Achieving Efficient Manufacturing and Quality Assurance through Synthetic Cell Therapy Design
New methods to manipulate gene and cell state can be used to engineer cell functionality, simplify quality assessment, and enhance manufacturability. These strategies could help overcome unresolved cell therapy manufacturing challenges and complement frameworks to design quality into these complex cellular systems, ultimately increasing patient access to living therapeutics.
manufacturability. These strategies could help overcome unresolved cell therapy manufacturing challenges and complement frameworks to design quality into these complex cellular systems, ultimately increasing patient access to living therapeutics.
Main Text
Design for Quality, Engineer for Manufacturability
Cell therapies, in which patients are treated with living cells, are being developed to cure a wide range of devastating diseases. Treating patients with living cells whose functionality is determined by cellular properties sensitive to small environmental changes poses significant challenges for manufacturing these complex cell therapy products (CTPs). We recently discussed how the quality by design (QbD) framework could be applied to mitigate risk in the development of manufacturing solutions for CTPs (Lipsitz et al., 2016). This framework can guide CTP manufacturing process development by increasing our understanding of the attributes critical for assuring product quality and safety and by identifying and controlling the sources of variability in those attributes. However, CTPs pose product and process development barriers that remain challenging, even in the face of rigorous implementation frameworks. These include ensuring robust product functionality, quantitative and rapid cell characterization, and cost-effective manufacturability.
Typically, the main criteria for identifying and developing prospective CTPs has been phenotypic alignment with clinically relevant in vivo counterparts combined with simple and reliable access to the desired cells or some ability to grow or process the cells ex vivo. This bottom-up approach does not typically enable intentional targeting of specific unmet clinical needs, but rather encourages testing of readily available cells in a variety of potential clinical applications. Our field has spent too much time and effort looking for clinical applications for cells we happen to be able to grow. A top-down approach to defining desired product profiles (functionality, identity and purity, and manufacturability) required to treat a specific indication, and to implementing technologies to generate these a priori designed CTPs, should accelerate CTP impact and efficacy (Figure 1). The target product profile, a tool endorsed by the pharmaceutical industry and the US FDA for 10 years (see Web Resources), continues to be a strategic development tool for structuring process development. Although originally intended for pharmaceutical development, this tool should also serve as the basis for the design of high-quality, manufacturable synthetic CTPs.
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