Regenerative medicine is a relatively new and fast growing industry with a product pipeline that offers a potential step change
in the treatment of diverse chronic diseases. Regenerative medicine products are broadly defined as those that use a biological
approach to restore, maintain, or improve tissue function. This covers a diverse set of therapies including cellular, biomolecular
therapeutics, and tissue-scaffold products. In recent years, pharmaceutical developers have increased their interest in products
incorporating a living cellular component because of their potential for dramatic clinical benefits in hard-to-treat and chronic
conditions. As a result, approximately 80% of companies in the industry are focused on this class of therapy, with the majority
in precommercial stages (1). Most products will use stem cells, or perhaps the differentiated progeny of stem cells, as their
cellular component owing to their replicative potential and ability to form different tissue types.
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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.