Overcoming challenges to optimize continuous manufacturing for biologics production

Continuous manufacturing is revolutionizing biologics production. Moving away from traditional fed-batch processes, continuous manufacturing continuously loads and processes material to provide efficient, cost-effective and high-quality biologics production. Despite these advantages, continuous manufacturing requires thorough optimization to unlock its full potential and gain widespread use in biologics production.

In this article Abijar Bhori, Senior General Manager, Head of Downstream Process Development and Shilpa Gadgil, Associate Vice President at Enzene Biosciences explores the challenges of using continuous manufacturing in biologics production and optimization strategies to overcome them.

Biologics and the potential of continuous manufacturing

Interest in biologics within the pharmaceutical industry has grown substantially. Transformative therapies have now been developed for cancer, rheumatoid arthritis, chronic inflammatory conditions and many other diseases¹. This increased interest has led to substantial market growth. In 2022, the global biologics market was worth $348.03 billion and is expected to grow at a compound annual growth rate (CAGR) of 6% to $620.31 billion by 2032².

An ongoing challenge in the biologics market is the affordability and accessibility of therapies. The development and manufacturing of biologics is challenging and expensive because of the complexity of these molecules. An increase in the production costs of biologics translates to an expensive final product. The average cost per patient to prescribe a biologic range from $10,000 to $30,000 per year³. The high costs of biologics limit their accessibility on a global scale. Healthcare systems and infrastructure can vary greatly between different countries, which unfortunately means that many patients cannot benefit from these life-changing therapies.

To address affordability and accessibility, biologics developers are increasingly partnering with contract development and manufacturing organizations (CDMOs). Partnerships with CDMOs give drug developers access to innovative solutions for biologics production. Continuous manufacturing is a revolutionary approach to biologics development currently offered by a small number of CDMOs. In continuous biologics manufacturing, upstream and downstream processes are performed continually to produce a drug substance⁴. Technologies exist that enable both upstream processing (intensified perfusion) and downstream processing (multicolumn chromatography till the last chromatography step) to be performed in an uninterrupted manner.⁴

It has been shown that continuous manufacturing can dramatically improve efficiency, enhance product quality (particularly for more complex biologics), reduce production costs and increase biologics accessibility. However, the biopharmaceutical industry has been slow to adopt continuous manufacturing, even though technologies are continuously developing. One reason for this is the optimization steps required to maximize the benefits of continuous manufacturing, which can be broadly categorized according to upstream and downstream processing.

Challenges in upstream processing

The first challenge in upstream processing is developing cell lines that can work with the continuous manufacturing process. Cell lines always need to be engineered and optimized for biologics production but continuous manufacturing requires extra considerations. The cells must remain viable throughout the entire continuous upstream process, while still producing high yields and maintaining product quality⁵. This requires a host cell line that can withstand continuous culture and a method of genetic modification that can enable long-term or stable expression.

Selection and optimization of cell culture media and feed combination is another challenge in continuous biologics manufacturing, which relates to cell viability and consistent biologics production. The main challenge here is maintaining cell viability and productivity for a prolonged time6. Balancing the concentrations of nutrients in the form of commercially available feeds or cocktail of amino acids, growth factors, and trace elements, that are added to the basal cell culture media is critical to achieve higher cell densities and productivities, maintaining cell viability and product quality⁶.

After cell lines and culture conditions have been optimized, continuous upstream processing also requires further optimization and monitoring to reach the optimal peak viable cell concentration (VCC). Achieving higher cell densities and productivities in cell culture requires maintaining consistent process conditions, including pH, temperature, metabolites, ammonia and glucose levels. Additionally, adjusting the process’s temperature helps to maintain the viability of the cell culture for an extended amount of time and prevents problems like excessive foaming and filter choking, among other things.⁷

Challenges in downstream processing

Downstream processing is often viewed as the bottleneck of biologics production and it has been recognized as a part of continuous manufacturing that requires thorough optimization⁴. Downstream processing follows a series of purification steps including multiple cycles/rounds of chromatography, viral inactivation, viral filtration, and diafiltration⁴. In fed-batch processing, these steps are performed sequentially as standalone unit operations. However, in continuous manufacturing, biologics developers need to consider how purification steps can be integrated and performed continuously through appropriatesequencing of unit operations and line up with continuous upstream processes.

Technologies unlocking continuous biologics manufacturing

Technologies have been developed that can help to overcome the challenges in continuous manufacturing and unlock its full potential in biologics production. The optimization of different aspects of upstream and downstream processing can help to maximize the benefits of continuous manufacturing of biologics. For example, using a robust and highly-expressing cell line in combination with media specifically designed for continuous cell culture can overcome some of the challenges in continuous upstream processing. However, by taking a fully connected approach that considers all aspects of the process (upstream as well as downstream), biologics developers can drive efficiency, cost-effectiveness and quality to unlock the full potential of continuous manufacturing.

Continuous upstream processing

Intensified perfusion was introduced with the development of single-use perfusion bioreactors⁴. In intensified perfusion, fresh culture media is continuously added into perfusion bioreactors while spent media and the product of interest are removed. Cells are retained using a cell retention device allowing for higher cell densities, which can increase cell titers⁸. Intensified perfusion also constantly harvests biologic-containing cell culture media and recycles viable cells back into the bioreactor. Compared to fed-batch, the perfusion process can achieve consistently higher quantities and high-quality products in a cost-effective way.

Continuous downstream processing

Continuous perfusion has been connected with multi-column chromatography to deliver continuous upstream and downstream processing⁹. Two or more columns are used as a capture step in multi-column chromatography either in parallel mode or sequential mode. The eluent from one column is captured onto another column. By arranging multiple columns in elution/regeneration phases, multi-column chromatography enables continuous downstream processing and increases productivity⁴. Multi-column chromatography can therefore be used to address the challenge of sequential purification in downstream processing.

Technologies supporting continuous manufacturing

Robust online process analytical technology (PAT) monitoring helps to ensure that all of the optimized conditions remain the same throughout the intensified perfusion process⁷. Factors such as pH, ammonia and glucose levels need to be monitored to determine cell viability, protein production and product concentration⁷. Effective monitoring requires integrating bioprocess sensors across continuous upstream manufacturing⁷.

Benefitting from continuous manufacturing in biologics production

Biologics developers can benefit from the efficient, cost-effective, and high-quality production that continuous manufacturing can offer by focusing on the optimization of upstream and downstream processes.

Combining intensified perfusion and multi-column chromatography can also provide fully integrated continuous biologics manufacturing. Expert CDMOs are taking these technologies one step further, developing proprietary approaches that can deliver the most benefits in terms of efficiency, quality, and costs to their customers. By partnering with CDMOs that have invested in overcoming challenges and optimizing processes, biopharmaceutical companies can benefit from cost-effective, efficient and high-quality biologics manufacturing.

References

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