Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products Proceedings of a Workshop (2019) / Chapter Skim
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5 Addressing Variability and Meeting Quality Expectations in the Manufacturing Setting
5 Addressing Variability and Meeting Quality Expectations in the Manufacturing Setting
Pages 57-70
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From page 57... ...
(Myers) • Elements of quality by design (e.g., critical quality attributes, process controls, systematic risk evaluation)
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From page 58... ...
Milton Endowed Chair and the director of the Center for Immuno ngineering at Georgia Tech, agreed with earlier discussions about e the value of embracing variability during the discovery and early-phase clinical trial stages. However, he said, during the final product manufacturing phase, reproducibility, consistency, standardization, and principles of quality by design, including defined critical quality attributes, are essential.
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From page 59... ...
Lastly, the early development stage consists of many process changes and different sources of input materials, which also complicate the assessment. Apheresis material for autologous cell therapy is subject to variability related to its limited quantity (i.e., product yield)
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From page 60... ...
Using GMP raw materials makes it possible, Burke said, to understand the impact of critical material attributes on the regenerative medicine product's critical quality attributes. The field of regenerative medicine is novel with regard to both the supplier of input materials and the developer, Burke said.
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From page 61... ...
He suggested working in partnership with the vendor to ensure that the vendor's incoming source material is appropriately screened, that there is appropriate testing and process control, that the vendor provides notification of process changes, and that the vendor conducts release testing to ensure the quality of batches. It is also important that researchers establish incoming testing requirements and remediate certain input components in the product process if needed (e.g., supplementation if certain components are subject to degradation)
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From page 62... ...
The goal, she said, is to "implement process and analytical improvements that will provide greater process robustness and enhanced product quality while minimizing the impact of changes." To achieve this, Myers proposed using elements of quality by design, which she defined as "a systematic approach to development that is based on sound science and risk management." It includes predefined objectives and focuses on product and process understanding and process control. Quality by Design Quality by design begins with defining the critical quality attributes of a product; that is, those attributes with the potential to affect product safety or efficacy, Myers explained.
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From page 63... ...
These included changes to the vector production process, such as switching from an adherent culture system to a suspension culture system; changes in the cell manufacturing process, moving from manual cell manipulation to implementing automation; and changing the final product formulation from fresh cells to a cryopreserved product. Each of these proposed changes should be systematically assessed as a function of the established critical quality attributes, she reiterated.
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From page 64... ...
A more complex scenario would involve an organ bank, where multiple tissues are harvested from multiple different donors, held in cold storage at the organ bank, and then matched to the most appropriate recipient. On a larger scale, tissue might be collected from hundreds or thousands of donors, cryopreserved, and used as source material for the production of mesenchymal stem cells, or perhaps for highthroughput pharmacology testing.
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From page 65... ...
In addition to the solution effects from the osmotic gradient, ice crystals that form during cryopreservation can damage cell membranes and intracellular structures, leading to cell damage or death and the release of immune mediators. Conventional cryopreservation only works for cells in suspension or for very small embryos, Finger said.
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From page 66... ...
. The newer-generation cryoprotective agents have much lower critical warming and cooling rates (e.g., a critical warming rate of 32,000°C/min for 6M glycerol versus 0.4°C/min for M22)
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From page 67... ...
In the case of CAR T cell products, Burke said, the research, development, supply chain, and manufacturing groups are situated physically close to each other, which creates a sense of integration. Many startup companies work quickly to reach the phase I clinical trial stage so that they can be acquired by large companies, a workshop participant said.
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From page 68... ...
For example, it can affect how an academic laboratory protects confidential or potentially proprietary data and when the laboratory decides to release or publish it. One suggestion offered by a workshop participant was to ask students at the Wharton School of Business at the University of Pennsylvania to conduct a study of the process improvements that happen when there is more integration across departments, such as the close integration mentioned by Burke among the departments working on CAR T cell therapy.
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From page 69... ...
Both programs are designed to help NIH-funded researchers translate their innovations to the clinic and to a commercial product. These centers and hubs serve as a nucleus where diverse teams can come together and share expertise and resources.2 Another workshop participant mentioned the work of the Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery, a nonprofit organization working to facilitate the development of standards.3 He encouraged other workshop participants to get involved and added that students can become involved as well.
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