Global Watch USA 2006 Report

GLOBAL WATCH MISSION REPORT
Advanced cell and tissue

therapies a mission to
the USA
SEPTEMBER 2006
Global Watch Missions

DTI Global Watch Missions enable small groups of
UK experts to visit leading overseas technology
organisations to learn vital lessons about innovation
and its implementation, of benefit to entire industries
and individual organisations.
By stimulating debate and informing industrial
thinking and action, missions offer unique
opportunities for fast-tracking technology transfer,
sharing deployment know-how, explaining new
industry infrastructures and policies, and developing
relationships and collaborations. Around 30 missions
take place annually, with the coordinating
organisation receiving guidance and financial support
from the DTI Global Watch Missions team.
Disclaimer
This report represents the findings of a mission
organised by bioProcessUK with the support of DTI.
Views expressed reflect a consensus reached by the
members of the mission team and do not necessarily
reflect those of the organisations to which the
mission members belong, bioProcessUK, Pera or
DTI.
Comments attributed to organisations visited during
this mission were those expressed by personnel
interviewed and should not be taken as those of the
organisation as a whole.
Whilst every effort has been made to ensure that the
information provided in this report is accurate and up
to date, DTI accepts no responsibility whatsoever in
relation to this information. DTI shall not be liable for
any loss of profits or contracts or any direct, indirect,
special or consequential loss or damages whether in
contract, tort or otherwise, arising out of or in
connection with your use of this information. This
disclaimer shall apply to the maximum extent
permissible by law.
Cover image: Fibroblasts labelled for actin (red), microtubules

(green) and nuclei (blue) courtesy of Andrew E Pelling, Brian M
Nicholls, Michael A Horton, London Centre for Nanotechnology
and Department of Medicine, University College London
Advanced cell and

tissue therapies
a mission to the USA
REPORT OF A DTI GLOBAL WATCH MISSION
SEPTEMBER 2006
Report prepared by
Philip Aldridge Centre of Excellence for Life Sciences (CELS) Ltd
Rosemary Drake The Automation Partnership Ltd
Bo Kara Avecia Ltd
Mike Leek Intercytex plc
Chris Mason University College London
Nick Medcalf Smith & Nephew plc
Angela Scott Angel Biotechnology Holdings plc
ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA
CONTENTS
EXECUTIVE SUMMARY
EXECUTIVE SUMMARY
FOREWORD
INTRODUCTION AND
OBJECTIVES
INFORMATION FROM COMPANY

VISITS
2.1
2.2
2.3
2.4
Manufacturing and automation

Distribution
Process validation and regulation
Commercialisation
6
14
16
23
STRATEGIC IMPLICATIONS FOR

THE UK
27
3.1 The state of the Californian industry 27

3.2 The Californian company position
29
on Europe
3.3 A strategy appropriate for the UK
30
4
CONCLUSIONS AND
RECOMMENDATIONS
34
4.1 Conclusions
4.2 Recommendations
34
34
APPENDICES
37
Acknowledgments
Mission participants
Terms of reference
Company visits
Glossary
Sources of information
List of exhibits
37
38
47
48
56
64
68
A
B
C
D
E
F
G
This report describes the outcomes from a

mission to Californian companies working in
the field of advanced cell and tissue therapies
and draws conclusions for UK policy.
After a brief introduction which sets the scene,
Chapter 2 describes the technology seen and
the issues it raises for all those concerned
with commercial activity in the field.
Chapter 3 addresses the lessons from the
mission in terms of the state of the
Californian companies and their views of the
UK. It then examines the issues raised for UK
strategy beginning with a summary of some
recent actions and how they might be
enhanced. That is followed by an analysis of
how the National Health Service (NHS) could
relate to UK company activity and how the
research councils could contribute.
The above topics lead to a number of
recommendations for future actions which
are dealt with in the final chapter.
The report is followed by appendices which
include a list of the mission participants and
the terms of reference plus acknowledgments
to those who made the mission and this
report possible. The companies visited are
identified and finally a glossary and sources of
information are provided.
FOREWORD
The UK faces major challenges in the field of

healthcare. Firstly, in common with many
countries it must meet the prospect of a rapid
increase in the old age dependency ratio. This
will bring a greater demand for all kinds of
healthcare but particularly for the treatment of
degenerative diseases. The second challenge is
that many countries, and not just developed
ones, have recognised that healthcare
technologies are worth assigning top priority:
they are knowledge intensive and can justify a
high price if they replace current poorer
alternatives with a better outcome. If the cost
comparison of old and new technologies is a
fair one taking account of social services and
home nursing needs it will demonstrate over
time that the new approaches are of lower cost
as well as greatly enhancing the quality of life.
Because the UK must deal with the challenge
of ageing and is unlikely to be able to
compete globally on less sophisticated
technologies, the sector of advanced cell and
tissue therapies is a crucial one for which to
build a coherent short and longer term
strategy. Part of that plan must be to
understand progress in other countries.
The focus of the visit was Californian

companies and the mission team had experts
on the range of issues that start-ups in the
new field face. I am immensely grateful to all
of them for the time they gave to pre-briefing,
the punishing schedule of visits and their work
on the report. I am also very grateful to
bioProcessUK the sponsoring organisation and
its Technical Director Malcolm Rhodes who
accompanied us, to UK BioIndustry
Association and DTI staff and to the local UK
Trade & Investment and UK Science &
Innovation teams in California whose hard
work laid the foundations for the visits. Most
of all I would like on behalf of all those
involved to thank our American hosts for their
openness, friendliness and willingness to give
us time and to entertain us. The visit has
already strengthened ties and shown
common interests. We share a conviction that
the new field can bring real benefits to
people.
Dr Chris Mason
Mission Leader
University College London
November 2006
In 2004 a Department of Trade and Industry

(DTI) Global Watch Mission visited countries
in South East Asia and was impressed by the
scale of activities and their ambitions. To
complement that mission the present one
visited California which is at the forefront of
US and global activities on particular
advanced cell and tissue therapies.
INTRODUCTION AND OBJECTIVES
This document describes conclusions of a

DTI Global Watch Mission to California to
explore the state of advanced cell and tissue
therapy companies. The California Institute
for Regenerative Medicine (CIRM) plus
14 companies were visited in San Francisco
and San Diego, and a further 80 stakeholders
in the sector attended a reception at the
British Consulate General. The report
describes how companies perceive key
commercial, technical and regulatory
issues. It concludes with an analysis of
the strategic implications for the UK and
recommendations for action.
in the future NHS with the public sector as a

key customer enabling growth of companies.
They in turn could provide a quality of
therapeutic material that the healthcare
industry is highly skilled at achieving. The
necessity for a close relation between clinician
or surgeon and the bioprocessor could also
make this an embedded activity which would
be less likely to be lost from the UK than a
conventional industry.
The activity of the largest companies visited

was centred on human embryonic stem (hES)
cell-based science and technology (S&T), and
CIRM, with a planned $3 billion (~1.5 billion)
research programme, is focused on the same
area at present, given the ban on federal
funds for derivation of hES cells. The term
regenerative medicine is useful in
distinguishing the activity from more
established biomaterial-centred technology.
Therefore we have used regenerative
medicine as shorthand in this report though
the expertise of the mission members is
wider and the conclusions apply to all
advanced cell and tissue therapies. The
mission did not include companies producing
agents such as erythropoietin, which has a
relevant impact on stem cells, because the
technology related to such materials is that of
molecular biopharmaceuticals.
A rapid increase in the old age

dependency ratio
Regenerative medicine has the potential to

become both a key commercial activity for the
UK and a crucial contribution to dealing with
the needs of a population with a growing
proportion of older people. With coordinated
management it could become a vital element
4
The field of regenerative medicine addresses

three of the policy challenges posed by the UK
Government Treasury to the research councils:
An acceleration in the pace of innovation

and technological diffusion
The intensification of economic
competition
As people live to older ages and need to be
sustained in an active independent state,
regenerative medicine will have a crucial role.
The commercial activities associated with it
are inherently highly knowledge intensive both
in the goods provided and the services
needed to deliver them. It is going to be
increasingly difficult for the UK to compete on
lower cost goods with a high labour input.
Regenerative medicine is by its nature high
value and, though labour costs are currently
high, the technology is susceptible to the
adoption of automation and the associated
clinical services are often highly sophisticated.
There are already commercial products
addressing severe burns, chronic ulcers and
damage to the cartilage of the knee.
Current research suggests that progress can

be expected in the next few years with the
treatment of heart failure and some
neurological conditions, for example,
Parkinsons disease.
For these exciting developments to come to
fruition it will be vital to understand the global
situation. This report describes a visit to
California which currently leads US activity in
key parts of the field and hosts the most
developed commercial activities in any country.
Exhibit 1.1 Mouse embryonic fibroblast cells (MEFs) are presently used as feeder cells for culturing embryonic
stem cells (Primogenix Inc)
INFORMATION FROM COMPANY VISITS
2.1
2.2
2.3
2.4

Distribution
Commercialisation
PBMCs) achieve blockbuster status, a

commercial manufacturing facility would
only require scale-up to batches of hundreds
of litres capacity in a dedicated
manufacturing stream.
This chapter addresses the technical,

commercial and regulatory information that
the mission team heard about during the
company visits. As is the requirement of
Global Watch Mission reports, individual
companies are not identified in terms of what
is described here and confidential information
is excluded. However, the visit reports
provide a valuable insight into the challenges
which all regenerative medicine companies
and their suppliers face. They also indicate the
kind of approaches which will help in
addressing these issues. The specific
Californian companies are described in
Appendix D.
2.1
2.1.1
Manufacturing overview
Generally the primary systems being used to

manufacture clinical product where cell
expansion was required were standard
tissue culture systems such as T-flasks for
initial expansion from cell banks and either
roller bottles and/or cell factories for the cell
production stage. These were incubated in
standard tissue culture incubators or warm
rooms. Where cells could be grown in
suspension culture, eg stem cells and
progenitor cells from peripheral blood
mononuclear cells (PBMCs), disposable bagbased bioreactors were used. The latter
provided a scalable system for one of the
companies visited, which noted that should
one of its universal products (an allogeneic
therapy based on cell enrichment from
6
Exhibit 2.1 Good Manufacturing Practice (GMP) cell

therapy production incubator loading (Cognate
BioServices Inc)
A small number of companies visited were

developing products which avoided the need
for cell expansion and relied on cell
enrichment only to deliver therapeutically
useful doses of the cell therapy product.
A schematic of the cell product systems
employed is provided in Exhibit 2.3.
Cell factory scale-up from single to triple units
was generally thought to be without any major
issues. However, a number of companies
visited indicated that further scale-up to higher
multiple layer units was limited by the
formation of unwanted gas and temperature
gradients. This was an area they would address
Scale of operation was primarily driven by the

therapeutic indication targeted by the cell
therapy product and potential market
opportunity and thus in some cases use of
systems with limited scale-up potential was
not considered an issue. Generally, with all
companies visited it was clear that scale-up,
cost of goods (CoG), market and
reimbursement were being considered at an
early stage of product development but not at
the expense of delaying proof-of-principle early
clinical trials. Automation of the manufacturing
process alone was thought insufficient to
achieve longer term CoG targets, with
significant process development being
required/planned during clinical development.
Exhibit 2.2 GMP cell therapy production incubator
checking (Cognate BioServices Inc)
following process optimisation during clinical

