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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As noted earlier, the microorganisms in a given fermentation broth are highly susceptible to the presence of impurities. Therefore, it is critical to guard against potential contamination. The most common sources of contamination are invasion by phage infections (rogue cells unique to each facility) and mutations within the bioengineered organism population. Such occurrences not only lead to the disposal of the valuable fermentation batch but also call for an immediate shutdown for sterilization and cleanout.

Master cell cultures are typically created and maintained offsite to minimize the possibility of mutations and phage infections. Nonetheless, the facility's approach for sterilization, cross-contamination prevention and routine cleaning must be identified early to ensure the piping and equipment configuration meets the intended cycle time and sterilization objectives.

When it comes to addressing sterility concerns, bioprocess facilities that produce high-value specialty chemicals and pharmaceuticals often can easily justify the very best sterile equipment and components. However, commodity biochemical facilities will not be able to afford such luxuries as large-pipe-diameter diaphragm and sanitary valves, sanitary tubing, specialized aseptic fittings, removable components and instruments, automated SIP/CIP systems, and ultra pure water for process use. Indeed, bioprocess facilities producing lower-margin commodity chemicals are often forced to balance budget-related engineering tradeoffs without compromising process sterility. This can be accomplished by using appropriate lower-cost equipment components (e.g., standard industrial valves with welded pipe connections) with more rigorous SIP/CIP procedures and valve preventative maintenance.

The compressed air system is one important example of an element demanding close attention. It provides the huge volumes of air used to deliver oxygen and air-lift capabilities to the fermentation vessel. Designing systems that adequately filter airborne contaminants and bacteria, and remain dried (to avoid entrained condensate carrying bacteria through filters) requires design rigor. This is particularly crucial for facilities operating in hot, humid climates. Retrofitting after the fact is very costly.

Extreme operating variances. Due to the cyclic nature of batch fermentation, bioprocess facilities typically have enormous tankage requirements and highly transient flow rates, which call for very complex pump and valve assemblies (both in terms of the number of components needed and their necessary turndown capabilities). To cost-effectively achieve turndown rates as high as 15:1 (flow requirements that can vary from 1,500 gpm to 100 gpm from a single device), bioprocess facilities often contain a significant number of pumps equipped with variable-frequency drives (VFDs) and extensive control-valve systems, both of which increase capital costs and software-programming effort.

Operating costs. Recycle and energy reuse are the standard for successful biologic commodity products. Commercial-scale fermentation facilities handle enormous volumes of water and steam (with varying composition and temperature) from fermentation, purification, evaporation and cleaning systems. Dynamic/transient mathematical modeling programs offer an invaluable tool to help designers identify the water and energy pinches and, thus, to strategically combine water streams of varying composition and temperature to achieve maximum water and energy recovery. Such modeling can ensure that the overall flowsheet has the appropriate number and size of tanks and piping arrays to maximize water and energy reuse. With non-mature processes, significant changes in these areas can be expected as new information surfaces throughout design.

The location of the facility provides another opportunity for cost minimization. For instance, the ability to co-locate a fermentation-based manufacturing plant near a low-cost source of carbohydrates, such as a facility that is processing grain, corn, beets, sugar cane and other farm-derived products, can help to reduce both raw-material and transportation costs.

Bioprocesses require removal of large volumes of water. So, considerable operating savings can be realized by opting for today's highly efficient separations technologies, such as evaporation with mechanical vapor recompression and multiple-effect evaporators. In general, low-energy evaporation is essential in commodity bioprocesses to keep operating costs aligned with product costs. However, getting from vendors design information essential in sizing utilities and building takes time; expect three to four months to pass before usable information is received. This, along with appropriate expediting resources, should be factored into the original design schedule and staffing.

Proper design of the waste-disposal facilities can also help to contain operating costs. Typically, the initial solids separation (cell/product) is done in complex unit operations, and the solids are further dried using standard press, plate, belt or drum dryers before being sent to a landfill for disposal.

Biosafety. The U.S. Environmental Protection Agency and the National Institutes of Health have issued guidelines for handling of many of the commercial microorganism strains. In addition, in the U.S., Toxic Substances Control Act regulations establish procedures for commercializing new or modified strains.

The biosafety classification of the microorganism used in the fermentation process will determine what level of containment is required for operations such as sampling, offgas venting and waste disposal to minimize the potential for biohazard risk to personnel and the environment. Certain criteria must be met for the containment and deactivation of the microorganism — using "any combination of engineering, mechanical, procedural, or biological controls designed and operated to restrict environmental release of viable microorganisms from the structure."

Long-lead equipment. While the design and operation of liter-scale fermentation vessels used during bench- and pilot-scale testing is relatively easy, considerable complexity enters the picture when the process makes the jump to commercial-scale capacities. Such facilities typically require a mix of ASME- and API-specified vessels. Fermentation vessel design must account for the high pressures and temperatures needed for sterilization as well as the large capacities required, up to several hundred thousand gallons. Such large-scale vessels require field fabrication, with internal finishes often calling for extensive hand polishing and passivation. Material lead times and site construction presence must be factored in during the planning stages. Other long-lead equipment typically include large vendor packages needed for purification — such as filtration skids, distillation and extraction columns, mechanical recompression equipment and spray dryers. Insufficient planning related to transportation, vessel fabrication and erection, welding and finishing — particularly when the work onsite could interfere with the timely execution of foundation preparation and other construction activities at the site — is often to blame for delayed startup.


Successful scale-up

The identification and genetic engineering of a suitable organism, followed by prudent piloting certainly is crucial to success with bio-based manufacturing. So, too, is effective technology transfer from the development effort and adequate attention to practical design issues. As is so often the case, a scale-up strategy that combines integrated teamwork with solid engineering efforts can go a long way to minimize costly rework and delays, and help today's promising manufacturing routes based on renewable feedstocks to achieve their full commercial-scale potential on time and on budget.


John L. Shaw, P.E., is a senior technology manager for CH2MHill Lockwood Greene, Spartanburg, S.C. E-mail him at


Scott A. Rogers, P.E., is a process engineer for CH2MHill Lockwood Greene, Spartanburg, S.C. E-mail him at

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