Single-Use Bioprocessing Equipment
To assess current trends in single-use bioprocessing equipment, BioPharm International turned to John Boehm, bioprocessing business unit manager, Colder Products Company; Mandar Dixit, head of product management–filtration technologies, Sartorius Stedim Biotech; Geoff Hodge, managing director of process technology Xcellerex, Inc.; Günter Jagschies, senior director of strategic customer relations, life sciences, biotechnologies, GE Healthcare; Mani Krishnan, director of product management, Mobius single-use technologies, Millipore Corporation; and Jerry Martin, senior vice president of scientific affairs, Pall Life Sciences, and board chairman and technology chair at BPSA.
Q: Single-use bioprocessing technologies have evolved a lot in recent years. What will be the most important developments in the next few years?
Boehm: The continued integration of monitoring and sensing technologies into single-use systems will be an important development in the coming years. Incorporating new sensor and RFID technologies will aid manufacturers by simplifying process monitoring activities as well as streamlining traceability and tracking requirements.
Dixit: Disposable bioreactors and chromatography columns.
Hodge: There is a great deal of work being done with disposable sensors, so we see developments emerging on that front. We also see developments in chromatography or alternatives to chromatography that will open new doors. As a maker and operator of technology-neutral bioproduction trains, we have the enviable position of looking at every emerging technology. There is some exciting technology out there.
Jagschies: Development of the supply chain leading to single-use products to the satisfaction of the biopharmaceutical industry. There are, however, significant quality assurance (QA) issues with less-than-satisfactory answers. The user community is divided into believers and non-believers, instead of solid facts turning this into a matter of demand only.
Krishnan: Implementation of single-use technologies today is manual and requires a lot of operator manipulation. Over the next few years, we will see the development of automated and integrated solutions that combine the benefits of single-use technologies with the ease-of-use elements of traditional stainless steel processing systems.
Martin: Bioreactors and mixers will continue to evolve with improved designs. Along with filtration systems and storage containers, the integration of sensors will bring PAT into single-use bioprocessing.
Q: Adoption of single-use technologies continues to increase, yet end-user questions and concerns remain. What do you see as the most important obstacles today to increased adoption?
Boehm: The largest obstacle that remains for many organizations in adopting single-use technology is effectively determining and comparing the true lifecycle costs of designing, validating, operating, and maintaining a traditional stainless steel facility versus a facility based on single-use manufacturing. Costs—including design expenses, initial capital outlay, validation services, ongoing energy, and operational costs, as well as maintenance expenses—are often managed by different groups and it can be difficult to obtain accurate information regarding fixed and variable expenses that constitute the true lifecycle costs of a new or existing facility.
Dixit: Scale limitations to about 1,000 or 2,000 L for disposable storage tanks, mixing equipment, and bioreactors. The other limitation is the need for extensive extractables and leachables studies with enhanced surface area of plastic polymers in direct contact with biologic fluids.
Hodge: The single largest obstacle to adoption of single-use technologies is education and understanding. Much of the user community is not yet comfortable because they are still learning about disposables. Others that are farther up the curve tend to get hung up on leachables and extractables. They are unfamiliar with exactly how these studies are done, so they don't realize how manageable they actually are. It is not as difficult as many people believe.
Jagschies: There are overheated expectations on the vendor side of things. For example, although single-use technology can cut the time to first run of a facility, companies still need qualified and GMP-aware operators, which is more of a bottleneck on the path toward a new facility than the question of using stainless steel or single-use equipment.
Krishnan: With the increased interest in the adoption of these technologies for product processing (as opposed to buffer and media processing), there is an increased focus on extractables and leachables, robustness, and maintenance of product integrity. There is also a need for systems that can facilitate closed processing. Another obstacle that end-users face is the inability, in certain unit operations, to run a fully closed process. Although connectivity technologies bridge the gaps to some extent, there are some unit operations such as ultrafiltration and diafiltration and chromatography that can't be fully closed in a single-use system.
Martin: Concerns over extractables and leachables will continue to be the primary obstacle.
Q: What application area is currently growing the fastest?
Boehm: Upstream processing remains a growth area, especially with the continued advancement in single-use bioreactors (SUBs) technology, but by far the fastest area of growth has been the transition of single-use technology into downstream processes, including formulation and filling.
