Author: Chad Schwartz, Senior Manager, Global Product Management at Thermo Fisher Scientific
Monoclonal antibodies (mAbs) are a class of biotherapeutics containing some of the most exciting drugs to come through the development pipeline in recent years. The mechanism of action for these biologics—the recognition and binding of different targets, including cell-surface receptors and proteins—gives them the potential to treat diseases that have, to date, been notoriously challenging. This means that a wide range of conditions, including various cancers, autoimmune disorders, and infectious diseases, may now have treatment options on the horizon.
Consequently, some of the most highly anticipated drugs of 2023 are mAbs, and many more are expected to reach the market over the next few years. Between 2023 and 2030, the global market size for monoclonal antibodies is expected to grow from around $210.1 billion to $437.1 billion, a projected compound annual growth rate of just over 11% [1]. With many biologics developers looking to bring the next blockbuster mAb to market, the current development landscape is fiercely competitive.
This is good news for patients. Competition will continue to drive innovation in biotherapeutic production, which will ultimately drive down manufacturing costs and lead to more potentially revolutionary drugs. However, for developers looking to launch new mAbs or biosimilars into the market, this poses a difficult question: how can they deliver high-quality, cost-effective, and efficacious biotherapeutics in a crowded and competitive market landscape? The answer may lie in a foundational manufacturing process component: the cell culture medium.
The importance of cell culture media in biopharmaceutical manufacturing
In any biopharmaceutical manufacturing workflow, the medium plays a crucial and foundational role in its overall success. To produce a high-quality therapeutic, it is necessary to keep cells healthy and viable while maximizing their growth and protein production. This is largely done through the cell culture medium (alongside any other functional additives and supplements used). As the chosen medium provides the necessary nutrients for maintaining healthy, productive cells, the specific formulation and any selected supplements are significant drivers of process performance.
However, when it comes to mAb production, developers face a unique challenge. The recent growth of the mAb market has driven substantial industry-wide improvements in cell culture process performance. This has meant that many off-the-shelf media and feeds are now able to deliver high titers and facilitate consistent product quality. While these improvements have allowed more developers to bring mAbs into the pipeline, they have also led to a more crowded marketplace. This has made it difficult for both innovator and biosimilar mAb developers to gain a competitive edge.
So, how can developers remain competitive within this tough market landscape? The solution could be the use of next-generation media and feeds that can not only facilitate maximum yields and consistent product quality, but also deliver efficiencies across the entire workflow. This streamlining of biopharmaceutical manufacturing relies on optimization at every stage of the process, from initial bench-scale development to commercial manufacturing.
Recent advances in cell culture media and feed development
As mentioned, the biopharmaceutical industry has seen huge improvements in the productivity that can be delivered through off-the-shelf cell culture media and feeds. A key driver of these improvements is the recent advances in media and feed development. These new, state-of-the-art approaches have opened the doorway to novel, next-generation formulations that can help developers maximize process performance, while unlocking efficiencies in other workflow areas.
Traditionally, media development has been conducted using spent media analysis, an approach that examines media before, during, and after a production run to understand nutrient utilization by the cells. This allows around 50 molecules to be examined, including certain water-soluble vitamins and amino acids, to understand which components are being taken up and used by the cells. This iterative, empirical approach can then be used to establish which components are driving productivity and how their relative quantities within the formulation can be refined to deliver optimal results.
However, a key innovation by media developers in recent years has been the implementation of multi-omics analysis [2]. This approach builds on the foundation of spent media analysis by providing even greater levels of detail and increasing the number of molecules that can be studied.
Multi-omics for media development consists of two main areas: proteomics and metabolomics. Firstly, by enabling the identification of specific proteins, proteomics allows the specific intracellular pathways that are being activated and inactivated to be recognized. This information can then be integrated with metabolomics data to assess how specific metabolites are flowing through these pathways.
Overall, this approach has enabled media developers to design next-generation media and feeds that can greatly improve the productivity and efficiency of biopharmaceutical workflows, while delivering high titers. In combination with other improvements to cell culture media, including the utilization of novel, granular dry formats, mAb developers can now leverage these efficiencies to help them maximize productivity.
Leveraging next-generation media and feeds across the mAb workflow
Optimized media and feed solutions can benefit the end-to-end development process, as they can enhance each stage of development to help maximize product quality and simplify production processes.
Process development
Process development and optimization is a crucial stage of the biotherapeutic production workflow, but it can often be a time- and labor-intensive endeavor. Establishing a process that can consistently produce a high-quality product, and deliver high enough yields to quickly progress to scale-up, can be a challenge.
This is where next-generation media and feeds can prove pivotal. These advanced media and feed systems are often designed with scalability in mind, meaning they can be used throughout development and manufacturing. This allows developers to move seamlessly through these stages without needing to switch their formulation or conduct any lengthy (and potentially costly) re-optimization. They can also facilitate the meeting of critical quality attribute (CQA) targets, with optimized glycosylation profiles, charge-variant profiles, and protein aggregation.
