Key Considerations: How CDMOs can Maximize Productivity and Scalability
By Kevin Mullen, Jason Lukasek, and Jonathan Foster, Thermo Fisher Scientific
Urgent demand for new vaccines and treatments has increased the biopharmaceutical industry’s need for resources in a way that requires transformational operational changes to address. To meet this demand and accelerate the delivery of lifesaving medicines, the industry must maximize development and manufacturing efficiencies, as well as increase production capacity, while maintaining high quality and minimizing risk.
Flexibility is key to successful operation in this quickly evolving paradigm, fueling increased industry reliance on contract development and manufacturing organizations (CDMOs). A recent BioPlan Associates, Inc., survey identified outsourcing growth, the need for bioprocessing production flexibility, supply chain diversification, and increased leverage of single-use systems as trends that will drive biopharmaceutical R&D and manufacturing in 2021 and beyond. To meet industry demand for these capabilities, CDMOs must grow and evolve, scaling up through innovative workflows — without sacrificing product quality or speed to market.
Unique Challenges Currently Faced by CDMOs
In response to the COVID-19 pandemic, vaccines and therapeutics were brought to market quickly. Biopharmaceutical companies and their vendor partners used innovative modalities and new formulations that had to be developed and manufactured in parallel, while maintaining conformance to rigid regulatory requirements. At the same time, the biologics pipeline for other life-saving therapies didn’t slow down. In fact, the U.S. Food and Drug Administration (FDA) approved nearly as many drugs and biologics in 2020 as in 2019. To achieve this level of output, entities across the industry — biopharma innovators, CDMOs, data management firms, raw material suppliers, etc. — collaborated to an extent never before seen.
Of course, this effort has placed significant pressure on every market player, CDMOs included. They face reduced timelines and cost pressures while also having to expand capacity. In other words: do more, do it faster, and make it less expensive. Additionally, drug development and manufacturing continue to increase in complexity. CDMOs are managing this large volume of molecules in the development pipeline while having to adapt facility design, new facility buildouts, and modernization of existing facilities to meet demand.
Lastly, CDMOs have contended with more problematic supply chains. They have had to shift from sourcing end products, like a bioprocess container or a bottle of cell culture media, to finding and securing secondary suppliers for raw materials.
Thermo Fisher Scientific strives to provide solutions that increase efficiency and reduce complexity for CDMOs via three avenues: innovation, optimization, and collaboration. In terms of innovation, we endeavor to design and build next-gen, cutting-edge products that help biopharma manufacturers accomplish their goals. Optimization can be achieved through outsourcing some non-critical activities, freeing your employees to focus on more vital daily activities or strategic priorities. And through collaboration, we offer a tremendous opportunity to accomplish our shared goals smarter, faster, with higher quality, and perhaps even at a lower cost.
Innovation in Biologics Manufacturing
Thermo Fisher’s high-performance, single-use bioreactors (S.U.B.) have been widely used and trusted since 2006, and we introduced 2,000L single-use bioreactors in 2010. Now, a trio of industry trends has pushed us to innovate further.
First, the industry’s demand for more volume in single-use technologies has become more voracious. Many molecules are developed through the clinical stage in single-use bioreactors, but the transition to the commercial stage requires more volume (and cost-effective production requires the efficiencies that accompany higher volume). Next, we recognize CDMOs need to maintain flexible and multi-product facilities, enabling them to utilize their capital equipment in varying ways — including seed train optimization and the capability to run various volumes within the same reactor. Finally, we identified the need for intensified cell culture: better mixing capability and better mass transfer capability in the bioreactors.
In response, Thermo Fisher has introduced the HyPerforma™ DynaDrive™ S.U.B., a reinvention of the single-use bioreactor capable of fulfilling demand for more intense cell culture and higher volumes, as well as bolstering production efficiencies. The 50L DynaDrive™ system launched in September 2020, followed by the 500L model in December 2020, and then the 3,000L and 5,000L models in February 2021 (Fig. 1). We can deliver each of these with relatively short lead times, particularly considering the constraints currently affecting the industry.
