Manufacturers of therapeutic proteins face immense pressure to stay ahead of market trends and deliver complex product portfolios. Choosing the right manufacturing system from day one can reduce that pressure and position you for ongoing commercial success.
The therapeutic proteins industry is continuously growing, ignited in part by COVID-related advances and the potential for AI-assisted technologies to shorten the development pipeline and bring more solutions to market, faster. According to some analyses, this momentum will push the industry’s global value north of $560 billion by 2030—more than double its estimated value in 2020.
To compete in this market, therapeutic protein manufacturers must make hundreds of high-stakes decisions, from choosing which molecules to prioritize in R&D to identifying the right moment for rapid commercial expansion. Within this complex landscape, choosing the right manufacturing approach is fundamental. Is a large-volume stainless steel facility the right fit for you, or will a flexible single-use strategy suit your needs? Then there’s the third option: a hybrid facility, which could help you leverage the advantages of both stainless steel and single-use—but only with careful planning and an eye to managing the tradeoffs and drawbacks unique to each approach.
To find the answer that’s right for your situation, start by asking the right questions. That’s exactly what we’ll do with this article, first by giving you a close look at the unique benefits and challenges of stainless steel and single-use technologies, then by looking closely at hybrid systems—how, when, and why they work, and what to consider if you choose to tailor your own fit-for-purpose hybrid solution.
When weighing the choice between single-use and stainless steel systems, it’s easy to over-focus on granular details, such as the number of vessels that will fit into your production suite. This tunnel vision can cause problems later on. For example, you may decide to pursue a fully single-use strategy after confirming that your production suite can accommodate four 2,000 L single-use bioreactors. But what about your downstream operation? You’ll need a lot of buffer prep to support that volume of production, for one thing—far more than most downstream single-use systems on the market can support.
That’s why it helps to start by defining your short- and long-term throughput goals, then consider the upstream and downstream capacity necessary to meet those goals.
Unlike single-use systems, stainless steel offers a wide range of equipment sizes to support manufacturers as they scale to commercial volumes. Most manufacturers operating above the following thresholds will choose stainless steel:
Today, the capacity of many single-use equipment begins to taper off at 2,000 L.
There are practical reasons for this threshold. The larger the single-use bag, the harder it is to handle in the production suite, and the greater the risk of product loss due to a spill or another type of incident. But even if solutions emerged to support efficient upstream manufacturing in high-volume single-use equipment, manufacturers would find themselves needing stainless steel further downstream, where single-use systems simply don’t exist or are only just emerging. New innovations in single-use centrifuge technology, for example, have not yet caught up with stainless steel options.
For these reasons, manufacturers targeting a large titer range will find it difficult—impossible, in many cases—to operate a fully single-use facility.
Do you expect to manufacture just a few products per year in your facility, or are you anticipating a high product turnover? The answer may steer you toward the system that best suits your needs today and far into the future.
Because of the permanent and durable nature of stainless steel equipment, product changeover is not a simple process. This may not be a problem for you if you’re manufacturing just a few products within the same modality, making change-outs a relatively rare event. If, however, you intend to switch between products frequently, you’ll find yourself losing time and money to extensive sterilization, cleaning and validation steps in order to clear your system’s lines and prepare it for production.
This is especially burdensome for CDMOs, who must meet the requirements of multiple clients—many of whom will not agree to follow another manufacturer’s product without extensive cleaning interventions and a full change-out of elastomers and other components.
Because of its durable and permanent nature, it’s much harder (and expensive) to modify a stainless steel system than a single-use system. For manufacturers with stainless steel systems, this means that adding feed tanks or making other modifications may not be possible—not without significant process interruption and capital investment.
Consider, for example, installing stainless steel fed-batch bioreactors, only to discover during early clinical trials that a perfusion system would increase productivity and result in larger product quantities. With bioreactors that are attached to the floor and fixed nozzles that are already in use by another instrument, adding perfusion capabilities isn’t as easy as rotating equipment to align it with a valve. Instead, it could require removing walls, repurposing equipment, and making other disruptive changes.
In addition to accommodating process developments, you may also find yourself wanting to integrate new and more efficient equipment as it becomes available. In a stainless steel facility, this can be difficult, requiring significant renovations or process modifications which can shut down production, cause regulatory complexity, and ultimately impact your speed-to-market.
Any manufacturer pursuing a single-use facility is likely doing it for one chief reason: flexibility.
