The Challenges of Downstream Operations in the World of Continuous Biomanufacturing

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Robust fed-batch manufacturing of biologic drug substance allows for seamless integration with the corresponding upstream manufacturing unit operations. Five decades of development and success in large-molecule monoclonal antibody (mAb) manufacturing have provided thousands of data points that support the more than 200 licensed products by FDA (1). With that level of success, why are companies expressing a growing interest moving into a continuous manufacturing platform?

The drivers that moved the small-molecule drug industry to implement continuous manufacturing included the need for cost improvements and operational efficiency, and a push from FDA and other regulatory agencies to promote emerging technologies (2).The success of this effort was incentive to explore the more complex adaptation of continuous biomanufacturing (CBM) for large-molecule drug substance. While a noble goal, it has proven to have much more complexity due to the science that drives large-molecule drug development involving living cells.

As a baseline, the benefits of CBM are as follows:

• improved utilization
• flexible batch sizes
• simplified scaling
• greater control over critical process parameters
• less energy consumption
• better adherence to schedules.

A continuous platform can process higher/lower quantities of a drug as needed, and it allows manufacturers to respond more rapidly to changing markets. It also enables recipes not possible using traditional batch methods.

Overcoming the downstream challenges in development

In a continuous system, materials are processed without interruption, moving seamlessly from one stage to the next as part of an ongoing process. This eliminates the downtime between production phases.

Higher yield and throughput

Continuous manufacturing often results in higher throughput and yield, thanks to the elimination of downtime inherent in traditional batch processing. The consistent, steady nature of continuous processing minimizes variability and optimizes the conditions needed for high-yield production, leading to more stable and predictable outcomes.

Advances in downstream purification technologies have played a pivotal role in improving downstream processing within continuous biomanufacturing. Enhanced filtration, chromatography, and other purification methods allow for more efficient separation of the desired product from impurities, ensuring high purity and product integrity. These advancements have streamlined the purification process, reducing purification time and cost while maintaining the quality required for therapeutic use. Efficient primary and secondary purification are essential for scaling up continuous production while meeting stringent regulatory standards for product purity.

Microfluidics has brought a new dimension to biomanufacturing by providing precise control over the movement of fluids at the microscale level. This innovation is particularly useful in applications requiring the manipulation of cells or biomolecules in continuous flow, especially during downstream processing. Microfluidic systems allow for the integration of multiple processing steps into a single, compact platform, eliminating the need for large-scale equipment and simplifying complex workflows. These systems are invaluable in early-stage research, small-volume production, and specialized applications where scalability, rapid iteration, and precise control are essential.

Downstream CBM requires end-to-end integration of all unit operations, which represents a major challenge in establishing reliable continuous processes. The integration must accommodate continuous flow from one downstream unit operation to another, leading to higher productivity. Such smooth operation requires understanding and synchronization of residence time distributions (RTDs), flow rates, and propagation of disturbances across the production process. To this end, the need for an RTD model-building platform for continuous bioprocesses is often recognized and implemented. If a key downstream unit operation or its subunit fails, the ability to redirect the flow of the process stream through redundancy and parallelization may be necessary. Automated process-control strategies based on modeling techniques and sensitive real-time sensor technologies are being implemented and control strategies that enable feedforward and feedback control can mitigate the risks associated with process integration and continuous downstream operations.

Downstream optimization

One of the most transformative innovations in downstream CBM is the integration of process analytical technology (PAT). PAT represents a paradigm shift in the way downstream biomanufacturing processes are monitored and controlled, enabling real-time oversight of critical process parameters, such as temperature, pH, nutrient levels, oxygen supply, and cell viability. This real-time monitoring is made possible through the use of advanced sensors and cutting-edge data analytics, which together provide a continuous stream of information throughout the downstream production cycle.

PAT reduces the reliance on traditional, time-consuming offline testing and inspections. With traditional methods, samples are taken at various stages of the process, and tests are performed in laboratories, often causing delays in detecting issues or making adjustments. In contrast, PAT enables real-time feedback of critical downstream operations, allowing manufacturers to make informed decisions quickly and without the need for waiting on lab results. This streamlining of the quality control process significantly enhances the overall speed and efficiency of biomanufacturing, leading to shorter production cycles, lower costs, and increased the increased throughput previously discussed.

Downstream CBM

The downstream manufacturing operations to support CBM must ensure compatibility with the upstream operations. A seamless integration with the output of the upstream operations must address:

• a continuous flow of harvest material, requiring consistent flow rates
• the ability to normalize fluctuations in the upstream flow rates when they occur
• having a robust capability for the removal of cells, debris, and other contaminants in real time
• maintaining consistent product purity and yield via robust chromatography operations
• address viral clearance without there being batch-driven interruptions
• allow for efficient buffer exchange rates and adjustments.

