Ultrafiltration (UF) is a low-pressure purification process that uses membranes to separate fine substances based on size and ionic charge. First developed during the late s, UF technology has evolved through the years. As a result of improved membrane materials and re-engineered manufacturing techniques, current robust UF processes now serve a critical role in many biopharmaceutical applications (Table I).
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Normal flow filtration (NFF) and tangential flow filtration (TFF) are two widely adopted ultrafiltration platforms that are related, but differ in fluid stream flow mechanics. In NFF processes, the fluid stream is introduced perpendicular to the membrane surface (Figure 1). Substances smaller than the membrane pores become trapped either on the membrane's surface or within the membrane matrix, whereas the filtrate passes through the membrane. Sometimes referred to as "dead-end" or "depth" filtration, NFF is commonly used in applications such as clarification, prefiltration, sterile filtration and virus removal.
In TFF processes, the fluid stream is introduced parallel to the membrane surface, resulting in a continuous sweeping of the filtration medium. Under low pressure, substances smaller than the membrane's pores escape as filtrate or permeate, and larger particles are retained as retentate. Because of TFF's inherent sweeping action and cross-flowing process stream, TFF-based platforms run more cleanly than NFF processes, in which separated particles can accumulate either on or in the membrane.
Table I: Biopharmaceutical applications for TFF-UF systems.
TFF systems exhibit highly predictable performance characteristics, scalability, ease of use, speed and reliability - all of which have contributed to establishing this platform as the preferred separation method for many biopharmaceutical applications. TFF systems are frequently used in applications in which small molecules (1- kD) in solution need to be separated (Table II).
The proper selection of UF membranes is critical to obtaining the desired separation results, and early users of membranes had few options. Today, a wide variety of membranes is available, allowing users to be very discriminating in their selection.
Figure 1: Fluid stream flow dynamics for NFF and TFF systems.
Membrane selection is based on several process parameters and, of course, the separation objective. The primary parameters are:
The biopharmaceutical industry benefits from continuous improvements to both membranes and substrates. High performance composite membranes constructed of both RC and PES are now available in void-free structures (Figures 2A, 2B). The consistent internal matrix of composite membranes offers a more robust performance when compared with conventional membranes, in which cavernous voids (Figure 3) beneath a thin, dense skin can result in surface defects and reduced membrane strength.
Table II: Membrane classification by size.
As a result of their unique structure and mechanical integrity, void-free membranes are highly stable, resist fouling and provide extremely high flux with consistent performance (Figures 4A, 4B). High performance membranes are manufactured with a more open average pore that allows % greater permeability with high flux, compared with conventional membranes (Figure 5). Therefore, production systems employing void-free membranes provide high retention in a smaller, more efficient footprint.
Today's high-performance RC membranes are highly hydrophilic and, therefore, resistant to both fouling and protein absorption. RC membranes are also compatible with organic solvents and cleaning solutions with pH levels of 2-13. These membranes range in molecular weight cut-offs from 1- kD.
Figure 2 A: Composite regenerated cellulose membrane. B: Composite polyethersulfone membrane. (In the UF membranes shown, the void structure has been eliminated.)
Unlike conventional PES membranes that tend to absorb proteins and other biological compounds, Biomax PES membranes (Millipore Corporation, Bedford, Massachusetts, USA) are hydrophilically modified to be more resistant to fouling. These membranes operate across the entire range of pH values and can withstand exposure to oxidizing
Figure 3: Conventional UF membranes exhibit cavernous voids beneath a thin, dense skin.
chemicals, making them suitable for applications in which harsh cleaning agents are used or when sanitization is required. Similar to high performance RC membranes, these advanced PES membranes are available in NMWL cut-offs that range between 1- kD.
The first step in deciding upon a UF membrane format is to fully characterize both the process stream and the separation objective. Considerations that need to be addressed include the following:
Once these questions have been answered, a membrane material can then be selected. High performance membranes are available in both PES and RC composite (Table III) and offer the best combination of performance variables.
Figure 4A: Void-free membranes significantly reduce the incidence of microdefects.
Membranes can be incorporated into a variety of configurations, including cassettes, spiral wound and hollow fibre (Figure 6), and each style has successfully been applied in a variety of applications for the biopharmaceutical industry. Determining the ideal UF membrane configuration depends on a number of factors such as cost, feed stream component characteristics, production volume and scaling needs.
Spiral wound modules are considered an economical option for very large process volumes. These devices incorporate alternate layers of membranes and separator screens wrapped around a central core. The feed is introduced at one end of the module and flows down the cartridge's axis, while the filtrate (permeate) spirals to the core, where it is removed.