development of their product with the
manufacturing system selected and would be
addressed prior to Phase 3 clinical
manufacture. One of the more advanced
companies in bioprocess terms indicated that
cell factory systems were not viable longer
term and it would ideally like to eliminate them
as soon as possible. There is an opportunity
here for the further development either of the
cell factory system or an alternative disposable
system that scales easily.
Cell bank
Primary
expansion:
multiple stages
Tissue
sample
Enrichment of
desired cell
fraction
With all of the manufacturing systems

described above, there was a strong focus on
the concept of maintaining a closed system
within the Good Manufacturing Practice
(GMP) facility throughout the manufacturing
process. This was facilitated by non-invasive
process monitoring, eg visual examination of
the cells, by limiting sampling to passage
stages and by using custom sterile welding
and connect technology. In some cases
proprietary integrated bioreactor systems had
been developed which addressed sampling
and further processing requirements in a
purpose designed system. Although these
Production
stage: roller
bottles or cell
factories
Bulk cell product
Expansion
Bulk cell product
Bulk cell
product
Exhibit 2.3 Overview of typical cell product manufacturing systems
could be beneficial there were concerns that

they could increase CoG and introduce risk in
the future in terms of cost and security of
supply of the proprietary bioreactor system
when compared to simpler off the shelf
disposable bioreactor systems.
2.1.2
In-house manufacturing versus

outsourcing
All the companies visited during the mission

that had a pipeline of cell therapy products
either had in-house GMP manufacturing
capability, typically simple single or multiple
clean room facilities for cell banking and cell
processing, or were considering establishing
in-house GMP manufacturing in the near
term. Two of the companies visited were cell
product contract manufacturing organisations
(CMOs). One had an established track
record in this area whilst the other was a
more recent entrant to the field and was
refocusing itself by offering capacity into the
CMO market.
The experience of the CMOs suggested that
the decision to manufacture internally rather
than outsource during the early phase of
product development was not driven primarily
by cost of product. It was more a need to
avoid technology leakage, a belief that only
they could handle their specific cell product,
or that by manufacturing in-house they could
more easily handle potential regulatory
approval delays, eg Investigational New Drug
(IND) applications or approval by Institutional
Review Boards (IRBs). Typically, in-house
manufacturing costs for an allogeneic product
for Phase 1 clinical trials were at a high level,
described by companies visited as closer to
that typical for autologous products. This was
seen as an area that would be addressed
later, during clinical development.
Both CMOs visited indicated there was a
significant market opportunity in this area for
companies with an established track record
of manufacturing both autologous and
8
allogeneic cell therapy products. Their

experience of the market to date was a split
between the two cell therapy product classes
in the ratio of 50:50. One of them noted their
customer base was a mixture of clients that
routinely outsourced clinical manufacture and
other activities and clients that had attempted
internal manufacture but for various reasons
had failed and had then looked at the services
of a specialist CMO for process development
and manufacturing.
The driver for companies partnering with
CMOs, in addition to accessing specialist
skills and know-how, was avoiding having to
devote capital towards GMP manufacturing
facilities, particularly when they would not be
fully occupied. In addition, one company
noted that venture capitalists generally were
not keen on funding companies at an early
phase of product development which were
capital-intensive, and preferred to reduce risk
going forward. This was due to a concern
that, should the activity fail, a significant
proportion of the value could not be recouped
from disposal of the manufacturing assets
and equipment.
It was interesting to note that both CMO
companies visited had existing operations on
the East Coast of the USA but had made the
initial decision to expand their manufacturing
capacity in response to existing demands in
California. However, both CMOs also
anticipated the potential impact of Proposition
71 (see section 3.1) on the number of cell
therapy products and the increased market
size as a direct result of the enormity of
additional state funding.
A number of companies visited indicated that
they would outsource early clinical
manufacturing but may consider bringing
manufacturing in-house for commercial
supply. Geographic location of manufacturing
was not thought to be a significant issue
particularly for allogeneic cell therapy
products especially if there were no
significant shelf-life constraints. Shipment of

product on dry ice or even liquid nitrogen was
not seen as a geographic barrier to the
location of manufacturing versus end use.
Ultimately, the view of one company visited
was that if the manufacturing process could
be automated, and access to specialist
technical skills was not required, commercial
manufacturing could be located in any low
cost geographic location.
2.1.3
Translation strategies
Distinct approaches to identify stem cell

and/or progenitor populations of cells were
exemplified by two established stem cell
therapy companies.
The first approach was a proprietary platform
technology invented by an hES cell company as
a means of rapidly identifying and isolating
novel embryonic cell lines but without infringing
on the all encompassing WARF (Wisconsin
Alumni Research Foundation) embryonic stem
(ES) cell patents. This technology was
developed from its conception to be easily
scalable. It is complemented by the ability of
the company to accelerate the differentiation of
cells from hES cells. For example, product
candidates discovered by the platform
technology are tested at a very early stage for
the capacity to be scaled up in roller bottles
before being designated a product candidate.
The company has already announced the
isolation of its first line, embryonic smooth
muscle cells which may have potential clinical
application in heart disease.
A different approach was exemplified by
another of the companies visited. It is
developing neural stem cells using a proven
approach to stem cell discovery and isolation.
This is based on use of proprietary panels of
monoclonal antibodies (MAbs) and high
speed cell sorting to establish proprietary
populations. They had found that conventional
cell culture techniques were requiring up to
100 days of culture to select the cell
population required. By using high speed cell

sorting they had reduced the time to do this
and had increased throughput.
The area in which their approach differed from
that used by others was that they cell sorted
aseptically in a GMP facility. Challenges such
as potential for cross contamination, and
adulteration from both direct and indirect cell
product contact materials and surfaces, were
overcome by a combination of bespoke
redesign of the cell sorting equipment and
the enclosures that the equipment was sited
in, and substitution of cost effective parts, eg
the flow path was considered as a single use
disposable. Cell sorting was seen as a viable
bioprocess if the number of cells required
was small, viability was not compromised by
the high pressures to achieve high speed cell
sorting, cell size was compatible with
fluids/nozzles, and cells sorted at the
beginning of a run were the same as those
isolated at the end.
A key advantage of the latter approach was
that once cells had been sorted under GMP
they could be further expanded and GMP cell
banks manufactured and characterised without
having to attempt to replicate the derivation of
a required cell line, for example, following
research and development (R&D) work using a
research cell line. The ability to sort cells at
high speed at an early stage clearly provides
an advantage in reducing research translation
and product development risks.
The company using GMP high speed cell
sorting had reviewed its strategy with the
Food and Drug Administration (FDA). The
regulatory focus was on reproducibility and
comparability. The company also indicated
that its quality function had a high degree of
involvement at every stage of development
including discovery and it believed that recent
FDA thinking on concepts such as Quality by
Design and Design Space will have
significant potential to influence cell-based
therapeutic products.
9
Getting involvement of a quality function early

in the development of a cell therapy product
and in the development of its manufacturing
process was seen by the mission participants
as a key message for organisations
developing cell-based therapies and tissue
engineering products in the UK.
2.1.4
Raw materials
A vital process factor being addressed by

most of the companies visited during the
mission was the variability seen with some of
the raw materials. With autologous cell
therapy products, processes developed were
required to be able to handle inherent
variability, such as starting tissue mass,
genetic variability and growth differences
between cells extracted from different
samples and/or patients.
An area that required a strategy to be defined
early was the sourcing of GMP grade MAbs
used to support cell sorting as well as
bioactive molecules or other manufacturing
components. MAbs were usually employed
at therapeutic grade and at the corresponding
cost. Future supply could present difficulties
since the licensing arrangements were
usually predicated at these low volumes. The
approach to alleviate issues in this area was
to form collaborations and partnerships
though even this route could potentially
impact on longer term CoG. Clearly, the
message here for companies in the UK is to
consider the security of supply and costs of
raw materials used as the research process
begins to be defined, and continue to
re-examine this area as the manufacturing
process is developed and optimised.
Feedback from the companies visited
indicated that, universally, antibiotics are not
used to avoid regulatory issues in this area.
Also of concern was the potential to overlook
endotoxin producing organisms in a
manufacturing process if antibiotics are used
since cell manufacturing processes typically
10
have no specific endotoxin removal step.

Lot-to-lot variability of some raw materials
was a major concern. In this case the
strategy adopted was to manufacture these
in-house or seek CMOs to manufacture
them. Alternatively, process development
work was undertaken to eliminate as many
undefined media components as possible.
However, changing raw materials required a
significant investment in testing and
characterisation to understand the impact of
the changes. It was evident that there was at
least an appreciation of and in some cases a
focus on ultimate CoG and economics of
manufacturing versus reimbursement within
most of the companies visited. One of the
CMO companies visited with significant
experience of manufacturing a large number
of cell therapy products did indicate that most
US companies did not consider CoG and
reimbursement early enough, a situation
generally similar to that in the UK and one
which requires addressing.
The use of mouse embryonic fibroblast cells
(MEFs), better known as feeders, to grow
hES cell lines was being addressed by one of
the companies visited. It had developed
methods to grow cells without mouse
feeders, had filed patents and avoided the
conventional use of media conditioned with
mouse feeders for the majority of its projects.
Some of the companies visited had indicated
that their work was based on use of the
limited number of ES cell lines approved by
President Bush. One companys view was
that the biggest issue for companies in the
USA was the intellectual property rights (IPR)
of the WARF patents (eg US 5843780) which
unusually had both multi-composition of
matter and methods. Also, even the so-called
Presidential lines are thought to have low
level microbial contamination due to their
origin in research laboratories.
2.1.5
Minimal manipulation
manufacturing
An alternative, if not unique, manufacturing

route to cell therapy commercialisation was
provided by one of the companies visited.
The therapeutic cell product market is
reached by providing equipment and
consumables for cell therapy manufacture at
hospital sites. Technology is based on the
enrichment of stem and progenitor cells
from adipose tissue. Original equipment
manufacture, distribution and servicing of
the next generation device and consumables
are being handled via a 50:50 joint venture
(JV) with a major established global medical
devices company.
These companies are initially targeting heart
failure secondary to acute myocardial
infarction (heart attack) and chronic ischemia
(angina) and have developed a proprietary
device to allow operating theatre cell
processing such that adipose tissue can be
processed and the autologous cell therapy
product be available for administration to the
same patient within one hour of collecting
the initial tissue sample. Manufacturing has
been simplified to an automated cell
processor/centrifuge with predefined
processing algorithms requiring the operator
to interface with the manufacturing system
via just three buttons.
However, although the final device
appeared simple at least in terms of
operability, product development had
involved 30-40 engineers and scientists to
develop the tissue and liquid handling
systems, microfluidics, cell handling/biology
and control systems over a significant
number of years. The development of the
medical device potentially provides a faster
route to market. The system is using the FDA
510(k) pre-marketing approval route in the
USA with a target of full approval in 2007.
2.1.6
Commercial manufacturing
Only two of the companies were in later

