Long playing second fiddle to R&D and considered to be the more mundane segment of the pharma value chain, manufacturing has abruptly been thrust into the limelight when it comes to taking cell and gene therapies mainstream.
“Manufacturing in the small-molecule world was an entirely different story that could be outsourced to junior partners. Now, all of a sudden, it starts to genuinely matter how good you are at production because if you cannot master this technically challenging and pitfall strewn stage of the process, you will almost certainly experience problems getting your product to market,” affirms Salim Syed, Head of Biotechnology Research at Mizuho Financial Group.
Indeed, not only do the pioneers of this novel class of medicines seem to be taking the fabrication stage increasingly seriously – Novartis recently set aside a full USD 500 million just to scale up its gene therapy manufacturing efforts – but, the global market for this type of activity is visibly taking off. For instance, according to the latest figures from market research entity, MNM, the global segment for production of viral vectors for cell and gene therapies, often said to be the most complex and resource-intensive process in the entire panoply of biologics manufacturing, is projected to reach a value in excess of USD 815.8 million by 2023.
“I would go as far as to say that the overriding outstanding challenge for this class of therapies is no longer the scientific discovery side, but the manufacturing component. In gene therapies, a full 85 percent of the product is embedded in the process,” insists André Choulika, chairman and CEO of French immune-oncology pioneer, Cellectis.
One way some companies like Cellectis 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.
“As Universal CAR T is not a personalized therapy, companies like ours should be able to produce hundreds of dosages at a time to treat a wide patient base… The product in a batch of made today could literally be the same as the product you will produce and give to a patient three years from now,” confirms Choulika.
By contrast, some analysts are suggesting that the only real viable way of producing autologous cell-based applications effectively at scale might be to have the cell production and processes occurring almost at the bedside. “The quest is to identify a cost-effective practical pathway such as migrating the manufacturing component to close proximity to the actual point of care,” ventures PhRMA’s SVP of Policy and Research, Anne McDonald Pritchett.
“Successfully coupling industrialization with mass customization is ultimately going to be quite a feat,” agrees Alberto Santagostino, SVP and Head of Cell and Gene Technology at the Swiss contract development and manufacturing organisation, Lonza. “Manufacturing for autologous therapies is riddled with complexity and yet it still requires very tight timeframes and considerable standards of quality to be successful,” he muses.
Determining whether to opt for the autologous or allogeneic route, however, is only part of the battle due to systemic capacity deficiencies worldwide. “In general, developers of this class of therapies still tend to be rather ill-equipped to complete the transition from a clinical orientation to more of a commercial posture,” observes Santagostino, implying that they will have to “compete fiercely” for the handful of existing contract manufacturers out there that do actually possess the knowhow.
“Having control of your own cell and gene manufacturing capacity is certainly now regarded as one of the biggest rate-limiting steps in being able to launch and grow revenues… In short, capacity has become king,” asserts Hussain Mooraj, NextGen Therapy Practice Lead at Deloitte. “Some organizations continue to invest in partnerships with external CMOs and are spending almost as much in leasing suites for long-term capacity, even if they are not currently being used. This has, in turn, placed a massive capacity constraint on the supply of GMP-grade materials sometimes leading to a 12 to 15 month waiting time for the supply of critical materials, such as viral vectors,” he explains.
“There’s been something of a reality check as suddenly drug makers have come to realize that they’re going to have to turn what, in essence, has been a cottage industry to an industrialized manufacturing process that is capable of being licensed and cost-effective… until rather recently understanding of economics was virtually absent from the field,” admits Keith Thompson, CEO of the United Kingdom’s Cell and Gene Therapy Catapult, a state-sponsored initiative to mature the niche sector.
A general lack of standardization of raw materials is clearly one of major pinch points with one of the most unique aspects of gene therapy manufacturing being the production of the viral vectors that are used to transport the new genes back into a patient’s cells. “This is a process that still lacks proper automation and where there is an urgent need to identify fresh efficiency gains,” points out Thompson.
Not surprisingly, industry is belatedly beginning to wake up, with several cell and gene therapy players investing heavily in building out their own hardware and booking manufacturing slots with the handful of CMOs with the requisite know-how. “Manufacturing has become foremost priority number one, two and three as firms come to realise just how much the process is the product…Since the start of 2019, there have been at least three major acquisitions of contract manufacturers: Hitachi Chemical’s purchase of Apceth, Danaher’s USD 21.4 billion takeover of GE Healthcare’s biopharma business, and Thermo-Fisher’s USD 1.7 billion acquisition of Brammer Bio,” reports Objective Capital Partners’ MD, David Crean.
The spending spree certainly shows no sign of letting up: last April, Catalent agreed to acquire Paragon Bioservices, a Baltimore, Maryland-based contract provider of viral vector development and manufacturing services for gene therapies, for USD 1.2 billion. In the CMO space, meanwhile, unprecedented risk and space sharing models are now being piloted. ElevateBio, for instance, has fashioned a dedicated cell and gene commercialization launchpad complete with a centralized facility, manufacturing and process development platforms and the requisite know-how.
Some believe that Korea, thanks to its well-honed experience in industrial assembly and manufacturing innovation, may be uniquely placed to offer solutions in such a complex and challenge-filled arena. “Companies like us are already well ahead of the game in developing state-of-the-art 3D cell culturing processes that can theoretically reduce the cost of manufacturing by as much as 80 percent,” confidently argues Woosok Lee, CEO of Korean group, Kolon Life Science.
What is for sure is that manufacturing is swiftly becoming the primary battleground upon which the winners of tomorrow will have to prove themselves. “Many entities will fail on the path to commercialization, and the winners will be those that invest in infrastructure and manufacturing partnerships … It is going to be an ecosystem of advances, no one is going to be able to do it on their own,” predicts David Lennon, president of Novartis-owned gene therapy biotech, AveXis.