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Advances in development, data management, and automation, and closer collaboration with contract development and manufacturing partners, are pushing more therapies closer to commercialization.
Cell and gene therapies (C>s) have made huge advances in a few short decades. By February 2020, five therapies were on the market and FDA had approved nine more, while 362 treatments were in the US pipeline, up 25% from the previous year, according to the Pharmaceutical Research and Manufacturers of America’s latest survey (1). In September 2020, the first patient was dosed with autologous chimeric antigen receptor (CAR-T) lymphoma treatment using an automated closed system. “Despite complex and mainly manual processes, we can produce these therapies. Now we must work on making processes reproducible,” says Joerg Ahlgrimm, president and chief operating officer at The Discovery Labs, who was previously head of global C> operations at Lonza Pharma & Biotech. Significant progress has already been made, he notes. “The fact that we can routinely upscale a viral vector to 200–500 L standard represents a huge accomplishment. Years ago, we could not even have imagined reaching this point. And now, we are approaching 2000-L batch sizes,” he adds.
The Discovery Labs is building a Center for Breakthrough Medicines to accommodate 80 to 120 C> customer development programs at any point in time. For now, the goals are clear, Ahlgrimm says: stable cell lines, better scalability, smaller footprints, and better automation. He sees autologous therapies dominating the space, and expects adeno-associated virus (AAV) and lentivirus vectors to remain the dominant vehicles for manufacturing.
IT systems such as manufacturing execution systems (MES) and electronic batch records (EBR) will help reduce errors and make the manufacturing process more efficient, he says, and allow connection with logistics systems. These IT systems will also allow development data to be leveraged, to find deviations and facilitate continuous improvement, he says.Both autologous and allogeneic therapies face steep hurdles to commercialization.
Where allogeneic therapies are a bit more similar to traditional biopharmaceuticals, autologous therapies change the manufacturing paradigm completely, adding the extra steps of cell collection from patients and transport to and from patients to manufacturing, necessitating a just-in-time approach that is new to the industry. On the autologous side, most processes are still extremely manual, and they are still coming into the manufacturing space as laboratory type setups, so they’re really going fresh from the bench to the GMP suite,” says Ahlgrimm, who sees the solution in closed equipment systems that remove human beings from the process as much as possible.
Additional challenges include the need to coordinate manufacturing activities to optimize scheduling, and the flexibility to accommodate changes in protocols that can be expected in brand-new manufacturing processes. The manufacturing setup for autologous therapies is different from anything that has existed in the past, says Alberto Santagostino, senior vice president and head of cell and gene therapy manufacturing at Lonza Pharma & Biotech, who spoke about these issues in a BioPharm International webcast (2). “It is important to integrate data management, chain of compliance, and chain of custody, by tracking every single unit operation, every activity, every piece of equipment, and every operator back to every batch, and connecting that data to the external supply chain,” he said. The company has partnered with Vineti to integrate Lonza’s MES and EBR with Vineti’s supply chain orchestration platform, using application programming interfaces to feed chain of identity and chain of custody data to Lonza’s manufacturing floor.
From a supply-chain standpoint, autologous treatments pose inherent risk since both supply and distribution are traced to a single source. “Anything as simple as needing to change a time or day for cell collection when a patient is ill can interrupt cycle times and deliveries,” says Mark Sawicki, CEO of Cryoport Systems, a logistics specialist that is working with Lonza and Vineti. However, allogeneic therapies pose problems of their own, particularly on the distribution side, notes Sawicki, including a host of shipping and distribution issues. An example would be performing a drug product label verification on a cryogenic product. “You can’t pull product out of a cryogenic shipping environment to verify the label,” he says, noting that most third-party logistics providers do not currently have the ability to support these products to any scale.
Automation and digitization will be key to improving autologous manufacturing, reducing error and cost. On a fundamental level, Santogostino explained, they will ensure patient safety, since there is no margin of error with autologous therapies. But they also promise to reduce costs by eliminating the errors caused by manual processes. “Robotics is likely to be more dominant in autologous C> than it might have been for biologics or traditional biopharmaceutical manufacturing,” says Ahlgrimm.
In September 2020, the first patient was dosed with autologous CAR-T therapy using the Cocoon platform, a closed and automated system developed by Octane Biotech, which Lonza acquired an 80% share of in 2018 and has helped develop. The device features a single-use cassette, including process operations, media, and consumables. The work took place at the Sheba Medical Center in Israel, which boasts an experienced cell therapy team and had an ongoing CAR-T clinical trial underway, explains Matt Hewitt, head of R&D and Clinical Development at Lonza.
