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Susan Haigney is managing editor of BioPharm International, firstname.lastname@example.org.
Despite the growing popularity of single-use technologies in biomanufacturing, there are still instances where stainless steel is the better option.
Single-use technologies are becoming increasingly popular in biomanufacturing. What does this mean for the fate of stainless-steel equipment, especially in commercial biomanufacturing? According to Brady Cole, ABEC vice-president, Equipment Solutions, stainless steel will be around for some time.
The continued use of stainless steel will be maintained by the process and output requirements of biopharmaceutical manufacturing, says Arleen Paulino, senior vice-president, Manufacturing at Amgen.
Parrish M. Galliher, CTO Upstream and founder, Xcellerex Inc., GE Healthcare Life Sciences, agrees. “As long as we are trying to develop more universal blockbusters such as treatments for cancer, inflammation, diabetes, dementia/Alzheimer’s, these will likely require very large annual capacities.”
When it comes to producing large volumes of product, the use of stainless-steel equipment saves money and fills gaps in the capabilities of single-use equipment, says Andrew Bulpin, head of Process Solutions at MilliporeSigma. “For instance, maximum flow rates in single-use technologies are not at par with stainless-steel. Manufacturers will also continue to leverage existing facilities and inherent expertise at these sites to manufacture new therapies. While we often focus on mAb [monoclonal antibody] production, the plasma and vaccine industries are likely to continue adoption of hybrid facilities where stainless steel carries out many core purification operations, but single-use can increase flexibility and efficiency in the bioreactor and fluid management operations,” says Bulpin.
BioPharm International spoke with Cole, Bulpin, Galliher, and Paulino about the areas where single-use may not yet venture and where traditional stainless steel is required.
BioPharm: In what instances are stainless-steel bioreactors the better, or more appropriate, choice to use over single-use bioreactors?
Cole (ABEC): We view the stainless steel/single-use bioreactor choice for commercial manufacturing to be case-by-case based on multiple factors, including cost of goods targets, process requirements, capital/operating cost considerations, validation/regulatory aspects, number of products to be produced in the facility, production quantities needed, and the development and manufacturing history of the product. As a provider of both types of bioreactors, we are assisting manufacturers with this decision in an unbiased manner. Some general trends favoring single-use include multi-product facilities, lower production quantities needed, and higher titer products, but even these are not absolute, and we see continued viability of stainless steel for many applications.
Paulino (Amgen): There are multiple factors where a stainless-steel bioreactor could be chosen over a single-use bioreactor. As an example, certain manufacturing processes may not work well in single-use bioreactors and, therefore, the option of using stainless-steel bioreactors will be required. Another factor could also be the required output over time coupled with titers of a given process (i.e., the larger the output and lower the titers, the more likely a stainless-steel bioreactor may be chosen).
Galliher (GE Healthcare): Stainless-steel bioreactors are more suited for very large-scale manufacturing for drug quantities over 3000 kg/yr. Also, if any non-polar solvents are used or produced by the bioreaction, stainless steel is more resistant to damage by those compounds.
Bulpin (MilliporeSigma): In the past decade, single-use bioreactors (SUBs) have gained traction over stainless-steel bioreactors (SSBs), mainly for early clinical trial phases when process development and process scale-up are occurring and the quantities of cGMP [current good manufacturing practice] drug material are still limited. When flexibility and quick changeover are key assets to move drug candidates forward and eliminate unsuccessful molecules from the pipeline faster, advantages provided by SUBs make a tremendous difference. The emergence of highly potent drug molecules is also playing a key role in the adoption of SUBs because they protect operators from harmful exposure.
Ten years ago, however, I don’t think anyone predicted such massive adoption. SUB providers, regulatory bodies, industry consortia, and-most importantly-drug manufacturers have made tremendous progress to overcome what the industry used to depict as major hurdles for adoption: extractable and leachable data, plastic film robustness, and hardware capabilities, especially with respect to single-use sensors.
Today, upstream process intensification strategies, supported by the increased use of perfusion operations, are carrying SUBs to the next level. Their enhanced sparging and mixing capabilities allow SUBs to support significantly higher cell densities with 60 x 106 cells/mL on average and greater than 100 x 106 cells/mL consistently being reported. Combined with their inherent flexibility, ease of use, and scalability, they can now be used for either high seed fed-batch or steady-state perfusion operations up to a 2000-L scale. Depending on the indication and dosage, the industry can now design fully single-use upstream suites, even at commercial manufacturing scale.
SUBs and SSBs are currently seen as tools in the upstream toolbox to be used appropriately depending on the manufacturing strategy. There are scenarios where high flexibility and quick changeover, along with relatively low drug quantities to be produced, will dictate the use of SUBs. There are scenarios where blockbusters (original molecules and/or biosimilars) will have to be produced in large quantities in traditional fed-batch, which will justify the investment of 15,000-L SSBs with the associated cleaning validation. There are also scenarios combining the advantages of both SUBs and SSBs, where the seed train will be done in SUBs (maybe in perfusion mode) and enable a faster transition to SSB production bioreactors.
