Background: Regenerative medicine and the need for large-scale stem-cell manufacture
Early "simple tissue" products for skin and cartilage, launched in the mid-1990s, were hampered by high production and distribution costs leading to a wave of insolvencies and consolidation in the industry (2). However, the re-emergence of more successful forms of these products combined with the recent approval of landmark clinical trials for more advanced indications (e.g., spinal cord injury and other neural indications) in both the United Kingdom and United States signal a maturing industry. In spite of this, the manufacturing science in terms of platforms, process control, and product analysis is still immature, necessitating an urgent drive for the development of scalable manufacturing solutions for cellular products. Although regenerative medicine is anticipated to be the major application for stem-cell-derived tissues, other applications such as pharmaceutical screening and disease modeling will also require consistent, high quality, and scalable production of stem cells.Challenges: Why is large-scale stem-cell manufacture so difficult?
The requirement of the regenerative medicine industry to manufacture commercial therapeutic products incorporating stem cells (or their differentiated progeny) as an active ingredient is a technological and scientific jump beyond conventional biologics production. The key distinction is the use of the cell culture itself as the product in regenerative medicine as opposed to the use of a purified biological molecule derived from a cell culture. Furthermore, the human stem-cell types in question are sensitive to culture conditions and appear less predictable than the microbial and Chinese hamster ovary (CHO) cell cultures with which the biotechnology industry has developed extensive experience (3, 4).
The measurement challenge. The stem cell, as a product, falls under the stringent quality control requirements imposed on a therapeutic product by industry regulators. These include validated measurements of purity, potency, efficacy, and stability. Problematically, there is no current measurement system that can completely define a cell using either an individual or a set of assays; i.e., there exists no measurement tool for cells equivalent to mass spectrometry for small conventional drugs or biomolecules (5). Perhaps the closest "definitive" measurement would be microarray technology. However, although this technology provides a map of the cell's gene expression, it does not indicate cell state at a post-transcriptional level and would require combining with proteomics. As a population assay, it would also be a poor tool for identifying a single unsafe cell in a large therapeutic population. The inability to completely define individual cells or guarantee the homogeneity of a cell population has left researchers, product developers, manufacturers, and regulators relying on functional tests or surrogate indicators of function. Functional tests tend to be time consuming, qualitative, and often destructive. Surrogate functional indicators are hard to validate, particularly when mechanisms of action are incompletely understood.
Large-scale stem cell manufacture is therefore currently being approached with a poor knowledge of product specification. An inability to precisely measure a product hampers validation of the production system, process- or postprocess purification. It also reduces the manufacturer's flexibility to modify the production process after clinical trials if there is low confidence in the ability to detect a consequent change in the product.