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Feature Articles : Apr 15, 2013 (Vol. 33, No. 8)

Single-Use Bioreactor Roundup

A number of bioprocess analysts estimate that the entire single-use market has been growing at about 15–20% per year. Single-use bioreactors (SUB), in particular, are rapidly increasing in popularity and seem destined to stay. GEN polled a number of leading SUB biomanufacturers for their insights on this technology.

What are the biggest challenges for manufacturers of single-use bioreactors?

Mr. Abellan: Manufacturing disposable equipment having high-quality/high-tech control systems at the same time is a big challenge, since these manufacturing processes need different core competencies.

Single-use sensors still have a lack of performance and, therefore, sometimes do not meet the needs for high-performance process control. Also finding materials free from leachables/extractables is still a challenge.

Another challenge is to manufacture single-use bioreactors that encompass microbial culture with, for example, high oxygen demand or a larger pH range than is possible with single-use equipment at the moment. The limits here are clearly the higher requirements for material stability and higher performance sensors, similar to nondisposable solutions.

Dr. Arnold: Well, it’s a question of philosophy. What kind of solutions and technology do you want to rely on to serve the users of single-use bioreactors? As a manufacturer that aims to provide single-use bioprocess solutions that can be easily adapted to proven processes and workflows in each customer’s lab, we see only one main challenge: we believe we need to combine the advantages and features of both single-use and conventional bioreactor technologies to create products that allow users to gain the most reliable and scalable results.

For us, developing single-use bioreactors means transferring the geometry and control capabilities established in glass and stainless steel bioreactor technology to new materials in the form of advanced polymers.

Mr. Clapp: The first challenge is the realization that single-use bioreactors are not the same as their SIP counterparts. A single-use bioreactor is composed of two highly integrated elements: the equipment and the bag assembly. An appropriate amount of specification and review takes place (by the end-user, owner, etc.) for the bag assemblies—usually.

Quite often, however, more scrutiny is placed on the equipment element than is necessary. In so doing, the full value of single-use bioreactors has not been realized by the industry. And, it is not limited only to bioreactors.

The second challenge is that balancing standardization, intellectual property, and commercial success will be critical to the pace and extent of innovation and progress. There are many lessons to be learned from SIP bioreactors so that old mistakes are not repeated and new ones may be avoided

Mr. Giroux: The two main challenges are the inertia of the biopharmaceutical industry in embracing change. The high costs of implementing changes and the risks associated with making such changes result in slow adoption of technologies that may be ultimately beneficial to the end user’s bottom line.

Another issue revolves around educating the users about all of the benefits of single-use technologies. Much of the advantage of single-use systems comes from their flexibility, small footprint, and ease of use, but these benefits must be understood to be realized.

Dr. Golightly: Lack of standardization represents a challenge to both suppliers and consumers: end-users would prefer both the flexibility and potential cost benefits of interchangeability, but suppliers are presently determined to introduce value-adding differentiation.

The standardization dilemma involves nearly every key aspect of the single-use bioreactor system, from the consumable (bioreactor bag) to its holder (tote) to the control system employed to operate the system. As a supplier, we seek to add value by improving upon existing technologies and operator ease-of-use/workflow optimization, but we are also cautiously aware of not being too different’ given the potential cost of justifying new technologies to regulators.

The second biggest challenge is addressing the varied process needs of the myriad end-use applications in the most economical manner possible. For example, today many customers are interested in adapting single-use systems originally designed for traditional batch/fed batch operations to perfusion applications. End users would prefer a comprehensive design that can serve both applications; the single-use manufacturer has to address the complexity and cost of successfully designing systems capable of high performance in both applications.

Dr. Greller: One challenge is the required mindset change to align the stainless steel project world with a single-use product environment. In the past, users were accustomed to specifying to a large extent their specific stainless steel bioreactor solution. A great variability of designs have been realized for different customers and processes. After delivery, the customers would then qualify the system for their needs and use it. Given the ready-to-use, disposable character of single-use bioreactors, considerably increased responsibility regarding qualification and security of supply has become the job of suppliers of single-use bioreactors.