Another benefit of next-generation medium and feed systems is their flexibility. They are typically designed to deliver industry-standard titers and product quality straight off the shelf with limited re-optimization; however, they can also be used as the foundation for further customization to be tailored to a specific workflow if required. This means that developers who are already partway through process development can implement a next-generation system relatively easily.
Storage and reconstitution
Overall productivity is a combination of both cell culture performance and process efficiency, with the latter becoming increasingly important as production volumes increase. As such, media storage and reconstitution become more important factors as developers scale up to commercial manufacturing. When working at these scales, the use of liquid format media is often less desirable due to the cost, transportation, and storage challenges associated with handling large volumes of liquid. Instead, many manufacturers purchase their media in a dry format which can reduce storage requirements and be reconstituted in-house when needed.
However, not all dry formats are created equal. Typically, dry format media comes in powder form (DPM), but these products can come with complexities associated with reconstitution. These can include the time and labor costs of dissolution and pH and osmolality adjustment; the latter of which can potentially introduce the risk of errors and batch-to-batch media variability. Granulated media formats—which consist of fine particles compacted into small, uniform granules through a process of fluid bed granulation—can help solve these challenges [3]. They allow for formulations that are designed for rapid dissolution and are pH and osmolality pre-adjusted. Granular formats also produce less dust, which can further simplify handling and reconstitution.
Expansion and production
Previously, innovations in cell culture media and feeds have been mostly limited to increasing cell density and cell viability which, over time, has led to a plateau in the mAb titers achievable using CHO cells. However, the utilization of multi-omics in the design of next-generation media and feeds has unlocked even greater productivity improvements, allowing developers to further optimize production.
New media and feeds have demonstrated increased specific productivity in several key bioproduction cell lines, which has enabled mAb developers to substantially improve their titers. Additionally, improvements to culture health and cell viability, as well as reduced levels of toxic metabolite production, can help facilitate longer bioreactor runs. This can extend the period when the cells are functioning optimally, which means they are not only producing maximized yield but also mAbs with the desired CQAs.
Feeding
The next stage of the workflow to be considered is the feeding protocols. Many commercially available feeds come in two or more parts—plus any additional components—that need to be added separately at different times during a production run. This means that developers scaling up to commercial volumes will need two or more feed lines, which may increase complexity and potentially require more regular flushing (or even the attachment of a new feed line) to remove precipitates. This may increase the risk of contamination and potentially decrease overall workflow efficiency.
Next-generation feeds can provide a solution to these complexities. By combining the use of multi-omics in feed development and the benefits of granulated dry formats, suppliers have been able to design feeds that are nutrient-rich and more easily reconstituted. As such, these newer formulations are available as single-part feeds that can simplify reconstitution and feeding protocols by requiring fewer additional components. These feeds are also often formulated to work optimally with specific cell lines, reducing the need for potentially time-consuming process-specific optimization.
Downstream processes
Downstream processing is a crucial step in mAb production, where the upstream product is recovered, concentrated, and purified to meet the necessary quality requirements. Though downstream and upstream processes are often tackled in silos, it is important to remember that upstream processes will have direct effects downstream. As such, it is worth considering how the chosen formulation(s) will affect this stage of the workflow.
The latest, next-generation media and feeds have been designed to allow developers to maintain industry-standard titers but with lower cell densities and, as previously mentioned, improved cell health and viability. These factors can help reduce the dysfunction and apoptosis of cells and therefore limit the impurities released in culture, ultimately helping to improve downstream purification efficiency.
Unlocking elevated efficiency within mAb manufacturing
With the potential to provide treatment options in many key therapeutic areas, the future of monoclonal antibody-based therapeutics is hugely exciting. As this well-established market continues to grow, it will be important for developers to make use of all the options in the biopharmaceutical toolkit, particularly their chosen cell culture formulation.
The latest advances in multi-omics media development have opened the door to next-generation media and feeds, and mAb developers are now able to leverage these to gain substantial productivity and efficiency benefits. These gains can help them accelerate their journey to market and optimize their process to achieve commercial success and deliver life-changing therapeutics to patients.
References
[1] Grand View Research (2023) Monoclonal Antibodies Market Size, Share & Trends Analysis Report. (Accessed: 06-20-2023) https://www.grandviewresearch.com/industry-analysis/monoclonal-antibodies-market
[2] Yao G, Aron K, Borys M et al. (2021) A Metabolomics Approach to Increasing Chinese Hamster Ovary (CHO) Cell Productivity. Metabolites 30;11(12):823. doi: 10.3390/metabo11120823.
[3] Fike R, Dadey B, Hassett R et al. (2001) Advanced Granulation Technology (AGT™). An alternate format for serum-free, chemically-defined and protein-free cell culture media. Cytotechnology 36(1-3):33-9. doi: 10.1023/A:1014045104525.