March 1, 2013 (Vol. 33, No. 5)

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.”

Setting up a Durapore sterilizing filter tester at EMD Millipore’s Jaffrey, NH-based manufacturing facility

Improving Efficiency

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.”

Advances in the field of direct flow filtration enable the incorporation of compact, high-throughput filter capsules into single-use systems. [Pall]

In other words, a specific filter product might cost twice as much as it did a decade ago, but its greater efficiency could help reduce ancillary costs or even the number of downstream steps. “Users increasingly view filtration as means to lower cost of operating the overall process,” says Mandar Dixit, director field marketing for filtration at Sartorius Stedim Biotech.

What about performance? According to Watson, forcing a tradeoff between performance and cost would not work very well in the highly competitive marketplace for bioprocess equipment. “It would be inconceivable to introduce new filtration products, in particular, that did not do a better job than the products they’re replacing.”

Disposables Still Topical

Arguably, the single most important trend in bioprocess filtration has been single-use membranes. Yet given the difficulty in pleating depth filter media at reasonable packing efficiencies, designing encapsulated single-use depth filters remains technically challenging. Yet some vendors have prevailed.

The design of new large-scale single-use depth filter systems has now enabled the adoption of disposable technology in larger scale processes. “There is greater and greater demand for new technologies in up-front clarification,” says L.P. Raman, manager of marketing development at 3M. “We believe disposable technology for this application is still at an early peak, or perhaps still growing.” Rising product titers, which subject filters to numerous filtration and fouling burdens, exacerbates this need.

This is part of a much newer approach by bioprocessors, particularly with respect to sterile filtration, to consider the overall cost of the unit operation rather than the price for any single piece of equipment. It comes down, Raman says, to throughput, performance, and ease of use. Achieving the correct balance of these characteristics is not easy, given the operational and validation issues associated with depth filtration.

Raman says 3M’s Zeta Plus Encapsulated depth filters solve one critical usability issue while addressing performance and throughput as well. Zeta Plus Encapsulated systems were developed in response to the need for operators to load and unload filter media at waist height, rather than lifting the capsules above their heads and risk exposure to fluid spills when handling used capsules or cartridges. They also save time by being easier to handle than conventional depth media. “You don’t want to spend your entire day loading or unloading lenticular depth filters in large-domed housings gowned in suits,” Raman adds.

Bioprocessors are trending toward implementation of larger-scale, ready-to-use, capsule filters integrally sealed into plastic housings. The largest of these devices can contain 3.5 m2 or more of filter media.

“These filters have creatively eliminated time and expense associated with change-out of filters from traditional stainless steel housings and the associated cleaning and reassembly of the filter/housing system,” says Chuck Capron, director of sales at Meissner Filtration. Additionally, this eliminates cleaning validation concerns for the filter/housing system. Time saved from cleaning and cleaning validation for filters and housings results in less downtime between filtration runs, and improved productivity, Capron adds.

New process methods also allow these filters to be manufactured in continuous lengths from 10-inch to 50-inch sizes to support small filtration campaigns through large-scale production runs. Meissner has developed a configurable platform that allows multiple pre- and final capsule filters to be secured into a presterilized, single-use filtration system for plug and play use (i.e., Meissner’s UltraSnap™ filter assembly), which effectively makes the scale of single-use filters unlimited, according to Capron.

Another trend is the demand for and advancement of high-flow, long-life filter membranes based on asymmetric construction. These have been on the market for well over a decade. Asymmetric pore structures allow for extremely fast flow rates and low pressure drops. The asymmetry of the membrane serves as a final filter with its own built-in prefilter.

Disposable dead-end filtration capsules have been available for quite some time, observes Dixit. “But disposable filtration still lags at larger facilities that have already invested in stainless steel and cleaning infrastructure. We still sell a lot of cartridges and stainless steel housings to legacy processes.” One growth area Dixit notes within single-use are “complete solutions” that are pre-assembled and gamma-sterilized. “We are seeing increasing inquiries into transfer sets—filters plus tubing and connectors, or filter assemblies connected to bags ready to go.”

Following the Industry

As bioprocessing technology goes, so goes bioprocess filtration. With filtration technology improving, and relieved by single-use filters of significant regulatory burden, end-users now have the luxury of focusing on sourcing and supply chain issues.

Bioprocessors are increasingly concerned about ready availability of filtration products, in addition to their traceability and validation, says 3M’s Raman. “These regulatory requirements are becoming more and more strict.” Perhaps as a result, end-users are seeking out secondary or backup sources for critical filter components. “They may have validated their process on one system, but to ensure supply chain integrity they will validate it with other filtration equipment to ensure their supply.”

Customers are looking not just at filter suppliers, but the suppliers’ suppliers to assure supply chain security, adds Dixit. Users try to minimize risk by sourcing through manufacturers with multiple, global manufacturing locations, “preferably on different continents, and with good technical support.”

Previous articleTakeda, Resolve Join in $255M+ Lupus Drug Development Deal
Next articleBaxter Buys Long-Idled Manufacturing Plant for Bargain Basement Price