Continuous Fermentation: Is It Right for Your Process?

One of the most frequent questions we receive is: What are the benefits of continuous fermentation compared to more common approaches like fed-batch or draw-and-fill? The answer, as with most things in fermentation, is that it depends on several key factors. Let’s explore.

Continuous fermentation is not a new concept. It has been successfully used for decades in biomass production (e.g., Quorn, Calysta). In its purest form, continuous fermentation is a steady-state operation: nutrients are constantly being added to the fermenter at the same rate that fermentation broth is being removed from the fermenter.

More recently, this definition of continuous fermentation has been expanded to include processes that use two-stage growth and production. In this configuration, there is continuous biomass growth in one fermenter, followed by product formation in multiple secondary fermenters.

This modified version of continuous fermentation is a much better fit for precision fermentation products and has also been built at scales of millions of liters. Our Richmond facility is capable of supporting this two-stage growth and production configuration.

For those deeply involved in commercial fermentation (“Ferm Nerds”), we’ve previously shared a technical analysis highlighting the challenges of continuous operations in precision fermentation, such as strain instability and contamination risks. Here, we’ll take a step back to provide a simpler analogy and focus on the perceived productivity gains.

Understanding Productivity: A Car Race Analogy

Think of continuous fermentation as a 24-hour race between a sports car and a minivan. This isn’t just a test of speed or endurance but a combination of both. The sports car can reach a top speed of 120 mph but can only run for 20 hours before needing a 4-hour break (83.3% availability). The minivan, on the other hand, has a lower peak speed of 90 mph but can run for 23 out of 24 hours (95.8% availability).

Who wins the race? It depends on which vehicle achieves the higher time-weighted average speed. In this example, the sports car travels 2,400 miles in 24 hours, while the minivan covers 2,070 miles. Although the minivan runs more continuously, its lower peak speed makes it less efficient overall. However, as the minivan’s speed approaches that of the sports car, the gap closes significantly.

In fermentation, “average speed” translates to productivity—how much product a process generates per unit of time. Productivity is the most critical metric in precision fermentation, and it’s the basis for comparing different approaches.

The Big Picture: Productivity and Process Economics

When evaluating fermentation processes, it’s critical to take a holistic view of productivity. This means considering not only how much product is generated per unit of time but also the total fermentation capacity required. In continuous fermentation for precision fermentation products, productivity often involves a two-stage configuration: continuous biomass growth in one fermenter, followed by product formation in multiple secondary fermenters. This is in contrast to fed-batch processes, where everything occurs in a single vessel.

To fairly compare continuous and batch processes, all fermenters in the system need to be accounted for, as well as the time required to clean, sterilize, and turn around batch fermenters at the end of each cycle. Productivity gains in continuous fermentation can sometimes come at the expense of complexity, requiring additional vessels or operational changes.?

However, optimizing fermentation productivity alone doesn’t guarantee better overall economics. Any gains upstream must align with downstream processing (DSP) capabilities. For example, pushing a strain to maximize product formation might increase impurities or byproducts that complicate DSP, offsetting any upstream improvements. The best processes strike a balance between fermentation productivity and downstream efficiency to achieve the most cost-effective outcome.

Downstream Processing: A Major Factor

DSP is one of the largest cost drivers in precision fermentation facilities, accounting for roughly half of the total capital investment. In a properly designed facility, DSP systems are engineered to handle the highest expected fermentation productivity without becoming a bottleneck. This ensures that fermentation and DSP operate in harmony, maintaining a steady flow of product through the facility.

While continuous fermentation can improve upstream efficiency and reduce fermentation-related capital costs, its impact on DSP costs is often limited. For instance, increasing the productivity of a continuous process may not simplify or reduce the cost of downstream recovery systems. In fact, if the continuous fermentation process introduces variability or additional impurities, DSP may need to compensate with more complex or costly operations.?

A good example is methanol-fed Pichia pastoris. While it is less productive than other organisms like filamentous fungi, it excels at producing target proteins with minimal impurities, simplifying DSP. This highlights why a holistic view of the entire process—fermentation and DSP combined—is essential to determine the most efficient and cost-effective overall setup.

Conclusion

At Liberation Labs, we view continuous fermentation as a valuable tool in the fermentation toolkit. However, its suitability depends on demonstrated performance and its impact on both upstream and downstream operations. By taking a holistic approach, we aim to ensure that any process improvements ultimately enhance the overall economics and efficiency of production.

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