From Pharmaceuticals to Beer: What Are Bioreactors?

From brewing beer to growing bacterial cultures to producing mammalian cells and pharmaceuticals, modern bioreactors have revolutionized the production of biological materials, enabling researchers to make significant advances in fields like biotechnology, pharmaceuticals, food production, and wastewater treatment and making it possible to produce high-quality products more efficiently and cost-effectively.

However, the concept of bioreactors, vessels that provide a controlled environment for the growth and maintenance of biological organisms, has been used for thousands of years in various forms. This includes using clay pots to create ideal aerobic and anaerobic conditions in which wine, beer, and food can ferment safely.

It’s doubtful anyone called a clay pot a bioreactor several thousand years ago, but the concept remains the same: create a controlled environment where an expected biological reaction can occur.

Curing meats is one of those things that feels like an art and a craft, something guided by a deft 

touch and loads of experience, but it can, in fact, boil down to an incredibly scientific process: controlling the environment in which the meat is cured to support the growth of specific bacteria that aids in the curing process.

The bioreactor that we know today, which uses advanced technology to precisely control environmental conditions and optimize the production of biological materials, has only been in use since the mid-20th century. Its development represented a significant milestone in biotechnology and paved the way for numerous breakthroughs.

In this blog post, we will explore the basics of bioreactors, including what they are, the different types of bioreactors, how they work, their advantages in various industries, and more.

What Is a Bioreactor?

A bioreactor is any device or system that provides an optimal and controlled environment for chemical and biological reactions, typically within an enclosed, cylindrical glass or stainless steel vessel. Depending on the application, these devices can drastically range in size from a few milliliters to many liters.

The ability to control environmental conditions like temperature, pH, oxygen concentration, and nutrient supply for a set period makes bioreactors suitable for various applications, including the production of biopharmaceuticals, enzymes, biofuels, and other products.

This is because living organisms, held within a controlled environment, can perform specific functions at scale: grow, reproduce, and carry out metabolic processes that allow for the production of a desired substance.

How Does a Bioreactor Work?

A bioreactor’s components can vary depending on the specific design and application of the bioreactor. However, there are some standard elements found in most types of bioreactors. These include:

• Fermenter vessel: The main body of the bioreactor, typically made of stainless steel or glass. It is a closed component designed to hold the biological material and nutrients and maintain optimal environmental conditions.
• Thermal jacket: An outer layer surrounding the inner chamber where biological reactions occur. The jacket is often made of stainless steel and contains a heating or cooling fluid, such as water, used to regulate and maintain the temperature of the culture inside the bioreactor.
• Agitation system: Mixes and distributes the vessel’s nutrients and biological material(s). It typically consists of a motor that rotates impellers or other mixing elements within the container.
• Baffles: Vertical plates or structures within the vessel that help prevent swirling or vortex formation within the liquid medium during agitation, reducing the chances that microbial colony growth occurs on the side of the fermenter. This can improve the homogeneity of the culture and prevent localized areas of high shear stress, which can be harmful to cells or microorganisms.
• Aeration system: Also may be referred to as an oxygen delivery system. It supplies oxygen to the biological material within the vessel and consists of a sparger or diffuser that releases sterile air or other gasses into the container.
• Foam control system: Prevents the buildup of excess foam in the vessel during a bioprocess. Foam can be a problem because it can overflow from the bioreactor, contaminate the surroundings, or even cause damage to the bioreactor itself.
• Temperature control system: Maintains a constant temperature within the vessel, consisting of heating and cooling elements that regulate the temperature of the vessel.
• pH control system: Maintains a specific pH level within the vessel. It typically consists of a sensor that monitors the pH level and a control system that adjusts the amount of acid or base added to the vessel to maintain the desired pH level.
• Sampling ports: Provide access to the culture medium for monitoring and analysis. Samples can be taken to measure cell density, nutrient levels, pH, or other parameters.
• Feed ports: Introduces additional nutrients, gasses, or other materials into the bioreactor during the bioprocess. These ports are usually fitted with sterile connectors or filters to maintain a sterile environment within the device and may be located at different positions depending on the specific needs of the process.
• Cleaning and sterilizing system: Used to clean and sterilize the device. Methods can range from steam or heat to chemical sterilization.

