Overcoming Scalability Barriers To Advance Cell Therapies in Development: CDMOs Can Be the Key to Success

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Research and clinical trials of cell/gene therapies (CGTs) have expanded greatly in recent years, and this area of the biopharmaceutical industry is showing no signs of slowing down. As of 2024, ClinicalTrials.gov in the United States lists more than 1,200 registered and active studies involving CGTs — a natural progression from a projection made by the US Food and Drug Administration (FDA) in 2019 (1). Before the global pandemic, the agency had predicted that by 2025, it would be approving 10–20 new CGT products every year. However, the industry has a long way to go before it will reach such a steady pace of approvals for these advanced therapies. As of 26 April 2024, the FDA had approved a total of 37 CGT products, including only seven in 2023 (2, 3).

We believe that early estimates did not account for some barriers to introducing new CGTs, including talent shortages, infrastructure growing pains, and outmoded technologies. However, the industry is making progress in those areas and turning its attention to the next milestone: evolving from autologous treatments intended for single patients to creating off-the-shelf allogeneic products that can meet the needs of entire patient communities.

Cell-based products such as those based on mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), immune cells, gene-modified cell therapies, and even exosomes face particular barriers to entry due to the complexities of mass-producing living cells (4). However, those barriers don’t limit the potential of such therapies. Experts recently valued the US cell-therapy market size at US$2.88 billion (as of 2023) and projected it to reach about $19.67 billion by 2033 (5). Ultimately, the solution to manufacturing concerns could lie in choosing the most applicable contract development and manufacturing organization (CDMO) to accelerate research and commercialization for each CGT program.

Barriers to Entry

Capacity Crunch: In 2019, PricewaterhouseCoopers predicted that a “war for manufacturing capacity” would “strain production capacity” among CGT companies (6). But an unexpected positive outcome from the subsequent COVID-19 pandemic was that the biopharmaceutical industry has been forced to address that challenge. Both small and large biotechnology companies caught the urgency to build infrastructure needed to scale up biomanufacturing in the race to meet the demand for COVID-19 vaccines and treatments (7, 8).

One of the most challenging barriers to CGT success is the ability to manufacture at scale while devoting increasing amounts of facility space to single-use technologies that protect against (cross-)contamination. A survey conducted in 2020 found that nearly 40% of CGT companies need more single-use systems such as bioreactors (9, 10). That was a dramatic increase from the year before, when only about 29% of respondents to a similar survey said that they needed more such systems. Bioreactors take up physical space, of course, and the capital required to purchase and house them can be a drain on financial resources.

Now four years later, innovators are turning to CDMOs for support. Such service providers are strategically positioned technology enablers and solution driven partners with the manufacturing capacity that cell-product innovators need to move quickly through research and development (R&D). Frost & Sullivan recently pointed out that, “due to the trend of specialization and especially contract development, the global biopharmaceutical landscape is increasingly shaped by CDMOs undertaking commissioned productions and offering unique solutions with higher added value” (11).

Some of those investments originally were driven by COVID-19; many of them continue now due to an industry-wide awareness of the great need for increased space and manufacturing capacity. This trend has increased the valuations of CDMOs such as Brammer Bio substantially. In March 2019, Thermo Fisher Scientific agreed to pay $1.7 billion to acquire that company — for the express purpose of expanding its own gene-therapy offerings (12). Other significant merger/acquisition activities and consolidations have occurred among CDMOs themselves. For example, Cognate BioServices acquired Cobra Biologics in November 2019 (13). Then in 2021, Charles River Laboratories bought Cognate (including Cobra) and Vigene Biosciences (14, 15).

Meanwhile, the demand for manufacturing expertise and capacity has driven a flourishing of new CDMOs. Collectively, they represent how a growing technology sector is meeting demand for services; individually, they offer different services, technologies, capacity, processes, and talent. Some new players include National Resilience, Pluri, SK pharmteco, List Labs, and Lonza — the latter being a company with a long history that only recently has entered the CDMO space as a service provider.

Lack of Trained Personnel: Talent scarcity was found to be a significant problem in Randstad Sourceright’s 2022 Talent Trends survey of C-suite and human-capital leaders in the life-sciences sector (16). The problem is particularly pervasive among cell-therapy companies, which require very specialized “niche” expertise. In 2023, Randstad further reported that a key barrier to entry into the CGT field is a lack of any “nationally recognized or standardized education curriculum” (17).

