For many, the key to solving these issues lies squarely in rethinking the manufacturing portion of the value chain. “Right now, the single biggest hurdle to mass adoption of CGTs is, without doubt, their manufacturing and the sheer logistical practicalities of transferring the product from patients to the manufacturing facilities and back again, both of which translate into untenable prices,” affirms Pierre Socha, Partner at global technology investor, Amadeus Capital Partners.
Because, in CGT, the process essentially is the product, agencies have a duty to look more closely at the quality and consistency of the manufacturing to ensure that the therapies always remain safe for patients
Meanwhile, increased regulatory scrutiny over the fabrication practices of cell and gene therapies also threaten to delay uptake. The manufacturing stage has not escaped the notice of regulators some of whom bemoan the prevailing lack of standardization and fret about the possible implications for the safety profile.
As Ana Hidalgo-Simon, Head of Advanced Therapies at the European Medicines Agency (EMA) explains, “because, in CGT, the process essentially is the product, agencies have a duty to look more closely at the quality and consistency of the manufacturing to ensure that the therapies always remain safe for patients.”
“The major issue here is comparability, because this field is so very new and the manufacturing processes being deployed vary so greatly. These changes need to be made in an extremely controlled and recorded manner so that we can evaluate and compare processes and so that we can use all the data collected linking all stages of development to the final product,” she insists.
Unique Characteristics & Immature Systems
Indeed, with CAR-T products especially – which require the extraction, genetic modification, expansion and re-administration of each individual patient’s cells – manufacturers find themselves grappling with the tricky conundrum of how to produce a consistently safe product from what are, in effect, highly variable starting ingredients.
“Because the quality of the final product is so closely tied to the biology of each particular patient’s cells and every patient is distinct, there is an inherent unpredictability and complexity in the fabrication process that renders it fundamentally different to the typical manufacturing scenario in which a well-defined cell line is used for each production run,” Socha explains. “Frankly, the industry is still trying to figure out the optimum approaches to dealing with these issues,” he adds.
Nor do the challenges stop there. “Beyond the variance in ingredients, there are aseptic considerations around processing to take into account and the fact that the supply chain is already pretty complicated even before you dock in the most important part which is, of course, the patient, their materials and the corresponding chain of identity,” reflects Stephen Ward, Chief Manufacturing Officer of the UK’s Cell and Gene Therapy Catapult.
Moreover, he is quick to point out that the enabling technology presently in operation remains relatively immature. “It’s important to remember that, thus far, many CGT manufacturing processes have been developed based on small patient populations, primarily through a manual process and in a rather inefficient, unscalable manner. Therefore, there remains considerable scope for improvement such as transitioning from open, manual systems to closed, automated ones.”
“If cell therapies are ever to go mainstream and become widely available across multiple indications, rather than just be deployed for rare disease patients or as a last in line treatment when all else has failed, then there are going to have to be some wholesale changes in the manufacturing space to render everything more platform-based,” warns Diane Blumenthal, Former Head of Technical Operations at Spark Therapeutics. “Optimization through automation, process simplification, and proper supply chain management could all have a very beneficial impact. There is a great deal still to do,” she affirms.
Unlocking Efficiency Gains
Other efforts to inject greater efficiency into the cell manufacturing process include relocating activities closer to where the patient is. “One fascinating trend that we’ve been noticing of late has been the development of on-site or Point-Of-Care (POC) manufacturing,” explains Professor Nicolaus Kröger, President, European Society for Blood and Marrow Transplantation (EMBT).
“Some companies have been developing very small manufacturing plants that could engineer the patient’s T-cells directly at the hospital or even by the patient’s bedside, which would be truly transformative. Certain centers in Germany have already received approval from the regulators to trial this out, and the government in Spain also appears to be supporting this concept of the pop-up, mini factory-in-a-box,” he enthuses.
“It’s certainly not overly futuristic to imagine that the engineering of the T-cells could eventually be performed next to the patient within the hospitals. We already see strong tendencies in that direction,” agrees Thomas Szucs, Director of the European Center of Pharmaceutical Medicine at the University of Basel.
A more streamlined and standardized regulatory approach could also prove helpful in keeping costs in check. “If regulatory frameworks could be developed specific to gene therapy manufacturing such as reusing certain vectors and changing out inserts, then we could see a significant reduction in manufacturing costs. Even just the enforcement of common manufacturing protocols and techniques could make a noticeable difference,” claims Dr Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA).
Autologous versus Allogeneic
Meanwhile one way some companies have been trying to de-risk the manufacturing process has been to come up with an off-the-shelf, so-called ‘universal CAR-T.’ Whereas autologous cell therapies are manufactured from the patient’s very own cells or tissue and require a separate manufacturing batch for each individual, a mass-market allogeneic cell therapy (i.e. derived from an external donor) could, by contrast, be produced in bulk and frozen for later use by multiple patients.
“Off-the-peg, allogeneic CAR-T therapies could well turn out to be better suited to catering for large patient groups, because the doses could be pre-manufactured ahead of time and greater economies of scale leveraged,” muses Szucs, though he acknowledges that such technologies are more complex to engineer because additional genome editing is required to avoid host rejection.
For many, the jury is still out as to which style of cell therapy will prove the more efficient over the long run. “In Japan, the regenerative medicine industry has very much developed around the concept of autologous regenerative therapy, which is using stem cells taken from the patient’s own body, as opposed to allogeneic therapy where you seek to harness stem cells from donors. The approval pathways are clearly faster for autologous therapies, but given the manufacturing, supply chain and commercial models end up being so different it is still difficult to tell [which of the two pathways will become dominant],” muses Ken-ichiro Hata, Representative Director and Chairperson at the Forum for Innovative Regenerative Medicine (FIRM) in Japan.
Scaling the Learning Curve
Meanwhile early pioneers of CAR-T therapies such as Novartis and Gilead have been investing deeply in the upgrade, round-out and fine-tuning of their cell manufacturing capabilities, conscious of the potential competitive advantages to be gained by getting it right.
Ultimately it’s a journey of discovery and experimentation. We are learning and fine tuning all the time
Novartis Oncology which today lays claim to the largest and most comprehensive manufacturing platform for cell and gene therapies in the world now boasts 5, soon to be 6, active manufacturing sites spread across four continents, and yet continues to invest. “We are currently busy assembling a next-generation manufacturing platform that has the potential for higher efficiencies, shorter turnaround times and hopefully better outcomes. It will also allow us to preserve a different subtype of T-cells that we believe will have a positive impact on durability of efficacy. Using this platform, we are developing a portfolio of novel CAR-Ts, addressing multiple antigen targets across different malignancies,” confirms Stefan Hendriks, Global Head of Cell and Gene.
“Ultimately it’s a journey of discovery and experimentation. We are learning and fine tuning all the time. One of our early realizations was that we should establish a balanced mix of in-house manufacturing capabilities and external partnerships,” he recalls. “We require the former because it’s important to build and master that manufacturing expertise ourselves, but it’s equally critical to enrich and complement that home-grown knowledge with outside impetus and ideas from around the world hence our collaborations with the Foundation for Biomedical Research and Innovation (FBRI) in Japan, Cell Therapies in Australia, and Cellular BioMed Group (CBMG) in China. When it comes to these partnerships, geography is not as important as the expertise and experience of our partners.”b
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