MANUFACTURING A


well-known semantic musing is whether a tree falling in the forest makes a sound when there’s no one there to


hear it. Another musing is whether a light bulb in a closed refrigerator is on or off, when no one can see it. This article considers a very significant semantic musing in stemgene clinical trial supply. Is the tissue stem cell-specific fraction or dosage a critical quality attribute, if no one uses it? Stemgene therapies are treatments that


employ either natural tissue stem cells or genetically-engineered tissue stem cells. A wide variety of natural tissue stem cells are currently under evaluation for regenerative medicine. The main types are haematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), but other tissue sources include, for example, liver, retina, and cornea. HSCs are sourced from bone marrow, apheresis of growth factor-mobilised blood donors, and umbilical cord blood. MSCs also have multiple tissue sources, including fat tissue, bone marrow, dental bone, and umbilical cord tissue. Many current gene therapy clinical trials have the goal of targeting HSCs to achieve lifelong durable cures of genetic diseases. Genetic engineering of long-lived tissue stem cells is also a strategy for achieving long-term cellular therapies for non-genetic illnesses. Greater success in stemgene therapeutics for regenerative medicine will require innovation in the biomanufacturing of stemgene therapy products. National industry consortia are now at work in the US to accelerate the development of quality biomanufacturing for cell and tissue- engineered medicinal products (TEMPs) for regenerative medicine. The Advanced Regenerative Manufacturing Institute (ARMI) is an excellent example of such organising industry groups. ARMI member companies have been assembled with a mission to increase progress in the development of modular, scalable, automated, and closed biomanufacturing processes that consistently produce effective treatment products for regenerative medicine, including stemgene therapies. A current major focus of organisations


like ARMI is the identification of critical quality attributes (CQAs) for cell and TEMP biomanufacturing. A CQA is a measurable factor in a manufacturing process whose value is predictive of the quality of the manufactured


product. In the specific case of stemgene therapy biomanufacturing, the manufactured products are preparations containing either natural tissue stem cells or genetically-engineered tissue stem cells. The desired aim is a reliable, effective treatment for patients. It follows from this analysis that tissue stem cell-specific fraction or dosage is a crucial CQA for achieving the desired success in the biomanufacturing of stemgene therapeutic products. Unfortunately for stemgene therapy products, tissue stem cell-specific fraction or dosage has been a “semantic quality attribute (SQA)” for many years; and currently, it continues to maintain this deficient character throughout the regenerative medicine industry. Here, a SQA is defined as a factor that is well-recognised to be important for a biomanufacturing process in concept, but it has not been widely implemented into practice. Like a tree falling in the forest with no one around, an SQA certainly makes great sense in concept, but will have no impact if there is no way or no one to implement it. Similarly, like a light bulb in a closed refrigerator, recognising that a SQA could provide a significant quality advantage in a manufacturing process is of little worth if no one is able to measure the SQA. Currently, the tissue stem cell-specific fraction or dosage is a SQA. Though it is a CQA in concept, it is missing from general practice at every segment of the stemgene therapy supply chain and clinical trials process. No expert in any area of the industry would argue against the point that the tissue stem cell-specific fraction or dosage must be an essential CQA for organ and tissue cell isolations, for biomanufacturing process steps, for storage and delivery of therapeutic tissue stem cells and TEMPs,


“Greater success in stemgene therapeutics for regenerative medicine will require innovation in the biomanufacturing of stemgene therapy products. The desired aim is a reliable, effective treatment for patients.”


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