Fermentation Facility Retrofit - What Makes the Best Sense?

Fermentation is the core technology behind a range of industries and products, from corn ethanol to active pharmaceutical ingredients. Based on the industry, there are direct implications for process requirements, fermenter design, and facility design standards.

Last month, we discussed the basics of fermentation and various operating modes that can be utilized to enable the most productivity from a facility. This month, we will expand into a detailed discussion of the different types of fermentation facilities to help determine the best fit for a process and whether legacy or idled facilities could be suitable for retrofit.

How Fermentation Process Impacts Fermenter Design (and vice versa)

In new build facilities, fermenters are designed to achieve process requirements and optimize product output. In existing facilities, a careful assessment of fermenter capabilities needs to be performed to understand potential process limitations. The key design criteria for fermenters are oxygen transfer rate, cooling capacity, and sterile design.

Oxygen consumption, or oxygen uptake rate (OUR), refers to how much oxygen the microorganism consumes to make the target product, while oxygen transfer rate (OTR) is how much oxygen is delivered and available in the fermenter for the microorganism to consume. In anaerobic fermentations, the microorganism does not need much oxygen to produce the target product (low OUR), so the fermenter is not designed to deliver much oxygen (low OTR). At the other end of the spectrum, in highly aerobic fermentations, the microorganism requires a lot of oxygen (high OUR), so the fermenter must be designed to deliver a lot of oxygen (high OTR).

How is oxygen delivered and made available to the microorganism in the fermenter? The key levers are:

• Aeration rate: how much air is bubbled in through the sparger.
• Mixing rate: how fast the agitator, or stirrer, is mixing determines how small the bubbles are broken up into. Smaller bubbles result in higher oxygen transfer.
• Fermenter backpressure: applying pressure in the fermenter helps dissolve oxygen into the liquid, resulting in higher oxygen transfer.

High OUR processes are likely to require significant mechanical agitation or stirred tank reactors (STR), while lower OUR processes may use airlift or bubble columns.

A secondary design consideration to oxygen consumption is cooling capacity. When microorganisms consume oxygen, they produce metabolic heat. This heat needs to be removed via fermenter cooling to maintain the fermenter setpoint temperature. When evaluating an existing fermenter, if the cooling capacity is limited or non-existent, then oxygen must also be limited, and process performance may become compromised. In fermenter design, there are a few ways to remove heat: internal cooling coils, tank jacket, and external cooling loop. These options range in efficiency of heat removal as well as sterility risk.

Aseptic or sterile design refers to the design considerations that keep the fermentation clean, or free from foreign microorganisms, for the duration of the fermentation. Some fermentation processes are inherently less prone to foreign contamination, operating at either high or low pH, using a non-sugar feedstock, or having high growth rates that enable the target microorganism to outcompete the foreign microorganism.

At the other end of the spectrum, fermentations that operate at a neutral pH, use a sugar feedstock, or have slow growth rates will be more susceptible to foreign microorganisms. For those more susceptible fermentation processes, the fermenter design must ensure sterility to consistently produce quality product.

For aseptic fermentations, sterile design is achieved by creating a boundary around the sensitive fermentation area. In other words, everything coming in or going out of the fermenter is sterilized by one of two primary methods: heat or filtration. Heat above 130°C is used to kill all undesired microorganisms. This can be done by sparging steam into the fermenter, or, in the case of raw material streams like sugar or media, heating up to a target temperature for a short period of time.

Components that are heat sensitive, like some trace media additives, are sent through a 0.2-micron filter (commonly known as a sterile filter in the fermentation industry) that ensures no organism makes it into the system. Figure 1 below summarizes how a sterile boundary is maintained.