How these systems are controlled can vary from being highly automated through computerized systems to simple manual control.

Additionally, the material used to construct a bioreactor can vary from glass to plastic to stainless steel or other types of metals, depending on the specific requirements of the biological system(s) being used in the application.

Most importantly, the material needs to be non corrosive, resistant to steam sterilization, able to withstand high pressure and pH variations, and not introduce toxins into the fermentation medium.

What Is a Bioreactor Used For?

Bioreactors play a crucial role in both scientific and industrial sectors by providing a controlled environment for the growth and maintenance of biological organisms, helping researchers study how cells behave under specific conditions and assessing the effectiveness of various treatments.

Bioreactors can be used to manipulate and monitor temperature, pH, and nutrient supply, creating optimal conditions within a vessel for cell growth and protein expression, making them well-suited instruments for extensive use in biotechnology, pharmaceuticals, the food industry, and wastewater treatment.

In the biotechnology industry, bioreactors are utilized to produce large amounts of proteins, vaccines, and other biologics. The ability to control the growth of biological organisms in a precise and controlled environment has revolutionized the production process, enabling the creation of more complex and sophisticated products.

Bioreactors have proven invaluable in developing and discovering new drugs in the pharmaceutical industry. By providing a controlled environment to study cell growth and function, researchers can assess the effectiveness of different treatments and optimize the development process. Bioreactors have helped scientists to produce biologics such as insulin, human growth hormone, and interferon.

The food industry has also seen significant benefits from the use of bioreactors. With the help of these devices, the industry has produced a wide range of products, including enzymes, organic acids, and various flavors. Bioreactors have also enhanced foods’ nutritional value and create sustainable food sources, such as plant-based proteins.

For example, the food industry uses bioreactors to produce fermented foods such as yogurt, cheese, and sauerkraut. In the pharmaceutical industry, bioreactors are used to make drugs and biologics, such as insulin and monoclonal antibodies. They are also used in wastewater treatment plants to remove organic contaminants from water.

Moreover, the use of bioreactors has also had a significant impact on environmental sustainability. Using bioreactors in wastewater treatment plants has enabled the efficient and eco-friendly removal of pollutants from the water supply. 

Additionally, bioreactors have played a crucial role in producing biofuels, where they are used to cultivate microorganisms such as algae or bacteria that can convert biomass into fuel, creating a sustainable and renewable energy source.

By optimizing conditions (light intensity and nutrient availability), bioreactors can increase the yield of these microorganisms, making the biofuel production process more efficient and sustainable.

Types of Bioreactor Processes

Using a substrate is essential in any bioprocess, even if it’s only mineral salts, light, and CO2 for algae. It can be supplied either at the beginning of the process or gradually added throughout. The time the culture is fed the substrate and how much is added is used to define the various bioreactor processes for feeding cells and managing cell growth within the device.

The most common bioreactor processes for culture feeding include batch, fed-batch, continuous, and perfusion. The choice of the method varies based on the organism, application, and final goal.

Each process can also involve strategies and phenomenons that are effective when used deliberately. Substrate inhibition is one such phenomenon where microorganisms are used to produce a product of interest during the bioreactor process. If the substrate concentration becomes too high, it can inhibit the microorganisms’ ability to produce the desired outcome, reducing the bioprocess yield and efficiency.

Batch Processes

In batch processing, all the nutrients are added at the beginning, and nothing else is added later except for control elements such as gasses, acids, and bases, making it a closed system. The process continues until all the added nutrients are consumed by the cells.

A batch process is suitable for rapid experiments, but the biomass and product yields are limited. Carbon source and oxygen transfer are typically the limiting factors, so microorganisms only grow exponentially for a short time. You can increase stirring speed, gas flow, oxygen concentration, or pressure to improve oxygen availability. However, it’s important to have good control processes to manage these changes.

This is where a bioreactor controller, a device or software used to regulate and optimize environmental conditions within a bioreactor, can be set to adjust dissolved oxygen concentration, maintain the process at the desired setpoints, and prevent deviations from optimal conditions that can affect productivity or quality.

