How single-use technologies can improve antibodies production  

Monoclonal antibody

DDW Editor Reece Armstrong speaks to David Chau, Global Bioprocess Application Specialist, Purification and Filtration Business, Solventum, formerly 3M Health Care, about challenges in producing monoclonal antibodies (mAbs) and how single-use technologies can simplify processes.  

RA: What are some of the current limitations for producing mAbs?

DC: For the past few decades, there have been many advancements in the biotechnology space. However, despite these advancements in process optimisation and cell culture engineering, there remain areas that we need to improve. Where the bottlenecks of achieving higher cell density and higher titers were once thought to be issues of the past, hurdles have now shifted to achieving speed and scale in mAb production without sacrificing quality. Although higher titers can be achieved more efficiently with the advancements in metabolic and genetic engineering along with the use of perfusion cultures, it will be imperative that we understand and better control our overall bioprocessing to ensure that we can reliably mass produce mAbs without any additional product-related impurities, as one example. mAb production involves extensive, complicated manufacturing operations with many biological raw materials that require detailed procedures and advanced technologies to ensure the quality and stability of the final product. It is up to the end-users and vendors to collaborate and put forth innovative solutions that will aid in driving quicker and more robust mAb production for complex biological processes, leading to quicker and cheaper drug product for patients. Ultimately, we owe it to patients to work together and come up with new and innovative manufacturing as well as process development approaches to accelerate the development and achieve speed to clinic.  

RA: In recent years, what improvements have we seen to cell-line engineering for antibodies?

DC: Antibodies have and remain a large product class within the biopharmaceutical market. The use of improved platform expression systems plays a large part in driving quick and easy mAb production, allowing manufacturers to have the confidence and speed to produce complex biologics such as antibodies. However, we’ve seen in recent years with cell engineering advancements – in RNAi or CRISPR-CAS, as a couple of examples – that better cell lines can be produced to create better strategies for antibody production. This means we are able to hijack the cell machinery to be even more efficient than before to produce more of what we want (mAb) and less of what we don’t want (impurities) through the different genetic editing tools for cell engineering. 

RA: How can anion exchange (AEX) chromatographic approaches improve production processes for antibodies?

DC: Anion exchange (AEX) chromatographic approaches have always been a workhorse and stable of downstream operations, specifically in the mAb space, and are widely used to separate molecules based on their net charge. AEX chromatography has primarily been used in the polishing AEX step for the removal of impurities, such as DNA, HCP, etc., as well as viral reduction and other product-related impurities. Most approaches primarily rely on using centrifugation or depth filtration which primarily involves relying on density or size to remove particulates and impurities. However, by utilising AEX in clarification, we now can remove both large particulates and small particles which in the past have been typically dealt with by downstream purification operations.  

RA: Are current mAb manufacturing processes impactful on the environment and if so, how can we make processes more sustainable?

DC: Current mAb manufacturing processes can have an extreme impact on the environment despite the benefits and value it can bring to human health. There are multiple metrics that companies have used to measure the improvements manufacturers can have on process efficiency as well as sustainability. Process mass intensity is a common metric for efficiency by measuring the number of raw materials it takes to produce the end-product, which ultimately tells us how productive and wasteful we are in a process. However, we’ve seen more and more studies come out where end-users and manufacturers are being asked to do a more holistic study, looking at a full life-cycle assessment that explores the bigger picture rather than a small snapshot in the manufacturing process. As a result, single-use technologies were explored as a more sustainable approach to mAb manufacturing. There are significant advantages to single-use such as reducing the chemicals and resources needed to sterilise and reuse systems when making new and different batches. However, in order to quantify the impact, we will need to be able to collaborate and share more with each other and within the industry. We’ve seen initiatives from organisations, such as BioPhorum Operations Group (BPOG) and Bio-Process Systems Alliance (BPSA), where multiple end-users and vendors are starting to work together to put forth initiatives and data packages to form guidelines for the industry on what a full life-cycle analysis would look like from the start of raw materials, all the way to the final drug product. If we are to be more sustainable as an industry, we will need to continue improving and innovating together to enhance our processes and become more efficient.  

