Designing Flexible Facilities for In Vivo Cell and Gene Therapies, Part 2

A single facility can be built to manufacture both lentiviral vectors and mRNA delivered by lipid nanoparticles (LNPs), but the two platforms place very different demands on its design. In the second part of a two-part interview with BioPharm International®, Emily Heffernan, PE, director of new process technologies at Arcadis, said multimodal plants have to be planned that way from the start.

“Facilities can be designed so that they can manufacture both LNP and mRNA as well as viral vector, particularly lentiviral vector platforms,” Heffernan said. “However, there are some differences, and there does need to be some planning up front.”

In the first part of the interview, Heffernan explained how facility scale, equipment, and containment change as developers move from ex vivo cell manufacturing to in vivo CAR T approaches delivered by viral vectors or LNPs. In this installment, she discussed how those differences play out when both platforms share one building, and how in vivo manufacturing affects quality control (QC) release testing.

What does it take to design one facility for both lentiviral vectors and mRNA-LNPs?

Scale is the starting point. Lentiviral vector production is a full bioprocess, with host cell culture upstream, purification downstream, and potentially fill-finish. “In general, the lentiviral vector is going to be much larger in scale, so it’s going to have a true upstream and downstream with cell culture using the host cells, and then a purification downstream as well as fill finish potentially,” Heffernan said. By comparison, “the mRNA process is much more efficient, so it tends to be a bit smaller in size.”

LNP formulation adds a hazard that vector suites do not typically need to accommodate. Because ethanol is used in the formulation step, rooms handling it must be electrically classified. “With LNP, there are the concerns around ethanol handling, so that needs to be built into the facility up front,” she said.

Heffernan described one facility that planned for this in advance. “They actually had an anteroom that was off the downstream purification room that was electrically classified, so that they could perform LNP there if they chose to bring mRNA products in house,” she said.

The biological profiles of the two product types also diverge. “mRNA is more synthetic, so there [are] really no biological concerns,” Heffernan said. A viral vector, by contrast, is produced in human host cells and is itself a biologically active product, often handled at biosafety level 2 (BSL-2) or BSL-2+. A facility built for both must meet the more demanding requirements, which means some degree of over-design compared with a plant dedicated to a single product.

Quality control is where the shift from ex vivo to in vivo manufacturing may be felt most directly. “There are definitely some differences in quality testing, probably most particularly in the quantity of tests that need to be performed,” Heffernan said.

In autologous ex vivo cell therapy, each batch starts from an individual patient’s cells, so each batch carries its own QC release testing. “Every batch is tied to a patient, and so every batch has to go through QC release testing,” she said. “Sometimes the product is released at risk just due to the time-sensitive nature of manufacturing cells.”

Standardized in vivo platforms decouple manufacturing from the individual patient. “With a more standardized platform, an in vivo approach like a lentiviral or an mRNA LNP, 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.”

Check out the first part of this interview here.

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.