High Specific Productivity For Leaner Sustainable Bioprocessing

By Mitch Raith, Biologics CMCs, Teva Global R&D

Since its inception in the 1980s, the biopharmaceutical industry has seen significant expansion, largely driven by the development and approval of mAb therapies. Each year, the number of approved mAbs increases, reflecting both the expanding range of diseases these therapies can address and the growing confidence in their efficacy and safety. Despite this progress, the market for mAbs has not yet reached its peak; forecasts suggest that demand will continue to rise for decades as new indications are discovered, costs are decreased, and more patients gain access to these life-changing treatments.

However, this growth brings significant operational challenges. As the diversity of antibody products expands, manufacturing facilities must adapt to more frequent changeovers and greater product variety. Building new facilities to meet this demand is not only capital-intensive but also carries a substantial environmental footprint. The industry has responded in part by focusing on maximizing the available facility capacity. Developing high-titer processes is one evident avenue to accomplish necessary efficiency. Higher titers necessitate fewer batches to meet demand, which in turn increases facility throughput and reduces the environmental impact.

Over the past two decades, the pursuit of higher titers for mAb production has become a defining feature of CHO cell culture process development. Where titers of 1-3 g/L were once the norm, today’s processes routinely achieve 10 g/L or more. This relentless drive for efficiency has yielded impressive gains, but it also raises important questions about how CHO cell culture processes interface with the other sectors of bioprocessing and sustainability. As we look to the future, it is essential to consider not just how much we can produce, but how we can do so responsibly and effectively. The relationship between CHO cell culture processes with harvest and downstream purification operations require consideration as developers and manufacturers continue to push the boundaries of cell culture.

Seeing Beyond The Bioreactor

In the race to achieve ever-higher titers, it is easy to lose sight of the broader totality that defines successful biomanufacturing. The prevailing mindset of “more is always better” can be alluring, but it risks oversimplifying the interaction of factors that determine process success. Improvements made in one aspect can create significant drawbacks elsewhere, and these negative effects become clear when we break our tunnel vision and look at the bigger picture. While fed-batch CHO culture remains the dominant modality for mAb production, the steps that follow, known collectively as the harvest process, are equally critical to overall process performance.

Harvesting CHO cell culture typically involves continuous disk stack centrifugation and subsequent depth filtration for cell separation and clarification. These steps are essential for removing cells and debris, ensuring a clean product stream for downstream purification. The effectiveness of the harvest process and, by extension, the success of downstream processing depends not only on how cells perform in the bioreactor, but also on their behavior during the harvest step. The upstream and downstream processes are inextricably linked.

Too often, process development focuses narrowly on maximizing bioreactor output, without fully considering the downstream implications. For example, pushing for higher cell densities can increase the burden on separation equipment, leading to operational bottlenecks or reduced product quality. Conversely, optimizing only for ease of separation may limit the achievable titer, undermining the efficiency gains sought in the first place.

Ultimately, the outcome of upstream processing is not determined solely by what happens in the bioreactor, but by the combined performance of the entire process train. Recognizing and addressing these interdependencies is crucial for developing robust, scalable, and sustainable bioprocesses.

Harvesting In The Era Of High‑Titer

The harvest stage, where the product is separated from the cell solids, represents the critical intersection of upstream and downstream processing. Despite its importance, innovation in harvest technologies has lagged behind advances in CHO cell culture. The standard approach, combining centrifugation with depth filtration, has remained largely unchanged since the early 2000s. Yet, as product titers and cell densities have increased, the limitations of this strategy have become increasingly apparent.

One of the primary challenges at harvest is the management of insoluble impurities, such as cell debris and aggregated proteins. These materials have a strong propensity to clog depth filters, reducing their capacity. Because depth filters are not easily replaced during processing, this creates a major risk for the entire batch. The most straightforward solution is to decrease the loading on each filter and increase the total number of filters used. However, this approach has significant drawbacks, as it not only increases the consumption of single-use filters, raising both costs and environmental impact, but also drives up buffer requirements. This increases energy demand to produce larger quantities of WFI and expands the carbon footprint. Additionally, storing and handling large volumes of buffer and filters occupies valuable space on the manufacturing floor.

Soluble impurities, such as DNA and lipids released during CHO cell culture and separation, present a different set of challenges. These substances can precipitate during downstream processing, particularly during protein A chromatography, leading to filter fouling and process interruptions. Removing these impurities during the harvest operation often requires the use of specialized chromatographic filters, which are expensive and may necessitate operational changes that complicate manufacturing. If impurities are not adequately removed, they can damage chromatography resins reducing their lifespan and further increasing manufacturing costs and waste.

The pursuit of higher titers can amplify these challenges. To understand how high-titer processes may increase risk during the harvest stage, it’s important to examine the methods used to achieve these results. Generally, the industry has focused on three main strategies:

• Increasing viable cell density (VCD): Raising the number of cells in the culture boosts the potential for protein production.
• Extending the production phase: This involves either starting with a higher seeding density or allowing the culture to run longer, giving cells more time to produce the desired protein.
• Enhancing cell-specific productivity (the amount of product produced per cell): Optimizing process conditions so that each cell produces more protein, rather than simply increasing cell numbers or culture duration.

