November 1, 2018 (Vol. 38, No. 19)

The pharmaceutical and biopharmaceutical industry needs to execute a shift from large-volume, single-product processes to small-volume, multiproduct processes. The shift is not restricted to development-stage activities. It extends to commercial-stage operations. Flexibility in accomplishing the shift will help biomanufacturers hit capacity targets, optimize facility utilization, and stay competitive.

With higher expression rates, cell culture processes that used to require 10,000–20,000-L bioreactors can now move to lower volumes. Smaller volumes permit the use of single-use technologies, as the maximum volume applicable to single-use bioreactor technologies is around 2000 L.

Large-scale, stainless-steel systems carry inherent risks. For example, large systems may be difficult to set up and clean, and they may cause facilities to become dedicated to only one product. Also, if these systems become contaminated, large bioreactor volumes are lost.

These risks can be reduced if multiple small-volume systems are installed. Smaller volumes may be processed more simply with the benefit of single-use components or unit operations. And if contamination occurs, it is possible to limit product and therefore financial losses.

Not too long ago, single-use equipment components within the pharmaceutical and biopharmaceutical industry were admired for their novelty and innovation but still viewed with skepticism. Nowadays, single-use equipment is widely utilized and an integral part of upstream and downstream processing.

Furthermore, the focus of single-use technology utilization is shifting from biopharmaceutical processes to aseptic processing streams in cell and gene therapies. Anywhere containment is a priority—inside a process, where product needs to be protected, or outside the facility, where the environment must be guarded—single-use technology is the process technology of choice. In addition, there is an urge to enhance flexibility, shorten batch cycle times, avoid cleaning validations, and reduce utility costs.

Uses of Single-Use Process Technology

Single-use technology vendors are numerous and diverse, delivering processes, unit operations, or specifically focused components, giving end-users a multitude of options for supplies and equipment. Options range from simple bags to bag/filter/tubing/valve/aseptic connector assemblies to entire unit operations, whether for cell culture or virus inactivation, to just name two processes.

Through their engineering and design functions, single-use process technology vendors are defining processing platforms for specific applications and rapidly deploying new processes when required. They are also providing scalability, with cell culture expanding to volumes as large as 2000 L, or shrinking, potentially, to volumes of 200–500 L, given the rapid evolution to continuous bioprocessing.

In single-use systems, the critical fluid path may be protected within a cleanroom area. Outside this area, media and buffer supplies may be held until they are needed. Then, they may be fed through ports to the point of use. With single-use process technology, specific cleaning and sterilization areas are unnecessary, so process designs show much smaller footprints. Water use is drastically reduced, which means that utility spaces can be condensed. Essentially, single-use process technology enables process intensification—allowing cleanroom infrastructures and entire facility layouts to become smaller.

Furthermore, single-use process technology creates solid containment options to protect the processed drug product, to utilize a facility as a multiproduct process, and to safeguard the personnel and environment of the facility. The containment requirement is becoming a focus with new therapies being introduced within the cell and gene therapy sector.

Fluid streams within these applications often cannot be finally sterilized, and therefore the entire process must be safeguarded by appropriate containment options, one of them being single-use process equipment. Fluid volumes within the cell therapy area are very small (batches being patient based), and contaminations would be detrimental. From needle to needle, the technologies used to process patient samples must not only support flexibility but also provide robust containment.

Single-use process technology is also changing cleanroom classifications. For example, new bioprocess facilities are designed into ballroom infrastructures, which are run at ISO 9 classification. The single-use process technology in this case is regarded as a closed system, which allows the reduced cleanroom rating.

From Single-Use Process Technologies to Modular Facilities

Because facilities and processes are distinctly different, they must be designed and constructed in different ways. A facility is not necessarily flexible just because the process employs single-use technology. The opposite is often true. Traditional facility layouts may void the flexibility of single-use processes, since these processes are often mobile.

