Success in the gene therapy space relies on embracing technological advances in upstream and downstream processes

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HURDLES PREVENTING GENE THERAPIES FROM REACHING PATIENTS
Over the past two decades, gene therapies have seen continuous improvements in efficacy, safety and manufacturability, made possible by groundbreaking research in virology and advancements in manufacturing techniques and technologies. Understanding the potential these improvements bring, the U.S. FDA has stated that by 2025, it anticipates 10-20 new cell and gene therapy product approvals per year (1). This projection is based on the number of ongoing clinical trials, with 522 gene therapies currently at phases 1, 2 or 3 (2).

 

Although continued research holds the promise of enabling the development of increasingly powerful gene therapies, a prominent hurdle currently stands in the way of delivering these new medicines to the patients who need them. Production costs remain a fundamental concern for gene therapy developers. We are now seeing gene therapy drug prices in the multimillion-dollar range, with AAV-based gene therapies consistently taking the top spot for “the most expensive therapy in the world.” The title currently sits with Hemgenix, a one-off infusion treating hemophilia B, costing $3.5 million a dose (3).

 

The driving force behind the high production cost of gene therapies comes down to three key factors:

• Gene therapies are typically a one-time treatment that is potentially curative.
• Gene therapies commonly address orphan or rare diseases rather than therapeutic areas with large patient populations.
• Some gene therapies need very high vector doses.

Addressing the burden of cost is critical to enable the treatment of a wider patient population.

 

The incorporation of new technologies in both upstream and downstream processes is crucial for the continued success of gene therapy. By implementing advanced technologies, drug developers can not only enhance safety and efficacy while reducing production costs. This can potentially lead to a decrease in drug prices, making gene therapies more accessible to patients.

 

However, the integration of revolutionary upstream and downstream technologies may not always be easy and will require biopharma companies to carefully consider how to best incorporate them into their existing systems.

 

REVOLUTIONIZING UPSTREAM PROCESSING
The design and optimization of upstream processing (USP) plays a vital role in developing successful therapies. Biotechnology innovations, such as genetic engineering, enable the development of optimized microbial strains and production processes. This results in increased yields, reduced production costs and improved scalability.

 

USP advancements are converging in various areas to benefit the gene therapy industry and we can expect more gene therapy developers and manufacturers to adopt new techniques and technologies in their upstream processes, including:

 

• Upstream single-use systems and scalability: Advancements in single-use systems (SUS) have made it possible to scale up manufacturing processes, with capacities of up to 6000 L achievable if required (4). Additionally, improvements in media and supplements have enabled high productivity in suspension-based gene therapy vector manufacture, even in the absence of fetal bovine serum (5).
• Suspension and proprietary cell lines: The gene therapy industry is witnessing a rising demand for large batches of products, leading to the adoption of suspension cell lines to facilitate scaling capacities. This trend is accompanied by a shift towards producing stably transfected proprietary cell lines, which can help reduce timelines and ensure high-quality products. Having proprietary cell lines in-house not only speeds up USP by reducing the need for outsourcing but it also allows companies to acquire intellectual property (IP) and build brand recognition (6). As a result, offering suspension cell line capabilities and proprietary cell lines is becoming increasingly important in maintaining a competitive edge within the gene therapy industry.
• Novel inducible systems for enhanced control: Inducible systems enable external cues to control the precise onset of gene expression. Novel inducible systems are being developed to enhance the regulation of gene expression, leading to improved safety and efficiency in the generation of packaging and producer cell clones.

 

Advancements in downstream processes
In gene therapy development and manufacturing, downstream technology advancements aim to minimize process-related contaminants for enhanced safety, quality and stability of the final product.

 

One notable trend in downstream processing (DSP) is the widespread adoption of SUS technologies, which can be integrated into depth filtration, crossflow filtration, chromatography and final sterile filtration steps. By utilizing SUS, gene therapy developers can minimize contamination risks and reduce the validation requirements compared with permanent fittings. Additionally, SUS enables rapid scalability of production, allowing for quick response to market demand changes and faster turnaround times, as cleaning or changeover processes are not necessary. The reduced cleaning requirements also bring sustainability benefits, including decreased water and energy consumption and reduced waste production (7).

 

Another significant trend in gene therapy DSP is the increasing utilization of sophisticated analytical technologies. As gene therapy products are typically manufactured with a cellular host substrate, the inherent complexity involved poses challenges for analytical characterization. However, the industry and researchers have made substantial progress in analytical instrumentation, particularly in the characterization of gene therapy viruses. The advancements in analytical technologies include digital PCR, nano-tracking analysis, analytical ultracentrifugation, bio-layer interferometry, flow virometry, flow-induced dispersion analysis and charge detection mass photometry. These developments have been driven, in part, by the growing demands of regulatory agencies to demonstrate specific safety and potency profiles for therapeutics undergoing clinical investigation.

 

PREPARING FOR THE CHALLENGES AHEAD IN GENE THERAPY
Despite being in an exciting era for healthcare for the advancement of gene therapies, there are still several challenges that must be considered before initiating gene therapy manufacturing. These hurdles typically revolve around the need to improve stability, regulatory compliance, scalability and patient access.

