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Now that the first genetically modified cell therapies are being manufactured, the industry must move beyond “whatever works” to meet growing demand.
In less than four decades, biopharmaceutical manufacturing has traveled light years from its origins in facilities such as Amgen’s Building Six in Thousand Oaks, California, which manufactured 200 grams of recombinant human erythropoietin per year with two stainless steel tanks and 3000 roller bottles (1). As increasingly sophisticated equipment was developed for upstream and downstream processing, standardization allowed for the engineering of new processes and platforms and faster development and scale-up.
Cell therapies, genetically modified cell therapies, gene therapies, and tissue engineering now stand where biotech was in the late 1980s; the first products have been commercialized and manufacturing them has become a question of doing whatever works.
“The greatest success so far has been the fact that the industry has even launched the cell and gene therapy products that it has introduced. Regulators have accepted them, and developers have figured out how to get them to the market,” says Phil Vanek, general manager of cell and gene therapy strategy, GE Healthcare.
The next phases of industrial development, Vanek says, will focus on streamlining the supply chain and the creation of increased therapeutic value; engineering new therapeutic value into the cells to achieve the highest potency per amount of production time and cost; and connecting both of these efforts, via an intricate pathway, directly to patients.
“We must draw on the valuable experience that we acquired in biologics manufacturing, where we evolved from small to large volumes and from stainless-steel to single-use platforms for flexibility,” says Lisa Krallis, head of business development, cell and gene technologies at Lonza Pharma & Biotech.
As the cell and gene therapy market grows, substantial pressure is on developers to meet commercial demand and supply clinical quantities of material. By the end of 2018, 1028 global clinical trials were underway for cell and gene therapies, 58% of them for oncology therapies; 57% of them in Phase II, and nearly 9% in Phase III, according to the Alliance for Regenerative Medicine’s 2018 Regenerative Medicine Data Report (2). That year, more than 906 companies focused on cell and gene therapies, generating $19 billion in merger and acquisition activity and $13.3 billion in corporate financing for research and development, up 73% from 2017.
Meeting increased demand will require a one-to-two-orders-of-magnitude improvement in gene therapy vector manufacturing, and a similar reduction in cost, as Peter Marks, director of FDA’s Center for Biologics Evaluation and Research noted at the 2018 Galien Foundation’s Forum (3). “Platforms need to become standardized, industrialized for yield, and then optimized for complexity,” says Krallis.
Today, efforts focus on improving existing manufacturing platforms for both patient-specific, or autologous therapies, and allogeneic treatments designed for many patients (4). They include in-vivo adeno-associated viral vector (AVV) technology, which enabled the commercialization of Spark Therapeutics’ retinal blindness therapy, Luxturna, which FDA approved in December 2017. Roche plans to acquire the company (pending approval by the US Federal Trade Commission) (5).
Also being developed are ex-vivo Lentivirus vectors, which modify cells that have been removed from a patient, then are combined with T or stem cells and injected back into the patient, an approach that Bluebird Bio is using for chimeric antigen receptor (CAR)-T cell therapies (3).
Novartis and Kite have developed faster autologous CAR-T processes, while ZIOPharm is refining its Sleeping Beauty non-viral gene transfer platform, which FDA approved for use in T-cell receptor cell therapy in June 2019 (6). That same month, FDA approved the first clinical trials using UCART123, an off-the-shelf, allogeneic cell therapy approach developed by the French company, Cellectis (7) that uses Talen, a proprietary gene editing technology. Trials are already underway for UCART19 and UCART123, other therapies that utilize the technology.
“With queues for new vector production frequently around 12 months, the industry isn’t where it needs to be in terms of production capacity,” says Andrew Bulpin, head of process systems at MilliporeSigma. “As a result, innovation focuses on improving scalability to enhance the amount of material produced per run.” Upstream, the best way to improve scalability is to move cell culture into suspension. “Current vector production is disproportionately done in adherent culture, which is only conducive to scaling out, not scaling up. There is also significant use of serum in cell culture media, which increases regulatory burden and creates a potential supply bottleneck,” says Bulpin. Moving culture into single-use bioreactors improves scalability and enables a shift to chemically defined media, solving a number of problems at once, he says.
For downstream processing, Bulpin explains, the picture is more complex because of the number of steps required in the workflow. “In addition to process complexity, there is a need to increase the scale that current unit operations can handle as well as to minimize the loss of vector in each unit operation. Innovations in chromatography and filtration will be important to achieving those goals,” he says.
