The curative potential of cell and gene therapies is well acknowledged, but access and affordability are significant issues. Experts discuss why access is the true measure of success and how more efficient, cost-effective manufacturing processes can help.
We asked: What has/have been the key disruptor(s) driving the industry over the past ten years, and how will this change in the next 10 years?
Here, we include views related to the manufacture of advanced therapies. Read about other areas of pharma drug development here.
The Evolution of Manufacturing – with David Smith, VP of Development, BioCentriq
To enable continued growth, these therapies need to be democratized to the masses, akin with how digitization of DVDs took reign over VHS; only through standardization was there a significant reduction in cost, improved production technology (consumable and hardware), and increased adoption even enabled films in the headrests of cars. The next step was online streaming…
The next generation of cell and gene products are already reducing manufacturing timelines, delivering more potent, smaller doses, reducing vein to vein time – and we are completing it with digitized, automated solutions. With this all-in place, acceleration will continue over the next decade. I hope to see standardization of agile manufacturing platforms across the industry, rapid analytical strategies enabling same day administrations, point of care treatment, and true democratization of cell and gene therapies.
Learning From Biologics – with Jason Bock, CEO, CTMC
The vast role played by the immune system across a spectrum of diseases has been the key disruptor in the biotech industry over the past decade. Biotech has developed therapeutic strategies to either activate or regulate the immune system for different purposes. For cancer treatment, checkpoint inhibitors are used to release the brakes on the immune system, while for autoimmune diseases like rheumatoid arthritis, anti-TNF medications are employed to suppress the immune response.
Precise targeting and long serum half-life of monoclonal antibodies have been utilized as tools to modulate specific pathways of an immune response. As our understanding of the immune system has deepened, the industry has shifted to a more direct path to utilize immune cells as the effectors. The ability to directly engineer an immune response that can persist for years – or even decades – through living cells has enormous potential. The emerging field of cellular therapy will generate new therapies to treat refractory medical conditions, and could transform how healthcare is administered through the single-dose, curative potential of this modality.
While current progress is promising, autologous cell therapy comes with challenges in chemistry, manufacturing, and control for developers. These therapies are the most complex ever developed as they are derived from each patient’s own cells. This uniqueness necessitates a complete reimagining of the traditional supply chain and economics. Since the starting material is the patient’s own cells and manufacturing occurs on demand, the relationship between the clinic and manufacturer is intertwined in such a way that the manufacturer functions like a pharmacy for cell therapies. Although the field has seen dramatic clinical efficacy responses, creating a fit-for-purpose supply chain infrastructure that meets demand at a manageable cost remains a significant hurdle.
One approach to overcome these challenges would be the creation of key regional manufacturing hubs around the country aligned with major medical and population centers. An industrial, built-for-purpose regional “cell pharmacy” could develop locally integrated supply chain and logistics to streamline the coordination of cell collection, production, and infusion. These hubs could provide cell therapies from multiple commercial sponsors to benefit from economies of scale and drive a shift from open and manual processes to closed, automated ones. Digital, cloud-based quality systems will be essential to maintain consistency and process control across such a network. Such interconnectedness is a key differentiator from the concept of fully decentralized, localized manufacturing.
We have a golden opportunity to transform healthcare from the continuous management of chronic conditions to a short-interaction, curative model. Cell therapies have demonstrated efficacy in illnesses ranging from terminal cancer to sickle cell disease. By leveraging what we have learned over the last decade in complex biologics manufacturing controls and applying those lessons in this new context, we can revolutionize health treatments. Future generations will likely look back in amazement at how medicine was practiced before the advent of cell therapy.
True Success is Measured by Access – with Carolyn Sasse, Head of Clinical Operations, Data Science and China Development, Astellas Pharma
Over the last ten years, gene therapy has transformed from an emerging technology to an area of immense growth. With hundreds of gene therapy clinical trials underway, many biotech and pharmaceutical companies are dedicated to making this new era of genetic medicines a reality.
