Frost & Sullivan recently invited industry leaders with gene therapy experience to participate in a new thought leadership forum, a Virtual Think Tank. This forum brought together leading minds in this emerging field to discuss key challenges and other insights related to reducing the cost of goods (COGs) for gene therapy.

The analyst’s perspective

A decade ago diligent efforts in the field of 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 one of the largest bottlenecks in the field. Vendor-pharma partnerships will help address the manufacturing gap. For instance, the strategic partnership between Prevail Therapeutics and Lonza will help scale up Prevail's pipeline of AAV-based gene therapies.

The entire sector is undergoing rapid evolution, 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 evolved, 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 discussion, the panelists explored the factors that challenge gene therapy manufacturing, starting with the biggest bottlenecks. The whole panel agreed that the shortage of capacity constitutes one of the major challenges. 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 adeno-associated virus (AAV) manufacturing, is going down, because doses are increasing but batch yields are not. Raw material costs for both lentivirus (LV) and AAV, both of which typically require transfection of cells with the gene of interest, are expensive. In addition, the acquisition costs of vectors and some of the GMP-certified plasmids are high.

Another huge issue is downstream purification; 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, focused on hold times and product and room turnover. Delays in production of both GMP plasmids and viral vectors constitute a major drawback. This fact becomes especially important for release testing. “Unfortunately, that is a very limited-selection field and that is becoming an increasing problem; I have gone from taking an average of nine months to about a year for about my first three productions over the last couple of years, and then, the current production that I am in right now for viral vector, before I get my vector enhanced from my clinical trials, it is going to have been a two-year process,” Rill emphasized. Unexpected delays or backlog when outsourcing biomanufacturing has a major impact on clinical trial timelines and final product release. Moreover, there is a large gap in how vector production facilities look at that production scale.

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, advantages and disadvantages of present technology, and to predict the evolution of this sector.

The panel highlighted the transfection step 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 we 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 the process to get good productivity at 250 L or 500 L scale after optimizing the transfection and purification will also add to the costs.

The experts mentioned additional 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 the cost of goods.

Sanket Acharya, Senior Manager, Strategy Search and Evaluation at Cytiva, said that plasmid production is a costly and time-consuming step. Acharya explained how Cytiva is working to potentially reduce the cost of plasmids by employing 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. Our next question is can cell-free amplification be used to make templates at scale, for example amplifying templates for mRNA that go into an in vitro transcription (IVT) reaction? We have just started looking into that,” Acharya said.

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. In addition, 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 considerable 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 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 lower number of 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 why to investors, telling them 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 just the production. Then layer in the regulatory burden, as far as what you need to accomplish by a certain point in your production to 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 cost of goods

Panelists were asked to speak about the potential for modular facilities to reduce cost of goods in gene therapy manufacturing. The whole panel agreed that modular approaches provide great flexibility and provide the ability to do the batches internally, which greatly 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 involve considerably longer times.

Rill said, “I think it’s important that companies do migrate to single-use and modular processing. And in my actual manufacturing processes, there’s no one fit model, one device or anything that can fill the need. But it’s a given because it’s single use and I’m glad to see that the whole field of vector production and plasmid production is moving that way. The whole modular process can be very advantageous.”

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 the modular use in the whole therapeutic cell therapy, gene therapy production world for a drug product,” she added.

Conclusions and future perspectives

Frost & Sullivan conducted surveys to capture the experts’ insights on key aspects of the discussion. 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:

  • Transfection
  • GMP plasmid production
  • Delays in release testing, and cell fermentation

Finally, panelists were asked if modular lab facilities can reduce costs of goods. All panelists agreed that they could.

Frost & Sullivan would like to thank the participants for their time and valuable insights, which made this discussion engaging and informative. 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.