Because of its disposability and modular, wheel-mounted design, single-use equipment brings flexibility to the manufacturing floor in multiple ways:
Switching between different types or sizes of single-use equipment is a relatively pain-free and cost-effective process, making this an attractive option for anyone with a multi-product pipeline and frequent changeouts. This is especially attractive for CDMOs, who may be supporting different clients back-to-back and need to ensure that all lines are clear between products. That’s a major benefit of single-use systems: when you dispose of equipment, all the residual product goes with it. You’re left with a fresh start in a fraction of the time required to change out a stainless steel system. In addition to accelerating product change-out, single-use equipment also enables fast reconfigurations of the manufacturing process itself. Consider, for example, switching from product A, which requires chromatography-TFF- chromatography-TFF and product B, which requires chrom-chrom-chrom-TFF. Simply wheel your single-use equipment into position and connect its tubing—no extensive workarounds or facility modifications needed.
For manufacturers still moving through early-phase clinical trials, when so much depends on the efficiency of your manufacturing process, flexibility is a major advantage. The adaptability of single-use equipment gives you room to integrate new process developments as they emerge, giving you a pathway to process intensification that isn’t limited by your equipment.
This is especially beneficial for CDMOs, who risk losing opportunities to capture new business if they don’t respond quickly to spikes in demand. With a single-use system in place, rapidly scaling out designed-to-order production trains is much easier.
Maintaining a competitive position in the marketplace often comes down to a manufacturer’s ability to keep up with the latest in highly efficient and digitalized upstream and downstream technologies, which are evolving rapidly. The portability and modularity of single-use equipment is a benefit here, too—integrating new pieces is often a matter of reconfiguring existing equipment flowpaths, rather than undertaking a larger, more expensive, and much more disruptive facility renovation.
Stainless steel requires a stringent cleaning process between product runs, but it eliminates the burden of managing, decontaminating, and safely disposing of a large volume of solid waste.
Stainless steel systems require clean-in-place (CIP) and steam-in-place (SIP) protocols to remove latent contaminants and any product carryover. Following those protocols means:
For some manufacturers, the benefits offered by stainless steel manufacturing outweigh the burden of washing out tanks between product runs. This goes back to the first two questions in our list: if you’re manufacturing large volumes of just a few products, these considerations may not be a great issue.
No need to transport and dispose of used components, which can be a complex and costly process in a single-use facility.
When you can dispose of manufacturing materials that have come into contact with a product, cleaning is not an issue. This can mean:
Charging clients appropriately for support services like cleaning and validation can be difficult. Manufacturers with single-use systems have a clearer pathway to recovering their expenses: many of them charge clients for the single-use bags, tubing sets, and other consumables involved in manufacturing their product. It’s a win for CDMOs, and clients are typically amenable to the arrangement—after all, from their perspective, it’s a short-term expense.
Removing and safely decontaminating large single-use components such as agitators can be difficult and expensive, particularly in regions facing a shortage of appropriate areas for solid waste disposal. Some manufacturers face the added expense of treating their solid waste prior to disposal, depending on local laws and regulations. Then there’s the environmental toll of adding significant volumes of solid waste to the landfill—though some disposable components can potentially be reused in R&D or to run test batches.
In regions such as Southern California, where access to water is restricted and costly, manufacturers have long been aware of the need to reduce water usage wherever possible. In today’s sustainability-driven environment, that mindset has expanded across all regions, driving manufacturing toward aggressive reduction targets, even in regions where water is abundant. The question of stainless steel versus single-use equipment has major implications when it comes to meeting those targets.
The CIP and SIP processes that manufacturers depend on to decontaminate durable equipment account for 50 to 70% of total water use in a stainless steel facility.
Because manufacturers simply dispose of single-use equipment rather than cleaning it, they can greatly reduce their water consumption compared to a stainless steel facility.
Single-use equipment opens the door to a smaller, more densely utilized production spaces, but it elevates the need for additional warehousing.
With very few disposable components to replace between product runs, stainless steel offers manufacturers some insulation against the risks of supply chain disruptions and long lead times. As a result, there’s far less need to maintain an on-site backstock of consumables, which lowers your warehousing needs and frees more facility area for production.
Consider chromatography columns, for example. Manufacturers targeting high titer ranges need stainless steel columns to generate sufficient yield from a single cycle, but this equipment introduces new complications. It’s large, for one thing, and can weigh up to 15 tons, which could impact your facility layout. A 120cm column may be too heavy for installation on an upper floor, for example, forcing a vertical scale-out even if expanding upwards was your original intention—a real scenario that recently impacted a client of ours.
