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The supply scenario for many biopharmaceutical drugs such as monoclonal antibodies (MAbs) is changing. With the implementation of personalized medicine resulting in drugs for specific, high-responder subsets of patients, market volume per drug will decrease. In addition, increasing fermentation titers of up to 10 g/L for MAbs are leading to smaller fermentation volumes necessary to accommodate individual biopharmaceutical market demands. That results in approaches such as flexible production in campaigns or decentralization of manufacturing using similar facilities with low risk of tech-transfer issues for regional markets.
In this regard, single-use technologies (disposables) play an important role in how biopharmaceutical development and production, particularly from mammalian cell culture, can nowadays be performed. Except for some large-scale unit operations such as centrifugation, chromatography skids, and UF/DF operations, all process steps can be performed in disposables up to a bag volume of around 3,000 L. Such steps include mixing, holding, and distribution of culture media and buffers; cell seed expansion; production fermentation; and cell removal by depth filtration, disposable chromatography columns, and UF/ DF/virus filtration. Although many single-use units have been an integral part of biomanufacturing for a long time now through integration into hard-piped set-ups (filters, and so on), the real progress toward completely disposable processing came with development of single-use bioreactors (SUBs). Several systems are now available up to a fermentation scale of 2,000 L. However, there are still limitations with single-use technologies, particularly in the areas of pretesting and the quality of disposables, standardization and qualification of bags and connections, and validation of leachables and extractables, as well as dependency on individual solutions from different vendors.
Advantages of Disposables
What are the major advantages of using disposables-based processing compared with standard production in a hard-piped, steel-tank–based setting? One major advantage is that presterilized single-use systems can be used in a laboratory-like environment. This is well suited for small-scale research and development activities, because no supporting engineering infrastructure regarding utilities, hard-piping, or automation (for example) is needed to set up and run such operations. This enables bioprocessing to be performed at a reasonable scale even in university laboratories. Another advantage is the time and cost savings in plant construction and operation. The main contributors here are lower capital costs; reduced consumption of utilities such as gas, electricity, and water (purified, WFI); no or limited hard-piping; and less-complex automation.
Time savings vary depending on the extent of disposables use. Most facilities still contain nondisposable unit operations. In hybrid designs, time savings in the early engineering project up to mechanical completion are sometimes marginal. But during start-up, including during
qualification and validation, time savings can be very pronounced (up to 70%) because equipment qualification using disposables is very limited, and no steam-in-place (SIP) and clean-in-place (CIP) processes are needed. Also the sometimes very lengthy cleaning validation of vessels and pipes that contact a product is not necessary for single-use because the bags are discarded after each run. Another advantage is the possibility to efficiently perform short product campaigns in multipurpose facilities, including fast product turnover by simply using new bags.
Addressing Limitations of Single-Use
On the other hand, a number of disadvantages, risks, and limitations of using disposables have to be addressed to make single-use-systems–based production a reliable alternative to standard production. First, there will always be a volume limit for handling and operating disposables. For fermentors and larger hold bags, that is expected to approach 3,000 L. For portable systems, the limit is currently in the range of 1,000 L. Another issue is standardization of single-use units and connections among vendors. Several integrated systems are being developed by individual suppliers, but those are not always compatible; that is, it is not possible to interconnect systems from different suppliers to a large, functionally closed processing unit. To comply with the desired second-supplier concept in biomanufacturing for SUBs, a company has to show biochemical comparability and consistent product quality in two bioreactor types before they can be used for commercial production. This is a substantial additional development and validation effort until two adequate systems are licensed. In addition, it is desired to get improved quality control by the suppliers. For example, bags should be pressure tested before delivery to reduce failure rates. It also would be advantageous to get full supporting validation packages, including extractables and leachables data as well as regulatory support files from the suppliers to make regulatory filing simpler.
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Many new developments for continuously improving technical support, materials, and quality of disposables are shown in the articles of this supplement, illustrating that single-use technology is still a rapidly evolving area. Promising contributions are being made by vendors to assure end users that manufacturing can be performed reliably and with high quality as needed for pharmaceutical applications.
There are several contributions in this issue to addressing quality and reliability of bag supply. Among these are the use of new plastic surface films with fewer side effects on cell growth, improvements in film robustness, and supply-assurance strategies. Other contributions address quality-control issues such as point-of-use bag testing and SUB qualification strategies. Finally, new processing approaches are shown such as use of disposables in design-of-experiments (DOE) studies, feeding strategies, concentrated cell banking to avoid open cell handling, and applications of single-use systems for continuous processing.
All together, these new developments show that single-use technologies are maturing so that the desired situation may become reality: a fully disposable production facility with closed systems in a GMP-lab– like environment as an alternative or supplement to standard hard-piped, steel-tank based production. This would fulfill the desire for easy and fast plant construction, simple and reliable operation, high flexibility, fast product turnover, low cost of goods, and easy technology transfer to different regions.
Dr. Berthold Boedeker is chief scientist at Bayer Pharma AG, GDD-GB-Biotech Development, Wuppertal, Germany; berthold.boedeker@bayer.com.