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CGTs offer hope for the future of treatments, but the costly manufacturing, slow turnaround time, and need for supplies hinder progress.
A treatment that has been top-of-mind in recent years is cell and gene therapies (CGTs). Many companies and organizations investigate the potential of this type of treatment to address unmet medical needs. While significant headway has been made, CGTs are in their infancy. But with the potential to cure diseases, CGTs could change the future of treatments for certain conditions.
“[CGTs] offer for the first time the possibility to offer truly disease-modifying treatments, providing options for conditions considered intractable or where the current standard of care is insufficient,” says Bayer AG company sources.
While headway has been made for CGTs, there is still much to consider for how manufacturing can be improved, which ultimately impacts the success of a drug product.
“Safety and efficacy of CGTs are strongly determined by production process quality,” says Bayer AG company sources. “Therefore, robust manufacturing processes are a fundamental factor for their success. Scalability and optimizing chemistry, manufacturing, and control [CMC] processes from preclinical research to early usage and ultimately full-scale commercialization remain critical aspects in the translation of these technologies to tangible treatments.”
What’s next for CGTs? Where has the industry made headway, and what challenges are still ahead? Moreover, what potential trends are on the horizon?
BioPharm International interviewed Elena Meurer, principal consultant, Biopharma Excellence, a Pharmalex company; Mathew Durdy, CEO, Cell and Gene Therapy Catapult; Matthew Hewitt, executive director scientific services, cell and gene therapy, Charles River; Emily Moran, vice president, viral vector manufacturing, The Center for Breakthrough Medicines; Chris Xu, CEO, Thermogenesis; and David Chang, CEO of WuXi ATU about challenges, breakthroughs, and trends in manufacturing CGTs.
BioPharm: What are the biggest challenges for manufacturing CGTs?
Meurer (Biopharma Excellence): One of the serious challenges is the affordability of cell and gene therapies for the healthcare system and for patients. Manufacturing costs often contribute significantly to the high price, although continuous efforts are being made to reduce these costs via improved manufacturing technology. Typical reasons for high manufacturing costs are the need for flexibility in the manufacturing schedule, scale limitations, expensive quality control, and complex logistics.
Durdy (Cell and Gene Therapy Catapult): We need to look at [the] manufacturing of CGTs in the full context of what it takes to deliver [the] manufacturing of these therapies in order to identify key challenges. Skills, supply chain issues, and access to flexible manufacturing capacity to meet patient and clinical timelines, as well as automation/digitization of documentation for batch release are some of the challenges that need to be addressed to enable these therapies to reach patients in an efficient way and at scale.
Hewitt (Charles River): A pain point more relevant for autologous cell therapies is how to efficiently manufacture them to minimize vein-to-vein times. Currently, companies are employing a centralized manufacturing approach, which is possible in the short term as the current slate of commercial therapies addresses small patient populations. Even so, there have been issues with this current model. A 2021 European Hematology Association conference poster described how vein-to-vein times can vary significantly when commercial cell therapies are manufactured far from the point of care (1). From this, a question arises whether autologous cell therapy manufacturing needs to migrate to a decentralized manufacturing model to reduce vein-to-vein times.
Moran (The Center for Breakthrough Medicines): Current therapeutic platforms are nascent, developed in academic labs, challenged by the ability to efficiently scale, replicate, and effectively manufacture their therapies. While the science behind these platforms will need to change over time, regulators need to keep pace. Close collaboration with regulators is required to develop a path to approval. Manufacturing solutions for advanced therapies require seamless and robust tech transfer processes to avoid delays in process development and inefficient scale-up models; this is a current gap that needs to be addressed.
Xu (Thermogenesis): The process is very lengthy with storage and harvesting having to yield to certain standards. There are not a lot of CDMOs [contract development and manufacturing organizations] that are well-equipped to handle the process that is required for cell and gene therapy manufacturing, and it takes years for a company to build their own, shall we say, formula of manufacturing. This leads to a shortage of CDMOs.
Chang (WuXi ATU): One of the biggest challenges still facing the cell and gene therapy industry is plasmid supply. There are often long lead times associated with GMP [good manufacturing practice] plasmid production; so, it can be very advantageous for a therapeutics developer to work with a manufacturing partner who can not only manufacture their viral vectors, but also their GMP-grade plasmids, and can supply these in the shortest possible timeframe. There’s also variability in plasmid quality, which can impact the titer and quality of the resulting viral vector.
BioPharm: What are significant breakthroughs for manufacturing CGTs?
Xu (Thermogenesis): The first human patient to be treated with gene therapy was a four-year-old girl suffering from severe combined immunodeficiency in 1990 (2). She received treatment for a congenital disease called adenosine deaminase (ADA). Since then, gene therapies have been used to treat diseases, such as cancer, cystic fibrosis, and hemophilia. In 2017, the FDA gave its first approval of a gene therapy called Luxturna, which is used to treat patients with established genetic vision loss that may result in blindness (3). Gene therapies are still being studied and developed, with over 1000 clinical trials currently underway.
Chang (WuXi ATU): CRISPR [clustered regularly interspaced short palindromic repeats] technology presented us with the opportunity to rewrite our genetic code, and for the last 20 years, the vision has been to bring this into the clinical phase and make it possible to alter genetic abnormalities in vivo. That vision is now extremely close to becoming a reality. But of course, it’s not just CRISPR technology that has reached this point, but viral vector engineering, too, to ensure specific packaging of CRISPR and Cas9 within AAV [adeno-associated virus] vectors for delivery to the target tissues.
