Sterilizing Filters: Right Flow, Right Size Critical

Filtration can be the quickest, most cost-effective means to achieve sterilization for large volumes of simple buffers or aqueous solutions. However, finding the right flow rate and filter sizing is essential to meeting FDA’s aseptic guidelines.

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By Jennifer Maynard, Six Sigma Black Belt, Baxter BioScience; Theodore H. Meltzer, Capitola Consultancy; Maik W. Jornitz, vice president, Product Management, Sartorius North America, Inc.; and Paul M. Priebe, head of Product Management, Process Filtration, Sartorius North America, Inc.

Sterilizing grade, 0.2-micron-rated membrane filters are used widely within the biopharmaceutical industry. They were also given more prominence by FDA’s Aseptic Guidelines, which specified filtrative sterilization as a key criterion for process validation (www.pharmamanufacturing.com/industrynews/2004/93.html).

Originally used in cases where thermal sterilization would degrade product, the filters have been redesigned and optimized to improve flow. They are now recognized as the quickest, most cost-effective means to achieve sterilization for large volumes of simple buffers or aqueous solutions.

Since such fluids typically contain only very low levels of contaminants, a sterilizing filter’s throughput is far less important than its speed in transferring fluid from a mixing vessel to either holding vessels or disposable bag containment. The longer the transfer takes, the longer equipment will be idle, directly affecting the manufacturing facility’s capacity.

Consider, for example, a common 0.2-micron-rated sterilizing-grade filter, which commonly achieves a flow rate of 2,500 L/hour/14.5 psi. It would take this filter 48 minutes to process a 2,000-L volume. In contrast, an optimized high-flow-rate filter with a flow rate of 6,000 L/hour/14.5 psi would require only 20 minutes, doubling equipment availability. In cases where that speed would be too high, it could be adjusted by reducing the filter’s effective filtration area (EFA).

Where, in the past, sterilizing-grade filters were designed to be used broadly for a multitude of applications and fluids, they are now customized for specific applications, some of which require a high flow rate through the filter at low differential pressure. This article will discuss the importance of flow within these applications, focusing on how best to test the filters for flow and how to size them accordingly.

Improved designs

Redesigning the filters’ membranes and cartridges allowed them to achieve higher flow rates. Otherwise, the only way to improve flow rate would have been to raise the differential pressure or increase surface area, neither of which was practical: higher differential pressures would mean a significant increase in energy consumption or could risk exceeding the filter’s operating pressure capacity. Larger filtration surfaces would mean an increase in consumable and capital investment costs.

Figure 1. Membrane breaks at the pleat edges.

Membranes

New filter membranes feature a high pore volume and are most often asymmetric and highly pleatable. The membrane polymer selected determines many of the membrane’s performance parameters, but other variables are involved as well. For example, if the membrane is not pleatable, the filter’s EFA will be low, and the pleat edges won’t be strong enough to withstand pressure pulsation (Figure 1, right).

High flow applications can create water hammer or excessive pressure pulsation. As a consequence, these membranes and filters require high mechanical stability (Figure 2, below). In other instances, the filters undergo multiple steam or sanitization cycles, dictating thermal stability. If the membrane casting does not allow for pleatability, the filter will be damaged during the filtration or sterilization process and jeopardize the sterility of the filtered fluid.

Cartridges and fleeces

Filter cartridge design is also a key element to optimizing flow rate. A single-layer membrane construction will usually achieve higher flow rates than a membrane double-layer combination, especially when this combination is a homogenous (e.g., 0.2/0.2 micron) configuration. The flow restriction of a homogenous double-layer design can be so high that a single-layer membrane filter of a smaller pore size, e.g. 0.1-micron-rated, might reach a comparable flow rate (Figure 3, below ).

Furthermore, the support fleece and pleat densities must be well balanced in order to avoid a limited EFA or uneven flow distribution within the membrane pleat pack. A support fleece with a small fiber diameter and high density might be so compact that it could end up resisting flow, eventually causing flow to drop due to a decrease in pressure over the fleece material. Optimizing filter flow rate requires thorough study, and balancing all of the parameters above.

Putting filters to the test

Despite the importance of filter flow, pharmaceutical manufacturers tend to take it for granted and to rely on data provided by filter manufacturers, instead of testing the filter within its future application. And even if manufacturers do their own testing, they may use inappropriate filter samples — for example, samples of the membrane alone, rather than a composite sample representative of the entire filter cartridge construction.

Another common mistake is using 47-mm discs for testing. Tests for flow rate using 47-mm discs are meaningless, since they can evaluate only the porosity and thickness of the membrane itself. Critical and beneficial parameters of the true filter element, which will be used within the process, are not evaluated. Side-by-side trials employing 47-mm discs cannot determine the true flow rate performance of the filter within the production process.

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