When bioprocess liquids bearing suspended particles are filtered, retained particles can block and clog membrane filter pores. The pore size rating of a filter should be selected to retain 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 require accommodation if filtrative removal 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: obtaining enough drug product to provide an adequate monetary return. Drug processing thus represents a technoeconomic challenge.

In the first half of this two-part article (1), we examined fluid effects and operations (particle load; interactions of filtration area, differential pressure, and processing time; and operating conditions) as well as reviewed the results of several experiments involving latex particles and surfactants. Here we conclude by examining particulate effects and filter pore structure as well as further experimental findings.

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

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Dilute Particle Suspension Effects

The liquid suspensions Emory et al. used in their study of the effects of different surfactant types were more dilute than is customary (2). Examination of dilute particle suspensions is considerably significant. The investigations disclose insights not apparent from experimental results garnered using more concentrated suspensions. Dilute suspensions represent “worst-case” situations, those least encouraging to particle retention.

In more concentrated suspensions, it is conceivable that so many smaller particles may simultaneously arrive at a pore/fiber matrix as to give the appearance of its immediate blockage by a larger particle. This would more rapidly reduce the number of larger pores, over time lessening the opportunities for smaller particles to penetrate. It is a matter of the rate at which a sufficient mass of smaller particles reaches those larger pores to block them, as well as the number of individual smaller particles that escape capture during the period leading up to that blockage.

The time that larger pores are available for penetration by the separate smaller particles of dilute suspensions is foreshortened in concentrated dispositions, in which sudden pore blockages occur. Thus, the same total number of particles impacting a membrane over different durations can yield different throughputs. In essence, more dilute suspensions represent worst-case conditions because smaller individual particles are more likely to escape through still-unclogged larger pores.

Particle Size And Shape

As we see it, the stage on which a filtration act is played out consists of an effective filtration area (EFA) marked by a pore size or retention distribution that is confronted by a particle size distribution. A range of particle sizes is differentiated into two groups, each of which is defined by their size relative to the membrane pores. One portion comprises larger particles (too large to fit through any distributed pores or fiber matrices, whether large or small); the other portion consists of particles small enough to penetrate a membrane's larger pores or fiber interstices, but not its smaller ones.

The pores or fiber interstices also comprise two size groups, only one of which covers a range of pore size ratings large enough to be passed through by the smaller particles. Depending on the relative proportion of smaller and larger particles present, and on the pore sizes they encounter (whether directed by the flow pattern or by chance), outcomes will be different for particle retention, the onset of filter plugging, and the quantity of throughput.

The definition of particle size is a bit too “neat” to apply absolutely to any particle shape except spheres directed toward circular pores. It begs an invariant sieving action based strictly on particle/pore sizes and ignores shape factors. Except for spheres, however, particle longitudinal and transverse axes may differ in size. In filtration, a particle's dimensional axis coinciding with the pore functionally determines a particle's size. Probability factors (e.g., a particle's axial orientations) governed by liquid stream velocity, viscosity, and drag can cause more elongated shapes (needle-like) to pass through or lie athwart the pore openings. Thus, in a mixture of particles characterized generally as being too large to permeate a pore or fiber matrix interstice, some particular shapes may actually do so depending upon how their flow pattern is directed by either filtration conditions or by chance.

Equation 1: The Hagen–Poiseuille equation

Q = volumetric flow rate of the test gas

P = applied differential pressure

d = pore diameter

µ = test gas viscosity

L = pore length through the membrane

It is not surprising that, in certain experimental trials, conclusions have been reached that some particles of a group-size seen as being “too large” to pass through a filter did, indeed, do so. This does not contradict the sieving mechanism, but rather more realistically describes size as defined by particle dimensions in an actual filtration. It might be simpler to refer to these particles as being “intermediate” in size. We are obliged, however, to describe such particles as they are referred to in the literature we're quoting: namely as “larger particles.” That implies that they are too large to pass through a filter's smaller pores, but that when properly aligned they can permeate a larger pore — bearing in mind, though, that pore size labels are generally descriptive and actual pore structures are typically larger than labeled. Keep this in mind during the following discussion.

Particle shape is not easily explained. Angular shapes (e.g., crushed stones), as seen while they rest heavy-side down under a microscope, can be expressed by a projected area. The diameter of a circle of equal area may be used to characterize such a particle, but the arbitrary nature of this designation is self-apparent. Nevertheless, it is the frame of reference underlying certain particle counters. Others may use the projected area or volume of a tumbling particle rather than its diameter. Both methods require development of correctional factors, which is not an easy undertaking. Characterizing particle size distributions is even more complex. To determine a filter's efficiency in arresting particles of given size, the size distributions in both feed stream and filtrate must be known. But such information is usually unavailable.