A Single-Use Bioreactor (SUB) is a type of bioreactor that is used for a single batch of culture and then disposed of, as opposed to being cleaned and reused. The bioreactor is made of plastic or other disposable materials, such as polymeric bags or containers. These materials are used for the cultivation of cells, microorganisms, or tissues, mainly for the production of biopharmaceuticals, vaccines, and other biomolecules.

Single-use bioreactors are designed to be easy to set up, operate, and scale-up, and they are becoming increasingly popular in the biopharmaceutical industry due to their flexibility, cost-effectiveness, and ease of use. They can be used for both small-scale research and large-scale industrial production, and they can be customized to meet the specific requirements of the application.

Single-use bioreactors offer several advantages over traditional stainless-steel bioreactors, such as reduced cleaning and validation costs, reduced risk of contamination, and improved product quality. However, it is important to note that single-use bioreactors have some disadvantages, such as limited process history, less robustness, and limited scalability.

Working Principle of Single Use Bioreactor

A bioreactor using a disposable bag instead of a culture vessel is a single-use or disposable bioreactor. Single-use bioreactors enable processors to use disposable technology, such as single-use bags, in manufacturing process stages that formerly required stainless steel equipment.

Stirred and rocking single-use bioreactors are the two most common varieties. A stirred bioreactor employs single-use components already contained within the plastic bag. In a bioreactor, the bag and stirrer are mounted, and the stirrer is either mechanically or magnetically attached. A rocking single-use bioreactor is stirred by rocking and does not require stirrers within the single-use bag. Multiple single-use process steps are currently available in R&D, including medium preparation, cell cultivation, process development, process optimization, and microbial processes. In the pharmaceutical manufacturing process, autoclaving a conventional bioreactor can be a time-consuming, expensive, and unreliable activity. Because single-use or disposable bioreactors utilise pre-sterilized bioprocess bags, they save the cost and time associated with sterilisation by a substantial amount. Having fewer moving parts than conventional bioreactors, single-use bioreactors are mechanically less expensive to maintain.

Parts of Single Use Bioreactor

The main parts of a Single-Use Bioreactor (SUB) include:

1. Bioreactor bag or container

This is the main component of the SUB and is typically made of plastic or other disposable materials. It holds the culture media and cells during the bioprocess.

• A single-use bioreactor typically consists of a container or bag made of flexible, sterile, and non-toxic material that is used to hold the liquid medium and microorganisms. These bioreactor bags or containers are typically made of plastic, such as polyethylene or polypropylene, and are designed to be disposable and easily replaced.
• The bags or containers come in a variety of sizes, typically range from few liters to thousands of liters, and can be customized to the specific needs of the application. They are designed to be easily connected to the other components of the bioreactor system, such as the sparging system, temperature control system, and sampling ports. The bags or containers are designed to maintain the sterility of the culture and prevent any contamination.
• Single-use bioreactors have the advantage of being faster to set up, lower in cost, and more flexible than traditional stainless steel bioreactors. The bags can be used for fermentation, cell culture and purification processes.

2. Mixing system

This component is used to mix the culture media and cells inside the bioreactor bag. It can be a mechanical mixer or a gas-sparging system.

• The mixing system in a single-use bioreactor is used to ensure that the liquid medium and microorganisms are well-mixed and that nutrients, gases, and other growth factors are evenly distributed throughout the bioreactor.
• The mixing system typically consists of a motor-driven impeller or agitation system that is suspended inside the bioreactor bag or container. The impeller creates circulation within the liquid medium, which helps to maintain homogeneity and prevent settling of the microorganisms. The mixing system can be designed for different types of mixing (such as turbulent or laminar flow) and different mixing speeds, depending on the specific requirements of the application.
• In addition to the impeller, other components of the mixing system may include a shaft seal to prevent leakage, a bearing system to support the impeller, and a control system to regulate the speed of the impeller. The mixing system is an important part of the single-use bioreactor system, as it plays a crucial role in maintaining the proper conditions for microbial growth and metabolism.

3. Sterilization port

This component allows the operator to sterilize the bioreactor bag and its components before and after use, to prevent contamination.