Staging stainless steel chromatography columns for production also requires advanced planning—you’ll need an on-site packing area, which has further implications for your facility layout.
Manufacturers operating single-use equipment rely on a constant supply of new bags, tubing sets, and other consumables. Multi-product manufacturers may need access to different sizes of the same equipment, further increasing their reliance on the external supply chain—as well as the risk of a serious disruption.
This risk is especially high given that many disposable products are not interoperable, leaving manufacturers dependent on a single-source supply chain for critical components.
To mitigate against the considerable risk of a disastrous supply chain disruption, most single-use facilities stockpile critical flow materials in a large on-site warehouse. The financial and operational burden of maintaining large, non-production spaces in a facility where every square inch matters can be great—but the risk of a shut-down as a result of a turbulent supply chain is even greater.
Staging and moving large, heavy single-use buffer totes is a logistical challenge, sometimes requiring cleanroom pallet jacks and other support equipment—and the space to move that equipment through facility corridors as needed.
Logistics aside, the capacities afforded by downstream single-use support systems are limited. Pre-packed chromatography columns are convenient (and they eliminate the need for a packing area), but just like single-use upstream equipment, they don’t scale easily. If you’re targeting a high titer range, you’ll need to run multiple cycles—a process that will take time, slowing your overall productivity.
The relatively low cost to build a single-use facility is attractive, but zoom out to consider the lifetime cost of continuously acquiring single-use components and you’ll see a different picture.
The figures are clear: it costs more to get a stainless steel facility up and running. And given that only a small number of products in development make it to commercial-scale production, that initial capital investment may be at risk—particularly since stainless steel offers limited flexibility once built.
The energy-intensive cleaning processes involved in maintaining and operating stainless steel equipment drive these support costs higher than in a single-use facility.
This is where the high cost to build and maintain a stainless steel facility earns its return: stainless steel equipment frees manufacturers from the continuous cycle of buying consumables. As a result, the overall costs to run a stainless steel facility can be far lower than in a single-use facility.
Manufacturers generally spend less to get a single-use facility up and running, in less time. Speed is important: it allows manufacturers to defer certain elements of capital delivery until commercialization is certain, which lowers the risk of their investment.
A single-use facility may consume less water and energy, but those gains are more than overshadowed by the spending required to cover the bill of materials. Maintaining a lifetime supply of single-use bags, filters, tubing sets and other components is costly.
A single-use facility may also generate higher labor costs, due to the manual nature of setting up and tearing down single-use equipment.
This 2017 study of a facility operating 2,000 L bioreactors demonstrates the relative difference in ROI between stainless steel and single-use systems, although the actual dollars may have changed since the study was conducted.
Stainless steel provides a safe, industry-standard option for containing hazardous materials and running closed processes. To gain these advantages, though, you must be willing to give up some flexibility.
The leachable or extractable potential of hazardous materials held inside a stainless steel vessel is relatively minimal.
In fact, when hazardous materials are fully contained within a closed stainless steel system, manufacturers may be able to justify a lower room classification, which in turn lowers their utility usage and other costs.
Though leaching isn’t likely with stainless steel, you do face another type of risk—corrosion. Manufacturers using stainless steel need to ensure that their equipment can withstand exposure to the chemicals and solutions involved in production, such as the salts, acids and bases used during buffer preparation. Choosing the right grade of corrosion-resistant stainless steel, such as 316L, is key.
In addition to the chemicals used during manufacturing, the materials in your stainless steel vessel must also withstand the pressure and temperature conditions in play during production, as well as exposure to regular CIP and SIP cleaning.
The vessel’s physical construction is also important. Standards such as the ASME BPE lay out specific criteria for details such as surface finishings, which should not contain any rough or porous surfaces that may encourage bacterial growth.
Unlike stainless steel, the polymer compositions that make up single-use materials may be vulnerable to chemical damage from certain media or buffers. Manufacturers must study, understand and monitor their single-use material’s compatibility with regards to those supplementary solutions.
A double containment strategy can help to mitigate this risk, as well as elevated room classifications and appropriate gowning, airlocking, and other strategies that come with those cleanroom spaces. In addition to protecting the product, this approach can help keep operators safe from burns or other hazards in the event of a puncture—a very real risk when working with soft-sided single-use components.
