Ronald A. Rader is senior director, Technical Research, at BioPlan Associates.

Ronald Rader

Current cellular and gene therapies, those relatively few marketed and the hundreds in clinical development, primarily involve autologous manufacturing: making one product at a time individualized for each patient. This is clearly very resource intensive, often involving weeks of labor-intensive manual processing to make a single patient’s treatment.

The long-term trend is for development of allogeneic cellular and gene therapies, involving batched manufacturing of products to be used for treatment of multiple patients (1). Many, if not most, cellular therapies in development involve genetic modification of cells—therefore, are also gene therapies—with cellular therapy manufacturing closely intertwined with gene manufacturing therapy (the vectors used).

Compared to current cellular therapies, gene therapy manufacturing is in a better position. Nearly all current gene therapy involves use of viral vectors, particularly adeno-associated virus (AAV), with related vector manufacturing similar to that long used for viral vaccines and recombinant processing plasmids production. A few companies now report scaling-up allogeneic viral vector manufacture to 2000-L scale.

But with large amounts of vectors needed for each treatment, this upstream volume will only treat at most several dozen patients. Cellular therapies involve running lots of processes at small, usually one-off, desktop scales often along with gene therapy vector production, while gene therapies (those administered to patients) involve running a good number of processes at larger scales.

Multiple interview- and survey-based studies (1), clearly indicate cellular and gene therapy fields are currently on track for, if not already experiencing, a serious “capacity crunch.”There is potential for a significant shortage of manufacturing capacity—measured as total volume of bioreactors in use—particularly at commercial scales, similar to a decade or more ago when there was widespread expectation of a severe shortage of capacity for mainstream recombinant products. Luckily, industry then responded with many new facilities and expansions; some presumed blockbuster products did not turn out to be blockbusters; and evolving technology, including higher titers, helped.

The problems with cellular/gene therapies manufacturing capacity particularly affect contract manufacturing organizations (CMOs). BioPlan Associates studies have shown that approximately 90% of cellular/gene therapy developers would much prefer to use CMOs to manufacture their products. But related CMO capacity is simply not available. With lead times for CMOs to begin cellular or gene therapy projects now averaging 18 months and increasing, more developers are deciding, often forced, to perform manufacturing, particularly later-stage and commercial, in-house. Many CMOs are entering the field or expanding their cellular/gene therapies capacities. But the leading CMOs and developers alike are busy trying to catch-up with capacity needs to support early-mid clinical needs.

BioPlan estimates that there is currently a 500% shortage of cellular/gene therapy manufacturing capacity, in the sense that five times the current capacity would likely be used if it were available, particularly from CMOs. The shortage of capacity and long lead times with CMOs has resulted in many pharmaceutical companies slowing R&D or delaying entry into the field. Unless more staff and capacity are brought online, a greater capacity shortage is projected in five years. This shortage will occur as more products enter and advance in development, particularly as more advance to commercial manufacturing.

Total capacity among facilities known to be producing cellular/gene therapies, which is not always the only products manufactured, is approximately 330,000 L (2). This capacity is approximately 2.0% of the total 16.7 million L worldwide bioprocessing capacity and is spread among 180 facilities; about two-thirds of the facilities engaged in cellular/gene therapy production perform gene therapy viral vector manufacturing either as therapies or for cellular therapies modification. Average capacity data are skewed by inclusion of the current largest viral vector manufacturing facilities, with many cell therapy facilities at much smaller scales and not publicly reported. Most cellular therapies are still autologous nearly all have under 500 L capacity.

In terms of in-house bioprocessing expansions, most respondents of BioPlan Associates 17th annual survey expect large capacity increases (1). For example, of survey respondents with current relevant capacity, 44% expect their facility to increase capacity by more than 100% during the next five years (see 

). This increase does not include expected new entrants and program expansions as more products enter the market, as investors finally see actual revenue from sales of these products.