phases of clinical development or operating
commercial manufacturing facilities. One of
the CMOs visited had manufactured cell
products for clients at Phases 1, 2 and 3 and
was now in discussion with a client in terms
of commercial production. Generic
information on the challenges faced by
companies as products moved to later clinical
development, process validation and
preparation for commercial manufacture was
therefore limited.
Only one of the companies visited was
moving to manufacturing a licensed product
following acquisition of the product licence
and an existing manufacturing facility. It was
fully recommissioning the manufacturing
facility after a short shutdown period. This did
provide some important messages/learning,
albeit based on one facility and one product.
The facility was originally designed to produce
a wound care tissue engineered product to
support a large market. However, low market
penetration resulted in the facility operating at
significantly below capacity. Its high-cost
location coupled with operation below
capacity had influenced CoG significantly. CoG
was primarily driven by the high fixed costs
associated with the facility. One important
message was that, with hindsight, if the
company were to establish the facility again it
would be planned for incremental expansion
and be located in a low-cost location.
Additional issues faced were that the batch
manufacturing time was long (12-13 weeks),
requiring continuous operation of the facility
and accurate predictions from the marketing
group on product requirements. Routinely,
during normal operation, full facility shutdown
was problematic, incurring an estimated 2-3
month facility restart-up time.
11
Consequently, a number of operational

strategies had been implemented to reduce
impact, eg initial cell expansion could be
initiated at risk and abandoned if additional
manufacture was not required, and significant
redundancy had been built into the facility
both in terms of some of the utilities and key
equipment as well as building up inventory of
materials such as water for injection (WFI)
and autoclaved parts to allow for breakdowns.
Routine facility maintenance and
requalification activities were scheduled into
short, typically weekend, time slots.
Key learning for cell product development
companies in the UK from this would be to
consider and understand overall commercial
manufacturing strategy as early as possible and
focus process development and automation
efforts during development to eliminate or
reduce any key factors likely to influence facility
operation and CoG for the product.
2.1.7
There are significant process challenges

associated with automating and scaling up
these steps, particularly for autologous
therapies, where each patients cells
represent a small batch (ie scale-out) and
there is inherent biological variability in the
source material. Most companies expressed
a strong preference for allogeneic over
autologous therapies for these reasons and
because allogeneic therapies can be
manufactured on a larger scale, which is
economically much more attractive.
Cell expansion was identified as the highest
priority for automation because it is labour
intensive, involving a lot of manual aseptic
processing over many days or even weeks,
and requiring repeated cell feeding and
passaging, harvesting then seeding into a
new culture vessel. Cell freezing (including
cell banking) and cell separation were also
mentioned as areas where automation may
be required in the future.
Automation
The process steps required to produce a cellbased therapy are highly variable, depending
on the cell type and intended therapeutic
application. The steps can include:
Biopsy
Cell separation/isolation/enrichment
Cell expansion
Cell encapsulation or seeding of a scaffold
Packaging
Cell freezing
Shipping
Generally the companies visited were using

standard cell isolation or separation equipment
and standard tissue culture vessels such as
T-flasks, roller bottles and cell factory systems
for cell expansion and processing. The two
CMO companies had experience of a broader
range of culture systems, including wave
bioreactors for suspension cell culture,
reflecting their need to serve a wide client
base, but neither CMO had yet invested in
significant levels of automation.
12
Exhibit 2.4 GMP cell therapy production cell

harvesting (Cognate BioServices Inc)
All the companies visited recognised that

automation would be necessary to enable
cost effective process scale-up and/or scaleout. The principle reasons are that it removes
people from the process and so will reduce
CoG where labour is a major cost

component, which was true for most of the
companies. Automation also was perceived
as improving staff productivity; for example,
several companies mentioned that
recruitment and especially retention of skilled
staff was an issue and thought this would be
an increasing challenge as the company grew.
Automation also reduces potential sources of
process contamination or errors.
Standard culture vessels, flasks and roller
bottles are still used in commercial application
in the biologics industry for animal cell and viral
culture, particularly for certain anchorage
dependent or fragile cell lines that are difficult
to grow in a bioreactor. These culture vessels
are therefore a potential route into production
for some cell-based therapies. Changing to
bioreactor technology may require substantial
time and effort in process optimisation,
whereas scale-up by increasing the number of
vessels is not a major process change, and
may be more suited to the smaller batch size
typical of low volume cell therapy products
such as for treatment of rare neurological
diseases. There may also be regulatory
considerations to take into account, such as if
clinical material has been produced in flasks or
roller bottles, or culture conditions have been
optimised using these vessels, which may be
a barrier to making significant process changes
2.1.8
Automation experience and

expectations
There was limited direct experience of using

automation for cell processing in the
companies visited, with the exception of a
company that recently took over the large GMP
facility (35,000 ft2 3,250 m2) that was built
and commissioned by another company in the
1990s. Significant investment had been made
by the earlier company in automation including
developing custom equipment for product
packaging and for processing the custom
cassettes in which the cells and support are
shipped. However, it was not successful
commercially, partly attributable to the high

fixed cost of the large facility necessitating the
sale of large numbers of units.
The production process takes approximately
12-13 weeks from the start of the expansion
of the fibroblast cells to quality control (QC)
test and release. The adherent cells grow in
roller bottles, and two robotic systems are
used to process large batches of up to 500
bottles per day. The robots are used for
aseptic processing of the cells through all
stages, including feeding and passaging, that
is harvesting cells and reseeding to expand
cell numbers. The resulting cells are then
seeded onto a support scaffold. The robotic
systems give improved process consistency
and reproducibility.
Most other companies were either at too
early a stage in their product or process
development to consider investing in
automation, or intended to outsource
production. At least two companies said they
plan to automate cell expansion in roller
bottles in the next two years.
2.1.9
Adoption of automation
The possible business models range from

central processing facility to distributed
regional centres. The model chosen has a
major impact on the type of processing
equipment and automation that is
appropriate. It is difficult therefore to make
appropriate choices about routes to scale-up
if a company has not yet developed its
business model.
Several of the smaller companies identified
the scale of financial investment required as
the main barrier to adoption of automation.
Others believed that it was too early in their
development process for them to be able to
specify appropriate automation. Process reengineering takes significant resource and
time, as well as the regulatory consideration.
It was understood by all that during the early
13
stages of development scientists are making

significant choices which subsequently lock
them into a particular technology that may be
extremely difficult or costly to automate or
scale up for production. Early involvement of
engineers was not a priority, the major driver
being speed to Phase 1, raising more finance
as a result and then re-engineering if
required. This is an important issue for all
stem cell and regenerative medicine
companies to ensure that potential scale-up
or scale-out routes are considered early, as
this can have a major impact on commercial
potential or even make the difference
between commercial success or failure.
There was little evidence of sophisticated
automated equipment for bioprocessing
being used by the companies visited, with
one exception. Generally companies were no
further advanced than their equivalent in the
UK and Europe, and few described specific
plans for how they would scale up.
2.2
Distribution
2.2.1
Overview
The regenerative medicine industry has now

reached the point that it must consider the
issues of cryopreservation, shipping,
distribution and end-point use as key
components in its aim to bring these
therapies successfully to the clinic. It is
imperative that these issues should not be
considered as separate processes at the end
of the development/manufacturing process
but should be an integral part in the whole
regenerative therapy process.
Issues to be considered include identifying
which methods of shipping have been
developed to ensure final product consistency
and delivery in order to achieve the required
clinical needs while still maintaining cell
viability. Furthermore, there are requirements
for consistent distribution and delivery of final
products to distant geographic sites; for further
14
processing post-production to prepare the final

product at these distribution sites; and any
requirements to involve training in final
product handling and delivery methods for
end users. There may also be a need for
this training to be formally implemented to
ensure consistency in meeting regulatory
requirements. Those providing stem cell
therapies need to be aware of new
developments in cryopreservation technologies
that involve the use of new materials and
equipment to achieve the cell type-dependent
requirements for storage and shipping without
compromising GMP standards.
Although storage and distribution of stem cell
therapies may be viewed as separate entities
it is more realistic or practical to consider that
shipping of cells is simply mobile storage.
2.2.2
Cryopreservation
All the companies visited deployed

either vapour phase or liquid nitrogen
cryopreservation for their master cell banks
(MCBs). However, for storage and distribution
of their cell-based products, a variety of
techniques and temperatures were being used.
The majority shipped either on dry ice or used
bespoke shipping cartons (shippers). Individual
products are first packed in a sealed sterile
inner pack complete with transport media. This
sealed pack is then placed in a secondary
shipping carton which is heavily insulated and,
through the use of phase-change packaging
material, can maintain the product within a
narrow predetermined range of temperature for
prolonged periods (3-4 days). The advantage of
this system is that it is in common use and has
been extensively tested by shipping companies
and airlines globally. However, transportation of
samples in these conditions has its limitations
and must comply with local hazardous material
transportation laws.
One common problem of shipping products
on dry ice or liquid nitrogen is the
requirement for cryoprotection of the cells.

The traditional use of dimethylsulphoxide
(DMSO) as a cryopreservant has limitations
due to it being associated with potentially
severe adverse reactions upon reinfusion into
patients and is restricted by regulatory
authorities, therefore suitable alternatives are
being sought and include naturally-occurring
disaccharides such as trehalose.
The best example of cryopreservation was
from a company with a wealth of experience in
tissue-engineered products. The company
manufactures a live product for use in wound
repair and has FDA approval for the treatment
of diabetic foot ulcers. For distribution, the
product is kept frozen at -70C using DMSO as
a cryopreservant (approved by FDA). The
product uses a biodegradable mesh scaffold
which provides product stability during
shipping and aids final product application to
the patients wound. Shipping is carried out in
unique shippers which were custom designed
by the company, extensively validated and
capable of maintaining temperature for over
100 hours, thus reducing logistical limits for
the location of clinics using the companys
product. The shippers have additional in-built
design features that allow use at the end-point
clinics as short-term storage devices where
suitable low temperature freezers are not
available; this is an important issue ensuring
that lack of correct storage conditions does not
become a limiting factor.
2.2.3
Shipping
Recent advances in temperature-controlled

packaging have seen the development of new
types of systems. These use novel
technologies to provide a closed system
package that can maintain 2-8C for up 72
hours and would be ideally suited for stem
cell-based regenerative therapies which can
be stored and shipped at these temperatures.
The technology relies on a prepackaged unit
which, following push-button activation,
causes evaporation of a small amount of

water under low pressure creating a cooling
effect that is seven times more effective than
ice packs to cool and maintain the package
interior at the required temperature. As this is
an active process, the package has the ability
to adjust to variations in ambient temperature
which can occur during shipping and
distribution and appears to be a significant
advance over conventional shipping methods.
Internal temperatures can be data-logged and
the process validated.
2.2.4
Local production
Two of the companies visited by the mission

