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Feature Articles : Jan 1, 2011 (Vol. 31, No. 1)

Single-Use Systems Become the Norm

Awareness of Economic Benefits Has Propelled This Trend
  • Angelo DePalma, Ph.D.

Over the last few years, disposable biomanufacturing has shed its reputation for isolated, low-tech storage and hold applications to an over-arching strategy appropriate for every stage in a product’s manufacturing life cycle. Aiding this trend have been awareness of the economic benefits of disposable equipment, the remarkable rise in titers from cell culture processes, and—to a lesser degree—a focus away from blockbusters and toward personalized medicine and orphan drugs.

Spencer Parkinson, senior product manager for single-use systems at Thermo Fisher Scientific, was not surprised to see that virtually every session at “BioProcess International” included presentations on disposables. “Just a few years ago we had to convince people of the compelling economic argument for disposables,” he said, “but now it’s becoming the norm, the predominant way of thinking of bioprocessing.”

Companies with large investments in stainless steel equipment may still hold back depending on the size of their investment, and globally, Asia appears to lag behind the U.S. and Europe in its adoption of disposables since “economics vary in different regions.” But the cost and flexibility arguments are compelling for new projects and facility expansions.

The trend toward ever larger single-use equipment notwithstanding, Parkinson does not believe there will be great demand for bioreactors larger than 2,000 liters. High titers and smaller batches are already eroding the need for mega-bioreactors, he says. “There are, of course, occasions where larger cell cultures are required, and that will continue, but there’s already enough capacity out there in stainless steel to handle that.”

Separations

Bernd H. A. Rehm, Ph.D., chief scientific officer at PolyBatics, addressed the need for lower-cost affinity media. PolyBatics, which specializes in customizable and/or biodegradable polymer beads for antigen delivery, biocatalysis, and medical diagnostics, recently developed beads that express the IgG binding domain of protein A at high density. Part of a fusion protein, the “ZZ” domain is crosslinked to the core of the polyester beads. “The binding capacity is approximately double that of commercially available protein A resins,” Dr. Rehm said.

PolyBatics employs engineered microorganisms to produce highly functional beads with superior binding capacities and affinities cost-effectively, according to Dr. Rehm. In addition to bioseparations, beads can be constructed for other useful protein-mimicking functions, for example enzymatic catalysis or antigenicity (as in vaccines).

What about cost? “That’s confidential,” he said, “but the current low production costs suggest a use as single-use resins.” If PolyBatics can demonstrate clear-cut economic advantages, new processes will have the benefit of fully disposable chromatography as well as single-use upstream equipment during development and beyond.

Membrane chromatography is a single-use technology traditionally used to remove trace impurities, as in polishing. But C. Howie Honeyman, Ph.D., vp of R&D at Natrix Separations, showed how membranes can compete with traditional chromatography resins. He described novel membranes with high binding capacity and throughput, suitable for bind-and-elute processing.

The Natrix membranes consist of a polymeric hydrogel formed within a flexible porous support matrix. The matrix provides mechanical strength, while the hydrogel dictates the product’s separation chemistry. The gel provides high binding-site density, high surface-binding area, and high mass transfer. The two components can be optimized independently, yielding a low-cost, high-performance membrane product, Dr. Honeyman said.

So far Natrix offers the membranes in cation- and anion-exchange formats that exceed those of membrane capacities by up to a factor of eight and often, on a by-weight basis, resin capacities as well. A test case presented at the conference showed a conventional resin binding approximately 20 mg/mL of an IgG at 10% breakthrough, while the Natrix C material bound 100 mg under the same conditions.

“The membranes are a perfect combination of high surface area, convective flow channels, and high functional group density,” said Dr. Honeyman. “Convective flow gives high throughput, while high surface area and high functional group density provides high binding capacity.” Natrix is looking into a carboxylic acid-based resin and affinity materials as well. “We’re particularly interested in developing a protein A and IMAC nickel chemistry.”

For large-scale, high-titer processes, four membranes, employed with the right fluid handling and recycling, could process products from a 20,000 liter bioreactor, according to Dr. Honeyman. Or, he said, each membrane may be “campaigned” by processing 400 liters at a time through five bind/elute cycles.

Impact on Facilities

Several speakers focused on the impact of single-use processing on facilities. Robert Steininger, senior vp for manufacturing at Acceleron Pharma, addressed this from the perspective of small or emerging biotechnology firms. His presentation was based on a recent project in which Acceleron assembled a new biomanufacturing plant within a building constructed for metal-working early in the 20th century. The production suites occupy what had previously been the plant’s office space.

While acknowledging the need for “a lot of capital” to produce “boatloads” of a protein, Steininger identified preclinical and early clinical batches as the sweet spots for single use, particularly for designing a facility around disposability and delivered media and buffers. Disposables-only facilities are particularly attractive to contract manufacturers, whose businesses thrive or fail based on responsiveness and controlling production timelines.

Another group that should consider the disposables-only approach is firms that deal with highly potent or toxic drugs, which require very high standards for cleaning and control. “Single use can mitigate most of the cleaning and containment validation associated with these products,” Steininger said.

In specifying single-use-only, the predominant time and cost savings for new facilities involves utilities—particularly water and steam—and associated capital costs. Deployment of single-use equipment exploits the utilities at the supplier’s end, for example water and steam used during media/buffer preparation and storage, and cleaning/sanitizing operations in the manufacture of bags, tubing, and connectors.

