Single-use technology is gaining ground in downstream bioprocessing, but challenges stall further adoption.
By Feliza Mirasol
Biopharmaceutical manufacturers have embraced the use of single-use technology upstream, but are now increasing its use in downstream processing (DSP) as well. “There are very few DSP unit operations that are not using single-use systems or components,” notes Donald Young, senior global product manager, Thermo Fisher Scientific, BioProduction Division. “Clarification via depth filtration or tangential flow membrane filtration (TFF) is just one example.”
As this trend continues, the concept of an end-to-end single-use manufacturing facility has moved from the world of theory squarely into reality. However, downstream single-use systems are still evolving, as vendors work to improve performance in critical areas. This article summarizes some of the benefits and the challenges of employing single-use technology downstream.
Reduction in bioprocessing time is one advantage that single-use systems offer. As Young points out, reusable systems can typically require more than 12 hours from set-up to tear-down, while single-use TFF systems require half that time.
Another area where single-use is gaining ground downstream is in buffer preparation, storage, and dispense. “Single-use mixers, coupled with single-use bioprocess containers (BPC), can increase a DSP suite’s annual throughput, because they offer turnaround times of around a day or less without the need for clean- or steam-in-place operations. Reusable systems can require three or more days to clean and sterilize,” Young explains.
Prefilled BPCs have only made the single-use option more popular, he says, noting that BPCs prefilled with water for injection or purification buffers can be delivered to customers, eliminating the need for them to perform these functions inhouse. These systems can be supplied in volumes ranging from pre-clinical and clinical scale to volumes large enough to satisfy current good manufacturing practice (cGMP)-scale production, he says.
“These large-volume-liquid BPCs are used as the primary source of sterile process liquids or as a second source/back-up supply to reduce demand on the customer’s in-house capabilities and capacities,” Young states.
Hindrance or help?
Many disposable chromatography columns meet cGMP and industry standards, and also offer reproducibility, scalability, speed, ease-of-use, and operational safety.
However, chromatography has been the last purification stage to move into disposable equipment. Although its use is growing downstream, it is still limited. In addition, the industry’s adoption of pre-packed, limited-use chromatography has been slow, even though the technology’s benefits have been demonstrated in the early stages of clinical manufacturing (1).
Among the common problems that single-use technology can help address is column packing. Column packing requires a stable bed with good flow properties, and, today, automatic packing solutions make packing the columns much more reliable than in the past. Bioburden can still result, however, and its source can vary—usually it is introduced before or during packing. Thus, good sanitation methods and familiarity with the most likely microbial contaminant species present in the immediate environment are needed to address bioburden. Using pre-sanitized single-use columns and flow kits is one way to minimize the risk of bioburden (2).
Single-use technology implementation in chromatography can greatly reduce cycle times, lower operating costs and energy consumption, and generate less waste, according to Young, who points out that DSP can be a process bottleneck because of a lack of single-use chromatography options or because of the expense, time, and labor of using existing chromatography components as single-use components.
With a facility set up for single-use system operations, facility design can be simplified and can be executed in about half the time needed to build a traditional facility with reusable systems, Young emphasizes. “Start-up/licensure times can be cut compared to traditional facilities using stainless-steel-only equipment and systems,” he states. In addition, construction costs are lower mostly due to reduced need for clean steam systems that can account for much of a production facility’s water needs, he adds.
“Single-use systems are an attractive option for emerging markets, not only in chromatography but all along the production workflow,” says Young, who sees this as the technology’s most important contribution today.
Despite wider adoption of single-use technologies, downstream bioprocessing, particularly chromatography, continues to pose challenges. Available technology may not always be adequate to meeting a specific facility’s needs. For example, not all downstream bioprocessing steps are available with single-use technology, and those that are available may be limited by performance, scalability, and cost (1).
For example, one unmet user need is the lack of affinity and ionexchange chromatography beads that are sufficiently cost-effective to be classified as single-use. These process steps continue to be the biggest process bottleneck in the DSP workflow, and represent a huge opportunity for suppliers, Young remarks.
Another area where single-use technology might be improved downstream is in combining it with process chromatography columns, according to Dr. Nandu Deorkar, vice-president of research and development at Avantor, a manufacturer and distributor of products, services, and solutions to the life-sciences and advanced technologies industries.
“[Adopting] single-use systems gives manufacturers the potential to move from a batch-based approach to something approaching a connected continuous process. It will be possible to minimize the number of large storage tanks required, and incorporate single-use systems to streamline sample collection and loading, and other operations. There are single-use systems that make it much more of a continuous process, and remove the time required to clean, dry, qualify, and validate sampling and storage systems between chromatographic steps,” Deorkar states.
Another unmet need for biopharmaceutical manufacturers is technology that reduces the cost of resins (3), to allow for greater use of single-use systems to address the resin fouling that occurs from repeated use of resin during chromatography. Manufacturers are unlikely to dispose of costly resins after one pass, unless costs are significantly reduced to make this practical.
In traditional industrial mAb processes, large volumes of both chromatography resin and buffer are required, which translates into high operating expenses. Because chromatography resins make up a large portion of the costs in downstream bioprocessing, switching a polishing step from resin chromatography to a single-use membrane column can significantly reduce expenses and is one alternative when looking to improve DSP.
In a study (4) that used modeling software to evaluate commercial monoclonal antibody (mAb) production, it was shown that the unit operation cost was 19% to 33% less for a membrane process used on 1000-L and 5000-L scales bioreactor volumes and various mAb titres. In addition, buffer volume was decreased by up to 55%. Further, an analysis has shown that operating costs per gram of mAb are 22% lower in a single-use facility than in a traditional stainless-steel facility (3).
Single-use in overall bioprocessing
Suppliers of single-use downstream chromatography systems continue to improve the options available to manufacturers, and to examine ways to reduce the number of processing steps required for biomanufacturing, by linking steps to improve process efficiencies. For example, the ability to use concentrated buffer components and mix them in-line under controlled conditions (i.e., in-line conditioning) has simplified chromatographic operations (2).
“Single-use systems have the potential to improve productivity across the entire mAb production process, especially in terms of sampling,” adds Claudia Berrón, vice-president of global commercial development, biopharma, Avantor. “Drug producers have to sample for quality and process control purposes many, many times continuously. Typically, to effectively sample, you sample more than what is needed, and, in some cases, it isn’t possible to sample exactly what is needed. Every time you take a sample out, you’re taking valuable material out of the process.”
For its part, Avantor has been creating single-use systems that incorporate design features that make it easy to customize sampling systems to extract only the amount of material required to perform a test or document process results. “These designs are also much easier for plant personnel to use, helping reduce the time and labor costs associated with sampling,” Berrón states.
1. C. Challener, BioPharm International 27 (6) 34–36 (2014).
2. C. Hroncich, BioPharm International 29 (9) 28–33 (2016).
3. R. Jacquemart et al., Computational and Structural Biotechnology Journal 14, 309–318 (2016).
4. A. Xenopoulos, Journal of Biotechnology 213, 42–53 (2015).