Succeed at bioprocess scale-up

While fermentation-based syntheses were once reserved for producing high-value specialty chemicals and biopharmaceuticals, bioprocess routes now are gaining increasing attention for commodity products.

By John L. Shaw, P.E., and Scott A. Rogers, P.E., CH2MHill Lockwood Greene

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A common framework

Irrespective of the microorganisms used or the end products produced, most fermentation-based facilities employ the same basic production blocks. And all commercial-scale bioprocess facilities can be roughly divided into two sections:

  1. The upstream biosynthesis operation, where the desired end product is made, typically involves highly proprietary methods and calls for rigorous sterility requirements.
  2. The downstream portion employs a site-specific mix of widely used chemical-engineering unit operations to extract and purify the target product, and appropriately dispose of all waste streams.

The particular engineering requirements (and challenges) associated with each of these two distinct portions differ, but must be tightly integrated during process design to ensure the most-cost-effective plant operation.

Fermentation. Each of multiple fermentation vessels required by a commercial-scale facility will have its own particular design and operating requirements. These include: the need to introduce the fermentation broth, sterile air (both to maintain the required dissolved oxygen levels and provide air lift for low-shearing mixing inside the vessel) and sterilized nutrients (such as vitamins, amino and fatty acids, minerals and even antibiotics that ensure the health and maximize the productivity of the microorganisms). When air lift in the vessel can't provide sufficient mixing, the fermenter may be equipped with low-shear agitation devices.

Fermentation vessels must also be designed to ensure adequate heat-removal capabilities (to handle heat produced by the metabolic processes) and promote cooling as needed (to maintain the narrow temperature range that can be tolerated by the bioengineered organisms). Sufficient safeguards must also be in place (both through design elements and operating procedures) to guard against contamination and cell mutation. These include double-block and bleed valves, and steam-in-place (SIP)/clean-in-place (CIP) systems. Meanwhile, the variable flow rates associated with different stages of the organism's metabolism and growth cycle, and the required cleaning cycles have tremendous design implications for the turndown necessary for process parameters (including flow and pressure). All of these factors complicate the internal geometry (in terms of baffles and agitators, for instance) of the vessel, as well as the number, location and type of tank nozzles and ports needed.

In addition, commercial-scale fermentation vessels must be equipped with a variety of advanced instruments, sensors and transmitters to monitor everything from pressure, level and temperature inside the fermenter to pH, dissolved oxygen and nutrient levels within the fermentation broth. In some cases, the number of in-line monitoring devices needed can be reduced by using external lab sampling or indirect relationships between key operating parameters. The appropriate number and location of the analytical instruments and in-process checks must also be reconciled against capital and operating cost constraints, and sterilization concerns (an increasing number of instrument ports raises the contamination risk to the bioreactor).

Because fermentation vessels and other specialized equipment components often require long lead times, the ability to make a firm commitment to the desired design specifications in advance — and withstand the urge to make subsequent changes later — will help to control costs and minimize delays.

Production and recovery of derived product. During fermentation, the desired product ends up in the fermentation broth (excreted from the microorganisms or within the cell body). At the end of each batch fermentation, the microorganisms are destroyed; the product is separated and purified; and the dead cell bodies, unreacted carbohydrate feedstock/nutrients and byproducts are removed, concentrated and neutralized prior to disposal.

Purification and concentration. A combination of classical separation operations (such as filtration, evaporation, ion exchange, distillation, crystallization, liquid/liquid extraction, spray drying and direct reaction) are typically used to purify and concentrate the product from the fermentation broth. Increasingly, newer separation techniques (such as liquid chromatography, liquid and catalytic membranes, and supercritical fluid extraction) are finding a role in commercial-scale bioprocess operations.

Waste handling. The dead cell bodies and other solid waste, and the high biochemical-oxygen-demand (BOD) aqueous streams produced throughout the process must be disposed of properly. They must be concentrated and neutralized prior to disposal; an aqueous waste-pretreatment facility is almost always required to reduce the bioload prior to discharge to a landfill or publicly owned treatment works (POTW). The specific handling and disposal requirements are ultimately dictated by the biosafety classification of the microorganisms in the waste stream.

Residual high-BOD aqueous waste streams result and are typically treated in onsite aerobic or anaerobic digesters prior to being sent offsite to a POTW. Aerobic digestion is economically applied for BOD up to 10,000 ppm. Anaerobic digestion is generally used from 8,000 ppm and up, and almost always when BOD exceeds 15,000 ppm. (Anaerobic systems will require further processing when discharging directly to a river but are commonly used for city sewer discharge.)


Pitfalls and opportunities

Several issues deserve particularly close attention during the design and construction of bioprocess facilities, to streamline the overall process, minimize rework and contain costs.

Sterility considerations and tradeoffs. The microorganisms that are used during biological-treatment processes at water- and sewage-treatment plants are notoriously hardy and can handle widely varying operating conditions. By comparison, microorganisms that have been genetically modified to yield a desired pharmaceutical, food or chemical product are typically viable over only a very narrow range of operating conditions and cannot withstand large or sudden variations in temperature, pH, dissolved oxygen, nutrient level, agitation rate and other critical operating parameters. The extreme sensitivity of these highly evolved yet fragile organisms — which has earned some the nickname "metabolic cripples" — creates unique design and operating challenges, particularly when it comes to maintaining close control over all of the critical operating parameters within vessels whose capacities generally exceed 50,000 gallons.

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