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While single-use systems have been widely adopted for upstream biopharmaceutical processing, implementation in downstream operations has been limited to date. A desire to better integrate all processes, as well as the clear demonstration of the upstream performance and benefits of single-use technology, are combining to drive interest in the single-use approach for downstream applications. Suppliers of single-use systems have made progress in some areas, such as tangential flow filtration (TFF), and are working to address the need for other single-use purification technologies. At the same time, they are building their product portfolios to assist biologics manufacturers with the integration of production processes.
Desire for integration
Higher cell densities in biopharmaceutical manufacturing have led to both higher titers and higher impurities, both of which are increasingly challenging downstream processing, according to Willem Kools, head of field marketing and the biomanufacturing sciences network with EMD Millipore. “Better process economics can be obtained if process optimization occurs on both the upstream and downstream sides,” he notes. On the upstream side, improving the output from cell culture by improving expression of the protein of interest and reducing the impurity challenges will put less stringency on purification, ultimately reducing the number of unit operations required, simplifying processes, improving productivity and efficiency, and driving the cost of goods lower, according to Christine Gebski, product manager for bioproduction at Thermo Fisher Scientific. For example, Kools points to new technologies that enable initiation of the purification process in the bioreactor itself, bringing upstream and downstream process development teams closer together.
Derek Masser, sales director with ASI-Life Sciences, also notes the continued emphasis on alleviating the bottleneck that is inherent in downstream processes rather than integrating upstream and downstream processes. “In particular,” he says, “we see efforts focused on the application of single-use technologies for continuous processes as opposed to strict batch operations.” New concepts for continuous manufacturing are indeed evolving to support higher throughput downstream and increase integration, according to Millie Ullah, senior product manager for single-use technologies with Thermo Fisher Scientific. She also notes that companies are developing approaches for reducing the number of processing steps and linking steps together to improve process efficiencies.
Collaboration and customization
Increased levels of integration can be achieved by focusing closely on developing complete solutions with the right components for any particular application and demonstrating that they will work as expected, according to Helene Pora, vice-president of single-use systems with Pall Life Sciences. As is still done for upstream applications, it is necessary for suppliers to collaborate with customers on the integration of downstream processes and the implementation of single-use technology. There is, however, a greater need for customer collaboration and personalized integration for downstream processes, according to Masser. “Downstream processing is very customer-centric. Biopharmaceutical manufacturers have their own unique ways of manufacturing their products, particularly when close to the final therapeutic; therefore, being able to custom-configure single-use systems for each process helps increase the level of integration. In addition, collaborating with customers enables integration of single-use equipment that is unique to their processes, can fit in their tight cleanroom spaces, and can monitor the results that are relevant to their products.”
Biopharma suppliers can also help to increase levels of integration and bring biological drugs to market faster by offering more insight on how various unit operations affect each other, according to Kools. “Coupling application knowledge with system design and introduction of high-performance technologies will lead to the increased levels of integration for which the industry is looking.” Integration is supported at Thermo Fisher through the use of an open architecture approach and working with standardized single-use components and a wide variety of vendors to offer customers more choice and connectivity, according to Ullah. “Suppliers need to develop and commercialize high-value, effective product and workflow solutions,” asserts Gebski. In the end, Pora believes that it is all about looking at the bigger picture and seeing how the pieces fit together to create quality solutions. “Without quality and product knowledge, the level of integration does not matter,” she states.
A lack of single-use technologies
The greatest barrier for adoption of single-use technology for downstream applications has been a lack of adequate technology, particularly in the sensor area, that provides for a robust automation approach, according to Pora. “Not all downstream process steps are available in single use,” agrees Ullah. For those technologies that are available, she adds, scalability, performance, and cost are typical limitations.
Chromatography is the last purification unit operation to move to disposability and has seen only limited use, according to Gebski. She notes that the adoption of pre-packed, limited-use chromatography in the industry has been particularly slow, even though the value proposition for early clinical phase manufacturing is clear (time savings, where time can be spent on more value-added activities). “It is possible that customers do not perceive column packing as a pinch point (non-value-add point) in their manufacturing process (i.e., the problem is not big enough) or perceive a decrease in flexibility with respect to defining the required column geometries,” she suggests.
From the larger perspective, Masser points out that the conversion of the traditional batch manufacturing processes currently used for downstream manufacturing to more continuous approaches requires the development of revolutionary technologies, such as continuous chromatography systems. On the smaller scale, Masser also notes that scrutiny by FDA and internal quality control becomes more intense the closer a process step is to the final therapeutic, and as a result there have historically been concerns regarding the evaluation of plastics in terms of extractables and leachables. “These concerns have, however, been successfully addressed by single-use suppliers through validation studies,” he stresses.
Drivers for adoption
The success that biopharmaceutical manufacturers have had with single-use technologies for upstream applications is providing significant impetus for their application to downstream operations. “Validation studies have proven that single-use technologies work, and as a result, companies are more inclined to trust them,” Pora comments. In addition, she notes that the industry is changing and requires more flexibility than any traditional set up can offer. “Single-use technologies are, quite simply, more agile and can be implemented much more quickly; the flexibility they offer is certainly a key factor behind the growing willingness of people to give them a try.”
Furthermore, according to Masser, the continued integration and extensive use of plastics in upstream manufacturing has meant that the evaluation and study of plastics has been extensive as well, and the comfort level achieved with upstream systems is now being transferred to downstream applications. “The level of bioburden reduction and elimination that single-use technology provides is another huge motivator for its adoption in downstream processing,” he says.
About the Author
Cynthia A. Challener is contributing editor for BioPharm International.