Liquids Membrane Filtration
Membrane filters are used for the terminal sterilization of heat labile liquid products, and for the sterilization of gases. Where possible, the FDA prefers sterilization by heat. The large-volume parenterals (LVP) solutions employed in intravenous administrations are rendered sterile by being steam autoclaved rather than by being sterile filtered, although either technique will be effective. Even when a product is heat or gamma sterilized, filtration finds its need, as a bioburden reducing filtration to avoid elevated endotoxin levels after the sterilization step. The LVP industry utilizes routinely 0.45 or 0.2 micron rated filters to reduce the bioburden before heat sterilization.
However, while thermal sterilizations are preferred, not all products can withstand damage by heat. Proteins may be denatured by heat, and oxidative degradations are promoted by it. Hence, the utility of sterilization by filtration. However, the achievement of a sterile filtration requires validation, a confirmation derived from documented experimental evidence (see Filter Validation).
The microporous membranes are usually designated by pore size ratings of 1.2 micron to 0.04 micron. The pores of these filters are artificial enlargements of the interstitial spaces that separate the polymeric chain sections as present in the bulk solid phase. Used as final filters for the sterilization of solutions, they are usually of the 0.45, 0.2/0.22 or 0.1 micron ratings. In their higher ratings they may serve as prefilters to prolong the service lives of final filters.
As depth filters retain contaminants within the fiber matrix, membrane filters are surface retentive filters and therefore have the distinct disadvantage of blocking faster. The filter industry therefore pleats such membranes to install a higher effective filtration area into a filter device. Still such effort has its limitation, due to a maximum allowable pleat density. Having reach the limit, the only option is the use of prefilters or membranes of different pore sizes or structure to gain a fractionate retention and therefore a prolong lifetime of the filter. Some membrane filter configurations have such membrane or depth filter prefilter build into the filter cartridge. This is convenient for the filter user in respect to lowered hardware costs and hold-up volume. In comparison to depth filters, membrane filters have a narrow pore size distribution, which results in a by far sharper retention. Pore size ratings are facilitated to differentiate membrane filters and the performance of such. Commonly a sterilizing grade filter is labeled 0.2 micron and retains 107 B. diminuta per square centimeter at a differential pressure of 2 bar (30 psig). Another advantage and necessity of membrane filters, is the fact that these are integrity testable, impossible with depth filters. Possible flaws or defects can be detected, which is critical due to the function of membrane filters, mainly to separate microorganisms from biopharmaceutical solutions.
Membrane filters are made in a wide variety of pore sizes. The effective pore size for membranes vary and membranes can be used in reverse osmosis (RO), nanofiltration (NF), ultrafiltration (UF), and microfiltration (MF). RO membranes are widely used in water treatment to remove ionic contaminations from the water. These membranes have an extreme small pore size and therefore require excellent pretreatment steps to reduce any fouling (organic) or scaling (anorganic) of the membrane, which would reduce the service lifetime. RO membranes are used by extensive pressures on the upstream side of the filter membrane to force the liquids through the pores.
Ultrafilter (UF) retention ratings are also not measured in pore size, but rather in MWCO (Molecular Weight Cut-Off), i.e. the molecular weight of the substance to be retained. UF filter systems are most often used in Cross-Flow (tangential flow) mode. The feed stream is directed over the actual membrane to diminish blockage of the membrane. Depending on the pressure conditions, the fluid (penetrate) penetrates through the membrane, whereby the remaining fluid is recirculated (retentate). UF filter systems find applications in concentration, diafiltration and removal steps within pharmaceutical downstream processing. Microfiltration (MF) can be used as dead end filtration (the feed is directed to the membrane resulting into a filtrate, separated from the contaminant) or tangential flow mode. The tangential flow characteristic for MF is commonly used for cell or cell debris removal in downstream processing. MF membranes typically differ from UF membranes in the morphology of the membrane's cross-sectional cut. The symmetry of sterilizing-grade microfilters usually ranges from being uniform to being slightly asymmetric. Ultrafilters on the other hand are highly asymmetric with the rejecting layer consisting of a tight skin (0.5-10 µm thick) supported by a thick spongy structure of a much larger pore size.
MF is used in a large variety of filtration applications, from fine cut prefiltration to sterilizing grade filtration in aseptic processing. Often sterilizing grade filters are the terminal step before filling or final processing of the drug product. MF is available for air and gas applications and liquid clarification or sterilization. For the different applications specific membrane configurations and materials have been developed.
