Shift to In Vivo CAR T Will Reshape Facility Design, Says Arcadis’ Emily Heffernan

As in vivo CAR T-cell therapies advance through clinical development, the shift raises a manufacturing question as well as a therapeutic one. In this first part of a two-part interview with BioPharm International®, Emily Heffernan, PE, director of new process technologies at Arcadis, explained how facility requirements change when developers move from ex vivo cell manufacturing to in vivo approaches delivered by viral vectors or lipid nanoparticles (LNPs).

“The facility really is going to change quite significantly if you’re going to go from a cell manufacturing facility, an ex vivo operation, to an in vivo operation using either a vector or an LNP-based therapy,” Heffernan said. “They’re very different facilities.”

At Arcadis, an architecture, engineering, and consulting firm, Heffernan focuses on life sciences, including newer modalities such as cell and gene therapies and mRNA, as well as the regulatory aspects of designing and building life sciences facilities.

How do facility requirements differ for cell therapy, viral vector, and mRNA-LNP manufacturing?

Scale is the first major difference. “Cell therapy facilities are going to be very small with individualized batch sizes,” Heffernan said. “So the equipment is bench top in nature, versus a LNP or a vector is more of a larger platform process.” Vector facilities in particular can move into large-scale bioreactors.

Each modality also brings its own facility risks. For viral vectors, cross-contamination is a central concern. “You don’t want those vectors to perhaps contaminate any other products that are being manufactured in the facility,” she said.

For mRNA and LNP manufacturing, the equipment itself can change. Where cell therapy and viral vector facilities rely primarily on single-use equipment, mRNA-LNP processes often use stainless steel, which may require clean-in-place and sterilize-in-place capability. The LNP formulation step also introduces a solvent hazard. “Ethanol is used in the manufacturing of LNP formulation, and so we have to have precautions in place to have those rooms electrically classified and to have the appropriate HVAC systems in place as well,” Heffernan said.

Despite these differences, Heffernan does not expect in vivo approaches to displace existing autologous products. “It doesn’t seem like ex vivo CAR T cell therapies are going to go away,” she said. “As in vivo CAR T advances through clinical trials, that is simply going to supplement the ex vivo CAR T cell therapies that are already approved.”

Facilities can be designed to manufacture both mRNA-LNP products and viral vectors, particularly lentiviral vector platforms, but Heffernan said this requires planning up front. A lentiviral vector process is typically larger in scale, with a true upstream cell culture stage using host cells, downstream purification, and potentially fill-finish. The mRNA process is more efficient and tends to be smaller, while LNP formulation requires ethanol handling to be built into the facility from the start.

In one facility Heffernan described, the design included an electrically classified anteroom off the downstream purification room “so that they could perform LNP there if they chose to bring mRNA products in house.”

The biological profiles of the two product types also differ. mRNA is a more synthetic product, while viral vector manufacturing uses human host cells and produces a biologically active product, often requiring biosafety level 2 (BSL-2) or BSL-2+ containment. “You’re definitely going to have some over design in a facility that’s going to accommodate both of those products in house versus a single product facility,” Heffernan said.

Quality control testing differs as well, most notably in the number of tests required. In ex vivo cell therapy, every batch is tied to an individual patient and must go through QC release testing. Because cell manufacturing is time-sensitive, product is sometimes released at risk.

Standardized in vivo platforms change that timeline. With a lentiviral or mRNA-LNP approach, “that is a batch that can be manufactured well in advance and be stored on a shelf until it is delivered to the patient,” Heffernan said. “So that allows for time of the full QC release testing before it is delivered to the patient, so that’s definitely an advantage.”

About the Speaker

Emily Heffernan, PE, US director, new process technologies at Arcadis
Emily Heffernan is a subject matter expert specializing in biological process and facility design. With more than 20 years’ experience, her expertise spans across multiple therapeutic areas including monoclonal antibodies, vaccines, cell and gene therapies, and RNA therapeutics. In her current role, Emily works with biotechnology companies to bring new and emerging life science technologies to market. She often works on projects that require creative solutions to scale up from pre-clinical development to commercial production. Emily holds degrees in both engineering and science, bringing a unique perspective to the table.