Single-Use Bioreactors: To Scale Up or Scale Out?

Published on: 
BioPharm International, BioPharm International-01-01-2020, Volume 33, Issue 1
Pages: 19–21

Industry experts debate the pros and cons of “going bigger” than the 2000-L industry norm in a single vessel.

As demand for biologics continues to increase, manufacturers must process higher volumes upstream, and more are turning to single-use bioreactors. Demand for single-use reactors has been growing by 13.5% per year, and is expected to continue at this rate through 2026, when it will exceed $1.5 billion, according to a report by Transparency Market Research (1). Mammalian and bacterial cell culture accounts for more than 85% of demand, according to the analysts.

Technology vendors have responded to the need for higher downstream capacity with larger-volume single-use bioreactors. Where 2000 L was once the upper bound, some bioreactors are now available in any volumes up to 6000 L, with 4000 L currently in operation (2,3). Experts question whether single-use bioreactors can operate efficiently above 2000 L, however (4,5). 

One fundamental question focuses on the structural soundness of the reactors, and whether leaking or other issues can be exacerbated at higher volumes. According to Transparency Market Research’s report (1), the plastic extrusion process used to manufacture single-use bioreactors can leave them vulnerable to leaking. Vendors have been optimizing equipment by stabilizing materials in order to reduce the risk of leaks. 

The debate over going bigger

When considering the capacity constraints for any single-use bioreactor, a number of important considerations must be kept in mind, says Kevin D. Ott, executive director at Bio-Process Systems Alliance (BPSA), whose engineering experts also weighed in on the topic. “In essence, economies of scale must be weighed, system integration planned for, and qualified engineering firms engaged in order to plan for the larger footprints and benefits of larger bags. This entails a user/supplier/engineering house relationship that starts early and is project-specific,” Ott says. 

It is not necessary to limit capacity, says Ott and his colleagues, but, he notes, “users/adopters need to plan, and plan some more, with suppliers as their partners, for integrating these bioreactors effectively into existing manufacturing facilities.”

“Classified areas need to get bigger to handle a larger footprint, and ceiling heights must rise to accommodate larger systems. Building floor loads are also a concern, especially with retrofitting in a previously built suite,” he says. In addition, BPSA experts note that, as the size of the bioreactor increases, so will the supporting infrastructure required for gas supply, power, waste handling, and jacket temperature maintenance. 

Bag size needs must also be taken into account, they say, because they will have an impact on such decisions as bag ports, tubing size, sterile connectors, and pump and filter capacity. Manufacturers must also consider the increased power that larger reactor outputs will demand.

Choice of size will also impact storage and handling. Larger single-use bioreactors may also require re-alignment of the warehouse shelving and demand that more attention be paid to material handling to ensure bag integrity. Finally, BPSA experts say, the larger bioreactors will also need to be validated/sterilized, emphasizing the importance of sterilization chamber size.

“There is no ‘one-size-fits-all’ bioreactor,” notes Parrish Galliher, chief technology officer, Upstream, at GE Healthcare Life Sciences, but 2000 L is the commonly accepted maximum commercial-scale volume, he says. “The productivity of the 2000-L scales system has found a niche in the industry as titers have increased over the last 10 years-they have been on the market for more than a decade and have also been proven commercially viable at many licensed facilities across the globe. Most companies choose to lower the risks of scaling out, investing in multiple identical 2000-L production lines versus scaling up,” he says.


“The industry has settled on 2000-L platforms as a norm in the design of the next-generation biotech facilities,” agrees Ott. “‘Going larger’” brings with it the challenges of integration, handling, storage, and removal,” he and fellow experts at BPSA point out. 

Others have a different view. “It is well known that the standard 2000-L systems currently on the market cannot achieve the mixing and mass transfer performance of comparable stainless-steel systems, with performance dropping off over a few hundred liters,” notes Brady Cole, vice-president of of equipment solutions, ABEC, which launched its 4000-L and 6000-L single-use bioreactors in 2017 and 2019, respectively. Cole points out that the performance of the standard 2000-L systems is not optimal for many high-density cell culture applications. 