Addressing The Titer/Impurity Tradeoff With Specific Productivity

As in many areas of life, there is no free lunch in biopharma. Each strategy for increasing titer comes with its own trade-offs and can significantly impact the harvest stage. Raising VCD leads to greater production of soluble impurities due to an increased number of cells. The increased cell mass can also strain separation equipment and potentially cause additional impurity generation after the bioreactor process. Extending the production phase to boost yield can negatively affect end-of-process cell health, increasing the likelihood of cell lysis during centrifugation and releasing additional impurities into the process stream. In some instances, the drive for higher titers can reduce overall process efficiency, as the added costs and complexities of managing these impurities may outweigh the gains from increased productivity.

In contrast, focusing on increasing specific productivity offers a promising alternative. At an overarching level, each cell within a given culture is capable of either proliferating or synthesizing the desired target protein. Strategies aimed at increasing VCD often compromise individual cellular protein production, as a greater allocation of resources shifts toward promoting cell growth. By engineering cells to be more efficient producers, it is possible to achieve high titers with lower cell densities. Decreased cell load in the reactor makes the CHO cell culture process robust and scalable by decreasing oxygenation and nutrient demands; moreover, these advances don’t stop at the bioreactors. Fewer cells reduce the impurities, ease strain on separations equipment, simplify downstream processing, and support more sustainable manufacturing practices.

Ultimately, the goal is to develop processes that deliver high yields without compromising product quality, operational efficiency, or environmental sustainability. By expanding the focus from simply increasing titer to enhancing specific productivity, the industry can achieve a more balanced and effective approach to bioprocessing.

The Complex Road To Higher Specific Productivity

Although boosting specific productivity in bioprocessing offers clear advantages, achieving this goal is inherently complex and cannot be solved with a universal approach. Unlike increasing cell density or extending production phases, which are often easier to implement and rely on chemical engineering principles, improving specific productivity demands a deeper understanding of cellular biology and protein expression. Each product and process may require unique optimization strategies, as biological systems are unpredictable, making innovation essential at every step.

High VCD and intensified fed-batch processes have become popular because they can be adopted more readily, for example by using high-growth parent cell lines or through process aspects like perfusion N-1 and temperature shifts. These methods, however, do not address the underlying biological mechanisms and can increase impurity loads, complicating downstream processing. In contrast, specific productivity improvements require a more detailed understating of cellular requirements, but results can vary widely between cell lines and products.

This variability highlights the importance of product- and process-specific optimization and encourages exploration into areas previously thought to be well-understood, such as media composition and feeding strategies. Innovations like in-line glucose monitoring and continuous feeding are already driving progress. Furthermore, the use of small molecule APIs as media additives presents an untapped opportunity to modulate cell metabolism and enhance productivity, though further research is necessary to identify optimal compounds and applications. Targeting high productivity through media supplements enables rapid updating of archaic processes without lengthy cell line engineering. This mindset provides avenues to allocate resources and improve the sustainability of CHO cell culture development practices. The utilization of APIs as media components also introduces considerations regarding their effects on regulatory documentation. While effects cascade through the entire workflow of drug approval, the potential benefits remain limitless.

Despite these challenges, integrating traditional process optimization with cellular biology insights can deliver high yields, consistent product quality, and improved sustainability, paving the way for a more balanced and efficient biomanufacturing future.

Specific Productivity As The Next Frontier In Antibody Production

The evolution of bioprocessing is at a crossroads. The industry’s past successes have been driven by a relentless pursuit of higher titers, but this approach is reaching its limits. As operational complexities and sustainability concerns mount, it is now time for a paradigm shift.

Striving for improved specific productivity offers a path forward. With a shift in focus to how the industry develops CHO cell culture processes, manufacturers can achieve high yields with lower cell densities. This approach not only supports operational efficiency and product quality but also aligns with the growing imperative for sustainable manufacturing.

The journey toward high specific productivity is not without its challenges. It requires a willingness to embrace new technologies, invest in advanced process development, and rethink traditional process strategies. However, the potential benefits — increased facility capacity, reduced environmental impact, and improved product consistency — make this a goal worth pursuing.

As industry continues to grow and evolve, those who adapt and innovate will be best positioned to meet the demands of the future. By learning from past advances and embracing new approaches, we can build a more efficient, sustainable, and resilient biomanufacturing ecosystem.

Author's Note: The opinions expressed in this article are those of the author and not necessarily those of Teva Pharmaceutical Industries Ltd. or its affiliates (collectively “Teva”).  Neither Teva nor any of its employees or representatives make any representation or warranty, express or implied, as to the accuracy or completeness of any information contained herein.

About The Author:

Mitch Raith, is a Scientist II at Teva Pharmaceuticals in West Chester, Pennsylvania. He leads a team specializing in CHO Cell Culture process development with a focus on bioreactor and harvest operations. His efforts span platform, early clinical, and commercial development. Mitch holds a Ph.D. in chemical engineering from the University of Tennessee–Knoxville and a B.S. in Chemical Engineering from The Ohio State University. Reach him on LinkedIn.