team have taken novel alternative approaches to
the issues of storage, shipping and distribution.
For example, one company has developed
portable equipment that can enrich stem and
precursor cell populations from adipose tissue
(fat) for treatment of cardiovascular disease and
return them to the patient in around an hour, as
described in section 2.1. By fitting its equipment
with single-use disposable components the
company has provided an ease-of-use system,
allowing change of consumables between
patients and the potential to use the equipment
for multiple different cell-dependent applications.
It has developed this in partnership with a major
technology and engineering company with a
proven track record in technical manufacturing,
an established distribution network and
extensive follow-up maintenance capabilities.
Furthermore, a second more compact version
of this equipment is currently under
development. There is also the potential to store
spare stem cells isolated from the patient for
future autologous therapies, and the company
planned to address the cryopreservation issues
associated with this as they arise.
2.2.5
Future storage and distribution
Based upon the technologies currently

employed by the regenerative therapy
companies visited, a number of suggestions
for the future were evident with respect to
15
allowing improvement on existing

cryopreservation, shipping and distribution
methods to achieve optimum conditions for
the products arrival at the clinic. These include
further development of current
cryopreservants which are GMP compliant.
The next generation of cryopreservants should
ideally provide product stabilisation that would
assist in global shipping and distribution, allow
resuscitation of high numbers of viable cells
from storage, and replacement of any
components which are not fully compliant
with the regulatory authorities. Certain
autologous processes that do not require
cryopreservation may employ interim stages
of quality release from the end of
manufacture and throughout the distribution
process. Otherwise, it may be preferable for
most processes to undergo quality release at
the point of manufacture rather than at the
end-point clinic, placing an emphasis on
effective shipping and distribution processes.
In autologous processes where time may be
at a premium, rapid sterility (including
mycoplasma testing) has proven invaluable
and is now being accepted by regulatory
authorities provided it is carried out in parallel
with standard tests. A number of
manufacturers are developing more
sophisticated rapid sterility tests to address
this need, at least one of which is already in
use with a cell therapy product, and some of
these have advantages over polymerase chain
reaction (PCR)-based detection methods as
they selectively detect only viable
mycoplasma. The current trend for rapid
release testing in the manufacture of
autologous cell therapies will facilitate the
release of product for patient treatment;
however, there is a requirement that these
tests are fully validated against standard US
pharmacopoeia testing methods.
Shipping equipment should ideally be a fully
monitored closed system in order to simplify
use and increase safety. Disposable
compartment components should be used to
16
minimise cross-contamination, and robust

equipment employed that can be used by any
courier or airline. There must also be
compliance with relevant hazardous material
transportation legislation. Important factors to
achieve will be to data log as well as validate
the storage and transport systems allowing
any risk reduction to be implemented and
ensure final product consistency. Final
product delivery systems should also be
engineered to provide ease-of-use at the
clinic. There should be cost-effective product
design where the costs of the deliverable
ideally should not outweigh the costs of the
process, and the delivery systems should
have low maintenance commitments.
The advent of these new stem cell therapies,
their progression to the clinic and their
predicted success will rely not only on their
scientific merits but on robustness of final
product formulation, effective and precise
shipping and distribution, and ultimately
ease-of-use in the clinic. These should be
major considerations for regenerative
medicine companies moving their products
forward to the clinical setting in the future.
2.3
2.3.1
Overview
When any bioprocess is executed it is

important to be confident that the product
will conform to the specification registered.
During processing, natural variations in the
process features will cause variations in
outcome. There are two ways of assuring that
these variations are acceptable:
The first method is to verify that all is well
during or after the step has occurred by
applying direct measurement. This is the
act of verification and an example would
be the confirmation that a cleaning
operation had been successful by taking
surface samples at all critical points in a
piece of apparatus and testing for residues.
The second method is used where

verification cannot be applied or where it is
not practical. In the example above it could
be the earlier development of a cleaning
procedure (complete with verifiable
parameters such as temperature, duration
and reagent quality) which, if applied
correctly, was known to produce an
acceptable level of cleanliness.
Removal of unwelcome sources of variation

in the raw materials for the process
Knowledge of critical control points (CCPs) for

any given process acts as a barrier to entry
for competitors so it was unsurprising that,
for almost all of the companies visited, the
exact identity of the CCPs of each process
was proprietary information and would not be
disclosed. However, some patterns were
evident. Every company visited expressed the
view that the first principle of process
validation should be to ensure patient safety.
2.3.2
The processes fell within two broad categories:

those that did not require control under a
manufacturing quality system (basic research)
and those that required an auditable quality
system related to manufacture. In the latter
category, the three systems that applied were:
Good Tissue Practice (GTP)
Good Laboratory Practice (GLP)
Good Manufacturing Practice (GMP)
Process validation applies with varying degree
to each of these three quality systems but
most particularly to GMP. In order to satisfy
claims to GMP it is necessary for a
manufacturing company to understand its
process, to have identified the CCPs and to
have designed a process around the CCPs
such that, under normal variation in
manufacturing controls, the product remains
within the desired specification.
It was evident that FDA had expectations that
had strongly influenced both process design
and the subjects that had been investigated
the most during development. Broadly these
subjects were:
Rigorous investigation of the process so as

to provide compelling evidence that the
industry understands the process in detail
Control of process variation using inprocess controls
Raw materials
Natural raw materials were universally

viewed as an unwelcome source of
unpredictability in the processing. Solutions
to the problem comprised:
The removal of animal-derived serum or
other materials of natural origin from the
growth medium to give processes based
on defined media (many of the companies)
Exclusion of feeder cell layers from
animal sources (usually murine) (all the
hES cell companies)
Replacement of a natural raw material with
one made in-house from recombinant
technology to a predictable specification
(one company)
None of the products affected by these
developments was yet on the market; however,
the implication is clear, ie it is important fully to
define the feedstock. Once the precedent is set
for a commercial product that is made by a
process that contains no highly variable natural
raw materials then the bar will be raised for
competitors. In the event of any disease scares
in the natural source of the raw materials it will
be unlikely that parallel products which still
contain such components will be acceptable
anywhere and the regulatory position will be
toughened. This subject represents a barrier to
entry for less well established companies but it
is also a potential theme for precompetitive
collaborative research in UK industry, eg the
creation of reliable libraries of serum-free media.
17
2.3.3
Cell source and banks
There can be a problem when working with

human stem cell lines as they may grow at
hugely different rates when harvested from
different sources. For this reason some
researchers had sought to develop
immunologically-acceptable lines that could
then be used as a single bank of known
(predictable) behaviour. At least one such
master line had been created. Some work on
the feasibility of establishing immunologically
simpler cell libraries had also been
undertaken, not single cell lines but a move
towards a small set of validated lines to cover
the whole patient population instead of a fully
autologous product. The aim here was to
produce one homogeneous genetic
background to the cells including only helpful
alleles. This subject (banks of cells with
reduced immunogenicity) is starting to be
addressed in the UK and may be a suitable
topic for UK-US precompetitive research.
The natural variability of the cell source was
clearly a problem at the design stage for
autologous processes. Assurances were given
by some providers that the process efficacy
had been validated for the natural envelope of
properties that were to be expected in cell
isolates from a normal population. However,
on further questioning it was recognised that
there is no simple or definitive way to do this,
and 90% capture of variation was the best
that could be hoped for. Inevitably some
batches had to be scrapped in production
because they fell outside specification on
maturity. The implication was that during early
phase clinical trials it was important to define
and capture a representative sample of
variation in the patients. Guidance for doing
this was not possible and changed for one
indication to another.
2.3.4
Asepsis
Aseptic validation was crucial in every case as

there were no instances of the inclusion of
18
antibiotics in-process and none of the

products could be terminally sterilised.
However, with the exception of the centres
that offered modular clean rooms for servicebased business models, there remained the
issue of finding suitable downtime for deep
clean operations (such as might be done
annually in a therapeutic protein production
plant). This seems to be a feature of scaledout processes, ie those where the production
is done in many small units rather than only a
few large ones (scale-up). The overlap in time
for prolonged periods of culture makes it
difficult to take the whole plant off-line and
may contain implications for facility design, eg
the creation of several parallel production
suites instead of one large one.
There was a trend, shown by several
companies, to set up non-accredited clean
suites containing identical apparatus to that in
the authorised clean rooms. This allowed
production dress-rehearsals at
manufacturing scale. Operator training can
thus be validated without compromising the
production floor, and the facility also allowed
debugging of the production protocols before
they were issued as controlled documents.
2.3.5
Manufacturing equipment
Manufacture using certain types of popular

equipment was limited in some areas by
validation problems. More than one company
alluded to the differences encountered on
scale-up when using cell factory systems
with multiple layers for cell growth. When
moving from three layers to ten layers
problems arise in control of buffer gas
content and temperature control. For fullscale work, triple layer machines with full
automation were therefore regarded as a
suitable upper limit.
Cleaning validation was also of primary
importance. In the case of autologous
therapies, individual patient, process lineclearance was of course critical to avoid
cross-contamination but in addition the

companies had found that surprisingly low
levels of some cleaning agents exerted a
detectable effect on product. Hydrogen
peroxide, now gaining popularity for intercampaign sterilisation in situ, was a good
example of this. The acceptable residue levels
had been determined, suitable analyses put in
place and the cleaning and sterilising cycles
had been constrained to protocols guaranteed
to reduce residues to an acceptable level.
Automation and design for manufacture
remains at a low level, with most
organisations using scaled-up versions of the
familiar T-flasks and roller bottles of their
primary research. On process scale-up, the
route to manufacture can be defined by this
choice as it becomes expensive to revisit
early work and repeat clinical studies using
more amenable systems due to lack of
comparability data. However, some
organisations had done just this. It appears to
be an issue of confidence and is related to
the value of the indication. If the therapeutic
target is high value and life threatening then
the value release by efficiency engineering is
worth making the investment for, but if a low
margin product is proposed then the financial
justification to repeat clinical studies for a
new manufacturing protocol simply will not
be justified.
2.3.6
Process Analytical Technologies

and in-process control
Science, risk management and Process

Analytical Technologies (PAT ie tests applied
in real time or near real time to ensure that
the process is conforming to specification)
are seen by FDA as important for new
bioprocesses. Cell markers derived by some
of the companies were based mainly on past
experience and used in-process to monitor
progress. FDA has advised that more
extensive characterisation will be needed
including real time, non-invasive monitoring.
There are surface markers for cell activation
but the envelope of the parameter is rather

too wide to be very useful.
The products in development were mostly
made by recipe-driven processes, ie
processes designed and validated early in
development in terms of passage number, refeed times for cells together with medium
delivery volume and supplements. There
were two notable exceptions to this. The first
was an instance of the development and
validation of a proprietary in-process control.
This biochemical example was based upon a
metabolite of energy production (adenosine
triphosphate (ATP) turnover) and was used as
an aid to define the time when product
should be harvested. The second was a case
where the batch manufacturing protocols
allowed for additional passages in cases
where cells were unusually slow-growing
(autologous source).
A general point was that early identification of
robust markers during research could help to
obviate the need for extensive requalification
during process changes in development since
it could be shown that little alteration had
taken place.
2.3.7
The product
There was considerable reliance on release