Hewitt says similar projects are being considered in other parts of the world, including the United States and European Union over the next 12 to 18 months. He sees the project as setting a new benchmark, proving that onsite, decentralized manufacturing at the point of care will be possible. “It won’t be the only way to do things in the future, but will be an option for some facilities,” he says.
The study also proved the technology’s potential effectiveness in reducing the cost of goods required to manufacture the therapies, Hewitt says, by addressing two main cost drivers: cleanroom space and skilled labor. “A traditional open manual process uses Class B cleanroom space, where the closed system with integrated culturing can run in Class C space. Even a back-of-the-napkin calculation suggests a 40% reduction in costs,” he says. The company is currently looking at ways to integrate MES and EBR, and logistics tracking, in the software.
Lonza is also working on new features for Cocoon that would improve performance, Hewitt says, including the addition of beads that would allow for magnetic separation as well as incorporating new sensors (e.g., for glucose) and process analytical technology (PAT) systems that would enable setpoint-based control.
More “forward facing” approaches to process development and scale-up, with Phase III and commercial stages firmly in sight, are also boosting manufacturing improvements, says Thomas VanCott, PhD, global head of Product Development at Catalent Cell & Gene Therapy. For example, he says, pre-process performance qualification activities (e.g., designing target product profiles, identifying critical quality attributes [CQAs] and critical process parameters [CPPs], and considering optimal scale-down models) are being done earlier in the cycle.
Before any process-development effort begins, or any external customer process is transferred to the company, initial gap analyses and risk assessments are done for both the process and raw materials to determine whether the process can be scaled to meet the product’s long-term clinical production needs, Van Cott says.
Analytical needs must also be determined, to assess whether the desired quality attributes are being achieved and in evaluating any critical raw materials. Quality problems can stem from manufacturing, when parts of the AAV’s native genetic material are removed and replaced by a transgene, the therapeutic gene and genetic elements that support the gene’s activity and expression, explains Stephen Gacheru, vice-president at PPD Laboratories GMP Lab.
For recombinant AAV (rAAV) vectors, good quality equates with having a high level of capsids that contain the full transgene, Gacheru explains. Empty and partial capsids are considered product-related impurities, which can impact product efficacy and safety, he says, posing risks of increased immunogenicity to the therapeutic vector and related immune responses, he says. At Catalent, assessing the analytical requirements for rAVVs at the earliest developmental stages has led to significant improvements, says Van Cott, allowing quality deviations to be found before scale-up, reducing the risk of cost overruns and delays.
In addition, there is an emphasis on scaling out, rather than simply scaling up, VanCott explains, and this is true for both suspension and adherent viral vector manufacturing processes, as well as autologous cell therapy production. There may be an evolution in approaches to scaling up allogeneic therapies, he says. Currently, larger scaleup has been precluded by the absence of stable producer cell lines and transient transfection processes in viral vector manufacturing. “For gene therapies, scaling out and combining multiple upstream runs into downstream processes has been more common,” notes VanCott.
For the viral vectors used to make gene therapies, use of perfusion, seeding and intensification has been less critical than it is for some traditional biologics because of unique processes associated with the transient transfection process used to produce viral vectors, VanCott says. However, perfusion is an advantage for other viral vectors such as the baculovirus/Sf9 platform, he says.
In addition, lyophilization strategies are being explored because liquid formulations require storage below -20° C, posing challenges for formulation and vial composition. Formulation research projects are underway to address these challenges, VanCott says. Stable producer cell lines for AAV production will be key to reducing costs and improving scale-up (e.g., by obviating the need for clinical-grade plasmid DNA for transient transfection processes), he says.
New equipment designs are helping to advance scale-up goals. For example, Univercells Technology recently commercialized a platform (NevoLine) that enables viral manufacturers to chain, integrate, and intensify processes, explains Mohammad Elfar, product innovation manager at the company, while the company’s fixed-bed bioreactors (Scale-X) have been improved to enable linear scalability from the bench to the plant.
Similarly, Pall Corp.’s fixed-bed bioreactors (iCELLis) have been optimized to improve scale-up from the bench to the production floor. As Byron Rees, Pall’s senior manager of process development services notes, cell and gene therapy developers often choose to adapt adherent cells to suspension for viral vector manufacturing because they think this approach will speed scale-up. However, that approach can add months to process development time. As an alternative, he says, Pall’s fixed-bed bioreactors can be used to scale up adherent cell-based processes to commercial scale while cutting process development timeframes down to three months.