After a batch process, only the biomass or medium is harvested and processed to obtain the desired product. Batch processes have an increased risk of substrate or product inhibition, which can drastically reduce yield.

Fed-batch Processes

A fed-batch process differs from batch processing in that it includes the addition of nutrient feeds throughout the process, which prevents nutrient depletion and promotes cell growth, ultimately resulting in a higher cell density and product yield.

In fed-batch processing, the bioreactor is filled with media and inoculated with cells, and fresh feeds of nutrients are introduced as needed throughout the run. Fed-batch processes are the most common and straightforward way to achieve high cell density capabilities and better results than batch processes.

Different fed-batch culture strategies include high cell density, constantly-fed-batch, and exponential-fed-batch. High cell density involves adding a concentrated feed to avoid diluting the cells, a constantly-fed batch consists of adding a constant stream of feed, and an exponential-fed batch increases the feed rate exponentially to match the cells’ exponential growth.

Perfusion Processes

Perfusion is a technique that involves the removal of unwanted compounds, such as lactic acid, to enable a more prolonged process compared to a fed-batch process, resulting in higher cell densities and increased product yields.

Tangential flow filters eliminate unwanted compounds, while some media is recycled. You must choose the proper pump and filter for perfusion processing to maintain sterility and prevent damage to the cells or filter clogging. Some manufacturers and scientists recommend pairing a tangential flow filter (TFF) and a diaphragm or peristaltic pump to achieve this.

Alternating tangential flow (ATF), a specific type of perfusion, is often used with single-use bioreactors. A disposable membrane or filter separates the cells or microorganisms from new media, allowing for a continuous process without needing sterilization or cleaning between batches.

The alternating part of ATF refers to the periodic reversal of the direction of the media flow, which helps to prevent buildup or blockages on the membrane or filter. This can be accomplished using a particular type of pump that can change the flow direction or by using a series of valves that can switch the flow from one direction to another.

ATF can help increase productivity and reduce the overall process time by maintaining a constant flow of fresh nutrients to the culture, leading to higher cell densities and improved product yields.

Perfusion processing ensures a constant fresh flow of media into the bioreactor to maintain volume, leading to higher cell densities and improved product yields. However, this process is not continuous, since the bioreactor doesn’t reach a steady state as the cells continue to grow and will ultimately reach a limit in cell density.

Continuous Processes

Continuous processing maintains a constant supply of nutrients to the cells or microorganisms being cultured within a bioreactor. In a continuous process, fresh media is added to the bioreactor regularly while an equal amount of spent media is removed from the system.

This allows the culture to grow and divide steadily, resulting in a constant cell or microorganism density and more consistent product output.

Continuous culture feeding is often used in bioreactors that employ perfusion techniques, such as alternating tangential flow (ATF) or tangential flow filtration (TFF). These perfusion methods provide a continuous flow of new media to the culture, allowing for a constant supply of nutrients and oxygen to support cell growth and metabolism.

The use of perfusion techniques in combination with continuous feeding can increase the productivity and yield of the bioreactor, as well as reduce the time required to reach maximum cell density.

However, continuous feeding also requires careful monitoring of the nutrient levels in the bioreactor and removing waste products that can accumulate over time. The feeding rate must be carefully controlled to prevent the culture from becoming overloaded or nutrient-deprived, which can lead to reduced cell viability and lower product yields.

Regular analysis and adjustment of the feeding rate are necessary to maintain optimal culture conditions and maximize the efficiency of the bioreactor.

Continuous bioprocessing has many benefits, including the lack of downtime between batches, reduced need for costly and time-consuming cleaning tasks, and minimized variability in the final product from batch to batch.

Types of Bioreactors

Photobioreactors

Not to be confused with Pabst Blue Ribbon (PBR), a photobioreactor (PBR), is a specialized bioreactor for cultivating photosynthetic microorganisms like algae, moss, and cyanobacteria by providing artificial light conditions.

PBRs provide an artificial environment that allows precise control of the light intensity, temperature, pH, and other environmental factors, resulting in higher growth rates and purer samples than natural environments.