Platforms specifically designed for viral gene therapy applications could address more of these challenges at once and will be essential for ongoing growth in the industry, says Bulpin. At this point, innovative therapies are still being developed in equipment that was designed for traditional biopharmaceuticals, and there is a disconnect. “In biologics, the cell is a byproduct, and material is purified by removing that byproduct,” explains Vanek. “In cell therapy, however, the cell is the final product, so we must be very careful to develop platforms and approaches that do not fundamentally change the biology of the cell. That’s a tall order,” he says.
As more is learned about innovative therapies in the clinic, equipment will eventually be customized for use with cell and gene therapies, Vanek says. “Every cell type will have a set of specific conditions that it thrives under, and those conditions will ultimately be developed into next-generation equipment, whether bioreactors, cell processing platforms, and ancillary materials, upstream and downstream methodologies, including everything from reagents to hardware, to consumables and software,” he says.
“In patient-specific therapies, you may not need more than a billion cells per batch, but if you start to scale up in allogeneic you might need hundreds of billions of cells per batch,” Vanek says. In order to scale up and increase the volumes of allogeneic cell therapies, manufacturers will need to be able to move seamlessly from adherent to suspension cell culture, says Krallis, and ultimately 2000 L single-use bioreactors of the type now used for viral vectors may be needed for allogeneic applications to achieve the required cell volumes.
“Suspension processes for allogeneic manufacturing have been established for some time, so there has been more work adapting processes for these needs than there has been for vector production,” says Bulpin. Closed, automated technology platforms will be critical in the future, he says.
Autologous therapy development will not be one size fits all, says Krallis, who emphasizes the need for “mass customization,” which she defines as “automating processes while remaining flexible from the clinical-to-commercial phase and adapting to the quality of the raw material.” Lonza launched its closed, automated Cocoon platform (acquired via its purchase of Octane Biotech in 2018), which aims to help developers achieve this goal and is currently being used by Sheba Medical Center to produce autologous therapies (8).
Although most biopharmaceutical companies are adopting automation, cell and gene therapies pose challenges, says Bulpin. “Unlike monoclonal antibodies that utilize robust and predictable immortalized cell lines, CAR-T therapy requires the patient’s own cells for further processing. Incoming cell composition from patient to patient is exceedingly variable. Automation and process control for CAR-T manufacturing will require a high degree of flexibility for variable cell inputs while also providing robust and predictive processing,” Bulpin says.
Data management will also be crucial for autologous manufacturing, which will require patient tracking to ensure that the product makes its way back to the intended recipient. “It is also extremely important, given that many of these patients have not responded to chemotherapy and radiation therapy, that the manufacturing process be short and patient scheduling seamless,” Bulpin says.
As he notes, the typical CAR-T manufacturing process can take anywhere from 20–30 days, with a significant portion of this time dedicated to release testing. Bulpin suggests that using in-line sensors for real-time quality control release testing could improve overall efficiency.
“To support this new type of manufacturing, we are going to need to replace as many manual processes as possible with closed and automated processes, so the labs will look very different as a result,” Krallis says. In addition, she sees the need for a new digital approach to managing manufacturing systems. “Especially as we increase the number of patients treated per week with autologous cell and gene therapies, it is key to have the right data-management systems in your manufacturing setup to track and trace all patient material in real-time, before, during, and after manufacturing,” she says.
Vanek agrees that digitalizing the overall process will be crucial to development of personalized medicine. “If you’re translating from a clinic and you have a therapeutic that’s progressing through clinical trials, there is a need for better data management and integration. Even at the unit operation level or the individual step of a larger process, just being able to connect data in a cohesive fashion is crucial,” he says.
Although many pharmaceutical companies are at a very early stage of digitalization, Vanek believes that capabilities can be adopted sequentially. The first step would involve connecting data with batch records and standard operating procedures (SOPs) so that the information becomes part of the manufacturing record. GE launched a platform called Chronicle in May 2019 (9) to enable e-notebook and e-SOP connection in a more streamlined way, he says.
“Entering data incorrectly at the production stage poses a very high risk to the manufacturing process, particularly for autologous therapies,” he says. “So, our goal is to get the devices used across the process, independent of vendor, to have a consistent way of reporting out data and having data available to operators, to the quality assurance and regulatory affairs teams that are ultimately responsible for the quality of that product.”