Dixit: Disposable fermentation.
Hodge: Disposable bioreactors and chromatography columns.
Jagschies: Single–use bioreactors (SUBs).
Krishnan: There is a significant amount of interest in adopting single-use technologies for intermediate product hold, bulk drug substance transportation, and final fill/finish applications. Essentially, we are seeing a move from buffer/media preparation/hold to product handling with single-use technologies.
Martin: Sterile filling.
Q: Is the relationship between suppliers and end-users different for single-use technologies compared to stainless steel? (For example, many end users are concerned that adopting single-use technologies may require reliance on a single-source in some cases).
Boehm: With the conversion to single-use systems, supply becomes integral with ongoing production capability, thus it is very common for manufacturers to form strong ongoing relationships with their single-use technology suppliers.
Dixit: Yes. Apart from the single-source constraint from time to time, one may have to rely on the vendor's extractables and leachables information with model solvents as opposed to doing a thorough analysis with the product when the project timeline does not allow for that.
Hodge: The relationship between end-user and single-use supplier is more like the traditional raw-material supplier relationship, because the single-use supplier becomes an ongoing part of the equation. There are some concerns about reliance on single-use sources. As an equipment maker that is also a biomanufacturer, we face the same concerns as our end-user customers. In response, we have established multiple sources for the single-use bags and components we use and sell to customers.
Jagschies: Indeed, there is a difference for managing QA with single-use products. One relies on the continued "survival" of the vendor in his business over a very long time, while with stainless steel one has the equipment and its maintenance in control. There is a series of new, additional aspects in the QA concept that need attention, nothing particularly difficult, but the risk assessment is different.
Krishnan: In some ways, the relationship is the same while in other ways, it is different. For example, end-users require that single-use processing systems are engineered and designed using principles similar to those used in traditional equipment. This requires a lot of collaboration, similar to what was done with stainless steel equipment. With stainless steel equipment, end-users control the cleanliness and sterility of the process equipment. Furthermore, because the equipment is fixed and contains the required level of automation, the reliance on the operator is much lower. With single-use technologies, end-users have to rely on the manufacturers to supply them with a sterile product that can be manufactured repeatedly to meet their processing needs. This requires a significant amount of partnership and trust between end-users and manufacturers of single-use equipment.
Martin: To the degree that end-users have sole responsibility for cleaning and resterilizing stainless systems, they may feel that they have more "control" versus by partnering with suppliers of presterilized disposable systems. Once the supply chain has been established with reliable suppliers who follow GMP quality systems, however, this concern about "outsourcing" equipment supply and external supplier reliance will diminish.
Q: What is the future of standardization for single-use technologies?
Boehm: With the continued evolution of single-use technologies and the varied product preferences of the different end-users, it is most unlikely that market will soon see industry-wide standards dictating specific resins or product configurations. However, it is likely that manufacturers will use established best use guides like those published by the Bio-Process Systems Alliance for product evaluation and validation; it is also likely that end-users will develop internal standards for single-use technologies and qualify multiple suppliers to these standards.
Dixit: Some standardization may be possible. However, because of the complexity involved, one would have to rely on the suppliers more for data on single-use systems.
Hodge: We don't see a major movement toward standardization. We see it in some pockets through natural industry consolidation and as partnerships develop. Our technology-neutral approach to designing production lines means we must know how to make any combination of brand and technology work together, so in a way, we would be a big beneficiary of any standardization.
Jagschies: We consider this a must. Single-use products do not make sense for any side, vendor or buyer, if there is no standardization. If a vendor has to make a different product for every buyer, then the business case for the vendor turns weak pretty soon. Adaption of a configuration is not the same as not adhering to such standard. But even the number of different configurations must be limited. Users need to oversee their “dogma” in their operations.
Krishnan: With filtration cartridges, there was an attempt to standardize the connectivity between the filter cartridge and the stainless steel housing (code 7, code 0, etc.) and the lengths of the cartridges (10", 20", etc.). With capsule filters, the standardization was limited to the end connection (1.5" TC or ¾" TC, etc.). Similarly, it is possible to standardize the sizes of the single-use biocontainers. It is, in fact, possible today to get the single-use containers made to fit multiple suppliers' holding vessels. If standardization is sought for the film used to make the biocontainers, the analogy is similar to what we have with filtration devices today—while the cartridge dimensions and the connectivity are standardized, the actual membrane material are different between suppliers. It will be difficult for the various manufacturers to switch to a common film source as each manufacturer has spent considerable resources qualifying their own film and their manufacturing process with that film.