PBRs can be categorized as either open or closed systems, with closed systems being the preferred choice for most applications due to their better control over environmental conditions and protection against contaminants. They are commonly used in research and industrial applications due to their ability to maintain aseptic conditions and better control environmental factors.

Continuous-stirred Tank

Continuous Stirred-Tank bioreactors (CSTRs) use agitators to create a controlled, homogenous environment by constantly moving their contents. This helps to ensure uniform mixing and distribution of nutrients, oxygen, and other critical factors necessary for the growth of cells, microorganisms, or enzymes.

In addition to the standard environmental controls that bioreactors offer, CSTRs have the added advantage of allowing the culture medium’s flow to be defined depending on the application. This means that the flow rate can be adjusted to maintain a steady state, which is vital for many applications, such as continuous fermentation or microbial growth.

There are several common types of CSTRs, including chemostats, which maintain a constant nutrient supply to the culture, turbidostats, which adjust the feed rate based on the cell density in the reactor; and autostats, which regulate the feed rate based on the growth rate of the culture.

These variations in CSTR design allow for more precise control of the culture conditions, resulting in improved growth rates, increased yields, and higher product quality. Stirred tanks are commonly used for the production of antibiotics and organic acids.

Bubble Column

A bubble column bioreactor uses a liquid cylinder or liquid-solid suspension and introduces gas through the bottom of the cylinder. The gas is then bubbled through the liquid in a process known as sparging or gas flushing.

The operation of a bubble column bioreactor is relatively simple. Gas, usually air or oxygen, is introduced into the bottom of the cylinder, creating a stream of bubbles that rise to the top. As the bubbles rise, they mix the liquid, providing aeration and promoting mixing. The sparging process can be adjusted to control the culture medium’s oxygen supply, pH, and temperature.

The mixing action produced by the gas bubbles creates a pneumatic mixed reaction, which is utilized for various processes, such as the production of enzymes and proteins, or chemical reactions, such as wet oxidation.

Bubble column bioreactors are versatile and easy to operate and provide high oxygen transfer rates and scalability, making them popular in the chemical and biotechnology industries due to their simple design, high oxygen transfer rates, and scalability. In addition, they can be scaled up or down depending on the size and needs of the application.

Air-Lift

Air-lift bioreactors are used to grow aerobic microorganisms, such as bacteria or yeast, in a liquid culture. It operates by circulating a mixture of liquid and air throughout the vessel using the buoyancy of air bubbles to move the liquid, and typically consists of a vertical cylinder with two sections: a riser and a downcomer.

Compressed air or oxygen is introduced at the bottom of the riser, creating bubbles that rise to the top, carrying the liquid with them. As the air bubbles rise, they mix the fluid, providing the necessary oxygen for the microorganisms to grow and promoting the efficient transfer of nutrients.

The bubbles burst at the top of the riser, and the liquid flows down the downcomer, a separate vertical cylinder adjacent to the riser, creating a continuous circulation of the liquid and allowing for the growth of large quantities of microorganisms.

The advantages of air-lift bioreactors include controlling the oxygen supply by adjusting the airflow rate and the low shear forces that minimize cell damage.

However, they may have lower mixing efficiency and require more energy than other bioreactors. Air-lift bioreactors are commonly used in industrial applications, including the production of enzymes, antibiotics, and biopolymers.

Fluidized Bed

A fluidized bed bioreactor uses fluidization to facilitate mixing and mass transfer. It consists of a bed of small particles (e.g., sand, glass beads, or plastic particles) suspended in a liquid, with air or another gas passed through the bed to fluidize the particles.

As the gas flows through the bioreactor, it creates bubbles that cause the particles to move and mix the contents of the reactor. This increases the contact between the microorganisms and the substrate, leading to a more efficient reaction.

Fluidized bed bioreactors can be used in various applications and industries, from wastewater treatment to bioremediation and biocatalysis. They can be used for aerobic and anaerobic processes and effectively treat high-strength industrial wastewater, including those containing toxic compounds. They are also used in producing biofuels, such as biogas and bioethanol.