In a collaborative project, the US Government Accountability Office and the Alliance for Regenerative Medicine (ARM) reported recently that a lack of trained workers is restricting research and development (R&D) efforts in cell therapy (18). Increasing demand for workers in developing markets such as China is contributing to the shortage (9). In simple terms, there aren’t enough workers with real-life experience in the world to meet the CGT industry’s current (and growing) demands.

Given that shortcoming, the need for qualified technicians and scientists will persist until universities around the globe can catch up their curricula to offer specialized courses, such as those currently offered by the University of Galway in Ireland, the Keck School of Medicine at the University of Southern California in the United States, or other programs recognized by the International Society for Cell and Gene Therapy (ISCT) (19–21). Following their education, the resulting cohort of graduates will require field experience to gain the necessary expertise for good manufacturing practice (GMP) careers. In the meantime, biopharmaceutical companies developing cell therapies must turn to CDMOs for the niche expertise that they require.

Technology Shortcomings: In one 2020 survey, researchers noted that the biotechnology market needs more purpose-built bioprocessing equipment and devices for cellular therapies (9). Most such options available are based on legacy technologies that have remained fundamentally the same for decades. Note that humans, animals, and plants are all three-dimensional (3D) “structures,” but most established culture technologies do not reflect how cells actually grow and develop in their native environment. Many early cell-expansion technologies for the biopharmaceutical industry are designed for suspension culture, which works fine for simple organisms such as microbes. Yeast cells can bloom and grow to make beer and bread, for example, even in a home kitchen. However, mammalian and even some plant cells need much more complex 3D structures to flourish. Scaling up such cultures in suspension requires immense force and other conditions specific to cell types. They simply do not grow as well when you try to scale up production using suspension technologies.

Note that a state-of-the-art production facility that complies with current GMP (CGMP) requirements is critical for producing pharmaceutical-grade products. Meeting criteria to earn that designation requires an extensive gap analysis audit and (often) upgrades of facilities, personnel, workflows, computer systems, and more. That’s one reason that studies by BioPlan Associates and others find that about 90% of CGT developers prefer to use CDMOs to make their products rather than delaying R&D to develop their own manufacturing facilities (9).

Solving for Scalability

Producing live, cultured cells as therapeutics is a new manufacturing paradigm with a market that is still in its infancy. Among the cells that are most in demand for such products are MSCs, iPSCs, immune cells, and gene-edited cells based on chimeric antigen receptor (CAR) and other technologies. Currently, there is no gold-standard option for large-scale production of all those cell types, and most of technologies currently in use are based on traditional suspension-based bioreactors or hard-to-scale two-dimensional (2D) flasks and trays. When it comes to bioreactor scale, however, bigger doesn’t necessarily mean better. Shear forces inside large bioreactors can damage cell quality and viability. As a result, sustainable and quality-controlled scale-up of production to hundreds or thousands of liters is currently impossible.

New technologies are demonstrating that scalability is a solvable problem. One 2019 Nature publication described a new method for manufacturing 3D cell-culture plates for mass production of MSCs (22). Using computer-aided design, the research team created a plate out of polydimethylsiloxane. Using that, they tested the biology and viability of cultured MSCs and found that they seeded well on the newly fabricated plate and aggregated to form 3D spheroids within one day of incubation, all while maintaining viability. Those results could lead to improved capacity for future mass production of cell spheroids for experimental and clinical applications. Although that and other advanced methods for cell manufacturing represent steps in the right direction, transforming and making them accessible for large-scale cell-production processes, particularly to meet today’s R&D demands, will require much more development work.

Pluri is an Israeli biotechnology company working on the problem with proprietary 3D cell-expansion technology based on scaffold structures inside bioreactors (23). As human cells attach to those scaffolds, they begin to create tissues. This technology represents a true 3D system in a “packed-bed” bioreactor rather than a suspension system. It’s a new way to grow cells that exposes them to the types of conditions they grow in naturally, which preserves many aspects of their biology. Development of this system has led to further innovation by enabling the interior bioreactor conditions to be tailored for expanding different types of human, animal, and plant cells. Mass quantities of cells can be grown quickly, reliably, and cost-effectively to meet the needs of regenerative medicine as well as other global concerns related to climate change and food scarcity.

Based on the potential of that technology and the resulting capacity availability, Pluri launched a CDMO division in 2024. Partners benefit not only from the technology, but also from over 20 years of expertise in cell research, process scale-up, validation, logistics, automation, and regulatory-approved comparability studies.

Identifying the Right CDMO Partner

Every drug sponsor has distinctive needs in choosing a CDMO partner. Some common considerations are related to expertise and focus, company size and available facilities/capacity, quality systems, experience, and workflows.

