According to the Collins Dictionary, the term “single use” describes things that are “blamed for damaging the environment and affecting the food chain.” So, when the publication announced that single use was the Word of the Year in 2018, the term’s negative connotations were emphasized. In biopharma, however, single use describes things that are praiseworthy.
Biopharma anticipates that single-use technology will enhance flexibility, boost efficiency, and reduce costs. Single-use technology may also satisfy the unique demands cited by the emerging cell and gene therapy sectors. Consequently, biopharma is stepping up its adoption of single-use technology—not just in preclinical and clinical development, but in full-scale commercial operations.
Some benefits of single-use systems select SUSs union such as the elimination of expensive, time-consuming cleaning steps, are obvious. Others are less plain, says Eric Langer, president and managing partner of BioPlan Associates.
“A key factor is the ability to reduce the capital expenditure and speed the commissioning of a suite or facility using SUSs,” he points out. “This enables the construction of facilities for the production of a wide variety of biologics including biosimilars.” He adds that with SUSs, these facilities could be sited in geographic regions where production would otherwise be impossible.
Stealing a march on steel
The first cell lines used by the drug industry were, to be frank, not good. Titers were low, sometimes in the sub-gram-per-liter range. To raise yields, firms used large cultures grown in stainless-steel tanks.
Since then, cell lines have improved, yields have increased, and downstream processing technologies have become more effective. As a result, it is now possible for firms to use small cultures and single-use technologies.
“As titers from bioreactors increase, the need for large tanks decreases,” explains Langer. “This makes SUS bioprocessing more feasible.
“As legacy stainless-steel facilities are replaced with newer, more flexible facilities, we will continue to see more SUS applications at commercial scale. The question now is which products and which biologics will make the transfer from SUS to commercial scale.”
Integrating diverse technologies
The range of single-use technologies available has also increased. Besides disposable reactors, there are disposable mixing bags, storage units, and tubing systems.
Single-use technology is expanding faster in some areas than others, depending on demand, suggests Gernot T. John, PhD, director of marketing and innovation at PreSens Precision Sensing.
“Single-use flasks are the typical type used nowadays for cell cultivation,” he says. “For microbial cultivation, reusable flasks are still widely used.”
Biopharmaceutical companies are attracted to single-use technologies partly because they can be more straightforward to set up than multiuse systems. To illustrate this point, John mentions that PreSens single-use shake flasks come with integrated sensors. “The main advantage is that they come precalibrated, so the user has a ready-to-start product,” he stresses. “In addition, they don’t need to be cleaned by autoclave, a step that more and more pharmaceutical companies avoid because cleaning needs to be validated.”
Disposable downstream techs are also becoming more common, says Pavel Marichal-Gallardo, a bioprocess engineer at the Max Planck Institute for Dynamics of Complex Technical Systems.
“Single-use chromatography systems,” he comments, “offer many advantages over traditional systems, such as easier process and product change, reduced facility footprint, lower capital investments and maintenance costs, and easier qualiﬁcation and validation.”
Striking the right balance in hybrid facilities
The growing range of single-use technologies is something of a double-edged sword from a facility design perspective. While they make it possible to create scalable manufacturing operations where cleaning requirements are minimized, choosing which systems will work best in combination is a challenge.
According to Langer, the question isn’t about favoring single-use technology or stainless-steel technology. Rather, the question is about determining the best mix of technologies. Some hybrid facilities may be tilted toward SUSs; others, toward stainless.
Economics also play a large part in determining which single-use technologies a manufacturer should use. “Where applications make sense for SUSs,” Langer says, “we will continue to see trends toward more disposables, and more hybrid facilities, as these lend themselves to the greater flexibility and adaptability that facilities managers increasingly demand.”
Enabling the production of cell and gene therapies
Increasing demand for SUSs is also attributable to the wider evolution of the biopharma industry. The approvals granted to axicabtagene ciloleucel select Yescarta®, Gilead) and tisagenlecleucel select Kymriah®, Novartis) kickstarted the commercial cell therapy industry. Similarly, the green light given to voretigene neparvovec-rzyl select Luxturna®, Spark Therapeutics) marked the emergence of the gene therapy market.
The approvals were great for patients and industry R&D teams. They were also something of a validation for single-use technologies. Disposable systems are ideal for the tiny batch sizes, even patient-specific batch sizes, that are processed.
And, Langer maintains, the growth of the cell and gene therapy industry is fueling innovation in SUS development: “Cell and gene therapies, specifically autologous ones, will most definitely rely on SUS technologies. However, custom, bespoke SUS for cell therapy applications are only now being developed.”
This observation is shared by Andrew Bulpin, PhD, executive vice president, process solutions, MilliporeSigma. He informs GEN that SUSs are ideal for cell therapies.
“In situations where the therapy needs to be delivered in a short time, such as CAR T-cell treatments or vaccines in an outbreak crisis, the need for single-use technologies becomes undeniable,” he states. “Moreover, these technologies, when integrated into a flexible manufacturing approach, enable the manufacturing of multiple products at a single location, maximizing efficiency.”
Boosting the production of viral vectors
At present, there is a shortage of viral vector production capacity. This shortage was called an “engineering opportunity” by a recent article that appeared on the website of the Alliance of Advanced BioMedical Engineering. The same article also indicated that the approval of Luxturna had accentuated “growing concern about the global supply of viral vectors.”
