• they are permanently installed systems integrated into the facility's piping network. This point makes the setup unsuitable for companies that requires frequent process changes or production of multiple products.

2. Cumbersome and routine cleaning + contamination can occur if cleaning is not done well

• The FIP bioreactor can only be cleaned using the Cleaning-In-Place (CIP) and Steam-In-Place (SIP) procedures. These 2 procedures are very time and resource consuming. CIP includes rinsing, detergent cycles (Akali rinse, inter rinse, Acid rinse inter rinse), and sterilisation, while SIP is done to reduce bioburden on the system or to kill harmful materials at the end of every production batch which can lead to prolonged downtime between production batches.

• Residual cleaning agents, dead spaces in piping (hard to reach so not cleaned) and biofilms in the system can compromise sterility if cleaning is not thorough, it increases the risk of cross-contamination. This result in the loss of entire production batches, significant downtime. Thus, cleaning needs to be done by trained personnel which ensures that the bioreactor is fully sterilised for the next use.

3. High utility costs

• Since FIP bioreactor requires CIP and SIP, this can lead to a demand for electricity and water for sterilisation to take place. CIP goes through at least 7 steps which requires a lot of water while SIP requires heating large volumes of water and generating steam for sterilisation.

4. Problem in piping and connections

• The complex network of pipes, valves, and fittings in FIP bioreactors is prone to issues such as leaks, blockages, or wear and tear over time.

• Dead legs or improper pipe designs can create areas where cleaning agents or fluids do not flow effectively, increasing the risk of contamination.

5. High maintenance Requirements for systems and utilities

• FIP require regular maintenance to ensure the proper functioning of components such as sensors, agitators, CIP/SIP systems, and pumps.

• Utility systems that support these bioreactors, such as steam generators and water treatment units, also demand routine inspections and upkeep.

• If the system breakdown, it will affect production

Magar, S. T. (2024, May 25). Bioreactor: Design, Principle, Parts, Types, Uses, Diagram. Microbe Notes. https://microbenotes.com/bioreactor/

Thermofisher. (n.d.). Single-use vs. stainless steel. In Manufacturing

1. Agitation (for mixing of cells and medium), 

2. Aeration (aerobic fermenters); for O2 supply,

3. Regulation of factors like temperature at 37 degrees Celsius , pH between 6.8 to 7.4, pressure, aeration, nutrient feeding (Water, carbon source, nitrogen source, inorganic salts, Vitamins and antibiotic if required) and liquid leveled.

4. Sterilization and maintenance of sterility

5. Withdrawal of cells/medium

Magar, S. T. (2024, May 25). Bioreactor: Design, Principle, Parts, Types, Uses, Diagram. Microbe Notes. https://microbenotes.com/bioreactor/

• Material: The bioreactor is made of high-quality plastic, the cultivation container is typically made from plastic approved by the Food and Drug Administration such as polyethylene.

• Sterility: Delivered pre-sterilized, usually via gamma irradiation, eliminating the need for sterilization procedures before use.

• Design: consist of a flexible plastic bag housed in a supporting structure and equipped with ports for gases, nutrients, and sampling.

• Compatibility: Can be integrated with sensors and control systems for parameters like pH, oxygen, temperature, and mixing.

Types of disposable bioreactors:

1. Stirred Tank: Mimics traditional bioreactors with an internal mixing system.

2. Wave-mixed: Uses a rocking platform to agitate the contents.

3. Air-lift: Relies on gas sparging for mixing.

Advantages & Disadvantages

Advantages:

1. Cost-effective: Reduces cleaning, sterilization costs, and water usage.

2. Fast setup: Saves time since there's no need for sterilization or preparation.

3. Reduced cross-contamination risk: Each batch uses a new bag.

4. Flexibility: Suitable for small-scale production or rapidly changing processes.

Disadvantages:

1. Limited scalability: Typically suited for small to medium-scale operations.

2. Waste generation: Produces more plastic waste, raising environmental concerns.

3. Durability: May not handle certain mechanical stresses or high pressures as well as traditional systems.

1. Material: made of high-quality stainless steel and sometimes glass as well that provides durability, cleanliness, non-contamination, corrosion resistance

   
   

2. Fixed installation: unlike disposable bioreactors FIP are installed and integrated into the facilities infrastructure and are connected to several key utilities like and water, compressed air pumps.

   
   

3. volume and scaling: FIBs are able to handle large volumes of ranging from hundreds of liters to tens of thousands of liters worth of production culture. They are often used for products that require a high yield such as vaccines.

   
   

4. CIP and SIP: they are equipped with clean in place and steam in place system functions making it easier to sterilize and clean it thoroughly without any disassemble required making it highly ideal for facilities to use.

   
   

5. Automation: integrated with pH control systems, temperature monitoring systems, nutrient supply systems and aeration systems. Making it easier for the industry to monitor and make sure that everything is running smoothly

6. Applications : FIB can be used for many different types of culture ranging from mammalian cell culture to plant cell culture to food and beverage and most importantly biologics productions.

   
   

   Refrences : Reactors, Tank and CIP&SIP Systems for Bioreactors/Fermenters | SOLARIS

   SIP/CIP Industrial 500l-30m3 Bioreactors - Solida Biotech

   Applikon BioProduction - Stainless steel bioreactor for cGMP production

   
   

Fixed-In-Place bioreactors are available in large capacities which are suitable for large-scale productions. They last longer than disposable bioreactors which is more sustainable and suitable for long-term operations. It has more advanced management and controls as well. However, fixed-in-place bioreactors have its disadvantages as well.

Since it is not a disposable bioreactor, fixed-in-place bioreactors need daily maintenance and cleaning as contamination could easily occur, the cleaning process would be very meticulous as some places could be very hard to reach so it may not be cleaned. Which can increase the rate of contamination. Also, since it needs a daily thorough cleaning, the utility can be costly.

Since multiple products can be produced, a fixed-in-place bioreactors cannot be changed according to the desired production set-up.

Although, the maintenance and cleaning fees seem costly. It is more sustainable than a disposable bioreactor. We still think that fixed-in-place bioreactors can achieve both efficiency and reliability in production.