But he acknowledges that this is only the first level of integration. Data must flow from the patient through the manufacturing process and then back to the patient, and all the elements of the complex supply chain must be coordinated, he explains, so the second level of digital integration will connect digital patient records, the materials flowing in, as well as the production process into one manufacturing workflow.
“Ultimately, you want to escalate that integration to the point where it’s part of a manufacturing execution system (MES), to start to schedule, coordinate, and orchestrate all the moving parts. This will require a much more sophisticated capability than the industry has today,” Vanek says.
Beyond digitization and automation, developers face a number of other challenges as they scale-up cell and gene therapies. One concern that Krallis notes is requirements for and availability of the complex raw materials (e.g., plasmids and lentivirus) required for manufacturing. In addition, she says, as the field evolves, developers must be careful about investing too-much too-soon in technologies that may soon be outdated, before they recover their capital expenditures, she says.
Ultimately, she says, developers face reimbursement challenges and the need to balance cost effectiveness in the scaled-up process with demands to reduce drug cost to patients. She believes that contract development and manufacturing organizations (CDMOs) can offer developers a way to control operating and capital costs, allowing them to focus on pipeline development.
Bulpin sees the shift toward personalized, point-of-care medicine as a challenge for the delivery of finished therapies. Another hurdle is the long timeline from development through manufacturing, he says.
As more companies get involved in personalized medicine development, all stakeholders including operating companies, CDMOs, technology vendors, and research organizations are forming alliances to stay ahead of challenges and share different perspectives. One example is the Centre for Advanced Therapeutic Cell Technologies in Toronto, Canada, whose members include GE Healthcare and the NJII Cell and Gene Therapy Development Center, which works with Pall Corp.
The dynamics of collaborations in this field may differ from those in traditional biopharmaceutical development. One reason is the complexity of the supply chain, especially for autologous therapies, because the starting material is the patient’s own cells, says Bulpin. “Closed and automated systems offer the potential for manufacturing sites to be located closer to the patient, regionally or even at the hospital. In this context, CDMOs may require satellite facilities, or academic medical centers may take on more of a CDMO role,” he says.
Another difference from traditional biopharma is the fact that many of the therapies originated from research and discovery conducted by the doctors and academics at hospitals and research institutes, says Krallis. “Institutes can manufacture therapies for clinical trials but most of them don’t have the expertise or the capacity to make product at commercial scale. Instead, the therapies get spun off to new companies and are usually tech-transferred to a CDMO,” she says, noting that CDMOs may have an advantage in being able to scale up or down, to adapt to changes in demand.
“People have succeeded with therapeutic production at small scale, but we don’t have industrial experience yet. All stakeholder groups must come together to share experiences and identify ways to retire risk, reduce costs, keep up with regulatory pace, and make safe and effective products available to patients who need them,” Vanek says. “The pace of change and approvals is faster in this sector than we’ve ever seen before. Everyone is figuring this out as we go,” he says.
1. Amgen, “Manufacturing Excellence That’s Decades in the Making,” amgen.com.
2. The Alliance for Regenerative Medicine, “Annual Regenerative Medicine Data Report, 2018,” alliancerm.org, March 2019.
3. A. Shanley, “Can Gene Therapy Deliver on Its Promise,” PharmTech.com, Nov. 14, 2018.
4. W. Colasante et al., “The Link Between Manufacturing and Commercialization in Gene and Cell Therapy,”Pharmaceutical Technology Biologics and Sterile Drug ManufacturingeBook (May 2019).
5. Roche, “Roche and Spark Therapeutics Receive Request for Additional Information from FTC,” Press Release, June 10, 2019.
6. Ziopharm, “Ziopharm Announces FDA Clearance,” Press Release, June 11, 2019.
7. Cellectis, “FDA Grants Cellectis IND Approval for UCART 22,” Press Release, June 4, 2019.
8. V. Barba, “CAR-T’s That Grow on Trees,” biopharma-reporter.com, June 11, 2019.
9. BioPharm International, “Software Automates Cell Therapy Manufacturing,” biopharminternational.com, May 15, 2019.
Supplement: Outsourcing Resources
When referring to this article, please cite it as A. Shanley, “Industrializing Cell and Gene Therapies," Pharmaceutical Technology Outsourcing Resources Supplement (August 2019).