Precision Fermentation
The Ghost of Scale-Up
in Precision Fermentation
Luigi Attaianese , Sergio Andreutti , Maria Fenizia
Co-founders, Pre-Fer.bio, Naples, Italy
KEYWORDS
Precision fermentation
Scale-up
Alternative proteins
Protein engineering
Novel Food
AI optimization
Bioprocess engineering design
Joint
Immunity
Abstract
The article discusses the potential of precision fermentation for sustainable protein production and the key challenges of scaling it up. As the global demand for sustainable and ethical food sources intensifies, precision fermentation has emerged as a promising technology for producing alternative proteins. This innovative process, which uses microbial hosts to create proteins identical to those found in animal products, offers a way to reduce the environmental footprint of food production while addressing ethical concerns associated with traditional livestock. However, despite its potential, precision fermentation faces significant challenges when scaling up from laboratory to commercial production. These challenges, which we defined as the "ghost of scale-up," include technological hurdles, economic barriers, regulatory complexities, and the need for environmental and social sustainability.
The Promise and Potential of Precision Fermentation
Precision fermentation is based on the genetic modification of microorganisms, such as bacteria, yeast, or fungi, to produce specific proteins or other valuable molecules. This technology, well-known in pharmaceutical production, has shown great promise in creating ingredients for food products, such as dairy proteins, animal-free. The process can theoretically produce these proteins at a fraction of the environmental cost associated with conventional farming, offering a solution to the pressing need for sustainable protein sources.
Technological and Economic Challenges
Scaling up precision fermentation is not a straightforward task. At the laboratory scale, conditions can be meticulously controlled to optimize the growth and productivity of microbial cultures. However, replicating these conditions on an industrial scale is much more complex. One of the key technological challenges is the optimization of fermentation processes to achieve high yields and consistent product quality at a larger scale. This involves refining the genetic modifications of microorganisms, as well as developing bioreactors that can maintain the necessary conditions for microbial growth and protein expression, defining the correct downstream pathway to obtain product with required specifications (i.e. purity, appearance) on a massive scale.
In addition to technological hurdles, economic challenges can be scary. The capital expenditure required to build and operate large-scale precision fermentation facilities is substantial. These facilities require significant investment in fermentation infrastructure and downstream processing equipment. For many start-ups as well as for smaller companies, securing the necessary funding can be a formidable barrier. Moreover, the cost of raw materials, energy, and labor can make the production of precision-fermented proteins more expensive than traditional animal proteins, at least in the short term. Achieving economies of scale and optimizing supply chains will be critical to making these alternative proteins economically viable.
Approach to Bioprocess Design
Scaling up is not a linear process. A specific approach is required to design a process suitable for commercial-scale production. Process design should start early, right after proof-of-concept, accompanied by a techno-economic analysis to optimize design and reduce the risks and costs associated with scaling up.
Key Considerations in Process Design
- Early Integration: Process design should start right after proof-of-concept. Early planning helps in anticipating potential issues and integrating solutions from the start.
- Techno-Economic Analysis: Perform a techno-economic analysis early in the process to evaluate the feasibility and cost-effectiveness of the design. This analysis helps in making informed decisions about the process and reducing the risks associated with scaling up.
- Iterative Optimization: Scaling up is not merely about increasing volumes; it involves refining the process through iterative testing and optimization to ensure it performs efficiently at a larger scale.
Comparison of Scale-Up Approaches
A classic approach to scale up can be simplified as follows:
- Basis: Design based on laboratory-scale data.
- Process: Involves transferring lab data to a larger scale, often leading to unanticipated challenges and inefficiencies.
- Drawbacks: Risks include unexpected issues during scale-up, potential inefficiencies, and increased costs due to reactive problem-solving.
An agile, integrated approach, that our team promotes, is the following:
- Basis: Integration of diverse expertise from the beginning.
- Process: Involves parallel work streams where lab and engineering teams work together, sharing insights and making adjustments in real-time.
- Advantages: Enhances process optimization, reduces time to scale up, and minimizes errors. Facilitates a proactive approach to problem-solving, improving overall efficiency and reducing risks.
This agile approach provides a more effective strategy for scaling up processes by integrating multiple areas of expertise early in the process and fostering continuous collaboration. Unlike traditional methods that often delay industrial optimization, this approach anticipates process design right from the proof-of-concept stage, allowing for early identification and resolution of potential bottlenecks. By involving both lab and engineering teams from the outset, key factors such as bioreactor configuration, raw material selection, and process conditions can be optimized in tandem, streamlining the scale-up.