 

• Effectively managing supply chains: Ensuring a secure and reliable supply chain of raw materials, critical reagents and specialized components is crucial to meeting the increased demand for gene therapies (8). Identifying vulnerabilities, establishing contingency plans and collaborating closely with suppliers will be increasingly important steps in mitigating risks as the need for gene therapies grows.
• Ensuring viral vector production scalability: The development of transient transfection systems and stable producer lines has improved the production of viral vectors at large scales. However, scaling up the production of viral vectors remains a challenge due to limitations in transfection efficiency and consistency across large volumes (9). Attaining high transfection efficiency becomes increasingly difficult as the scale increases. Ensuring consistent vector quality and meeting regulatory requirements for safety and potency are crucial considerations.
• Maintaining regulatory compliance in a changing space: Gene therapies are subject to rigorous regulatory requirements that are constantly evolving with new advancements to ensure patient safety and product efficacy. Manufacturers must be familiar with and adhere to good manufacturing practices (GMP) and demonstrate robust assurance systems throughout the manufacturing process to meet changing requirements (10).
• Optimizing cost: Despite advancements to improve production efficiency, gene therapies remain expensive due to the complexity of manufacturing processes and the specialized facilities and equipment required. Identifying opportunities for process simplification, improving productivity and optimizing resources is essential for achieving cost optimization. Ensuring the scalability of these manufacturing processes is essential for cost optimization (11). The development of high-yield cell lines, improvements in transfection techniques and optimization of bioreactor designs could all help to enhance vector productivity and yield.
• Improving affordability to enable broader patient access: Despite technological advancements and process optimization, ensuring affordable access to gene therapies for patients remains a significant challenge (12). Collaboration with payers, providers and policymakers is necessary to develop finance options and establish equitable access programs.

 

Moving forward, it will be vital for manufacturers to regularly reevaluate and address these considerations to adapt to changing trends and ensure seamless gene therapy production processes.

 

ADAPTING TO GENE THERAPY TRENDS IN THE FUTURE

Gene therapy developers and manufacturers must stay attuned to advancing technologies in USP and DSP to keep pace with the evolving landscape.

One of the key challenges they can expect to continue to face is the scalability of viral vector production, which is crucial for efficient gene therapy manufacturing. Cost optimization will also remain a priority, and manufacturers must explore process development, cost modeling and process intensification to drive down the cost of doses. As guidelines and market access agreements continue to evolve alongside the rapid advancements in gene therapies, regulatory compliance will remain a challenge.

Collaborating closely with expert manufacturing partners, gene therapy developers can adapt and optimize their processes as needed. By addressing these challenges, gene therapy manufacturers can ensure seamless production processes and enhance patient access and affordability.

 

REFERENCES AND NOTES

1. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. Available from: https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics
2. American Society of Gene and Cell Therapy Gene, Cell, & RNA Therapy Landscape Report Q1 2023.
3. Naddaf M. $3.5-million hemophilia gene therapy is world’s most expensive drug (Internet). Scientific American; 2022 (cited 2023 Jun 7). Available from: https://www.scientificamerican.com/article/3-5-million-hemophilia-gene-therapy-is-worlds-most-expensive-drug/
4. Bhatkhande S. Single-use bioprocessing technologies enabling more rapid vaccines production (Internet). 2023 (cited 2023 Jun 7). Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/596309-Single-Use-Bioprocessing-Technologies-Enabling-More-Rapid-Vaccines-Production/
5. Subbiahanadar Chelladurai K, Selvan Christyraj JD, Rajagopalan K, Yesudhason BV, Venkatachalam S, Mohan M, et al. Alternative to FBS in animal cell culture – an overview and future perspective. Heliyon. 2021;7(8). doi:10.1016/j.heliyon.2021.e07686
6. Nielsen J, Tillegreen CB, Petranovic D. Innovation trends in Industrial Biotechnology. Trends in Biotechnology. 2022;40(10):1160–72. doi:10.1016/j.tibtech.2022.03.007
7. Hederman J. Single-use systems: The future of biopharmaceutical processing (Internet). 2023 (cited 2023 Jun 7). Available from: https://www.medicaldesignbriefs.com/component/content/article/mdb/pub/features/articles/40742
8. Digiusto D, Leistler B, Walls T. Overcoming raw material challenges in Cell & Gene Therapy Manufacturing. Cell and Gene Therapy Insights. 2020;6(2):415–26. doi:10.18609/cgti.2020.050
9. Shupe J, Zhang A, Odenwelder DC, Dobrowsky T. Gene therapy: Challenges in cell culture scale-up. Current Opinion in Biotechnology. 2022;75:102721. doi:10.1016/j.copbio.2022.102721
10. Addressing the unique regulatory challenges of Gene Therapies (Internet). 2022 (cited 2023 Jun 7). Available from: https://www.biopharma-excellence.com/articles/addressing-the-unique-regulatory-challenges-of-gene-therapies/
11. Cost reduction in cell and gene therapy 2023: Cost-efficiency coupled with efficacy is key moving forward – researchandmarkets.com (Internet). 2023 (cited 2023 Jun 7). Available from: https://www.businesswire.com/news/home/20230105005524/en/Cost-Reduction-in-Cell-and-Gene-Therapy-2023-Cost-Efficiency-Coupled-With-Efficacy-is-Key-Moving-Forward—ResearchAndMarkets.com
12. UK BioIndustry Association. Ensuring patient access to cell and gene therapies – the case for an innovative payment model (Internet). 2021 (cited 2023 Jun 7). Available from: https://www.bioindustry.org/resource-listing/ensuring-patient-access-to-cell-and-gene-therapies—the-case-for-an-innovative-payment-model-pdf.html