Navigating the Manufacturing Process and Ensuring the Quality of Regenerative Medicine Therapies Proceedings of a Workshop (2017) / Chapter Skim
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2 Transitioning from Discovery and Development to Manufacturing
2 Transitioning from Discovery and Development to Manufacturing
Pages 7-24
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From page 7... ...
• Investigators should focus on demonstrating the efficacy of their products before engaging in further product development because understanding potency and the important biological effects of a given cell or tissue therapy is the most critical aspect of being able to generate reproducible results and reach production scale. (Niklason)
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From page 8... ...
During the first session following Gee's keynote presentation, a panel discussed the challenges and opportunities associated with bringing new discoveries from the laboratory to manufacturing and with navigating the process of scaling the production of new regenerative therapies. The three speakers -- Bruce Levine, the Barbara and Edward Netter professor in cancer gene therapy at the University of Pennsylvania Perelman School of Medicine; Laura Niklason, a professor of anesthesiology and biomedical engineering at Yale University; and Robert Preti, the president and chief executive officer at PCT Cell Therapy Services and chairman of the Alliance for Regenerative Medicine -- also described potential opportunities and models to enable the scaling of regenerative medicine therapies for production using the currently available infrastructure and addressed probable future needs as the regenerative medicine field evolves and grows.
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From page 9... ...
An ideal regenerative medicine product would have a starting material that was easy to collect or generate from iPSCs or embryonic stem cells, its manufac turing would be automated and use simple closed systems, and there would be rapid and predictive testing methods to determine whether the product has met appropriate release standards. The product would have a long shelf life under simple storage conditions, it would be easy to distribute and administer, and its production would make possible a high-quality, low cost therapy.
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From page 10... ...
If the starting material comes from the intended patient, those autologous cells are likely to be affected by the disease state of the patient and any prior therapies the patient has received, and they may be more difficult to collect. Cell therapy products that use allogeneic cells obtained from healthy donors are more likely to be uniform, Gee said, because fewer screened donors will provide the starting material for most of the product and their target cell populations are less likely to contain variations because of disease, but not all therapies will be amenable to using allogeneic cells (Malik, 2012)
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From page 11... ...
"I think it shows that even in one particular field, advances can be made moving toward the goal of the ideal product," Gee said. With regard to testing and release protocols for regenerative medicine products, Gee said, there are a few rapid testing assays, such as that for endotoxin, but there is still a need for a rapid assay to test for sterility.
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From page 12... ...
Specifically, Gee wondered if it would be feasible to return a portion of the profits from the sale of cellular therapy products back to the original centers where they were developed since many products arise from publicly funded research. Additionally, many products are developed at academic manufacturing centers or hospitals to treat a small number of patients, making them unattractive for large-scale commercialization and the challenge, Gee said, is that "most hospitals do not want to be in the business of manufacturing cell products." "Cellular regenerative medicine therapies are likely to revolutionize the practice of medicine in the future," Gee said, but ultimately, researchers and manufacturers of regenerative medicine therapies must adapt their production processes and environments to best suit the needs of patients.
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From page 13... ...
and allowing the cell to produce both its original antigen receptor and the CAR. In his presentation, Levine reviewed the technology and methodology behind the first CAR clinical trials that used a murine retrovirus to edit the T cell genome.
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From page 14... ...
conducting its initial clinical trial and permitted the company to open its own investigational new drug application and conduct global clinical trials. Still, Levine said, there is the issue of individual patient variability.
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From page 15... ...
• Addressing ethical questions of patient access and moving from an investigational clinical trial for a potential new therapy with strong positive results to a larger clinical trial, given the complexities of scaling the production of these therapies and allocating enrollment in larger clinical trials. with acute lymphoblastic leukemia.
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From page 16... ...
The function of each of these connective tissues relies, in part, on cellular components, but the extracellular matrix confers many of their functional attributes, she explained. In the late 1990s Niklason and her collaborators developed methods to collect autologous vascular smooth muscle cells, culture them in a bioreactor for approximately 8 weeks, and generate autologous blood vessels that functioned like normal blood vessels when transplanted into the host that provided the original cells.
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From page 17... ...
FDA has since approved a Phase III trial that will compare the performance of Niklason's grafts against expanded polytetrafluorethylene and Propaten vascular grafts in 350 patients, which she said is the largest clinical trial ever conducted in vascular access for hemodialysis. The first patient was enrolled in May 2016, and preliminary results should be available in late 2018.
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From page 18... ...
Potency, she said, is turning out to be a combination of mechanical properties, biochemical composition, cell remnants, proteomic characterization, dimensions, and cell interactions. Concluding her presentation, Niklason emphasized to the academic investigators attending the workshop that the key to developing a reproducible production process is to understand the vital aspects of a cell system, rather than cataloguing all potential identifying cellular markers, and to maintain control over the process parameters that affect those aspects.
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From page 19... ...
The field is at an inflection point where mass production and treating patients with these transformative therapies is a reality, Preti said. The goal for product developers and manufacturers such as Preti's company is to achieve commercially viable manufacturing strategies, but the complexity of manufacturing regenerative therapies has proven to be a significant barrier to this goal.
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From page 20... ...
DISCUSSION Addressing Technical and Scientific Hurdles The panel of speakers discussed the scientific and technical challenges of finding donors of cells and tissues that could be used for research and product development. There is variability in both the quality of donor cells and the ability to increase the number of donor cells in vitro prior to the inoculation step, said Laura Niklason, describing the challenges she and her team encountered in finding donors for the development of Humacyte's vascular grafts.
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From page 21... ...
"For a long time," he said, "we said we could not [characterize the mechanism of action] in cellular therapy, but I have seen evidence that it is possible." Those in the regenerative medicine manufacturing industry, Preti said, need to begin to focus more heavily on critical process parameters when considering the types of assays that are needed for inline testing to monitor how cells and tissues are growing during the manufacturing process.
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From page 22... ...
There are training courses for those who work in blood processing and banking operations, and a workshop participant suggested that those programs could serve as a foundation for training programs for the regenerative medicine industry. There are a few potential candidates from blood banks and from medical technology schools, both of which train people in procedures and documentation, which are the underpinnings of GMP, Levine said.
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From page 23... ...
In his area of research on CAR T cells, he said, there are now many companies with products in advanced clinical trials, and the clinical results from these different trials appear to be validating the superior performance of this category of product versus conventional therapies. Manufacturing standards are available, including clear standards for GMP and good tissue practices from FDA,7 Preti said, and the Alliance for Regenerative Medicine8 has standards covering different types of therapies.
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From page 24... ...
Collaborations will be important in addressing technical challenges as the regenerative medicine industry moves forward, Levine said, and academic institutions and companies can only do so much in isolation. The National Institute of Standards and Technology (NIST)
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