• A sterilization port is a feature found on some single-use bioreactors that allows for the introduction of sterilizing agents, such as hydrogen peroxide or ethylene oxide, into the bioreactor bag or container. The sterilization port is typically located on the side or top of the bag and is sealed with a removable cap or plug prior to use.
• The purpose of the sterilization port is to ensure that the bioreactor bag or container is sterile prior to use, which is crucial in preventing contamination of the culture. Sterilization can be performed before or after filling the bioreactor with the liquid medium and microorganisms.
• The sterilizing agent is typically introduced into the bioreactor through the sterilization port using a syringe or other injector device. The sterilizing agent is then circulated through the bag or container to sterilize the interior surfaces. Once the sterilization process is complete, the sterilizing agent is typically removed and the sterilization port is sealed to maintain the sterility of the bioreactor.
• It’s important to note that the sterilization port is not a standard feature in all single-use bioreactors, and it is not always necessary for certain applications, such as when the bioreactor is used for downstream processing or when the cells are grown under low bio-burden conditions.

4. Temperature control system

This system maintains the proper temperature for the cells to grow.

• The temperature control system in a single-use bioreactor is used to maintain the proper temperature for the growth and metabolism of the microorganisms. The temperature control system typically consists of a heating and/or cooling system, a temperature sensor, and a temperature controller.
• The heating and cooling system is typically placed outside the bioreactor bag or container and is used to transfer heat to or from the liquid medium inside the bioreactor. This can be done using a heating jacket, heat exchanger, or a temperature-controlled water bath. The temperature sensor, such as a thermocouple or RTD, is placed inside the bioreactor to measure the temperature of the liquid medium and provide feedback to the temperature controller.
• The temperature controller is an electronic device that receives the temperature readings from the sensor, compares them to the set point temperature and adjusts the heating or cooling system accordingly. The temperature controller ensures that the temperature of the liquid medium inside the bioreactor is maintained within a specific range and is stable.
• The temperature control system is an important component of the single-use bioreactor, as different microorganisms have different optimal growth temperatures, and it is essential for maintaining the proper conditions for microbial growth and metabolism.

5. pH control system

This system maintains the proper pH for the cells to grow.

• The pH control system in a single-use bioreactor is used to maintain the proper pH level for the growth and metabolism of the microorganisms. The pH control system typically consists of a pH sensor, a pH controller, and a means of adding acid or base to the liquid medium.
• The pH sensor, such as a pH electrode, is placed inside the bioreactor and is used to measure the pH level of the liquid medium. The pH controller receives the pH readings from the sensor, compares them to the set point pH, and adjusts the acid or base addition accordingly.
• The means of adding acid or base to the liquid medium can be done through a pump and a dosing system, or manually by adding an acid or base solution to the medium. The pH control system is an important component of the single-use bioreactor, as different microorganisms have different optimal pH ranges, and it is essential for maintaining the proper conditions for microbial growth and metabolism.
• It’s worth mentioning that some microorganisms such as E. coli have a pH range of 7-7.5 and some microbes such as yeast have a pH range of 4-5, thus depending on the microorganisms, the pH range will be adjusted accordingly.

6. Oxygenation and aeration system

This system provides oxygen to the cells and maintains the proper level of dissolved oxygen in the culture media.

• The oxygenation and aeration system in a single-use bioreactor is used to introduce oxygen into the liquid medium to support microbial growth and metabolism. The oxygenation and aeration system typically consists of a gas source (such as a compressed air or oxygen tank), a gas distribution system (such as a sparger or diffuser), and a means of controlling the flow rate of the gas (such as a flow meter or mass flow controller).
• The gas distribution system is typically located inside the bioreactor bag or container and is used to introduce the gas into the liquid medium. The sparger or diffuser breaks the gas into small bubbles and distributes it evenly throughout the liquid medium, which increases the surface area of the gas-liquid interface and allows for efficient oxygen transfer.
• The flow rate of the gas can be controlled using a flow meter or mass flow controller, which ensures that the proper amount of oxygen is being supplied to the liquid medium. The oxygenation and aeration system is an important component of the single-use bioreactor, as it plays a crucial role in maintaining the proper oxygen levels in the bioreactor, which is essential for the growth and metabolism of the microorganisms.
• It’s important to note that the oxygenation and aeration system might be different for different types of microorganisms, for example, for microaerophilic microbes, the oxygen levels should be kept low, and for anaerobic microbes, the system should be designed to exclude oxygen from the bioreactor.

