Frost & Sullivan invited industry leaders with gene therapy experience to participate in a thought leadership forum. The forum brought together leading minds to discuss key challenges and insights related to reducing the cost of goods (COGs) for gene therapy.
The analyst’s perspective
A decade ago, diligent efforts in gene therapy were restricted to a handful of pioneering labs that had to battle naysayers. Today, key biopharma players are involved in multibillion-dollar mergers and acquisitions (M&A) deals and other partnerships in the gene therapy space. 2019 witnessed many acquisitions for vector manufacturing capacity to address the lack of capacity that is a huge bottleneck in the field. Vendor-pharma partnerships will help address the manufacturing gap. For instance, the strategic partnership between Prevail Therapeutics and Lonza will support scale-up of Prevail’s pipeline of adeno-associated virus (AAV)-based gene therapies.
The entire sector is evolving rapidly, and novel methods, platforms, and solutions have emerged in the last three years. Given the various challenges faced by the cell and gene therapy manufacturing industry due to capacity shortage, high investment costs, and other factors, some innovative solutions have emerged, such as single-use systems and modular biomanufacturing facilities. These innovations have been directly associated with capital expenditure (capex) benefits and other advantages.
There has been much progress in moving potentially life-saving gene therapies to the market, but they are extremely costly to produce. To address the need to reduce COGs, we invited a panel of industry experts to join a discussion.
Biggest challenges in vector production
To kick off the forum, the panelists explored the factors that challenge gene therapy manufacturing, starting with the biggest bottlenecks.
The whole panel agreed that the capacity shortage is a major challenge. According to Ricardo Jimenez, VP, Technical Operations at Neurogene, it is crucial to determine if it makes sense for a biotech company to build their own capacity and use newer technologies such as modular solutions for faster ramp-up. “You need to start having the discussions of GMP batches very early because the lead time can be a year, year and a half, two years from when you actually get the material to when you have to start doing work,” Jimenez said.
Productivity of the batches themselves, especially in AAV manufacturing, is going down, because doses are increasing but batch yields are not. Raw material costs for lentivirus (LV) and AAV, both of which typically require transfection of cells with the gene of interest, are expensive. Also, the acquisition costs of vectors and some GMP-certified plasmids are high.
Another huge issue is downstream purification; up to 70% of viral vectors are lost during purification using current equipment, because processes are based on antibody purification methods. There is a need to optimize the equipment specifically for viral vectors.
Donna Rill, CTO at Triumvira Immunologics, emphasized that hold times and product and room turnover caused delays in production of both GMP plasmids and viral vectors. This fact becomes especially important for release testing.
Critical steps that impact the manufacturing workflow
Panelists discussed how to address challenges in critical steps that impact the manufacturing workflow. They were invited to share potential solutions and the advantages and disadvantages of present technology, and to predict where this sector is headed.
The transfection step was highlighted as one of the most critical. “Right now, we’re using the triple transfection process, and it’s just not a very efficient process. And the yield there, the productivity of transfection, is not great, and it does generate a large amount of empty particles. So, if you can optimize the packaging step so that it packages more full particles, you can definitely increase your productivity out of a batch,” Jimenez said. He noted that scaling up to get good productivity at 250- or 500-L scale after optimizing transfection and purification will also add cost.
The experts mentioned technologies that might help, some of which are protected by intellectual property (IP) for instance, producer cell lines, baculovirus systems, and herpes virus systems. However, they noted that the process becomes more complex with the need to create bacmids, the genomes of a baculovirus, which substantially increase COGs.
Sanket Acharya, Senior Manager, Strategy Search and Evaluation at Cytiva, said that plasmid production is costly and time consuming. Acharya explained how Cytiva is working to potentially reduce plasmid cost by using a cell-free process. According to Acharya, cell-free amplification could greatly reduce the number of purification steps and make the process significantly faster. “Cytiva is working on cell-free technology that amplifies the plasmid templates based on extension of random primers. Our data show that this process saves time and cost.”
Cell culture was mentioned as another critical step, especially regarding the major cost of getting stable cell lines or packaging cell lines with a high titer. According to Acharya, process analytics could help reduce risk substantially. “Better sensor technology would improve the risk profile for losing a batch,” Acharya said. In particular, process monitoring could reduce the loss of a batch or stop production at an early stage.