• Sterile Filters (SF) are 0.2 micron filters that provide a sterile barrier for gasses/liquids entering the system
• High Temperature Short Time (HTST) heat sterilization thermally kills organisms with 130C heat
• Clean in Place (CIP) is a hot (60C) caustic solution sprayed in the top to clean the fermenter to bare metal
• Steam in Place (SIP) is steam directly injected into the fermenter to heat to 130C
• Surfaces Matter – fermenter and piping surfaces are polished to keep organisms from grabbing on
• Double block and bleed is a system where all valves in the system that are open to atmosphere are double valved with a steam bleeding through a small drain so no organism can make it into the boundary

Fermenter Design Standards based on Industry

Fermenter design standards can vary significantly due to the diverse range of fermentation processes used across various industries. However, the similarity in core technology often prompts the question of whether existing facilities can be repurposed for precision fermentation. Before diving into the economic benefits of repurposing or retrofitting, it is important to understand the fermentation design standards for each industry:

• Pharmaceutical facilities have the most stringent design standards. Their fermentations are typically aerobic and operate aseptically, meaning they aim to have no foreign microorganisms other than the target organism at the end of the process. To achieve this, pharmaceutical fermenters are pressure vessels capable of steam sterilization, equipped with high agitation and substantial cooling capacity. Despite being modest in scale, they result in the highest capital cost for construction.
• Industrial biotechnology facilities, for food and chemicals, follow the pharmaceutical standards as a guide but often make risk-based decisions to reduce cost and increase capacity. While their focus is on clean batches, strict sterility may not always be a requirement, as certain products have limits on allowable non-target organisms. Like pharmaceuticals, these fermentations are usually aerobic and require pressure vessels for steam sterilization, though they may have a lower polishing finish than pharmaceutical vessels.
• Wine-making facilities require a different design standard primarily because their fermentation is anaerobic. As oxygen is unnecessary in this process, fermenters are designed with minimal cooling capacity. The presence of alcohol inhibits foreign microbial growth, reducing the need for high sterility requirements. Because these simple fermenters use a lower design standard, they are more cost-effective compared to pharmaceutical or industrial biotech fermenters.
• Beer brewing facilities are similar to winemaking but involve larger-scale and faster fermentation. Typically anaerobic, beer fermentation requires minimal mixing and cooling capacity. The fermenters are often polished to a similar standard as food-grade vessels but are not pressure vessels capable of heat sterilization.
• Traditional corn ethanol fermentation follows a low-cost standard and differs significantly from advanced biotechnologies. Sterile design is less critical in corn ethanol production, relying instead on the core microorganism to outcompete foreign microorganisms. These fermenters are simple in design, with lower polishing finishes, limited cooling capacity, and no agitation or aeration requirements.

The following table (Figure 2) outlines key technical parameters, highlighting the key differences in design and operational standards across industries:

Why Retrofit Fermenters Often Don’t Work

Whether an existing fermenter designed for one purpose can practically and cost effectively be used for another depends on the key design criteria described above: oxygen transfer rate, cooling capacity, and sterile design. If there is good alignment across those design criteria, a retrofit scenario warrants a closer look. Conversely, a highly aerobic fermentation that requires aseptic operation, as many precision fermentation processes do, has a low probability of success in a non-sterile beer, wine, or corn ethanol fermenter.

The appeal of retrofitting and repurposing existing fermentation capacity comes down to capital savings. Aseptic, aerobic fermenters can be about 10X the capital cost of non-sterile, anaerobic corn ethanol fermenters on a fermenter volume basis.

What drives that cost difference? To ensure aseptic operation, the fermenter needs to be steam sterilizable, which means it needs to be pressure rated to at least 25 psi and vacuum rated. Interior surfaces need to be polished for cleanability, and sterile filters can be expensive. To provide enough oxygen, the fermenter needs a high-powered agitator and high aeration rates, which means large air compressors. High oxygen consumption requires subsequent heat removal and large cooling capacity, which requires chillers. When properly designed, aseptic aerobic fermentation systems are capital intensive, and building new can cause sticker shock.

While retrofitting can initially save on capital expenditures, the long-term success and viability of the fermentation system hinge on its ability to meet the necessary design criteria, especially regarding sterility. A fermenter that is purchased without the ability to be steam sterilized cannot be practically retrofitted for aseptic processes like most precision fermentations. If the system does not run sterile, there are limited options to correct it.

Ignoring these critical factors may lead to compromised process performance and potentially incur higher operational costs in the future. Capital cost savings from a decreased sterile design are real and could be a significant benefit, but need to be proven effective before heading down what can be the RRP - Risky Retrofit Path.