Expertise and Focus: Meet with a CDMO’s leadership and support teams to learn about their experience with cell therapeutics. Without relevant expertise, a CDMO cannot provide all the support and advice that a drug sponsor needs to take its products from research stages all the way through to commercialization. And not all expertise is relevant to every development program. Choose focused experts who understand and treat your product as the big fish in their small pond.

Size, Facilities, and Capacity: Some small companies might prefer smaller CDMO partners for increased alignment of company culture and mission, which can be important in building successful business relationships. But sponsors need to evaluate both a CDMO’s available technologies and its facility and personnel GMP certifications. Can the company scale up production to meet industry demand for a newly approved product?

Quality Assurance and Workflows: Ask questions about outcomes from recent audits of quality systems, safety records, facility inspections, data-gathering methods, and approved suppliers. Review and evaluate the company’s standard operating procedures (SOPs) and workflows. Does the CDMO have an established, tested control algorithm to maintain optimal conditions required to expand your cell type?

Regulatory Knowledge and Experience: Does a given CDMO have experience working with one or more regulatory agencies in multiple regions around the world? Comprehensive understanding of different governmental bodies’ requirements and timelines is essential to bringing new drug candidates to market efficiently.

Many early stage companies originate from an academic context, and the entrepreneurial spirit often makes them want to do everything themselves. That tendency can lead to unnecessary program failures due to a lack of resources, inexperienced managers, or flawed business models (24). Some innovations — up to 70%, according to a study in Nature — are simply too difficult to reproduce at commercial scales (25). If your objective is to make a viable biopharmaceutical product, then you need to begin with that goal in mind. A CDMO can help to spread out the risks inherent in R&D while providing the vital resources and experience to guide your innovation from mere biological hypothesis to a real marketed product.

Commercializing Cell Therapies

Once regulatory approval has been received, your work is not complete. Commercialization is a long journey that should not be undertaken alone. According to McKinsey & Co., CGT launches thus far have had mixed results, with only some bringing improved patient outcomes and high rates of success (26). Other launches have been undercut by significant challenges in getting products to patients. Because so few CGTs have launched in the past decade, the industry has much left to learn about best practices. Companies working with CDMOs have additional partners to help them check all the necessary boxes during commercialization.

Based on an analysis of several recent CGT launches with related expert interviews and roundtables, McKinsey explains that preparing a product for market should start before regulatory approval has been attained (26). CDMOs that have done their job correctly will have gathered all the data that their partners need both to present to regulatory reviewers and to demonstrate the long-term outcomes for health-care providers who are in the position of prescribing cell-based therapies (27).

When it comes time to begin manufacturing and shipping products, your CDMO also should take steps to optimize the supply chain so that patient-specific doses of those therapies can be provided in time to the appropriate sites of care. Currently, most cell-based therapies are based on autologous processes that make medicines to serve one particular patient at a time. Great leaps in the speed of development and other factors have taken place since the first such products were launched in 2017, most notably in the oncology space with CAR T-cell therapy treatments (28).

However, autologous processes have a major shortcoming in that each product batch only can serve a single patient. Cell processing does not require scale-up; instead, the manufacturing facility itself must be made capable of producing many unique batches of small quantity. That’s a matter of both speeding up and scaling out. Thus, one critical aspect of evaluating CDMOs for making autologous cell-based products is ensuring that a given company understands those challenges and what scale really means in relation to them.

Toward the Future of Cell Therapy

To meet demands for off-the-shelf products that can be made available to large numbers of patients, allogeneic therapies are likely to replace most autologous processes. With healthy donor cells expanded (and often genetically modified) into mass-scale production, allogeneic products could transform this critical area of medicine. The CGT industry could move beyond the individualized approach that was the early hallmark of advanced therapies to create a world where more patients can be treated more easily in less time. Allogeneics also can be more cost-effective, with each batch treating potentially hundreds of patients, which could bring down treatment costs as well.

CDMOs are working through the necessary technologic innovations with automation and process standardization toward future allogeneic platforms. Replacing open systems with closed and automated ones will help biomanufacturers transition to mass production of cells and commercialization of allogeneic therapies to treat as many patients as possible. For example, the 3D expansion system described above is designed to scale cells of all types significantly, with the intent of creating large allogeneic batches in a relatively small facility footprint. Robotics will help to advance cell production as well, further improving the precision and efficiency of CGT production while artificial intelligence (AI) and machine learning (ML) help to optimize cell growth, reduce waste, and improve yields. Note that environmental sustainability is essential for the future of biomanufacturing. Oversized traditional bioreactors soon could be replaced with technologies that can do more in the same space or less, requiring fewer resources such as electricity and water.