Figure 4B: Void-free membranes demonstrate consistent return of water permeability after cleaning.
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Hollow fibre modules consist of a bundle of membrane tubes that range in diameter from 0.1-2.0 mm. Feed is introduced inside the tube from which permeate passes through the tube wall and is collected in a shell. Hollow fibre modules enjoy the advantage of low shear and thus are better suited to specific applications. In general, however, hollow fibre modules are less efficient than cassettes for processing protein-rich feeds. Larger systems require high pumping capacities to achieve fluxes that are comparable with other membrane configurations, at the expense of yields and recovery.
Cassette (or flat plate) configurations are the most common and versatile membranes in biopharmaceutical applications. Here, alternating layers of membrane and spacer screens are stacked together and then sealed. Cassettes accommodate numerous membrane and screen types and have high packing densities. Most importantly, cassettes containing high performance membranes allow linear scaling, which, for many research and development applications, makes them the obvious choice. Any benchtop or pilot plant work performed with a scalable membrane will greatly reduce the potential for surprises later in the development cycle.
Figure 5: High flux membrane versus conventional polyethersulfone UF membrane.
Once a membrane material and configuration is determined, the actual membrane can be selected, using NMWL data as a guide. It is important to select a membrane with sufficient retention to meet yield goals. For most applications, the membrane's NMWL rating should be 20-30% of the molecular weight of the product to be retained. The morphology of proteins and molecules is usually complex - rarely do these non-spherical particles align optimally with a membrane pore. Additionally, proteins can assume different shapes when the pH changes. Therefore, changing a buffer or cleaning solution can affect membrane performance. Membranes also retain finer components from highly fouling feedstocks than they retain from cleaner feeds. For all these reasons, membrane ratings are nominal as they typically separate 80-90% of species at the rated molecular weight. Select at least two, preferably more, membranes for testing based on this criterion.
The initial testing process can begin once the membrane type, NMWL rating and the device configuration are determined. Several key process parameters must be set, including cross-flow rate, transmembrane pressure, filtrate control, membrane area and diafiltration design (if any). Once these variables are established, testing of the selected membrane filtration devices can begin. Tests of each membrane should be conducted across the entire range of potential process flow rates and concentrations. Additionally, this battery of tests should be repeated for at least five different transmembrane pressures for each concentration.
Table III: Void-free membane properties.
Today's high performance, void-free membranes offer high-purity, high-yield and fast processing in a scalable cassette format. The membranes are available in both PES and composite RC in numerous NMWL ratings. These UF membrane devices enjoy widespread usage throughout the biopharmaceutical industry in which quality, reliability and performance are essential.
Figure 6: UF devices are available in a variety of configurations.
Membrane selection starts with a good understanding of the stream or streams in need of filtration. To achieve the best performance, you’ll want to consider what materials are present in the stream to be treated, the concentration, pH range, and process conditions, like temperature and flow rate, as each of these will have some bearing what membranes will work best for your application.
A critical first step determining what type of membrane is needed is first determining what type of filtration is needed. This is done by identifying all the materials present in the stream, and selecting the type of filtration based on the size and molecular weight of the substances present in the stream, and which constituents need to be separated out.
This is because membrane separation works on the principle of size exclusion—in short, the membrane acts as a barrier for any particles too large to fit through its pores. There are four main types of membrane filtration, each defined by a specific range of pore sizes:
Type Size Range Types of Contaminants Microfiltration (MF) 0.1 – 10 μm Algae, bacteria, protozoa, yeast, sand, clay, metal particles Ultrafiltration (UF) 0.001 – 0.01 μm Colloids, plastics, proteins, silica, silt, some viruses, and endotoxins Nanofiltration (NF) 0.002 – 0.005 μm Larger organic molecules, most viruses, pesticides, and multivalent ions such as calcium or magnesium Reverse Osmosis (RO) 0. μm Nearly all minerals and monovalent ionsIn general, it’s best to use the coarsest type of filtration possible while still achieving the desired level of separation. As an example, let’s say a dairy processing plant needs to separate out proteins from whole milk. Ultrafiltration (UF) would be useful here because its pores are fine enough to collect the desired protein molecules, but open enough to permit higher flow rates than NF or RO. It is also very common to see multiple types of membrane filtration deployed in sequence. So, in this example, you might see MF used first to separate out large particles like fats and bacteria, followed by UF for protein separation, and finally RO to remove excess water from whey concentrate. Combining different types of membrane filtration in this way allows for very selective separation of liquid streams, allowing for efficient operation with minimal clogging and fouling, as well as recovery of byproducts.
