Where some gene therapy players might “go big” and put down brick and mortar facilities, Avrobio went the opposite direction.
The biotech's portable manufacturing units are automated, self-contained and tailored to the company’s specific ex-vivo lentiviral process. They’re also about as big as a washing machine.
The units can run in parallel, and because they’re self-contained—which effectively means the drug product isn’t exposed to the outside environment—they can be set up in lower-class clean rooms, Kim Raineri, chief manufacturing and technology officer at Avrobio, said. Eventually, the company could set up “ballrooms” of machines to make gene therapies across its pipeline in the same facility, he said.
That isn't typical. For most cell and gene therapies, teams of highly trained workers spend weeks on each patient’s treatment in top-grade clean rooms, churning out mountains of batch records in a pricey endeavor that often amounts to just a few thousand doses a year.
There are now 22 cell and gene therapies of various kinds approved in the U.S., according to a recent FDA tally. With hundreds of companies ushering their own prospects toward the clinic, that number is expected to skyrocket over the next decade.
“The clinical and scientific case for cell and gene therapies has been proven,” Jason Foster, CEO at Ori Biotech, which is developing a platform to automate cell and gene manufacturing, said in an interview. “We can actually make these products … but right now we just can’t make them widely available for patients,” he said in an interview.
Current cell and gene manufacturing needs to catch up fast to help make the next wave of products at scale. Approaches like automation, robotics and point-of-care manufacturing, packaged in small-but-mighty production setups, could hold the key.
The CGT skinny
Not all cell and gene therapies are made the same, of course, but the process typically works like this: First, a patient’s cells are harvested in a process called apheresis. Autologous therapies are made from a patient’s own cells and are currently more widespread than their allogeneic counterparts, sometimes called “off-the-shelf” therapies, which begin with healthy donor cells.
That material is frozen and sent off to a manufacturing site where specific cells are isolated. The cells are often prepped in some way before the next step, transduction, when genetic material is introduced to the cells using viral vectors.
From there, the genetically-modified cells are grown—in a process also known as expansion—and then washed and diluted. Finally, they’re packaged up, frozen and shipped back to treatment centers to close the patient loop.
Naturally, products are tested before they're infused back into patients. This takes the form of typical end-of-manufacturing-run quality checks, plus hundreds of chain-of-identity controls that crop up during the production of each personalized medicine.
In many cases, the process takes weeks for every patient’s dose. Take for example Bristol Myers Squibb’s large B-cell lymphoma CAR-T Breyanzi, which was approved in February with a 24-day target turnaround time from cell collection to delivery back to the patient.
In the case of CAR-Ts specifically, which have been approved to treat very sick cancer patients, reducing those manufacturing timelines is paramount.
Stuck in a rut
Delicate, costly and tricky-to-scale, current CGT production demands a great deal of manual labor. “The clinical development of cell therapies happened faster than the industry was able to develop a mature manufacturing workflow,” Parker Donner, cell and gene therapy business development leader at Cytiva, which has partnered with Multiply Labs to pilot a robotic cell therapy manufacturing system, told Fierce Pharma.
Part of that workflow is already semi-automated, but it could be automated even more. Production will always need the “brainpower” of skilled and trained scientists, Donner said, but “the parts of the manufacturing process that are most prone to human error need to be automated.”
As for automation already at play in the field, “I think we’re at a point now where, for the majority of the workflow, there are devices that are closed” that are “probably what you would describe as being semi-automated,” George White, general manager for cell and gene therapy product management at Cytiva, said in an interview.
Working with those closed or self-contained systems—like the units Avrobio has developed—the person operating the system has some interaction, “but they’re not directly manipulating cells or processes,” he said. Aside from protecting the product from the room around it, closed systems also help manufacturers “collapse several steps into single automated unit operations,” White explained.
By and large, cell growth has also been automated, but when it comes to “manipulation steps,” the industry still hasn’t connected all the dots, he said. It’s those lingering touchpoints—like record-keeping, loading components with raw materials and fill-finish—where manufacturers need to “take the person out of the process as much as we can,” he said, noting that about half the cost of producing cell therapies is rooted in labor and overhead.
