The biggest bottleneck in manufacturing cell and gene therapies continues to be hiring for manufacturing. Although, during Covid, most industries have been experiencing hiring challenges, in these advanced therapy areas, these have resulted in acute challenges getting life-saving, novel technologies through the pipeline.

According to BioPlan Associate’s 19th Annual Report and Survey of Biopharmaceutical Manufacturing,¹ over half (51.3%) of the Cell and Gene Therapy (CGT) industry can’t get their products manufactured due to inability to hire experienced staff. 

Contract manufacturers have been critical in de-bottlenecking cell and gene therapy production. With more than 1,000 cell and gene therapy candidates in clinical trials, this critical shortage of expertise and manufacturing capacity, which emerged at least five years ago, is not going away.

BioPlan Associates’ 19th Annual Survey interviewed 147 end-users and more than 100 suppliers, and it is clear that manufacturing improvements will require hiring more staff with key expertise. While staffing has been an issue industry-wide, the more niche segments experience more substantial impacts on production (Figure 1). 

Staffing and expertise needs

Our industry research has long noted progressively worsening staffing shortages in the CGT areas. The rapid growth in these sectors is making hirable experienced staff even rarer.  Further, the continued biopharmaceutical industry sector growth and rapid expansion in Covid vaccine areas are poaching staff that might otherwise be working in gene and cellular therapy areas.

With hiring staff with needed expertise now the number one most needed improvement, any company planning to enter or expand in this area should consider their manufacturing and hiring strategies.

The common strategy to address the lack of talent and capacity has been to turn to contract development and manufacturing organizations (CDMOs). This demand has fueled the growth in the CDMO segment for these services. Those organizations with demonstrated competence are in high demand. 

In mainstream biologics, Mabs, and other recombinant biologics, a company’s manufacturing strategy, and their “make-vs-buy,” in-house or outsource decision is often made based on economic factors, or corporate orientation toward manufacturing as a core competency.  Smaller, under-funded facilities in particular are not given a choice. They may have neither the financial ability to build out capacity, nor the staff to operate it. So, they would need to outsource manufacturing, and turn to a CDMO. However, today, with Covid absorbing much of the available capacity, wait times for projects can exceed 18 months.

And for niche areas like cell therapy, access to skilled staff, or capacity is even worse. This makes it all the more critical that CDMO capacity and competence be available.

In professional sports, a team may draft the most talented player just to keep them from playing for the competition. Similarly, some companies are hiring in anticipation of manufacturing operations coming online even if new hires must wait until lab or manufacturing facilities are fully operational.

Contract manufacturing organizations (CMOs) have traditionally been turned to when staffing and other problems occur, but with CMOs also experiencing the same staffing problems as developer companies, this is not a viable option.

Training new staff

On top of staff shortages, BioPlan’s report indicates that it takes 6-12 months to provide the specialized training required for many biologics operations. Cell and gene therapy manufacture is a new area, and there is limited experience or institutional knowledge, or and standard training to get new staff up to speed does not exist. 

Capacity constraints

For all biologics manufacturing, not just cell and gene therapy, capacity issues dropped to the number two position, from number one last year—but these capacity bottlenecks are still concerning. Most cellular therapy facilities today have much less capacity requirements compared with Mab production. Mostly cell therapies are autologous, and fully individualized, manufactured as one-off products—while viral vector manufacture for gene therapies has been scaled up by a few facilities for use with 2,000 L bioreactors. Production tends to be smaller scale. For this year’s survey, 57.1% reported a capacity of under 500 L.

Our published data concerning current and future CGT manufacturing capacity needs, include projections of a worsening “capacity crunch” similar to the crunch in mainstream bioprocessing that was feared but largely avoided in the early 2000s. However, in these niche areas, this shortfall will increase many times over the next 5 years, and some have projected 50-times the current capacity will be needed when cell therapies in the pipeline emerge as commercial scale.

On the other hand, this does not necessarily presage major problems. For example, over half (58.5%) either agreed or strongly agreed that cell and gene therapy manufacturing will advance sufficiently by 2023, reducing capacity and bottleneck issues. They expect platforms for cellular/gene therapies to advance over the next 5 years, with this expected to significantly reduce manufacturing bottlenecks and other issues.