Secondly the integration of new sensor technologies, e.g., to enable implementation of process analytical technologies must be anticipated for different single-use bioreactor types.

While some of these smart sensor technologies are already mature, others are in an early development stage. In the latter case, a collaborative approach between the single-use bioreactor vendor and user is required. It involves a joint learning curve to bring the concept from the prototype stage to a reliable, robust industrial state.

Dr. Jagschies: One of the biggest challenges for manufacturers of single-use bioreactors is controlling the supply chain particularly at the start, and ensuring robust quality of the film and components in contact with cells. The start of the chain is normally a petrochemical company for whom biopharma is still a relatively small market and therefore not a top priority.

Then the initial film manufacturers are often reluctant to give the assurances of consistent and tracked manufacturing processes, which are required by the biopharma industry. Despite this, robust supply chains of plastics do exist.

Secondly, sensor technology and the availability of specifically designed single–use sensors is limiting. Having to use sensors designed for use in stainless steel systems immediately introduces the need for washing protocols and validation, negating some of the benefit of using single-use.

The ideal single-use bioreactor would contain single-use sensors of the same or superior quality to those currently available.

Mr. Lamproye: One of the biggest challenges that concerns every single-use bioreactor user is bag reliability. High-volume bag manufacturing is technically challenging. It requires mastering high-quality welding to ensure sterility and long-term resistance. The cultivation step can go for several days and the bag has to cope under operation pressure. This is also why the availability of high-volume bags, i.e., more than 1000 liters, is limited today.

The second challenge is reliability and the lack in diversity of disposable probes. For industrial applications, we are limited to pH and OD and optical probes. That means that cultivation parameter monitoring is still quite limited and the only way to measure another parameter is to do it off-line, with all associated risks in terms of sterility or batch integrity. It is then crucial to increase the number of non-invasive measurement systems adapted for single-use bioreactors.

Mr. Marner: One challenge for single-use implementation is translation of these models for gas transfer, mixing, and process control to our equipment in a way that makes transition for the end-user as smooth as possible. Over the last 50 years, the bioprocessing industry has developed a rich understanding of bioreactor physics and its influence on cellular growth/performance. From both a vessel perspective and from a controller perspective, we work to provide scalable, well-characterized systems that perform well for our users.

Another challenge is updating our traditional process-analytics instrumentation to a single-use format.

Mr. Phillips: From the manufacturer perspective, the biggest challenges we face are customization requests and conservative implementation on the customer side.

Single-use bioreactors are more than just plastic bags—there is a great amount of design behind them, so customization requests cause delays in time and production. To keep single-use bioreactors innovative and effective, the industry has to minimize customization, which would allow better scalable manufacturing process and creation of scale of economy. It would also lead to users benefits like lower cost and better service levels in delivery and quality.

End users must not be too conservative when transitioning to single-use. For instance, if they had a yield of 5 g/L in stainless steel and they work to the same specs with single-use, then they will end-up with 5 g/L in SUT bioreactors and will not capture any of the process efficiency of single-use bioreactors.

To avoid this, customers need to be open to redeveloping and optimizing their processes to the technology, which will result in an increased overall yield.

Dr. Rapiejko: Single-use bioreactor manufacturers are faced with increased challenges as the technology matures and adoption expands. The initial value proposition of single-use bioreactors was an increase in efficiency through reduction of turn-around time and labor for new cell culture process development.

Now that users have realized the potential of this approach, they are asking for more detailed characterization of films, raw materials, and other plastic components with the goal of better assessing the patient risk associated with production single-use bioreactors. Manufacturers need to be proactive and work to develop and implement a new generation of films and plastics keeping these requirements in mind.

A second, perhaps even larger challenge is to provide the flexibility and customization capability users demand, while at the same time reducing overall cost. New sensors and the promise of superior process monitoring and control are the drivers. Manufacturers need to invest in new production technologies for cost reduction and work to develop designs with the flexibility engineered-in.

Mr. Serway: Finding a completely disposable perfusion assembly that is scalable for varying sizes of disposable bioreactors while, in parallel, having a disposable reactor meeting the needs of higher disolved oxygen for the expanded cell density cell perfusion provides

Mr. Whitford: There has been a rapid and truly remarkable acceptance of single-use bioreactors (SUBs) throughout the industry. This includes manufacturers of such products as protein biologicals, vaccines, and now even cell-based therapies.

