Bioreactors Redefine Upstream Productivity

Decades ago, bioreactors were little more than the vessels in which fermentation or cell culture took place. Each bioreactor was a bit like a black box, as developers focused on process measurements that would keep cells viable and boost output. As their efforts have shone more light on the biopharma design space, the bioreactor is no longer viewed as a black box, but an integral part of a much larger interactive ecosystem. On the very front end, cell-line and antibody expression platforms have reduced the time required for cell-line development and antibody expression, with some platforms reported to reduce the time required from months to days (1). Knowledge of processes, cells, and media and their interaction has led to process improvements, but also improvements in bioreactor design, and virtually redefined upstream productivity. “We’re seeing a significant shift in what we consider normal productivity for a protein biological process,” says Patrick Gammell, executive director for process development at Amgen.

Results are being seen upstream, in improved single-use bioreactor systems. Once used exclusively in research settings, single-use systems have become entrenched in the late development scene, as data showed their potential to boost production capacity (2). As designs improved, the contract development and manufacturing organization (CDMO) Lonza Pharma and Biotech became an early adopter of single-use systems for Phase II and III programs, says Atul Mohindra, Lonza’s R&D director for biomanufacturing. 

Another major trend is the widespread use of process intensification (e.g., the application of perfusion to boost cell density). Bioreactor design efforts continue to focus on integrating spectroscopy and better sensors and to improve process control. Over the next few years, experts predict a focus on single-use bioreactors better designed to handle the higher cell densities that result from perfusion, by offering improved mixing and oxygen transfer (3).  

At Millipore-Sigma, says Darren Verlenden, the company’s head of bioprocessing, one area of focus in bioreactor development is in new sparger and impeller designs. Their goal is to improve the volumetric mass transfer coefficient, KLa (a measure of the rate of oxygen used for fermentation) and mixing so that the bioreactors will be better able to handle increased cell densities.  

Reducing shear

Another focus will be optimizing shear and improving cell retention, through use of fixed-bed bioreactors and other technologies (3). To meet these goals, Pall offers the iCELLis fixed-bed bioreactor as well as the Cadence product line, which incorporates acoustic wave separation technology, designed  to improve cell retention without increasing shear. 

Also using the fixed-bed approach is a hybrid single-use bioreactor design developed by Univercells, which links a structured fixed-bed bioreactor to an automated tangential flow filtration concentrator. This design reduces process footprint, processing time, and building and operating costs, according to product manager Alex Chatel. It also reduces the solid impurities sent for downstream processing, reducing the time and number of operations required to generate materials for downstream processing, he says. 

Univercells has been focusing mainly on applications in vaccine development and manufacturing. In March 2020, it launched a new CDMO, Exothera, that will use its own as well as other technologies to develop viral vector processes for gene and cell therapies, with the goal of reducing costs and time to market. The company will perform this work at a 15,000-m2 site in Jumet, Belgium. 

In general, the industry is moving towards intensified, connected, and continuous bioprocessing, says Verlenden. GE Healthcare Biotech is updating its bioreactors to enhance process intensification (e.g., by introducing an automatic perfusion system that can be integrated directly into the Xcellerex bioreactor platform). 

Upstream and downstream operations are being integrated more closely, and downstream bottlenecks addressed by technologies such as continuous capture chromatography and flow-through polishing tools and improved buffer and media preparation, says Verlenden. Currently, he says, the company’s customers expect that 40-50% of their processes will use continuous capture and flow through polishing technologies over the next five years.

Analytics and control

Improved analytics and control is also guiding new product development. Pall Life Sciences has incorporated supervisory control and data acquisition capabilities into its bioreactors, while Sartorius’ latest Biostat STR bioreactors incorporate automation and process analytical technologies, in an effort to simplify configuration changes for users, not only during development but also for manufacturing. GE Healthcare is using improved sensors, to help users better assess critical quality attributes (CQA) and aggregate the data sets that will be the basis for process modeling, the development of digital process twins, and use of artificial intelligence, according to Avril Vermunt, strategic technologies partnerships leader at GE Healthcare’s life-sciences division. 

Design enhancements

Amgen Corp. is putting many of these concepts into practice at a new facility in Rhode Island, which is expected to start up in 2020. Patrick Gammell, Amgen’s executive director for process development, shared insights with BioPharm International. 

BioPharm: What are the most significant improvements you have seen in bioreactors within the past few years?

Gammell: Single-use bioreactors have evolved significantly in terms of design enhancements to drive leak-free robustness, mixing, and gassing improvements to allow these bioreactors to sustain long-term high-density cultures. A number of these enhancements have come as a result of the continued push within the industry to drive process intensification through improvements in cell lines, media formulations, and through the use of perfused formats. 

In addition, the application of computational fluid dynamic modeling as well as other advanced modeling techniques has been instrumental in helping to optimize bioreactor design. These improvements in bioreactor and perfusion technologies (e.g., filter formats) have come from close collaboration between the manufacturers of biologic medicines and the single-use suppliers. 

