Rapid advancement of gene therapies into the clinic carries with it a challenge for developers and manufacturers. Why? Because demand for virus currently exceeds supply—and demand is growing at a rapid pace. Companies developing gene therapies and organizations assigned to produce them have been compelled to pursue solutions that, until now, have not been feasible.
“The investment necessary to develop commercial-scale manufacturing processes and facilities [to manufacture viral vectors] are extremely expensive,” James M. Wilson, M.D., Ph.D., director of the gene therapy program at the University of Pennsylvania, told GEN.
Production of an adeno-associated viral (AAV) vector for a Phase I study involving a non-ocular treatment candidate would cost around $5 million, while the cost of a facility to manufacture the vector at the Phase I through commercial scale is in excess of $100 million, he said.
The cost, he said, has driven gene therapy developers to hold off addressing manufacturing until they have evidence that their product is likely to be effective. Companies then have two options: build a facility or rely on CMOs.
“The investment necessary to accomplish those goals was really only justified after there was evidence in the clinic that the technology was working,” added Dr. Wilson, who chairs the scientific advisory boards for Regenxbio and Solid Bio, and serves as clinical development editor of Human Gene Therapy, a journal published by GEN publisher Mary Ann Liebert Inc.
“It’s not surprising with an emerging new technology that the commitment to this commercial-level manufacturing would occur after the science and the platform were de-risked through initial proof-of-concept clinical trials.”
Regenxbio has expanded its bulk production platform process to three contract research and manufacturing organizations—ABL, WuXi AppTec, and an undisclosed CMO.
Curran Simpson, Regenxbio’s SVP of technical operations, said the company and WuXi AppTec have established efficient, scalable cGMP processes to produce AAV gene therapies incorporating Regenxbio’s NAV® Technology. Regenxbio has contracted with ABL to manufacture its lead product—the homozygous familial hypercholesterolemia (HoFH) gene therapy candidate RGX-501—for human clinical trials.
Continuity > Cost Savings
“Cost savings hasn’t been the primary motivation [for expanding Regenxbio’s bulk production platform process]. It has been more continuity of supply chain, because we’re still in early-stage clinical development,” Simpson said. “By going to three different CMOs, you learn things that each CMO does that you might not have learned at the other. And you incorporate that into the process that you’re operating.”
ABL says it has seen growing demand for gene therapies as part of an overall increase in all types of virus-based products, including vaccines and oncolytic therapies. “ABL has responded to this demand by adding global capacity, increasing scale, as well as diversifying capabilities,” said Rebecca Harston, Ph.D., ABL’s director of business development.
Capacity was added last year when ABL’s European subsidiary acquired Transgene’s GMP production facility in Illkirch, near Strasbourg, France. The commercial-ready facility is designed and equipped to manufacture viral vector-based biopharmaceutical and vaccine products.
The Strasbourg site, ABL’s second manufacturing facility, allowed the company to expand into the European CMO market. ABL’s 16,000-square-foot Strasbourg facility houses four controlled and segregated manufacturing suites with airlocks, independent HVAC per suite, separate double door autoclaves for both sterilization and decontamination, and a liquid waste collection and decontaminations system. The facility also provides drug product manufacturing via an isolator-based automated vial and ampoule-filling machine.
AveXis President and CEO Sean Nolan said his company has developed a scalable, GMP commercial process that uses HEK293 cells and an adherent cell line. For AAV9 vector production, AveXis uses a novel adherent cell culture approach that can more reliably manufacture product and has greater surface area to potentially increase productivity relative to Corning’s HYPERStack® (High-Yield PERformance) line of closed-system modular cell culture vessels, designed to enable manufacturers to increase cell production without expanding the footprint of their cell culture operations.
Nolan said AveXis has invested approximately $55 million to build its own 50,000-square foot manufacturing facility, which has the capacity to meet planned clinical and commercial demand for initial proprietary gene therapy candidate AVXS-101, now in a pivotal trial in patients with spinal muscular atrophy type 1.
“The company has identified and implemented additional process development improvements, both up- and downstream, in its GMP commercial process. The company currently anticipates that it will be able to meet projected global patient demand” for AVXS-101, Nolan said.
At bluebird bio, virus supply has been addressed by growing both external and internal capacity: “We’re trying to make sure that we have robust and reliable supply for all of our products, for all the patients, well after we have launched the products and the hype is gone,” said Derek Adams, Ph.D., the company’s chief manufacturing and technology officer.
Internally, capacity concerns prompted bluebird bio to acquire a manufacturing facility in Durham, NC for $11.5 million. The facility will produce lentiviral vectors for therapies that include the cerebral adrenoleukodystrophy treatment Lenti-D™, as well as LentiGlobin™ for transfusion-dependent β-thalassemia and severe sickle cell disease, and multiple myeloma treatments bb2121 and bb21217.
To increase external supply of virus, Dr. Adams added, bluebird bio has signed agreements with three commercial suppliers—Brammer Bio, MilliporeSigma, and Novasep.
Florida, Massachusetts Expansions
Brammer said it invested $50 million this year to expand its Florida clinical supply operations and launch Massachusetts operations for late-stage studies and commercial supply.
In September 2017, the company doubled its clinical manufacturing capacity in Alachua, FL, to support Phase I/II cell and gene therapy clinical trials, using production and purification platforms up to 500-L scale for manufacturing therapeutic vectors via mammalian and insect cell host systems.
Two months later in Cambridge, MA, Brammer completed renovations at a 66,000 square-foot Kendall Square manufacturing facility acquired from Biogen in January 2017. Brammer also acquired a 49,000-square-foot GMP distribution center in Somerville, MA, offering storage and clinical and commercial distribution capabilities.