It’s also important to note that most membrane separation units will require some form of pre-treatment. This can include processes like clarification, media filtration, or chemical addition, as appropriate to the feed stream. Pretreatment is important to improve membrane efficiency, and prevent issues like membrane degradation, fouling and scaling, particularly for finer separation technologies like nanofiltration and reverse osmosis.
Membrane elements come in a variety of shapes and sizes, each of which offer their own advantages and disadvantages. Common element types include:
Certain constituents in a stream or process conditions can create some added constraints around what membranes might be appropriate for the application at hand. To ensure the best performance, be sure to account for these types of challenges when selecting a membrane.
Streams with a high level of total suspended solids (TSS) contain a lot of floating particles, which can include sand, clay, silt, metal particles, microorganisms or other materials. These particles can wear the membrane material, build up on the surface of a membrane or become lodged in tight spaces of the membrane element. High TSS streams can impede flow or cause pressure to build up, resulting in subpar performance, and the potential for premature membrane failure.
For streams with high TSS, it is generally best to pretreat the feed water using technologies like sand filters, cartridge filters, or clarification to remove excesss solids. In general, the larger the pore size, the more resistant a membrane is to clogging. For this reason, MF and UF are often used ahead of NF and RO to enhance downstream membrane performance. Additionally, choosing membrane shapes with a more open structure, like tubular elements or flat sheet membranes, will also help to prevent clogs and simplify routine cleaning. Finally, if the stream contains abrasive particles, like sand or metal fragments, it is important to choose a membrane material that resists mechanical damage. Some polymeric materials stand up to abrasion better than others; these include cellulose acetate, cellulose nitrate, and polyvinylidene fluoride (PVDF). Ceramic and metal membranes are much more durable than polymeric membranes, however, they are more costly.
Filtering thick liquids like oils, sugar syrups, chocolate, paints, solvents, waxes, adhesives, coatings, silicone, glycol, and other products all pose challenges because their innate flow resistance makes it difficult to pass them through a filtration membrane. High-viscosity liquids will typically demand membranes with larger pore openings and higher operational pressures, as well as membrane materials that can withstand high differential pressures. Additionally, the stream composition should be considered when selecting a membrane material. Hydrophilic (or “water loving”) polymer materials tend to perform best for filtering aqueous streams, since their natural affinity for water helps to reduce flow resistance. Examples of common hydrophilic membrane materials include polysuphone (PSU), polyethersulfone (PES), polyamide (PA), or cellulose acetate (CA).
Conversely, hydrophobic materials like polyvinylidene fluoride (PVDF) or polytetrafluoroethylene (PTFE) are best for streams comprised of oils, alcohols, or organic solvents, since these materials reduce resistance and back pressure from non-aqueous streams. It’s also worth noting that some membrane materials can be chemically modified to either repel or attract water. An example of this is modified PES, which is innately hydrophilic, but can be modified to take on hydrophobic qualities for certain applications. In some cases, flow resistance can also be mitigated by using a wetting agent.
Aggressive chemicals like acids, bases, chlorine, or solvents can degrade polymeric membrane materials, leading to premature membrane failure, and potential contaminant leakage. Many of the polymers typically used in membrane elements resist damage from some chemicals but not others, so it is important to pay close attention to chemical compatibility. Take, for example, the very common membrane material PES, which stands up to hydrochloric acid (HCl), but is not suitable for use with nitric or sulfuric acid. Similarly, PVDF membranes are suitable for use with cyclohexane but not cyclohexanone, although both are organic compounds used to manufacture nylon.
For streams that contain particularly aggressive organic solvents, strong acids, or strong bases, it is worth considering inorganic ceramic membranes. Comprised of materials like aluminum oxide, zirconium oxide, titanium oxide or silicon carbide, ceramic membranes are more durable and chemically inert than polymeric membranes, allowing them to stand up to harsh chemicals. While they typically cost more than polymeric membrane materials, ceramic membranes can more than make up for their higher upfront cost by delivering a long service life.
If you deal with hot liquids or use heat sterilization as part of your process, be sure to select a membrane material that supports the needed range of operating temperatures. Thermal stability can vary greatly from one polymeric membrane material to the next, and some materials may melt, rupture, or deform if they are exposed to high temperatures. Many polymeric membrane materials like polyamide, PSU, and PVDF are thermally stable at moderately high temperatures of 300°F or less. CA and PES have somewhat higher heat tolerance, at 354°F and 437°F, respectively. For very high temperatures, it is best to use inorganic ceramic or metal membrane materials, as these will tolerate temperatures exceeding 600°F.
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