Navigating the Manufacturing Process and Ensuring the Quality of Regenerative Medicine Therapies Proceedings of a Workshop (2017) / Chapter Skim
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3 Identifying and Measuring Critical Quality Attributes
3 Identifying and Measuring Critical Quality Attributes
Pages 25-40
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From page 25... ...
• Establishing acceptance criteria using known reference and patient samples before clinical trials and identifying criti cal reagents will help streamline the manufacturing process. (Kelley)
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From page 26... ...
The quality attributes of regenerative medicine products can include identity, quantity, purity, sterility, viability, and markers of biological activity, Plant said. While FDA defines a number of quality attributes that must be provided with any regulatory submission, there are many different types of products in development, each with its own set of unique characteristics, making it challenging to develop common assays for product characterization.
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From page 27... ...
FDA requires validated assays for registration-enabling clinical trials. However, Plant said, validating assays as early as possible leads to better decision making at each step along the translation process and to more 1 The FDA guidance document Potency Tests for Cellular and Gene Therapy Products is available here: https://www.fda.gov/downloads/biologicsbloodvaccines/guidance complianceregulatoryinformation/guidances/cellularandgenetherapy/ucm243392.pdf (accessed August 11, 2017)
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From page 28... ...
Plant noted that a NIST-led consortium, in partnership with the Standards Coordinating Body, is working to improve measurement assurance in gene editing.3 This project will compare existing assays, define minimum metadata to report, design benchmark materials, and compare informatics platforms. A number of elements can contribute to more robust assay development, Plant said, including • inter-laboratory studies • experimental design • testing assumptions • traceability to a reference material • statistical methods • assay qualification • consistent reporting 2 Background information on the Flow Cytometry Quantitation Consortium can be found here: https://www.federalregister.gov/documents/2016/07/15/2016-16761/flow-cytometryquantitation-consortium (accessed August 16, 2017)
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From page 29... ...
POSSIBLE OPPORTUNITIES AND CHALLENGES FOR DETERMINING CRITICAL QUALITY ATTRIBUTES IN EARLY-PHASE CLINICAL TRIALS The comparability testing of CQAs could be carried out more efficiently by tapping into global collaborations as a way of accessing a larger number of patients and managing costs, Linda Kelley said. As of April 2017, there were 55 approved cell-based therapeutic products (Bersenev, 2017)
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From page 30... ...
and the European Pharmacopeia play similar roles. As an example of an international, multi-centered trial, Kelley discussed her experience carrying out Phase I and Phase II clinical trials with autologous CAR T cells.
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Another reason for the dual site manufacturing was to create flexibility in the production process to accommodate the European regulatory agency's regulations regarding audits that can require facilities to shut down completely. The challenge for Kelley and her collaborators was to demonstrate that the two manufacturing sites could produce comparable products so that the data from both sites could contribute to the results of the clinical trial.
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In thinking about testing for every TABLE 3-1 Critical Quality Attributes, Analytical Methods, and Acceptance Criteria Criteria Methods Limits Viability Flow cytometry ≥ 70% Purity (CD3+ cells) Flow cytometry ≥ 80% Cell count Flow cytometry Specified dose ± 25% Identity (NKG2D+ cells)
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. Based on their findings, the study authors proposed that master cell banks used for production of infectious virus should continue to undergo rigorous RCR testing but argued that final T cell products that incorporate retroviral vectors and patient peripheral blood samples do not need to undergo active screening at defined time intervals.
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From page 34... ...
Once industry scientists had identified what Deans called the black box benefit they observed when their cells were injected into an in vivo animal model, they developed an in vitro surrogate assay that had comparable benefits to those seen in the animal model. The company next worked on identifying a negative control by using a cell line that did not stimulate angiogenesis, Deans said, and it used 6 The FDA Guidance for Industry and Review Staff on the target product profile can be found here: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/ucm080593.pdf (accessed September 19, 2017)
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Overarching Challenges to Product Identity Testing On the subject of product identity testing, Deans said that he sees many potential challenges with using individual markers or cell surface markers as a distinguishing mark if they do not correlate to a specific cellular function. Instead, his company has used a unique approach to identify a functional distinction between its product and another product and then defines a molecular surrogate that correlates with that distinction that could be used reproducibly as an assay for in-process development or lot release.
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From page 36... ...
A challenge for the field, he said, will be to develop efficient and effective assays linked to key safety attributes so that the development cycle can accelerate. One potential solution may involve implanting cells into pre-existing tumors, which would provide a tumor microenvironment that might speed up the development of teratomas, if they were going to develop at all.
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From page 37... ...
There are still many details to work out, she said, which is why she is currently speaking with experts about the state of the science and the issues associated with using gene editing for therapeutic purposes. With regard to whole-genome sequencing, Plant said that NIST formed a public–private academic consortium called Genome in a Bottle that is establishing important benchmarking data on a limited number of human genomes from de-identified individuals.9 A number of groups using different platforms are sequencing these genomes and analyzing the results using unique bioinformatics tools.
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His team is developing an imagingbased convolutional neural network, which is a computing system inspired by physiological neural networks that is used to analyze visual imagery. The research goal is to use the convolutional neural network to effectively predict measurable cell functions.
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From page 39... ...
Potential Opportunities for Developing Reference Materials The MSC research community has debated the value of a gold standard reference MSC line and the idea of agreeing on standards that adequately define an MSC product, Deans said. It can be frustrating that the community has not been able to agree on a consensus identity definition or to work collectively together to harmonize cell characterization, he said, noting that there currently a few hundred different names being used to describe very similar cell products.
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A unique challenge to certain cell-based regenerative medicine products is that part of the manufacturing process occurs in the patient, where the cells expand, proliferate, and change phenotype after injection. A workshop participant asked the panelists for their thoughts on the responsibilities that developers have to understand that part of the process and what type of assays might be needed to understand what is happening to the product.
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