DynaDrive combines best-in-class performance (power, mixing, and mass transfer) with a low turndown ratio and a convenient form factor. Regarding performance, we recognized that to optimally cultivate higher cell densities, better mixing is necessary. As mixing ultimately depends on power input per volume ratio, we’ve designed all sizes of the DynaDrive™ to achieve up to 80 Watts per cubic meter (W/m³) power input per volume. Also, the mass transfer has been improved at least twofold: we’ve increased the oxygen and stripped CO2 out of the reactor to more effectively promote high-density cell cultures, in addition to making the reactor more efficient when demand is lower. DynaDrive™ reactors can be run at lower sparge rates when needed, reducing gas entrance velocity and, consequently, reducing cell shear that can occur within the reactors.
We also designed DynaDrive reactors to produce similar results when running multiple terminal volumes within the same reactor. For example, 5,000L reactor users get similar performance running, say, a 2,000L culture. Therefore, CDMOs can optimize the volume needed within the reactor based on their clients’ needs.
Another benefit of the DynaDrive design is its minimal reactor footprint: both the 3,000L and 5,000L reactors occupy a space similar to our 2,000L reactor, providing more volume in roughly the same footprint. Additionally, while the 5,000L DynaDrive rises to 16 feet, the 3,000L DynaDrive is 12 feet tall, enabling users to install it in a facility designed for a 2,000L reactor and instantly gain 50% more capacity without having to adjust the facility build.
We also improved the way DynaDrive reactor doors open and close versus a traditional bioreactor, allowing for full access to the bioreactor and easy connection of the bioprocessing container (BPC) to the motor. Numerous cutouts in and below the door enable users to load the BPC without concern about tubing or ports being pinched or disconnected during the loading process. We also include cutouts with alternating tangential flow filtration (ATF) and tangential flow filtration (TFF) ports in mind, so users can adapt the ports for both current and future applications (Fig. 2).
Moreover, all DynaDrive reactors feature a lift mechanism. While the 50L DynaDrive system is operated manually, the 3,000L and 5,000L iterations offer a pneumatic lift that allows users to load the BPC at ground level, make all connections — motor connection, filter connections, tubing connections (e.g., for anti-foam) — at ground level before raising the BPC up into the reactor.
Finally, one of the key advantages of DynaDrive reactors is their low turndown ratio. DynaDrive reactors can achieve ≥10:1 in-vessel turndown in the 50L model and ≥20:1 in-vessel turndown in the 5,000L. This low turndown ratio optimizes seed train, enabling manufacturers to progress from flask to bioreactor without using rocker reactors. Consider that a typical seed train to a 2,000L reactor progresses vial > flask > two or more rocker reactors > 50L reactor > 500L reactor > 2,000L reactor. The DynaDrive can progress vial > flask > 50L > 5,000L, cutting the number of single-use reactors necessary from five to two by optimizing the seed train.
Benefits of reducing the number of reactors include lower operating costs: fewer consumables and reduced labor, meaning less risk. Additionally, fewer preps, transfers, and BP seed are necessary, and fewer tubing assemblies must be inventoried and managed. Reducing consumables also helps to minimize necessary warehouse space and waste created (i.e., consider the waste generated by single-use BPCs and their packaging).
Financial modeling has confirmed these cost savings (results published in October 2020 in BioProcess International): by utilizing the DynaDrive, manufacturers can reduce operational expense (OpEx) by about 27% and capital expenditure (CapEx) by about 18%, leading to a potential ~25% reduction in cost per gram by reducing cycling times and number of batches (hence, reducing labor costs) while increasing throughput.
Optimization Through Outsourcing
CDMO clients rely on their processes and quality systems to produce the intended molecule. Accordingly, CDMOs need a supplier capable of matching their internal quality — someone with the flexibility, global scale, and outsourcing expertise to meet their specifications and satisfy their unique workflow needs.
With our sourcing capabilities and global supplier and manufacturing network, the Production Chemicals and Services team at Thermo Fisher can match any CDMO’s buffer and process liquid chemical requirements. Whether it’s a specific CAS number or grade of raw material, or a particular vendor and part number, we have an extensive network of suppliers supported by manufacturing facilities.