Process intensification

At this point, some observers say, the industry prefers smaller single-use bioreactors and process intensification over scaling up with larger bioreactors. “The volume requirements for commercial cell-culture bioreactors are getting smaller, not bigger,” says Melisa Carpio, technology consultant, cell culture technologies at Sartorius Stedim Biotech. “According to BioPlan’s 2019 Biomanufacturing Report, the greatest demand was for 1000-L single-use bioreactors, followed by 500 L, and then 2000 L,” she says.

When manufacturers implement larger single-use bioreactors (e.g., 4000-L models), they are usually doing so to address a specific facility need (e.g., facility fit), notes Hemanth Kaligotla, segment marketing manager, monoclonal antibodies, at Sartorius Stedim Biotech. Larger volume single-use bioreactors may also be used by contract development and manufacturing organizations that continue to manufacture legacy low-titer products for large biopharma companies, he says.


Assessing potential risks When considering the size of a single-use bioreactor, the risk of increasing overall size should be assessed, and the following considerations should be made, says Galliher:

  • Ease of logistics and handling (i.e., warehouse space, ease of unpacking, inspection, loading into the tank, and disposal at the end of the run)

  • Time considerations (i.e., the amount of time needed to fill or drain the bioreactor due to limitation in the size of filling and draining ports-a 2000-L bioreactor generally takes two hours to fill or drain)

  • Impact on other equipment as the bioreactor scale goes up (e.g., the size and cost of the larger inoculum preparation train required to inoculate larger bioreactors with potentially more tanks and more bags needed per batch; the increased size and cost of media and buffer prep systems; and the size and cost of the larger harvest and capture step required to harvest larger volumes)

  • Technical and operational costs, including the increased risk of scale-up problems, such as negative effects on cell viability, product quality, and final yield; additional costs of larger bioreactor bags with additional and/or larger impellers; and the risk and increased cost of contamination as scale increases.

Often, failure to optimize processes will dictate use of larger single-use bioreactors. “Processes that have not been optimized will generally produce lower titers and will require larger bioreactors. For these processes, a 4000-L might be required to meet market demand,” Galliher says.

Cole, meanwhile, explains that 4000-L single-use bioreactors provide much better economies of scale because batch sizes are doubled for a similar amount of floor space, and mixing and mass transfer performance (therefore titer) is comparable to stainless-steel systems of that scale. Importantly, the productivity benefits are achieved with no added risk to cell viability and product quality because the designs and scaling are based on methods proven for decades, and the bioreactors can be customized for wide process windows. 

Maintaining cell viability and product quality 

Among the challenges to deal with when selecting a single-use bioreactor larger than 2000 L are cell viability and product quality, says Galliher. “The strength and scientific and engineering expertise of the process development team will be tested more extensively as bioreactor scale increases, and cell viability and product quality are potentially at higher risk,” he comments.

It can take a long time and be very costly to unravel and rectify cell viability and product quality problems, resulting in delays to market, which is another reason why more companies are choosing to scale out rather than up to a larger single-use vessel, Galliher says.


In addition, as bioreactor scale goes up, clean-up, disposal, media requirements, and in-line/at-line monitoring become more expensive. “Waste disposal permits for larger volumes and solid waste may be more difficult to obtain, or may not be permitted,” he explains.

