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Apr 15, 2013 (Vol. 33, No. 8)

Single-Use Bioreactor Roundup

  • 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.

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