Manufacturing systems for therapeutic human stem cells to improve health and quality of life
Submitting InstitutionLoughborough University
Unit of AssessmentAeronautical, Mechanical, Chemical and Manufacturing Engineering
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Information and Computing Sciences: Artificial Intelligence and Image Processing
Technology: Medical Biotechnology
Summary of the impact
Since 2003 Loughborough University has worked with industry to create
future manufacturing systems to enable large scale production of human
stem cells. The research, development and demonstration of consistent,
optimised, automated expansion in culture of human stem cells at
Loughborough has led to the commercial sale by July 2013 of 47 systems
worth £20.1M to companies developing stem cell-based and other therapies.
Their use is contributing to the health and quality of life of patients,
whilst creating a new industry sector with significant economic and
employment benefits. Loughborough leads internationally and nationally in
this emerging field with research at significant scale contributing new
manufacturing and regulatory science and standards.
Research at Loughborough University since 2005 has generated new and
important methods of automatically and consistently culturing human stem
cells for therapeutic use. These cells are key to regenerative therapies
that replace or regenerate human cells, tissues and organs. It is
predicted these developments will transform healthcare and the creation of
a new industry sector is envisaged, as is evidenced by the creation of the
Cell Therapy Catapult. The research arose from the industrial experience
of Professor David Williams in terms of addressing scale-up challenges
towards the end of pharmaceutical product life cycles. Returning to
academia in 2003 as an EPSRC funded Research Chair at Loughborough he
committed to address the automation, process design and scale-up
challenges for emerging industries, in particular those commercialising
Williams headed the EPSRC Grand Challenge in Regenerative Medicine - remedi
[Grant Ref EP/C534247/1][G3.1], which began in 2005. The most
significant work package of remedi addressed systems for the
automation of therapeutic human stem cell culture. It was a collaboration
of Loughborough's manufacturing, quality, process, process design and
biological engineering skills. The Automation Partnership (now TAP
Biosystems) providing machine design skills, and multiple user partners
who provided key understanding of the requirements for the manufactured
product. Following the specification of a machine by the collaborating
partners it was constructed and installed at Loughborough University in
With user collaborators, the consistent automated adherent culture of
human mesenchymal stem cells (hMSC) [3.1], human embryonic stem
cells (hESC) [3.2], human foetal progenitor cells [3.3],
cord blood derived stem cells and smooth muscle cells was demonstrated at
the level of quality required by clinical and commercial therapeutic use.
Also, quality engineering and process design techniques were applied for
the first time to improve the quality of stem cell bio-processing,
including the measurement and comparison of manual and automated culture
Process Capability (Cpk) [3.4], methods of product
characterisation [3.5] and use of Design of Experiments including
Taguchi Screening Experiments and Response Surface Methods to improve
process consistency and product quality and reduce the Cost of Goods as
summarised in [3.6].
The work has been executed within a quality system for translational
research allowing transfer to an industrial environment requiring the use
of Good Manufacturing Practice (GMP), essential for therapeutics.
Since the initial transformative research in remedi (2005-2010) [G3.1],
research has continued with EPSRC [G3.5-7, G3.11-13], BBSRC BRIC [G3.2],
TSB [G3.8], MRC UKRMP [G3.14-15], Darpa [G3.4] as
well as other funding [G3.3, G3.9, G3.10]. Although other
universities have been involved with some of these grants, the most
significant of these activities in manufacturing are and have been
Loughborough University researchers were David J Williams (Professor,
2003 to date), Robert J Thomas (Research Associate, RCUK Fellow, Lecturer,
Senior Lecturer, EPSRC Early Career Fellow 2006 to date), Yang Liu
(Research Associate, RCUK Fellow, Lecturer, Senior Lecturer 2006 to date),
Paul Hourd (Research Associate 2005 to date), Amit Chandra (Research
Associate 2005 to date), Elizabeth Ratcliffe (Research Associate 2008 to
date), Erin Rayment (Research Associate 2008 - 2010), Patrick Ginty
(Research Associate 2008 to 2013), Jasmin Kee (PhD student 2006 - 2009),
Pawanbir Singh (PhD student 2007 - 2010). Williams, Hourd, Kee and Chandra
worked from manufacturing and quality engineering perspectives; Thomas,
Liu, Ratcliffe, Rayment at the biology engineering interface and Williams,
Hourd, Singh and Ginty integrated the commercial, clinical and evolving
regulatory science and standards environments.
