October 2, 2018 PAP-Q3-18-CL-008
Gene therapies have the potential to not only treat but also cure diseases that were once thought to be untreatable. Safety issues have long hindered the development of these next-generation therapies, but newer approaches have addressed these concerns, and early clinical results have been dramatic.
As a result, investigators and investors have both been attracted to this research area. In 2016, over 900 gene therapies were estimated to be in development for the treatment of a host of disorders.1 While the global gene therapy market was rather small in 2017, with an estimated value of $7.6 million, market research firm Grand View Research predicts it will expand at a compound annual growth rate above 19% through 2026.1
Traditional biopharmaceutical manufacturing facilities producing recombinant proteins and/or monoclonal antibodies (mAbs) tend to be engineered and constructed in a similar manner, regardless of the pharmaceutical company or design firm. In many cases, manufacturers develop platform technologies that allow use of the same equipment and processes across many product lines. These facilities typically operate in the biosafety level (BSL)-2 range, and most safety requirements are satisfied through compliance with good manufacturing practice (GMP) guidelines.
Gene therapy production facilities can be quite different. Platform technologies are typically not applicable, because processes for the production of these next-generation medicines can vary significantly, not just from company to company, but from one product to the next. Cell-based gene therapies can be highly personalized treatments produced on a patient-specific scale, versus larger-volume products like viral vector therapies that are manufactured with equipment similar to those associated with mAbs.
The level of containment required for gene therapy processes is much higher. Unlike mAb facilities, where the manufacturing controls are designed to protect the drug substance and drug product, controls in gene therapy production plants must also protect the operators and the environment.
The risk to operators is much higher because these products — viruses and viral vectors — are designed to invade human cells. A very different design paradigm is required as a result, and many manufacturers opt for “enhanced BSL-2," which can include BSL-3 facility design standards.
For BSL-1 and -2 facilities, most safety requirements are met via compliance with GMP requirements, such as segregated flows for materials and waste, air locks on clean rooms and segregation of laboratory spaces from general population flows. In many mAb facilities where significant segregation is not required, large ballroom operation areas containing several fully closed processes are becoming increasingly popular.
For “BSL-2+” and -3 facilities, however, the ballroom approach is not recommended; there are many additional design elements for segregation that must be incorporated. Examples include fully exhausted biosafety cabinets; full-room exhaustion; segregated air handling units with separate intake air; segregated material flows throughout the facility, including unidirectional flows in spaces where viruses and viral vectors are being manipulated; and full-room sterilization systems, which require welded steel ducting, various enhanced mechanical elements and equipment that can withstand fumigation chemicals, such as vaporous hydrogen peroxide (VHP) or chlorine dioxide. As a result, gene therapy facilities typically require additional floor space and have a larger footprint than mAb facilities of equivalent process scale.
Given that gene therapy is a new and evolving field within the pharmaceutical industry, an understanding of current regulations is essential.
Given that gene therapy is a new and evolving field within the pharmaceutical industry, an understanding of current regulations is essential. Many regulatory guidelines have been released or actively updated to include new information specific to gene therapy processes and products, in an attempt to keep the documents in line with the advancing science. It is critical to be aware of these guidelines and how to interpret them into compliant facility design.
Because gene therapy manufacturing processes can vary and require advanced engineering controls, an in-depth understanding of both the scale and flow of each process is also essential to ensure the design of compliant and efficient workspaces. Given that only a handful of gene therapy products have been approved for commercial sale, there is no real measurable industry benchmark for facility design and equipment selection comparable to what is available for mAb manufacturing.
The key, therefore, is that the facility design team possesses a deep understanding of current trends and developments with respect to gene therapy manufacturing. Knowledge about existing and upcoming facilities, in combination with current regulatory trends, will enable the design of a facility that is both cutting-edge and compliant.
The design team must also have extensive working knowledge of the mechanical design elements and engineering systems required to construct a BSL-2 to -3 facility. Full-room fumigation requires that a room be completely isolated, fumigated and fully exhausted, despite integration with the rest of the facility. In addition, door seals and other construction materials and equipment chosen for rooms that will be fumigated must be designed to withstand repeated exposure to the fumigation chemicals. Given the high level of integration within advanced gene therapy production facilities, improper choices can lead to the entire facility being shut down to make corrections, as it is often not possible to retrofit just one room.
