that point. In some applications, the filter can be used only to 50% blockage because progress beyond that point can cause yield losses due to bridging and unwanted sieve or adsorptive separation.

In the event of particulate loading in excess of a filter area's ability to accommodate, fluid flow will be blocked prematurely, and a batch filtration will be incomplete. The consumed filter must be replaced before filtration can continue. Such an action, arduous in itself, is best prevented when product sterility is required. It could expose an entire filtration train to the needless risk of asepsis. So the EFA necessary to process an entire batch is calculated from flow-decline studies before processing activities are initiated (3).

Such studies use frequent sampling and filtrate analysis and can also indicate what blockage rate can be allowed without yield loss. However, flow-decline studies are too often based on models using flat filter disks 47 mm in diameter. They are seldom adequate prototypes for pleated cartridges. Carefully designed and implemented flow-decline studies are needed to secure dependable results. Studies with 47-mm discs are commonly recognized as “indicator trials” that require follow-up “verification trials” using small-scale pleated devices to establish a sound foundation for scaling work (3).