7. Control system

This system allows the operator to control and monitor the various parameters of the bioreactor, such as temperature, pH, and oxygen levels.

• The control system in a single-use bioreactor is used to monitor and control various parameters such as temperature, pH, dissolved oxygen, and agitation speed, in order to maintain the proper conditions for microbial growth and metabolism.
• The control system typically consists of a central controller, such as a programmable logic controller (PLC) or a computer, which receives input from sensors, such as temperature sensors, pH sensors, and dissolved oxygen sensors, and uses this information to control the various subsystems of the bioreactor, such as the temperature control system, pH control system, and mixing system.
• The central controller also interfaces with the user, displaying the real-time process data, and allowing the user to adjust the set points and control the bioreactor operation. The control system can also be programmed to run in automatic mode or manual mode, which allows the user to run the bioreactor with pre-defined parameters or to change the parameters manually.
• The control system is an essential component of the single-use bioreactor, as it allows for precise control of the bioreactor conditions and provides real-time data on the status of the bioreactor, which is important for maintaining the proper conditions for microbial growth and metabolism.

8. Sampling port

This allows the operator to take samples of the culture media for analysis without disrupting the growth of cells.

• A sampling port is a feature found on some single-use bioreactors that allows for the withdrawal of a small sample of the liquid medium and microorganisms from the bioreactor for analysis or measurement. The sampling port is typically located on the side or top of the bag and is sealed with a removable cap or plug prior to use.
• The purpose of the sampling port is to allow for the monitoring of the culture and to check the growth, metabolism, and product formation of the microorganisms. The samples can be taken at different stages of the fermentation process to check the growth, metabolism, and product formation of the microorganisms.
• The samples can be analyzed for various parameters such as pH, dissolved oxygen, cell density, viability, metabolite production and many other parameters depending on the application. The sampling port also allows for monitoring of the fermentation conditions and to detect any issues or deviations from the expected conditions.
• It’s important to note that not all single-use bioreactors have a sampling port, it’s not always necessary for certain applications, such as when the bioreactor is used for downstream processing or when the cells are grown under low bio-burden conditions. It’s also important to minimize the number of sampling to avoid contamination and to minimize the disruptions to the fermentation process.

9. Fittings and tubing

These components are used to connect the various parts of the SUB and to transport the culture media and cells.

10. Impeller System

The impeller system of a Single-Use Bioreactor (SUB) is a key component that is responsible for mixing the culture media and cells inside the bioreactor bag. The type of impeller system used in a SUB will depend on the specific model and application, but some common types include:

• Axial-flow impellers: These impellers are designed to create an axial flow of fluid in the bioreactor, which is useful for applications that require good mixing and oxygen transfer.
• Radial-flow impellers: These impellers are designed to create a radial flow of fluid in the bioreactor, which is useful for applications that require good mixing and shear protection for the cells.
• Pitched-blade impellers: These impellers have angled blades that create a flow pattern in the bioreactor that is useful for applications that require good mixing and oxygen transfer.
• Gas-sparging systems: These systems use a gas, typically air or oxygen, to mix the culture media and provide oxygen to the cells.
• Wave-based impellers: These impellers use mechanical waves to mix the culture media and cells, and are similar in design to wave bioreactors.

The impeller system of a SUB can be controlled and adjusted by the operator to optimize mixing and oxygen transfer for the specific requirements of the cells and the bioprocess. Always consult the manufacturer’s documentation for a detailed description of the impeller system of the SUB before use.

11. Pumping

The pumping system of a Single-Use Bioreactor (SUB) is a key component that is responsible for circulating the culture media and cells inside the bioreactor bag. The type of pumping system used in a SUB will depend on the specific model and application, but some common types include:

• Peristaltic pumps: These pumps use a flexible tubing to move the culture media and cells by compressing and releasing the tubing. They are suitable for applications that require gentle pumping and low shear stress on the cells.
• Diaphragm pumps: These pumps use a diaphragm to move the culture media and cells. They are suitable for applications that require precise control of the flow rate and pressure.
• Centrifugal pumps: These pumps use centrifugal force to move the culture media and cells. They are suitable for applications that require high flow rates and high-pressure pumping.
• Screw pumps: These pumps use a screw-shaped rotor to move the culture media and cells. They are suitable for applications that require high-pressure pumping and low shear stress on the cells.

