Personalized cell therapy, because of its individualized nature, carries with it a unique set of manufacturing challenges compared to both “off-the-shelf” cellular therapeutics and traditional pharmaceuticals and biologics. Chief among these challenges is the need to manufacture such therapies, for clinical and ultimately commercial use, in a way that takes into account cost of goods, quality, scalability and sustainability.
Contrary to the common belief that securing sufficient capital to construct a manufacturing facility overcomes the primary constraint to commercial manufacturing, the very nature of (and the continued operating costs related to) the manufacturing facilities that are required can create in themselves obstacles to achieving optimal efficiency for manufacture. The needed facilities are actually relatively inexpensive to construct, further perpetuating this myth that the industry’s barriers to success can be overcome simply by each cell therapy developer opening a new manufacturing facility—and it is this very belief that has effectively brought commercial deliverability to its knees.
In truth, the primary manufacturing constraint to delivering commercially viable cell therapies is actually the current state of the art of patient-specific cell therapy manufacture itself. Further, any attempt to design an appropriate facility around today’s technology will soon be rendered obsolete as truly scalable and deliverable manufacturing methodologies become available, which they must do in order to ensure the long-term viability of the industry. We as an industry have now had the opportunity to witness this phenomenon multiple times, and if we pay attention to these business cases, we have much to learn from them.
In a traditional cell therapy manufacturing model, a developer invests a great deal of time and resources into creating a dedicated manufacturing facility intended for the manufacture of one or two therapeutics. In this case, the operating costs, inability to scale appropriately to meet demand and other potential pitfalls can be daunting, and have proven over and again to be insurmountable obstacles to commercial viability. Only the ability to provide for a steady flow of scalable, automated, high-volume, mass-produced product can effectively distribute the costs and risks. No facility in itself can overcome (and in fact, facilities often contribute to) the obstacles associated with uncertainty of market demand and shrinking reimbursement. In addition to the difficulty in precisely predicting market size over time for a product that is still in clinical-stage development, market penetration for new modalities of our more complex and less-than-traditional therapeutics makes it difficult to be prepared for real-time scale in either direction to react to market forces. Likewise, planning ahead for labor intensity, human resources (manpower) and scheduling needs can lead to further stresses on output.
The current nature of cell therapy manufacturing processes relies upon a great deal of time, manpower and cleanroom space being devoted to the process, which can lead to burdening costs of goods with the overhead operating expenses associated with idle capacity. Idle capacity of the manufacturing facility—underutilized technologies, people, facilities and resources—drives cost of goods for delivery of the eventual commercialized product to unsustainable levels. The result can lead to, and has tragically already lead to, the failure of a product to ramp up production in line with market demand, with results as dire as bankruptcy in some cases. It is this burden of facility operating expenses and idle capacity that is the secondary manufacturing constraint to commercial deliverability.
Shared-risk approach
Clearly, a straightforward and readily achievable solution to this industry-wide problem is one in which a “shared risk” approach allows for the spread of idle capacity among a greater number of therapeutics, and ideally removes the vast majority of the idle capacity through efficiency of utilization. Lower entry costs and much-reduced—and to-market scalable—operating expenses begin to remove the manufacturing facility and its high operating costs from being a liability to deliverability. There is the additional, critical benefit of concentrating a great deal of world-class expertise within a single pharmaceutical quality system that will support our right to operate as an industry.
The shared commercial delivery model has already been tested—and proven to be successful—at a clinical scale through the utilization of contract manufacturing organizations (CMOs) for clinical production. At a CMO facility, a single infrastructure with a few cleanrooms is shared between several cell developers, with closed processing systems and data protections in place to make sure that each developer’s work stays isolated, compliant and proprietary. In such a CMO model, each developer may be requiring a small volume (10 to 100 patient batches) of product. The idea of a shared manufacturing facility is to take this concept to the next level, now looking at what might be needed for cell therapy developers to co-exist in different rooms and perhaps different buildings within the same facility complex—now in the thousands of therapeutic batches of product as needs scale to meet demands of the market.
A shared facility model incorporates several key design principles. First, in addition to the mindset of manufacturing, a pharmaceutical-level quality assurance system—both temporal and spatial—must be in place for process isolation, separation and segregation. Such quality assurance aims to prevent any crossing of material, processes or confidential information between individual developers and their products. Equally important is the organization of various types of data (materials, inventory, clinical trial data, etc.) through the use of electronic record-keeping, to account for the scaled-up capacity that a commercial facility entails. Use of electronic databases including document management systems, electronic batch records, laboratory information management systems and manufacturing execution systems ensure that proprietary information stays organized, controlled and confidential all the way through the manufacturing process. A shared facility model would also include additional important shared site resources, such as materials control/warehousing/procurement, facilities/equipment management, validation, regulatory and compliance monitoring, scheduling and logistics, manufacturing development and technical services.
Envisioning facilities of the future
Despite the clear benefits of the shared-risk model, it is important to note that in its current state, the manufacturing facility is not only such where, as discussed, it is impossible to deliver the product effectively, but, without the benefit of innovation resources, the developer is locked into a manufacturing process that cannot be successfully scaled, regardless of whether the facility is shared or not. When all of the company’s focus and resources go toward production and no efforts are spent on engineering, innovation and automation, the paradigm remains unchanged. To put it another way, simply building a better and bigger clinical manufacturing infrastructure is not enough for a successful commercial manufacturing infrastructure.
Too often, when a cell therapy developer decides to undertake the creation and management of a single-use facility, the focus gets completely absorbed in manufacturing rather than in the development and quality of the product itself; the company inevitably shifts from being an innovation machine to a production machine. Innovation and production in the cell therapy industry—indeed, in any industry—are two vastly different skill sets that require different mentalities and different practical execution. The more a cell therapy developer is forced to focus on manufacturing, the more the innovation gets pushed to the wayside.
The truth is that commercial cell therapy manufacturing facilities, even those built on the proposed shared facility model mentioned here, will still fail if built on today’s manufacturing processes. What we need is an industry-wide effort of innovation and engineering, thoughtful and staged rebuilding of unit operations for cell therapy manufacturing from the ground up, to transform cell therapy manufacturing processes and test methods in a way that achieves true scalability and sustainability.
At some point, all manufacturing processes have been weaned from the research labs in which they were born, allowed to mature into adolescent cell therapies in the cleanroom space. For the continued growth and evolution of the industry, these processes must now be weaned from the cleanroom and sent to the “back of the facility” into production spaces more suited to high-volume production, where the focus is not on cleanrooms but on delivery through complete maturation to adulthood of the entire manufacturing environment. Only with this achievement can patient-specific cell therapies enjoy commercial success.
Dr. Robert A. Preti is president of PCT, a Caladrius company. He is also senior vice president of development and technical operations and chief technology officer of Caladrius Biosciences.