“Being able to support clients from early development to commercialization provides efficiencies that save time and maintain consistency in product quality,” Brammer CSO Richard Snyder, Ph.D., said.
Tony Hitchcock, technical director for Cobra Biologics, said his company has begun a “mid- to long-term” R&D project to address viral vector production issues. Cobra is looking to address cost and timeline across the supply chain by shortening plasmid DNA delivery costs through the establishment of a high-quality plasmid supply process.
“To expedite these developments, we have established a number of collaborations with industrial partners and innovation centers, leveraging over £1.75 million ($2.34 million) in government grants,” Hitchcock said.
Cobra has committed to investing up to £15 million ($20 million) over the next two years toward a phased expansion of manufacturing capacity, projected to create 50 new jobs in the U.K. and Sweden.
The initial phase will extend Cobra’s viral vector Phase III and commercial manufacturing capabilities in the U.K. to support customers through clinical trials to commercialization. The second phase, in Sweden, will double Cobra’s capacity for high-quality DNA plasmid production and characterization. These service upgrades will help Cora better support early clinical-phase AAV and lentivirus vector manufacturing. The vectors will be used by CAR-T therapy developers for investigational candidates that target acute lymphoblastic leukemia and chronic lymphocytic leukemia. The third phase will add larger clinical and commercial capabilities for cGMP DNA production.
“We expect to see the expanded manufacturing facilities come on-line over the next 12 months and [we also expect to] see significant outputs from ongoing research projects during that same timeframe,” Hitchcock added.
A Direct Response
In the Houston suburb of Pearland, TX, Lonza is completing a new 300,000-square-foot cell and gene therapy manufacturing facility, which the company says will be the largest dedicated facility of its kind when it starts operation.
“Our new Houston facility, which is on schedule to start production in Q1 2018, is a direct response to the viral gene therapy supply challenge, which we saw coming five years ago,” said Ryan Scanlon, head of viral gene therapy at Lonza.
The new facility will include a fully segregated fill/finish suite and will showcase Lonza’s single-use disposable platforms up to 2,000 L in volume. By optimizing engineering designs and operational concepts, the company said, it maximized commercial cost-of-goods in dedicated modular trains capable of making more than 40 batches batches of 2000 L per year.
“Over time, depending on how our product/process mix evolves, our new facility could support production of several hundred batches of viral vectors per year,” Scanlon said.
Lonza is also recruiting alpha and beta testers for the CocoonTM platform for the autologous cell and gene therapy manufacturing projects being developed with Octane Biotech. The goal of Cocoon is “to provide a scalable and cost-efficient solution to current autologous cell and gene therapy manufacturing bottlenecks.”
Lonza has also invested in internal process R&D innovations designed to improve viral vector manufacturing productivity, scalability, and robustness. In the coming months and years, Scanlon said, Lonza plans to reduce cost-of-goods and shorten timelines by rolling out industrial platforms that standardize with regard to suspension cell culture, versatile single-use technologies, and cutting-edge applications of automation concepts.
MilliporeSigma’s Carlsbad, CA-based facility for manufacturing BioReliance® viral and gene therapy products completed both FDA Pre-License inspection and a European Medicines Agency Marketing Authorization Application inspection. The facility grew last year from 44,000 to 65,000 square feet, and now includes 16 modular viral bulk manufacturing cleanroom suites with single-use equipment and two fill/finish suites for gene therapy, viral vaccine and immunotherapy products.
“Given our extensive manufacturing experience, our expanded capacity will allow us to address more of the market imbalance [in vector production] going forward,” said Chris Ross, head of integrated supply chain operations at MilliporeSigma.
‘Supply and Improved Processing’
Ross said MilliporeSigma is working to make its core process template more scalable and efficient, with the goal of enabling more robust virus vector production from existing infrastructure.
“We are exploring higher-volume reactors and the process changes required to enable that. In addition, we are always considering further expanding our capacity,” Ross said. “Addressing viral vector supply is going to come through a combination of supply and improved processing. The timeline is difficult to predict given the constant growth in demand as therapies reach milestones in the clinc as well as commercially.
Spark Therapeutics, on November 7, 2017, disclosed the completion of an FDA preapproval inspection at its manufacturing facility in West Philadelphia, saying the agency raised no critical observations.
“This is a remarkable achievement given it involves a process that has never-before been validated for commercial use, features operation of novel analytical methods, and relies on the investment into a new facility,” Spark CEO Jeffrey D. Marrazzo told analysts during a recent earnings call.
Vigene Biosciences last year acquired Omnia Biologics’ cGMP facility in Rockville, MD, for an undisclosed price. The facility consists of three cGMP manufacturing suites and one process development laboratory for viral vector production. Since then, Vigene has doubled the lab space to 14,000 square feet, and plans to open a third manufacturing site in Rockville in late 2018.
“It is a direct response to demand for AAV-based gene therapy-product manufacturing,” said Jeffrey Hung, Ph.D., Vigene’s chief commercial officer. “We continue to see demand going up. We would like to meet that demand by providing manufacturing for clinical materials.”
To meet that demand, he added, Vigene is investing in personnel, facilities, and technology—both internally and through product development as a result of in-licensing.
Dr. Wilson expects the industry will need about five years to address virus supply. He said the time from concept to opening of a new GMP facility ready for production, with money in hand, can be about three years.
“What’s unfortunate is that we can’t pool our collective experiences to accelerate product development,” Dr. Wilson said. “Everyone is pursuing their own approach, at a tremendous duplication of effort and wasted resources for the companies involved.”