By MaryAnn Labant
Cell manufacturing trends should encourage optimism. The number of approved cell and gene therapies is bound to rise from today’s total, which is about 30 in the United States, because thousands of cell and gene therapy candidates are being evaluated in clinical pipelines. And besides contributing to the clinical success of cell and gene therapies, cell manufacturing represents an expanding market. According to Vantage Market Research, the global cell and gene therapy manufacturing market should maintain an annual growth rate of 18.2% through the rest of the decade, attaining a value of $15.4 billion by 2030.
Despite these promising trends, cell manufacturing faces serious challenges, some of which are common to the biopharma industry as a whole, and some of which are particular to what are sometimes called living drugs. Challenges of the former type have been highlighted by the 2023 Global Biopharma Resilience Index, a metric devised by Cytiva, a global biomanufacturing company.
The metric summarizes survey responses that were offered by 1,250 biopharma and pharma executives on what Cytiva calls the “five pillars of resilience.” Two of the pillars—supply chain resilience and manufacturing agility—were seen to be improving. But three of the pillars—talent pool, R&D ecosystem, and government policy and regulation—were seen as weakening. Since 2021, overall resilience was deemed to have fallen from 6.60 to 6.08 (on a scale of 10).
The survey results were accompanied by a report that concluded, “[Sustained] high growth is not a certainty for the industry.” If this caution is warranted for the biopharma industry, it should be taken even more seriously for cell manufacturing, where the supply chain and manufacturing agility pillars need strengthening. For example, in cell manufacturing, the procurement of raw materials may entail the collection of cells from patients. Also, the manufacturing processes for cell therapies are largely manual and far more complex than those for monoclonal antibodies or recombinant proteins, and leave the door open for inconsistencies and potential human error.
To maintain growth, the cell therapy industry is addressing challenges across the five pillars of resilience. For example, as this article shows, the industry is focusing on automation, talent acquisition, and supply chain management. This article also highlights challenges that are particular to the cell therapy industry. These challenges include managing product pipelines that encompass autologous and allogeneic cells, and that are becoming increasingly complex and diverse.
Leveraging deep expertise
Cytiva’s vice president of cell therapy, Martin Westberg, is optimistic that the automation of cell manufacturing processes will facilitate scale-up. “Once we are able to automate and standardize processes,” he says, “it should be easier to replicate processes and manufacture safely and efficiently, with much greater output and productivity than today.”
However, scale-up requires more than automation. It also requires bespoke equipment, software, and reagents, as well as highly trained personnel. One way to tackle this last challenge is to create tailored educational experiences. This is an approach Cytiva is exploring through collaborations with the National Institute for Bioprocessing Research and Training, the Testa Center, the Guangzhou Bioprocess Academy, the Jefferson Institute of Bioprocessing, the National Horizon Center, and other organizations.
To facilitate industrial-scale cell therapy manufacturing, Cytiva offers a complete and clinically proven workflow that integrates hardware, consumables, and software solutions. “Our deep expertise in this area and our service offerings that enable security of supply make us a proven partner,” Westberg asserts. “Whether it is early-stage clinical research or a company with an approved product, we work collaboratively with our customers.”
One of the biggest hurdles is scaling up at later phases of clinical trials and regulatory approvals. Westberg emphasizes that Cytiva has made significant investments in capacity and is working to future-proof its supply chain with significant patient population growth in mind. To support this goal, Cytiva opened a 7,400-square-meter Swiss manufacturing facility in May 2022. The facility, which is home to Cytiva’s Center of Excellence for cell and gene therapies, is powered by 100% renewable energy.
“New technologies are needed to address scalability issues and response durability, particularly for allogeneic therapies, batch-to-batch discrepancies, and poor transferability of workflows,” says Elizabeth Woo, PhD, vice president of cell, gene, and advanced therapies, Thermo Fisher Scientific. She adds that there is a need for increased automation and standardization, as well as improved access to quality raw materials, and global harmonization of regulatory requirements, including clear guidance defining quality standards to reduce manufacturing variability.
