INSIDE THE SCIENCE
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How intensified purification approaches are improving efficiency, throughput, and cost-effectiveness
Why Protein A Capture Is Evolving
Protein A chromatography has long been the foundation of monoclonal antibody purification. It is a highly selective, reliable, and well-established step that consistently delivers strong product purity.
At the same time, biologics manufacturing has advanced significantly. Improvements in upstream processing have led to much higher antibody titers and increased productivity.
As a result, there is growing interest in how downstream processes—particularly Protein A capture—can continue to evolve to support these gains and maintain overall process efficiency.
In a recent publication in Bioprocessing Journal, Avid Bioservices scientists explored how membrane chromatography and multi-column chromatography can be used to enhance the performance of the Protein A step, improving throughput, resource utilization, and overall process efficiency.
In this edition of Inside the Science, we spoke with Sayali Kulkarni and Anupama Kante about the findings from that work—and what they mean for biologics manufacturing today.
Meet the Experts
Sayali Kulkarni, Ph.D.
Senior Scientist, Process Development Downstream
Avid Bioservices
Anupama Kante, Ph.D.
Scientist, Process Development Downstream
Avid Bioservices
Dr. Anupama Kante has extensive experience developing downstream processes for broad range of modalities, including monoclonal antibodies, bi-specifics, scFv fragments, fusion proteins, recombinant proteins, and enzymes.
Anupama is also developing a three column, two column, and two membrane based purification tool-kit that can be applied to reduce the development timeline and cost of early phase antibody drug molecules.
In addition to her scientific work, she serves as a peer reviewer for multiple scientific journals and as a reviewer and judge for national scientific conferences.
Q&A
Q: You recently published work on intensifying the Protein A step. What prompted this research?
Sayali Kulkarni:
Over the past several years, we’ve seen significant improvements in upstream productivity, with antibody titers increasing substantially. That’s a great advancement for biologics manufacturing, but it also changes the dynamics of downstream processing.
As more product is generated upstream, there’s a need to ensure that downstream processes can handle that increased volume efficiently. Our research was focused on understanding how the Protein A step—while already highly effective—can continue to evolve to support these changes.
We wanted to explore practical approaches that could improve throughput and reduce processing time, while still maintaining the robustness and product quality that Protein A chromatography is known for.
Q: For those less familiar, what role does Protein A play in antibody manufacturing?
Anupama Kante:
Protein A capture is one of the most critical steps in monoclonal antibody purification. It’s where we isolate the antibody from a complex mixture that includes host cell proteins, DNA, and other impurities.
Because of its high specificity, it provides a strong initial purification step that sets the stage for the rest of the downstream process.
It’s also a very well-established and trusted technology, which is why it continues to be widely used across the industry.
Q: What are the limitations of traditional Protein A approaches as processes scale?
Sayali Kulkarni:
Traditional Protein A chromatography relies on packed-bed columns filled with resin particles, where binding depends on diffusion into those particles.
That naturally limits how quickly mass transfer can occur. As production volumes increase, this can lead to longer cycle times or the need for larger columns and more resin.
So the focus becomes how to improve efficiency while preserving the reliability and performance that Protein A chromatography provides.
Q: Your paper explores membrane chromatography. How does that improve the process?
Anupama Kante:
Membrane chromatography changes how mass transfer occurs.
Instead of relying on diffusion, it uses convective flow, which allows proteins to bind more quickly. This enables higher flow rates and shorter residence times.
In practical terms, this can significantly increase throughput and reduce processing time, which becomes especially valuable as production volumes grow.
In our study, we found that Gore’s Protein A Capture membrane increased the productivity and reduced the cost by several folds.
Jeffrey Cassel, Gore®:
Gore® Protein Capture Devices with Protein A enable both convective and diffusive mass transport for binding and elution, with a prepacked membrane bed that is stable and exhibits low pressure drop at high flow rates. This enables order-of-magnitude increased purification productivity compared to packed bed resin systems.
Q: And how does multi-column chromatography fit into this?
Sayali Kulkarni:
Multi-column chromatography improves how the chromatography media is utilized.
Instead of operating a single column in batch mode, multiple smaller columns run in a coordinated sequence. While one column is loading, others are washing, eluting, or regenerating.
This allows for more continuous operation, reduces downtime, and increases overall productivity without requiring a larger footprint.
Q: What impact can these approaches have on manufacturing performance?
Sayali Kulkarni:
Both approaches can improve how efficiently the Protein A step operates, particularly in terms of throughput and processing time.
They help create a more balanced process overall, allowing downstream processing to keep pace with advances in upstream productivity.
They also improve how manufacturing resources are utilized—whether that’s chromatography media, equipment, or processing time—which contributes to more efficient and cost-effective operations as programs scale.
Q: The paper also highlights cost efficiency. How do these approaches impact manufacturing cost?
Anupama Kante:
Cost efficiency in downstream processing is closely tied to how effectively you use your materials, equipment, and time.
In traditional Protein A processes, resin cost, cycle time, and equipment utilization all contribute to the overall cost structure. As production volumes increase, those factors become more significant.
Approaches like membrane chromatography and multi-column systems improve how those resources are used. For example, Gore pro A membrane’s shorter cycle times allow more material to be processed in the same amount of time, and multi-column systems help maximize resin utilization.
So rather than focusing on cost reduction alone, these approaches improve overall process efficiency—which naturally translates into more cost-effective manufacturing.
Jeffrey Cassel, Gore®:
Gore membranes enable the end user to maximize their investment in the Protein A media. At any given bioreactor size, due to the high binding capacity, high flow rate, and rapid cycling enabled by the membrane, the end user needs much less Protein A membrane by volume compared to traditional resins. This enables the end user to save costs while increasing throughput.
Q: Are these approaches applicable to all programs?
Anupama Kante:
It depends on the specific molecule and stage of development.
Traditional Protein A chromatography remains very effective and is often the right choice, particularly in later stages. Membranes have a cost benefit in early-stage programs. Intensified approaches are additional tools that can be applied when there is a clear benefit in terms of efficiency, scale, or process design.
The key is selecting the approach that best fits the needs of the program.
Q: How do you see Protein A purification evolving going forward?
Sayali Kulkarni:
We expect to see continued innovation in purification strategies as biologics manufacturing evolves.
There is increasing focus on improving efficiency, flexibility, and scalability across the entire process, and intensified approaches are part of that progression.
Anupama Kante:
Ultimately, it’s about designing processes that are not only effective, but also adaptable and aligned with future manufacturing needs.
“As upstream productivity increases, purification strategies are evolving to improve efficiency, resource utilization, and overall manufacturing performance.”
Protein A chromatography remains a cornerstone of monoclonal antibody purification, providing a reliable and well-established foundation for downstream processing. As biologics manufacturing continues to advance, approaches such as membrane chromatography and multi-column systems are helping enhance efficiency, improve resource utilization, and better align purification with modern upstream performance.
By incorporating these strategies where appropriate, manufacturers can design more efficient, scalable processes that support both current programs and future innovation.
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