The most important thing to consider for drug manufacturers will be making the right choice at the beginning of their project to prevent any process change that can add significant burden and slow down their move to the next phase.
BioPharm: Are there other instances in commercial biomanufacturing processes where stainless-steel materials/equipment would still be necessary because single-use technology would not necessarily be a benefit?
Bulpin (MilliporeSigma): Currently, single-use equipment is limited in terms of larger process scale implementation. Dedicated commercial manufacturing in stainless steel still provides large volume capability for large-scale production where single use cannot. Therapeutics with broad indications or large patient populations, such as Alzheimer’s, will continue to leverage stainless steel to process these large volumes. Advantages can be gained with the implementation of a hybrid approach, benefiting from single-use where appropriate. As manufacturers advance therapeutics, they will need to carefully weigh initial speed and flexibility with long-term cost advantages and processing of large volumes.
Galliher (GE Healthcare): In the downstream purification process, if more than 10 kgs/batch of drug are being processed, larger stainless-steel piped systems are typically used.
Paulino (Amgen): Single-use technology is not as well advanced for purification processes. Some processes require large-scale centrifugation, which may not be as advanced in single use.
BioPharm: Can you give an example of a situation where a biologic product would require the use of stainless-steel equipment vs. single-use equipment? How is that decision made?
Galliher (GE Healthcare): Drugs over 3000 kg/year (such as Humira and Insulin) are produced in stainless-steel bioreactors and purification systems.
Cole (ABEC): Single-use microbial fermentation is limited to 1000-L maximum volume at the moment due to heat generation of the microbial process and the subsequent heat transfer. However, many products require volumes far in excess of 1000 L, so stainless steel is often the only option. Single-use can be an option for the seed fermenters before scaling to larger volumes in stainless steel.
Bulpin (MilliporeSigma): At its core, the stainless-steel versus single-use debate has become a balance between capacity and flexibility. If the expected drug substance requirement is enough to justify a facility that is dedicated to one to three products, based on dosage and patient population, then the decision is typically made for a stainless-steel facility. The cost of a stainless-steel facility is largely driven by capital and overhead expenses, which can easily be spread over the large quantity of drug substance produced.
Conversely, a single-use facility that is flexible enough to handle four to six molecules per year is justified if the expected drug substance requirement is constrained by low dosage and/or patient population.
The cost of a single-use facility is largely driven by operating and consumables costs, which have significantly lower overhead and are less sensitive to change-over time.
Paulino (Amgen): Companies take different factors into consideration when making the choice between stainless steel and single-use technology. Factors such as compatibility with cell lines, required output, cell line productivity, cost, etc. are just a few that are considered.
BioPharm: As more biomanufacturing facilities move toward single-use, what will be the fate of older/legacy stainless-steel bioreactors and their facilities?
Paulino (Amgen): Facilities and equipment will continue to evolve, and lifecycle management will determine how to best repurpose legacy equipment and facilities.
Cole (ABEC): We are generally seeing investment in aging facilities since these assets can often be modified cost-effectively to improve productivity, flexibility, reliability, and regulatory compliance. We are actively working with customers to engineer and deliver facility modifications, including introducing single-use elements. With respect to bioreactors, we are modeling and retrofitting systems for new products, higher titers, multi-product capability, and improved sterility, thereby extending their lifecycles.
Galliher (GE Healthcare): The typical physical and financial lifetime of stainless-steel facilities has traditionally been 15–20 years. They eventually corrode away and have to be replaced because they are in direct contact with process solutions.
Bulpin (MilliporeSigma): Stainless is still alive, and I foresee SSBs will stay around for a while. It is very unlikely that all manufacturing processes using SSBs in fully depreciated facilities will be dismantled in the future. This does not make a lot of sense from a long-term investment perspective, especially for established drugs which will likely be used for some decades. The [return on investment] is the driving force in this case to maintain the existing manufacturing process without new submissions to the regulatory bodies.
The single-use market has largely consolidated around the 2000-L bioreactor and associated downstream systems. This scale balances the risk of film or component failure with the benefits gained from operating highly-productive cell culture batches in a single-use format. While there are some suppliers that provide custom single-use bioreactors at greater than 3000 L, most biomanufacturers have chosen to scale out with multiple 2000-L bioreactors rather than scale up to a larger bioreactor.
Therefore, bioreactor operations that would require higher volumes have to be in stainless-steel. Similarly, in downstream unit operations, manufacturers will continue to leverage existing facilities while incorporating single-use where it can increase efficiency and lower cost or overhead.
Vol. 32, No. 8
When referring to this article, please cite it as S. Haigney, "The Case for Stainless Steel," BioPharm International 32 (8) 2019.