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The Arduous Path to the Clinic – Plan Early to Avoid Late Attrition!
A Guest Blog by Michel Fischbach, Chief Scientific Officer, TNCBio
Stem cell therapies (SCTs) are heralded as the cure of the future for a large range of ailments that remain untreatable in the current therapeutic setting. Together with gene therapy and tissue engineering they represent the so-called ATMPs (advanced therapy medicinal products).
The set standard for this class of therapeutic products is cGMP, no way around this. The European regulation is extremely clear: “All medicinal products for human use … are to be manufactured in accordance with the principles and guidelines of good manufacturing practice.” (Commission Directive 2003/94/EC). In the US, the Code of Federal Regulations, CFR parts 1270 and 1271, sets the requirements for donor selection and cGMPs for Cellular and Tissue-Based Products (HCT/Ps).
GMP by itself is no guarantee for efficiency but:
First, GMP ensures that the cell preparations are produced in a standardized manner according to validated SOPs in order to contain batch variability and to allow for seamless technology transfer and
Second, and most importantly, GMP sets also the safeguards for the patient’s health.
Regarding the latter, besides obvious risks of contamination by all sorts of infectious agents, a major health threat consists in potential allergic reactions to xenogeneic protein. Presence of anti-calf serum antibodies in blood of patients treated by MSCs expanded in FBS-containing medium have been reported; also, severe anaphylatoxic reactions after administration of other cellular products prepared with FBS are not uncommon.
In view of all of the above, in order to obtain ‘clinical grade’ cell therapies, the complete manufacturing process has to be GMP-compliant, from procurement, harvesting, testing, processing, preservation, storage to distribution after release criteria are met. To date SCTs have never been beyond the ‘research grade’ which restricts their clinical usefulness for only short and limited studies, approved on a case-by-case basis, and this only if it can be demonstrated that there are no residual animal products of any kind left in the final cell preparation, a daunting task. Hence it is clear that research grade cell lines are not fit for widespread human therapies.
The assertion that it is possible to apply GMP to animal components if no better options are available has become a challenging stand. And even as use of adequately controlled bovine sera is still allowed, it won’t be for long as regulatory standpoints will predictably adapt to technical progress in cell culture technology.
‘Research grade’ cell therapies, originally created using animal products for research may still be converted to clinical grade, but this only after a long and laborious vetting process, spanning over numerous passages during which attrition issues can put the whole process at risk.
To put an end to all these considerations, today all GMP-related constraints can be easily addressed by implementing sound and validated SOPs that should be built on a completely defined cell culture process. This includes operating chemically defined, GMP-quality, xeno-free culture and cryopreservation media containing no animal-derived substances, as well as GMP-quality recombinant enzyme versions and extracellular matrix components for cell attachment and spreading.
A perfect completion along these lines is exemplified by the achievement of Peter Braud’s team from King’s College, London, January 2012 (see http://www.nature.com/news/stem-cells-that-are-pure-enough-for-the-clinic-1.9566 and http://dx.doi.org/10.3109/14653249.2011.623692 for the full article).