True progress and success will be measured by patients’ ability to access treatments. Trials must be designed in a way that will support approval and reimbursement. Payors must see the value of a potential one-time gene therapy treatment and be able to approve treatments based on endpoints that are expected to predict the clinical benefit and durable effect. Industry, health authorities, and payors must adapt their strategies to account for what patients and their caregivers value. Only through this collaborative approach can we effectively seize the tremendous opportunity to broadly deliver gene therapy for patients.
Production Efficiency is Crucial – with Hideki Shima, Chief Manufacturing Officer, Astellas Pharma
Cell and gene therapies can play a key role in addressing unmet medical needs, but a step change in manufacturing is needed to enhance affordability and supply to reach patients in need. Over the past few decades, the antibody yield has also increased by hundreds of times. At Astellas, we have observed a similar trend with AAV production. Continuous efforts will enhance productivity with reduced manufacturing costs, enabling these new innovative medicines to truly support patients.
Three elements can help increase production efficiencies. First, we need to increase productivity per unit volume; for example, if we can increase the cell density by ten times in one reactor, the yield will also increase. Second is output per host cell or individual organism per unit time. Through advanced cellular genetic engineering, we can modify cell characteristics and their environmental tolerance to increase productivity. Third, I believe that scale up can be assisted by digital technology. Digital technology will allow us to conduct more simulations with even more precise predictivity. Improvement of monitoring and analytical technologies will also support the pursuit of a robust process in handling cell and gene therapies.
The next ten years will be an exciting journey of exploration and significant advancements in the field.
Overcoming Outdated Processes – with Jason C. Foster, CEO, Ori Biotech
Manufacturing remains a critical barrier to scaling cell and gene therapies, limiting the clinical and commercial impact of this life-saving new class of therapies. As we look ahead to the next decade, a pivotal focus must be placed on scaling impact by ensuring these treatments are approvable, accessible, and affordable.
Autologous cell therapies present challenges that the industry has never faced before – both in manufacturing and supply chains. The industry has applied the best learnings from biologics and other modalities in the first iteration of processes, but repurposing equipment from other modalities has only gotten us so far. We now need a second generation of more bespoke, automated technologies to solve these challenges and really make a step change in patient access. CGT developers are essentially manufacturing companies. To achieve commercial viability, we need to prioritize manufacturability, CMC, and viability as equally as we do safety and efficacy early in the development journey.
The cell and gene industry is at a crossroads. It must transition from its traditional, labor-intensive methods to more modern, efficient systems that automate better biology, accelerate product development, and scale the clinical and commercial impact of this new generation of therapies. To enable widespread patient access, manufacturing platforms must support a seamless transition from R&D to commercial-scale GMP manufacturing. This will allow innovative advanced therapies to reach the market and patients faster by reducing development time, increasing throughput, lowering COGS, and reducing batch failures.
Furthermore, the manufacturing of cell and gene therapies is hampered by outdated, paper-based practices carried over from large-batch pharmaceutical manufacturing. A 1,000-paper batch record is appropriate when it represents thousands of doses, but it’s a different story when the same type of record is required for every batch of a personalized autologous cell-based therapy. Practices like these are only one way in which outdated manufacturing practices hinder efficiency and, more importantly, limit the ability to scale cell and gene therapies to meet growing patient needs.
To overcome these challenges, a radical transformation is needed. Moving away from paper-based records to digital systems will introduce much-needed flexibility and real-time data access, facilitating better decision-making and faster responses to process deviations. This shift, when combined with automation, will streamline workflows, reduce human error, enhance overall throughput, and reduce batch failures, making it possible to scale production to meet increasing demand.
Advanced, automated manufacturing technologies can significantly improve efficiency by eliminating batch processing inefficiencies and reducing the need for extensive human intervention. Smart manufacturing systems that incorporate sensors and data analytics will further enhance equipment uptime and provide valuable insights into process performance, ensuring that manufacturing processes are both scalable and adaptable.
