Revolutionizing biologics production: Harnessing continuous manufacturing to drive efficiency

Biologics have the potential to revolutionize the treatment of various life-limiting diseases. However, the challenges associated with their production often mean that they are expensive and therefore inaccessible to the patients who stand to benefit from them.

In this article, Abijar Bhori, Senior General Manager at Enzene Biosciences discusses the trends in biologics development and manufacturing and how they can impact affordability and accessibility. Continuous manufacturing will be presented as a potential solution for overcoming the challenges in biologics development (both for novel biologics as well as biosimilars), including the benefits of this approach and how it can revolutionize biologics production in the future.

Innovation in the biologics space

The interest in biologics has increased dramatically over recent years and these molecules now make up a substantial proportion of all drugs currently in pharmaceutical development. Around 70-80% of the top-selling drugs currently on the market are also biologics¹. Synthesized from biological sources, such as microbial and mammalian cells, biologics offer the potential for life-changing treatments for patients. Biologics have been developed that target many different debilitating diseases, including cancer, rheumatoid arthritis and other chronic inflammatory conditions². The global biologics market was valued at $348.03 billion in 2022 and is expected to be worth $620.31 billion by 2032, growing with a compound annual growth rate of 6%³.

Monoclonal antibodies (mAbs), including cetuximab and bevacizumab, are a widely researched class of biologics. With mAbs, it is possible to achieve highly targeted treatments for cancer and other diseases. However, technologies have also progressed from mAbs with the introduction of antibody-drug conjugates (ADCs) and bispecific antibodies. These next-generation biologics build on the targeting capabilities of mAbs: ADCs add a cytotoxic payload for highly targeted and potent treatments⁴ and bispecific antibodies bind to two different targets, increasing their clinical utility⁵.

The cost of biologics development and manufacturing

One of the main challenges in biologics development and manufacturing is affordability and therefore accessibility. The complex structure of biologics makes the development and manufacturing of these therapies more challenging and increases production costs. Higher production costs translate to an expensive final product. The average cost of biologics is between $10,000 and $30,000 per year, with some of the more expensive treatments reaching over $500,000 per year⁶.

The expense of biologics can severely impact their accessibility, particularly on a global scale, due to differences in healthcare systems and infrastructure between different countries. Unfortunately, this leaves many patients unable to receive the transformative benefits of biologics products⁷. Drug developers are under pressure to reduce the costs of biologics, increasing their accessibility while continuing to develop innovative products⁷.

Drug developers frequently partner with contract development and manufacturing organizations (CDMOs) to help them overcome the challenges in biologics production. However, the traditional fed-batch processes often used in biologics production are limited in efficiency, which can mean that the costs associated with biologics remain high and these innovative treatments cannot reach the patients who need them. To drive efficiency in manufacturing and overcome the challenges in biologics production, CDMOs are increasingly exploring continuous manufacturing as an alternative to fed-batch.

What is continuous manufacturing?

Continuous manufacturing is a process that continues without interruption, where materials are constantly loaded and processed to manufacture a final product⁸. Many industries, including the chemical, food and mechanical industries, have adopted continuous manufacturing as it can offer efficient processing, reducing costs while maintaining high levels of quality⁸. The Food and Drug Administration (FDA) encourages the use of continuous manufacturing in the development and manufacturing of drug substances and finished drug products, because of the advantages that this method can bring⁸. Despite this, the pharmaceutical industry has been slow to embrace continuous manufacturing for biologics production.

Continuous manufacturing is an approach that can help to overcome the challenges in biologics production, increasing affordability and accessibility. Technologies have been developed that allow both upstream and downstream biologics processing to be performed continually:

Continuous upstream processing

With perfusion bioreactors, fresh cell culture media is fed in and spent media containing the product is removed at the same rate, increasing cell titers⁹. Perfusion cell culture improves consistency, increases productivity and reduces the production of metabolites and other impurities⁸.

Continuous downstream processing

Although continuous upstream processing has seen more development, continuous downstream processing can be achieved using multicolumn chromatography¹⁰. Multiple chromatography columns are organized in loading and elution/regeneration phases to enable uninterrupted feeding without manual loading, increasing productivity⁸.

Continuous end-to-end integration and process analytical technologies (PAT) must also be considered in continuous biologics manufacturing. Continuous upstream and downstream processing techniques can concentrate products for drug substance processing. The output from continuous upstream and downstream processing is highly compatible with liquid biologics products⁸, and lyophlization as a drug substance manufacturing technique. Fully integrated continuous manufacturing approaches that go from the bioreactor stage to drug substances have demonstrated increased productivity along with cost reductions when compared to fed-batch processes¹¹. The FDA also encourages the use of PAT, which is a method to design, analyze and control pharmaceutical manufacturing processes. By using PAT, product quality is ensured by monitoring critical quality attributes (CQAs) and critical process parameters (CPPs)⁸.