Technology advancement is not expected to much help avert capacity problems. A minority (47.1%) of respondents agreed that “Within five years, platforms for cell and gene therapy manufacturing will have advanced to significantly reduce manufacturing capacity problems or bottlenecks.”Also, reflecting the primitive state of much cellular/gene therapies bioprocessing, only 16% each cited, “Our commercial manufacturing will or does use only closed systems, aseptic transfers/connections, etc.” and “Anticipate no problems with meeting good manufacturing practice (GMP) requirements.” One third (34%) of respondents report planning for GMP-compliant manufacturing of viral vectors/gene therapies this year, while 26% reported already attaining GMP, but with few yet planning for worldwide commercial manufacturing.

A decade ago, a capacity crunch would have affected nearly all biopharmaceutical facilities. Today, the industry is far more diverse. There are more classes of products, more single-use manufacturing, more flexible facilities and suites, more ability to scale-out commercial manufacturing, more options for continuous bioprocessing, etc. Further, with the focus on the COVID-19 pandemic and related product development, many companies that would otherwise be entering or expanding into cellular/gene therapies are not yet doing this, and governments are not expected to address cellular/gene therapies manufacturing shortfalls.

Even with near-term investments in new facilities and expansions, most facilities still need to catch-up to support current development needs, including building or contracting for capacity to support their early- and mid-stage clinical development efforts. Commercial GMP manufacturing for cell and gene therapies is done by very few developers and CMOs, and even fewer are currently constructing capacity. The industry will ultimately attain future needed commercial manufacturing capacity, but the options for expanding capacity today are greater than they were just 10 years ago, and from our research, many in clinical stage have not fully defined how this expansion will take place.

One of the major problems in addressing capacity shortfalls for cell and gene therapy manufacturers is the shortage of staff.Most operations today are complex, and often fully manual (vs. automated), making cellular/gene therapy viral vector manufacturing very labor-intensive. This manual processing requires highly trained, often over-qualified, staff at all levels involved with bioprocessing. This has created staff shortages that are particularly affecting cellular products bioprocessing.Here, experienced doctorate-level personnel are often needed. Technicians can sometimes lack the needed expertise. Viral vector manufacture also requires considerable hands-on experience. While only a minority of biopharmaceutical developers and CMOs are involved in cellular/gene therapies, problems related to hiring rank rather high in the BioPlan annual survey, as follows:

One-third (34.6%) of survey respondents cited significant problems hiring cellular and/or gene therapy staff.

19.8% of all respondents (this is greatly higher if just included the cellular/gene therapy players) citing difficulties hiring gene therapy staff.

14.8% having difficulties hiring for cellular therapies. This indicates that the great majority of cellular/gene therapy developers and CMOs are experiencing hiring problems.

Overall, shortages of cellular/gene therapy bioprocessing staff will likely worsen as the most experienced ‘baby boomer’ staff retire and as the product pipeline moves from R&D to clinical and commercial production. Also, unprecedented growth in pandemic vaccine/therapeutics bioprocessing will worsen the overall hiring situation, particularly for gene therapy, with many with virus-experience moving into pandemic vaccines and therapeutics (3).

17th Annual Report and Survey of Biopharmaceutical Capacity and Manufacturing, BioPlan Associates

, April 2020. www.bioplanassociates.com/17th
2. Rader, R.A., Editor, 

Top 1000 Global Biopharmaceutical Facilities Index

, www.top1000bio.com.
3. R.A. Rader, E.S. Langer, and K. Jhamb, “COVID-19 Impact on Bioprocessing:Accelerating Trends and Long-term Impact of Novel Coronavirus-19 on Biomanufacturing and Bioprocess Supply Chains,” White Paper, BioPlan Associates, July 2020.

Ronald A. Rader is the senior director, Technical Research, BioPlan Associates, rrader@bioplanassociates.com, +1.301.921.5979, www.bioplanassociates.com.


Volume 44, Number 10
October 2020
Pages 56–59

When referring to this article, please cite it as R. Rader, "Cellular and Gene Therapies Face a Manufacturing Capacity Crunch," 

Articles

Cellular and gene therapy fields are currently on track for, if not already experiencing, a serious capacity crunch.

