Ultrafiltration Operation And Process Development

Since the concentration of proteins in biological systems involves fairly complex fluids with unknown fluid dynamic behaviour, process development depends almost entirely on empirical data collection. Although several models do exist to help the process scientist, it is typically too risky to rely exclusively on them when implementing a UF/DF process for high-value products. Therefore, process development involves conducting small-scale experiments with representative

Diafiltration Retentate Valve to Buffer Return Apply Pressure

Diafiltration Retentate Valve to Buffer Return Apply Pressure

Diafiltration
Figure 17.3 Schematic of a tangential-flow filtration process showing the feed/recycle tank, feed pump, UF device, diafiltration buffer, retentate control valve and feed and retentate pressure gauges. (Reproduced by permission of Millipore Corporation.)

feed stocks, membranes and devices and then scaling that performance to meet industrial-scale requirements. Generally for a protein concentration and diafiltration process, the only known elements are the starting and final product concentrations and buffer compositions. Membrane chemistry, device format, process control strategy and target process time are important first choices to make before exploring specific process parameters. It is important to conduct development studies with the same device format to be used at production scale, since the fluid dynamic conditions differ greatly among the available device formats. In addition, the critical process parameters for the concentration step must be identified and conserved across scales so that the development studies can reliably predict production-scale performance.

A typical TFF experimental system is shown in Figure 17.3. This simplified system contains a feed/recycle tank, feed pump, filtration module, diafiltration buffer inlet, filtrate outlet, retentate control valve, and feed and retentate pressure gauges. During a UF process, the feed flows tangentially along the membrane surface and pressure is applied to send a portion of the feed, called the filtrate or permeate, through the membrane pores. The remainder of the feed is called the retentate and returns to the recycle tank. For protein concentration, the product remains in the retentate where it is concentrated to the desired value through the removal of the filtrate. Unlike MF, UF applications rarely employ a filtrate pump and instead use the retentate pressure and feed rate to control the filtrate rate. Retentate pressure may be controlled either using a retentate valve as shown in Figure 17.3 or by using overlay pressure on the recycle tank. When the product is in the retentate, the diafiltration buffer may be added directly to the feed tank at the same rate as the filtrate is removed to exchange the buffering components. Processing parameters that are controlled or monitored during UF/DF operations include feed and filtrate flow rates; feed, retentate and filtrate pressures; transmembrane pressure (TMP); diafiltration volume and rate; and product concentration in the retentate and filtrate. TMP (AP) is defined as:

where Pfeed is the feed pressure, PR is the retentate pressure, and Pfilt is the filtrate pressure.

Key measured parameters include product yield, quality and filterability; process time; membrane regeneration (as measured by pre- and post-use flux); filtrate flux decline; and clearance of the initial buffer components. Development efforts typically focus on maximizing the filtrate flux

Ultrafiltration System
Figure 17.4 Automated Process Development System (APDS) manufactured by Millipore Corporation for small-scale ultrafiltration studies. (Reproduced by permission of Millipore Corporation.)

and minimizing the filtration area. Multiple lots of UF membranes/devices as well as multiple lots of product are tested to ensure reproducibility. Since process development studies require a significant investment of resources and material, the use of a small-scale automated system such as that shown in Figure 17.4 can greatly assist the process scientist. The unit shown incorporates the smallest UF devices and components into a programmable system able to control feed flow, temperature, recycle volume, retentate pressure and filtrate flow, and to simulate production-scale operations. This system, manufactured by Millipore Corporation, can be used to simulate even the more complicated control strategies used for industrial-scale ultrafiltration and diafiltration processing. Examples of industrial-scale ultrafiltration systems are shown in Figure 17.5. These systems show how the individual flat-plate cartridges can be stacked together to create a larger system area.

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