Martin: Standardization of designs will not occur until users opt for standardization over customized systems, which is the current environment despite desire by a minority for standardization. Commoditization, however, will not occur as suppliers will maintain their proprietary positions. As with sterilizing filters, users will need to qualify alternate sources or systems to reduce sole-sourcing risks. Some of this may be done through primary integrators.
Q: Many end users want to understand the cost comparisons between single-use and stainless steel equipment. How should people approach this question?
Boehm: If end users do not already have established internal lifecycle analysis tools that take into account all fixed and variable costs associated with design, validation, operation, and maintenance of a facility whether based on stainless or single-use technologies, there are a number of consulting companies that can provide end-users with appropriate packages and expertise to do this type of evaluation.
Dixit: One should consider the overall cost of ownership including the cost of utilities, cleaning validations, etc. when comparing the cost of operating single-use versus already installed stainless steel equipment. For a green field facility, single-use solution looks more attractive than for an already existing facility with re-usable stainless steel tanks. Hybrid solutions would have to be adopted in the latter case.
Hodge: There are several models out there, including our own. We believe it is very important to look at all the variables that affect the success of the client's business. So, in addition to capital expense and operating expense comparisons, we also want to look at deployment speed, plant flexibility, process optimization costs, training, validation and start-up costs, and other dimensions.
Jagschies: To date, this is still an individual exercise. Published case studies from vendors often have a bias in cost comparisons in favor of their product lines (e.g., high cost of water, no additional QA efforts, long start up time when that may not be on the critical path, or other factors not relevant for everyone in the same way; all of this usually favoring the single-use product someone wants to sell).
Krishnan: Much has been written about the relative cost of ownership of single-use versus traditional equipment. Modeling software such as Biopharm Services' BioSolve can be used to run these comparative calculations. Because the input variables such as utility cost or differential utility cost for water, electricity, gas, etc. and labor cost and utilization vary between companies (and sometimes between different sites within one company), it is beneficial to do the cost modeling on a case-by-case basis.
Martin: Cost comparisons are quite complex with multiple variables and results can vary from case to case. Some computer models are available through suppliers, consulting, and engineering firms.
Often, there are over-riding benefits such as WFI production, space availability, containment, sourcing, installation and, validation, etc. that clearly indicate cost savings of single-use.
Q: In the future, how close do you think we will come to fully disposable process trains?
Boehm: The market is closing in on the ability to provide fully disposable process trains for small to medium production capacity. There are a number of single-use components and technologies that will need to be developed in the coming years to make this possible for large-scale production.
Dixit: Up to 1,000-2,000 L scale for cell culture processes; most unit operations could be done with disposable fluid path except centrifugation and certain chromatography steps such as Protein A.
Hodge: For some processes, we are already there. For other processes, especially those that use chromatography, there is still work to be done, and a true single-use solution may never materialize. However, with reusable and disposable options that are being worked on, we can get pretty close.
Jagschies: There will be cases, such as certain personal medicines, or cell therapies (a special case of personal medicine), and also certain emergency-driven production (could be vaccines or medicines needed in areas with a pandemic or natural catastrophe, or a war-like situation). Apart from that, regular production with many batches per product and per year, will be difficult to make economically viable with an "all disposable" approach.
Krishnan: It is clearly possible to manufacture MAbs and certain vaccines using fully disposable purification trains—but not a 10 kg scale. We are likely to see fully disposable process trains within the next 2-3 years that can process up to 5 kg of MAb per batch. There are a few technology gaps that must be filled and companies such as Millipore are working vigorously to make this a reality.
Martin: For some smaller volume processes, e.g., vaccines and specialized therapeutics (e.g., <100–1,000 L), fully disposable process trains exist today. Any large-scale processes, however, will likely never be fully disposable, particularly with regard to large-scale bioreactors, purification chromatography columns, and ultrafiltration systems, so hybrid processes will dominate at that end of the scale.