Manufacturers can close their process with both stainless steel and single-use systems, opening the door to lower-cost production spaces. With single-use systems, however, manufacturers can gain both process closure and flexibility, allowing them to integrate new processes or technologies without major modifications. There is a risk, though: operators must set up single-use systems correctly in order to ensure full process closure. In other words, to gain that flexibility, they must also accept the possibility of human error.
At this point, you may be thinking that the pros and cons attached to each system, stainless steel or hybrid, are complex enough—and impactful enough—that a decision of one or the other isn’t possible. If that’s the case, consider a hybrid approach, which combines stainless steel and single-use systems in unique ways to deliver a facility that’s tailored to your needs and the makeup of your product pipeline.
Though virtually all stainless steel facilities include some disposable elements, a truly hybrid facility incorporates both single-use and stainless steel equipment in its production trains. There are several pathways to achieve this within the same facility:
A well-planned hybrid system has the potential to deliver higher long-term ROI than stainless steel or single-use systems. To see how that may impact a typical facility’s cash flow, let’s return to that 2017 study of a facility operating 2,000 L bioreactors.
Actual dollar amounts may have changed since this study was conducted (2017).
Motivated by this potential ROI and the many other benefits offered by a hybrid system, manufacturers from across the life science landscape are increasingly choosing this approach. As part of our Horizons: Life Sciences cross-industry survey in 2023, for example, we asked manufacturers of antibody-drug conjugates about their particular approach to the stainless steel/single-use question. They revealed a strategic integration of technologies across the whole manufacturing lifecycle, with a concentration of hybrid systems used for preparing solutions.
To decide if this direction is right for you, consider a few top-line objectives that have recently guided our clients toward a hybrid solution:
By strategically integrating single-use technologies with stainless steel equipment in the same facility, you have the potential to unlock the best of both worlds: a high degree of configurability and speed from your single-use systems, and large-volume capacities from your stainless steel production trains.
For many manufacturers, this approach works best with parallel production trains. A CDMO, for example, may offer stainless steel production trains for clients seeking high-volume commercial manufacturing, while also providing clients in early-phase clinical studies with the versatility, speed, and low validation requirements of single-use production.
For a good example of this approach to hybrid manufacturing, look to the clinical manufacturing facility that our team engineered for Pfizer. To help them meet their goal of accelerated product turnaround with the option for high-volume production, we delivered five manufacturing suites: two are stainless steel, and three are single-use. We extended that hybrid approach into the facility’s downstream production, which includes stainless steel chromatography skids as well as both single-use filtration capabilities and a stainless steel centrifuge. Thanks to our closed processing design, Pfizer can locate upstream production, harvest, and all chromatography steps inside the same suite, as needed.
The result is a highly flexible and integrated facility capable of servicing a wide range of client needs, from low-volume, high-turnover projects to rapid scale-up into large-volume manufacturing. Its unique stainless steel/single-use integrations contributed to the project’s recognition as a 2020 ISPE Facility of the Year winner.
The disposable nature of single-use equipment eliminates CIP and SIP processes, which (as we’ve established) greatly reduces a facility’s overall water consumption and energy load. To take advantage of these reductions, manufacturers can easily integrate single-use in a few key areas where smaller-volume processing is possible.
Reduce water usage by integrating single-use systems in:
You can continue to work with single-use systems while meaningfully reducing the solid waste they generate by integrating stainless steel equipment at strategic points throughout your production train. Be aware, though: adding stainless steel systems could require extensive CIP/SIP processes and will simply replace one problem (solid waste) with another (time-consuming and energy-intensive cleaning). Instead, look for opportunities to bring in stainless steel equipment that won’t add significantly to your cleaning regime.
Reduce solid waste by integrating stainless steel systems in:
Buffer preparation
Chromatography skids
How will the decision between stainless steel, single-use and hybrid manufacturing change in the future?
That will depend on the convergence of several factors. First, there’s the rapid evolution of novel products which have not yet scaled beyond single-use technologies, such as cell and gene or mRNA-based therapies. Vendors of single-use technologies are responding to this wave of small-scale innovation by introducing new and expanded single-use options. Meanwhile, new approaches to single-use/stainless steel harmonization strategies are helping more manufacturers walk the line between these systems, cherry-picking the best of both while carving out their own tailor-made manufacturing approach to suit complex pipelines, diverse clientele, and growing demand for life-enhancing medicine.
Where does the future of your own manufacturing operation fall along this spectrum of potential choices? For help considering that question and finding an answer that’s unique to your manufacturing and business goals, reach out to our team.
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