assays (an example of verification, eg PCRbased mycoplasma assays, analysis for tissue
matrix components, cell viability and cell
number). In one case, release testing was done
pre-shipment with some features at risk, ie
the results not known before the product had
been used. For this to be an acceptable risk the
statistics of process validation have to be very
robust. Several companies expressed
aspirations to move to fully responsive
manufacturing based upon in-process controls
as time went on. A sterility test based upon the
supernatant medium alone was negotiated
with FDA by one company.
19
FDA places emphasis on confirmation of

potency of the product batches. This is based
on a multiparametric approach. It was felt by
the organisations visited that there was too
high a risk associated with relying on just one
outcome measure cross-calibrated to in vivo
potency, and there had been cases where
such a marker had eventually turned out to be
indicative of undesirable features that could
not later be disentangled from the potency
question. Therefore several such outcome
measures per product, independently
determined, were favoured by regulator and
industry alike.
Validation of product shelf life seems to be an
issue that continually recurs during a
companys development. The extension of
shelf life in certain indications was of such
high economic benefit that it justified the
expense of revisiting the early work and
repeating (and extending) ageing studies.
In some organisations, development activity
has been carried out on the stem cell banks
to find out what happens to the cells postdifferentiation under some of the growth
conditions. This takes the process validation
beyond the lifetime of the process into posttherapy areas on the assumption that some
changes may not become apparent until later
in development and raises a question about
how long such studies should or could last. If
this subject becomes the accepted custom
and practice then it must be taken into
account in the calculation of product
development costs.
On a related subject, FDA is concerned about
potential problems with certain stem cell types
where the starting preparations might
potentially form cancerous tissues under some
conditions. There may therefore be a need to
confirm the absence of significant numbers of
such cells in the final preparation. At present,
preclinical tests cannot be done in the
numbers required to give statistical
significance for such tests so the current
20
implication is that at-line analysis must

supplement an already validated process.
2.3.8
Delivery
For products in which the transit to the

customer is made in a refrigerated state it
was necessary to validate the chosen carrier
container during transit trials. In spite of this
some customers had requested that
verification for their particular route and
holding conditions be made with temperature
mapping during special transit trials. This
request produced problems because the very
presence of thermocouple arrays within the
package led to thermal conductance across
the insulated boundary and invalidated the
outcome. A compromise was reached to
provide some measurement without rigid
adherence to this request. Similarly there was
some variation in the approach to end-user
training with preference for company field
staff offering training to new clients in the
thaw process (previously validated for cell
recovery and product potency). This effectively
means that the manufacturing company has
qualified specific named individuals only for
use of goods. Formal validation ended with
the thawing of the product.
2.3.9
Impact of process understanding
There was evidence from several organisations

of an emerging confidence in understanding
the CCPs for different classes of operation
during development. It was clear that for
specific activities that were addressed
repeatedly for different products (eg cell sorting
and expansion in different classes of bioreactor
such as the wave bioreactor and the cell factory
systems) the parameters that will turn out to
be the dominant process features are now
more predictable than they were even a few
years ago. This emerging know-how holds out
the potential that a unit operations approach
can now begin to be applied to cell therapy
processing along similar lines to those enjoyed
by the molecular pharmaceuticals industry.
2.3.10
Validation of training
Staff training is paramount with such labourintensive operations. There is much turnover
of manufacturing staff in the Californian
biotechnology sector because of the close
proximity of so many related industries, and
this creates a burden of ongoing training for
employers. A positive outcome, however, is
that there is a growing pool of technical and
production staff in the area who are fluent in
clean production of cell and tissue therapies
and that the training is always fresh. This is a
benefit of having so many companies in one
geographical location.
2.3.11
Examples of company approaches

to regulations
Regulatory awareness is a vital component in

business planning for the successful medical
company. In addition, California occupies a
unique position in the American legal
landscape because of the special state funding
for ES cell research that was voted in after the
veto on Federal funding by President Bush.
Some of the companies visited were solely
focused on stem cell activity and were still
engaged in research work. As a result their
awareness of regulatory and quality issues was
high as it had a bearing on how they were to
move towards commercialisation. The mission
team observed a high level of pragmatism with
regard to the generation and maintenance of
statewide regulations on this subject.
Broadly there were three levels of operation
evident in the companies visited, depending
on the state of maturity of the business and
the business model. At the preclinical, preGMP stage were several of the organisations
visited. One example was a company
focusing on the commercial development of
ES cells for use purely as assay-based
screens. In order to achieve this, the research
concentrated on a robust understanding of
the biochemical switches that drive the cells
down the alternative differentiation pathways;

specifically to pancreas, heart, liver,
endothelium, blood and nerve. The
commercial aim was to offer the cells as a
means of assessing the potency of
therapeutic treatments (eg by acting as a
calibrated control against active
pharmaceutical ingredients (APIs) that are
intended to drive the regeneration of different
organs or tissues). The target markets are
cardiovascular, diabetes, drug screen and
predictive toxicology. It was not necessary to
manufacture to GMP as the technology is
intended as a research tool; the company
does, however, work to GLP.
Moving closer to the marketplace, another
company was commercialising allogeneic cell
therapies derived from ES cells. Fully aware
of all quality and regulatory issues it will need
to address with regard to commercialisation,
for nearly a decade the company has been at
the leading edge of developing human ES
cell-based therapeutics for several diseases
including neural cells for spinal cord injury and
Parkinsons disease, and cardiomyocytes for
heart disease. It has developed proprietary
methods to grow, maintain and scale up
undifferentiated hES cells using feeder cellfree, chemically defined culture medium,
before differentiating them into
therapeutically relevant cells. The companys
most advanced programme is hES cellderived glial cell for acute spinal cord injuries.
It has already had multiple FDA pre-IND filing
meetings, and the GMP grade MCB has been
produced and stored. The GMP cell line has
now been rigorously qualified for human use
after extensive animal and in vitro testing. The
data generated will be used to support the
IND filing in 2007. If successful, this will be
the worlds first hES cell-derived product to
enter clinical testing.
The mission team also met with two CMOs.
Some saw the European Quality Procedures
(QP) system as a potential barrier to entry in
exporting cell therapy products from the USA
21
to the EU. All were keen to develop rapid

release assays and as a consequence some
have implemented automated bacterial
contamination detection systems but still
follow up with a conventional 14-day sterility
test. Many had also looked at PCR-based
mycoplasma assays. Product is generally
released at risk based on standard tests such
as cell count, viability and gram staining,
whilst awaiting sterility data.
One of the few companies in the clinic had
two product approaches:
Cell-based delivery of missing lysosomal
enzymes in Battens disease
Re-myelination of axons to restore
motor function
The companys approach was predicated on
use of fluorescence-activated cell sorting
(FACS) to isolate a population of stem cells
which are then reintroduced into the patient. In
its discussion with regulatory agencies, focus
has been on GMP-related issues, such as use
of clinical grade material and techniques to
reduce potential for contamination. It tries to
avoid use of antibiotic as yield and phenotype
may be affected.
Taking a two-pronged approach to cell
therapy, one company was developing both
autologous and allogeneic products through
the clinic. Its first product, an autologous
population of mesenchymal stem cells
derived by plasmapheresis and indicated for
treatment of sickle cell anaemia and
thalassaemia, is minimally manipulated and
derived from the patients own blood. It was
able to progress from Phase 1 safety studies
straight to Phase 4 studies. Because of yield
issues there have been problems with quality
testing of batches whilst still retaining enough
product to treat an individual.
The companys second product is allogeneic
and consists of human universal myeloid
22
progenitor (hUMP) cells. Currently at the

preclinical/Phase 1 stage, it comprises pooled
samples from multiple donors. The initial
indication will be neutropenia (abnormally low
levels of a particular type of white blood cell);
however, the product may offer some
protection from the effects of radiation. The
company claims an expansion of 30-50 fold in
culture. Interestingly it treats the product
more like a primary culture than an MCB and
uses routine hospital testing as a means of
screening for adventitious agents so that the
approach is more like transfusion.
One company was able to fast track its
development programme by acquiring
technology approved by FDA in one indication
and shoehorn it into another. Regulated as a
biological it is currently in Phase 1 trials, and
will need a potency assay for subsequent
studies. The company currently performs
basic assays including standard colorimetric
MTT and Sirius red as release criteria.
Taking the minimal manipulation approach to
cell therapy, one company has developed an
autologous system to isolate stem cells
from fat. As a simple system the
concept/service can be sold with little need
for clinical trial or regulatory involvement via
the GTP pathway. CE approval has been
obtained for the isolation device, facilitating
selling direct into the EU. The main clinical
indications will be the prevention of heart
failure following a heart attack. The company
has already conducted a Phase 1 safety study
earlier this year and is planning additional
clinical studies in peripheral vascular disease
and aesthetic applications.
By far the most advanced, one company was
in the process of reintroducing a wound care
product back to the US market having
acquired it in a post-Chapter 11 of the United
States Bankruptcy Code sale. As a well
established product there were no major
quality or regulatory issues to be addressed.
However, as a consequence of bankruptcy-
induced hiatus in manufacture the acquirer

was able to initiate a thorough overhaul of the
facility, which has the advantage of not
requiring to be reinspected as there has been
no material change to product or facility.
2.4
Commercialisation
A range of Californian companies was visited

and their approach to commercialisation
assessed. Overall the mission team looked at
the types of business models and strategies
being used as well as the barriers and risks
they faced.
During the mission formal meetings were had
with 15 stakeholder organisations including
CIRM, a leading venture capitalist in the
sector, plus 13 stem cell and regenerative
medicine biotechnology companies. Eight of
the companies were targeting therapeutic
products, two were CMOs, one a drug
discovery tools company, one a technology
holding company and one a consultancy.
2.4.1
Therapeutic companies
The majority of companies were firmly

focused on the therapeutic sector of
regenerative medicine involving tissue
engineering and cell therapy. California has
had a long association going back to the early
1990s with tissue engineering companies
with headquarters and manufacturing facilities
in the state. Indeed one of the earliest
pioneers, Advanced Tissue Sciences, set up
in San Diego, listed on NASDAQ, achieved
FDA approval of its products and at its peak
employed over 200 people.
This background of early pioneers has left
California with a wealth of talent and
experience capable of forming, leading and
growing new companies in the sector.
Experience with the sector extended to all
the stakeholders, eg venture capitalists, angel
investors, service companies, clinicians,
distribution companies as well as the
workforce. Every company almost without

exception had leading management people
who were on either their second or even third
regenerative medicine related venture. Thus
not only were the companies being led by
seasoned management but also all the
individuals knew one another. An informal
club of managers was evidently in play both
within California and also throughout the
USA. Where key people had not been
available from the pioneers in the sector, the
shortfalls had been made up from the local
biotechnology communities both in the Bay
Area and around San Diego. The links to the
UK via this informal network are minimal.
Funding the companies did not appear to be a
significant problem although individual
company funding is not on the scale of the
hundreds of millions of dollars poured into the
pioneers in the late 1990s with just one
exception. This was a leading human
embryonic stem cell/cancer therapy company
which was the first to enter the stem cell
sector and thus enjoyed the sharp rise in the
NASDAQ stock market prior to its major
downturn in the early 2000s.
Funding was extremely diverse including
angel investments, venture capital, defence
monies (Project BioShield and Defense
Advanced Research Projects Agency
(DARPA)) and stock market. All the companies
expected Proposition 71 funding to help them
in the near future with many having already
applied as the partner of an eligible academic
or non-profit organisation.
Several angel investors attended the official
mission reception; whilst some were already
invested in the area and planning to invest
further, the remainder expressed a strong
desire to become involved in the not too
distant future. Leverage with the Proposition
71 funding was certainly a driver with none
expressing an interest to invest outside the
State of California.
23
Venture capitalists had wider geographical