The shortage involves several difficulties. One difficulty is that making viral vectors can take up to a year. Another difficulty is that very few contract manufacturing organizations select CMOs) have the capabilities required for such production. Yet another difficulty is the need to produce enough vector material to meet dose and cost requirements, while ensuring its purity and establishing a robust and reproducible process for commercial manufacturing.
Resolving any of these difficulties using current technologies is a challenge because the yields are so low. As a result, the industry is still looking to increase upstream titers and improve process efficiencies. And growth of the cell and gene therapy sectors is likely to exacerbate the issue.
“As the gene therapy market grows rapidly, available capacity is lagging behind demand,” explains Bulpin. “Compounding this challenge is that many of these therapies are on accelerated regulatory pathways. Therefore, development and the manufacturing of the viral vectors used in these treatments need to be accelerated.”
Single-use technologies can ease these bottlenecks because, Bulpin says, they address the operational, biosafety, and regulatory challenges that constrain production.
“Single-use technologies help accelerate the development and manufacturing of viral vectors,” he maintains. “Their ease of use, scalability, reduced contamination risk, and lower labor and validation requirements enable manufacturers to release their products faster to clinic.”
Similar points are made by Marichal-Gallardo, who expects that single-use technology will be adopted more widely as it demonstrates value to producers of gene therapies.
“One extremely relevant advantage [of single-use technology] is the reduced risk of cross-contamination and impurity carryover, especially in multiproduct facilities,” he points out. “This advantage is even more pertinent in the viral gene therapy ﬁeld, where the product is an infectious virus that has to be handled with special care.”
In the emerging gene therapy ﬁeld, commercial facilities are still scarce. Here, Marichal-Gallardo asserts, “single-use design considerations can be applied from the very beginning without having to adapt existing sites.”
Marichal-Gallardo also thinks single-use technologies could help industry boost vector production capacity in particular. “A continuous tubular bioreactor for virus production [that] was developed recently at the Max Planck Institute … reduces reactor volumes by as much as 20 times,” he says. “This means that a single-use 2000-L continuous reactor could deliver the same product output as a 20,000-L reactor.”
Putting “single use” at biopharma’s disposal
In discussions of SUSs, an often-overlooked factor is, surprisingly, disposability. Perhaps this factor is taken for granted because “single use” is practically synonymous with “disposable.” Yet the disposal of SUSs is rarely straightforward.
Practically any biopharma production technology poses contamination risks. To minimize such risks, manufacturers that use stainless-steel systems must observe strict cleaning protocols. Proper cleaning ensures that potentially hazardous materials are removed from stainless-steel systems before the systems are reused.
Users of SUSs, in contrast, must confront the problem of disposal. Doing so requires process knowledge and expertise.
The recycling of single-use devices poses unique challenges. “Single-use devices can be classified as biohazardous,” notes Bulpin. “They cannot be recycled by ordinary means. In addition, single-use devices contain mixed materials and different types of plastic that are difficult to separate out from the device itself. Current recycling infrastructure is not able to separate and sort the plastics.”
To address recycling challenges, MilliporeSigma has teamed up with Triumvirate Environmental, a commercial waste management and environmental services provider. Together, the companies are working on what MilliporeSigma claims is a first-of-its-kind recycling program for single-use technology. In this program, plastics from single-use devices are turned into industrial-grade construction materials.
“This program has been operating since 2015 and has recycled approximately 22% of the waste generated by single-use facilities along the East Coast,” Bulpin declares. “There are 18 manufacturing sites using the program, and while this is the first of its kind, there is hope that this program will help to increase investigation into other technologies that can further reduce the environmental impact of SUSs.”
Biomanufacturing Facility Design
At the recent BPI West Conference in Santa Clara, CA, Peter Genest, director of automation offerings and strategy at GE Healthcare, discussed the advantages of taking a pragmatic approach to layout and automation in the design of new biomanufacturing facilities. He stressed that there are tangible benefits to integrating equipment into one continuous network of systems and data early in the process.
“The cost and effort to integrate the multiple pieces of equipment will be noticeably lower when considered early in the design phase rather than the production phase,” he said. “It is 100 times more expensive to make a change during the production phase as compared to making the same change during the requirements specification phase of a project.”
Other points to consider include aligning internal and external teams on flexibility, redundancy, and future expansion needs. Also, try not to be at the tail end of a technology or a communication architecture, he cautioned.
Simplify communication architecture
“We have helped drive some of our vendors to deliver Ethernet IP I/O faster than they originally planned,” Genest noted. “Ethernet IP will simplify communication architecture in facilities and allow for future expansion without having to rip up walls and ceilings.
“Synchronizing process hardware and automation hardware designs across multiple sites can realize time and cost savings over multiple projects. We have customers with projects across multiple global sites. These customers have designed for and realized easier tech transfers by standardizing process equipment configurations.”
Larger capacity downstream single-use equipment is allowing for process solutions to become completely single use, according to Genest, who emphasized that the more single-use equipment you have, the simpler and smaller the facility can be. The equipment and infrastructure to support stainless-steel systems is no longer needed, he added.
“The validation effort to start up and commission a single-use plant is a fraction of that of a stainless-steel plant. I don’t think anyone will miss climbing into a tank to check the sprayball pattern or having to Temp-Stik a low point in process
piping,” he remarked. “That all goes away in single-use systems, and the start-up team can focus on the process, the product, and ultimately, the patient.”