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Review
. 2015 Mar;4(3):217-23.
doi: 10.5966/sctm.2014-0233. Epub 2015 Feb 3.

Enabling Consistency in Pluripotent Stem Cell-Derived Products for Research and Development and Clinical Applications Through Material Standards

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Free PMC article
Review

Enabling Consistency in Pluripotent Stem Cell-Derived Products for Research and Development and Clinical Applications Through Material Standards

Anna French et al. Stem Cells Transl Med. .
Free PMC article

Abstract

There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.

Figures

Figure 1.
Figure 1.
Overview of standards. Standards are a set of guidelines, rules, or requirements, typically set by a regulatory body or product manufacturer. They ensure that either during manufacture of a product or in the final product, some aspect, such as safety, performance, or quality, is consistent. Standards are either written, in the form of guidance, standard operating procedures, and pharmacopoeia, or they are physical (material). Physical standards are characterized materials used as a benchmark against which to compare attributes of a product and ensure consistency. They can be agreed on across organizations and countries (consensus) or can be developer-specific and local (in-house) (i.e., the standards are only adopted within the organization in question). These in-house material standards, called RMs, are the focus of our review and can be further divided into a product RM, which is a representative batch of the product, or a method (measurement) RM, which provides a reference for analytical measurements. Abbreviation: RM, reference material.
Figure 2.
Figure 2.
Reference materials are required to demonstrate product comparability over time (product RM) and to validate assay results (method RM). Product RMs are representative of some aspect of quality of a final product, and method RMs are used within assays to confirm the accuracy of the analysis of the product. They have multiple applications, two of which are depicted. (A): Product RMs are required to demonstrate that product drift does not occur. Product drift is the gradual change in a “product,” potentially caused by a gradual change in a manufacturing process that can occur through iterations over time. Product RMs are a representative batch against which other batches can be compared to demonstrate consistency in characteristics such as identity and purity. For example, RMs generated with batch B, such as a sample of the iPSC batch, will be retained to use as a comparator with batch D to ensure that characteristics of batch D are within the expected range according to batch B. (B): Method RMs are needed to validate assay results alongside the product sample. For example, specific embryonic carcinoma (EC) lines, whose cell-surface antigens are well characterized, can be used as a quality control for flow cytometry assays in which human embryonal stem cells (hESCs) are also tested. If the score for the EC line is less than a certain predetermined threshold, the results of the accompanying assay of hESCs would not be included in additional analysis. Thus, the results will be representative of the actual hESCs and not of any problem in the assay, because the assay has been validated against a method RM with known characteristics. Abbreviation: RM, reference material.

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