A number of suppliers and academic institutions are also working on the potential to directly integrate sensor technologies into single-use systems to further dematerialize the process and ancillary equipment required for robust manufacturing. The outcome of all of the recent work on bioreactor optimization and, in particular, the use of modeling technologies is also driving improvements in the tech transfer and scale up of processes. Where, in the past, developers used to take a somewhat empirical approach to these efforts, the use of models allows us to digitally optimize prior to use with actual cells, and this practice continues to transform the way that we work today.  

BioPharm: What overall improvements have been made in commercial-scale upstream bioprocessing? 

Gammell: Over the past two to three years there have been significant improvements in terms of process intensification resulting from technological advances across the lifecycle of the upstream process. Cell-line development and innovations in automated clone selection have had a great impact, along with the development of enriched nutrient media formulations. These formulations promote and then sustain highly viable cultures and process formats that allow unprecedented cell densities and productivities. 

In addition to developments in upstream technologies, the continued advancement of high-throughput analytical product characterization has allowed us to better understand the regulation of how products are formed within living cells. This knowledge allows manufacturers to design process control strategies to ensure consistent and reliable product quality.  

Future innovations

BioPharm: What will be key areas for innovation in the near future? 

Gammell: Continuous manufacturing for biologics is an area of intense focus for many academic and industrial researchers, and creates new and interesting challenges for innovative thinking, in particular the challenge of integrating appropriate in-line analytical technologies in combination with complex multivariate model-based control systems to ensure that, over an extended process format, the process remains in a state of control and that product output remains consistent. A number of these individual components already exist today. The innovation will come from integrating them to ensure robust performance in a continuous format.

BioPharm: Is biopharm improving upstream-downstream integration?   

Gammell: In the old paradigm, upstream process designers were focused on titer and did not necessarily consider the impact of upstream process design decisions on harvest operations or purification complexity or yields. A significant improvement came as a result of the application of the QTPP (quality target product profile) concept, which drives us to design products by starting at the patient and working backwards. The QTPP approach necessitates very careful integration from device designers, formulators, purification scientists, and upstream developers. This [collaborative] approach is key to an integrated process design strategy that has already allowed us to better integrate from upstream, through harvest and into purification. 

The continued intensification of upstream processes in terms of cell densities and titer creates new opportunities for harvest/cell separation technology development, and the higher product concentrations also lead to challenges in terms of sizing the purification operations and how they are cycled. Continued research into higher capacity and cleanable purification resins will remain important.

Next-gen bioprocessing

BioPharm: What are Amgen’s plans for the new Rhode Island facility?

Gammell: The new biomanufacturing plant in Rhode Island will be structurally complete in 2020 and will use Amgen’s prove next-generation biomanufacturing capabilities to manufacture products for the United States and global markets. In contrast to conventional plants that leverage fixed bioreactors and tanks at scales of up to 20,000 L, next-generation manufacturing plants have adopted a flexible, modular design that leverage much smaller 2000-L vessels that are portable and accommodate single-use bioreactor bags.

These smaller, modular bioreactors can produce as much protein as the large stainless-steel tanks currently used at conventional plants. The impact of these innovations results in a 50% reduction in construction time and approximately one half of the operating cost of a traditional plant. Next-generation biomanufacturing plants also offer greater environmental benefits. Within the plant, the equipment is portable and smaller, with a significant deployment of single-use components, which results in much greater flexibility and speed when manufacturing different medicines simultaneously.

Data management

BioPharm: Amgen recently started a project that aimed to improve digital data management for raw materials.  How is that work progressing?

Gammell: Amgen has invested heavily in our data infrastructure to allow us to integrate all of our data sources, including process monitoring, sensors, equipment, and product testing via an enterprise data lake. This capability allows an unprecedented ability to detect and understand the sources of process and product variation.

A significant potential source of variation comes from raw materials, so Amgen has been working with suppliers such as GE to integrate supplier data with process and product data. This [integration] not only allows us to better understand and predict issues as a result of material variation, it also allows us to collaborate with key suppliers to continuously optimize and improve the consistency of our materials. Our goal is to continue to gain access to data sources, including data from the suppliers to our suppliers, which increases our understanding and, again, our ability to predict and prevent issues that may impair our ability to serve every patient every time. 

References

1. Pharmaceutical Technology editors, “New Berkeley Lights Workflow Speeds Drug Discovery,” PharmTech.com, January 7, 2019.
2. GE Healthcare Life Sciences, “Process Economy and Production Capacity Using Single-Use vs. Stainless Steel Fermentation Equipment,” White Paper, gelifesciences.com, 2015.
3.Shanley, BioPharm International 33 (3) (2020).

Article details

BioPharm International
Vol. 33, No. 4
April 2020
Pages: 14-17

Citation

When refering to this article, please cite it as A. Shanley, "Bioreactors Redefine Upstream Productivity," BioPharm International 33 (4) 2020.