Flexibility, Automation, and Leadership: Drug-Sponsor Perspectives on Modern Biomanufacturing Facility Design

The title of this featured report — Smart(er) Facilities — came about in conversations with our KNect365 colleagues as they worked to plan this year’s BPI West conference, which took place 19–22 March 2018 in San Francisco, CA. For decades, biopharmaceutical facilities have incorporated cutting-edge designs for supporting processes, products, and human development. Each year, design innovations are rewarded for creating workspaces that facilitate both worker comfort and essential movement of promising drug candidates toward commercialization. In that context, biomanufacturing facilities around the world are getting smarter than ever before — applying a number of related definitions to the term smart — but that does not mean that one size fits all. In fact, a central theme behind most presentations at BPI West was that the more knowledge a company has about its products and processes, the smarter the decisions it can make about designing workspaces that capitalize on essential similarities, shared resources, and smart(er) transfer of process knowledge from stage to stage.

Flexibility
Like most industry buzzwords, the concept of flexibility in facility design (and design of unit operations) can benefit from deeper scrutiny. In general, most everyone agrees that modern biopharmaceutical companies need to plan for agility, flexibility, and mobility to respond quickly to market demands — with the capacity to respond to market demand (e.g., pandemics) and prevent drug shortages, while avoiding overproduction as well. Business drivers for flexible designs include cost pressures and needs for managing complex supply chains for multiproduct facility use.

Successful biopharmaceutical facilities of the future will need to respond to unknowns affecting sites in different geographical locations. As markets around the world experience growing and aging populations, their needs for drug products increase. In a number of regions, a rising middle class in need of healthcare and increasingly able to afford medicine encourages in-country manufacturing to control the cost of those medicines for local populations. Many governments have instituted price-control measures that make it necessary for drug sponsors to keep cost in mind while supplying those controlled markets.

End-user needs for smart facility design were nicely encapsulated by Jeffrey Johnson (director and new technology lead in global engineering solutions at Merck & Co., Inc.) who spoke at BPI West on a “Large-Scale Single-Use Bulk Drug Substance Freeze and Thaw Platform.” When we talked about it, he noted that future biotech drugs are likely to be targeted to smaller patient populations (personalized medicines) and that future modalities such as antibody fragments and antibody–drug conjugates may well result in lower drug substance demand. To prepare for such a future, biofacilities will need to be highly flexible, with modular-plug-and-play equipment skids that enable very rapid changeover between products and processes. He explained modular as “very lightweight equipment (such as single-use equipment) with very limited connections (no clean- or steam-in place).”

By plug-and-play, he means use of simple automation and information technology (IT) requirements with limited data and control connections through standardized quick-connect plugs into an IT infrastructure that can accept those rapid and flexible skids. Connections need to be made with minimal requirements for configuration between changeover.” He noted that current technologies still focus on traditional fixed equipment — and that the more automation is added, the more fixed and difficult systems can be to change out. End users need to work with equipment and automation suppliers to develop the flexible facilities that the industry’s future will require. Johnson pointed to current publications on these issues by groups such as the Biophorum Operations Group (BPOG).

In a keynote address on “Future Facility Design Considerations with Single-Use Based on Prior Experience,” Ken Green (head of manufacturing science and technology at Shire) encapsulated a number of key elements that are driving smarter approaches to facility design — elements that center on implementing single-use and modular technologies. He noted that increasing focus on supply assurance and manufacturing costs are driving driving improved biofacility use by reducing processing times, increasing batch cycle cadence, and shortening maintenance and changeover times. Adoption of single-use and/or modular systems provides facility flexibility by enabling diverse process technologies and volumes with rapid process and product changeover.

Green also noted the advantages of manufacturing clinical and commercial products within the same manufacturing facility, introducing options to maximize available capacity. Although challenges can come with implementing phase-appropriate operational and quality system, he said that “the flexibility to manage lower production volumes driven by advances in host cell productivity and targeted patient therapies is complementary, with available sizing for single-use equipment and options for ‘plug and play’ operations. Advances in robust and scalable single-use technologies also provide effective process platforms for scale-up and efficient technology transfer, enabling faster development cycles and speed to launch. Advances in automation and IT also significantly enhance manufacturing operations such as deployment of manufacturing execution systems (MES), data acquisition, and analytics.”

Modularity: Clearly single-use equipment is not the only component that drives increased flexibility, although it has arguably been the primary enabler of efforts to reduce operating cost and facility footprints. Other options for flexible designs of production and processing suites include modular designs and pods — whether in combination with an open of “ballroom” design or as part of a more traditional floor plan. Efforts toward process intensification also can reduce a facility footprint by enabling continuous unit operations, automation, and shared resources. Newer classes of biologics (autologous therapies, for example) are likely to be produced at smaller scales than traditional protein therapeutics have been, lessening capacity concerns whether in-house or outsourced.

