Concise review: mind the gap: challenges in characterizing and quantifying cell- and tissue-based therapies for clinical translation

Abstract

There are many challenges associated with characterizing and quantifying cells for use in cell- and tissue-based therapies. From a regulatory perspective, these advanced treatments must not only be safe and effective but also be made by high-quality manufacturing processes that allow for on-time delivery of viable products. Although sterility assays can be adapted from conventional bioprocessing, cell- and tissue-based therapies require more stringent safety assessments, especially in relation to use of animal products, immune reaction, and potential instability due to extended culture times. Furthermore, cell manufacturers who plan to use human embryonic stem cells in their therapies need to be particularly stringent in their final purification steps, due to the unrestricted growth potential of these cells. This review summarizes the current issues in characterization and quantification for cell- and tissue-based therapies, dividing these challenges into the regulatory themes of safety, potency, and manufacturing quality. It outlines current assays in use, as well as highlights the limits of many of these product release tests. Mode of action is discussed, with particular reference to in vitro surrogate assays that can be used to provide information to correlate with proposed in vivo patient efficacy. Importantly, this review highlights the requirement for basic research to improve current knowledge on the in vivo fate of these treatments; as well as an improved stakeholder negotiation process to identify the measurement requirements that will ensure the manufacture of the best possible cell- and tissue-based therapies within the shortest timeframe for the most patient benefit.

Figure 1

Product design processes for cell- and tissue-based therapies. The top panel outlines the current approach to therapy design, where the process is tightly controlled to maintain high quality. In the bottom panel, an “ideal” product process is outlined, where understanding of the product's mode of action tailors the specifications to provide a beneficial clinical outcome.

Figure 2

Dynamic feedback process for determining effective in vitro surrogates for release testing. As the eventual fate of the cell once implanted is still unknown, continual feedback will be needed to improve cell- and tissue-based therapy product design from the original bench-based development through clinical trials and eventual postmarketing surveillance.

Figure 3

General test process for cell- and tissue-based therapies. This process is divided into the three main stages of development, including safety, efficacy, and purity of manufacture. In each stage, there are a number of requirements that must be met to allow the product to continue through the next stage of the process.

Figure 4

Product development negotiations. Entrepreneurs and public policy actors have different goals, each required to manage risk, reward, and time to market. Management of risk/reward tradeoffs requires both negotiation and consensus on the evidence requirements for product adoption. The science base has a critical role in defining the evidence requirements and collecting necessary data.