January 15, 2013 (Vol. 33, No. 2)
Angelo DePalma Ph.D. Writer GEN
Judging from the session presentations at many bioprocessing conferences, single-use technology remains topical. All experts interviewed for this article say that disposables are growing in relevance, penetrating more deeply and broadly than ever into production at all scales.
Moreover the single-use idea is positively affecting how bioprocessors run their businesses, even how they set up and lay out production facilities.
Yet, despite growing adoption industry-wide, penetration of single-use equipment throughout large organizations has been uneven. Boehringer Ingelheim recently developed a program for applying disposable technologies globally—mostly during early-stage production—to ease process transfers between different locations while maintaining its quality standards at every facility. The company still uses stainless steel or hybrid equipment for 90% of its processes. Approximately 10% of products in Boehringer’s pipeline experience some form of transfer.
Michael Dieterle, Ph.D., associate director of purification development, presented a paper describing Boehringer’s initiative at Informa’s recent “Bioproduction” conference.
“In the past, disposables were adopted mainly for storage vessels that did not come into contact with product, e.g., bags for buffer storage. Today, the complete process is single-use.”
Sourcing Complete Systems
As more and more unit operations switch over to single-use, biopharm companies are outsourcing more of the fabrication of manifolded assemblies to OEMs like EMD Millipore, Sartorius Stedim Biotech, Pall, and Saint-Gobain. The assemblies may be up to 30 feet long, with up to 40 drops for bags, bottles, carboys, aseptic connectors, disconnectors, sensors, and probes—any operation that makes a bioprocess tick.
“Customers used to assemble these themselves, but their labor rates are much higher than ours,” says Saint-Gobain’s Christopher Shields. “Plus it’s not a core competency for them, so their efficiencies are not as good as ours, and they are generally unable to innovate in terms of design.”
According to Shields, who spoke at the meeting, Saint-Gobain’s business for complete manifolded assemblies has risen from 10–15% of the firm’s single-use business to fully half today. “It’s our fastest-growing market segment.”
The manifold story reflects the inroads single-use equipment has made into bioprocessing, but also underscores current limitations. While disposables are definitely mainstream, few processes employ them from start to finish and this, said Shields, is “due to difficulty getting every unit operation in single-use component form.”
To wit, Roche Diagnostics has deployed a single-use assembly from EMD Millipore in a multiproduct final filling suite for prefilled syringes. The suite also employs isolator technology to reduce reliance on classified space. Christian Matz, Ph.D., who heads the user group responsible for this project, says that this approach delivers several benefits related to efficiency and flexibility, but depends on a thorough qualification and validation approach designed to mitigate manufacturing and regulatory risk.
The Millipore equipment is delivered gamma-irradiated and fitted with all necessary connectors, filters, bags, filling needles, and tubing. A filtration step occurs between the compounding and storage vessels.
“The benefits in terms of efficiency and flexibility include reduced complexity on the filling line in the aseptic core and easy handling during setup since the main equipment sits outside the closed isolator system,” explained Dr. Matz.
Other benefits are expected from single-use filling: reduced risk of microbial contamination and cross-contamination, and a high level of flexibility for a multiproduct and multipurpose line.
Contract manufacturers need to balance flexibility with standardization, which is why Lonza continues to fine tune its GS Gene Expression System™ manufacturing platform, now available in Version 8. The platform incorporates Lonza’s chemically defined, animal component-free media and feed addition strategy. GS Gene Expression is designed to work with the GS-CHO cell line, for which Lonza claims yields of up to 9.6 g/L.
“Many CMOs have platform manufacturing technologies,” noted Lonza principal scientist David Valentine. Lonza’s technology is applicable from lab to manufacturing scale. “Platforms provide predictable performance. They’re the fastest, and most cost-effective approach and often do not require optimization.”
As the platform evolved over time, bioreactor designs have had to keep up with process demands. Single-use systems have been shown to enable the most flexible and fastest response to change. Also, their process controllers only require updates for their cell culture capability, and are not subject to additional complexity often involved in hardware modifications on stainless steel bioreactors.
Lonza will continue to improve its platform processes, but with CHO v. 8, said Valentine, the process “is as operationally complete as we want to go. It appears to be a good time to lock down the process, control systems, and bioreactor design. We’ve learned the limits of bioreactor technology.”
Lonza also accepts and runs “drop-in” processes, which are pre-existing, externally developed processes specified by customers. The bioreactor designs must also enable flexibility to accommodate such drop-in processes.
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.
Because bioprocesses constantly evolve, flexibility has become a sought-after characteristic, and one that single-use equipment increasingly serves.
“Even in commercial supply, processes and products will change over the 20-plus year lifespan of a commercial plant,” noted David Wilson, director of engineering operations at the Abbott Bioresearch Center.
Wilson described efforts at his facility to enhance flexibility at plants utilizing bioreactors of up to 20,000 L, but noted that the same ideas apply to nearly any plant, process, or scale.
Single-use equipment is one of more than 20 different “concepts” that may contribute to operational flexibility. Wilson suggested using those that work, applying them incrementally “as needed for a given area or unit operation.”
Adopting single-use equipment helps existing stainless steel-based plants produce new products, more products, or reduce the production cost of existing products. This can be achieved by supplementing the capabilities of existing stainless steel equipment, or by adding parallel production trains.
For example, if a new product requires an additional feed for a cell culture reactor, a single-use tank will fit the bill. Another example from Wilson involves staging media in single-use bags with disposable steam-on connectors to reduce bottlenecks in media prep and increase throughput.
“Flexibility concepts should be applied to all areas and operations,” Wilson added, mentioning generic batch records and recipe-driven configurable control systems as examples of add-ons to existing biopharmaceutical operations. “Space can be rearranged or processes closed for greater segregation, and workers can be trained to handle multiple products and different unit operations.”