interests, but they too fully understood the
potential benefits of Proposition 71. Indeed
one leading venture capitalist had nearly
completed the formation of a $150 million
(~77 million) fund. Interestingly the same
venture capitalist was preparing to invest in
UK companies because they were by current
US standards very undervalued.
Four of the companies visited had publicly
traded shares (three on NASDAQ and one on
the over-the-counter (OTC) market but was
expected to transfer soon to NASDAQ).
California also had a third vital ingredient for
the future success of its regenerative
medicine companies, namely an experienced
service sector. Two of the companies visited
were established CMOs in the cell therapy
sector. The leading one had experience of
growing more than 20 different cell lines in a
wide range of bioreactors. It provided a
turnkey operation including expansion,
storage, distribution and regulatory matters.
Other local supply chain companies included
major culture media and reagent
manufacturers, bioreactor designers and
international distribution companies. For
example, one of the pioneers in the sector
had originally planned to produce cell culture
media using 100 litre stainless steel media
vessels. However, after a short period of
operation it became apparent that it was far
easier, cheaper and more reliable to
outsource the supply of media. This initial
approach of being totally self-sufficient has
been turned around as the local supply chain
industries have become established. The
more recently established regenerative
medicine companies were considering total
outsourcing of the eventual production
including outside the USA such as Singapore
and the Irish Republic.
The therapeutic cell companies have adopted
a wide range of cell types and approaches.
24
All the major cell types were represented

including human embryonic, foetal and adult
stem cells and progenitor and somatic cells.
The companies business models very much
reflected the state of the science that their
respective chosen cell type had reached. For
example, companies with somatic cell based
products had either FDA approved product or
products in clinical trials whilst the human
embryonic stem cell based companies were
at a much earlier stage in their product life
cycles. The most advanced was at the stage
of being just about to file its FDA IND
application prior to being able to commence
Phase 1 clinical trials.
This range of stages was likewise reflected in
the investor base and its expectation with
respect to size and timing of likely returns.
However, the uncertainty with respect to
returns had not put off some of the
companies with very early stage products
from investing heavily in GMP production
facilities. For example, one hES cell company
had invested considerably in the purchase of
a 10,000 ft2 (~930 m2) GMP exbiopharmaceutical factory complete with
modest automation capability. The plan
was to be ready for when scale-up is required
and also to perform contract manufacture in
the meantime. Future staffing of the facility
was not perceived by the management
to be a problem as local talent was
relatively abundant due to the plethora of
biotech companies.
During the course of the mission it became
apparent that two distinct business models
were being considered. At one extreme was
the idea of a central bioprocessing plant and
distribution to individual hospitals; at the
other extreme was local bioprocessing at the
hospital with, at its simplest, recovering
tissue from the patient, extracting the cells
and immediate implantation, all within the
same operating theatre session. These two
approaches, central bioprocessing and
distributed bioprocessing, very approximately
divide along the lines allogeneic and

autologous therapies respectively.
2.4.3
The distributed bioprocessing model has the

great attraction of having no need for
expensive cell culture facilities, distribution
challenges or delay in a patients therapy since
there is no requirement for a cell expansion
step. The potential drawbacks include the fact
that the number of cells available for therapy
using this technique may not be adequate
depending upon the particular application.
However, it is too early to tell as the therapies
are yet to be proven, let alone the response
characteristics determined.
There is a well developed cellular therapy

CMO infrastructure in California which
indicates that the industry is well into the
product development stage. These CMOs
were handling clinical trials production
including Phase 3 supply, although not all
intended to provide in-market supply.
2.4.2
Tools companies
The traditional view of the stem cell sector has

been to provide therapies. However, many
stem cell companies, like previous
biopharmaceutical start-ups, have realised that
the timelines from discovery through to the
clinic are too long for venture capitalists to get
a return on their investment in the period they
expect. Therefore nearer, short-term goals have
been targeted by companies either exclusively
or as part of their portfolio. One small hES cell
platform company was already successfully
commercialising its proprietary platform with
larger biotech and pharmaceutical companies
with plans to expand greatly over the next
12-18 months as the pharmaceutical industry
begins to embrace hES cell-based drug
discovery and development.
Interestingly, all the hES cell companies with
offerings in the drug discovery and
development sector were aware of
Recommendation 1 of the UK Stem Cell
Initiative (UKSCI) which addresses the use of
stem cells for this purpose. Currently,
predictive technologies are being developed in
the areas of toxicology, especially of the liver.
Contract manufacturing
organisations (CMOs)
There was the classic CMO model offering:

consultancy, process development, assay
development, production and regulatory
services. The mission team also saw the mixed
CMO model from a company with the dual aim
of developing its own products and offering a
range of services to the other companies.
This CMO sector had a wide range of
expertise and experience across a broad
range of cellular therapies. These companies
were in a position to provide the equivalent
services to traditional protein therapeutic
CMOs and enable cellular therapy discovery
companies to access services and technology
to speed their products to the clinic and
market. Such a well developed CMO
infrastructure will be a crucial element in
making sure the large Californian investment
in cellular therapy discovery is realised.
An interesting and potentially scalable model
was observed. The basic idea was to have a
number of regenerative medicine companies
that were commonly funded, eg a single
venture capital fund, with one central
company which acted as CMO for all the
others, thus freeing them up to develop the
science, marketing and reimbursement
issues without requiring them all to invest in
expensive GMP facilities and staff.
The mission team met with a small
consultancy which offers validated mouse
embryonic stem (mES) cell lines, culture
protocols and expertise in ES cell culture. This
company contracts out its animal work, legal
25
and financial aspects. Most of its business is

with academics as big pharmaceutical
companies are not comfortable dealing with
such a small concern. However, to counteract
this and with its solid track record the
company is now looking to expand.
2.4.4
Good Tissue Practice (GTP) route

to market
A number of companies have chosen the

GTP route to market. In the case of products
that are minimally manipulated and for
homologous use, they are not biologics but
personalised therapies. This means that
clinical studies are not required to market the
product and this is obviously a great
advantage. Despite these products resulting
from simple processes they were targeting,
in some cases, severe indications. This
suggests that complex processes are not
always required for cellular therapies to reach
the market.
26
STRATEGIC IMPLICATIONS FOR THE UK
3.1
3.2
3.3
The state of the Californian industry

The Californian company position
on Europe
A strategy appropriate for the UK
3.1
The state of the Californian industry
The Californian commercial regenerative

medicine sector was found to be an
extremely vigorous one as indicated in the
earlier sections.
It was evident that the position of President
Bush on derivation of hES cells using Federal
funds had not prevented a number of
relevant companies proceeding to clinical
trials. The companies nevertheless regret
the lack of Federal funds for research.
Proposition 71 allows the State of California
to sell bonds to provide funding for human
stem cell research and research facilities in
California and to establish CIRM to award
grants and loans. The success of this
proposition reflects the support of the public,
politicians and the business community
together with patient groups.
The global interest in hES cells is because such
cells offer greatest flexibility in the kinds of cells
which can be derived and the extent of
expansion possible. Issues of immune
response remain to be resolved. There are
certainly applications and potential ones which
use either human adult stem cells or allogeneic
cell lines derived from tissues such as neonatal
foreskin. However, for many diseases the only
option may be therapies based on hES cells.
The Californian companies realise that the
translational research pathway is expensive
and, for example, have made large investments
in GMP facilities: one leading hES cell company
had a 10,000 ft2 (~930 m2) GMP facility.
Exhibit 3.1 GMP cell therapy production cell splitting

and seeding (Cognate BioServices Inc)
Unlike the DTI Technology Programme

initiative, the CIRM programme is initially
funding only academic and non-profit
organisations. However, the Institute is
formulating its policy for granting funds to forprofit organisations. Particularly given the
present ban on Federal funds for deriving hES
cell lines the provision of these lines from
companies and their collaboration is helpful to
universities. At present most US university
translational bioprocess research is heavily
bioreactor centred which is an important
component but only one of those needed.
However, a notable feature of US academic
research groups is their preparedness to
redirect their focus when major new funding
opportunities appear. The potential size of
Californian funds is likely to be such a magnet.
Because of funding pressures there is a great
drive to meet milestones in achieving
completion of Phase 1 and 2 trials. This
means that at the present stage there is a
tendency to use any procedure that delivers
27
and to re-engineer later to achieve larger

scales. However, the dangers of this
approach are recognised. One of the
advantages in California is the number of
senior executives who have had experience in
pioneering activities of regenerative medicine
or at least of related biotechnology start-ups.
Early experience by US companies in the field
also has given a good deal of insight on
issues of distribution of the products of
regenerative medicine.
The focus of the companies
will be able to apply conventional scale-up for

the cell expansion stage. This will be more
challenging than culturing mammalian cells for
biopharmaceutical protein production. In that
case the state of the cells at the end of the
process is not too big a concern so long as
they have produced an acceptable product
whereas with human cells as product their
quality is critical. Nevertheless, the scale-up
involved is much simpler than scale-out the
cultivation of many separate autologous cell
types each of which demands the same
stringent control.
In the CIRM initiative and several of the best

funded companies visited, the focus on
embryonic cell based therapies, to the
exclusion of more classical approaches and
the use of adult stem cells, is not harmful to
California or the USA. It has strong research
and commercial activities in these other fields
to give critical mass. There is a degree of
separateness in the UK also and it will be
sensible to encourage a broad dialogue
across these areas. One reason is that
commercial activities in the more established
areas have many lessons for the newer more
advanced ones in terms of regulations,
automation and commercial management.
This outcome will be best achieved by
encouraging the existing nascent information
exchange activities rather than by establishing
a large bureaucracy with a heavy central
secretariat expenditure (Recommendation 4).
There are circumstances where for the

present autologous cells are preferable. For
example, less life threatening conditions do
not so readily justify immunosuppression and
the balance will be determined by a risk to
benefit analysis. However, it will be crucial to
decide carefully where this distinct
bioprocess technology can be sustained
commercially. It will also be important to
judge how quickly new research will have an
impact. This may indicate that cells derived
from human embryos are not significantly
immunogenic, or studies of reducing
immunogenic components may reach fruition.
The greater challenges for scale-out may
reappear again for allogeneic cells when the
material is to be used in the form of
engineered tissue because manufacture by
scale-up to yield consistent results is
problematic at present.
Californian companies were also primarily

focused on allogeneic cell therapies. The issue
of whether the future of regenerative
medicine lies in allogeneic cells applicable to
large numbers of patients to a greater
degree than autologous cell therapies is not
only scientifically important but vital in
determining the nature of future commercial
practice. If there is an adequate market in the
short term for allogeneic cells with use of
immunosuppression, particularly with older
patients or patients with life threatening and
presently untreatable diseases, the companies
3.1.2
3.1.1
28
Importance of bioprocessing
The progression from chemical smallmolecule pharmaceuticals to