The other big challenge developers face is documentation and stringent sign-off requirements to clear the therapies for delivery back to the patient. Cytiva’s Donner flagged record-keeping as one of the more error-prone stages of production in need of an automation facelift.
The other piece relates to factories and manufacturing systems themselves. Most cell and gene therapy production setups today are “very low throughput per square foot,” Ori CEO Foster said. Current processes require many people working side by side in plants with hundreds of thousands of square feet of cleanroom space. Those facilities can take millions of dollars and multiple years to outfit, all to produce a slim few thousand doses, he explained.
A culture of automation
To cut the risk of human error and speed up production on an “industrial scale,” Cytiva has partnered with robotics technology company Multiply Labs to design a robotic system that would automate the manual portions of cell therapy production.
The Cytiva-Multiply pilot will center on Multiply Labs’ robotic cluster, in which a robotic arm surrounded by manufacturing modules slides and pivots to move materials through production.
Controlled by cloud-based software, the cluster would also allow parts of the production process to run in parallel, as opposed to being done consecutively, which is more common today, Fred Parietti, co-founder and CEO of Multiply Labs, said.
As for one example of how this would look, Cytiva and Multiply’s cluster will house multiple bioreactors—the equipment used to grow vector-modified cells before delivery back to the patient—where many developers currently use just one bioreactor per clean room, MIT News reported earlier this year.
Multiply’s robotic arms are already being used to make personalized pallets of capsules and can be seen in action in the video below, though Parietti pointed out that the limb on display is different from the system his company is developing with Cytiva.
By leaving the handling of cell therapies to robotics instead of people, Multiply and Cytiva figure their system could cut the risk of contamination and manufacturing errors, Parietti said.
Meanwhile, the cloud-based software is designed to tackle some of the record-keeping challenges that Cytiva’s White and Donner raised. The platform is being designed to “upload, store and visualize digital records that can be easily integrated with an electronic batch record,” Parietti said.
“As we look to make more and more products, it is not possible for an operator to track everything that must be recorded,” he added.
For its part, Ori Biotech is wrapping up the first-generation design of its closed, automated and flexible manufacturing platform, which it expects to debut on the market by the end of 2022, Foster said. The company’s been testing the platform with its global partners for about a year now, he added.
A big part of cell and gene therapy production involves moving “cells or media or beads around a process,” he explained, and it often takes “human beings with a lot of expertise to move them through the steps.” The Ori system automates the workflow and moves through the steps without the need for human help, he said.
That’s the physical footprint, as it were. The other arrows in Ori’s production quiver are software and a data platform that lets it capture information in real time. That software component allows operators to peek inside the bioreactors where cells are grown, helping them to “understand how they’re growing, how they’re metabolizing,” Foster said.
The company hopes to pair that data with multivariate analysis—a subclass of statistics used to parse complex data sets—predictive models, machine learning and more to streamline the information-gathering process, which is currently very “lab-intensive” and “analog,” Foster said.
Ori’s approach also leverages an “intensified” manufacturing footprint, Foster said. A drug developer might spend four years and $150 million to set up 150,000 square feet of sterile production space that ultimately turns out “a couple thousand doses,” Foster said. With the Ori platform, “we think we can shrink the requirement for GMP space by 95% to deliver 1,000 doses” using about 1,000 square feet to run 30 doses in parallel, he said.
Removing some of the complexity by intensifying its footprint and subtracting people from the process, Ori thinks its first-generation platform could drop the cost of goods by 50%, which is a “great” number when accounting for products that cost hundreds of thousands of dollars to make, Foster said.
From in-house to in-pod (and in-hospital, too)
Others, like lentiviral gene therapy player Avrobio, were quick to read the writing on the wall. “Early on, as the company was founded, Avro recognized that manufacturing in the cell and gene therapy space is a major challenge,” manufacturing and technology chief Raineri said in an interview.
Unlike others working solely in the domain of manufacturing, clinical-stage Avrobio is advancing a pipeline of gene therapies against genetic disorders like Fabry disease, Pompe disease and Hunter syndrome. Alongside those efforts, it’s built out a gene therapy platform called Plato to help deliver its personalized medicines at scale, should they pass muster with regulators, Raineri said.
The platform goes beyond software and Avrobio’s compact manufacturing pods, he said. It also extends to plasmid and vector design, cryopreservation, or freezing, and the way Avrobio “conditions” its patients prior to infusion, Raineri explained.