Continuous manufacturing has primarily been explored in mAbs but also shows a lot of potential for newer and more complex biologics. Difficult-to-express proteins and human-engineered molecules, such as bispecific proteins/antibodies, are challenging to work with because they have stability issues. These complex molecules are prone to degradation when using traditional fed-batch processes. Continuous manufacturing minimizes the product contact with other proteases and metabolites present in cell culture media, making it advantageous as a potential solution for complex biologics prone to degradation.

Continuous manufacturing: A revolution in efficiency

Continuous manufacturing has the potential to revolutionize biologics production by increasing productivity and efficiency. The best way to illustrate this is to compare the output from a traditional fed-batch production to that of a continuous manufacturing process, such as intensified perfusion. A typical fed-batch approach for a mAb would produce 0.6 kg of product over 15 days, for example. Switching the production of the same mAb to a continuous manufacturing process would produce 7 kg of product over 25 days with the same setup of bioreactor. With biologics that have been converted from fed-batch manufacturing to continuous manufacturing, a higher yield has usually been shown in the continuous manufacturing approach compared to the fed-batch.

Although this increase in productivity has been demonstrated, continuous manufacturing has yet to see widespread uptake in biologics production. Drug developers have questions regarding the high costs of the raw materials required for continuous manufacturing. Intensified perfusion requires large quantities of culture media, which can increase costs. However, these cost increases can be offset by the high yields that can be achieved with continuous manufacturing, meaning that the overall costs for biologics production will be lower.

What is particularly interesting about continuous manufacturing is that these productivity increases can be achieved by using much smaller instrumentation compared to that used in fed-batch. Continuous manufacturing processes will typically use single-use bioreactors, which have a much smaller capacity than stainless steel bioreactors generally used for biologics production but have advantages in terms of efficiency and product quality. As the process is running constantly, the smaller capacity does not negatively affect productivity and has advantages when scaling up production. Instead of a traditional scale-up that would increase the capacity of the bioreactor, additional single-use bioreactors of the same size can be added in a “scale-on” process. If additional capacity is required, multiple bioreactor suites can be used, which will still have a smaller footprint than a large-scale stainless steel bioreactor. Smaller instrumentation can dramatically reduce the running costs because less area is required in the manufacturing facility and fewer people are required to manage the manufacturing suite.

A reduced instrument scale is continued in downstream processing, which can be made possible as the product is being continually fed through the process instead of being performed in batches. Small chromatography columns can be used instead of large 1-2 m columns that are required for large bioreactors. Downstream processing is usually an expensive part of any manufacturing process. However, smaller chromatography columns use resin more efficiently, meaning that continuous manufacturing can get the maximum capacity out of chromatography resins before they need to be changed.

Ultimately, improving productivity and efficiency can help to address one of the main challenges facing biologics today. The high costs associated with biologics mean that these therapies are inaccessible to many patients who would stand to benefit from them. If biologics developers improve their efficiency with continuous manufacturing, the affordability of their products can also be improved, enabling more patients to access them.

Even molecules that have been traditionally produced using fed-batch for several decades can be converted to continuous manufacturing. By switching to this process, developers can see a real impact on the productivity and efficiency of their manufacturing processes, potentially increasing the affordability and accessibility of their products that are already on the market. This also extends to more complex molecules, such as bispecific antibodies and ADCs, which can also benefit from the high-quality production seen with continuous manufacturing.

The future of continuous manufacturing in biologics production

Although continuous manufacturing can drive efficiency, improve affordability and increase access, it has yet to see widespread use in biologics production. One possible reason for this is the legacy equipment currently used by many CDMOs in fed-batch manufacturing, including large stainless steel bioreactors. It requires a significant investment to replace this legacy equipment with continuous manufacturing facilities and then optimize the processing. As not many CDMOs offer continuous manufacturing, fewer drug developers may have explored it for their biologics production.

However, progress in the biologics field is rapid. Molecules are becoming increasingly more complex, which has a knock-on effect on production, affordability and accessibility. To deliver on the potential of these innovative therapies and improve the lives of as many patients as possible, biologics developers should take a proactive approach and explore revolutionary processes such as continuous manufacturing. Partnerships with CDMOs that are experts in continuous manufacturing can help developers drive efficiency in their biologics production, improving affordability and increasing the accessibility of their products.

References

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