biopharmaceutical proteins was accompanied
by a large increase in the importance of
bioprocessing knowledge because of the
greater complexity of the product.
Regenerative medicines will take this trend
much further. The production of large
amounts of living human cellular material for
therapy is at least an order of magnitude
more difficult than that for molecular
medicines so that intellectual property (IP),

skills and systems associated with their
bioprocessing will be of central importance.
The CIRM initiative intends to specifically
commit $60 million (~31 million) on
bioprocess engineering and automation.
CIRM may also commit substantial funds to
GMP facilities and cell banking facilities
(maximum $107 million (~55 million),
however this amount will also have to fund
some other core areas).
The importance of bioprocessing also was
recognised by the Californian companies visited.
The need for consistent processing extends to
material for research and at present poses a
major problem.
Exhibit 3.2 GMP cell therapy production

cryopreservation (Cognate BioServices Inc)
It is clear that as regenerative medicine

expands to treat many more people the
present processing methods, which are in
many cases just stretched laboratory
procedures, will neither cope nor be economic.
The UK has several excellent automation
companies with relevant experience and
together with university bioprocessing groups
which are addressing the issues they can
represent a competitive capacity.
3.2
The Californian company position

on Europe
The US companies were not generally yet

interested in Europe as a market though
several individual companies have links. This
US focus partly relates to the very large and
homogeneous market of a continental country.
One of the advantages to companies in the
USA versus Europe is that healthcare providers
such as Medicare cover all 50 states.
The fragmented nature of individual European
government regulations was perceived as a large
disincentive to address this market in terms of
either supply of products or the establishment of
subsidiaries (see Recommendation 3). At first
sight this protects the European market but the
reality is that most companies in Europe also
recognise the vital importance of the large and
coherent US market so it is not helpful except
perhaps for autologous cell procedures with a
high local service element. There was also a
concern about the uncertainties of European
patenting on embryonic cell-related subjects
though this shows signs of easing.
The negative US perception was enhanced by
a view that it was more difficult to deal with
the European Medicines Agency (EMEA) than
with the US FDA and a view that the latter
allowed an early dialogue. There was concern
that the UK NHS as single purchasing body
showed resistance to new technology and
that the UK National Institute for Health and
Clinical Excellence (NICE) required new
evaluation even when there was substantial
experience in the USA.
One of the other perceived disadvantages of
the UK was that the regulations on animal
studies are more rigorous and hence more
costly. Publicity about past animal rights
activity, actually now addressed, was also
having an effect.
It is unlikely that the US position on Europe
will change quickly with so much local
growth potential.
29
There was very limited knowledge of UK

companies and universities. Though the size of
the home market in relation to the relatively
small current commercial activity in the USA
means that there is no immediate need to look
further, the companies are very much focused
on developing the capacity to have products
sufficiently stable to provide buffer stocks and
be shipped from one point to others across
the American continent. By implication this
means they could later supply Europe.
The knowledge of related UK research activity
was limited among the Californian companies
to a few centres and there was for example
some confusion between the UK Stem Cell
Initiative (UKSCI) and the UK Stem Cell
Foundation (UKSCF). They were in general
unaware of the level of UK government and
EU funding in the field. It will be important for
DTI and its consular colleagues to sustain a
good dialogue and at appropriate intervals to
fund new missions to the USA in the field of
regenerative medicine (Recommendation 10).
3.3
A strategy appropriate for the UK
The UK has a small number of world class

advanced cell and tissue technology
companies and related equipment suppliers.
Similarly it has a number of international class
hES cell research groups interested in
regenerative medicine. This is complemented
by several bioprocess research groups of
comparable international quality and a strong
established research base in biomaterials,
human somatic and adult cell therapies and
tissue engineering.
3.3.1
Strengthening the foundations
The UK position has recently been greatly

strengthened by a number of government
agency actions. The creation of the worlds
first national stem cell bank designed to allow
preparation of GMP ES cell lines has been a
key step. Similarly DTIs Technology
Programme funding of company and
30
collaborating university translational research

groups has been crucial in strengthening the
foundations. It will be vital for this initiative to
continue with maximum recognition of the
very limited financial resources of the start-up
companies. Much of the activity funded is
actually translational (basic technology)
research which should qualify for the highest
DTI support component. Equally it will be
important to keep the financial data required
as simple as possible because in the brief
window of time for agreeing collaborations
and bidding, any complex financial requests
are especially hard for start-ups to meet
(Recommendation 5).
One of the potentially serious obstacles to
the full commercial development of new
technologies is the lack of acceptance of
common standards. DTI has sponsored
discussions leading to a forthcoming
Publicly Available Specification (PAS)
report as a first step to the creation of a
suitable set of standards for the
regenerative medicine industry and in total
has committed about 25 million to
regenerative medicine-centred activities.
UKSCI, originating from the Chancellor The Rt
Hon Gordon Browns March 2005 Budget,
has produced a document which discusses in
detail many of the key issues which will affect
UK policy and has made a number of
recommendations (see Appendix F).
Addressing one of these recommendations it
has offered funds to examine the use of stem
cells for studies of new drug candidate
toxicology. While this is not a regenerative
medicine project it is likely to draw in
pharmaceutical companies. That could later
be important because, as with
biopharmaceuticals, they may well enter the
field once success has been established in
some therapeutic applications. Nevertheless,
it will be important that in future phases of
UKSCI it provides direct support for
regenerative medicine translational activity.
Much ground-breaking translational research

in regenerative medicine is funded in the USA
by rich donors and their charities. UKSCF, a
separate new charity, is intended to provide
similar funding for activities which have
reached the clinical trials stage in public
institutions. The potential of the Foundation is
very great in sustaining regenerative
medicine research through the difficult and
expensive stages of human trials in cases
where commercial activity is not yet justified.
This challenge applies particularly to
autologous cell therapies for applications
where at present small numbers of patients
are treated. Here there are new problems in
the shape of more stringent regulations for
the methods by which human cell materials
are prepared and for the relevant facilities.
These can be so costly that it is hard for
medical schools and similar organisations to
afford them. However, the complexity of the
materials and the extremely close relation
demanded between physician or surgeon and
bioprocessor makes it vital that such facilities
are close to medical centres. This is
recognised by UKSCI in its recommendations.
One of the great virtues of the UK as a place

to conduct regenerative medicine is the
sensibly balanced approach to the ethical
issues of using human embryonic material.
This avoids some of the problems that the
USA is having to contend with. To date the
Human Fertilisation and Embryology Authority
(HFEA), which evolved from regulating and
controlling assisted conception, has dealt
sensitively with human embryo research
within pragmatic legislation. It will be
important that this policy continues as HFEA
is integrated with the Human Tissue Authority
(HTA) (Recommendation 6). HTA has a less
happy origin in the wake of the Alder Hey
Hospital and Bristol Royal Infirmary enquiries
but it will be vital that this does not lead to
overregulation which would impede the
establishment of new therapies. Research on
human embryonic and related cells is
evolving rapidly and it may well be that with
intensive research in several countries,
solutions are found which address some of
the most sensitive ethical problems. The fact
that such approaches could well be more
practical provides an additional incentive.
3.3.2
In regulatory terms, there may be lessons to

learn from the way in which the US FDA is
operating. It has the discretion to waive
certain procedures or assays when it is felt
there is no impact on safety. Such a move
would meet practically a recommendation of
UKSCI that regulation is risk-based and
proportionate and does not stifle the
development of the full range of safe and
effective new cell therapies for the benefit of
patients. Nevertheless there will still be
considerable additional research costs and it
will be important for research councils and
the Department of Health (DH) to fully
recognise the challenges to research groups
of this new legislation that demands
exceptionally high quality facilities
(Recommendation 7). The above UKSCI view
on regulation also applies to the way in which
UKSCF trials need to be regulated.
The National Health Service (NHS)
The role of the NHS could be pivotal in devising

a regenerative medicine strategy appropriate to
the UK (Recommendation 1). Dealing with the
harmonisation of European manufacturing
regulations is a high priority (Recommendation
3). However, this will take time and though UK
leadership will be important, there are many
political forces at work.
In the interim it will be vital to address the
situation of UK regenerative medicine
companies. As things stand the US market is
the obvious target because not only is it a
large and a coherent one in regulatory terms
but also one where private healthcare
purchasing power is exceptionally large. This
factor and the higher market capitalisation
which the UK companies would have if
purchased by US organisations pose a
31
potential challenge in that the company

research focus at a crucial stage could leave
the UK.
There are developments occurring in the UK
healthcare field which have a bearing on
regenerative medicine. In 2003 the Bioscience
Innovation and Growth Team (BIGT) made as its
top priority the recommendation Build a
mutually advantageous collaboration between
NHS and industry for patient benefit through the
creation of a National Clinical Trials Agency
(NCTA). In 2006 the Chancellor of the
Exchequer, The Rt Hon Gordon Brown, asked Sir
David Cooksey to lead a review to establish the
best institutional arrangements for a new, single
fund for health research. The Cooksey Report is
due to be published in early December 2006.
The Governments determination to gain value
from the unique potential of the NHS to
evaluate patient responses could be applied to
Beyond this it should be possible for the NHS
to become a customer providing a market for
effective regenerative medicines from UKbased companies (Recommendation 1). This is
particularly important because the NHS
dominates UK medical care, and the much
smaller private sector does not generally
precede NHS in innovating new therapies
except in cosmetic treatments. That is in
marked contrast to the USA whose many
private hospitals are prime innovators. Most
UK regenerative medicine companies
developing therapeutic materials have been
obliged to focus their primary attention on the
large and receptive US market and this means
focusing on FDA regulations rather than
EMEA ones. To change that the NHS will need
to represent an equally attractive market.
For autologous (person specific) cells the
linkage between the physician or surgeon and
the bioprocessor of the human cells must be
especially close. The intimate connection
between product and service could also
make the resulting sector an embedded one
32
less likely to be lost from the UK and it

represents a large potential source of
employment. Though the throughput of
autologous cell therapy will not match that for
allogeneic cells, the commercial value per
patient can be high and the UK may be able to
compete particularly well with overseas
companies. The future capacity of the NHS to
share data electronically and to work to
common standards applying to a population of
60 million people represents a very powerful
environment within which to develop and
apply such regenerative medicine.
For the NHS to be a champion of
regenerative medicine it will have to see real
gains to patients and society. One of the
challenges is that in some parts of
regenerative medicine, such as in treatment
of chronic skin ulcers by tissue engineered
skin rather than bandaging, its products offer
the prospect of a better outcome than
existing treatment. However, they are at first
glance more expensive if a policy of
minimising point-of-purchase cost is applied
by the purchasing authority. A proper
assessment must include the speed with
which the patient returns to self sufficiency
with reduced reliance on social services and
community nursing. Such analyses will be
important in any assessment of the new
technology as it bears on the NHS.
A number of Californian and other US private
hospitals generate large incomes from the
treatment of patients from other countries. The
UK also already welcomes a considerable
number of overseas patients for private
medical care and the effective development of
regenerative medicine could greatly enhance
this activity. It would link clinical excellence to a
bioprocessing activity marked out by
government as an important advanced industry
in which the UK could expect to have a strong
position. If the NHS activity was truly world
class in regenerative medicine the expertise
spilling over into private hospital care would
represent a powerful magnet for such activity.
3.3.3
The research councils
The Californian company recognition that the

blockage of US Federal funds for derivation of
hES cells is damaging represents an
acknowledgment of the vital function of
government funded research. The role of the
UK research councils will be critical in
underpinning such an advanced technology.
The Medical Research Council (MRC) has
recently made major grants for basic stem
cell research together with the Biotechnology
and Biological Sciences Research Council
(BBSRC) which has also funded some joint
biology-engineering research. The Engineering
and Physical Sciences Research Council
(EPSRC) has made one major grant in this
area of translational research and it and
BBSRC have both made contributions to
funding the relevant DTI Technology
Programme awards.
However, compared with just the proposal
for CIRM, which plans to specifically commit
$60 million (~31 million) to research on
bioprocess engineering and automation, the
research councils commitment to
underpinning this aspect is small. There is a
tendency to aggregate it with the much more
established biomaterials spend but, though
important, that sector is not rate limiting in
The research councils role, and particularly
that of EPSRC in translational research, will
be crucial especially bearing in mind the
very limited financial capacity for external
research of the UK start-up companies
which dominate the field, and the impending
large manufacturing research investments in
the USA (Recommendation 8).
Where UK translational research in
regenerative medicine is strong or can be
strengthened there will be real value in
developing collaborations with California and
other US centres. This could be enabled by
joint UK research council-National Science
Foundation (NSF) or National Institutes of