Avrobio spent more three years developing the equipment itself, by configuring off-the-shelf manufacturing units for its specific gene therapy approach. It uses a bespoke application to control the way Avrobio’s software executes a gene therapy manufacturing run.
Avrobio must first get its hands on a patient’s stem cells following apheresis. Next, Avrobio uses its manufacturing units to go from cell selection, transduction, washing, filling, finishing and freezing, all in the span of about three days, Raineri said. Quality control takes a bit longer at about six to eight weeks, he explained, though the company is “always looking at ways to streamline that.”
The key, he said, is that the three-day process is the same for all of Avrobio’s lysosomal prospects. For each indication, “all we’re doing is switching out the vector of interest in the gene” that needs to be repaired in the patient, he said.
Because Avrobio’s manufacturing units are closed, the company can bypass the need for high-grade clean rooms, which are pricey and hard to book. Workers don’t need complicated training, and the company doesn’t need to build new factories.
“Instead of having to go into new facilities, train operators on how to do the nuanced pieces of cell culture, it’s all self-contained,” Raineri said. Whether Avrobio’s workers are “pressing the button to initiate a run in North America or Australia, it’s all self-contained within the manufacturing system and it runs the drug product manufacturing process regardless of where you are,” he said.
Like Avrobio, Orgenesis is another manufacturing player juggling process innovation with its own cell and gene pipeline. The biotech hopes to take flexible manufacturing one step further, though, by bringing it right to the doorstep of the hospitals where patients are treated.
To pull this off, it’s teamed up with hospitals around the world to deploy its automated, closed and flexible Orgenesis Mobile Production Units and Labs, which the company calls OMPULs, CEO Vered Caplan told Fierce Pharma.
While it’s easy to assume that point-of-care production all comes down to technology, it also depends on a “much wider scope of services” like on-site quality control, standardization, supply and process consistency, Caplan said.
That process also needs to be standardized no matter where it is if developers hope to run multi-center trials, she added. By building out its point of care network—which has partners in the U.S., Europe, Asia and beyond—Orgenesis believes it’s effectively uniting these needs under a single platform, she said.
In essence, the company’s OMPUL is an automated “parallel processing system”—meaning it can perform certain production steps at the same time—that offers a manual component when needed, Caplan explained.
As for how that might work, Caplan floated the example of a hypothetical CAR-T production run. If a developer has automated the expansion piece, but not transduction, they can tackle the first step manually, move the drug product over to an “isolation chamber” for the automated phase, and then, because the previous material is closed off, start on the manual portion of the next patient’s dose in parallel, she explained.
Orgenesis, which owned Masthercell before it was sold to Catalent in 2020, is already rolling out its OMPULs through partnerships with major U.S. hospitals such as the University of California, Davis and Johns Hopkins University, plus others that it’s keeping under wraps for now, Caplan said.
Pace of change
While the situation looks a bit different for Orgenesis and Avrobio, which have rolled out manufacturing setups tailored to their own therapies, it remains to be seen how widely these various production approaches will be used across the industry. Many top players have already invested heavily in manufacturing and will need to be convinced before abandoning the established way of doing things.
Still, heavyweights like BMS—which bagged two CAR-T greenlights this year courtesy of its Celgene buyout—are already looking at ways to catch the automation wave. Bristol Myers plans to set up electronic batch records, automated bioreactors, automated flow cytometers and more at a pair of cell therapy factories it’s standing up in Europe and the U.S., Snehal Patel, BMS’ vice president of global cell therapy manufacturing, said in an interview earlier this year.
The future holds "more automation and more equipment that is tied together,” he said at the time.
Allowing companies to keep some portions of their process manual is an essential part of the platform being rolled out by Orgenesis, which is taking a step-by-step approach to point-of-care production, Caplan said. Companies can add more and more automation to their OMPUL setups as they advance through clinic, she said.
“Even if you’ve automated half the process, that means you can get twice as many, maybe more, products to the patient,” Caplan said.
Developers don’t need to find “every solution to every problem,” nor do their production systems need to be perfect and all-encompassing, she said. “Even solving [production] step by step gets so much benefit to the patients.”