January 15, 2015 (Vol. 35, No. 2)

Modular Facilities Get Creative, from Beating Resource Constraints to Innovating Processes

The concept of modular pharmaceutical manufacturing facilities began in the 1980s with the advent of plants designed and built to be disassembled as multiple shipping containers, transported to a prepared foundation site, then reassembled and reconnected with locally supplied utilities. “Pipework connections between modules was a critical challenge,” says Jerold Martin, senior vice president, global scientific affairs, Pall Life Sciences. “But the advent of single-use technologies eliminated the need for complex pipework”

The result, elaborates Martin, is “a simpler modular concept of prefabricated open suites filled with single-use systems such as mixing, media and buffer filtration, bioreactors, cell harvesting, and purification.” Pall and other leading suppliers are working with clients and engineering companies to apply this idea to the global manufacture of biotherapeutics and vaccines for both developed and emerging economy countries.

Modular design/construction makes sense under several scenarios. Conventionally, biomanufacturing plants take three to four years to build and commission, whereas modular facilities take one-and-a-half years or less. “So when speed is of the essence, modular is the way to go,” comments Olivier Loeillot, general manager, bioprocessing in Asia, GE Healthcare Life Sciences.

Modular design lessens the skill level required to get a new bioprocessing plant up and running. This is particular beneficial in countries or regions that lack a construction workforce experienced in ducting, electrical work, HVAC, and clean rooms.

Modularity also supplies consistency across geography. “Companies that wish to install nearly identical manufacturing plants in several different locations can achieve this only through modularization,” Loeillot says. “Companies may begin with a modular approach and then, later on, duplicate the original plant at different locations around the world.”

Addressing Supply Insecurity

Security of supply is a related need. At a 2011 World Health Organization conference, GE identified vaccines, biosimilars, plasma, and insulin as critical markets where local production could make a difference during emergencies. The vaccine pandemic scenario is familiar to GEN readers. For biosimilars, modularization can assist in delivering platform facilities that at one level provide consistency, but on another may be tweaked to meet local regulatory requirements.

“Modular facilities are economical everywhere, but they are usually mentioned in the context of limited resources, for example developing countries,” asserts Rachael Felberbaum, Ph.D., director, corporate communications and shareholder relations, Protein Sciences. “Flexible, modular facilities can make flu vaccine before flu season, and other vaccines for diseases endemic to the region at other times. The infrastructure would be in place for any emergency, without the need to invest in a separate facility.”

Prefabricated module assembly on site. [M+W Group]

Recognizing Limitations

Whereas time to market is the most-cited driver for going modular, consistency may be equally critical. That, at least, is the view of Josef Trapl, global technology manager, M+W Group, a company in the process of launching the first “off the shelf” biotech facility in China. “A high degree of design standardization is possible,” notes Trapl,  “particularly when the process comes from a predefined platform.” Modularization reduces project risk when executing a project in a country where qualified workforces are unavailable or where import restrictions are in force.

In principle, any type of processing may occur within a modular facility. Practically speaking though, deployments tend to house small to mid-size pilot plants or clinical trial production facilities. Alternatively, in the case of vaccines, deployments tend to produce relatively small batches of highly potent products.

Modular plants are not without their limitations. Size and logistics—how to transport and deliver such a facility to a location where basic utilities are available, for example—limit facility location. Since the modules are prefabricated and predesigned, flexibility in terms of on-site modifications may be limited as well, as are subsequent redesigns later in the facility’s lifecycle.

Moreover, for processes requiring a high degree of customization, or where process equipment has a long delivery lead time, the advantage compared to a conventional build approach is difficult to assess. “The location and contract strategy can have also a significant impact on the delivery,” Trapl advises.

Platform technologies can play a huge role in the design, integration of process equipment, and execution of highly standardized, modularized facilities. “The platform can be viewed as a toolbox, and the interfaces or so-called hook ups, which are the connections between the process equipment modules and facility modules, can be standardized and easily connected and disconnected,” explains Trapl. “In an ideal case, this can result in a highly flexible manufacturing plant out of the box with plug-and-play process equipment and skids.”

Modular Facilities, Modular Processes

Truly modular facilities would probably not be possible without equally flexible platform unit operations. Single-use equipment is just one enabling technology.

“It makes sense to pair modular or platform processes with modular facilities,” says Protein Sciences’ Dr. Felberbaum, who adds that her company produces the licensed, hemagglutinin-based FluBlok® vaccine through insect cell culture. All the company’s products are made via its expressSF+ insect cell line, so the same equipment is used throughout—a boost for modularization. “The only thing that changes is the baculovirus transfection agent.”

Emerging process trends and new product understandings are contributing to a new set of goals in bioprocess platform development, maintains William Whitford, senior manager, cell culture, GE Healthcare. He mentions high-throughput screening, omics, metabolic flux analysis, and advanced modeling as approaches that “are yielding fruit.”

“From a business perspective, there is heightened demand for process flexibility, technology transfer, and outsourcing ease, Whitford says. In addition, there is an appreciation of “the economic considerations consequent to increased globalization of manufacturing and follow-on entities.”

Upstream, high titers support the scale of single-use technology, fed-batch, and now intensified-perfusion approaches. Downstream, new equipment and technology from single-use heat exchangers, centrifuges, depth and diafiltration, to continuous-countercurrent multicolumn chromatography augurs the possibility of entirely disposable protein biological purification trains.

“We are now seeing the orchestration of such incremental advances to support a synergy of the efficiency, scale, connectivity, and reduced risk contributed by each component,” Whitford observes. “In fact, technology has progressed to the point that pre-engineered, modular, modular microenvironment, and turn-key facilities with discrete and limited classified space are within reach.”

This is evident in modular microenvironments, controlled environmental modules, dedicated isolator cabinets or chambers, and even prefabricated trailers or pods. He expects that as this trend toward flexible modules and plug-and-play factories continues, modular facilities will become available with higher-level integrated system management.

Continuous processing is another generally enabling technology that Whitford believes will further help promote modular facilities: “Continuous processing at large scale has increased dramatically of late, to the extent that many now predict its eventual dominance.” This is in part due to its ability to support process intensification, which is highly desirable in modular facilities.

Operationally, the time-effected product mass accumulation inherent in continuous processing allows for a continuously variable manufacturing rate and inherently promotes “scaling out” or “numbering up” to increase maximum capacity—another must-have for flexible, efficient, multiproduct modular facilities. “Continuous processing contributes to overall process flexibility in that equipment is easy to clean, inspect, and maintain,” Whitford remarks. “Plus it facilitates ease of product changeover because it tends to be more modular, reconfigurable, and transportable.”

Scientists Katia Esqueda and Cuitlahuac Chavez-Pena evaluate a digital chromatogram following a purification run in the product realization laboratory at Protein Sciences. [Meredith Gazdzinski]

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