Cellular and Gene Therapies Face a Manufacturing Capacity Crunch

	The vaccine industry, particularly, in major Western markets, continues to be dominated by a few major, long-established players that primarily manufacture aging, long-marketed, non-recombinant (nongenetically engineered) vaccines. The industry, however, will be changing in the coming years and this change may come rather rapidly. According to BioPlan's recently released analysis of 10-year industry trends (1), a confluence of technological advances in bioprocessing is making vaccine manufacture cheaper, faster, and simpler. These advances include:

		Single-use systems (SUS)/disposable bioprocessing systems

		Modular/transportable bioprocessing facilities

		Novel expression systems/improved cell lines

As these technologies advance and are increasingly adopted for commercial-scale manufacturing, the industry will see an evolution in vaccine manufacture. Significant improvements are now commonly being reported as companies develop, adopt, and adapt bioprocessing technologies to vaccine manufacture.

BioPlan's 10th Annual Report documents increasing adoption of these technologies and their impact on biopharmaceutical manufacturers. Survey data show that bioprocessing at pre-commercial scales, such as manufacture for clinical trials, is now thoroughly dominated by SUS (i.e., disposables) use. This increase included 78% of those surveyed reporting current use of SUS bioreactors and 92% using SUS filter cartridges at some level in bioprocessing (see 

SUS have moved into large-scale vaccines manufacture more slowly, partly due to the demands for large-scale equipment. In the BioPlan study, vendors were asked if they provide sufficiently scalable single-use disposables and techniques. Overall, 53% of the industry considers scale to be a significant adoption restriction. And vaccine manufacturers place inability to scale up SUS devices high on the list of concerns. SUS involve one-time use of bioprocessing equipment composed of plastics, not traditional stainless steel. SUS allow flexible manufacture when, and at the scale needed, with substantial reductions in costs and time, including presterilized equipment. In contrast, stainless-steel bioreactor-anchored facilities require costly and complex infrastructure, which further includes complex piping, including steam used for sterilizing stainless-steel equipment so it may be reused, which adds weeks to batch turnaround time.

	Currently, SUS bioreactors top out at 2000 L, with many engineering challenges (e.g., weight) when larger. Where this does not provide sufficient manufacturing capacity, multiple parallel SUS process lines can be implemented. With advancing SUS technology, better plastics and new designs are being developed using SUS (vs. stainless steel) for their application in precommercial R&D, clinical-trial-material supply, and commercial manufacture. This use of SUS is projected to result in the market (primarily US and EU) for SUS equipment at a commercial scale growing 1000% in five years to $1.5 billion/year (2).


	Going modular is the next advancement in bioprocessing hardware. It is closely related to the adoption of SUS technologies and involves housing SUS bioprocessing equipment within their own cleanroom cabinets-whether portable prefabricated trailers or equipment sealed within dedicated isolator cabinets-with these increasingly designed for plug-and-play simplicity. Bioprocessing facilities that formerly required years for planning and construction can be brought on line in a matter of months or even weeks. SUS have become common in less than a decade, in as short as 5 or 10 years; however, we may comparably be talking about industry widespread adoption of flexible bioprocessing modules and plug-and-play factories. Vaccines are expected to be one of the first product sectors affected by this trend. Modular technology will accelerate worldwide proliferation of vaccine manufacturing, including transfer of bioprocessing to lesser-developed countries. Even easier than with SUS process lines, modular systems allow whole plants to be essentially cloned, potentially allowing cGMP manufacture in many developing countries. Many foreign countries are and can be expected to demand local vaccine manufacture, particularly once modular facilities become commonplace, and equipment vendors plan to actively pursue this market.