Because of this sudden incorporation of an entirely new technology, the industry is currently operating in an environment where individual stakeholders rely upon 1) their own drawings for many system components requiring custom manufacturing, and 2) their own standards and specifications for such things as materials validation, incoming materials quality control, and shelf-life testing.

To address this, manufacturers are now working through a number of channels, such as the BPSA, ISPE, ASTM, and BPOG to establish industry standards or guidance providing specification, conditions, and methods for the above. Other related issues include connectivity within and between unit operations, integration of control systems, and system integrity assessment.

Dr. Zoro: Flexible single-use reactors constructed from thin film or laminates are inherently susceptible to weakening from physical deformation or strain concentration at joints such as around ports or connectors. This sensitivity to manual handling during production requires strict manufacturing procedures and complex testing and QC protocols.

Due to the flexible nature of the materials used for single-use construction and novel impeller configurations used, providing good mixing and delivering sufficient power to support high density microbial cultures in flexible single-use reactors remains as a major challenge.

Small-scale single-use reactors have been able to sidestep these issues by appling a combination of robust, rigid molded plastics and rigorous engineering design. Rigid plastics are not susceptible to weakening by deformation, providing a robust solution, and carefully engineering traditional impeller shafts and blade geometries can easily deliver sufficent power in culture for animal and, in the case of ambr250, microbial cultures.

What are the two biggest challenges for users of single-use bioreactors?

Mr. Abellan:The two biggest challenge for users are finding systems appropriate to their applications (size, measurement, and control capabilities) and the problem of being tied to a particular manufacturer’s vessels. The range of applications where there is a good single-use product is rather limited compared to the wide range of cultivation methods and microbes or cell cultures used.

Single-use systems also tend to be limiting in key areas such as addition of sensors plus the various control methodologies for oxygen transfer and feeding. This also limits the systems when trying to fulfill the complete QbD approach of the FDA. As the equipment supplied with the single-use system is usually adapted to one type of vessel from one manufacturer, there is little chance to repurpose expensive equipment if needs change. Extra costs are also generated from treatment and disposal.

We also see many companies who are taking their environmental responsibilities more and more seriously, which is difficult to reconcile with single-use bioreactors.

Dr. Arnold: The main drawbacks of the wide variety of single-use bioreactors in the market, including bag solutions and rocking table technologies, is the lack of compatibility with conventional bioreactor technologies: Orbital shaking, for example, is not comparable to stirring. Especially in the biopharmaceutical industry, where the FDA’s QbD approach has to be kept in mind, one of the major aspects is maintaining reliability and scalability across the entire development cycle.

Although changes in cultivation and control methods do not have to impact the process itself, they can. Eliminating potential process variations afterward can be a time-consuming, and, therefore costly, effort. For small- to medium-scale cell culture production processes, where users can maintain their chosen technology through the development and production phases this is not relevant.

For development activities targeted at large-scale production processes, however—stainless steel bioreactors for instance—this does represent a major issue. And currently only a handful of single-use products on the market meet these demands.

Mr. Clapp: Process conversion from conventional technology (glass or stainless) to single-use is one. Despite widespread single-use acceptance, the long-standing, extensive level of experience with the legacy technologies is not quite there yet. Process scaleup also is impacted by the relative newness of single-use technology as well. And, depending on which bioreactor an end-user chooses, it may be easier or harder.

Connectivity is another limitation, i.e., variation and lack of standardization. There are many choices and the choices sometimes vary by process scale. The end-user needs to consider and plan, perhaps more than before, which ties back into my first answer with the experience levels.

I also want to thank Patrick Guertin, our upstream process development manager, for his input on this question.

Mr. Giroux: For users of single-use systems, one challenge is the lack of flexibility in configuring these systems for early-phase process development. Equipment modifications that would traditionally be accomplished in-house in a matter of hours or a few days now require the participation of the single-use manufacturer and this generally extends the cycle-time substantially.

