Continuous bioprocessing, a production approach where the input materials are fed into a bioreactor continuously and the product is harvested without stopping the process, now represents a transformative innovation in the biotechnology industry. This method stands in contrast to the more traditional batch processing, where production happens in discrete, self-contained steps with stoppages between stages. Continuous bioprocessing has gained significant attention because of its potential to improve process efficiencies, lower costs, and provide better quality control. However, it comes with its own set of drivers, opportunities, and limitations that influence its adoption and development in the biotechnology space.
In this article we will discuss the topic in the context of monoclonal antibody production because it is the biologic most in demand at this moment in time.
1. Drivers of Continuous Bioprocessing
1.1. Increased Demand for Biologics
The biotechnology industry has seen a dramatic increase in the demand for biologics, especially monoclonal antibodies but not exclusively for cell and gene therapies, and vaccines too. These products are often complex and expensive to produce, which has led manufacturers to explore more efficient production methods. Continuous bioprocessing offers the potential for increased productivity and reduced cost per gram of product, making it an attractive option for meeting the growing demand.
If you consider how biologics are produced at this moment, there are four general types of commercial bioreactor that need considering. These are batch, fed-batch, concentrated fed-batch, and perfusion bioreactors. The fifth which should be the continuous bioreactor has only just started to be become a commercial reality. In monoclonal antibody production, batch and fed-batch bioreactors are the main methods of manufacture. The sizes range from 5,000-L to 25,000-L over a duration of 10–17 days.
1.2. Cost Reduction and Efficiency
One of the primary drivers for adopting continuous bioprocessing is its potential to reduce production costs and improve efficiency. Continuous processing can lead to beter resource utilization, lower energy consumption, and reduced labour costs. The continuous nature of the process allows for steady-state operations, which reduces downtime associated with cleaning, setup, and validation steps required in batch processes. Batch systems take up much more time because of these demands for cleanliness.
The potential for higher yields from the same amount of input materials is another major driver. When biotechnology first became a commercial reality, the cell lines available simply could not produce enough protein. Because continuous bioprocessing often operates at a steady state, it can achieve higher product concentrations and more efficient use of bioreactor space. One of the most interesting approaches to raising productivity which was referenced earlier has been the development of perfusion technology. This approach has allowed for cell numbers (cell counts) to remain constant and at a high level whilst ensuring that supernatants used for cell culturing are replenished regularly. This, in turn, results in increased productivity, meaning more product can be generated per unit of time even though the protein concentration might be relatively low.
Are there any good examples that can be referenced when it comes to assessing costs? There are certainly a large number of EU-Horizon projects which have had to discuss the need for funding to bridge the gap in moving from batch to continuous production and processing. These are not widely available but a few organizations (including ourselves) can establish economic and commercial cost developments even for specific proteins. In the research literature, there are studies that have described the scale of improvement from batch to continuous platform processes especially in antibody production. One example comes from Klutz et al., (2016).
1.3. Flexibility and Scalability
Continuous bioprocessing offers greater flexibility in terms of production capacity. Unlike batch processing, where scaling up requires larger and larger bioreactors, continuous systems can often be scaled more incrementally by simply running for longer periods or adding more modules to the process. This allows manufacturers to be more responsive to fluctuations in demand, reducing the risk of overproduction or underproduction.
The modular nature of many continuous systems also allows for easier scale-up from laboratory to commercial production. This makes it an attractive option for companies developing new biologic products, as it allows them to gradually increase production capacity without the need for significant capital investment in larger equipment.
1.4. Improved Product Quality and Consistency
Continuous processing offers the potential for more consistent product quality. In traditional batch processing, each batch may vary slightly due to differences in starting materials, equipment conditions, or operator variability. Continuous bioprocessing, by contrast, operates at a steady state, which can reduce variability and lead to more consistent product quality.
Additionally, continuous systems often allow for real-time monitoring and control of critical process parameters. This enables manufacturers to quickly identify and correct any deviations from the desired conditions, reducing the likelihood of producing out-of-specification products and leading to higher overall product quality.
1.5. Regulatory Support and Alignment
Regulatory agencies like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have been increasingly supportive of continuous manufacturing practices in recent years. The FDA has even provided specific guidance to encourage the adoption of continuous processes in the pharmaceutical industry, recognizing their potential to improve efficiency, product quality, and safety.
This regulatory support is a critical driver for the adoption of continuous bioprocessing, as it reduces some of the uncertainty and risk associated with switching from batch to continuous methods. Companies can be more confident that their continuous processes will meet regulatory requirements and that they will be able to gain approval for their products.
2. Opportunities in Continuous Bioprocessing
2.1. Development of New Therapeutics
The rise of personalized medicine, including cell and gene therapies, presents a significant opportunity for continuous bioprocessing. These therapies often require the production of small batches of highly specific biologic products, which can be difficult and expensive to produce using traditional batch methods. Continuous bioprocessing offers the potential for more efficient and flexible production of these therapies, making it easier to scale up and meet patient demand.
For instance, continuous processes allow for more controlled and consistent environments, which is critical for maintaining the quality and efficacy of cell and gene therapies. These therapies are often sensitive to changes in process conditions, and continuous bioprocessing can provide the necessary level of control to ensure that they are produced to the required specifications.
2.2. Process Intensification
Process intensification refers to the ability to produce more product in a smaller space and with fewer resources. Continuous bioprocessing is a key enabler of process intensification, as it allows for higher cell densities, more efficient use of bioreactors, and reduced need for large amounts of raw materials.
This is particularly important in the production of biologics, which often require large quantities of cells and other inputs. By using continuous processes, manufacturers can reduce the amount of space and equipment needed for production, leading to lower capital costs and more efficient use of resources.
