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The growing demand for antibody and other bio-therapeutics will require long-term scale-up solutions.
Scale-up solutions are needed to create cost-effective capacity to meet increasing demand for antibody and other bio-therapies. In one approach to enable scale up, companies such as ABEC and Thermo Fisher Scientific have launched the biggest volume single-use bioreactors on the market to date. In recent years, ABEC introduced its 4000-L and 6000-L single-use bioreactors, and Thermo Fisher introduced its 5000-L single-use bioreactor.
In gauging the market’s need for scale-up solutions, ABEC recognized several unmet market needs for single-use clinical and commercial manufacturing, including the need for larger-scale production to allow for lower cost of goods; performance at large-scale that is comparable to what stainless-steel systems allow for maximum yield and productivity; and customizability to allow for more seamless process transfer and scale up as well as the ability to accommodate critical operational needs and address facility integration constraints, says Brady Cole, vice-president Equipment Solutions, ABEC. ABEC was the first company to commercially launch large-scale single-use bioreactors at a scale larger than 2000 L (the industry norm).
In addition, the market has need for a multi-source, open-architecture structure that can supply control systems, instruments, and components, which would allow for greater supply-chain flexibility and assurance, Cole states.
Mark T. Smith, PhD, senior manager, R&D Single-Use Technologies, Thermo Fisher Scientific, adds that the advantages of large-volume, single-use bioreactors became clear about 15 years ago “when single-use systems were highly valued in the process development, pilot, and clinical manufacturing space, primarily for their flexibility and speed of changeover.” The demand for preclinical and clinical-phase production continues to grow substantially making the easy and relatively low-cost, low-risk installation of smaller single-use system (SUS) facilities attractive.
“Initially, the maximum volume considered for single-use bioreactors was 1000 L, as industry experts indicated that would be the maximum reasonable size prior to shifting to ‘more economical’ large, stainless-steel bioreactors (e.g., 6000 L–25,000 L). Today, we know that 2000 L single-use bioreactors became desired by the industry, in large part to help sustain capacity into further or more clinical phases and to mitigate risk around large new facility buildouts,” Smith states.
Smith also acknowledges that the target patient populations for biologics are getting smaller, and, therefore, the likelihood of blockbuster drugs requiring tens of thousands of liters in dedicated reactor volume is extremely low. “Estimates from more than a decade ago projected median annual capacity demand for any given antibody product as approximately 200 kg/yr with a heavily weighted bias towards lower capacity demand (1). Today, with all the emerging target indications and emerging modalities, experts estimate that this median production demand is closer to 80 kg/yr for antibody or antibody equivalent production,” Smith says.
The combination of smaller patient populations, lower anticipated median demand capacity, and the need for speed, flexibility, and multi-product facilities thus support the case for single-use technologies. Smith points out that 2000 L is not the most economical choice for long-term production. “Evaluations of flexible facilities suggest that a larger volume, such as 5000 L, balances the flexibility of single-use with the economies of scale that, typically, larger-scale stainless facilities would provide,” Smith states.
Besides antibody therapeutics, other newer biologic modalities will also require large-volume scale up in the near future. Cole notes that ABEC has already implemented systems for vaccines as well as non-antibody recombinant proteins.
While antibodies still make up a large fraction of the biologics pipeline, recombinantly expressed proteins may also fit into this paradigm, Smith notes. The number of these recombinant proteins are increasing in the clinical pipeline. In addition, production of viral vectors for gene and cell therapies also could make sense at large scale (e.g., 5000 L), if the associated process technologies are provided, such as more scalable and consistent solutions for transfection reagents and complexation process, overall transfection efficiency, harvest clarification, and chromatography, among other technologies, according to Smith.
“Additionally, allogeneic cell expansion is likely going to need a more tenable solution for scale, especially for indications with large patient populations. This need for larger scales has yet to be demonstrated and demand is currently limited because of the small number of products approved and requiring such volumes,” Smith adds.
Now that large-scale single-use bioreactors beyond the 2000-L mark have been on the market, what have been some key successes in their performance so far? In ABEC’s case, the company has dozens of systems in the field that have been operating for multiple years. According to Cole, these systems “have successfully proven the benefits of our large-scale approach, with respect to cost of goods, process performance, customizability, and open architecture.”
“For example, we are demonstrating the ability to achieve the mass transfer performance needed for the latest high-density cell-culture processes,” Cole states.
Smith says that ensuring quality and robustness is paramount. “Performance and scale are also core to their success. Large-scale, single-use bioreactors provide economies of scale at a time when labor is tight and production capacity is critical, primarily due to pandemic response and increasing investment in biotech,” Smith explains.
Furthermore, scale-up challenges have helped to fine tune the design/technology of these large-scale single-use bioreactors. Thermo Fisher’s development of its new single-use bioreactors product line, for instance, was built on more than 15 years of experience in single-use bioreactors and other single-use systems. This experience, combined with extensive customer feedback, helped fine-tune the design of the company’s large-scale bioreactors prior to its release.
Some other challenges addressed along the way were related to packaging and installation. Providing simple and robust packaging for shipment, sterilization, bioprocessing container (BPC) loading, and BPC disposal for customers was a priority, says Smith.
Another challenge has been reactor installation. “Very large, monolith bioreactors can require walls to be removed or door openings to be expanded for install, but single-use facilities are meant for flexibility and change,” he says. Thermo Fisher’s system is therefore modular; it can be disassembled into three parts that fit through typical double-doorways and hallways. “This modular design enables easier, lower risk reactor install that equates to lower overall facility downtime,” says Smith.
Cole notes that ABEC hasn’t seen any fundamental challenges to the design/technology of large-scale, single-use bioreactors, but the company has implemented continuous improvements, such as an updated disposable container installation hoist. “We have also implemented customer-specific changes to accommodate specific process or operational needs,” says Cole.
Moving forward, the types of biologic products that are expected to be the core business for large-scale bioreactors include monoclonal antibody (mAbs) products. “We view mAbs as being a primary driver for these bioreactors,” says Cole. He notes that cell-culture based vaccines and gene therapy applications are also seeing growth.
Smith anticipates that the most prolific products produced in large-volume reactors will be recombinant expression of all types, primarily mAbs. “However, with a myriad of emerging modalities and growing interest in new expression hosts, there are likely new options that could emerge and drive demand for flexible, high-performing, and robust large-volume single-use bioreactors,” he states.
1. B. Kelley, mAbs 1 (5) 443–452 (2009).
Feliza Mirasol is the science editor for BioPharm International.
Vol. 35, No. 4
When referring to this article, please cite it as F. Mirasol, “Large-Scale Single-Use Bioreactors Can Maximize Long-Term Scale Up,” BioPharm International 35 (4) 22–23 (2022).