While the dynamics have shifted dramatically since 2018, there have been relatively few technological advances entering beta testing. Because major advances in biologics areas need years before industry adoption occurs, these results may be overly optimistic. 

If the needed advances, such as in automation, or assays do not commercialize before the pipeline outputs commercial scale therapies, then manufacturing problems and bottlenecks will likely occur. Thus, it will be a question of timing of commercialization and how rapidly capacity or automation bottlenecks can be resolved. Physical capacity may not be the challenge, so much as the need for processing improvements that haven’t occurred as rapidly as many have hoped.

CDMOs with cell and gene therapy platforms

Specializing in certain cell and gene therapy platforms could help a contract manufacturer gain an edge. In 2019, about half of the respondents indicated that “Cellular therapies, allogeneic (multiple patients, batch production)” (52.1%) and “Cellular therapies with genetic modifications” (44.6%) were the two platforms that had the greatest growth potential.

The third was “Virus vector-based gene therapies, allogeneic (multiple patients, batch production)” at 43%. And more than one-third of respondents indicated that future cell and gene therapy platforms would involve “Virus vector-based gene therapies, autologous (personalized, single patient)” (38.0%).

Growth in capacity over 5 Years

Some cell and gene therapy developers are planning to expand their in-house manufacturing capacity. In 2020, those with cell and gene therapy facilities indicated that, over the next 5 years, expansions will generally be in the 25% – 200% range, with just under half (40%) expecting such expansions. Only around 6% expected no expansion.

Some of the projections for internal expansion are due to long wait times at CMOs to start new cell and gene therapy projects (Figure 2). Digging deeper, many manufacturers like to keep these projects in-house to maintain more control over them and to protect intellectual property. The rapid advance in demand for cell and gene therapies will inevitably lead to capacity shortfalls and open opportunities for CMOs. Further, simply increasing physical capacity will not be enough, if staff are not available for operations. So, in addition to the manufacturing growth strategy, the hiring and retention strategy will be keystones for growth.

This anticipated increase in capacity is further supported by respondents in Figure 3, indicating that they plan to commercially manufacture cell and gene therapies soon. Of the 12 areas noted, nearly half (43.8%) of respondents indicated that they “Will scale out (add or use more process lines, clean rooms, etc.), which was a nearly 20-percentage point increase from 23.9% to 43.8%, in 2022. More than half, including the top-rated responses showed significant increases this year vs. 2021, indicating that the development of manufacturing capacity is accelerating in the gene and cellular therapies areas.

Conclusions

So far, relative to demand, few CMOs are offering significant cellular and/or gene therapy bioprocessing services. More CMOs are entering the field and the number and intensity are expected to ramp up in the coming years as more cellular and gene therapy products enter world markets. CMOs are particularly needed to provide cellular and gene therapy bioprocessing services, with this by far the preference within the industry.

Cell and gene therapies are developed by smaller companies and relatively few of them license their intellectual property. These same small companies do not have the facilities or expertise to manufacture at the commercial scale so if the trend toward increasing capacity for cell and gene therapy continues, they will have little choice but to rely on CMOs. Larger cell and gene therapy developers will also prefer to outsource commercial production of their products rather than invest in developing the platforms, recruiting the experts and creating specialized facilities for this.

One key area that will very likely be required is automation to support GMP commercial scale production. As the industry segment progresses toward commercial scale, each year, this is noted by more respondents, starting at only 14% 3 years ago, to 31.5% this year. Expectations that automation will be necessary for commercialization continue to rise.

Cell and gene therapies have great future potential. However, the expertise to grow them to the commercial scale and the facilities to produce them have held them back. Enterprising CMOs can fulfill an industry need if they proactively hire experts and develop the bioprocessing infrastructure to support their growth. 

References

1. 19th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates, Inc. ~500 pages, April 2022. www.bioplanassociates.com
2. 18th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2021. www.bioplanassociates.com

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Joel Ranck is a market strategist with extensive experience in science, medicine, public health, healthcare, research and higher education. His expertise includes primary and secondary research and market analysis of biopharma segments. His work has spanned the globe from Central Europe, South America, and the U.S. jranck@bioplanassociates.com, +1 301-921-5979, BioPlanAssociates.com.