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Thanks to technological advances, process chromatography challenges are surmountable, but increasingly complex therapies in the pipeline will demand more efficient processes in the future.
According to market research, the chromatography systems segment within downstream processing (DSP) is dominant, comprising the largest revenue share of 40.6% of $21.4 billion (1). This dominance is reflected in various business strategies being employed by companies, such as expanding chromatography portfolios, improving efficiencies with single-use technologies, seeking out new products for more continuous processes, and developing technologies to deal with newer therapeutic modalities more effectively.
However, process chromatography in DSP is still challenging, and it is an area that can further benefit from a greater adoption of more technologically advanced approaches, given the fact that therapeutic modalities are seemingly becoming more complex as time goes on. To learn more about some of the difficulties of process chromatography in DSP, the various technological advances available and those in the pipeline, details about continuous chromatography, and potential future trends, BioPharm International spoke with Daniel Kutscher, product manager, Liquid Chromatography Separations Division, Agilent Technologies, and Hans Johansson, applications director, Purolite Healthcare & Life Sciences.
BioPharm: Could you run through the major challenges/difficulties of process chromatography in DSP?
Kutscher (Agilent Technologies): There are various steps that take place during the purification of the product/downstream process. These steps are typically not interconnected and are monitored offline. Biomolecules are tremendously complex molecules, and moving from one step to another whilst maintaining their integrity is certainly a challenge. Another challenge is quality control and obtaining information on the actual status quo of the molecule during each step, all the way through to formulation in a timely manner.
Johansson (Purolite): This can be answered in many ways. Today, many new biologics are antibody based. For those types of antibodies that bind to Protein A, companies already have established purification platforms.
If you investigate the difficulties within the existing platforms, as the upstream process evolves and the titers increase, some facilities, which were designed to handle a certain amount of antibody, five to 10 years ago, are now struggling to cope with increasing amounts of monoclonal antibodies (mAbs). The challenge now is how these facilities can adapt and handle this within the current facility fit.
Secondly, we see a new range of antibody derived biopharmaceuticals. These new classes of mAbs sometimes don’t fit well into existing platforms. It’s common to make the mistake that ‘one size fits all’ with antibodies, but they are all unique proteins with different sequences. Some can be more prone to aggregation, sensitive to acidic conditions, or contain more unwanted variants than others.
With more advanced molecules, we are seeing more and more characteristics that may need more flexibility within existing platforms or even new platforms entirely.
BioPharm: What advances have helped to overcome the challenges associated with process chromatography in DSP?
Johansson (Purolite): Similar to the previous question, the major challenge is handling the number of antibodies being developed in existing facilities. To counteract this challenge, companies are seeking ways to increase the capacity and productivity of resins. Additionally, a particular design facet, being employed by Purolite specifically, is for the resins to fit into continuous manufacturing processes where manufacturers will encounter further challenges. All of these types of actions help to minimize facility constraints for the customer.
Kutscher (Agilent Technologies): Process chromatography challenges can be technical in nature, such as capacity and breakthrough issues during column loading. Others concern the biomolecule itself—aggregation for example can pose a serious problem. The good news is that through the implementation of online real-time monitoring, analytical chromatography is now moving closer to the process. Online real-time monitoring allows for highly sensitive monitoring of multiple critical quality attributes (CQAs) at various stages during the process, including process chromatography, which provides real-time answers and hence also contributes towards quality-by-design (QbD) approaches.
BioPharm: Are there potential technologies/techniques in the pipeline, that you believe will be helpful in improving downstream process chromatography bottlenecks/difficulties in the future?
Kutscher (Agilent Technologies): Driven by the trend towards continuous manufacturing, the pairing of purification chromatography with analytical chromatography will become more important. Fully integrated analytical chromatography techniques, such as high-performance liquid chromatography (HPLC), can help the pharmaceutical industry not only to monitor, but also to better understand and ultimately directly control the process through real-time feedback.
For example, to help customers deliver high quality drugs to market quickly, Agilent recently launched a dedicated Online LC system as a PAT (process analytical technology) tool for continuous insight into the process and into the quality of the drug substance. The system will soon also allow for automated data transfer into areas such as process control software and direct communication with other process devices using generic software communication interfaces.
