Stainless Steel Approach
Traditional stainless steel equipment is probably the best approach for large plants that produce a single, blockbuster monoclonal antibody product in ton quantities per year, with the cutoff for stainless vs. plastic somewhere in the 500–2,000 L working volume range.
Above 1,000 L, manufacturers must think seriously about factors other than simple scale, for example, legacy manufacturing systems, technology transfer from disposable to stainless, the likelihood that the molecule will be promoted, other pipeline drugs competing for manufacturing resources, and the related need for flexibility and agility. “There are lots of different scenarios and factors. You have to consider them all.”
GE has recently been pushing “smart” manufacturing approaches that combine stainless steel and plastic components and utilize those unit operations efficiently. Part of this effort has been “straight-through processing” enabled by QbD concepts and PAT technologies.
One straight-through strategy diverts column effluent directly from capture to ion-exchange columns, which eliminates the need for thousands of liters of buffer-storage capacity. Product from the ion-exchange column may then be filtered directly. Another approach involves mixing buffers directly, in-line, guided by precision dispensing pumps, sensors, and feedback control. A typical purification scheme taking three to four days can be reduced to 24 hours, Dr. Muranyi explains, and time savings are possible with all stainless, all disposable, or hybrid systems.
“Engineers are becoming more broad-minded when it comes to stainless steel and plastic, mixing and matching them for their particular situations, and applying process understanding to create efficiencies.”
Lack of Integration
Detlev Szarafinski, global program manager at Sartorius Stedim Biotech, maintains a list of challenges driving adoption of single-use bioprocess equipment, including reductions in cost-of-goods and increased flexibility; specialized capacity needs across global markets, for example greenfield facilities in Asia; the after-effects of mergers and restructuring in Europe and North America; and adoption of technology platforms.
Despite its use in niche markets and at certain scales, disposable bioprocessing has achieved only a 13% penetration in biomanufacturing. Companies producing large-scale proteins (particularly monoclonal antibodies) generally shy away from single-use.
Even the 13% figure is open to interpretation, Szarafinski says, because the overwhelming majority are hybrid processes—particularly when upstream and downstream operations are viewed together. Most disposable manufacturing processes use both fixed-tank and plastic components. “The number of fully disposable facilities is really low at the moment, but I’m convinced that the number will increase.”
One reason, Szarafinski explains, is the current lack of component integration within unit operations. “We talk about single-use components such as filters and bags, but these represent process steps. Our approach is to combine those steps into a process sequence or unit operation.” This general approach, he says, applies to single-use, hybrid, and reusable formats.
Sartorius Stedim Biotech’s FlexAct platform consists of custom-configured single-use products encompassing entire unit operations. FlexAct is based on a configurable, central operating module and specific components, for example, the currently available FlexAct BP for buffer preparation. Over the next year the company plans to introduce modules for media preparation, cell harvest, crossflow ultrafiltration/diafiltration, virus removal, virus inactivation, virus adsorption, polishing, formulation/filling, and formulation/ transfer.
Szarafinski raises important issues that are coming to the fore as industry adopts more single-use components and systems:
- Platform technologies and pre-assembled, presterilized systems may help mitigate regulatory and validation issues. Systems that are not pre-assembled are not necessarily ready to use despite the fact that their components may have been individually validated.
- Monitoring and control issues include the need to incorporate PAT into totally single-use and hybrid manufacturing systems.
- Integration of upstream and downstream single-use technology is lagging behind adoption at either end of the processing train. In addition, the emergence of hybrid (steel/plastic) systems underscores the need for aseptic connectors and tubing. Upstream-downstream integration is complicated by rising titers, particularly for antibody manufacturing.
- The supply chain can be problematic since single-use components are consumables and users must secure their supply throughout a campaign.
- Sustainability is more complicated than people realize. Although numerous analyses have demonstrated the green aspects of single-use process equipment, users must still formulate recycling and waste disposal strategies.
- Finally, cost savings have similarly been illustrated at certain scales and development stages, but users still must demonstrate process design and cost optimization for their specific process.
Platform technologies are of great interest to Dethardt Müller, Ph.D., group leader for technology development at Rentschler Biotechnologie. Dr. Müller says that modular combinations of “high-performance platform technologies enable robust, generic bioprocesses.” He is also interested in such operations as clone selection and expression through purification. According to Dr. Müller, the goals of such efforts are streamlining and reducing costs without adversely affecting yield or quality.