After an evaluation period during 2006 and 2007, comparing the full range of SUB scales against products manufactured in stainless steel, Lonza settled on Thermo Fisher as its primary SUB design, integrated to a Finesse TruBioDV process control system. Lonza uses off-the-shelf SUB hardware, but with some customization of the single-use bioreactor bag and control systems for Lonza’s platform processes.
All work with the same gassing and agitation but with sensors and connectors appropriate for the process. Lonza has internal capabilities to manufacture bioprocess container holding and storage operations, but no internal capability to manufacture bioreactor bags.
When Lonza first began evaluating SUBs, it made use of its capability of running pilot-scale batches in parallel, in both stainless steel and plastic.
“We built up a strong dataset of comparability with stainless steel,” said Valentine. Once they had 30 comparable batches under their belts, Lonza engineers invested in single-use GMP capability.
“We continue to see good comparability, after 80-plus batches in single-use bioreactors, for both our platform processes and drop-ins. Disposables of this type will not be a replacement for large-scale stainless steel for us. However, given the satisfactory comparability in performance, we are in a good position to take advantage of the benefits disposables offer. A product lifecycle can expect to see different reactor designs and materials of construction as it moves through lab, pilot, GMP early, through to late-phase manufacture.”
Like the CMO industry in general, Valentine sees the SUB marketplace as a balancing act between standardization and flexibility. Standardization brings lower cost and higher predictability, while flexibility allows rapid adjustment to changing needs, albeit at potentially higher unit prices for a nonstandard offering.
All commercial SUBs conform to regulatory and industry standards for materials of construction. Differentiation exists, said Valentine, with connectors, which for vendors are a point of differentiation.
While uniformity is desirable at some level, that is the domain of the vendor communities. End-users can only suggest standards. Reliably sourcing appropriate SUBs and other single-use equipment (“standard for Lonza”) that works with processes and control systems is standardization enough.
Nowhere is the issue of flexibility vs. standardization more apparent than in connectors and disconnectors—an area where improvisation in terms of assembly design remains difficult.
“There is no compatibility between vendors,” commented Jens Rumsfeld, head of application specialists for fluid management technologies at Sartorius Stedim Biotech. Selection of connector/disconnector depends in part on whether the bioprocess is all-disposable or hybrid (plastic and stainless steel).
For all-disposable systems the best approach is to stick with connectors provided by the container vendor, and attempt to source as much equipment as possible from one supplier. Rumsfeld calls the latter approach the “best option.” Currently six companies sell connectors and five offer single-use disconnect technologies.
Another compatibility option involves using the same thermoplastic tubing in assemblies of different vendors. Using thermal welding and sealing tools it is then possible to connect and disconnect single-use systems from the same and different suppliers, without a laminar flow hood.
This approach provides some degree of versatility, but at a cost: Companies will have to invest in a sealing system, and perhaps a dedicated laminar flow hood. The trade-off is between higher capital costs in this scenario, and higher cost of consumables/disposables when dedicated connectors are used.
Rumsfeld believes that before committing to a supplier, biomanufacturers need to examine the validation packages provided, to assure that they cover issues the end-user is likely to encounter.
“Users should be concerned about product robustness, supply, the vendor’s quality system, and ability to supply standard validation packages for standard tests such as leachables and extractables,” he explained.
Rumsfeld noted that volumes for large single-use systems has topped off at around 3,000 liters. “I don’t think we can go much farther than that in terms of size,” he said. While volumes may have reached a practical limit—at least for now—the penetration of single-use into biotech is still increasing. Disposables are doing best in low-volume production and during development stages, but many full-scale production processes now include some single-use equipment.
“Everyone knows the benefits now. At conferences a decade ago, vendors had to mention the advantages over and over. Now nobody has to, and even users are presenting spreadsheets illustrating cost savings and other benefits,” he said.