Carpio adds that high pressure (especially around port windows) and the consistency of control (e.g., of temperature) are other potential challenges to working with larger single-use bioreactors. The larger devices will also weigh more, posing installation challenges, she says, and scalability will be another factor to consider. “Any single-use bioreactor larger than 2000 L, especially a bioreactor with a different geometry from most 2000-L bioreactors, would need to show scalability with regard to cell growth, productivity, and product quality,” Carpio says. She notes that Sartorius Stedim Biotech has emphasized the need for geometries that enable single-use scalability to match that of traditional stainless-steel devices from 250 mL to 2000 L

An advantage to scaling up to a larger capacity vessel, however, would be to reduce the need for production-stage bioreactors to meet market demand. This has often been the primary rationale behind scaling up (rather than out), because it may reduce some limited capital and space costs, according to Galliher. Another advantage is that larger scales result in lower manufacturing labor and quality control costs per gram of drug produced. “These surface benefits may be overwhelmed, however, by the total risks and cost,” he says.

Going bigger also offers several advantages with respect to cost and flexibility, says Cole. These advantages include:

  • Lower cost of goods with approximately two times the productivity per unit floor space, giving process performance, and therefore yield, similar to stainless-steel systems

  • Lower capital cost as fewer systems are needed to achieve high capacity

  • Lower facility cost since less floor space is needed with fewer systems needed

  • More process flexibility in that production quantities needed for a given product can be achieved with fewer batches, thereby freeing up capacity for other products.

Capacity size of the future?

Despite the risks involved, “going bigger” than the current industry norm is not only feasible, but Ott and BPSA experts encourage it. “BPSA has had such discussions during its annual summits held in Washington, DC, within our ‘factory of the future’ presentations,” he says. 

“For system performance at larger scale, preparation, planning and implementation are essential for larger(er) systems to perform to expectations, and to yield the expected economic benefit(s) to the user-adopters,” Ott adds.

“We have demonstrated 6000 L and hypothetically could go larger,” says Cole. “The limitations would be based more on practical considerations rather than engineering hurdles.”

Galliher is cautious about making the move. “The holistic risks and costs at the [larger] scale are already pushing many of the critical issues,” Galliher says, singling out mixing, mass transfer (oxygen and carbon dioxide management), and heat transfer. “Stainless-steel bioreactors are operating old legacy processes today at 20,000-L scale and, in fact, may have lower operating economies when fully utilized. Designing a single-use liner at 6000-L–10,000-L scale that keeps all the potential collateral risk and costs at bay will probably be prohibitively risky and costly,” he says.

Meanwhile, Kaligotla believes that more analysis is still needed to evaluate the technical and economic feasibility of using larger commercial scale single-use vessels. In the short term, manufacturers might implement larger capacity single-use bioreactors, but this may not be sustainable in the long term, he notes. One benefit would be in media, which are likely to developed at lower cost in the immediate future, he says.

“While it is potentially feasible to go to 4000-L, 6000-L, or even higher-volume single-use bioreactors, the feedback we have received from customers suggests that flexibility, performance, and robustness are crucial drivers,” adds Carpio. “With the industry moving towards process intensification, the focus is on smaller operating volumes and the ability to run different, higher performance processes on the same equipment.”


So far, she says, customers tend to prefer smaller volume single-use bioreactors (e.g., 500-L or 1000-L models), or to scale out processes employing multiple 2000-L bioreactors in a “ballroom” approach, depending on product quantity needs for a particular process. “There is also skepticism for extra-large volumes with regard to scalability and user operation,” she states.


1. Transparency Market Research, “Single-Use Bioreactors Market,”, accessed Dec. 17, 2019.
2. ABEC, “ABEC Sets a New Benchmark in Single Use Bioreactor Capacity,” Press Release,, July 10, 2017.
3. ABEC, “ABEC Advances Single-Use Bioreactor Volumes to 6,000 Liters,” Press Release,, Sept. 10, 2019.
4. A. DePalma, “Single-Use Bioprocessing: How Far Can it Go?”, May 10, 2017.
5. C. Niemic, “Throw-away Culture,”, April 17, 2019.

Article Details

BioPharm International
Vol. 33, No. 1
January 2020
Pages: 19–21


When referring to this article, please cite it as F. Mirasol, “Single-Use Bioreactors: To Scale Up or Scale Out?” BioPharm International 33 (1) 2020.