Designing advanced, efficient and compliant gene therapy manufacturing facilities requires both expertise and the ability to apply existing technologies and systems in new ways, as well as an understanding of the driving forces behind regulatory recommendations and requirements. As we move into the new territory of gene therapy production, the first step is to establish a philosophy for how a facility should operate. Relevant building blocks can then be selected from existing and familiar facility designs.
For large-scale gene therapy manufacturing processes, equipment developed for mAb cell culture and purification can generally be transitioned, because many of the unit operations at larger scales are similar for both classes of biologics.
For personalized gene therapies produced on a patient-specific scale, however, there is a lack of commercially available advanced equipment. Manufacturers have typically fallen back on “antiquated” options, such as open flasks in high environmental classification biosafety cabinets using highly manual operations — processes that are highly prone to human error and contamination. The alternative — designing customized, advanced equipment — introduces a high level of risk.
There are few equipment solutions on the market for patient-specific applicability. At CRB, we are waiting for vendors to embrace this market. The development of advanced industry standards like those for larger-scale equipment will also have an impact. Moving from antiquated open, manual processes to closed, automated processes will significantly reduce the complexity of facility designs.
Facilities for gene therapy production are not straightforward and typically do not resemble facilities for mAb production.
To facilitate efficient facility designs, process development groups must adopt a commercial manufacturing mindset from the start. Sometimes, types and control of process conditions that ensure the best results in the lab only provide incremental improvements and are not practical for GMP commercial production application. Process development groups should have an understanding of how their processes will be both scaled out and scaled up and an appreciation for how defined parameter ranges and control definition will affect commercial process design.
Process development groups should try to frame process parameters, such as time constraints or transfer rates, in a form that can scale with volume or quantity in their process characterization. In addition, process development groups should be aware of the implications to the manufacturing equipment and facility design when they impose requirements on processes with respect to process temperature, hold times, mixing speed and flow rates.
Finally, process development groups should be aware of the significance of closed versus open processing and how their equipment models for development work can impact larger-scale processes. Open processing can only be performed at volumes that can reasonably be handled in biosafety cabinets, and even in these cases significant risk is introduced. Using scalable pieces of equipment even at small scale is important for developing efficient processes that can be incorporated into efficient and compliant facility designs.
At CRB, we recognize that facilities for gene therapy production are not straightforward and typically do not resemble facilities for mAb production. Gene therapy is a young field with rapidly evolving science and technology. Processes can change even after facility design work has been initiated. While designing a facility around a moving target is challenging, we have developed a flexible approach that enables accommodation of future facility needs.
Clients are encouraged to not only provide strong definitions of their processes with as much detail as possible on how they will be executed, but also identify the areas that are open to adjustment. In some cases, CRB carries multiple designs forward as long as possible before committing to just one — which requires an understanding of how late in the design period it is possible to postpone selection. Close communication with vendors is essential to have clarity on equipment lead times in order to identify drop-dead decision dates.
CRB designs flexible spaces, utilities and equipment based on our understanding of where potential future changes may occur. Examples include providing utility expandability, designing footprints for additional pieces of equipment or utilities, leaving routing paths for future piping and building connection points to limit future downtime. Flexibility is also needed when processes are transferred either from an operating company to a CMO, or from a CMO back to the pharmaceutical company as part of a growth strategy. In some cases, processes are transferred with incomplete information. CRB uses its knowledge of the gene therapy industry to fill in those blanks, and also designs flexibility into the process to accommodate a wide range of possibilities and future changes.
Peter Walters is a lead process engineer at CRB, specializing in biological process and facility design. He oversees conceptual and detailed design, multi-discipline coordination, and generation of design deliverables, including design narratives, P&IDs, material and energy balances, facility arrangement drawings, process simulations, cost analysis and specialized reports. Peter graduated from the University of California, Davis, with a degree in chemical/biochemical engineering. He is a Southern California native and enjoys playing soccer and spending time with his family in San Diego.
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