Digitalization of the cell therapy manufacturing process is essential for scaling and industrialization. Remote process monitoring and optimization, which are commonly used by pharmaceutical developers, are being adapted for cell therapy development to speed up workflows while improving standardization, quality, and reproducibility. According to Woo, artificial intelligence and machine learning technologies will also play a key role in adapting and optimizing processes to achieve higher quality and more cost-effective therapies.
Thermo Fisher offers a broad portfolio of fit-for-purpose instruments and software, media, supplements, reagents, and consumables that can be integrated into flexible workflow solutions. The company’s global supply chain capabilities, expertise, as well as CDMO services help developers transition from R&D to clinical and commercial scale-up.
Services extend to process optimization, regulatory compliance, and quality control to support clients who manufacture their own cell therapies, as well as clients who outsource manufacturing. The latter can benefit from Thermo Fisher’s global pharmaceutical services network of state-of-the-art GMP manufacturing facilities.
In March 2023, Thermo Fisher opened a new cGMP cell therapy manufacturing facility at the University of California, San Francisco (UCSF). According to a USCF press release, the facility has the potential to demonstrate that having scientists, clinicians, and patients closer to a manufacturing site may expedite the development of breakthrough treatments. “In this facility, Thermo Fisher offers UCSF, and other customers, process and analytical development capabilities, as well as clinical and commercial manufacturing services, for advanced therapies derived from either a patient’s cells or from a donor source,” the press release noted. “Customers can also benefit from Thermo Fisher’s drug development capabilities from discovery to clinical research to commercialization.”
“We also want to ensure that clinical trials reflect the real world by including diverse patient populations,” Woo declares. “We recently announced a collaboration with the National Minority Quality Forum to help bring clinical research to historically underserved patient populations.”
Designing end-to-end solutions
Labor-intensive workflows have many open steps and human touchpoints that can increase batch-to-batch variability or, even worse, result in contaminated batches and manufacturing failures. To avoid these problems—and ensure the delivery of safe and efficacious products—the cell therapy industry has adopted closed and automated manufacturing strategies.
“De-risking and streamlining the manufacturing process at an early stage—through simplifying the supply chain, selecting the appropriate raw materials, increasing the quality and yield of the final product, and improving the logistics—is vital for success,” says Nirupama (Rupa) Pike, PhD, senior director and global head of strategic alliances, Catalent Pharma Solutions. “Designing end-to-end integrated solutions will help to reduce costs and improve accessibility, eventually leading to the democratization of cell therapies.”
Catalent is a CDMO with expertise across a broad range of biologics. As a cell therapy CDMO, Catalent works with patient cells and donor cells (for autologous or allogeneic therapies, respectively). Also, Catalent maintains a cell therapy portfolio that includes CAR T cells, T-cell receptor cells, tumor-infiltrating leukocytes, natural killer cells, induced pluripotent stem cells, and mesenchymal stem cells.
“Our scientific know-how and scalable manufacturing have set a variety of complex customer programs on a path of success,” Pike remarks. Process efficiency methodologies such as Process Assessment and Manufacturing by Design are implemented with a future commercial mindset to offer labor savings and swifter production cycles at scale. The use of process automation and integration of different manufacturing steps, along with a flexible, state-of-the-art manufacturing infrastructure, further elevates cost and labor efficiencies.
Catalent recently launched its UpTempo CAR T-cell platform/process workflow to address common pain points. The platform enables a fully closed compliant workflow and leverages data-driven guidance to accelerate CAR T-cell therapy process development. In lieu of cookie-cutter solutions, individual solutions are designed that meet specific needs.
In addition, case management services provide end-to-end professional supply chain management and 24/7 support from initial cell collection through delivery of the finished therapy for patient administration. With a global cell therapy footprint and facilities in the United States and Europe, Catalent can help customers serve patient populations globally.