References to the research
3.1. Thomas RJ, Chandra A, Liu Y, Hourd P, Conway P, Williams DJ,
Manufacture of a human mesenchymal stem cell population using an automated
cell culture platform, Cytotechnology, 55 (2007) 31-39; DOI:
10.1007/s10616-007-9091-2. Impact factor 1.35.
3.2. Thomas RJ, Anderson D, Chandra A, Smith NM, Young LE, Williams
DJ, Denning C, Automated, Scalable Culture of Human Embryonic Stem Cells
in Feeder-Free Conditions, Biotech and Bioeng, 102
(2009) 1636-1644; DOI: 10.1002/bit.22187. Impact factor 3.65.
3.3. Thomas RJ, Hope AD, Hourd P, Baradez M, Miljan EA, Sinden JD,
Williams DJ, Automated, serum-free production of CTX0E03: a therapeutic
clinical grade human neural stem cell line, Biotech Letters, 31
(2009) 1167-1172; DOI: 10.1007/s10529-009-9989-1. Impact factor: 1.85.
3.4. Liu Y, Hourd P, Chandra A, Williams DJ, Human cell culture process
capability: a comparison of manual and automated production, JTERM,
4 (2010) 45-54; DOI: 10.1002/term.217. Impact factor 2.83.
3.5. Rayment EA, Williams DJ, Mind the Gap: Challenges in
characterising and quantifying cell- and tissue-based therapies for
clinical translation, Stem Cells, 28 (2010)
996-1004; DOI 10.1002/stem.416. Impact factor 7.70.
3.6. Williams DJ, Thomas RJ, Hourd P, Chandra A, Ratcliffe E, Liu Y,
Rayment EA, Archer RA , Precision manufacturing for clinical-quality
regenerative medicines, Phil. Trans. R. Soc. A,
370(1973) (2012) 3924-3949; DOI:10.1098/rsta.2011.0049. Impact factor
The significance of the research is indicated by the total award of £37M
over an 8 year period, see below, and invited presentations
internationally (including Auckland (New Zealand), Boston (US), Bremen
(Germany), Erlangen (Germany), Hilton Head (US), Hong Kong, Leipzig
(Germany), Madrid (Spain), Singapore, Stuttgart (Germany), Wroclaw
(Poland)). Loughborough was also the only academic institution invited to
give oral evidence on manufacturing to the 2012-2013 House of Lords Select
Committee on Regenerative Medicine [5.4, 5.5], a clear indicator
of national academic leadership in the field.
Key Research Grants:
G3.1 2005-2010 EPSRC Remedi Grand Challenge Regenerative Medicine
- A New Industry £7M (Williams).
G3.2 2008-2011 BBSRC/BRIC Developing scalable and standardised
manufacturing methods for human pluripotent stem cells £377k - Hewitt
(Loughborough University), Thomas, Williams & Young, Denning
(University of Nottingham).
G3.3 2008- 2010 emda Centre for Biological Engineering Facility
£650k - Williams (Loughborough University).
G3.4 2008-2012 Darpa Large Scale Human Placenta Progenitor
Cell-Derived Erythocyte Production - Continuous Red Blood Cell Production
Phase 1 & Phase 2 £2.13M - Thomas & Williams (Loughborough
G3.5 2008-2017 EPSRC LSI DTC's Doctoral Training Centre in
Regenerative Medicine £6.1M - Williams (Loughborough University),
Shakesheff (University of Nottingham), El Haj (Keele University).
