As an integral part of biomanufacturing, filtration tends to follow larger industry and processing technology trends.
These have been summarized by James Blackwell, Ph.D., president of the Windshire Group, in several presentations over the years: cost savings and reduced regulatory/validation burden, use of platform technologies, simplification of process development, risk reduction, and adoption of disposables whenever possible.
The market for bioprocess filtration products is driven by a mixture of “voice of the customer” and new technology, says David Beattie, Ph.D., senior director of R&D at EMD Millipore. “Market need and innovative technical solutions must come together or products cannot make an impact. A supplier’s job is to align those two factors.”
One customers-inspired need is expanding the scope of sterility assurance to address novel organisms, or by applying filtration at different steps within the process.
Dr. Beattie cites a recent example of bioreactor contamination by spirochetes, which due to their unique physical size and shape can penetrate standard 0.1- or 0.2-micron media filters. One highly visible spirochete contamination incident interrupted supply, which caused processors and suppliers to think hard about contamination from “unlikely” sources.
The result has been strong interest in examining (and in some cases re-examining) both process solutions (e.g., how to run sterile filtration more effectively) and new technologies. The latter involve designing filters that retain organisms that normally escape standard filtration—without losing the high-process throughput and efficiency that the current generation of filters provides. “This involves what we call ‘enhanced sterility,’” says Dr. Beattie, “and the justifications are business continuity and process consistency.”
At the same time stakeholders are renewing interest in “virus barriers” whose basis is removing viruses that may be part of the raw materials or the finished product of a cell culture medium. Note the distinction between this form of virus removal, and late-stage filtration undertaken mainly for patient safety.
“The question is, can we remove/inactivate viruses early in the process rather than later? That would help assure consistent, productive cell cultures, and reduce the likelihood of shortages due to contaminated facilities,” Dr. Beattie says.
Virus barrier technologies include physical steps such as ultraviolet UV or short-time high-temperature treatment (essentially pasteurization). Another approach, under increasing consideration, is upstream virus filtration. The challenge has been that filtration products designed for keeping media sterile will not remove viruses, and filters designed for removing viruses downstream are incapable of handling complex cell culture media.
“Many cell culture media components are not filterable given the volumes and processing times involved. This strategy demands a novel filtration design,” Dr. Beattie says. “EMD Millipore has been working internally with customers, and through academic consortia to enhance virus safety through both physical steps and filtration. The trick is to do this cost-effectively, allowing therapeutic protein pricing to remain intact. Adding a lot of up-front cost is not acceptable.”
Improving process efficiency applies both globally to bioprocessing, and to filtration. “This means downsizing existing filtration systems, and installing the most efficient filtration unit operations in new facilities,” says Tom Watson, global product manager for sterilizing-grade filters at Pall.
The direct benefit of smaller filtration systems is lower filtration costs per batch, Watson explains, “but they also minimize many of the auxiliary operations around filtration, such as flushing to minimize extractables, flushing to wet the filters out for integrity tests, storage, and so on, all of which entail costs in addition to the cost you’d spend on the filters themselves.”
To reduce filter system sizes, filter suppliers are improving filtration technology at the membrane level, increasing the unit membrane area capacity for contaminant removal. Asymmetric membranes, for example, capture contaminants through the entire depth of very thin membranes. Simultaneously, vendors try to maximize the membrane area within traditional filter formats. Novel pleating technologies are one strategy for achieving this.
These design features, combined with membrane enhancements, allow end-users to reduce their filter footprints dramatically, and thereby improve process efficiency at multithousand-liter scales. “The same holds for smaller production batches,” Watson says. “Those end-users as well benefit from much smaller filtration footprints and more compact processes compatible with single-use processing.”
Just a few years ago, Watson explains, a typical sterilizing filter process may have consisted of a prefilter and a sterilizing-grade filter, both held in stainless steel housings. Today, thanks to advances in membrane and device technology, a dual-stage operation may be reduced to a single step through one single-use filtration capsule.
Many end-users are still concerned about the high cost of filtration, particularly sterilizing-grade filtration products. Watson advises looking not only at the individual unit price, but the performance-value characteristics.
“The right view is to account not only for unit filter costs, but the entire cost of the operations that occur around the filtration of a batch of fluid. Users who perform the accounting this way discover immediately that employing high efficiency, single-use filters is economically favorable, particularly where the prefiltration step is eliminated.”