Packaging and producer cell lines as potential sustainable alternatives
The panel agreed that it takes a long time to generate processes to introduce alternative technologies, such as packaging and producer cell lines. Also, it is important to consider IP needs. According to the experts, these technologies offer advantages, mainly focused on reducing time and costs, and disadvantages, such as lower titers. Another big disadvantage is directly associated with toxicity issues. “There are packaging cell lines that have integrated helper plasmids and need transfection of only the gene-of-interest plasmid to make virus particles. Then there are producer cell lines that have all the components integrated including the gene of interest. Both options are being developed by players in this space,” Acharya explained. Several companies are working on inducible expression to avoid cell toxicity.
According to Acharya, process efficiencies can be increased by shifting to a single-use process that uses higher capacity chromatography resins tailored specifically for AAV. “Single-use technologies only make sense if you’re using them with higher-capacity resins because, in a study we did internally, this led to lower column volumes and fewer purification cycles,” Acharya said. “Without this combination of factors, stainless-steel equipment had a similar throughput to single-use. So, the process efficiencies depend on incorporating different aspects throughout, making the whole process more efficient.”
Dawn Wofford, Director of Regulatory Affairs at Cytovance Biologics, emphasized the challenge of managing timelines and investors’ expectations. Small biotech companies face the problem of adjusting and managing timelines and explaining to investors that return on investment (ROI) within four or five years, followed by exit, is not possible in the cell and gene therapy space. Heidi Hagen, Chief Strategy Officer at Vineti said, “The timeline is not only for the production. One should ‘layer in’ the regulatory burden, as far as what you need to accomplish, by a certain point in your production, and align with the lead times on raw materials and production schedules.”
Rill brought up critical issues around GMP plasmid production and delays in the release packaging, “There are companies both from the plasmid and the vector production side that are expanding and building new facilities. These organizations have run into significant delays in getting FDA approvals. These delays were unexpected, which has further impacted timelines.”
Modular lab facilities to reduce COGs
Panelists were asked to speak about the potential for modular facilities to reduce COGs in gene therapy manufacturing. The panel agreed that modular approaches provide great flexibility and the ability to do the batches internally, which markedly reduces production costs.
According to Jimenez, companies need to consider the buy-versus-build, outsourcing-versus-insourcing paradigm and do the math, which strongly depends on scale, capacity to be built, and number of internal programs. Acharya highlighted the importance of in-house production as a huge factor in selecting these modular facilities, which include Cytiva’s KUBio box solution for viral vectors. “KUBio box is a modular manufacturing facility specifically for gene therapies that intends to be a highly flexible facility that can be retrofitted to an existing lab space,” Acharya explained. “The KUBio BSL-2 environment provides a lot of flexibility, and it can also be expanded or contracted as production needs change so as to speed the process and save time; developing an in-house manufacturing facility really helps, and introducing modularity as an industry increases the output and shortens the manufacturing times.”
Acharya believes the next challenge is for both gene therapy and cell therapy to develop modular workflows with automated and closed systems, to reduce contamination and process variability by eliminating manual handling of material. Such workflows are included in KUBio, which can be built in 12 to 18 months from start to finish; a company can plan to start its production in 18 months, whereas the production phase using outside capacity through CDMOs may take much longer.
According to Rill, it is especially important to migrate to a single-use and modular process when working with multiple products that will enter clinical trials at different phases. “The management of the workflow and the staffing just literally demand modularity in the whole therapeutic cell therapy, gene therapy production world for a drug product,” Rill added.
Conclusions and future perspectives
Frost & Sullivan conducted surveys to capture the experts’ insights on key discussion points. The panelists said that capacity, apart from other factors, was one of the biggest cost drivers in their companies.
When asked about the most time-consuming workflow step in vector manufacturing, the responses included:
- Hold times and product and room turnover
- Process development, then plasmids, then purification (from a process standpoint, it’s cell expansion)
- The unexpected delays and backlogs that significantly impact clinical trial timelines
- Releasing the final product
Responses to the question about which workflow step leads to most variability included:
- GMP plasmid production
- Delays in release testing, and cell fermentation
Finally, the experts were asked if modular lab facilities can reduce COGs. All panelists agreed that they could.
The panelists established key trends around managing technological challenges and production costs for cell and gene therapies. The outlook points toward a modular, automated approach that is likely to reduce timelines and costs while increasing product consistency.
Learn more about Cytiva’s solutions for gene therapy process development and manufacturing at cytiva.com/genetherapy.