Evaluating Uses for Both Single-Use and Stainless-Steel Bioreactors

The changeover to single-use bioreactors has become more common in biomanufacturing; however, stainless-steel bioreactors still have their place. Stainless-steel bioreactors are important for certain monoclonal antibody (mAb) products that depend on bulk manufacturing, for instance.

Although single-use technologies (SUTs) are becoming increasingly popular in biomanufacturing, stainless steel is expected to remain in use for some time, especially for universal blockbusters such as treatments for cancer, diabetes, and others in which large volume is required, says Luis Velez, executive vice-president, US Operations, AGC Biologics. Furthermore, while the focus is often on mAb production, the plasma and vaccine industries are likely to continue adopting hybrid facilities where stainless steel carries out many core purification operations, but where SUT can increase flexibility and efficiency in the bioreactor and fluid management operations, Velez explains.

Although single-use adoption is not absolute, most companies are not overhauling their facilities from stainless-steel to single-use, notes Lorenz Hasler, vice-president Global Manufacturing, Science, and Technology, KBI Biopharma. “Instead, there seems to be a sweet spot, depending on the demand, flexibility, and scales that we’ve seen really fit well leveraging the advantages that single-use technologies can bring, particularly on the front-end of product lifecycles,” he says.

Cost evaluations

In considering the cost effectiveness of building a new single-use bioreactor facility versus converting a stainless-steel facility into a single-use facility, it is generally more cost-effective to build a new (or start with) a single-use facility, rather than convert a stainless-steel facility, says Hasler. “With the cost of construction, commissioning, and automation, it often doesn’t make financial sense to convert an entire facility. It’s more likely for someone to recognize the benefits single-use can bring in addition to existing stainless-steel capability in their network,” he points out.

“The benefits of SUTs compared to stainless-steel have been compared in economic models, specifically in terms of total cost of ownership and consumables, as well as facility buildout,” explains John P. Puglia, PhD, senior director of Research and Development in Thermo Fisher Scientific’s bioprocessing business focusing on single-use technologies. “Hardware for SUTs is significantly less expensive than stainless-steel, and the lower upfront capital expenses of single-use facilities provide economic flexibility that stainless-steel facilities cannot offer when looking at total bioproduction capacity and molecule pipeline approvals.”

Build-to-suit bioproduction facilities can take several years to design, construct, and meet quality control guidelines. Single-use facilities boast the benefits of shorter facility development and deployment timeframes, Puglia observes.

Another factor to take into consideration for biomanufacturers when approaching final capacity demand is continuous product and process improvements, Puglia continues. “Because stainless-steel facilities must be built-to-suit at maximum capacity, this can lead to complete standardization of processes regardless of running from hundreds to thousands of kg/yr demand. And while standardization can be beneficial to consistency of product, this could create inefficiencies when considering advancements in bioprocess operations down the line,” he explains.

Thus, if a biomanufacturer is considering new technologies aimed at reducing costs or increasing productivity or yield, they may encounter difficulties in implementing these technologies in an established stainless-steel facility. As molecule demand increases and new single-use facilities are constructed, however, it will be become easier to implement new technologies, Puglia adds.

Meanwhile, Velez notes that, from his perspective, the cost effectiveness of single-use facilities versus stainless-steel facilities will be directly related to the product(s) to be manufactured and the annual capacities. “Manufacturers will also continue to leverage existing facilities and inherent expertise at these sites to manufacture new therapies in which single-use bioreactors could fit very well,” he states.

“Rather than convert a stainless-steel facility, single-use bioreactors can be flexible to scale and to fit each process,” adds Shunsuke Shiina, PhD, principal downstream development scientist, AGC Biologics R&D Center, who notes that single-use bioreactors can also reduce costs for utilities and operations related to cleaning and sterilization.

Retaining stainless steel?

With the trend toward single-use bioreactors growing more common in the biomanufacturing sector today than a decade ago, is there still a strong argument for retaining large-scale, stainless-steel bioreactor facilities?

Puglia notes that, “with sizeable patient populations and demand for large product volumes, commercial-scale manufacturing via stainless-steel bioproduction has dominated the market, even after the first single-use bioreactors emerged in the late 1990s. Stainless-steel is a well-established method for large-scale biopharmaceutical production.”

Puglia goes on to say that, because of their size, stainless-steel bioreactors can support large-scale commercial manufacturers across a variety of higher volumes, including those between 10,000 L and 20,000 L. “Though stainless-steel has higher upfront cost, if you have a blockbuster drug, it could provide more long-term savings because of its durability,” he remarks.

Velez adds that, “Indeed, large-scale stainless-steel bioreactor facilities represent a solid, efficient option to manufacture large-scale volume products. That is one of the unique benefits of large-scale stainless-steel manufacturing to commercial needs.”