G3.6 2010-2017 EPSRC E-TERM Cross Disciplinary Research Landscape
Award £2.9M - Williams (Loughborough University), Fisher (University of
Leeds), Shakesheff (University of Nottingham), El Haj (Keele University),
McNeil (University of Sheffield), Genever (University of York) .
G3.7 2010-2015 EPSRC Centre for Innovative Manufacturing in
Regenerative Medicine £5.3M - Williams (Loughborough University),
Shakesheff (University of Nottingham), El Haj (Keele University).
G3.8 2010-2011 TSB GMP Automated Stem Cell Culture £198k -
Williams (Loughborough University).
G3.9 2011-2012 KTA Supporting the Improvement and Optimisation of
Cell Culture for Regenerative Medicine Products Companies £91k - Williams
G3.10 2011-2012 KTA Supporting the Establishment and Validation of
a Regulated Manufacturing Facility for Contract Research and Manufacturing
of Cell Therapies £142k - Williams (Loughborough University).
G3.11 2012-2015 EPSRC National Centre Uplift £534k - Williams
G3.12 2013-2018 EPSRC Early Career Fellowship £1.5M - Thomas
G3.13 2013-2018 EPSRC Manufacturing Fellowship £1.08M - Medcalf
G3.14 2013-2017 MRC/UKRMP The Pluripotent Stem Cell Platform £5.6M
- Andrews (Sheffield University), Smith (Cambridge University) and
Williams (Loughborough University).
G3.15 2013-2017 MRC/UKRMP The Pluripotent Stem Cell Platform
Capital Investment £3.1M - Andrews (Sheffield University), Smith
(Cambridge University) and Williams (Loughborough University).
Details of the impact
Our research as cited in [3.1-3] led to the creation and
application of an automated system, the CompacT SelecT, to the culture of
large numbers of human stem cells. This is now being put to use
internationally to develop therapeutics [5.1]. As of July 2013, 47
of these systems worth £20.1M have been sold in laboratory and GMP
configurations and are being used to benefit current and future patients
by both enabling translational research and manufacturing therapeutics.
TAP are in discussions with potential purchasers of 50 further systems
with half of these to be applied to either cell therapy development or
stem cell research. As a result of the orders, TAP Biosystems and their
build partners have created 15-20 new jobs [5.2].
The Loughborough research uniquely allows the transfer of manual stem
cell culture processes to automation and pioneered process design
techniques for their subsequent optimisation. The research was
collaborative with the science base, manufacturing industry and its
suppliers and end users and designed with embedded direct dissemination
After some initial work, human (h) dermal fibroblasts were cultured on
the automated CompacT SelecT in collaboration with Intercytex (2006-2009),
human smooth muscle cells with Cook Myocyte (US) (2008-2009), hMSC with
Oreffo of Southampton (2006, [3.1]), foetally derived neural
progenitors with Reneuron (2008-2009, [3.3]), hESC (differentiated
to cardiomyocytes) with Denning and Young of Nottingham (2008-2009, [3.2])
and latterly human induced pluripotent stem cells (hIPSC) with Vallier and
Pederson of Cambridge (2011-2013) and GMP grade hESC cells with WiCell
(US) (2012-2013). Consequently the work has significantly contributed to
the development of cell-based therapeutics for blood replacement, stroke
and degenerative diseases of the brain, leukaemia and other cancers and
tissue repair including for the bladder [5.1].
The product launched by TAP Biosystems has a global reach: 40% of the
systems sold are in Europe and 60% in the US with concentrations on the
East (MA) and West Coasts (CA) [5.2], and new markets are emerging
in Russia, China and Korea. Loughborough further enabled the exploitation
process by demonstrating the capability of the machine to culture complex
cell types of significance to customers and to operate to GMP.