“You’re benefiting from the economies of scale at suppliers who can make water and steam in much higher quantity,” Steininger noted. “Of course, since you’re tied into their quality and regulatory systems, you have to buy into the fact that they are reliable vendors.”

The adoption of platform technologies, particularly for monoclonal antibodies, has aided the cause of single-use processing, and with it the emergence of facilities designed specifically for that purpose. Platform technologies consisting of one major upstream operation and two or three predictable separation steps minimize uncertainty with regard to equipment, supply, and facility.

Companies with substantial investment in stainless steel piping can also benefit when expanding or augmenting pipelines with several early-stage clinical or preclinical products. But here the economic arguments become murky if, for example, piping can be introduced easily from an adjoining suite. “It’s tough to ignore your original investment,” Steininger notes.

Scaleup and technology transfer are additional considerations. When large-scale production inevitably occurs in stainless steel regardless of the early-stage production equipment, many established firms prefer to run processes as similarly as possible at large and small scales.

Platform Technology Enablers

Benefits of the platform approach were amply illustrated by a talk presented by Jonathan Royce, bioprocess category leader, bioprocess at GE Life Sciences.  Royce walked listeners through an antibody manufacturing project in case-study style, which included a comparison between GE’s single-use ReadyToProcess™ (RTP) manufacturing platform and conventional processing steps. The bottom line: RTP can reduce processing times by half, he said.

Dr. Royce began with the question of what is realistic in terms of directing investment toward disposable processing, particularly for clinical materials. “If you really wanted to do everything in disposable format, you probably could, given the varying degrees of maturity within existing technology,” he explained.

For example, bioreactors range widely in size, formats, stirring, aeration, and other capabilities. Options are also available in the automation of filtration and chromatography operations, but not as many as for fermentation and cell culture. “They still have room to grow, in terms of variety and options, to reach the capabilities of stainless steel. But there is no question that if you were determined, you can do everything in disposable format. The question then becomes, is it worth it, and how do you make that decision?”

A naïve view would conclude that the decision reduces to “mere” accounting, of which examples abound. But this tack is self-limiting, Royce explained, because until recently accounting focused primarily on cost, or more narrowly cost of goods and capital preservation.

“My thesis is that there is a lot more opportunity gain that can be made available through smart investments that either speed the flow of products through the pipeline, or that improve process reliability, than there is money to take out in the form of cost of goods,” he said. “We need to start thinking more of investment to unlock revenue potential—to get more products through the clinic and into the marketplace faster—rather than preserving capital.”

One consideration for optimizing opportunity costs—and for utilizing disposables generally—is how to treat high-ticket equipment such as ultrafiltration membranes and chromatography resins. Here Royce suggested the hybrid approach, whereby equipment is used for a campaign and then discarded, rather than using every last cycle promised by vendor specifications. Ancillary equipment like bags and tubing would be used once and discarded as usual. One area where GE and some of its competitors are already pushing this philosophy is for prepacked chromatography columns.

The hybrid approach can be viewed as a balance between strict single-use, which is often too expensive for high-value equipment, and the difficulties in transitioning high product-contact materials from one molecule to another. Ultrafiltration membranes require time, materials, and personnel to recondition; chromatography columns even more so.

Associated costs may be justified given the high investment in these products. However, the validation burden is significantly higher when switching molecules. These costs, added to safety and quality concerns, may tip the economics in favor of “discarding” the last 20% to 30% of a resin’s or membrane’s usability.

At the same time, Royce cautioned that saving time does not always translate to financial savings. “It works if you can operate with fewer people, or move more product through the plant with the same number of workers. If trading labor costs for increased consumables cost is the only trade-off, it generally makes sense to go through single use.” But saving time at the expense of idle capacity brings no benefit.

Mimicking Large-Scale Reactors

One of the knocks on early-stage use of disposables is significant difference in form factor between low-volume, development-stage cell culture performed in plastic, and full-scale processing in stainless steel. Richard Mirro, a product manager at New Brunswick Scientific (NBS) provided some insights into this discrepancy and how to overcome it.

He described new products from NBS that include 5 L and 14 L stirred-tank single-use vessels that replicate traditional autoclavable bench-scale reactors “while providing all the benefits of disposable technology.” A key component of the new reactors is their stirred-tank design, which mimics agitation mechanisms in larger stainless steel bioreactors.

“The downside of competing products is the difficulty in transferring from a rocker-based system to a 5,000 liter fixed-tank system,” Mirro said. “Unless you’re transferring to a similar system, there are scalability issues.”

The new bioreactors are constructed from translucent, USP Class 6 polycarbonate or polystyrene, making the reactors light and easy to move around, Mirro noted. They are fitted with noninvasive pH and dissolved oxygen sensors. As fully disposable systems, they require no cleaning or autoclaving or unthreading of ports or head plates. “You wouldn’t ever think they were made of plastic,” he said.

What if someone is tempted to re-use them? “The reactors are designed specifically to prevent re-use,” Mirro assured. “You can’t clean or disassemble them without damaging them. They’re basically uncleanable, and because they’re made from plastics they can’t be autoclaved without deforming.”

The single-use bioreactors are a bit more expensive than plastic film bio-bags, but their advantages more than make up for the extra cost, according to Mirro. “Compared with a traditional reactor, dollar for dollar, you’re either breaking even or saving significant money if you calculate in autoclaving, cleaning solutions, and validation, plus the additional effort saved in tech transfer and upscaling.”