br Acknowledgements The authors are grateful to Dr Viktor Do

Acknowledgements The authors are grateful to Dr. Viktor Dombrádi (University of Debrecen) for suggestions and comments on the manuscript. The authors would like to acknowledge the excellent technical help of Iren Mezo and Maria Balogh. We thank Michael Kyba (University of Minnesota, MN, USA) for providing the ZX1 mouse ES cytotoxicity and the p2Lox plasmid. This work was supported by the UD Faculty of Medicine Research Fund (Bridging Fund), TÁMOP-4.2.1/B-09/1/KONV-2010-0007 and TÁMOP 4.2.2.A-11/1/KONV-2012-0023 projects.
Introduction Since the first report of pluripotent hESC isolation in 1998 (Thomson et al., 1998) there has been an aspiration to use these cells in regenerative medicine to repair disease and damaged tissue. This has driven efforts towards establishing benchmarks for the field (Andrews et al., 2005; Andrews et al., 2015), development of reagents, methods and tools to reduce or obviate the risk of transmitting adventitious pathogens (De Sousa, 2013) and the application of evolving standards of quality assurance (QA) and Good Manufacturing Practice (GMP) to satisfy regulatory aims of product safety, quality and efficacy (De Sousa et al., 2006). There have been at least two reports of “clinical grade” hESC lines compliant with US Food and Drug Administration (Crook et al., 2007; Tannenbaum et al., 2012) and numerous cell lines deposited in stem cell repositories such as the UK stem cell bank (UKSCB) designated as suitable for clinical use based on bank assessment of depositor information (go to: http://www.nibsc.org/science:and_research/advanced_therapies/uk_stem_cell_bank/cell_lines/approved_by_the_bank.aspx). Ultimately whether a cell line qualifies as source material for a cell therapy product (CTP) depends on its acceptance by regulatory authorities when authorisation for clinical evaluation is sought. Since cellular therapy is a relatively new science, the requirements of the regulators continue to evolve as their understanding of the issues surrounding this type of treatment has advanced. New guidance is being generated fairly rapidly, and the suitability of any cell line will be judged as and when an application is made for licensure to a particular regulatory body. The first US FDA authorisation of an hESC derived cell product in a clinical phase 1/2a safety/efficacy (i.e. an oligodendroglial progenitor for spinal cord repair sponsored first by the Geron Corporation and then Asterias Biotherapeutics, http://www.nature.com.eleen.top/news/funding-windfall-rescues-abandoned-stem-cell-trial-1.15350) was founded on hESC source material first isolated using research grade reagents and laboratory conditions and subsequently transitioned into current Good Tissue Practice (GTP) and GMP. More recently, there have been several independent authorisations in the US and the EU of hESC based cell therapy products for the treatment of variant forms of age-related macular degeneration with comparable or improved provenance (www.clinicaltrials.gov). Assessment of risk and retrospective testing, such as for adventitious pathogens, can help qualify source cell material and reagents not originally isolated under standards suitable for clinical use. However, negative results from these tests are always qualified by their limits of sensitivity. If available, source material qualified as suitable for clinical use from the onset of its derivation constitutes a preferable starting point for next generation advanced cell therapies. This is more likely to withstand elevations in the expectations of regulatory standards than non-GMP grade alternatives whose use requires more robust risk assessment. In the EU, market authorization of Advanced Therapy Medicinal Products (ATMPs) encompassing gene, somatic and tissue engineered therapies is governed today by the European Medicines Agency (EMA) via a compulsory centralized process valid in all EU countries as well as some European Economic Area countries (Iceland, Norway and Liechtenstein). Governance is informed by European Commission (EC) directives (see Table 1) that are transacted into regulations and laws in EU member states that retain freedom to set more stringent standards or set policy regarding use of specific cell types. In the course of the effort described herein and at time of writing, the UK has developed and empowered governing bodies to regulate the procurement, processing and use of human embryo derived cells for clinical applications which aligned with EU commission directives and EMA requirements, namely; i) The Human Fertilisation and Embryology Authority (HFEA) for the procurement, processing, storage and use of human gametes and embryos. HFEA licensure requires that hESC lines are deposited in the UKSCB, whose terms of deposition dictate agreement to make the line available for research approved by the Medical Research Council. ii) The Human Tissue Authority (HTA), for the procurement, processing and storage of all human cells for human application, and iii) the Medicines and Healthcare Products Regulatory Agency (MHRA), as regards inspection and authorization of sites of production and application of medicines and devices such as may use cells sourced as starting materials. EU and UK authorities benefit from guidance provided by advisory committees such as for example the EMA Committee on Advanced Therapies (CAT) and UK Department of Health Advisory Committee on Safety of Blood Tissues and Organs (SaBTO). By comparison at time of writing in the US cell manufacturing processes involving substantial manipulation are deemed to be a subclass of somatic cellular therapies and regulated as biologics under section 351 of the Public Health Act and associated codes of federal regulation (see Table 2). In the US the FDA office of Cellular Tissue and Gene Therapies (OCTGT) and Centre for Biologics Evaluation and Research (CBER) authorizes/regulates investigational new drug (IND) applications for licensure of cellular and gene therapy products and associated devices, also with advisory committee input. Both jurisdictions emphasize the implementation of the highest possible quality assured practice for procurement, processing, storage and distribution, for which licensure and accreditation provide important warrants through associated inspection and audits.