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Jennifer Markarian is manufacturing editor of BioPharm International.
Modular building and process designs allow faster time to market for COVID-19 vaccines and treatments.
The COVID-19 pandemic has accelerated demand for quickly expanding capacity for manufacturing vaccines, including the facilities for viral vector production and for fill/finish. This capacity crunch is exacerbated because the industry was already capacity constrained before the pandemic began.
Running additional production campaigns in existing plants and adapting existing, suitable buildings for additional current good manufacturing practice (CGMP) lines are two avenues being taken for expanding fill/finish and existing virus- and vector-based vaccine processes, says Stefan Kappeler, technology manager of the global business unit, Biopharma & Life Sciences, at Exyte. For new vaccine platforms, such as mRNA vaccines, however, he says, “The short-term CGMP-compliant production is more difficult, as a completely new production and release process has to be designed and validated for the commercial scale, and then checked and approved by the national authorities.”
These new types of vaccines require new technologies and processes that have to be built from the ground up, and accomplished rapidly without interruption, adds Maik Jornitz, president and CEO of G-CON Manufacturing.
“Manufacturing capacity is the biggest hurdle for producing COVID-19 therapies right now. Companies with frontline options are scrambling to design and order equipment while in parallel designing and building the facility production space,” says Peter Walters, director of advanced therapy medicinal products (ATMP) at CRB. “Many of these therapies are based on pivoting process platforms, so development is being performed in parallel with design and construction of the facility, which makes flexible adaptable spaces so critical right now.”
Modular and prefabricated cleanrooms for manufacturing, which have been promoted for several years for the benefits of fast delivery and flexible capacity, stand ready to meet these needs. Modular process equipment is also finding use.
An established benefit of modular facilities is that they are constructed off-site and then delivered to the site where they will be put into use. Off-site construction has been shown to be particularly valuable under the limits imposed by the pandemic, says Jornitz.
“In an on-site construction, there may be a multitude of delays due to the limited headcount being allowed on-site, if at all. Off-site construction is not affected, because it is considered an essential business and has not stopped or slowed down since the start of the pandemic. As soon as the states opened travel, G-CON shipped four projects [of its prefabricated cleanroom PODs],” Jornitz reports. “The off-site prequalification also helps, as we can shorten the time and resources needed on-site, again to create the lowest headcount density needed and therefore lowest risk.”
The drive to produce COVID-19 vaccines and treatments has led to much faster building of cleanroom infrastructures and entire facilities than in the past, says Jornitz. “Delivery times of three to six months instead of years became the new normal, and this new normal will stay,” he predicts. He believes these short timelines are not unrealistic. “Any application could be predesigned to abbreviate the design timelines and can be prefabricated to stock to be much faster in the construction of the cleanroom infrastructure,” says Jornitz. G-CON introduced six standard cleanroom PODs that enabled them to shorten the delivery timeline further; these structures can be mass produced and then delivered from stock. Jornitz notes that, in addition to fast delivery, the industry requires reliable delivery timelines and robust cost budgets. “Too often we see a time and cost overrun, which puts any planning in jeopardy and cause a tremendous stress on project management. With off-site prefabrication, we avoid these overruns,” he notes.
Walters agrees that a key benefit of modular facilities is faster time to production compared to other construction models. “Use of fully modular cleanrooms allows a large bulk of the critical technical facility to be constructed in parallel with the remaining facility, creating a more compressed overall facility timeline,” he explains.
CRB’s SlateXpace was introduced in September 2020 as a “suite-based” modular facility design for cell and gene therapy. “SlateXpace is a templated production cleanroom platform to address the growing need for flexible multi-modal capability,” says Walters. “The platform has a pre-engineered design to accommodate changes in processing technology and processing platforms, while also providing consistent and easily scalable design. One big benefit of templated design is that it can provide greater cost predictability and certainty up front, with a more predictable and consistent construction schedule, both of which greatly help in early facility planning.”