Hasler agrees with the sentiment of retaining stainless-steel bioreactors, saying that, “Depending on the demand and needs of your customer base, I would say there is an argument to retain large-scale stainless-steel bioreactors, if that’s what you have, especially at larger scales.” For example, Hasler explains, “with high demand of primarily large-scale commercial products, it may make more sense to retain stainless-steel bioreactors, from a capital expenditure perspective, given the number of batches required for [for instance] biosimilars.”

Hasler emphasizes, however, that each organization needs to determine where the inflection point is regarding their specific product portfolio to determine the most appropriate technology.

In the years to come, stainless-steel bioreactors still have a role to play. For example, Velez also points out that biosimilar products will be more popular in a high-demand market; therefore, large-scale stainless-steel bioreactors could be more suitable than multi-single-use bioreactors.

Shiina, however, says that it is likely that stainless-steel bioreactors will continue to be used for products that are already on the market (including biosimilars), as these products require production on a large scale. “Stainless-steel is also effective for development in which future demand and scale can be predicted (particularly those that need larger scales and yields),” Shiina adds.

“The processes being employed in the future will depend as much on economic benefit versus process risk and control,” says Puglia. “Obviously, practical deployment of a single-use system becomes more difficult beyond 10,000-L batch sizes, but with the regulatory demands for contamination and process control, the risk mitigation by using smaller single-use systems may outpace the economic advantages of larger stainless-steel systems.”

Accommodating new therapeutic modalities

Considering the different modalities of biotherapeutics in development today, determining the correct path forward will be crucial.

Deciding between single-use and stainless-steel is unique to each biomanufacturer’s situation, Puglia emphasizes. “Factors to consider when deciding between the two types of technologies include molecule type, titer range, cell density, demand stage (pre-clinical, early-phase, late-phase clinical, commercial, etc.), patient population, quantity of product, single-product versus multi-product facility, and new versus existing facility. Other areas to consider are run rate and the number of molecules to change at the site, including tech transfer and downtime for the site involved,” he states.

Puglia notes that SUTs are ideal for multi-product facilities and instances where process flexibility, in terms of volumes and product requirements, is vital. “This includes R&D, which is not always planning for the commercialization stage. With benefits in flexibility, scalability, and overall performance, coupled with reduced water consumption and facility energy usage, SUTs are the clear option for biomanufacturers who are looking to increase yield, improve efficiencies, and make strides toward achieving ESG [environmental, social, and governance] goals,” he explains. Puglia also points out the fact that single-use bioreactors have been shown to reduce cost of consumables by 37% compared to stainless-steel (1).

Velez emphasizes the flexibility of single-use bioreactors, noting that SUT and related materials allows for one to change the configuration of a manufacturing line, exchange or add unit operations, and cover various scales of operation—adding flexibility for developers at early stages. “Flexibility helps if you are seeking to build clinical manufacturing programs and want the flexibility to hold off on scaling drug products in early development stages until demand is well understood, saving internal resources, time, and money. The benefits also extend to later stages—developers can scale out based on need and demand,” he states.

Velez adds that stainless-steel bioreactors are also effective and, as noted previously, are a powerful technology as the scenario moves into larger scales and later phases, particularly as manufacturers look for commercial-level production.

Shiina points to the production of vaccines, which, he notes, need to be flexible to respond to pandemics and changing circumstances, and the production of cell and gene therapy products. These are areas that will potentially drive more single-use market growth.

“Beyond bioreactors, even the well-established monoclonal antibody platform processes can benefit from modernized single-use technologies,” Shiina adds. For example, an R&D team at AGC Biologics has been working to scale up and implement a new disposable membrane-based protein A capture device for antibody purification, Shiina says. “By leveraging these new single-use protein A purification devices … one can reduce the cost of the protein A purification step, remove storage and bioburden challenges, condense the overall manufacturing footprint, and even quicken your timeline to the clinic,” he explains.

Hasler adds that viral vectors are most effective in single-use situations. Messenger RNA development and, generally, clinical scale-level development of new therapeutic modalities may also be better suited in a single-use bioreactor; whereas, a mammalian blockbuster or commercial product may be better suited in a stainless-steel bioreactor, Hassler states.

Reference

1. Thermo Fisher Scientific. Single-Use vs. Stainless Steel: The Biopharmaceutical Manufacturing Debate. Thermofisher.com, 2023.

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article Details

BioPharm International
Volume 37, No.4
April 2024
Pages: 17–20

Citation

When referring to this article, please cite it as Mirasol, F. Evaluating Uses for Both Single-Use and Stainless-Steel Bioreactors. BioPharm International 2024, 37 (4), 17–20.