Fermentation optimisation: challenges and opportunities

Fermentation is a key biotechnological process for the production of various bio-based products, such as fuels, fine chemicals, personal care products, agrichem products, pharmaceuticals and food ingredients. Fermentation process development and optimisation involves the intensification of microbial cell factories and strains, culture media, bioreactor design and operating parameter conditions to increase titre, productivity, yield and attributes critical to quality. However, fermentation process development faces several challenges, such as the complexity of microbial metabolism, the variability of biological systems, biomanufacturing scale-up and technoeconomic challenges. In this article, we discuss fermentation process development, focusing on fermentation screening, optimisation, robustness testing, scale-up, fermentation characterisation, strain improvement and bioreactor optimisation.

fermentation optimization

What is fermentation optimisation?

Fermentation optimisation is the process of finding the optimal values of process variables, such as temperature, pH, dissolved oxygen, nutrient composition, critical substrate delivery and mixing characteristics that maximize desired fermentation and commercial performance. Fermentation optimisation can be performed using various methods, such as design of experiment (DoE), classical experimental design or machine-learning / AI-guided approaches. Fermentation optimisation has many product-specific objectives. For instance, improving fermentation efficiency (the ratio of the product yield to substrate consumption), to reduce the production of unwanted by-products (such as ethanol, acetate and lactate), to reduce the time of the overall process and to reduce the overall cost of the process in other ways, such as reduced costs of raw materials and unit procedures for the process. Product quality can also be improved through fermentation optimisation, by finding optimum parameter ranges that facilitate production of a fully functional and highly active product. Fermentation optimisation also helps to enhance the consistency and robustness of the fermentation process.

What is involved in fermentation scale-up?

Fermentation scale-up is the process of transferring a fermentation process from small-scale (laboratory bench) R&D to a large-scale industrial setting (technology transfer), while maintaining or improving the fermentation performance. Fermentation scale-up involves the consideration of various factors, including:
  • Geometry, size and configuration of the bioreactors
  • Mass transfer and mixing characteristics
  • Heat transfer and temperature control
  • Aeration and oxygen supply
  • Feed and product removal
  • Process monitoring and control.

Fermentation scale-up can be performed using various approaches, such as geometric, dynamic and kinetic similarity, or empirical correlations and models. Fermentation scale-up aims to achieve high product concentration, productivity and purity, whilst minimising the capital and operating costs and ensuring the safety and reliability of the fermentation process.

What is fermentation characterisation?

Fermentation characterisation is the process of measuring and analysing the physical, chemical and biological properties of the fermentation process, including:

stirred tank reactor fermentation improvement
  • Reactor design, geometry, mixing characteristics and fluid rheology
  • Biomass, substrate, product, and by-product concentrations
  • Metabolic flux and rates
  • Enzymatic activity and gene expression

Fermentation characterisation helps to understand the mechanisms and dynamics of the fermentation process, identify the key factors and parameters that affect fermentation performance and to provide data and information for the development and validation of fermentation models and simulations.

How can strain engineering and strain improvement help in fermentation optimisation?

Strain improvement is the process of generating and screening variant microbial strains to select those with enhanced or novel fermentation capabilities. Strain improvement can be performed using various methods, such as random mutagenesis (chemical or UV), directed evolution, metabolic engineering, synthetic biology and genome editing. Strain improvement can be facilitated by the use of various tools, such as low volume or microtiter plate systems, automated liquid handling and sampling, design of experiments (DoE) and rapid and sensitive analytical methods. High-throughput strain improvement aims to select for improved microbial strains with more consistent and improved fermentation capability.

What is the role of bioreactor optimisation in fermentation optimisation?

Bioreactor optimisation is the process of designing and operating the bioreactors that support the fermentation process (microbial strain cultivation), to provide the optimal environment and conditions for the microorganisms and the product formation. Bioreactor optimisation can be performed using various methods, such as computational fluid dynamics, process technoeconomic modelling, simulation, process control, automation, online sensors and actuators. Bioreactor optimisation aims to improve the mass transfer coefficient, mixing efficiency and reduce heterogeneity to improve heat transfer, temperature control, aeration, critical oxygen levels, limited substrate feed, product, and the monitoring and control of the bioreactors. Optimisation of these parameters helps ensure optimal and consistent fermentation performance, and acts to prevent the occurrence of problems, such as shear stress, foam formation and contamination.

What is Quality by Design (QbD) and how can it help with fermentation optimisation and process development?

Quality by Design (QbD) is a systematic approach used in various industries, including pharmaceuticals and biotechnology, to ensure product quality and process efficiency. QbD is a holistic methodology that focuses on designing quality into products and processes from the outset rather than relying solely on testing and inspection at the end. It emphasizes understanding of the critical quality attributes (CQAs - the specific characteristics of a product that directly impact its safety, efficacy, and quality) of the final product and then designing a production process that consistently meets these attributes. Variations in process parameters and material inputs are considered within a defined design space (the range of experimental conditions within which variations in process parameters do not adversely affect product quality) to ensure that product quality remains unaffected. Process materials and parameters are evaluated and mapped against their potential to affect the product CQAs. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified which can then be controlled using specific strategies and mitigation plans. This approach focuses on quality with the end in mind and can be part of a process risk management strategy which can ensure resource and development are efficiently applied.

QbD encourages a deeper understanding of the fermentation process, leading to better control and optimisation, it helps ensure consistent product quality, facilitates smoother scale-up from lab-scale to production, minimizes variability and improves regulatory compliance. Overall, it is a powerful approach that integrates science, risk management, and process optimisation to achieve consistent product quality and efficient process development in the field of fermentation optimisation. 


In conclusion, fermentation optimisation is a complex and multidisciplinary field that requires the integration of various aspects, such as strain engineering, media formulation, bioreactor design, process optimisation, scale-up, characterisation, and control. Fermentation optimisation offers many challenges and opportunities for the advancement of biotechnology and the production of bio-based products. Fermentation optimisation can benefit from the application of various technologies and methods, such as high-throughput screening, -omics analysis, mathematical modelling, risk assessment and artificial intelligence, to accelerate the innovation and discovery of new and improved fermentation processes.

The team at Isomerase are highly experienced at fermentation optimisation and are happy to answer any questions, discuss and/or quote for your project.

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