Continuous Fermentation Technology: Methods, Control Mechanisms, and Biotechnological Uses

What is continuous fermentation?

The process stimulates microbial fermentation by continuously adding substrate (feed containing nutrients) to the bioreactor and then removing the used medium and product. This technique ensures a constant fermentation environment, as opposed to fed-batch or batch fermentation, which includes changing variables throughout the process. There are several benefits to using continuous fermentation for the manufacture of biochemicals, biofuels, and other goods that need efficient and consistent manufacturing (see image below).

continuous fermentation Types

Advantages of continuous fermentation

Continuous systems have the ability to produce better productivity in comparison to batch systems due to the fact that the microorganisms are consistently kept in their exponential development phase.

Continuous systems can optimize the use of substrates and nutrients, resulting in less waste and the possibility for decreased production costs.

Product quality consistency is achieved by maintaining continuous operating conditions, resulting in a more consistent outcome compared to batch fermentation.

Scaling up a continuous process for industrial production is typically simpler since the process dynamics remain consistent regardless of scale.

Avoided repetitive fermentation preparation, cleaning, and sterilization between batches in the discontinuous process; required no additional manpower, effort, and time.

Extended the exponential microbial growth phase of the culture process compared to the batch process, thereby reducing processing time and ensuring a high production level of final products.

Eliminated inhibition of substrates or by-products as final products are harvested continuously.

Improved Equipment Utilization and Production Efficiency: Unlike batch fermentation, which requires cleaning and reloading after each fermentation cycle, continuous fermentation allows the fermentation tank to operate continuously. This maximizes the production capacity of the equipment, leading to higher output per unit of time.

Easier Automated Control: Parameters such as temperature, pH, and dissolved oxygen are easier to maintain within a relatively stable range, which is conducive to automated control, reducing errors in manual operations and labor intensity.

Extended Microbial Exponential Growth Phase: By continuously supplying fresh media and removing aging cells, the microbes remain in a nutrient-rich and optimal environment, which allows for a longer period of exponential growth. This is beneficial for increasing the synthesis rate of metabolic products.

Ideal Model for Studying Microbial Metabolism: Continuous fermentation under steady-state conditions provides a relatively stable and controllable environment for physiological and biochemical research of microorganisms, helping to better understand their metabolic patterns and growth characteristics, as well as explore the impact of external environmental factors on microbial growth and metabolism.

Disadvantages of continuous fermentation

Susceptibility to Contamination: Due to the long fermentation cycle and the open system, the risk of contamination from external microbes is increased. Once contamination occurs, it could lead to the failure of the entire fermentation process.

Strain Degeneration Issues: Over prolonged continuous fermentation, microorganisms are prone to genetic mutations, which can result in traits unfavorable to fermentation production, such as slower growth rates and reduced synthesis capabilities of metabolic products, ultimately affecting fermentation stability and product quality.

High Equipment and Operational Requirements: Precise flow control devices and reliable automatic control systems are necessary to ensure that the flow rate of the medium matches the discharge flow rate of the fermentation broth, maintaining a constant liquid volume within the fermentation tank. This also places high demands on the sealing and reliability of the equipment, as any failure could interrupt the fermentation process or lead to parameter instability.

Low Nutrient Utilization and Product Concentration: Compared to batch fermentation, nutrient utilization in continuous fermentation is relatively low. Moreover, since the fermentation broth is constantly being discharged, the concentration of metabolic products is difficult to achieve at the level found in batch fermentation.

Continuous fermentation process

Continuous fermentation necessitates a specifically engineered bioreactor that is equipped with inlet and outlet streams to continuously introduce substrates and eliminate products and waste, respectively. To maintain sterility and promote the growth of certain bacteria, both the bioreactor and the input substrates undergo sterilization procedures.

A specialized group of microorganisms, which have adapted to the specific conditions required for fermentation, is put into the bioreactor that has been thoroughly sterilized. The culture is let to proliferate and establish a stable presence within the bioreactor, attaining an ideal level of biomass concentration required for uninterrupted functioning.

The temperature, pH, oxygen levels (for aerobic processes), and agitation, which are critical process factors, are constantly monitored and modified in order to maximize microbial activity and optimum product creation.

As the microorganisms break down the substrates, they constantly create the required product(s) through metabolism. The architecture of the bioreactor enables the uninterrupted extraction of the culture medium that contains the product. This process is carried out at a rate that maintains a balance between the addition of new substrate and the prevention of dilution or buildup of products and by-products.

The discharge from the bioreactor consists of the product along with microbial cells and other constituents. The desired product is isolated and purified using further processes, including centrifugation, filtering, and purification. During the whole process, the product's quality and the functioning of the bioreactor are consistently checked to guarantee constant product quality and optimal system efficiency.