The pumping system of a SUB can be controlled and adjusted by the operator to optimize flow rate and pressure for the specific requirements of the cells and the bioprocess. Always consult the manufacturer’s documentation for a detailed description of the pumping system of the SUB before use.

12. Drive System

The drive system of a Single-Use Bioreactor (SUB) is a key component that is responsible for providing the power to operate the impeller and pumping systems. The type of drive system used in a SUB will depend on the specific model and application, but some common types include:

• Electric motors: These are the most common type of drive system used in SUBs. Electric motors can be used to power the impeller and pumping systems.
• Pneumatic motors: These are powered by compressed air and are less common in SUBs. They may be used in cases where electrical power is not readily available.
• Manual: Some SUBs may have manual drive system, which means the user has to manually turn the impeller or pump.

The drive system of a SUB can be controlled and adjusted by the operator to optimize the mixing and pumping for the specific requirements of the cells and the bioprocess. Always consult the manufacturer’s documentation for a detailed description of the drive system of the SUB before use.

13. Baffles

The baffles system of a Single-Use Bioreactor (SUB) is a key component that can be used to improve mixing and oxygen transfer inside the bioreactor bag. Baffles are usually plastic plates or flanges that are placed inside the bioreactor bag, and they can be used to create a flow pattern that promotes mixing and oxygen transfer. The type of baffles system used in a SUB will depend on the specific model and application, but some common types include:

1. V-shaped baffles: These are V-shaped plates that are placed inside the bioreactor bag to create a flow pattern that promotes mixing and oxygen transfer.
2. Tri-clamp baffles: These are triangular-shaped plates that are placed inside the bioreactor bag to create a flow pattern that promotes mixing and oxygen transfer.
3. internal-coil baffles: These are coils that are placed inside the bioreactor bag to create a flow pattern that promotes mixing and oxygen transfer.

The baffles system of a SUB can be adjusted by the operator to optimize mixing and oxygen transfer for the specific requirements of the cells and the bioprocess. Always consult the manufacturer’s documentation for a detailed description of the baffles system of the SUB before use.

14. Sparging

A sparging system in a single-use bioreactor is used to introduce gases (typically air or oxygen) into the liquid medium to support microbial growth and metabolism. The sparging system typically consists of a gas source (such as a compressed air or oxygen tank), a gas distribution system (such as a sparger or diffuser), and a means of controlling the flow rate of the gas (such as a flow meter or mass flow controller). The sparging system is important for maintaining the proper oxygen levels in the bioreactor, which is essential for the growth and metabolism of the microorganisms.

SUBs are designed to be easy to set up, operate, and scale-up, and they can be customized to meet the specific requirements of the application. Some SUBs may also include additional parts or accessories such as sensors, filters, valves, and monitoring devices, depending on the specific model and application. It’s important to note that the specific parts of a SUB may vary depending on the manufacturer, and it’s important to consult the manufacturer’s documentation for a detailed description of the parts of the SUB before use.

Types of Single Use Bioreactor

Single-Use Bioreactors (SUBs) come in a variety of types, each with their own unique features and advantages. Some common types of SUBs include:

1. Bag-based SUBs: These are the most common type of SUBs, and consist of a plastic bag or container that holds the culture media and cells during the bioprocess. They are simple to set up and operate, and are suitable for a wide range of applications.
2. Stirred-tank SUBs: These SUBs use a mechanical stirrer to mix the culture media and cells, and are similar in design to traditional stirred-tank bioreactors. They are suitable for high-density cell culture and large-scale production.
3. Wave-based SUBs: These SUBs use mechanical waves to mix the culture media and cells, and are similar in design to wave bioreactors. They are suitable for applications that require gentle mixing and reduced shear stress on the cells.
4. Gas-sparging SUBs: These SUBs use gas, typically air or oxygen, to mix the culture media and provide oxygen to the cells. They are suitable for applications that require high oxygen transfer rates.
5. Single-use Cell Factories: These are the most complex type of SUBs, and are used for the production of biopharmaceuticals. They are typically based on cell factories, which are automated systems that allow for the cultivation of cells under controlled conditions.
6. Disposable Bioreactors: These are the most basic type of SUBs, which consist of a plastic container. They are typically used for small-scale applications.