Understanding how to manufacture stem cell based products is one of the
key critical translational steps required to allow such therapies to reach
the market and for successful business investment and sector growth. The
new manufacturing science researched at Loughborough has allowed the
reduction to practice of complex research laboratory based biological
This capability has significantly influenced the development of the new
Cell Therapies Catapult. The Group was joint leader of one of the three
bids, reaching the final round of the subsequently withdrawn academic
competition for leadership of the Catapult during 2011. The Catapult was
then created in a top-down process by the Technology Strategy Board with a
CEO being appointed in April of 2012 and a Chairman in September 2012. An
MOU establishing a strategic collaboration between the Cell Therapies
Catapult and the manufacturing, automation and process capability at
Loughborough University was signed on 21st January 2013 [5.6].
Further, Williams chaired the meeting (09/07/08) that led to the founding
of the Regenerative Medicine RGM/1 committee of BSI. Whilst creating the
first two Publically Available Specifications, PAS, (PAS 83 and 84) was
straightforward being solely descriptive of the status quo, a third, PAS
93 on Cell Characterisation [5.7], was more problematic, requiring
a Loughborough intervention [5.8] to meet the needs of the
innovative businesses. It is important to recognise that this third PAS [5.7]
is the first of its kind in the world and is likely to lead to an ISO
Our track record was also key to securing essential follow-on research
funding, in particular the leadership of major national consortia
including The EPSRC Centre for Innovative Manufacturing in Regenerative
Medicine (2010) [G3.7], its uplift to act as a national centre
(2012) [G3.11], the translational research fellowship programme,
the EPSRC ETERM Cross Disciplinary Landscape Award (2010) [G3.6],
the EPSRC Early Career Fellowship of Dr Robert Thomas (2013) and other
subsequent grants [G3.2-5,G3.8-10,G3.13-15].
The work has also generated a large number of skilled individuals with
contributing research assistants and PhD graduates from the group being
employed as lecturers and senior lecturers (Thomas and Liu, Loughborough)
in academia and as technical and commercial professionals in international
translational and technology transfer organisations (Rayment, Griffith
University, Australia; Ginty, Cell Therapy Catapult) and businesses (Kee,
Organogenesis, US; Singh, Stem Cell Technologies, Canada) with a
consequent impact on technology translation.
Sources to corroborate the impact
The following sources of corroboration can be made available at request:
5.1 Therapeutic Development: Example press release http://www.reneuron.com/press-
5.2 Commercial Exploitation of Automation: TAP Biosystems, Royston, SG8
5.3 Economic Impact of Research: EPSRC Economic Impact of the Innovative
Manufacturing Research Centres, DTZ, 15th April 2011. http://www.epsrc.ac.uk/SiteCollectionDocuments/Publications/reports/EconomicImpactOfTheI
MRCs.pdf Page 45: Table showing total impact of Regenerative
Medicine Grand Challenge new product £21.5M sales to date, Leverage of
£28M of follow-on funding (between all partners). (Additional potential
share of market, 0.5% worth £650M p.a.)
5.4 Policy Impact.
Oral Evidence to the House of Lords Select Committee in Regenerative
Medicine. Weblink to session http://www.parliamentlive.tv/Main/Player.aspx?meetingId=12149;
5.5 Policy Impact. Web link to Report of House of Lords Select Committee
on Regenerative Medicine http://www.publications.parliament.uk/pa/ld201314/ldselect/ldsctech/23/23.pdf
5.6 Relationship with Cell Therapies Catapult/MOU. Cell Therapy Catapult,
Guy's Hospital, Great Maze Pond, London SE1 9RT London, Web link to press
PAS 93:2011, Characterization of human cells for clinical applications,
BSI, 2011. ISBN 9780580698507. http://shop.bsigroup.com/en/ProductDetail/?pid=000000000030213318
Centre for Biological Engineering contribution acknowledged on page iv.
5.8 Characterisation Standards Influence on PAS 93
BSI, 389 Chiswick High Road, London, W4 4AL