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Making Proteins

Companies tackle challenge of scaling up production of biopharmaceuticals

by Patricia Short
October 2, 2006 | A version of this story appeared in Volume 84, Issue 40

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Credit: SAFC
Segregated facilities for plant and animal protein purification will be added at SAFC's St. Louis site.
Credit: SAFC
Segregated facilities for plant and animal protein purification will be added at SAFC's St. Louis site.

Last month, SAFC began construction of a protein purification facility that will be, when it is completed next April, one of the largest such facilities in the world. Built to current Good Manufacturing Practice standards, the $16 million facility will process proteins from natural and transgenic plant biomass, as well as from the more traditional animal sources.

The facility, at SAFC's home complex in St. Louis, will be capable of purifying commercial quantities of therapeutic recombinant and nonrecombinant proteins, marking the company's entry into this business.

In all, it will have 22,000 sq ft for processing of plant proteins, according to Frank Wicks, president of SAFC, the fine chemicals business of Sigma-Aldrich. A separate, segregated unit for animal-sourced proteins will have another 20,000 sq ft of space for production and an adjacent 5,000-sq-ft clean room for downstream purification.

The St. Louis facility has long been able to extract proteins from plants and animals, but it hasn't been able to carry it out to the current Good Manufacturing Practices (cGMP) standards required by pharmaceutical industry customers. "We've tried to do it with existing capacity," Wicks said, but that worked only for early-stage products.

"Because some of those early-stage projects are now moving down the pipelines, the supply requirements have been increasing. We believe this is a new and growing market," he added.

SAFC officials say the new facility will be one of the few in the world capable of extracting therapeutic proteins from transgenic plants and animals in commercial quantities and to cGMP standards.

Biotech-modified plants and animals are joining microbes and mammalian cells as new mediums in which to grow biopharmaceuticals. But regardless of the host organism they use, drug firms are under pressure to make biopharmaceuticals more efficiently. That was one of the points made at last month's "Biopharm Scale-up" conference in Geneva, which addressed the topic of how to scale up production of such materials from the laboratory to the manufacturing plant.

At the heart of such work, said keynote speaker Florian Wurm, professor of biotechnology at the Swiss Federal Institute of Technology, Lausanne, is a holistic understanding of the process involved. "We have to understand the complete systems' not just the mechanics such as stirring or oxygen transfer," he said.

Process scale-up, however, poses a raft of engineering problems, said Bo Kara, head of expression and cell sciences at Avecia. Some of these, he said, are predictable problems such as oxygen transfer, mixing times, heat transfer, power input, and aeration.

Less predictable, though, are problems such as genetic stability, product stability and degradation, foam, cell debris, and sterilization, which can affect temperature-sensitive components.

Wurm predicted that mammalian cells will be the dominant means of producing biopharmaceuticals "for at least the next 20 years," given the high yields that can be obtained for large and complex proteins. "In 1986, the typical yield was 50 mg/L," he said. "In 2004, it was more than 5 g/L. Each time we've expanded the number we've said, 'that's high.' But there is no reason why we can't go to 25 g/L."

On the other hand, Rainer Fischer and Stephan Hellwig, of Germany's Fraunhofer Institute for Molecular Biology & Applied Ecology, argued that the niche market of plant-based processes-which SAFC is pursuing-"has come of age."

Researchers received a tremendous morale boost in January, when Dow AgroSciences received the first regulatory approval from the U.S. Department of Agriculture for a plant-made vaccine, said Hellwig, head of the institute's integrated production platforms department. "Dow doesn't intend to market the product," he pointed out, "but this sets the stage???it is paving the way for something they have in mind for later."

Fischer, senior executive director of the institute and head of its molecular biotechnology department, drew some comparisons among the three main protein production systems: microbes, mammalian cells, and transgenic plants.

Microbe-based systems are currently commercial, he noted, providing low-cost, proven fermentation technology. On the other hand, he pointed out, more complex proteins "absolutely cannot be done in an Escherichia coli system." And animal cell expression, using animal and insect cells, can handle active complex proteins but tends to be high cost, he said.

Transgenic plant technology, Fischer argued, has several advantages: low initial investment, use of edible crops, and no pathogen contamination. On the other hand, he conceded limitations: Some crops cannot be regenerated, and they are all vulnerable to weather conditions.

"Leaves give the highest biomass but the lowest stability," he said. "You must harvest and process them very quickly. Seeds have slightly lower yield but very high stability."

Fischer is a strong proponent of the tobacco plant—cultivars in the genus Nicotiana—for biopharma expression. "We have cloned five new, different proteases from tobacco. The higher the cell density, the higher the proteolytic activity," he added.

But Fischer conceded that plant systems for biopharma production "are five to 10 years behind" the other systems in terms of process development and investment.



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