It’s worth noting that these are general categories and there are many different models and variations available within each type of SUB. Always consult the manufacturer’s documentation for a detailed description of the specific type of SUB before use.

Operating Procedure of Single Use Bioreactor

The operating procedure for a Single-Use Bioreactor (SUB) will depend on the specific type and model, but generally it involves the following steps:

1. Assemble the SUB: The SUB is assembled by attaching all the necessary parts and components, such as the bag, tubing, and sensors, to the bioreactor.
2. Sterilize the SUB: The SUB is sterilized before use to prevent contamination.
3. Prepare the culture media: The culture media is prepared according to the specific requirements of the application and cells, and is added to the bioreactor.
4. Add the cells: The cells are added to the culture media in the bioreactor.
5. Initiate the process: The process is initiated by starting the mixing and agitation of the culture media, and maintaining the temperature, pH, and oxygen levels within the optimal range for the cells to grow.
6. Monitor and control the parameters: The various parameters of the bioreactor, such as temperature, pH, oxygen levels, and mixing, are continuously monitored and controlled to ensure optimal conditions for the cells to grow.
7. Take samples: Samples of the culture media can be taken periodically for analysis to monitor the growth of the cells and the progress of the bioprocess.
8. Harvest the cells: Once the cells have reached the desired level of growth and productivity, the cells can be harvested for downstream applications, such as protein production or cell therapy.
9. Dispose of the SUB: After the bioprocess is complete, the SUB is disposed of according to the manufacturer’s instructions and local regulations.

Applications of Single Use Bioreactor

Single-Use Bioreactors (SUBs) have a wide range of applications in the biopharmaceutical, biotech, and bioprocessing industries, including:

1. Biopharmaceutical production: SUBs are widely used in the production of biopharmaceuticals, such as monoclonal antibodies, vaccines, and other biomolecules. They are particularly useful for applications that require rapid scale-up and flexibility.
2. Cell culture: SUBs are used for the cultivation of various types of cells, such as stem cells, primary cells, and cell lines. They are particularly useful for applications that require high cell densities and high productivity.
3. Microorganism cultivation: SUBs are used for the cultivation of various types of microorganisms, such as bacteria, yeast, and algae. They are particularly useful for applications that require high cell densities and high productivity.
4. Gene therapy: SUBs are used for the production of viral vectors for gene therapy, such as lentiviral and adenoviral vectors. They are particularly useful for applications that require high virus titers and scalability.
5. Algae cultivation: SUBs are used for the cultivation of algae for the production of biofuels, bioplastics, and other bioproducts. They are particularly useful for applications that require high cell densities and high productivity.
6. Research: SUBs are used in research settings for small-scale experiments and pilot studies, they are particularly useful for applications that require flexibility and ease of use.

Advantages of Single Use Bioreactor

Single-Use Bioreactors (SUBs) offer several advantages over traditional stainless-steel bioreactors, including:

1. Reduced cleaning and validation costs: SUBs eliminate the need for cleaning, sterilization, and validation of traditional stainless-steel bioreactors, which can be time-consuming and costly.
2. Reduced risk of contamination: SUBs are disposable and are used for a single batch of culture, which reduces the risk of contamination and cross-contamination between batches.
3. Improved product quality: SUBs can improve product quality by eliminating the potential for carryover of impurities from batch to batch.
4. Flexibility and scalability: SUBs are easy to set up, operate, and scale-up, which allows for quick and easy changes to the process and increased production capacity.
5. Cost-effective: SUBs are typically less expensive than traditional stainless-steel bioreactors, and can be more cost-effective for small-scale and large-scale production.
6. Easy to transport: SUBs are easy to transport, and can be shipped pre-sterilized and pre-assembled, which makes it easy to move them to different locations.
7. Reduced footprint: SUBs typically have a smaller footprint than traditional stainless-steel bioreactors, which allows for more efficient use of space in the laboratory or production facility.
8. Reduced energy consumption: SUBs are designed to be more energy efficient than traditional stainless-steel bioreactors.