RA: What are the benefits of using single-use technologies for cell culture harvest?

DC: In the last few years, we’ve seen a lot of innovation in the cell culture harvest space, specifically in the use of single-use technologies. New and improved depth filters that can provide longer lasting filters with higher throughputs and better impurities will ultimately lead to better process economics. We’ve also seen new and innovative single-use technologies with the invention of single-use centrifuge and now, single-use chromatographic clarification approaches. The goal of these approaches is to improve process economics by eliminating steps and the amount of reagents, water and buffer. By doing so, the use of single-use technologies can be translated to having a higher process mass intensity or lower cost of goods.   

RA: Are there other areas of the mAb production process that can be simplified using single-use technologies?

DC: We’ve seen in the last decade or so a lot of research and interest in the use of single-use technologies. As a result, there has been a lot of innovation and new approaches to transforming a traditional stainless mAb manufacturing process to be more modular and flexible with the use of single-use technology. Ultimately, the goal is to increase process flexibility and process economics by helping manufacturers deliver high quality drug products to patients at a record pace. There have been numerous studies that have documented the ability to reduce time and labor, along with reagents and consumables, with single-use technologies compared to its counterpart. You can already see that traditional legacy technologies that previously relied on stainless steel now have a single-use alternative. For example, stainless steel plumbing now has its corresponding single-use tubing and traditional stainless steel commercial scale bioreactors now have a single-use bag and bioreactor system. Single-use depth filters and membrane filters have emerged as one of the most popular approaches for filtration compared to traditional centrifugation approaches and we are now seeing an emergence of centrifugation in single-use format as well. The traditional approaches of using columns, for example, in the affinity step with Protein A resin is now seeing an emergence of newer formats of single-use Protein A membranes, and polishing columns now have single-use alternatives as well. Currently, we’re already seeing the industry move toward a reality where there will be a single-use alternative format to each of the unit operation, allowing the end-users to decide which is best suited for their process and scale.  

RA: What impact do improvements to these processes have on drug discovery and development?

DC: Single-use technologies can have a dramatic impact in the drug discovery and development space by providing researchers a quick way to develop and screen different processes. As molecules continue to evolve and become more complex, especially with the emergence of cell and gene therapy, there will be a need for quicker and smaller runs with the flexibility that single-use technology can provide. 

RA: Can using single-use technologies for mAb production result in a reduction in cost of goods?

DC: Several studies have already shown that by using single-use technologies, dramatic savings and lower cost of goods can be achieved through reductions in time, labor and consumables (water and energy) used. While single-use technologies may have more cost upfront, they typically provide manufacturers with faster turnaround time leading to more batches of high-quality product. 

RA: What are some other tips and strategies you can offer for achieving more efficient mAb production processes?

DC: Currently, we are seeing a push for the industry to deliver more with less – drive the cost of goods down while still delivering high quality mAb product. As a result, this will require new and innovative solutions to meet more efficient mAb production processes. In order to achieve this, it will require collaboration between researchers, end-users, and vendors to put forth an engineered solution that best fits the industry’s needs. There are currently many technologies with varying formats on the market for end-users to pick from, but it will take efforts and cross-talk between end-users and manufacturers to pick the right material for the right application.    

Biography

David Chau is a Global Bioprocess Application Specialist in Solventum’s Purification and Filtration Business. He has over fifteen years of experience in the biotechnology industry. Currently, he is responsible for developing product application strategies and driving collaborations with key industry leaders. He manages technology projects, collaborations, and alliances around the globe. David is an active member of multiple biotechnology chapters and associations including serving as the chair for the Bio-Process Systems Alliance Continuous Processing Committee. He earned his Ph.D at the University of Minnesota in Twin Cities and his B.S at the University of Texas.  

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