The Processes - - BioPharm International


The Processes

BioPharm International

Stirred-tank reactors are simple and familiar, and they scale-up easily from laboratory scale to full production. The problems they present have mostly to do with the damage that can be done to cells by the stirring and aeration process. Collision with the impeller or with the walls of the tank can break down cells, especially delicate animal cells. Gas bubbles released by the sparger subject the cells to surface tension forces; and to fluid mechanical forces from motion, disengagement, and bubbles bursting. Foaming can break cell walls or membranes, killing the cells and releasing lytic enzymes that denature proteins. Designers of bioreactors attempt to control these problems by modifying the design of the impeller and by adding baffles and other elements.

Airlift fermentors are designed to provide a gentler stirring action. Instead of using an impeller, these reactors create circulation pneumatically. Gas is sparged through the base of the vessel, rising in a cylindrical draft tube (the riser) to the surface, creating circulation of the contents of the reactor. They offer good oxygen transfer and easy scale-up, good mass transfer characteristics, and easy control. However, airlift fermentors do expose cells to considerable sparging and thus possible damage. Large-scale systems can require considerable space and large quantities of gases.

Packed bed reactors grow cells on a bed of glass or plastic beads, stainless steel bars, or a number of other materials — fibers, composite fabrics, even bits of seashell. A separate unit oxygenates medium that is circulated through the bed, and an aeration reservoir is used as an airlift pump. In two-chamber reactors , biomass growth occurs in a lower chamber, and cells are lifted to the upper chamber by the moving substrate and settle back down.

Some newer reactor designs attempt to create conditions closer to those found in the body to increase the productivity of animal cells.

Hollow-fiber reactors provide cells with a way to circulate oxygen and nutrients that is a little like the human circulatory system. Animal cells are grown attached to the outside of porous hollow fibers — the same type used in kidney dialysis machines. Fresh medium is circulated through the fibers, allowing nutrients to diffuse through the porous fiber walls to the cells, while toxic metabolites produced by the cells diffuse into the stream flowing away.

Hollow-fiber reactors can achieve great cell densities. In the human body, there are about 108 cells/mL. Stirred tank bioreactors can normally support only about 106 cells/mL. Using hollow-fiber units, biotechnologists have been able to support concentrations of about 107 cells/mL.

High cell density means that more protein can be produced in a relatively compact bioreactor. Complex hollow-fiber reactors are not easy to control. Dead cells can secrete proteases and contaminate the protein products, complicating the process of isolating and purifying the desired protein. Fiber breakage can pose a sterility risk, and the fibers, which come bundled in single-use disposable cartridges, can break, causing a sterility risk.

There are other systems for allowing animal cells to grow in dense concentrations that approximate mammalian tissue. Ceramic matrix systems provide cells with a large surface area to attach to, and pack it into a relatively small volume.

One of the latest developments in bioreactors is the appearance of disposable manufacturing systems. In these systems, cells are grown in plastic bags or in tanks equipped with disposable plastic liners. Disposable systems offer many advantages in terms of scaleup, and they are a cost-effective way to eliminate much of the risk of cross contamination. At the moment, most disposable systems have a capacity of hundreds of liters, but larger systems are already in use for some applications.

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