Modular options enable speed of setup for biomanufacturing operations. They can reduce and lessen risk by providing closed, self-contained spaces within a larger facility. They also enable vertical expansion, maintaining an original footprint — a facility can expand up instead of out. But as BPI West speakers from G-CON (Dennis Powers, director of sales engineering, and Sue Behrens, senior director of process design) pointed out, modular construction does not necessarily improve flexibility. Once brought to a site and assembled in place, modules might be connected to one another and/or to water-for-injection (WFI) and other utility systems — thus becoming less conducive to scaling and reproduction. So they may be most convenient as components for installing new operations or retrofitting older facilities.

The Swedish company Pharmadule was an early proponent of modular bioprocessing units, helping to pave the way for it beginning in the mid- to late 1980s. According to the company’s website, 70 projects have benefited from its modular concepts for companies such as Eli Lilly, Merck, Baxter, GlaxoSmithKline, Genentech (Roche), Pharmacia, and AstraZeneca. Other design and construction advances followed suit, the most notable being GE’s KUbio modular technology, which has been profiled in a number of recent reports about construction of a facility in Wuhan, China, in collaboration with JHL.

In that project, 62 modules were transported by ship and truck to the Chinese site, then assembled into a single structure in only eight days. In parallel processes, the modules had been assembled in a controlled environment, each unit equipped with specific materials needed for that specific room in the finished facility. Installation of electrical, water, and ventilation equipment and factory acceptance testing were performed before transport. Process equipment was manufactured and tested at GE before the modules shipped. Simultaneously, JHL prepared the Wuhan site for their arrival. Once the modules were assembled, an on-site team completed the facility’s exterior and certified the KUBio module’s readiness for installation of 250 pretested GE FlexFactory processing components. This project has been profiled in a number of publications (1).

Modular designs can enable rapid facility construction, but they are not the only option for ensuring flexibility in design. Any biopharmaceutical company exploring alternatives to facility design and construction must examine the technical needs of its own unit operations and analyze associated assumptions about process platforms — what equipment and utilities are needed, for example, that might be shared. An alternative design option was presented in a G-CON presentation, “A Suite-Focused Flexible Facility Design for Biologics Production.”

In such a facility, different modes of operation would be accessible through the use of hybrid modular pods as self-contained units or building blocks that house segregated unit operations. As the company website says, G-CON Pod systems are “prefabricated, turnkey cleanroom systems” equipped with deployable, mobile, and scalable cleanrooms that can be placed inside buildings. The use of such units may be ideal for multiproduct sites, operations with rigorous containment needs, and on-demand scaling of production and laboratory space.

When a completed unit is delivered, connections are made quickly to water and electricity on the Pod exteriors. Each enclosure then is completely self-contained and simple to maintain, “replacing the need for sophisticated and expansive purpose-built facilities that require specialized maintenance” (2).

Another company, Just Biotherapeutics, also creates and configures self-contained modules as small, intensified bioprocessing units that reduce expensive manufacturing space and overall plant size. According to the company website, these pods are designed with disposable technologies and intensified processes to create flexible and relatively low-cost biomanufacturing facilities that minimize technology transfer risks.

Leadership: Managing People and Working Environments
When I spoke with Paul Ko (senior scientist in cell technologies for large molecule APIs at Janssen R&D) at BPI West, he also emphasized the need for modern facilities to adapt quickly to manufacturing needs that may not be shared by more than one product or type of product. Ko spoke at the conference on “Evolution of a Flexible Development Facility to Accommodate the Increasingly Fast-Paced Pharmaceutical Landscape.” He explained that his company’s operational suite is “quite open, with the goal of containing as many related process steps as possible in one room” and encouraging interactions between upstream and downstream teams. As product leader, his goal is to enhance that collaboration and communication. But he also pointed out that one design may not fit all needed processes in a multiproduct facility and that closed systems are still advisable for producing some products, such as certain cell therapies and vaccines.

Encouraging Creativity/Teamwork Through Facility Design: At the start of his keynote presentation on “Achieving Efficiency through a Comprehensive Approach to Facility, Organization, and Process Design,” Jason Bock (vice president of biologics CMC at Teva Pharmaceuticals) reminded the audience that the role of leadership is to create a space in which people can do their best work. He and other presenters noted that some external factors driving creation of “smart” facilities include manufacturing in regions that support life-science businesses and educational development. Along with appropriate regional infrastructure, technologies that enable rapid setup anywhere in the world through modular units can help provide essential flexibility toward manufacturing for local populations and meeting emergency needs.