Packed Bed

Packed bed bioreactors consist of a cylindrical column filled with a porous material, typically solid support matrices such as beads, pellets, or fibers, that provides a large surface area for microbial growth or immobilized enzymes as catalysts. The support matrices can be made of various materials, including ceramics, plastics, and metals.

The packed bed bioreactor passes the liquid medium containing the substrate and microorganisms through the packed bed, where the microorganisms attach to the support material and metabolize the substrate. The substrate is converted to the desired product as the liquid medium passes through the bed.

Compared to other bioreactors, packed bed bioreactors have a high conversion rate per unit weight of catalyst and offer a cost-effective means of producing large amounts of bioproducts.

Packed bed bioreactors are used for various applications, including wastewater treatment, bioremediation, and the production of different chemicals, pharmaceuticals, and enzymes. They are particularly effective for continuous flow processes and are commonly used in industrial-scale processes.

Membrane

Membrane bioreactors (MBRs) are chemical reactors that incorporate membranes in their processes to perform the functions of separation, concentration, and purification. MBRs combine the principles of biological treatment and membrane separation in a single system.

These membranes are used to separate reactants and products, facilitate chemical conversions, and can be used for various applications, including wastewater treatment, biogas production, and high-value compounds such as pharmaceuticals and enzymes.

MBRs can be classified into two types: internal/submerged and external/sidestream. Internal MBRs use membranes installed inside the bioreactor, while external MBRs have filtration elements outside the reactor. MBRs are often used in wastewater treatment and offer advantages such as high-quality effluent, compact size, and low sludge production.

They offer many advantages over traditional separation methods, such as improved product purity, reduced waste, and increased productivity. Additionally, MBRs are often smaller and more cost effective than traditional systems, making them an attractive option for many applications.

Immersed Membrane

An immersed membrane bioreactor (IMBR) is a type of membrane bioreactor (MBR) that uses a filtration membrane to separate treated water from microorganisms, suspended solids, and other contaminants in a wastewater treatment system.

The main difference between IMBR and conventional MBR is the position of the membrane in the wastewater treatment system. In a conventional MBR, the filtration membrane is located outside the bioreactor, and the wastewater is circulated through the membrane module using pumps.

In contrast, the IMBR uses the membrane as a submerged membrane module located directly in the bioreactor, eliminating the need for pumps and reducing the system’s overall footprint.

The iMBR provides several advantages over the conventional MBR, such as a higher treatment efficiency due to greater contact between the microorganisms and the membrane, better control over the fouling, and lower energy consumption due to eliminating the need for circulation pumps.

However, the IMBR also has some disadvantages, including a higher potential for membrane fouling and the potential for higher capital costs associated with the larger membrane area needed in the submerged configuration.

Rotating Drum

Rotating drum bioreactors are used to treat wastewater or cultivate microorganisms. These devices consist of a rotating drum partially submerged in the wastewater or medium and usually made of a permeable material like stainless steel or plastic.

A rotating drum bioreactor uses the rotating motion of the drum to mix the wastewater or medium and promote the growth of microorganisms. As the drum rotates, the wastewater or medium is circulated through the drum and comes into contact with the microorganisms attached to the drum’s surface.

The microorganisms attached to the drum perform the biological treatment of the wastewater, breaking down organic matter and nutrients through aerobic or anaerobic digestion. The treated water is separated from the microorganisms by the drum’s permeable surface and discharged from the system.

Rotating drum bioreactors offer several advantages over other bioreactors, including a smaller footprint, lower energy consumption, and higher treatment efficiency.

However, the system is limited by the available surface area for microorganisms to grow, which can restrict its use in large-scale wastewater treatment.

Mist

A mist bioreactor cultivates microorganisms, such as bacteria, fungi, and yeast, in a mist or aerosol form. The mist bioreactor operates by generating and dispersing a mist of nutrients and microorganisms into a growth chamber, where the microorganisms grow and proliferate.

A mist bioreactor generates the mist with a nebulizer or spray nozzle, which atomizes the nutrient solution into tiny droplets. The droplets are then directed into the growth chamber, circulating and contacting the microorganisms. The microorganisms absorb the nutrients and grow, forming a biofilm on the walls of the growth chamber or solid support within the chamber.