And when using single-use equipment, the end-user must establish a solid long-term relationship with the bioreactor manufacturer on multiple levels: quality, engineering, and supply chain. The relationship with the single-use equipment vendor is much more important on a long-term basis than it would be with a traditional equipment supplier, since the single-use parts purchase and qualification is a recurring event.

Dr. Golightly: Ironically, some of the industry’s challenges are found both with the developer/manufacturer and eventual end-user of single-use bioreactors. Again, lack of standardization resonates across all involved parties, but resolving this impasse still seems unlikely.

Just as it is difficult for a supplier to change a differentiating design option in the effort to standardize to its peers/competitors; most end-users find it difficult to contemplate the reciprocal change required to re-qualify/re-validate to a new standardized option. If we could re-start the single-use market from its nexus today, things might be different. But in reality, we now face over a decade of installed use and therefore considerable inertia against change.

There remains a persistent discomfort generally put in the category of risk mitigation/supply assurance/business continuity planning for single-use system users. Although this extends from the lack of interchangeability, it also relates to issues even further back in the supply chain, namely those few global entities responsible for the plastics and films used to create single-use systems.

Coupled to general supply assurance is the factor of unknowns associated with these critical components. Although classical L&E (leachable & extractable) studies can provide good background information, what transpires during irradiation, storage, exposure to various components in media, and how certain cell types might simply be more sensitive to certain things remains part of the generally less-well-defined aspect of cell culture bioprocessing.

Dr. Greller: The biggest challenge a cell culture user can face is nonconforming cell growth in a single-use bioreactor bag. Besides the typical issues related to scaleup known from stainless steel bioreactors, new aspects may need to be considered in a risk assessment/root cause analysis of such polymerbased alternatives.

The most discussed topic during the recent years has been leaching of trace levels of cell growth inhibiting substances from films used in single-use bioreactors. During the development of our next-generation film platform, we were able to identify such a component in cooperation with resin suppliers, our strategic partner for the extrusion of the film, and end-users providing sensitive cell lines and analytical tools.

While few bag suppliers might have the buying power to control the resin formulation used in their films as well as the extrusion process, most will need to buy films off the shelf and they may be unable to provide proper change control and traceability all the way to the resin. This may lead to concern at the user side.

Dr. Jagschies: Single-use bioreactors are relatively expensive and have to be handled correctly to avoid damage. Construction of the bags requires mechanical welding of the seams and this needs to be of the highest quality in order to ensure that welds do not come apart and result in lost sterility and consequently loss of the entire run.

The bags are at risk of mechanical failure at three key points: during the vendor’s assembly process, when being removed from the packaging by the end-user, and when being unfolded into the reactor support shell. Manufacturers are continuously looking at ways to improve the robustness of the materials and reduce the risk of such mechanical issues occurring.

The ability to work closely with a vendor is vital as both parties are involved in working to ensure that a complete QA process is in place to make using single-use bioreactors a smooth trouble-free operation. Single-use bioreactor vendors work closely with customers to address QA and so support them in minimizing their risk.

Customers are also looking for additional verification of the bioreactors, including details of leachables and extractables etc., as well as support in the modification of existing processes to develop processes designed specifically for single-use bioreactors. In order to be successful, transferring a process from traditional stainless steel to a single-use bioreactor requires modification to the process because of the difference in features, such as mixing and gas requirements. In addition, customers are also looking to dual-sourcing to address security of supply.

Mr. Lamproye: The main challenges for users are scalability and the transfer from disposable systems to traditional steel cultivation technologies. Nowadays, disposable bioreactors are commonly used from early development steps to clinical trials. Generally these do not offer enough capacity to fulfill the material needs of Phase III trials.

Being sure the disposable systems are representative of what the user will experience with a traditional steel reactor is a key success factor. The problem is the same when scaling-down.

Another thing that has to be addressed is leachables. These elements from the bag that can be released into the culture medium can interact with the product, generating safety or quality issues. Previously, due to limited use of single-use systems, regulatory authorities only required limited data. Since the use of disposable solutions is spreading, it is now necessary to regulate the way users deal with them. Identification and characterization of leachables are a minimum, but it can also be necessary to demonstrate that they are treated in the appropriate manner during the downstream processing step to limit any risks.

