Batch Bioprocesses

The workhorse of the bioprocess industries is still the batch fermenter (also spelled fermentor). There were already fermentation vats such as those for beer, whiskey, pickles, or sauerkraut, but conventional design evolved during World War II in the 1940's as the antibiotic companies scaled up from shake flasks and milk bottles to stirred tanks with features to discourage entry of contaminating organisms. Typical sizes for production fermenters are 60,000 to 200,000 liters, but there are a few that are considerably larger. One famous fermenter known as the Merck hot dog was a cylinder laying on its side with four or five agitators mounted along the top. Its dimensions were 3.6 m (12 ft) diameter by 27m (89 ft) long. The world's largest industrial fermenter is still the ICI's air lift system first operated at the Billingham, U.K. plant for making single-cell protein in 1979. See photos from previous assignment about industrial fermenters.
The size of a fermenter is limited by ability to remove the heat generated by metabolism. Volume goes up by a dimension cubed while area depends on a dimension squared. This means that the volume of culture fluid overwhelms the heat transfer area when the fermenter is very large. Products based on genetic engineering tend to be produced in small amounts and are suited to much smaller bioreactors. Furthermore, they tend to be associated with plant or animal cells that grow slowly and are very easily contaminated by microorganisms.

It is incorrect to call protection of the desired culture sterile technique because sterility means that no life is present. Harboring the desired organisms while preventing the growth of others is aseptic technique. Precautions in the laboratory can be relaxed somewhat to expedite work output because occasional losses are not costly. A pilot plant that very infrequently encounters contaminated runs is considered excellent, but the economic loss of one full-size, production fermenter to contamination is cause for alarm. This was not always the case, and the first large scale antibiotics plants battled contamination while aseptic technique was perfected. Infections by phage were particularly difficult to combat because the virus particles are small enough to escape capture by the filters used to sterilize the air provided to the fermenters. Phage attacks were overcome by switching to resistant strains of the microorganisms.
 If you need review on phage (bacteriophage), click here. This is not a local URL; you may have to wait while it downloads.

Production cultures derived from plant, animal, or insect cells grow on expensive medium that contains many more special nutrients than found in the media for antibiotics, vitamins, and other products with bulk markets. The organisms that make antibiotics, in particular, are relatively easy to cultivate because their products discourage the growth of other microorganisms. Cell cultures, in contrast, have no self-protection and cannot compete with hardy, rapidly-growing microorganisms that find the media delectable.

Although there are many alternative designs, roughly 85 per cent of the fermenters in the world resemble closely the traditional design. Much more about fermenter layout could be added to our computer exercise. Foam sensing and the delivery of antifoam agent were not shown. The header for inoculation and harvest, pH electrodes, feeding systems, and other appurtenances are important to biochemical engineers. Also of great interest is interfacing with computers to monitor and control fermenters. You can appreciate that the pipes, fittings, wires, and sensors of a fermenter constitute a complicated system in which many things can go wrong.

Typical bioprocessing is considered a batch operation even though air and antifoam are added during the run. Adding nutrients or precursor compounds during the run gives rise to a fed batch system. The fed batch fermentation has become highly popular because concentrations and conditions can be adjusted to maximize production.

  • Concept of the limiting nutrient
  • Fedbatch culture
  • Relating product to growth
  • Backseeding
  • Using differential equations
  • Synchronous culture
  • Teaching games
  • References 
    Taken from BASIC Biochemical Engineering.