Bioseparations, the Evolution Continues

Angelo De Palma, Ph.D., Contributing Editor

Disposables and Hybrid Systems Tweak Decades-Old Unit Processes

For years, forward-looking engineers and observers have urged biopharmaceutical manufacturers to embrace new manufacturing technologies, just as the food and chemical manufacturing sectors have. Even the U.S. Food and Drug Administration, through its Process Analytical Technology (PAT) initiative, exhorts biomanufacturers to be more creative and experiment.

But, alas, regulatory uncertainty can make cowards of us all. Demonstrating product equivalence late in development is so costly and risky that many successful biotech companies "just say no"--at least publicly--to downstream process innovation.

Future downstream process innovations will probably trickle up into the conservative mainstream from nontraditional biotech areas such as transgenics and gene therapy, as well as from the plasma products industry, which predates fermentation-based biotechnology. But for now, downstream innovations primarily build on decades-old unit operations. Nevertheless, many of these technology tweaks are reducing manufacturing costs and speeding up commercialization, allowing manufacturers to achieve larger economies of scale or to clear regulatory hurdles faster.

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Throw It All Away

Because of cleaning costs and associated validation issues, disposable purification equipment often appeals to engineer and accountant alike. From filters and housings to chromatography columns and fittings, disposables are sterile out of the box, eliminate product cross-contamination, and best of all, require no cleaning or cleaning validation.

Throw-away equipment is even more appealing when augmented by disposable connectors, valves, and piping. Leading filter and chromatography vendors, including Pall Corp. (East Hills, N.Y.), Sartorius (Edgewood, N.Y.), Millipore Corp. (Billerica, Mass.) and Meissner Filtration (Camarillo, Calif.), are moving headlong into disposables whenever the economics warrant it.

Completely disposable downstream processes have not yet hit the big time for bioprocessors, but pieces of the disposability puzzle are filling in. Combinations of disposable filtration systems, chromatography, and concentration/desalting are available for medium-sized and smaller processes.

"The decision to go disposable is usually based on the value of product, cost of manufacturing, and, to a certain extent, overhead costs of facility and labor,"says Pall's Derek Pendlebury, Ph.D. "Fifteen years ago everyone we talked to said --great idea, not interested. But increased understanding of true biomanufacturing costs has changed their view," Pendlebury says.

Traditionally, purification was be-lieved to make up half of biomanufacturing outlays, assumed to be mainly material and consumables costs. Today, drug-makers also factor in the costs for infrastructure and personnel, which shifts the center of gravity for costs slightly upstream. System time accounted for 54% of total manufacturing costs for one of Pall's European contract manufacturing customers. Of remaining costs, 36% came from materials and 10% from personnel.

To cut its overall process costs, the company focused on reducing system time. It could either lower per-batch costs by increasing the number of batches, or increase batch size. Because sponsors usually fix batch size, increasing throughput was the only remaining option. And because 64% of its manufacturing costs were already fixed, the company decided to increase the number of batches it could process by deploying disposable purification equipment wherever possible.

Chromatography Meets Filtration

Combined unit operations, such as centrifugation and filtration, are improving downstream bioprocess operations. However, hybrid technologies also are taking shape, notably membrane chromatography (MC), which combines filtration and chemical affinity in a single device.

MC, which uses filter media modified with typical chromatography chemistries such as ion-exchange groups, is replacing column chromatography in some niche applications such as final polishing and virus/endotoxin removal. Because membranes are thin, companies stack them to achieve desired capacity. Newer formats such as spiral wound membranes are another way to achieve higher specific capacity.

Lately, MC has begun to take on the look and feel of traditional column chromatography. Sartorius, for example, now specifies its MC products by bed volume, just as chromatography vendors have done for decades. More significantly, bioprocessors have stretched MC's protein-binding capacity beyond polishing to medium-volume bioseparations.

Although MC?s capacity still doesn't touch that of classical media, multiplexed MC media offers surprisingly robust ---and lightning-fast---separations.MC and gel chromatography are complementary, says Maik Jornitz, group vice president at Sartorius North America. "Processors appreciate the combination for its simplicity, speed and reusability," he says. Typically, users run MC cartridges in parallel for scaleup, then serially to obtain a sharper breakthrough curve, according to Jornitz. MC media resist degradation at up to 1,000 cycles and are also easier to clean than chromatography gels.

What they lack in capacity, chromatography membranes make up for in speed, especially for removing low-concentration contaminants. For example, Pall's Posidyne membranes are functionalized with cation exchangers for removing endotoxins.

Mustang, another Pall membrane chromatography product, uses low protein binding polyether sulfone backbones and a higher cationic exchanger loading for protein polishing and purification of oligonucleotides. The membranes offer potential savings in complex bioprocesses such as conjugate vaccine manufacturing.

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