Mr. Marner: One challenge for users is similar to that for manufacturers: How can users quickly translate traditional models of bioreactor performance to a single-use architecture?

Users also face the challenges of supply uncertainty, and they want to know that they have a stable partner that provides consistent single-use components year after year. Despite the rapid expansion of single-use technology in the past several years, we see that customers continue to gravitate toward suppliers that have solid histories of quality systems developed using stable supply chains.

Mr. Phillips: Beyond learning what capabilities single-use bioreactors can offer them, customers are faced with the challenge of knowing when to apply single-use technology and when not to.

The other great challenge for customers is that the single-use market is still relatively new. They can have trouble finding exactly what they need and being able to rely on the technology. Some manufacturers are not fully testing products, which results in leaks or contamination, either of which can have hugely negative impacts.

Dr. Rapiejko: One of the biggest challenges for users of single-use bioreactors is the associated inconsistency and unknowns around films and plastics. This is highlighted by Steiger and Eibl (Chemie Ingenieur Technik 2013, 85, No. 1-2, 26–28), which showed that 20% of bioprocess containers tested had a negative impact on cell growth or viability for some cell lines. Lot-to-lot variability is also known to exist for some vendor’s process containers, further adding to the complexity.

The industry is working to understand these issues through partnerships with manufacturers, but this remains a challenge. Users embracing single-use bioreactors are also challenged by concessions they must make to their bioreactor manufacturer. They must accept the basic design (e.g., impeller, sparger, etc.), and limits on its customization. This can be difficult for process engineers who have developed and optimized designs over several years or decades.

Manufacturers must work closely with users to engender their trust by demonstrating that good science and engineering practices were used as the foundation for the design and development of their single-use bioreactors.

Mr. Serway: Ease of set up of a perfusion system to a disposable bioreator due to limited port sizes and locations available, as well as maintaining good agitation/mixing of the cell suspension without damage to cell/cell viability.

Mr. Whitford: As the technology is so new, the field of providers is young and robust. This creates a challenge for users to select the particular product and system provider meeting their diverse and dynamic requirements.

Factors users must consider include the manufacturer’s history in this field, ability to maintain and support the installation throughout the product lifecycle, and their demonstrated propensity to innovate and keep up with the field over time.

Another challenge arises from the nature of the industry. In small molecule manufacturing materials, and equipment are often sourced from disparate and independent providers. But in many cell-based manufacturing modes there is a harmony and interdependency between the manufacturing equipment, the culture materials employed, and efficient operation of the system.

Therefore, it is incumbent upon the user to either carefully validate each component of the platform as part of a compiled system, or to purchase from a supplier who can supply validated systems of equipment including SUBs, culture materials such as media, and any required ancillary tools such as mixing and storage supplies.

Dr. Zoro: The relative fragility of thin film reactors (vs. stainless steel) neccesitates complex, painstaking, and time-consuming manual handling procedures when preparing the reactors and connections. Sterile sampling is also key issue, requiring sacraficial connector arrays and/or considerable operator time for drawing samples, particularly for multiparallel small scale systems.

Has the adoption of single-use bioreactors and single-use equipment plateaued in general? If yes, why? If not, what are future growth areas?

Mr. Abellan: The market for most of the existing types of products may well be close to a plateau. However, growth is still mainly coming from specific cell culture applications. The products from such cultivations (usually therapeutic proteins) are of sufficiently high value to make the costs-versus-benefits of using a disposal solution in production-scale attractive. Algal cultures and microbial cultures are still growing areas, where nondisposable solutions have clear advantages over single-use bioreactors. Single-use equipment could be interesting here for peripheral equipment around the bioreactor, such as media storage tanks.

Dr. Arnold: We see a steadily growing market for reliable, scalable, and fully functional single-use bioreactor solutions. There is tremendous demand, not only in conventional applications such as the cultivation of animal and human cells in the biopharmaceutical industry for instance, but also in traditional microbial biotechnology. Customers from all fields of bioprocessing are asking for advanced systems that meet their needs. That’s why we are focusing on the development of new solutions that satisfy their requirements.