Further, we offer experienced specialists that can help CDMOs determine the best way to streamline and simplify their process liquid and buffer manufacturing. What are the formats? What is the scale? What are the packaging requirements? Optimization could be a matter of outsourcing a few process liquids or trusted-weight dry powders, avoiding the capital requirement to build a new facility or expand your existing weigh-dispense-hydration suite.
Ultimately, identifying the right fit depends on your process, as well as your current step in that process. To deliver the chemicals needed as buffers and process liquids, we start with understanding your needs from chemical sourcing through delivery of the final process liquid. We do this through a Gemba walk of your process (Fig. 3). As we move deeper into a process, we aim to provide a solution tailored to your unique needs or the needs of your customer.
For example, we can provide weighed-and-certified powders delivered in the volume and the package type required, enabling you to add those materials directly to your process without additional weighing or testing. We also can serve CDMOs’ increasing demand for concentrated stock solutions applicable to inline dilution, as well as various container shapes and sizes that connect directly to your unit operations and feed into your system (e.g., 1X buffers).
Through these capabilities, to combine and mix materials as needed across your processes, we aim to help our clients reduce their total cost of ownership and maximize productivity, taking better advantage of current investments and avoiding extraneous future investments. Trusting outsourced buffer prep to a single vendor also allows you to reduce multi-vendor risk by minimizing concerns associated with mis-formulation, leaks, and contamination.
Collaboration That Produces Results
During the heat of the COVID-19 pandemic, biopharma innovators, CDMOs, regulators, and raw materials vendors communicated and collaborated in ways that shattered industry notions of a “realistic” project timeline or a “feasible” level of efficiency. As the worldwide leader in serving science, Thermo Fisher is committed to being the right collaborator for CDMOs by supporting them as they continue pushing the limits of what is possible.
We offer innovation that adapts to the evolving industry landscape, spanning from our involvement in the inception of single-use stirred tank reactor applications to the creation of the DynaDrive S.U.B.s. This pattern also is evident on the process liquid side, where Thermo Fisher was a pioneer in media in the cell culture market. We have continued to innovate in media (developing serum-free formulations), offering unprecedented flexibility in specifications for process liquid and buffer manufacturing, as well as building state-of-the-art facilities that operate under a meticulous quality system.
Combining capability with capacity, Thermo Fisher provides our customers the skills and resources to take on any project, regardless of size or complexity, based on our decades of experience and process expertise. We are well positioned to support CDMOs across various projects and workflows, and we look forward to being a valued resource as you consider adding new bioreactor capacity and make decisions about how to focus more on core priorities by outsourcing process liquid and buffer preparation.
To learn more, visit us at our bioprocessing solutions for CDMOs hub, or view our on-demand webinar Key Considerations for CDMOS to Maximize Productivity and Scalability
About The Authors
Kevin Mullen is a Sr. Product Manager at Thermo Fisher Scientific based in Logan, Utah. He joined Thermo Fisher four years ago and is the primary product manager for Single-Use Bioreactors and Single-Use Fermentors. He is primarily responsible for new hardware development and strives to ensure single-use systems are developed and maintained to meet performance requirements today and in the future.
Jason Lukasek is the Sr. Sales Director for Bioproduction – Americas at Thermo Fisher Scientific based in Salt Lake City, Utah. Prior to this role, he was the Global Commercial Leader for the Single-Use Technologies business. His 20+ year career spans a variety of sales leadership roles in the life science industry, with the past eight years focused on bioprocessing and bioproduction
Jonathan Foster is Sr. Product Manager at Thermo Fisher Scientific based in Salt Lake City, Utah.
About Thermo Fisher Scientific
Thermo Fisher Scientific Inc. (NYSE: TMO) is the world leader in serving science, with annual revenue exceeding $30 billion. Our mission is to enable our customers to make the world healthier, cleaner, and safer. Whether our customers are accelerating life sciences research, solving complex analytical challenges, improving patient diagnostics and therapies, or increasing productivity in their laboratories, we are here to support them. Our global team of more than 80,000 colleagues delivers an unrivaled combination of innovative technologies, purchasing convenience and pharmaceutical services through our industry-leading brands, including Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific, Unity Lab Services, and Patheon. For more information, please visit www.thermofisher.com/bioprocessing.