2.3. Digital and Automation Integration
The integration of digital technologies and automation into continuous bioprocessing presents another significant opportunity. Advanced sensors, control systems, and data analytics tools can be used to monitor and optimize continuous processes in real-time, ensuring that they are operating at peak efficiency and producing the highest-quality products.
Automation can also reduce the need for manual intervention, which can help to minimize the risk of human error and reduce labour costs. This is particularly important in the production of complex biologics, where even small deviations from the desired process conditions can have a significant impact on product quality.
2.4. Environmental Sustainability
Continuous bioprocessing offers several environmental benefits compared to traditional batch processing. By reducing the amount of energy, water, and raw materials needed for production, continuous processes can help to lower the environmental impact of biologics manufacturing. Additionally, continuous processes will usually generate less waste and require fewer disposable materials, such as single-use bioreactors and filters.
As sustainability becomes an increasingly important consideration for both manufacturers and regulators, the environmental benefits of continuous bioprocessing are likely to become an even more significant opportunity for the industry.
3. Limitations and Challenges
3.1. High Initial Capital Investment
One of the primary limitations of continuous bioprocessing is the high initial capital investment required. Although continuous processes can lead to cost savings over time, the upfront costs of implementing a continuous system can be significant. This includes the cost of new equipment, facilities, and process development, as well as the need for specialized expertise in continuous processing.
For smaller companies or those with limited resources, these upfront costs can be a significant barrier to adoption. Even for larger companies, the decision to switch to continuous processing must be carefully weighed against the potential risks and uncertainties involved.
3.2. Complexity of Process Development
Developing a continuous bioprocessing system can be more complex than developing a traditional batch process. Continuous systems often require more advanced process control and monitoring technologies, as well as a deep understanding of the interactions between different process parameters. This can make process development more time-consuming and resource-intensive.
Additionally, continuous processes may need to be customized for each specific product, as the optimal process conditions for one biologic may not be the same for another. This can make it difficult to standardize continuous processes across different products, leading to additional complexity and cost.
3.3. Regulatory Uncertainty
While regulatory agencies have been increasingly supportive of continuous bioprocessing, there is still some uncertainty around the regulatory requirements for continuous systems. In particular, there is a need for more specific guidance on how to validate and control continuous processes, as well as how to ensure that they meet the necessary quality and safety standards.
This regulatory uncertainty can be a significant challenge for companies considering the adoption of continuous bioprocessing, as it adds an additional layer of risk to the decision-making process. Companies must carefully navigate this uncertainty to ensure that their continuous processes are compliant with regulatory requirements, which can sometimes slow down adoption and innovation in this area. The USA’s FDA and regulatory bodies in the European Union are especially stringent and rightfully so when it comes to preventing abuse of any biochemical process.
3.4. Technical Limitations and Risk of Failures
Continuous bioprocessing, though innovative, can be technically complex and presents inherent risks. The continuous nature of the process makes it vulnerable to system-wide failures. For example, if a problem arises in one part of the system, it can affect the entire production line, leading to significant downtime and loss of product. Unlike batch processes, where errors can be isolated to a single batch, continuous processes require rapid troubleshooting and interventions to avoid prolonged disruptions.
Moreover, there are technical challenges in ensuring sterility over long periods of operation, especially when producing biologics. Continuous bioprocessing often involves extended runs, which increases the risk of contamination. Maintaining aseptic conditions over weeks or months without interruption is a critical concern and can require advanced technologies and stringent quality control measures.
3.5. Talent and Expertise Shortages
Another limitation is the shortage of trained personnel with the necessary expertise to develop, manage, and optimize continuous bioprocessing systems. Continuous bioprocessing is still a relatively new area, and there is a need for skilled professionals who understand the unique technical and operational requirements of continuous systems. This includes expertise in process automation, real-time analytics, and advanced control systems, which are not always readily available in the existing biopharmaceutical workforce.
As companies shift toward continuous processing, there will be a growing need for training programs and educational initiatives to help develop the required expertise. This is particularly important for small and medium-sized enterprises (SMEs), which may not have the same resources as larger companies to recruit and train specialized talent.
4. Future Prospects and Conclusion
Continuous bioprocessing holds great promise for the biotechnology industry. It offers the potential for significant cost savings, improved product quality, increased flexibility, and enhanced sustainability. The ability to scale incrementally, reduce downtime, and integrate advanced digital technologies makes it an attractive option for companies developing and manufacturing biologics. Moreover, the growing demand for personalized medicines and cell and gene therapies is expected to further drive the adoption of continuous processes, as these therapies require more agile and efficient production methods.
However, the transition to continuous bioprocessing is not without its challenges. The high initial capital investment, complexity of process development, technical limitations, and regulatory uncertainties are all barriers that must be overcome for the widespread adoption of continuous bioprocessing. Addressing these challenges will require collaboration between industry, academia, and regulatory agencies to develop new technologies, establish best practices, and provide clearer guidance on regulatory requirements.
To summarise the end of this article, while continuous bioprocessing is not yet the industry standard, its adoption is likely to increase in the coming years as companies seek to improve efficiency, reduce costs, and meet the growing demand for biologics. By investing in the necessary infrastructure, training, and innovation, the biotechnology industry can unlock the full potential of continuous bioprocessing and drive the next generation of biomanufacturing.
References
Klutz, S., Holtmann, L., Lobedann, M., & Schembecker, G. (2016). Cost evaluation of antibody production processes in different operation modes. Chem. Eng. Sci. 141, pp. 63–74 (Article)
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