Simply put, a bioreactor is a stand-alone cell culture vessel enabled with sensors. Bioreactors differ fundamentally from traditional R&D cell culture in their ability to monitor and control key parameters such as temperature, pH, and dissolved oxygen (DO). Continuous, in situ monitoring of these parameters allow for a deep understanding of the growth environment of a given cell population -- creating avenues for process improvement. Paired controls enable dynamic, real-time responses as cells grow and the culture changes over time. With these capabilities, bioreactors can overcome limitations of traditional cell culture enabling the use of cell culture for commercial or clinical purposes.
Different Types of Bioreactors
There are many different types of bioreactors. The most commonly used is a stirred tank reactor (STR). STRs can also have many different geometries, enabling different types of culture. The most common type of STR is a cylindrical vessel with one or more submerged impellers that allow for continuous stirring. Bioreactors (mainly STRs) have been widely adopted by the bioprocess sector to culture bacteria or yeast. Bioreactors have been used for decades in a wide variety of processes ranging from alcohol fermentation, to biodegradation of organic wastes, to antibody and vaccine production. Though they are still used for these purposes today, bioreactors are an important enabling technology that is increasingly being adopted for the production of cell and gene therapies.
How can Bioreactors Facilitate Process Development?
Adherent cell culture faces many scale-up challenges. Large-scale adherent culture performed using traditional methods (e.g. culture flasks and incubators) is costly and requires a physical footprint that is prohibitive for many commercial applications. Many adherent cell types can be adapted for suspension culture in bioreactors allowing for a drastically reduced footprint, scaling-up into the hundreds of litres, and enabling translation to a commercial scale.
- Monitoring of Parameters:
With the help of probes and sensors, bioreactors can monitor and record culture parameters in real time. This allows for identification of critical factors that either promote or inhibit cell growth. Armed with an inventory of data about how the cultures change over time, what drives their growth, and what inhibits them, developers and researchers can chart a plan to optimize the overall process to meet manufacturing and regulatory goals.
- In-Line Controls and Feedback Loops:
In addition to monitoring, bioreactors can also actively control key parameters in response to real-time changes. For example, changes in pH and DO can be controlled by shifting the flowrate or composition of gases. This can be accomplished by manual adjustment, or in some cases, automatic feedback loops. In more sophisticated systems, the user establishes DO and pH setpoints and the bioreactor responds with appropriate changes in these parameters to achieve and maintain these setpoints. This can optimize cell growth conditions while providing a hands-off approach to cell culture.
- Continuous Perfusion:
Although many different feed regimes can be paired with bioreactor culture, typically one of the most successful process improvements is the implementation of perfusion. Perfusion ensures that cells are provided with ample nutrients, while any inhibitors are continuously removed or diluted. Since perfused reactors have a continuous flow of media into the culture and continuous removal of spent media out of the reactor, enabling a cell retention technology to keep your cells in the reactor is crucial. There are many such technologies available, each with their own strengths and drawbacks, and users must find one that works for their cell type of interest. Consequently, this feed strategy might not be optimal for all cell types. However, bioreactors allow for the use of several feed strategies with the aim of improving cell growth and can greatly intensify your process.
Bioreactors are versatile. Options to add or remove probes, controls and feedback loops allow them to be specifically tailored to overcome challenges or address questions associated with a specific process. For example, sensors for parameters such as lactate, glucose and biomass are common in other industries and are currently being examined for their applications in cell and gene therapies.
- Regulatory Considerations:
One of the biggest hurdles in the commercial manufacture of cells is developing processes that satisfy complex regulatory requirements. Bioreactors can assist in the development of processes with built-in controls that help to address these requirements. Firstly, as standalone culture vessels, bioreactors offer closed and aseptic environments. Increasingly, the industry is turning towards single-use, disposable bioreactors to mitigate risk associated with sterilization of reusable vessels. Furthermore, single-use disposables such as cell bags, weldable tubing and syringes allow for cell inoculation, harvest, monitoring and sampling to occur in a completely closed and aseptic manner. In-line sensors and automated feedback loops are driving the development of processes with hands-free or virtual control. The ability to scale, close and tightly control bioreactor-based processes facilitates translation into current Good Manufacturing Practices facilities. This is a critical step in meeting regulatory requirements and moving new therapies towards the clinic.
How to Take the Next Step in Moving your Process into a Bioreactor
There are many factors to consider before moving a process into a bioreactor. Partnering with an experienced CDMO will help you to ask the right questions and develop a custom scale-up solution. It is important to remember that scale-up is not just about “numbering-up” to the next order of magnitude; it is a technique that will be applied uniquely for each process.