Hewitt (Charles River): Gene editing has the potential to transform cell therapy manufacturing, making it truly personalized and flexible. Manufacturing GMP plasmid and vector is a time-consuming, expensive process. Moving to gene editing could significantly simplify cell and gene therapy manufacturing while reducing costs. The use of gene editing also provides the ability to target specific sequences for knock-out and specific loci for knock-in. Future cell therapies may be manufactured at the point of care to address specific patient indications using advanced analytics data to identify the specific edit sites and/or antigens required to eliminate tumor cells.
Meurer (Biopharma Excellence): [T]he use of iPS [induced pluripotent stem cells] in the manufacturing of allogeneic therapeutics is an important milestone. Even though there are still many constraints regarding [the] large-scale production of iPS cells, it is just a question of time before the manufacturing technology catches up.
Durdy (Cell and Gene Therapy Catapult): The development of CAR T-cell [chimeric antigen receptor T-cell] technology and approval of those [have] opened the way to many clinical trials and therapies now in the clinics. Industry, regulators, payers, healthcare providers, and national healthcare systems have all [learned] a lot from CAR T-cell therapies, reaching patients both from manufacturing requirements as well as [from a] health, economics, regulatory, and supply chain perspective. The manufacturing and administration of living therapies that have the potential to cure diseases [have] triggered a complete shift in how therapies should be evaluated.
Moran (The Center for Breakthrough Medicines): The significant breakthroughs include process automation that is fully integrated with equipment, closed disposable systems for a variety of processes, and flexible facility design with a modular approach. Building on these foundational needs will allow manufacturers to flex and support different platforms such as plasmids, viral and non-viral vectors, and autologous and allogeneic cell therapies. This can be further expanded to in-line analytics, to meet the ever-evolving demand.
BioPharm: What trends are you seeing in the CGT space?
Hewitt (Charles River): Therapeutic developers have been watching the field and [have] seen that [CMC] issues have been the focus of many regulatory delays. Because of this, we’ve seen a renewed focus on ensuring analytical methods are able to be implemented for commercial products. The regulators have been clear they will require analytical methods that are able to consistently measure product critical quality attributes (CQAs). Certain cell therapy modalities are more difficult than others when doing this development, such as unmodified tumor-infiltrating lymphocytes (TILs), to identify reliable cell characterization and mechanism of action (MoA) potency/functionality assays. Even [with] this, many are making progress.
Durdy (Cell and Gene Therapy Catapult): It is encouraging to see that there [are] now more upfront thoughts about data and data handling. The implementation of comprehensive manufacturing execution systems and integrated digital systems is traditionally embarked upon in readiness for commercialization once the manufacturing process is completely tied down and just requires churning out the same process over and over again. In CGTs, it is being embarked upon earlier and earlier in the phase of clinical development; it is not unusual for an MES [manufacturing execution system] to be considered in Phase I.
Moran (The Center for Breakthrough Medicines): Manufacturing facility design is evolving to accommodate [the] flexibility required to address shifting needs in the marketplace. Manufacturing facilities will need to be flexible multi-product facilities that can manufacture a variety of advanced therapeutics. There will be more exploration into non-viral delivery methods and more patient-focused processes, requiring a greater level of adaptation than ever before. Improved tropism, vector and capsid design, and delivery mechanisms will have a dramatic impact on the field as well as better production methods that result in higher yield in both upstream and downstream.
Xu (Thermogenesis): In the past, traditional chemical or small-molecule drugs were made for millions or billions of people. Cell and gene therapies are personalized drugs, using your own cells, and are specifically made for each individual … Current infrastructure only can handle thousands of patients. We need infrastructure for cell and gene therapy that can potentially handle millions and hundreds of millions of patients. The investment in cell and gene
manufacturing infrastructure capabilities will increase dramatically.
Meurer (Biopharma Excellence): Enormous progress has been made in the application of CRISPR and gene-delivery technologies. One of the trends we’re seeing is the combination of different technologies such as CRISPR, viral and non-viral gene delivery, and the potential of CAR-T and CAR-NK applications for creating powerful therapeutic approaches. Progress in RNA-based gene delivery and transposon technology should not be underestimated either. Different gene modification and delivery tools are often used together.
Chang (WuXi ATU): The [CGT] industry is expanding rapidly, with emerging trends that can best be described as either therapeutic or process-based. Therapeutic advances, such as in vivo gene editing, were unheard of a few years ago, but some in vivo CRISPR/Cas9 therapeutics are now in the clinical phase. The growing preference for allogeneic over autologous cell therapies—including allogeneic CAR T-cell therapies—is another notable therapeutic trend. As for process-based trends, there’s an increasing focus within cell and gene therapy to improve the scalability of manufacturing processes and reduce the costs associated with manufacturing. A similar focus is being paid within viral vector engineering and other production technologies to improve the quality of viral vectors in terms of packaging efficiency, infectivity, and even specificity for a target cell type.
Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.
Vol. 35, No. 3
When referring to this article, please cite it as M. Rivers, “Opportunities for Growth and Breakthroughs for Cell and Gene Therapies,” BioPharm International 35 (3) (2022).