The mist bioreactor offers several advantages over other bioreactors, including a high surface area-to-volume ratio, allowing a large population of microorganisms to be cultivated in a relatively small space.

It also allows for precise control of the nutrient supply and environmental conditions, such as temperature, humidity, and gas composition, which can be adjusted to optimize the growth of specific microorganisms.

Single-Use vs. Multi-Use

Decades ago, a new type of bioreactor called a single-use bioreactor was introduced into the biopharmaceutical market, offering an alternative to traditional stainless steel or glass bioreactors. These bioreactors are equipped with a disposable bag made of multiple layers of polymer, each layer serving a different function. They are widely accepted within the research and industrial sectors due to their benefits for process development and clinical manufacturing.

Single-use bioreactors are used for small, mid, and large-scale production runs and have many advantages compared to traditional multiple-use bioreactors. They eliminate the need for cleaning and sterilization between runs, saving time and reducing contamination risk. Additionally, they are less expensive and require less space than traditional bioreactors.

Smaller-scale systems are usually made of glass and can be sterilized in an autoclave, while larger bioreactors are typically stainless steel and require additional plumbed-in systems for sterilization, such as cleaning in place and steaming in place. Single-use bioreactors have rapidly gained popularity due to their cost-effectiveness, flexibility, and ease of use.

What Are the Advantages of Using Bioreactors?

Bioreactors are highly flexible and adaptable, making them versatile tools for microbial and cell culture production. They offer many advantages over traditional methods, providing a more efficient, controlled, and reproducible method of culture production. Some of their key benefits include:

• Cost-effectiveness: Bioreactors are a cost-effective solution for the large-scale production of microbial and cell cultures, as they allow for the continuous and consistent production of high-quality products. They also require less manual labor and space compared to traditional methods, which can reduce operational costs.
• High efficiency: Bioreactors provide a high level of process efficiency and productivity as they create optimal growth conditions for cultured microorganisms or cells. This can result in higher yields and faster production times than traditional methods.
• Precise control and monitoring: Bioreactors provide precise control and monitoring of growth conditions, such as pH, temperature, oxygen levels, and nutrient supply. This supports optimal growth conditions throughout the culture process, leading to better quality and more consistent results.
• Safe and controlled environment: Bioreactors provide a safe and controlled environment for the growth of microorganisms or cells, reducing the risk of contamination or infection. Bioreactors can be designed with sterile, closed systems, reducing the risk of contamination and increasing product quality.

Bioreactors can be designed to accommodate different types of cultures (suspension cultures, attached cultures, and immobilized cultures) and customized (adding growth factors or removing waste products) to meet the specific needs of different types.

They can also be integrated with downstream processes, such as filtration, purification, and formulation, effectively streamlining production and resulting in further cost savings and increased productivity.

Conclusion

Bioreactors are used to produce and cultivate microorganisms, cells, or biological molecules, using a controlled environment.

Because they can help scientists produce high-quality products precisely, efficiently, and cost-effectively at scale, they are quite valuable for industries such as biotechnology, pharmaceuticals, food and beverage, and environmental monitoring.

They have made processes faster, more efficient, and less labor-intensive and have even made it possible to manufacture products that were previously impossible or impractical to produce using traditional methods.

In a very real way, the bioreactor has become an essential tool in many industries, offering numerous advantages over traditional microbial and cell culture production methods.

Leasing a bioreactor can be a good idea for specific situations and may offer several advantages. Here are some potential benefits of leasing a bioreactor:

• Reduced capital investment: Leasing a bioreactor can allow for a reduced capital investment compared to purchasing one outright. This can significantly benefit small businesses or startups that need more resources or funding.
• Access to the latest technology: Leasing can provide access to the newest technology. This can allow businesses to stay up-to-date with the latest bioreactor technology advancements without constantly purchasing new equipment.
• Maintenance and repair services: Excedr provides maintenance and repair services as part of the lease agreement, which can help reduce downtime and ensure the equipment is always in good working condition.
• Tax benefits: Lease payments for bioreactors may be tax-deductible, providing additional financial benefits for businesses.