Continuous viral inactivation

Viral inactivation in CBM must focus on the same attributes as would be expected for traditional batch operations. Equipment design must address the key parameters for effective and compliant inactivation that include:

process monitoring and control that produce real-time pH monitoring flow rate control to provide acceptable residence times, and the ability to control temperature, especially for low pH viral inactivation

mixing operations that produce a raid homogenization of acid/base components to produce the desired inactivation conditions

downstream neutralization capabilities that will allow for precise addition of neutralizing buffers to facilitate pH adjustment

validation of the viral clearance that both supports the executed spiking studies and demonstrates the equivalency of batch processes.

Virus filtration would implement high-capacity filters and in-line flow control for steady-state operations (Figure 1).

Figure 1 Continuous In-line Viral Inactivation. (Figure courtesy of the author).

Cell retention technology

The function of the cell retention is to separate cells from the product-containing supernatant material, allowing particulate-free supernatant to enter subsequent downstream purification steps and the separated cells are then returned to the bioreactor to synthesize more product. Cell retention devices are typically either filtration or centrifugation devices.

Filtration devices provide a physical barrier that prevents cells and cell debris from entering downstream purification operations, but they can become fouled over time and thereby restrict flowrates and throughput. Filtration-based cell retention devices can be hollow fiber cross flow filters or alternating flow filtration systems. Centrifugation devices are less common and provide less of a barrier to particulates passing downstream; however, they also do not foul and allow downstream flowrates to be maintained

Continuous tangential flow filtration

As with all tangential flow filtration (TFF) operations, the integration between the upstream and downstream overall operations is critical. As TFF is often a precursor operation between the upstream perfusion bioreactor operations and downstream continuous chromatography, ensuring the integration between these is important.

TFF also improves the efficiency of buffer exchange management and optimizing buffer consumption for downstream chromatography operations. In addition, when used as a diafiltration step, the critical balance between throughput and product retention is more efficiently balanced during dilution operations.

Continuous chromatography

There are advantages to implementing continuous chromatography operations that both improve operational efficiency and reduce manufacturing costs. Improved resin utilization coupled with reduced buffer consumption leads to a reduction in overall cost of goods.The implementation of continuous chromatography operations also increases downstream output by simply reducing the downtime between different chromatography steps. A detailed cost analysis of the impact of continuous chromatography operations can be found in the case study developed by BioSolve (3) (Figure 2).

Figure 2. Counter current chromatography. (Figure courtesy of the author)

There are three primary types of continuous chromatography systems. The most widely used for biologics, primarily for mAbs and viral vectors, is periodic counter-current chromatography (PCC). This is a multi-column system with continuous loading and elution operations that produces efficient results. Simulated moving bed chromatography (SMB) is a more complex system operating in a cycle, where elution flow is through different sections of the system. It is used of higher resolution operations such as oligonucleotide products. The third system is counter-current tangential chromatography (CCTC). These systems implement a membrane-based approach instead of a traditional resin-base system, a hybrid between a TFF and a chromatography operation. It is also used for viral vector applications.

Conclusion

Results to consider from the previously referenced BioSolve case study identify the focus on considerations for the implementation of CBM related to downstream processing (3).

One of the key challenges in this approach is the management of buffer solutions, which can account for over 50% of the cost of goods (CoG); therefore, developing and optimizing a robust solution management strategy is essential to maximizing manufacturing efficiency. Additionally, CBM offers reduced cycle times compared to traditional fed-batch processes by allowing simultaneous production steps and minimizing wait times between stages, thereby accelerating the overall production timeline. Furthermore, CBM supports the integration of multiple downstream unit operations into a single continuous flow, reducing the need for intermediate storage and handling, streamlining production, and lowering the risk of contamination or product degradation.

The transition to CBM significantly enhances operational productivity by enabling real-time monitoring and control of critical process parameters, which improves process stability and reduces product variability, deviations, and rework.These enhancements will be the key drivers in the industry’s acceptance of this manufacturing platform.

References

1. FDA. 2024 Biologic Approvals. Biologics Approvals by Year, CBER. FDA.gov.
2. FDA. Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization, Guidance for Industry (September 2017).
3. Biopharm; “BioSolve Process.” biopharmservices.com/biosolve-software/biosolve-process/

About the author

Jeff Odum, SME, CPIP, NCBiosource

Article details

BioPharm International®
Vol. 38, No. 5
June 2025
Pages 16–18

Citation

When referring to this article, please cite it as Odum, J. The Challenges of Downstream Operations in the World of Continuous Biomanufacturing. BioPharm International 2025 38 (5).