Digitization is another component of the puzzle that will enable real-time monitoring and control of the manufacturing process, providing critical insights that can be used to optimize operations. By leveraging data analytics, manufacturers will be able to identify trends and patterns that may not be apparent through manual inspection, allowing for proactive adjustments to improve efficiency and quality. Advanced sensors that monitor critical parameters in real time allow for immediate detection and correction of any deviations from the desired process conditions.
Data collected from these sensors can be analyzed to identify opportunities for further optimization, driving continuous improvement in the manufacturing process. Critically, this empowers scientists to take back control. Current systems constrain their ability to innovate and optimize processes. By providing a platform that allows scientists to design processes according to their needs rather than being dictated by the system, we put control back in their hands.
Addressing these critical bottlenecks and embracing modern manufacturing solutions will enable the industry to scale its impact and ensure the viability of advanced therapies. This holistic approach is crucial for transforming healthcare and meeting the growing demand for innovative treatments. By leveraging the latest technologies and approaches, the industry can overcome the limitations of traditional methods and pave the way for a new era in drug development and manufacturing.
Aiming for First-in-Line – with Brian Burke, Chief Commercial Officer, Tozaro
The near-term value is very much around oncology and rare diseases, with autoimmune disease also now a consideration. The big question is how do we get the economics and safety profile of these therapeutics to a level where they can be deployed routinely as a first line treatment, or even in individuals who are not already presenting with serious symptoms or who are at risk of death?
For example, neurological and cardiac health tend to decline on a gradual basis over several decades until there is an acute presentation of ill health. In some cases, genotypic or other biomarker evidence may have offered pre-disease insight. Over the next 10 plus years, the challenge, therefore, is to be able to prescribe the correct cell or gene therapy at the right stage, potentially even prior to full presentation of the pathology. This requires a different paradigm for designing, personalising and manufacturing treatments to ensure they are safe and can be generated in an affordable manner.
Within cell and gene therapy manufacturing, viral vectors are often a crucial component in providing treatment, however manufacturing remains both opex and capex intensive. As manufacturing becomes more decentralized, new tools are required to increase efficiency of production while reducing the footprint required to achieve this. Exploration of new technologies, such as synthetic affinity reagents, is helping to solve the challenges in viral vector processing by increasing yield of functional virus per manufacturing run, which consequently increases total capacity whilst reducing manufacturing costs – a key pivot point.
Over the coming years, advancements in how we manufacture cutting-edge therapies will be a main driver in broadening their uptake.
Moving to Automation – with Alex Sargent, Director of Process Development, Cell & Gene Therapy, Charles River Laboratories
With over 4,000 cell and gene therapies currently in development, according to the American Society of Gene and Cell Therapy, this market will continue to grow at an accelerated pace over the next 10 years.
As the number of approved cell and gene therapies continues to expand around the world, it will bring new challenges about how to increase affordability and availability. The focus will shift from feasibility to fulfilment in cell and gene therapies, and we will need to come up with new and better ways to manufacture and deliver these types of drugs. Shifting how we manufacture cell therapies could dramatically improve cost and access. Adopting automation for both the manufacture and testing of cell therapies has the potential to improve this industry. Current methods for manufacturing are often laborious and rudimentary, relying on systems and technologies developed decades ago to produce and grow cells in research laboratories. As the need to grow cells clinically and commercially for therapies has emerged, so too have fully automated systems and new technologies. Shifting more towards automation and technology, when appropriate and applicable, can elevate the way we make cell therapies so that they are affordable, safer, and more attainable for the patients who need them.
I would like to see the cost of cell therapies go down and their availability go up. I believe investing in automation and new technologies to manufacture these therapies can help achieve that. I also believe going from autologous, individualized therapies to allogeneic, universal therapies, where appropriate, can also help significantly drive new and effective cell-based treatments to patients on a global scale. If we continue to work towards these goals, we may see the promise of cell and gene therapy realized in our lifetimes, and diseases that today are a death sentence will become treatable and curable.
