The machine that makes the module
Xcellerex's FlexFactory platform includes enclosed unit operations that can be housed in an unclassified clean space.PHOTO:
COURTESY OF XCELLEREX
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Stainless-steel equipment. Biopharmaceutical production processes can be the same, whether a CMO uses a traditional or modular approach. Likewise, the
equipment inside the modules can be much the same as it is in a traditional facility. A modular facility can incorporate familiar
stainless-steel equipment. Likewise, a process skid of stainless-steel equipment can serve as a module. This equipment must
be easily movable, and CIP and SIP operations should be set up as part of the modular manufacturing process. "It would actually
be more efficient for stainless-steel equipment manufacturers to use modular designs so that their equipment allows for capacity
increases simply by adding modules," says Ron Trudeau, vice-president of facilities-engineering services at Baxter Healthcare
(Deerfield, IL).
One complication is that improved yields from high-producing cell lines may result in downstream product-pool volumes that
are larger than upstream volumes, thus creating the need for an array of large tanks for process pools and buffers. "The solution
is to apply a modular engineering approach and assemble these tanks as process modules that are still constructed and tested
off-site as entire modules, but are disassembled for transport and installation in the facility on location," says Niels Guldager,
senior consultant for bioprocess and technology of NNE PharmaPlan (Copenhagen).
Stainless-steel equipment alone is not the ideal approach to modular manufacturing, partly because it requires cleaning and
related downtime. Also, to attain flexibility, a CMO must buy a lot of stainless-steel machines up front. "You may get the
scale wrong—a lot of 10,000-L cell-culture vessels are standing idle today," says Eric Grund, senior director of biopharmaceutical
applications at GE Healthcare (Waukesha, WI). Some stains-steel components will always be required, he adds, but they can
be designed better to enable flexibility and ensure safety.
Single-use equipment. "It is the arrival of plug-and-play and ready-to-use components that is enabling most of the modular-manufacturing revolution,"
says Grund. Cleaning operations for reusable equipment entail the risk of cross contamination and, therefore, require development
effort. Procedures must be tested and validated and require extra utilities. Disposable, presterilized equipment solves these
problems by eliminating the need for cleaning and cleaning validation. In addition, disposable components enable rapid changeover
between batches or products and make it easier to establish multiproduct facilities.
Disposable equipment is increasingly available in a unit-operation format. Companies often can install these units within
six to eight weeks, which is much faster than they can install stainless-steel equipment, says Thomas Paust, global director
of marketing integrated solutions at Sartorius (Göttingen, Germany). The caveat is that disposable components that contact the product must be tested for extractables and leachables, qualified, and validated.
Single-use components facilitate modular manufacturing more than traditional equipment because they enable modules to be small
by reducing the amount of complex piping and resulting automation dramatically, says Xcellerex's Galliher. A module with less
complexity often is simpler, more reliable, and requires less operator training and maintenance.
Disposable media-preparation devices, cell-culture vessels, and harvesting equipment already are available, making it possible
for a CMO to establish a completely single-use upstream module. Downstream applications such as membrane chromatography for
protein purification are being accepted and validated for commercial processes, too. Sartorius soon will introduce a single-use
crossflow-filtration device that incorporates a disposable fluid path, pressure sensor, pressure valve, and flow sensor, says
Paust.
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