A crucial element of this agile strategy is continuous strain engineering, where microbial strains are iteratively refined to improve yield, robustness, and consistency. This allows for faster adaptations to changing conditions, enabling microbial hosts to achieve higher production efficiencies at every step of the scale-up. Simultaneously, strain improvements are assessed in real time for their impact on productivity, cost, and scalability, ensuring that the organism and process are both optimized before reaching industrial scale.
Additionally, the agile approach follows a clear criterion for increasing production volume, based on achieving specific production efficiencies and reducing production costs. Rather than scaling up in a linear fashion, decisions about increasing capacity are driven by measurable performance indicators such as yield, energy use, and resource consumption. By targeting these efficiencies early, this method ensures that volume expansion occurs only when the cost per unit of product is minimized, moving faster towards the Target Price.
In summary, this agile and integrated approach not only accelerates the scale-up process but also significantly reduces associated costs and risks through early process design, continuous strain optimization, and a production scale-up criterion based on efficiency and cost reduction.
The above chart - Based on our real life experience - compares the two approaches, showing the different trend in production costs over time: the classic approach is represented by the red line and the agile integrated approach by the green line which appears to be more effective in lowering costs quickly, reaching the target price in a few years.
Navigating Regulatory Hurdles
Regulatory approval is another significant challenge for scaling up precision fermentation. In order to bring precision-fermented products to market, companies must navigate complex and varied regulatory landscapes. In regions like the United States and Europe, regulatory bodies such as the FDA and EFSA require rigorous safety and nutritional assessments to ensure that these products are safe for human consumption. This process can be time-consuming and costly, especially for novel products that involve genetically modified organisms (GMOs).
Moreover, companies must implement robust quality control measures to prevent contamination and ensure that their products meet the highest safety standards.
Environmental and Social Sustainability
Scaling up precision fermentation production introduces new sustainability challenges. The process requires significant water and energy inputs, and waste management becomes increasingly important as production scales up. Companies must work to minimize the environmental impact of their operations by optimizing resource use, reducing waste and reusing byproducts, and implementing sustainable practices throughout the supply chain.
Social challenges, including consumer acceptance and cultural adaptation, also play a crucial role in the success of precision fermentation. Consumers may be skeptical of foods produced through biotechnological processes, particularly those involving GMOs. Building consumer trust through transparent communication, education, and engagement is essential. Additionally, precision-fermented products must be tailored to fit into diverse cultural and dietary contexts to achieve widespread adoption.
Pathways to Overcoming the “Ghost” of Scale-Up
Despite these challenges, the potential of precision fermentation is too significant to ignore. Overcoming the ghost of scale-up will require a multifaceted approach that includes continued investment in research and development, strategic partnerships, and collaboration across the industry. Innovations in genetic engineering, fermentation technology, and downstream processing are essential to improving the efficiency and scalability of precision fermentation.
Furthermore, building effective regulatory frameworks and engaging with regulators early in the development process can help companies navigate the complex approval processes. By working together, companies, governments, and research institutions can create a supportive environment for the growth of the precision fermentation industry.
Finally, sustainability must be a core focus. Companies must conduct comprehensive life cycle assessments to understand and mitigate the environmental impact of their products. By committing to sustainable practices and addressing social equity, the precision fermentation industry can ensure that it not only scales up successfully but also contributes to a more sustainable and equitable global food system.
Conclusion
The journey from laboratory-scale precision fermentation to large-scale commercial production is loaded with challenges, but it is also filled with opportunities. By addressing the technological, economic, regulatory, and sustainability challenges—and by carefully selecting the appropriate scale-up approach—the precision fermentation industry can overcome the ghost of scale-up and unlock its full potential. With continued innovation and collaboration, precision fermentation can play a pivotal role in shaping the future of food, providing sustainable, nutritious, and widely accepted alternatives to conventional animal proteins.
References and notes
References and notes
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- Leber, J., et al. (2022). "Challenges in Scaling-Up Fermentation Processes for Alternative Proteins." Biotechnology Advances, 50, 107815.
- Miller, C. (2020). "Precision Fermentation: The Future of Alternative Proteins." New Food Magazine.
- Crater, JS & Lievense, J.C. (2018) “Scale-up of industrial microbial processes.” FEMS Microbiology Letters, Volume 365, Issue 13, July 2018 https://academic.oup.com/femsle/article/365/13/fny138/5026621
- MarketsandMarkets Research (2023). "Precision Fermentation Market by Application, Microbe, and Geography - Global Forecast to 2028."
- Towler, G., & Sinnott, R. K. (2013). Chemical Engineering Design: Principles, Practice, and Economics of Plant and Process Design (2nd ed.). Butterworth-Heinemann.