Cellulose acetate: Filters composed of cellulose acetate have the good properties here described. However, if the filter were intended for a long term duration, such as would be the case for a reverse osmosis membrane, then pH range should be limited between pH 4 and 8. In the pharmaceutical time and temperature contexts common to ordinary filtration applications, the hydrolysis rate of cellulose acetate should not cause problems. Cellulose acetate is a polar molecule because of its oxygenated ester groups. Therefore, it is a low adsorber of proteins. Proteins, it will be remembered, undergo hydrophobic adsorptions. Hydrophobic polymers usually have no oxygen atoms in their structure and may be non-polar as a result. They can be "hydrophilized", i.e. modified by having ester groups chemically cross-linked to them. This reduces the tendency of filters prepared from them to adsorb proteins.
Polyethersulphone: Microporous membranes of polyethersulphone are used extensively. They have a wide range of pH compatibilities, as indicated.
Manufactured as asymmetric membranes, they exhibit the fast flows that are consequent to that format. Such asymmetric membranes, also called anisotropic, have a pore disposition wherein the larger size pores are arranged at one surface and where the pore sizes become progressively smaller as they approach the opposite surface. The overall result, in effect, is an assembly of "V" shaped pores. The filters cartridges are so constructed that the more open ends of the "V" shaped pores of the membrane are directed upstream. This enables them to accommodate larger deposits in their more open regions. The result is a possibility of larger dirt-holding capacity. By the same token, asymmetric filters flow more rapidly than do the conventional isoporous membranes. Yet their retention mirrors the size of their smaller retaining pores. The overall effect, when fully realized, can be that of a prefilter/ final filter combination. The extent to which the beneficial results possible from asymmetric filter structures are realized depends, in part, upon the number, sizes and shapes of the particles being restrained from passage.
Polyamide: The amide linkage that characterizes the polyamide polymer most widely known as nylon has a weak polarity. It is sufficiently hydrophobic to invite considerable adsorption by non-specific proteins. Yet, in membrane form it is hydrophilic enough to be wet by water. Consequently, it can be used to filter aqueous solutions. This seeming contradiction may be due to the hydrolysis, during the casting of the membrane, of the surface amide groups into strongly hydrophilic carboxylic acid groups and amine groups.
A leading manufacturer of nylon membranes informs that their 0.2 µm-rated filter would be rated 0.46 µm by latex particle retention measurements, while their 0.1 µm-rated filter would be classified at 0.28 µm by the same means. This more open membrane explains its large flow properties.
The extreme sensitivity of the amide linkage, whether the nylon 6, or nylon 6,6 polymer, to the oxidative degradation by strong oxidants such as chlorine is not of importance in the usual pharmaceutical filtrations. However, contact with oxidants is to be avoided when polyamide filters are used in reverse osmosis water purification applications. Polyamide polymers undergo oxidative and thermal degradation by an "unzipping" mechanism. That is to say that their degradation manifests itself by a depolymerization that gives rise to low molecular weight polyamides. Such may be found upon the steaming of polyamide membranes.
Polyvinylidenefluoride: PVDF, along with PTFE and polypropylene, is perhaps the hydrophobic polymer most widely applied in pharmaceutical filtration contexts. PVDF is used in microporous membrane fabrication both for its hydrophobicity, chiefly as vent filters, and in its hydrophilized form for the filtration of protein solutions, wherein its non-specific protein adsorption is very low. PVDF is a high cost filter material. Its high fluorine content confers a strong resistance to aggressive chemicals. It is, however, susceptible to strong alkali, and is not quite impervious to ultraviolet radiation. Nevertheless, its inertness, as its hydrophobicity is quite high; both are a consequence of its being a fluorocarbon. It bears repeating that not PVDF but its "hydrophilated" modification is low in protein adsorption. If the surface treatment is chemically attacked hydrophobic spots will appear, which raises the unspecific adsorption properties of the membrane. Therefore chemical compatibility of the membrane requires focus to avoid yield losses.
Polytetrafluoroethylene: PTFE, because of the strength of the carbon-fluorine bond, is chemically very inert. Membranes made from it are, therefore, very suitable for the filtration of aggressive reagents, including strong oxidants. For the same reason, the high temperature properties of PTFE filters are outstanding. However, the polymer is degraded by gamma radiation. PTFE is perhaps the most hydrophobic of all the commercial polymers. It was originally known as Teflon®, a name now extended to all fluorocarbon materials trade-marked by DuPont. Unless first wet by alcohols or alcoholic-aqueous solutions, PTFE membranes will not be made wet by water. If used in this manner for the filtration of aqueous solutions, the initial alcoholic rinse must not be allowed to dry, and, may therefore, add contamination to the first volumes of filtrate. Because of its extreme hydrophobicity PTFE is avid in its hydrophobic adsorptions, such as of proteins.