One question, though, is how companies are striking a balance between encouraging collaboration through open facility designs and allowing employees the necessary room to focus and concentrate. Shire’s Green says that “open facilities ease personnel and material management flow with improved ergonomic and environmental aspects. In addition, open facilities potentially allow the flexibility for multiple operations and/or products within the same area. The application of lean management tools such as visual performance, value stream mapping, standard work, and gemba walks (3) have enhanced colleague collaboration and performance management. Open office space is increasingly becoming the norm, with a balance of common and private areas to encourage engagement and collaboration while allowing spaces to conduct private meetings as required.”

But one size has never fit all in the biopharmaceutical industry. The existence of relevant infrastructure that provides an educated workforce and a regional support network of suppliers and service providers also is an important factor behind facility design and location. As Green points out, “many companies have close collaboration with academia, including opportunities for personal interactions that include internships, secondments, and graduate programs. The options to provide facility/laboratory space are evolving through partnerships, leasing arrangements, or company sponsorship for laboratory space initiatives. A close industry– academic collaboration is a key driver for future success and is exemplified by biotech/academics within industry hubs in San Francisco and Boston.”

The attraction that such hubs can offer may lead some companies back toward the design of centralized sites — still taking advantage of open and collaborative designs within those facilities — and perhaps to the best of both worlds for some smaller companies. That has been the case with Teva, which was the subject of Bock’s keynote address. His company decided to revert from a highly decentralized to a centralized site for biologics development in Westchester, PA. The idea was to take advantage of the company’s small size to create better, clearer handoffs between upstream and downstream processes while removing ambiguities in accountability.

As he described it, Teva created one US group focusing on development and operations to which all other groups report. The approach is based on intentional engineering-in of efficiencies and solutions, a strategy that encourages and rewards cooperation and simplifies the dynamics of information exchange among employees. They approach their work in two major cycles of activities: platform development (for speeding toxicology and other early stage processes) and a second cycle focusing on scale-up and manufacturability. Bock described the overall strategy as “internalized manufacturing from end to end,” in which a facility is designed toward improving “adjacencies” rather than relying on a ballroom design or sequestration of process stages/operations in now old-fashioned operational “silos.”

Teva staff get proximity to cell banks and drug substance and drug product manufacturing through available smaller-footprint technologies (e.g., using a GE FlexFactory system and other single-use technologies). Media and buffers are “piped through the wall” as needed. Working groups intentionally are given opportunities for interaction: Bock described a layout in which like groups (e.g., quality personnel, up- and downstream operations managers) are seated together so that process scientists can walk past them on the way into the building and thus approach one group for multiple input from all those involved in a given project. Employees can park their cars near entrances near to their own work areas, but they also can interact easily and quickly with other support teams. The recognition that physical barriers to work flows and knowledge exchange can impede success led to designs that encourage people to collaborate under a philosophy that could be referred to as “transparency by design.”

To ease technology transfer, an expert (along with his or her knowledge) is transferred together with a process to decrease both time and risk in moving it along. Manufacturing staff thus participate with development groups to make a toxicology batch, and the manufacturing team is joined by someone from product development — who is of course trained in SOPs and then goes on to participate in the next stages of manufacturing. Such knowledge transfer also brings challenges back to process development laboratories, thus internalizing what otherwise would be the company’s far-flung experiences.

Shared Circumstances, Many Solutions
I’ve highlighted just a few examples of modern biopharmaceutical facility concepts in which people, processes, and products benefit from smarter integrated technologies as well as improved relationships among colleagues. It is clear that smart facility designers can strive to create simplicity rather than reflect the increasing complexity of new systems and product categories. The many connotations of smart involved here include modular, single-use, automated, and other technological solutions that improve collaboration and teamwork while making the best of individual expertise, all with an eye toward future needs.

References
1 MacDonald G. JHL Completes Assembly of GE-Built Off-the-Shelf Plant in Wuhan, China. BioPharma-Reporter.com 29 February 2916; www.biopharma-reporter.com/Article/2016/02/29/JHL-completes-assembly-of-GE-built-off-the-shelf-plant-in-Wuhan-China.

2 G-Con Manufacturing. Bioprocess Online www.bioprocessonline.com/ecommcenter/gcon.

3 Lindquist R. The Many Sides of a Gemba Walk. iSixSigma 2018; www.isixsigma.com/methodology/lean-methodology/many-sides-gemba-walk.

S. Anne Montgomery is cofounder and editor in chief of BioProcess International; PO Box 70, Dexter, OR 97431; [email protected].