What’s Next: Advancements in cell research are increasingly exciting, and we see a bright future for regenerative medicine as a whole. Although CGTs accounted for just over 1% of worldwide drug sales in 2022, forecasted growth rates are astonishing. One estimate suggests that CGTs could experience a compound annual growth rate (CAGR) of 46% through 2028, reaching about $86 billion in sales globally by then (29). CDMOs will be key to scaling up cell production to the point at which such lofty goals can be achieved.

References

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2 Approved Cellular and Gene Therapy Products. US Food and Drug Administration: Rockville, MD, 2024; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

3 Senior M. Fresh from the Biotech Pipeline: Record-Breaking FDA Approvals. Nat. Biotechnol. 42(3) 2024: 355–361; https://doi.org/10.1038/s41587-024-02166-7.

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6 Gene Therapies Require Advanced Capabilities To Succeed After Approval. PricewaterhouseCoopers: London, UK, September 2019; https://www.pwc.com/us/en/industries/health-industries/library/commercializing-gene-therapies.html.

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12 Thermo Fisher Scientific To Acquire Brammer Bio, a Leader in Viral Vector Manufacturing. Thermo Fisher Scientific: Waltham, MA, 24 March 2019; https://ir.thermofisher.com/investors/news-events/news/news-details/2019/Thermo-Fisher-Scientific-to-Acquire-Brammer-Bio-a-Leader-in-Viral-Vector-Manufacturing-2019-3-24/default.aspx.

13 Press Release. Cognate BioServices Announces Acquisition of Cobra Biologics. PR Newswire 4 November 2019; https://www.prnewswire.com/news-releases/cognate-bioservices-announces-acquisition-of-cobra-biologics-300951144.html.

14 Charles River Completes the Acquisition of Cognate BioServices. Charles River Laboratories: Wilmington, MA, 29 March 2021; https://www.criver.com/insights/charles-river-completes-acquisition-cognate-bioservices.

15 Charles River Integrates Cell and Gene Therapy Acquisitions To Enhance End-to-End Offering for Developers. Charles River Laboratories: Wilmington, MA, 3 January 2022; https://www.criver.com/insights/charles-river-integrates-cell-and-gene-therapy-acquisitions-enhance-end-end-offering-developers.

16 2024 Talent Trends Life Sciences & Pharma Sector Report. Randstad Enterprise: Atlanta, GA, 2024; https://www.randstadenterprise.com/insights/life-sciences-pharma/4-talent-trends-life-sciences-companies-need-address-right-now.

17 Overcoming Staff Shortages in Cell and Gene Therapy. Randstad Enterprise: Atlanta, GA, 23 May 2023; https://www.randstadusa.com/business/business-insights/future-workplace-trends/overcoming-staff-shortages-cell-gene-therapy.

18 GAO-23-106030. Regenerative Medicine and Advanced Therapies: Information on Workforce and Education. United States Government Accountability Office: Washington, DC, March 2023; https://www.gao.gov/assets/gao-23-106030.pdf.

19 MSc (Cellular Manufacturing and Therapy). University of Galway: Galway, Ireland, 2024; https://www.universityofgalway.ie/courses/taught-postgraduate-courses/cellular-Manufacturing-therapy.html.

20 Training and Education. Keck School of Medicine, the University of Southern California Cell Therapy Program: Los Angeles, CA, 2024; https://keck.usc.edu/cell-therapy-program/training-education.

21 Workforce Development and Training. International Society for Gene & Cell Therapy: Vancouver, BC, Canada, 2024; https://www.isctglobal.org/resources/training-programs.

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27 Kaplan H. Addressing the Problem of Product Revenue Underperformance. BioProcess Int. 22(9) 2024: 17–21; .

28 CAR T-Cell Therapy and Its Side Effects. American Cancer Society: Atlanta, GA, 1 March 2022; https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html.

29 Lohr A. 2023’s Market Outlook for Cell and Gene Therapies. Cell & Gene 14 February 2023; https://www.cellandgene.com/doc/s-market-outlook-for-cell-and-gene-therapies-0001.

Andy Lewin is chief commercial officer for PluriCDMO, and corresponding author Lior Raviv is chief technology officer at Pluri Biotech Ltd., Matam Park Building 5, Haifa 3508409, Israel;

972-74-7108600; [email protected]; https://pluri-biotech.com.