Mr. Clapp: Adoption. That is an interesting word compared to, say, utilization or implementation or even accepted. Like other technologies, single-use and its application to bioprocess unit operations is following a fairly typical curve. Utilization or adoption continues to expand. There is a large body of knowledge now established: what works, what does not, the supplier playing field, etc. This began with the early adopters. Next was the move to process development activites. Biomolecules born from in single-use based process-development that have remained a viable market candidates are progressing through clinical trials; and even into production.

Areas of growth include microbial fermentation, cell therapy, personalized medicine, sensing technologies, and, of course, purification. With this in mind, single-use acceptance is a given. I would venture to say that our children’s children or their children will make routine use of single-use “bioreactors” as therapeutic aids—tools, at the hands of clinicians (physicians). These new bioreactors will not resemble what we know as bioreactors today, but the lineage will be undeniable. Looking back from that point in time, the era we are in now will be seen as the dawn of a medical treatment revolution.

Mr. Giroux: I do think that this technology has plateaued. Future growth in single-use can still be expected.

Future growth areas include:

1) Replacing equipment in existing markets. Even though the sunk cost of traditional systems may delay the adoption of single-use in manufacturing, the operational costs in these facilities are increasing yearly, which should lead to higher single-use adoption over time.

2) Taking a large share of emerging markets. We are now seeing the beginning of stem cell manufacturing, and we believe this field (and the next wave of cell-derived products) will predominantly adopt single-use, owing to its regulatory and cost-related benefits.

3) Creating new markets. Getting away from steam-in-place sterilization allows design flexibilities, which should lead to development of single-use bioreactors that could outperform traditional systems in some areas, resulting in market growth. Also, the lower capital outlays resulting from single-use adoption can also lead to the development of new markets.

Dr. Golightly: We do not believe the use has leveled. In fact, we believe it will continue to grow into the foreseeable future. As biopharmaceutical manufacturing groups continue to seek platform approaches and modularized unit operations, they are amenable to using single-use, ideally to its full extent, whereas today the vast majority employing single-use systems take a hybrid approach with some process equipment still being re-usable. Optimizing facilities, especially for multipurpose/product manufacturing, personalized medicine, e.g., cell therapy (T-Cell expansion), unique recombinant “eplacement enzymes or even unique mAbs requiring efficient smaller batch sizes (ideal for single-use), and the evolution of cell-based vaccine production (whether adherent cells on microcarriers or cells in suspension), all give rise to further employment of single-use bioreactors.

Dr. Greller: From our point of view the implementation of single-use solutions in upstream processing is still growing. While some solutions like the rocking motion-based single-use bioreactors have become the standard for cell expansion in the seed-train, there is still a lot of investment ongoing in stirred single-use bioreactor solutions not only for clinical manufacturing but also for commercial production. Especially due to the increased titers and smaller indications, the use of single-use bioreactors in commercial drug manufacturing will grow significantly.

Due to the integration of single-use sensor technologies in these workhorses they can now also support more advanced cell culture control approaches by using single-use pH, DO, and biomass in off-the-shelf bags. In the future, we expect to see more of these advanced control approaches in support of QbD-driven production approaches.

Moreover, biosimilars or biobetters will require a lean development and production approach implicating the use of off-the-shelf products. Also, in the diverse field of vaccines, the implementation of single-use bioreactors and process solutions is still on the upswing. While the user can select between different suppliers for mammalian cell culture single-use bioreactors, only a few of them just started the first steps into the field of microbial fermentation.

Dr. Jagschies: The adoption of single-use bioreactors and single-use equipment continues to grow as users are building new facilities with smaller capacities relative to traditional stainless steel. Also, companies are now bringing on line single-use plants, as recently announced by Shire, and are beginning to utilize bioreactors.

Geographically, we are seeing growth in all areas, especially where biologics are being produced. This increased use across the industry is resulting in double-digit growth figures for single-use technologies. New areas of use such as microbial fermentation and cell culture-based vaccines are also contributing to this growth.