Regular sampling and microbiological testing are essential. Regular cleaning and maintenance are necessary, however they are needed less often compared to batch operations. The frequency of these tasks depends on the system's design and operating lifespan.

Applications of continuous fermentation

Continuous fermentation systems offer important economic advantages with improved fermentation rates, especially when continuous fermentation is combined with cell immobilization techniques. The continuous fermentation process can utilize mixed cultures to afford chemicals, and this technology holds great promise for the efficient production of fermented beverages such as beer, wine, cider, and bioethanol. Continuous fermentation is also used to produce certain bioproducts, including polyhydroxyalkanoates (PHA), lactic acid (LA), butanol, citric acid, and 1, 3-propanediol.

Industrial Production: Continuous fermentation can be used for large-scale and efficient production of products like alcohol, lactic acid, and citric acid, reducing production costs and improving economic benefits.

Environmental Engineering: It can be applied in wastewater treatment, where certain microorganisms in continuous fermentation systems can effectively degrade organic pollutants, leading to wastewater purification and resource recovery.

Bioenergy: It holds potential for applications in biohydrogen and biomethane production, improving fermentation efficiency and increasing bioenergy output.

Biopharmaceuticals: Continuous fermentation is used for the production of pharmaceutical proteins, antibiotics, and other bioproducts. By precisely controlling fermentation conditions, product yield and quality can be improved while lowering production costs.

Penicillin Production: Penicillin is one of the typical antibiotics produced through continuous fermentation. By using the Penicillium chrysogenum strain and continuously supplying raw materials while discharging waste liquids during fermentation, microorganisms remain in a high-efficiency production state, thus increasing the yield of penicillin.

Cephalosporin Production: Some cephalosporins are also produced using continuous fermentation, which helps shorten the production cycle, reduce costs, and improve product quality and yield.

Aminoglycoside Antibiotic Production: Continuous fermentation can also be applied in the production of aminoglycosides like gentamicin and kanamycin, where it enables better control of fermentation conditions and optimizes the metabolic process of microorganisms, thereby improving the synthesis efficiency of antibiotics.

Insulin Production: Using genetic engineering techniques, human insulin genes are inserted into microorganisms like Escherichia coli. Through continuous fermentation, microorganisms synthesize insulin in large quantities. Continuous fermentation maintains the cells in a good growth state, which facilitates high expression of insulin and increases production efficiency.

Human Growth Hormone Production: Some companies use continuous fermentation technology to produce human growth hormone, achieving stable control of the fermentation process, improving the expression levels and quality of the product, and meeting market demand for recombinant human growth hormone.

Viral Vaccine Production: Continuous fermentation is used in the large-scale cultivation of viruses for vaccine production. For example, in influenza vaccine production, continuous fermentation technology is used to culture chicken embryo cells or other host cells infected with the influenza virus, increasing the virus harvest and, consequently, the vaccine yield.

Bacterial Vaccine Production: For some bacterial vaccines, such as the pneumococcal vaccine, continuous fermentation can optimize bacterial growth conditions, promote bacterial proliferation, and facilitate the synthesis of capsular polysaccharides and other antigenic substances, improving vaccine production efficiency and quality.

Nucleotide and Derivative Synthesis: Continuous fermentation plays an important role in the production of some nucleotides and their derivatives. For example, microbial fermentation is used to produce nucleotides such as cytosine and guanine, as well as nucleotide-based antiviral drugs like acyclovir. Continuous fermentation helps maintain high microbial activity and stable metabolic flux, improving the synthesis efficiency and yield of nucleotides and their derivatives.

Peptide Drug Production: Continuous fermentation technology is used for large-scale production of biologically active peptide drugs, including calcitonin and growth hormone-releasing peptides, improving production efficiency and product quality.

Biopharmaceutical Intermediates Production: Continuous fermentation can also be applied to the production of biopharmaceutical intermediates, such as chiral compounds and biologically active epoxides, providing essential raw materials for subsequent drug synthesis.

Batch vs. continuous fermentation

(a)During batch fermentation, no more nutrients are introduced and no final products or biomass are extracted until the fermentation is completed. The process of continuous fermentation involves a constant supply of nutrients and the continual production of products (see image below).

(b) Batch fermentation often necessitates less complex equipment and setup in comparison to continuous fermentation. Continuous fermentation necessitates sophisticated methods for monitoring and regulating process parameters to avert departures from the intended condition.

(c) Batch fermentation is a frequently employed method for manufacturing items that are manufactured in several batches, such as medications. This approach allows for the customization of conditions to suit the individual requirements of each product. Additionally employed in less extensive projects when the attributes of simplicity and adaptability have greater significance. Continuous fermentation is most suitable for the efficient and reliable manufacture of large quantities of commodities such as biofuels and bulk chemicals, where maintaining a high volume and consistent output is of utmost importance.

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