Further upstream, the company’s nano bioreactor (iCELLis Nano) has been designed to optimize benchtop-scale (i.e., 0.53 m2–4 m2) work and transfer to the large-scale manufacturing bioreactor (iCELLis 500). Using the larger bioreactor, customers can scale their production from 66 m2 to 500 m2 within the same footprint, allowing more manufacturing flexibility with the ability to accommodate various molecules with different scales of demand, says Rachel Legmann, director of technical consultancy for gene therapy and viral vectors at Pall. The company’s suspension bioreactor (Allegro STR) has been optimized for viral vector production, with low shear mixing for HEK293 growth with minimum clumping to improve transient transfection efficiency, she says.
At Cytiva, equipment lines used for traditional biopharmaceutical manufacturing are also being optimized for use with cell and gene therapies in single-use process equipment but also in areas such as harvest clarification, affinity resins for viral vectors, and low shear pumps and systems, says Joe Joe Makowiecki, director of business development for Cytiva’s FlexFactory and KuBio products. “New and standardized analytics are also being developed, including newer products that can separate out empty vs. full capsids, which will improve overall efficiencies,” he says.
Industry standards promise to clarify best practices and requirements, and help move more cell and gene therapies to market. The International Standards Organization’s (ISO’s) Standard 21973 (3) outlines best practices for manufacturing and distribution, Sawicki told webcast attendees. Most notable have been its provisions for full traceability and the management of equipment used to ship the therapies, he said. “This equipment gets reused, so requalification processes are crucial to preventing product failures from occurring,” he told webcast attendees. Sawicki expects future work to focus on cleaning recommendations to reduce risk of cross contamination. Cryoport is evaluating the use of technologies, such as analysis of equipment performance data trends with artificial intelligence, to predict the likelihood of failure during shipping and prevent it from happening.
One area that regulators may need to address is establishing universal conventions around label templates, said DuRoss. “Different labeling conventions in different markets, even on same continent, introduce unnecessary risk,” she said on the program, noting a need to move from the use of pre-printed shipping labels to on-demand printing capability.
There will also be a need to optimize analytical testing to ensure quality control with cell and gene therapies. In January 2020, FDA released preliminary guidance clarifying some aspects of this problem. Various analytical methods have been developed to determine an rAAV product’s composition of full vs. empty/partial capsids, says Gacheru, including analytical ultracentrifuge (AUC), transmission electron microscopy (TEM), spectroscopy (A280/260 ratio), anion-exchange high-performance liquid chromatography (AEX-HPLC), size-exclusion chromatography with multi-angle light scattering (SEC-MALS), and capillary isoelectric focusing (cIEF) assays. Efforts are underway to make these methods faster and easier to use for release testing, says Gacheru, who sees the industry moving to use of multiple orthogonal methods.
Cleaning validation also needs to be optimized for cell and gene therapies. Based on traceability requirements mandated in Australia, Cryogen developed a specialized cleaning validation approach for cell and gene therapies, as well as a customized shipping container to move C> products.
New technologies promise to bring additional improvements to innovative therapy development and manufacturing. Ahlgrimm sees artificial intelligence playing a key role and notes that digital technologies, such as augmented and virtual reality, are already being used to help The Discovery Labs improve employee onboarding. The new industry faces a lot of questions. Will production become decentralized and move entirely to healthcare centers or points of treatment in the future? DuRoss doesn’t expect that shift to be possible for at least another 15 to 20 years. As the market grows, every new C> submission and product in development will continue to educate the industry and regulators. “We can only expect that more will be learned and that requirements will change as the field of C>s matures,” Ahlgrimm says.
1. PhRMA, “Medicines in Development: Cell and Gene Therapy 2020,” phrma.org, 2020.
2. PharmTech webcast, “Editors’ Series: Cell and Gene Therapies: Laying the Foundation for a New Supply Chain,” pharmtech.com, July 29, 2020.
3. ISO, “Standard 21973:2929: General Requirements for Trasportatio of Cells for Therapeutic Use, iso.org, June, 2020.
Vol. 34, No. 1
When citing this article, please refer to it as: A. Shanley, "Can Cell and Gene Therapies Achieve Their Potential?" BioPharm International 34 (1) 2021.