Microporous membrane filtration is the technique often applied to the aseptic processing of drug preparations. This is especially appropriate when the ingredients are heat labile. Certain filter performance qualities are of specific interest in such filtrations, namely, the extent of organism removal, the rate of liquid flow, and the total throughput volume. Essentially, it is the numbers and sizes of the pores relative to the number and sizes of suspended particles that determine the filter retention performance, although there are other factors that also affect organism removals (1). The total aggregate space of the pores within the solid filter matrix represents the membrane's porosity. It is constituted of the total number of pores of whatever dimensions. The importance of pore size is obvious. The filter pores are the sites through which the liquid flows. Simultaneously, its suspended particles, such as organisms, are retained at the pores. Ultimately, the throughput is limited by the accumulation of the particles at the pores causing their blockage.
Microporous membranes prepared by the reverse-phase casting process are available from several manufacturers in a series of pore sizes ranging from 0.04 to 8 μm. Curiously, the rating values are not determined by direct pore-size measurements, although several different methods for sizing have been proposed.
Tests such as bubble-point measurements and bacteria challenges are used to assign pore-size ratings. The propriety of translating bubble-point values into pore-size ratings will be discussed later in this article. The assigned numbers are meant to imply particles-size retentions, not dimensional mensurations from which flow properties might also be derived. The bubble points are indicators of the largest size pores present in a membrane; the focus in filtrations being chiefly upon particle retentions.The significance of pore sizes lies in their implication to particle-size retentions. The quantitative characterization of pore sizes derives from bubble-point measurements coupled with bacterial challenges. These tests are correlative. The former does not compromise subsequent use of the filter. It is a nondestructive test. The latter, although more direct in its diagnosis, is a destructive test in that it contaminates the filter with the test organisms; thus obviating its later application to process filtration.
The organisms used in the microbial challenges differ in accordance with the filter's presumed pore size. The log reduction values necessitated by FDA's definition of a sterilizing filter is the retention of 1 × 107 colony forming units (cfu) per square centimeter of effective filter area (EFA) (2). Such a retention produced against a Brevundimonas diminuta ATCC-19146 confrontation characterizes the 0.2/0.22 μm-rated membranes. Serratia marcescens is the organism commonly used in challenging 0.45 μm-rated membranes. Because Bowman et al. determined that the 0.45 μm-rated membranes retain B. diminuta to approximately the 1 × 105 /cm2 level, that test is sometimes used for testing the 0.45-μm membranes (3). The 0.1 μm-rated pore size is mostly tested against Acholiplasma laidlawii. It is fair to say that the testing of 0.1 μm-rated membranes is not yet fully in place within the industry.
Intermittent bubble-point measurement also is used as a process guide during the membrane-casting operation to ensure that the intended pore-size ratings result. The point being made is that the relevant measurements being performed are of bubble points, not of pore sizes. From these, as will be discussed, pore-size ratings and log reduction values (LRVs) are derived.
The pore-size ratings are the remnants of early efforts at membrane classifications that developments in pharmaceutical filtrations have reduced to rather insignificant utility. Pore-size ratings are administrative devices. They serve only as parts numbers or catalogue listings for filter manufacturers. The selection of filters for sterilizing applications is made primarily on the basis of the LRVs that the various filter types impose upon B. diminuta challenges in accord with FDA's definition of a sterilizing filter (2). The relationship of LRVs to experimentally determined bubble-point values enables use of the latter to identify potential sterilizing membranes subject to verification by microbiological assays performed by the filter manufacturer. The putative pore sizes are affixed accordingly. The membranes that meet FDA's stipulation of retaining the 1 ×107 /cm2 challenge are listed as being rated as 0.2/0.22 μm.