If the layout of the facility does not allow easy access or movement, the benefits of flexible process equipment are squandered. For example, if a cleanroom space is built to house one fermenter and one tank with no allowance for other equipment or additional personnel, and the required cleanroom ductwork is interconnected into the cleanroom from the larger facility area, a change as small as the addition of a second fermenter or tank could result in having to rebuild the entire room. If, however, the cleanroom is built with its own air handler, and if the process requires the addition of another fermenter and tank, a second cleanroom can be added easily without interrupting the existing process.

The ability to scale cleanroom infrastructures without interrupting existing processes may become a priority during bioprocessing or the production of personalized medicines. When demand grows, so must the manufacturing area, the expansion of which should not conflict with existing capacities. If, however, the cleanroom infrastructure is not modular and autonomous, that is, if it lacks its own air handling system and automation, any expansion will cause major disruptions.

That said, single-use technology has been and is an enabler for designing more flexible and confined manufacturing areas. Process intensification and the shrinking of the manufacturing footprint have facilitated the design of cleanroom modules that can be built off site, prequalified, and moved into a shell building when ready (Figure 1).

The cleanroom infrastructure build is much faster, and delivery time and cost estimates prove reliable enough to satisfy industry demands. Delivery time and cost estimates are robust because off-site construction teams can work flexibly, shifting to higher productivity levels or reconfiguring schedules if necessary, and because modular/podular cleanroom infrastructure units can be moved in rapidly.

Figure 1. Podular cleanroom cluster (14 PODs built in eight months, installed in three days)

There are times when clients awaiting delivery of prefabricated structure request that delivery be delayed. For example, one such client, after learning that a shell building was unavailable, asked to delay its project three months. Then the client changed its mind again and asked for the original delivery date to be reinstated. With the off-site build approach, such requests can be met without additional costs. In the case just cited, the client was accommodated by deploying additional resources and utilizing overtime. Instead of an on-site productivity level of typically 80%, an off-site build can run at a productivity level of 100–140%—without working in shifts.

The idea that prefabricated solutions enable more robust planning may be developed yet further. New, predesigned, turnkey facility solutions are now being established to shorten the build time and reduce the cost impact by creating standardized options (Figure 2). As an example, a 4 × 2000 L mAb turnkey site can be built in 12 months versus 24–36 months at an all-in price tag of $75 million instead of $200–300 million.

Transitioning one’s thinking from standardized, prefabricated cleanroom units to predesigned turnkey facilities does not require a conceptual leap, only a small change in mindset to a standardized, off-the-shelf approach. Instead of spending many hours on new designs, instead of reinventing the wheel, one may proceed more simply and directly. By following the standardized, off-the-shelf approach, one may shorten design and build times, acquire valuable experience, and reduce costs.

Figure 2. Predesigned, turnkey facility solution for multiple scales of mAb production (iCON™)

Conclusion

Facility design requirements are evolving just as bioprocess technologies did in the transformation from stainless steel to flexible and agile single-use process technologies. These innovative technologies have created new opportunities for facilities, and modular solutions are clearly part of the new facility future. Facilities and processes are approaching a crossroads. Processes are shifting from multiuse to single-use, and facilities are moving from single-use (product dedicated) to multiuse (multiproduct).

Flexible processes lose their flexibility if they are forced into uncompromising, inflexible facility and cleanroom infrastructures. Total flexibility is achieved, however, when flexible processes are fused with flexible facilities. The cleanroom enclosures can be smaller, produced in assembly-line fashion, and completed in shorter timeframes. They can also be more readily repurposed or scaled.

Some major pharmaceutical companies and architecture and engineering firms have started to embrace the modular cleanroom revolution, recognizing that the familiar “brick-and-mortar” and “stick-built” approaches have succumbed to advances in technology. It is expected that more adopters will follow, leading to additional growth and collaboration in the modular space.

The future holds promise for turnkey solutions that speed the design and building of biomanufacturing facilities. Such solutions allow biomanufacturers to delay capital decisions and expedite capacity gains. Traditional structures do not reduce capital expenditures and operating costs, but rather decrease the competitive advantage of the operation.

Maik W. Jornitz is president and CEO of G-CON Manufacturing.

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