Johansson (Purolite): It is key to make incremental improvements to existing resins. In relation to Protein A, more robust resins with high capacity at short residence times allow productivity benefits.
In addition, affinity chromatography in general has been driving the downstream development evolution for antibody purification. As we move into new areas of therapy such as messenger RNA (mRNA), this requires a completely different downstream process to the way antibodies are manufactured, and this is one area where Purolite is working to develop new solutions.
This goes for other therapeutic areas as well for areas such as gene therapy and cell therapy so there is a never-ending need for new resins to match new technologies.
BioPharm: Could you provide some details on continuous chromatography in DSP? What are the advantages and disadvantages of this intensified process?
Johansson (Purolite): If we talk about continuous Protein A chromatography, it is about increasing the productivity by using multiple columns under over-loading conditions to create a continuous flow over a system of batch operated columns.
The advantage is that this approach drives productivity, minimizing buffer and resin consumption. As we talk with our clients more about their sustainability goals and initiatives, it becomes clear that this approach supports a greener way of manufacturing.
The disadvantage of continuous chromatography, due to being such a regulated industry, is that if the company is an originator with a novel molecule and a need to get to market as soon as possible, then using the already established platform minimizes risk and time. To validate a continuous process with a large number of columns and valves, running across many cycles, means that you could increase the risk of something going wrong within the batch. The conservative nature of the industry means that these are important factors to bear in mind.
Kutscher (Agilent Technologies): In continuous chromatography, the purification columns are loaded continuously, which supports automated processing. This is achieved by using multiple columns. The key here is to optimize each individual phase—loading, washing, eluting, and regeneration—to improve the efficiency of the process. Analytical chromatography can assist with this step, when used online. For example, by providing real-time data which reveal when to optimize and automate pooling decisions or to prevent column overload.
BioPharm: Has there been wider adoption of continuous chromatography more recently, or are companies still hesitant and remain using batch operations? Will there be a change in the near future?
Kutscher (Agilent Technologies): Even though DSP is still largely done via step-by-step batch operation, there is a clear trend in the industry to move towards continuous chromatography, which is needed to keep up with recent improvements in upstream bioprocessing. We see that the industry is now past the evaluation phase and moving forward with establishing continuous workflows. We see more and more customers implementing automated processes and online chromatography—things are changing as we speak, as companies adopt this technology.
Johansson (Purolite): Larger companies, to some extent, have implemented continuous techniques in clinical manufacturing. To my knowledge, it has not been adopted as heavily for commercial process. For biosimilars where cost is even more important, I believe we will see a more rapid adoption of continuous manufacturing.
BioPharm: What changes can we expect to see happen in DSP process chromatography as a result of the evolving therapeutic landscape?
Johansson (Purolite): With more and more new modalities, completely different approaches will be required, with some not requiring chromatography at all. In most cases, these will not be produced by mammalian cell lines, so you don’t need to consider viral clearance, which is essential in a mammalian-derived, cell-based processes.
From Purolite’s perspective, developing both new affinity resins, multimodal and ion-exchange resins that meet the requirements of these new modalities for downstream processing is an important factor looking forward.
Kutscher (Agilent Technologies): The rise of mAbs in the past decade has accelerated the trend towards more automation and continuous-/PAT-based processes. Other trends are single-use technology and membrane absorbers, which seem to be an interesting alternative to traditional resin-based columns. As we continue to see nucleic acid-based therapeutics and cell and gene-therapy increase in prevalence, the demand for more efficient and faster pharmaceutical manufacturing processes will likewise be accelerated. This also includes the need for real-time release testing and smaller, decentralized manufacturing floors.
1. Grand View Research, Downstream Processing Market Size, Share, and Trends Analysis Report by Product (Chromatography Systems, Filters), by Technique (Purification, Formulation), by Application, by Region, and by Segment Forecasts, 2021–2028, Market Research (February 2021).
Felicity Thomas is the European editor for BioPharm International.
Vol. 35, No. 6
Pages: 25–26, 31
When referring to this article, please cite it as F. Thomas, “Advancing Process Chromatography in DSP,” BioPharm International 35 (6) (2022).