Mr. Lamproye: It is obvious that the disposable equipment market will increase in the coming years: a fourfold increase in the next four years, according to experts. We at Novasep are even more inclined to believe that single-use solutions have a great future when we look at the adoption rate of our Sius® single-use solution for tangential flow filtration by both CMOs and biopharmaceutical companies. This future growth has to also be associated with the growth of biopharmaceutical and biotech markets by around 15% a year.

Another parameter is that in emerging countries, it is often not possible to register a drug without a local production plant. This stimulates the use of disposable solutions as it is necessary to limit investments and transfer issues. To conclude, most of the single-use technologies are not yet fully mature but they will meet the user needs more and more. In biomanufacturing especially, it is quite probable that disposable systems will outclass traditional steel reactors for a specific ranges of applications.

Mr. Marner: I don’t think we’ve seen a plateau, but I do think we are seeing an evaluation period of the systems that have quickly moved into the field. CMOs have quickly recognized the economic value of single-use systems for their flexible facility needs. Now, they are evaluating the performance of the manufacturing processes to decide whether to press the single-use concept down through the smaller platforms used in development and discovery.

Noncontract manufacturers will likely follow the path that CMOs have taken. Cell-line productivities continue to increase, permitting smaller bioreactor batches. So, traditional manufacturers are at the tipping point where the increased materials cost of single-use technology greatly outweighs the capital, cleaning, and contamination risk costs of sticking with traditional bioreactors. I think we’ll see continued single-use adoption at all scales.

Mr. Phillips: Adoption is far from plateauing. As mentioned before, the market is still young—it has only really been around for 10 to 12 years and still growing at a rate of about 20% or more. At ATMI LifeSciences, we believe this will continue to grow.

The fastest growing segments right now are single-use mixing and bioreactors. While single-use bag adoption has seen a bit of a plateau, the overall adoption of these technologies will continue to grow as companies are seeing the process and cost efficiencies of implementing these technologies in the new flexible facility model. Adoption will also grow as companies innovate new ways to apply the technologies to the needs of the market.

Dr. Rapiejko: The full potential of single-use bioreactors has yet to be realized. As the biopharmaceutical industry expands towards the development of a new generation of therapeutics, the single-use bioreactor will be leveraged to its fullest potential.

Start-up companies bringing their first molecules to clinic as well as CMOs will be the drivers of continued growth of single use bioreactors now that they have become accepted as a proven manufacturing platform.

Vaccine manufacturers that are moving from traditional, egg-based production methodologies to microcarrier-based bioreactor production are evaluating single-use bioreactors for their needs, as are researchers developing therapies based on stem cells. Other growth areas include personalized medicine, local flex-factory manufacturing sites, and/or biomolecules developed to treat orphan diseases.

These applications require smaller production batches as compared to blockbuster mABs and single-use bioreactor are ideally suited to meet the need versus traditional stainless steel systems. These growth areas, coupled with the manufacturer’s focus on quality, economy, and reliability insure that the best days of single use bioreactors remain ahead of us.

Mr. Whitford: We don’t see the adoption of single-use plateauting at all. On the contrary, we see interest accelerating in existing product types as innovations increase volumetric productivities and push required bioreactor working volumes to those supported by SUBs.

Furthermore, we see the industry moving to newer product types and manufacturing platforms that are well-supported and even synergized by SUBs. Initiatives toward such products as personalized medicine, cell culture manufactured vaccines of all types (including VLPs) and targeted therapies also demand SUB features at the production scale they support.

Manufacturing trends that continue to require SUB features include the renewed interest in transient transfection in process development, and continuous processing at the manufacturing scale through enhanced perfusion culture. Finally, the trend toward globalization and outsourcing is feeding the demand for low entry cost and flexible manufacturing facilities—characteristics that are hallmarks of SUBs!

Dr. Zoro: For small-scale bioreactors, it seems that incremental time savings (vs. glass reactors) have been insufficient to drive widespread adoption of single-use vessels alone. With the future in bioprocessing looking towards high-throughput parallel bioreactors and DoE applications, single-use technology must be combined with a major step change in productivity.

This can be realized through full bioreactor automation, delivering attendent benefits in experimental consistency and enabling larger and ever more powerful experimental studies, delivering ever faster and more efficient bioprocess development programs.