• Eliminates validation issues because the cleaning process is avoided. 
• Shortens downtime and turnaround time because no cleaning is required. 
• Lowers risk of cross-contamination with use of new bags for each run. 
• Offers multiple advantages based on the elimination of the cleaning process. 
• Decreased operating costs and capital investment: savings on start-up capital costs as well as utilities, space, and labor requirements. 
• Cost savings from reduced cleaning needs: less space and stainless steel equipment needed; decreased cleaning validation and decreased use of WFI and cleaning solutions; cleaning and sterilization of bioreactors or process tanks can be ‘outsourced’ to disposable bag suppliers. 
• Elimination of the design elements of traditional stainless steel vessels that are dictated by CIP and SIP requirements: validation is reduced because systems are less complex. 
• Ease of installation. 
• Ease of moving when empty. 

Disadvantages of Single Use Bioreactor

Single-Use Bioreactors (SUBs) do have some disadvantages when compared to traditional stainless-steel bioreactors, these include:

1. Limited process history: SUBs are typically used for a single batch of culture, which limits the amount of process history that can be collected and analyzed.
2. Less robust: SUBs are typically made of plastic or other disposable materials, which can be less robust and less durable than traditional stainless-steel bioreactors.
3. Limited scalability: SUBs are typically designed for small-scale and mid-scale production, and may not be suitable for large-scale production.
4. Limited process flexibility: SUBs are typically designed for a specific application and may not be suitable for other applications.
5. Limited cleaning and sterilization options: SUBs are typically designed to be disposable and may not be cleaned or sterilized for reuse.
6. Limited control over process conditions: SUBs may have less precise control over process conditions than traditional stainless-steel bioreactors.
7. Limited ability to troubleshoot: SUBs may have limited ability to troubleshoot problems that may occur during the process.
8. Cost of disposal: Disposal of SUBs can be costly and may not be environmentally friendly.

• Limitation in liquid transmission.
• Scalability is a concern; larger bioreactor bags are required than are currently available.
• Expensive to use: repeated purchases are necessary.
• New technology is unproven in terms of performance.
• Slight rise in variable per-run costs
• It is difficult to justify the use of disposable bag systems for specialty goods or bioreactors larger than 10,000 litres.
• Most large-scale operations have already made the necessary investments in tanks and cleaning validations to facilitate the usage of numerous products.
• The presence of leachables and the inability to store hot liquids.
• Potential for puncture.
• Move with difficulty when full.
• Temperature and pressure sensitivity
• Disposal expenses.

Precautions

When using Single-Use Bioreactors (SUBs), it is important to take certain precautions to ensure the safety and success of the bioprocess:

1. Follow the manufacturer’s instructions: Always read and follow the manufacturer’s instructions for use, assembly, sterilization, and disposal of the SUB.
2. Sterilize the SUB: Make sure the SUB and all its components are sterilized before use to prevent contamination.
3. Handle with care: Handle the SUB and its components with care to avoid damage or leaks.
4. Monitor and control the parameters: Continuously monitor and control the parameters of the bioreactor, such as temperature, pH, oxygen levels, and mixing, to ensure optimal conditions for the cells to grow.
5. Take samples: Take samples of the culture media periodically for analysis to monitor the growth of the cells and the progress of the bioprocess.
6. Use appropriate personal protective equipment: Wear appropriate personal protective equipment, such as gloves and goggles, to protect yourself from potential hazards.
7. Properly dispose of the SUB: Dispose of the SUB according to the manufacturer’s instructions and local regulations to minimize environmental impact.
8. Train operators: Make sure the operators are properly trained in the use of SUBs and the bioprocess that is being run.

References

• https://www.sartorius.com/en/products/fermentation-bioreactors/single-use-bioreactors#:~:text=Single%2Duse%20bioreactors%20are%20used,and%20disposed%20of%20after%20use.
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• https://bioprocessintl.com/upstream-processing/upstream-single-use-technologies/superior-scalability-single-use-bioreactors/
• https://bioprocessintl.com/2016/design-performance-single-use-stirred-tank-bioreactors/
• https://web.wpi.edu/Images/CMS/BEI/parrishgalliher.pdf
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