	Companies developing modular systems for vaccine manufacture include G-Con, which is working with partners, including Sartorius Stedim Biotech and GE/Xcellerex. For example, Project GreenVax, a private

public consortium, is currently constructing an influenza vaccine manufacturing facility (to be operated by G-Con, developer of the modular units being used) in Texas for manufacture of recombinant tobacco plant-expressed influenza vaccines, with a projected final scale capacity of 100 million doses per month [1.2 billion doses/year], according to company projections and production costs of pennies/dose compared with conventional dollars/dose for conventional egg-culture manufacturing. The Project Greenvax influenza vaccine-manufacturing facility, subsidized by biodefense funding, uses single-use equipment, housed within plug-and-play-type modular trailers, using tobacco plant expression technology. Medicago and other companies are also developing vaccines using tobacco-plant expression.


	Improved versions of currently-predominate expression systems (i.e., genetically-engineered cell lines such as Chinese hamster ovary [CHO], yeast, and 

) for recombinant protein expression are further making vaccine manufacture easier and cost-effective and reducing the scale and investment required to manufacture products. The BioPlan annual survey of bioprocessing professionals and other studies show a rather consistent doubling of mammalian-cell protein expression and product yield about every five years, with yields now typically in the upper 2-3 g/L (bioreactor volume) range. Newer expression systems coming on line promise even higher yields and/or cost-effectiveness, with yields of more than 30 g/L being reported. These upcoming systems include plants (both laboratory-grown and field-grown), such as from iBio (Newark, DE); transgenic animals; PER.C6 and other novel high-yield human-cell lines; and various bacteria other than the usual 

 Using the same manufacturing systems and culture media, these new systems produce the same amount of product at commensurately lower cost and often much faster. This higher yield has lead to US biodefense programs providing R&D support for diverse vaccine-expression systems.

	Thus, the same equipment can essentially be used to manufacture twice as much product as what was possible only about five years ago. These improvements, however, come amidst intense regulation as major changes in products' bioprocessing are only implemented for new bioprocesses/products as they are developed with established processes rarely undergoing major changes. Upcoming new bioreactor technologies will further increase vaccine-manufacturing flexibility and reduce costs. This includes perfusion. Capillary hollow fiber perfusion bioreactors being developed by FiberCell Systems, for example, are expected to comparably produce up to 1000 x (based on bioreactor size) the output from conventional bioreactor (e.g., a 50-L desktop perfusion bioreactor matching the overall output of a 5000-L bioreactor).


	Novel purification technologies are also in development. These improvements are much needed, as advances in upstream manufacturing (everything through product formation in the bioreactor) causing capacity constraints and problems, because later downstream processing, primarily purification, have not advanced as rapidly as expression systems, and other upstream technolgies have. The BioPlan study shows that many facilities are considering upgrading (i.e., adopting, new purification technologies). This trend includes 54% considering high-capacity chromatography resins; 44%, single-use filters; 38%, automated buffer dilution systems; and 35%, single-use tangential flow filtration. Other advances being adapted for large-scale use include simulated moving bed chromatography systems and membrane filters, which are starting to replace chromatography columns. Cast-in-place "monolithic" chromatography media, rather than labor-intensive packing of columns, are yet another example of improvements approaching adoption for commercial-scale manufacture.


	Further practical advances and synergies can be expected when these technological advances are combined, thereby resulting in simpler, cheaper, and transportable vaccine manufacturing. A number of other vaccines currently in the development pipeline are being manufactured in SUS, are being developed for manufacturing using modular units, are using novel, higher-yield expression systems, and/or are adopting newer purification technologies. Besides federal biodefense programs funding, many of these efforts are independently funded or also being funded by PATH and other vaccine development-oriented philanthropic organizations.

	The confluence and combination of ongoing bioprocessing technological advances will increasingly enable manufacture of vaccines quicker, simpler, and at significantly-reduced costs, often just pennies/dose, with many future vaccines likely to be sold at prices that are comparable or even below current manufacturing costs.

is senior director, Technical Research, at BioPlan Associates. 

 is president of BioPlan Associates, tel. 301.921.5979, elanger@bioplanassociates.com and a periodic contributor to 

10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

Advances in techniques and single-use systems are revolutionizing vaccine manufacturing.