Cell and gene therapies are relatively new areas for commercial biopharmaceutical development. These sectors involve relatively new applications of both old technologies used for decades (e.g., bone marrow stem cell transplants), and many new technologies. These sectors also are populated by many new players, including startup companies—but also much more than the broader biopharmaceutical industry—these sectors currently involve academic/nonprofit research organizations performing much R&D and even early product development.

The overall situation with cell and gene therapies is rather similar to that of the biopharmaceutical industry about three decades ago, in the mid-1980s: just a few pioneering products entering the market; information about these industry sectors not yet existing or of poor quality; information being scattered and not readily retrieval; lack of good information slowing commercial progress (e.g., investors finding it difficult to justify investments); and available manufacturing capacity to handle projected commercial manufacturing insufficient for near-term needs. Plus, “capacity crunches” are getting worse as more products enter the market.

The information resources currently available concerning cell and gene therapies in commercially relevant development remain limited at best. This includes information on developers, technologies, manufacturing activities, and capabilities. There are wide variations in reporting of the number and types of organizations actively developing products, and in the reported size and composition of these industry sectors. Identifying cell/gene therapy developers or products in commercial development is difficult—there are different organizations and products reported, with many new ones and many missing in each source. Part of this problem, is simply due to definitional issues that can confound reporting about cellular and gene therapies.

There is a lack of information on the pipeline, players involved, and organizations—such as contract manufacturing organizations (CMOs)—providing R&D and manufacturing services. While this is normal for most new industry sectors, cell and gene therapies are not technically new. Gene therapies have been around and even in commercial development for decades now, but safety, inadequate technology and other problems have held back commercialization. Cellular therapies have been in use for decades, although these were not developed nor approved as products (in the United States). Instead, most of these types of therapies are considered medical procedures, such as bone marrow (stem cell) transplants. Those involved in cell therapy manufacturing are clearly concerned about how future commercialization will be undertaken. For example, In our global industry survey, 14th Annual Report on Biopharmaceutical Manufacturing Capacity and Production, we found that respondents are now beginning to see that cell therapy manufacturing is an merging concern, with 6.2% of global respondents indicating it is the single most important trend (Figure). While this overall percentage is relatively small, when considering that the cell therapy segment represented in the study is relatively small, we can infer that manufacturing may be a top-of-mind concern for a great many of those who are involved in that segment.

BioPlan preliminary estimates show there are about 150 cellular therapy and 150 gene therapy commercial developers that are targeting the U.S. and other major markets (with considerable overlap). But much as with the very earliest days of genetic engineering, many of these include universities and nonprofit research organizations involved in early R&D and trials. The great majority of the >1,000 ongoing cell/gene therapies clinical trials (another area with poor information and definition) primarily only have proof-of-principle–level evidence that a therapy approach has promise or is not obviously unsafe. 

Capacity Crunches May be Coming

Since the mid-1980s, when the biopharmaceutical industry was just moving into antibody manufacturing, requiring large-scale manufacturing facilities, there have been several serious “capacity crunch” periods where dire shortages of capacity were projected for upcoming waves of mAb manufacture. The industry generally managed to avoid major problems (with some notable exceptions). Rapid construction of facilities, a steady increase in upstream titers, adoption of single-use systems, and other factors allowed industry to avoid major capacity crunches. But the cell and gene therapies industries are different, and it clearly appears to be on a trajectory for major capacity crunches in both R&D and commercial manufacturing.

For some, capacity crunches for both cellular and gene therapies may already be here. The wait times for CMOs to start projects now average ≥1.25 years, and are only increasing, with insufficient CMOs with technical competence entering the field. Further, new dedicated facilities have yet to be constructed, and staffing is likely to create a critical bottleneck. BioPlan Associates estimate that the current shortfall in worldwide cell/gene therapy may be about 5× current capacity (based on cumulative bioreactor volumetric capacity)—in other words, that much more CMO capacity would be used if available. And within perhaps five years when current pipeline products reach clinical scale, unless significant changes occur, the required platforms and capacity will not be there.

Further, the current cell and gene therapies tend to be super-orphan products, with limited market demand. But once more mainstream therapies enter the market, including diverse gene therapy viral-vector and allogeneic cell therapies—unless manufacturing platforms are developed, along with single-use technologies, and the staffing for these facilities are ramped up, the demand for capacity may dramatically outstrip supply. Many companies with projects now set for approvals may find production hurdles, and others may not yet be able to enter the fields due to lack of CMO access. Keep in mind that CMOs are a likely resource for avoiding the costs, complexities, and risks involved in developing the specialized in-house R&D and manufacturing for cell and gene therapies. While many of the major biopharmaceutical companies are likely to establish a presence in cell and/or gene therapies, (as with biosimilars, ADCs and other newer-product classes), even the giants may not have the technical competence that will be needed.

Factors contributing to a lack of needed cell/gene therapies manufacturing capacity include:

• CMOs are and will be a primary manufacturer of cell and gene therapies.
• At present, according to industry observers, most commercial cell/gene therapy developers today would prefer to outsource their bioprocessing, presuming cost-competitive and capable CMO services are available.
• More than or equal to 80% of commercial product developers currently outsource product manufacturing (mostly academic/nonprofit research organizations’ early-phase work).
• With cell/gene therapies a new area, very few developer companies have the necessary dedicated facilities, hardware, experienced staff, in-house platform, and licensed technologies, etc.
• Staff with needed expertise will be a major limiting factor. Overly qualified staff, including many PhDs, are currently used in both R&D and manufacturing, because seeing and fixing problems, at present, are not resolvable by technicians.

Development of cell/gene therapy manufacturing capacity and these industry sectors will be largely dependent on CMOs. Further pushing use of CMOs for cell/gene therapies manufacturing at all stages of development is the fact that manufacturing-relevant technologies, particularly platforms, do not yet exist—or they are proprietary—and it may be up to CMOs to do the needed licensing of multiple bioprocessing-related technologies.

Conclusions

Current bioprocessing technologies in use are primitive by mainstream biopharmaceutical standards. This is particularly true with many cellular therapies involving large numbers of manual fluid transfers (pipetting, no aseptic connections, manual handling of cells, use of glove boxes, shake flasks vs. bioreactors used for cell culture, etc.). Manufacturing is often complicated by the inability to sterilize viral and cellular intermediates and final products by filtration or heat. The many autologous (patient’s cells returned to same patient) cell therapies in development are often labor intensive, with a good portion requiring man-weeks of labor just to produce therapy for a single patient (a reason, perhaps, for very high prices for these products). With cell therapies, there is also wide variation in where or who will perform product manufacturing, which can include the developer or its CMO—and many cell therapies are expected to involve local or in-hospital or even patient-bedside therapeutics manufacture. With related bioprocessing automation largely lacking, bringing such products to market will be very difficult, if even feasible. However, the situation with gene therapies, most involving culture of viral vectors, is much different—better, even—because the associated vectors are generally already being manufactured in conventional, single-use bioreactors.