Thinking about the whole process
Whether traditional biologics or cell therapies are to be produced, early development is usually a good time to resolve biological and operational issues. Production processes are still at the laboratory or pilot scale. However, when the time comes to shift to commercial scale, gaps can open—particularly in cell therapy manufacturing, where products include cell types that have different growth requirements.
“There are many benefits to thinking about the whole process—from R&D through scale-up—in the early development stages of a therapeutic,” advises Janice Simler, PhD, director of business operations for bioproduction, Corning Life Sciences. “You need to consider the total numbers of cells needed to address the indication or patient population and whether a different option than the current process or platform will be required. Also, to speed up the commercialization transition, you should be proactive about costs and regulatory requirements. This prework will pay off in the long run.”
Diverse products and tools are needed to support different cell types. Tools that employ the same basic technology at both smaller and larger scales enable faster technology transfer. Corning’s large R&D product portfolio provides platform fidelity during the transition from research into production. “Process changes can affect the cells,” Simler notes. “The platforms’ continuity can save time and money as companies scale up their process.”
Corning offers a wide array of products for scaling up and out in the cell and gene therapy space. For example, Corning’s CellSTACK is akin to a cell hotel with plenty of surface area for adherent cell expansion. Also, Corning’s HYPER technology platform allows more efficient gas exchange and decreases the vessel’s physical size while also increasing the growth surface area.
For certain applications, specialty coated or dissolvable microcarriers are applicable. In addition, the Ascent fixed-bed bioreactor system and the CellCube are options. All products can be operated as closed systems.
Corning’s field application scientists are armed with knowledge and experience to help work through scientific variables, operational factors, and logistics issues that can make or break a therapeutic’s path from the laboratory bench to the commercial-scale process.
“Because our scientists have extensive experience across many application areas, we have the expertise to successfully advise on strategic process design, recommend optimizations, or support troubleshooting,” states Whitney (Cary) Wilson, PhD, field applications scientist. “These are areas that can deliver efficiencies as well as significant time and cost savings.”
Forming a joint venture
To better serve cell therapy developers, three established market players—Bio-Techne, Fresenius Kabi, and Wilson Wolf Manufacturing—have partnered to form ScaleReady, a joint venture that offers scalable, flexible platforms that incorporate technologies from the partners for cell culture, cell activation/expansion, gene editing, and cell processing.
“Even though the effects of the therapy can be astounding, we are only addressing a small portion of the patient population,” says Josh Ludwig, global director, ScaleReady. “We have to become expert manufacturers and simplify the process, eliminate potential human error, and reduce the cost to increase capacity and provide drugs to more patients in need.”
Basic tools and manual interventions impact the process. While complex bioreactors automate many actions, they typically do not eliminate any of the complexity, and often their mechanisms can be less than ideal to produce a healthy cell population that prefers a gentler environment for expanding cells.
To enable rapid cell expansion, Wilson Wolf provides a standalone bioreactor called G-Rex. It allows cells to sit on a static surface at the bottom of the device, where a gas-permeable membrane supplies oxygen to cells as they need it. Nutrients come from the media on top, automatically providing what the cells require as they consume the nutrients, simplifying the cell growth process. The closed system bioreactor platform is applicable from early research to clinical and eventual commercial production.
“Scientists add the cells and a predefined cocktail of media and gene modification reagents, and then they put G-Rex in an incubator to do the work on its own,” Ludwig explains. “T cells have evolved for a long time, and they know when to eat and breathe. The G-Rex provides unlimited oxygen and unlimited nutrients, and it allows the cells to interact and form a large population.”
Easy-to-use tools are imperative. To simplify and automate the front end of the process and prepare the sample for culture, Fresenius Kabi, a global leader in cell processing instruments for blood and dialysis centers, applied its expertise to create Lovo, an automated front-end cell processing system that pairs with G-Rex. On the back end, the recently launched programmable Cue delivers highly accurate concentration, formulation, and aliquoting.