Standardization of modular facilities allows replication, which is a faster route to operational availability either at the same manufacturing site or a different location, adds Kappeler. An additional benefit of facility replication is production consistency across a site or different locations. He notes that, in addition, Exyte’s ExyCell prefabricated cleanrooms have been designed to be flexible and configurable, so that the modular units can follow the optimized process flow.
Flexibility is another benefit of modular designs that allows companies to quickly add capacity to meet demand.
“One lesson from the current pandemic is the greater emphasis on security of supply and national independence. Modular systems enable the manufacturer to produce regionally on the required scale and thus to react flexibly to the current situation and local requirements,” says Kappeler. When vaccine manufacturing capacity is not in high demand, the facilities can be used instead for viral vectors for the ATMP sector, to combat neglected communicable diseases, or for animal vaccines. “At Exyte, we strive for a high degree of layout flexibility, process adaptability, and design standardization in plant design in order to convert and expand existing manufacturing capacities for new purposes,” he concludes.
“Designing in flexibility is paramount for the current manufacturing industry,” agrees Walters. “The ability to accommodate new processing technologies or swap to different processing platforms without a dramatic schedule-breaking renovation is where the industry needs to be headed to adapt to and accommodate the ever-changing and evolving product pipeline demands.”
Whether capacity constructed for COVID vaccines will be needed for short or longer term is unknown, says Jornitz, but the facilities can be used for other production if it is designed with containment, segregation and repurpose in mind. “Podular infrastructures have the benefit of being mobile, autonomous, and built for segregation. These units can either be used for other applications, moved to a different location where capacity is needed, or broken down to smaller segments for totally different needs. Repurposing cleanroom infrastructures is part of the total cost ownership value,” explains Jornitz.
The industry is moving toward the use of turnkey, predesigned facility platforms, says Jornitz. “Today, most of these facilities are piecemeal and at the end everybody hopes it will work, but it really all depends on the experience and capabilities of the project management,” he says. Moving to turnkey facilities reduces the dependence on project management and allows more predictability. G-CON and IPS partnered to offer the iCON turnkey modular facility platform solution for biomanufacturing, and Jornitz says it can be used for vaccine production. “It is a complete package, tying together the facility, utilities, cleanroom infrastructure, equipment, and automation,” explains Jornitz. G-CON also partnered with Pall to offer a viral vector manufacturing platform with process equipment from Pall inside a G-CON POD cleanroom. The platform is offered in four scales, from process development through CGMP clinical and commercial manufacturing.
In May 2020, Exyte and Univercells Technologies announced a partnership to deploy modular, standardized facilities for manufacturing vaccines (1). Univercells’ NevoLine vaccine manufacturing platform is an intensified process that uses continuous/semi-continuous process equipment with automation, and the small manufacturing footprint can be housed inside the ExyCell cleanroom. The facilities can be commissioned quickly, regardless of location, says Kappeler.
“Univercells’ process … allows an unprecedented reduction in the necessary scale and the required floor space. We see these developments as fundamental for future vaccine facilities, as they enable a significant downsizing of the plant design and a reduction in complexity regarding the provision of utilities or the biosafety level requirements for building and installations,” explains Kappeler.
The COVID-19 pandemic has put a spotlight on the need to be able to respond quickly and be better prepared for the next time. In the future, although some of the more traditional, large-scale processes for vaccine manufacturing may not see dramatic change, cell-based vaccines will have smaller, more flexible footprints with more single-use process technologies, suggests Jornitz. “We see a strong pull for in-country/for country manufacturing sites [that] are ultimately smaller and still meeting the capacity needs. COVID showed that dependency on supplies from other countries could jeopardize the fulfillment of healthcare needs in one’s own country. These types of facilities will see a higher utilization even with seasonal vaccine needs and could potentially be used for multi-product purposes,” he predicts.
“Companies need to have a way to pivot spaces between different production platforms without having to gut them and renovate every time,” says Walters. “Leveraging the flexibility of single-use technologies, equipment can be rearranged within flexible production spaces to allow for shifting to production of different products. Companies having more facility spaces with this level of flexibility in mind may just help set the stage for a more rapid industry response to the next global shortage.”