Succeed at bioprocess scale-up

The ability to produce valuable end products via batch biological processes, using such diverse microorganisms as E. coli and other bacteria, algae, mammalian cells, transgenic plants and other host cells, is proving to be a versatile and promising synthesis route for a growing slate of end products (Figure 1). Because such processes rely on the fermentation of renewable carbohydrate feedstocks (from cane, beets, corn, grain and other sources), they have the potential to offer an environmentally friendly and less costly alternative to conventional synthesis routes that are based on petroleum-based feedstocks, which face supply and price pressures (Figure 2).

Figure 1. Biprocessing provides an increasing variety of products, including some commodities, with many more likely.

Figure 2. Crops and agricultural wastes offer a source of renewable feedstocks and more control of raw material costs.

While fermentation-based syntheses were once reserved for producing high-value specialty chemicals and biopharmaceuticals (whose end products may command prices on the order of $400,000 for a 5-mL vial), bioprocess routes now are gaining increasing attention for commodity products. For instance, commercial-scale bioprocess facilities are already producing: vaccines and therapeutic pharmaceuticals (such as Amgen's Epogen and Wyeth's Mylotarg), food products (L-phenylalanine, a building block for NutraSweet), and food-grade additives (such as the algae-derived fatty acid DHA & ARA from Martek Biosciences, which is used as a nutritional additive). Other specialty and commodity biochemical facilities are in the works. For example, BP and DuPont are teaming up to commercialize bio-based butanol as a gasoline blendstock in 2007 (CP, August, p. 15).

Scale-up challenges

While the scale-up of any chemical process can involve a host of issues, the challenges are compounded when the process involves batch fermentation. Due to the typical fragility of the engineered microorganisms, large-scale fermentation vessels must be designed with the ability to:

• remove the heat buildup that results from metabolic processes;
• manage agitation and mixing with minimal shear damage;
• effectively control the highly variable liquid flowrates and turndowns that are associated with batch fermentation; and
• execute safeguards and sterilization techniques to guard against potential contamination.

The engineering challenges are more acute when the fermentation process will be used to make commodity-type chemicals. Because such products don't command premium prices like higher-end specialty chemicals, food additives and biopharmaceuticals, their production facilities often are forced to make engineering tradeoffs in the face of capital, maintenance and operating cost constraints and leaner profit margins.

Additional challenges arise because emerging (non-mature or unproven) synthesis routes often exhibit a high degree of change throughout the scale-up and design stages. With relatively limited project experience with a given route to draw upon, the design team must anticipate and manage changes to the design and construction specifications to minimize cost creep and keep the project on schedule.

One of the most commonly made mistakes during the design of bio-based manufacturing processes is the failure to adequately integrate the experience, expertise and proven techniques developed by the pilot-plant engineers, facility microbiologists and chemists into the criteria for the overall flowsheet, equipment specifications, process and instrumentation diagrams, and waste-handling systems. The members of the design, operations and maintenance teams that will set these criteria are generally added closer to startup and face tremendous task and time constraints to be ready for commercial operation, diminishing their availability for technology-transfer efforts. However, during the specification of commercial-scale equipment and controls, it is crucial to study and adapt the administrative and manual tasks carried out during pilot-scale operations, such as those related to closed-vessel policies, material handling, cleaning, waste handling and other operational aspects. A well-integrated team approach, with a common project view of the need to balance cost constraints against sterility needs, is essential.

"Bio" issues

When producing pharmaceuticals and food additives, product contact streams are regulated by the U.S. Food and Drug Administration and, possibly, by the U.S. Department of Agriculture in the case of biosynthesis. By comparison, chemical facilities are only regulated to keep the genetically engineered organism out of the surrounding environment.

Experience shows that the performance characteristics of various organisms — even those already in use to produce a given product — can be improved through ongoing bioengineering efforts. As a result, "next generation" bugs (such as those with enhanced metabolic activity or less sensitivity to process conditions) are constantly being pursued, to increase the yield of the target product, decrease the batch cycle time, reduce the amount of effluents or undesired byproducts, and cut energy consumption.