Gene Therapy for Common Ailments – with Curran Simpson, CEO, REGENXBIO
Gene therapy has the potential to change the way medicine is delivered for millions, and we are only at the beginning of seeing its impact and unleashing its full potential. Today, more than 30 cell and gene therapies have been approved by the FDA and thousands of patients with rare diseases, such as sickle cell disease and hemophilia, have benefited.
I believe the next wave will be even more transformative – bringing gene therapies from rare disease communities to the masses. Clinical researchers are exploring gene therapies for common ailments such as retinal, cardiovascular, metabolic diseases, and cancer. As we continue to advance this science and identify additional gene delivery mechanisms, significant breakthroughs are on the horizon.
But the path forward isn’t easy. Each gene therapy product will require a highly specialized manufacturing process, which can be difficult and costly to standardize and scale. Quality manufacturing is crucial to all stages of gene therapy development for both rare and common diseases, and I believe that the sponsors who invest in manufacturing and process development early will be the ones to succeed in this field.
The challenges in bringing these new medicines to patients are significant, but I’m confident we will overcome them. With researchers, physicians, sponsors, payers and patient communities working together, we have the potential to truly unleash the curative potential of gene therapy.
Incorporating AI into Manufacturing – with James J. Cody, Associate Director, Technical Evaluations, Charles River Laboratories
Some of the biggest disruptors to the field over the past ten years have been the market approvals of AAV vector-based gene therapies such as Glybera (by the EMA in 2012) and Luxturna (by the US FDA in 2017). Though gene therapy has been an active area of investigation for several decades now, these approvals set the stage for an increasing number of AAV approvals.
Similarly, oncology-directed therapeutics have also seen an increasing pace of clinical approvals, including the adenoviral vectors Gendicine (first approved in China in 2003) and Adstiladrin, as well as other modalities such as CAR-T therapies. The recent COVID-19 pandemic also prompted the swift commercialization of mRNA-based and adenoviral vector-based genetic vaccines.
It is reasonable to assume that the pace of approvals will continue to accelerate over the next 10 years. In fact, the FDA itself anticipated approving 10-20 cell and gene products per year by 2025, according to a statement released in 2019. In parallel, there is also a trend towards streamlining vector manufacturing to increase efficiency, shorten timelines, and drive down cost both for the vectors themselves and for critical raw materials such as plasmids. A number of technologies are likely to see wider adoption. For example, engineered and novel capsids will improve targeting and potentially reduce off-target effects. Engineered cell lines (both packaging cell lines and stable producer cell lines) may be employed to boost upstream productivity, perhaps through synthetic biology techniques.
I also believe that manufacturing as a whole (both upstream and downstream) will increasingly involve AI and mathematical modeling for in silico process optimization. However, while these techniques may guide the overall strategy and/or help identify key conditions, any type of process optimization will need to be backed by data collected from actual manufacturing runs. To that end, there will also be advances made on the product testing front, with new testing methods developed to shorten turnaround times and reduce required sample volumes, preserving material for clinical and commercial use. To date, many manufacturing challenges have already been addressed by taking a platform approach to both manufacturing and testing. A platform approach enables similar products to be more rapidly advanced through development.
The challenge going forward will be to balance the advantages of having a robust platform with the increasing variety of novel products and new manufacturing technologies. In this regard, having a modular approach (incorporating new technologies into “tried and true” platforms) will be advantageous.
Finally, the regulatory review process will also likely become more streamlined, aided by the ever-accumulating data of platform processes. The recent reorganization of the FDA’s Office of Tissues and Advanced Therapies into the Office of Therapeutic Products demonstrates an anticipation of the growing tide of new product applications and a dedication to streamlining the review process.
Read more about the future of pharma here.
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