Health (NIH) programmes of the kind now
under discussion as a broad concept
(Recommendation 8).
US experience for UK postdoctoral
researchers and academic staff will be
valuable but it will be essential that the UK
has centres resourced at a comparable level
to attract researchers and retain staff
(Recommendation 9).
At present the number of UK graduates being
trained in translational research related to
regenerative medicine, as distinct from basic
research, is small. Later this will represent a
restriction particularly as it is likely that the
USA in particular will attract a significant
number of people from the pool produced.
Training graduates in translational research
has particular challenges. Few, even from the
biological side, have any close experience;
experimental studies are slow and complex;
and the costs in terms of reagents and
consumables plus the investment for
instrumentation are very high.
It is hard to establish CASE (Cooperative
Award in Science and Engineering) and EngD
(Engineering Doctorate) projects because
there are relatively few companies and most
are start-ups whose venture funders are often
not sympathetic to training activities versus
meeting tight commercial goals. In this
situation it would be helpful if CASE and
EngD schemes specifically targeted at this
sector were formulated to recognise the high
value of cell lines provided and access to high
cost resources (Recommendation 9). Even
then the small number of companies and
their staff will restrict such training activities,
and studentships for translational (basic
technology) research will be essential to fill
the gap.
33
CONCLUSIONS AND RECOMMENDATIONS
4.1
Conclusions
The mission observed that Californian company

activity in regenerative medicine was very
intense and ambitious. Perhaps one crucial
message from the mission is that California will
drive for commercial outcomes and cures
rather than wait patiently for all the answers to
basic questions to be available. As was the
case for biopharmaceuticals, this US philosophy
will define the competitive timelines.
The UK does not have the same availability of
senior industrialists with pioneering
experience nor a comparable number of
relevant local university centres so that, as
the UK Stem Cell Initiative report recognised,
it will be vital to ensure good interaction
between those that are in place
(Recommendation 4).
The Californian companies were, as expected,
very aware of the commercial imperatives and
the mission heard, for example, exciting ideas
for automation from one company.
Nevertheless, it was felt that UK companies
involved in bringing through more established
human cell-based therapies have a comparable
grasp of the issues and there are several UK
automation suppliers who are world leaders.
The UK has the science base to underpin the
next phase of even more advanced
technology. However, to convert this into a
really significant financial return to the UK it
will be vital to resource and manage the
translation stages.
The mission visit demonstrated immediately
the potential for additional company
collaboration over and above an already
active interaction. This can only be good for
34
UK companies but plainly it would be

advisable to create a local focus of the kind
the NHS could represent.
From this and a previous Global Watch
Mission it is clear that worldwide competition
in regenerative medicine will be severe. It is
also evident that several of the competitors
visited in these missions, such as Singapore
and California, have coherent long term plans
covering all aspects of what is needed to
achieve a practical outcome in commercial
and healthcare terms. These plans are being
actively and continuously managed by the top
people in the field.
For regenerative medicine, which at all levels
from the most basic science to advanced
bioprocessing and clinical trials is in a state of
great flux, oversight by leaders directly involved
in the field scientifically, technologically and
commercially will be crucial if the UK is to
succeed (Recommendation 2).
4.2
Recommendations
1 DTI and DH should establish a coordinated

dialogue with industry to examine how the
NHS could act as a research partner and
supportive customer of the products of UKbased regenerative medicine companies.
2 The field of regenerative medicine is so
fast moving and internationally competitive
that for the UK to succeed there needs to
be continuing oversight by a group of
leaders who are directly involved
scientifically, clinically, technologically and
commercially in translational activities.
They should report jointly to DTI and DH
and, among other things, help to ensure
an outcome from recommendation 1.
3 It is vital that the UK Government gives

the strongest possible lead to encouraging
a consistent regulatory framework
throughout Europe for commercial
processing related to regenerative
medicine and one which is consistent with
the US Food and Drug Administration
(FDA) regulations.
4 In terms of stimulating national dialogue
on regenerative medicine, government
funds should be directed to encouraging
active groups to develop their nascent
dissemination organisations and to
enhance their cooperation by support for
regular meetings to create a community. It
is important that at least some of the
groups create an interface for industrial
participants and speakers.
5 The recent tranches of funds from
DTI have been very important both in
underpinning start-up developments in
regenerative medicine and in stimulating
their linkage to university translational
research centres. It will be vital for this
approach to be sustained with maximum
recognition that for the start-ups
dominating the field there is a lot of
basic technology research to be done
which should command a high proportion
of DTI support.
6 The UK position on ethical regulation of
the use of human tissue and embryos
must maintain its pragmatism so that
the country is seen as a firmly regulated
but progressive environment for research
and commercialisation.
7 University clinical research in this field has
a particularly urgent requirement for
expensive facilities and operations which
are inherently of high cost. It is essential
that this is recognised by the research
councils and DH and that centres are
helped to deal with the demands of new
legislation in this area.
A POSSIBLE UK 2016 SCENARIO

A successful UK regenerative medicine
industry is underpinned by an effective
relationship with NHS and its clinical
research activities.
The activity is linked closely to a set of
university centres of excellence which
have distinctive individual inputs and a
common forum for exchanging ideas.
Links with US companies are well
developed before they seek European
markets to a greater degree and also
subsidiary bases.
Strong UK influence has helped to
create a uniform European regulatory
framework for processing and
classification of material.
A pragmatic system of ethical
regulations together with growing
evidence of real value to patients has
further strengthened the UKs position
as a good place to do business, conduct
research and to come for treatment.
Exhibit 4.1 A possible UK 2016 scenario
8 It will be important for EPSRC to provide

underpinning funding of bioprocess
engineering-centred translational research.
There is scope for US-UK translational
research collaboration provided that the UK
groups are world class. Research council
plans to encourage joint funding with the
USA should be pursued and would be
especially valuable in regenerative
medicine.
9 As a corollary to recommendation 8 it is
vital that some of the UK-based
postdoctoral researchers who choose to
work in the USA, including through any
35
collaborative schemes, should have

attractive posts to return to in wellresourced centres and that these have the
capacity to retain academic staff. This
requires concerted action between funding
councils, research councils and universities.
10 Though at present US companies have no
great incentive to look outside the country
it is vital that links be sustained by DTIfunded approaches such that when the
time is right for European bases the UK is
well placed.
A possible UK 2016 scenario that could
emerge if the foregoing recommendations are
implemented is outlined in Exhibit 4.1.
36
Appendix A
ACKNOWLEDGMENTS
The mission team would like to express its

gratitude to the following people for their
generous help in making this Global Watch
Mission a success and in preparing the
subsequent report:
Greg Bonfiglio
Ben Burch
Jeff Champkins
Janet Coyle
Sean Croson
Peter Dunnill
Graham Dyer
Guy Harrington
Mindi Hertzog
Lolita Juarez
Narpal Juttla
Rachel Lawley
Charlotte Leiper
Gareth Lewis
Stephen Lynn
Dan Mara
Louise Mason
Malcolm McLean
Patricia Murray
Harsha Patel
David Phillips
Doreen Reid
Sally Anne Reiss
Paula Thomas
Beverly Xu
37
Appendix B
MISSION PARTICIPANTS
Chris Mason
Mission Leader and Academic
University College London
Malcolm Rhodes
Mission Coordinator
bioProcessUK
Philip Aldridge
Centre of Excellence for Life Sciences Ltd
Rosemary Drake
The Automation Partnership Ltd
Bo Kara
Avecia Ltd
Michael Leek
Intercytex plc
Nick Medcalf
Smith & Nephew plc
Angela Scott
Angel Biotechnology Holdings plc
Profiles of the participants are given on the

following pages
38
Chris Mason MB BS, BSc, PhD, FRCS

Mission Leader and Academic
Group Leader, Regenerative Medicine

Bioprocessing Group, Advanced Centre for
Biochemical Engineering
University College London (UCL)
Roberts Building
Torrington Place
London
WC1E 7JE
T 020 7679 0140
F 020 7209 0703
chris.mason@ucl.ac.uk
www.ucl.ac.uk/biochemeng
UCL is one of the UKs top four universities and
UCL Biochemical Engineering is the countrys
leading bioprocessing group. Today over 35
company partners collaborate in its research.
From the 1970s it pioneered the processing
methods by which modern biopharmaceuticals
are produced. Over the last decade it has
begun to build a similar bioprocessing
foundation for human cell and tissue therapies.
It is distinctive in being concerned with the
whole bioprocess and not just the bioreactor
stage. It has developed microbiochemical
engineering methods to derive bioprocess
design data which are especially valuable for
precious human material.
The Regenerative Medicine Bioprocessing

Group has world-class expertise in the
translation and scale-up of stem cell and
regenerative medicine therapies. It has 20
researchers with translational interests across
the spectrum of regenerative medicine
including stem cell (adult and embryonic) and
somatic cell therapy through to tissue
engineering. The groups projects span every
aspect including hES cell line derivation
through to clinical trials. The group has
research collaborations with a number of
academic groups, commercial organisations
and government bodies.
Chris Mason is at the forefront of the
emerging field of stem cell and regenerative
medicine bioprocessing and is involved in a
number of committees, networks, scientific
advisory boards, editorial boards, working
groups and initiatives related to the academic,
clinical and commercial advancement of stem
cells and tissue engineering.
Originally graduating from Imperial College
with a degree in molecular biology and St
Thomass Hospital Medical School with a
medical degree, Chris then specialised in
surgery. He is a Fellow of the Royal College
of Surgeons of England, Fellow of the Royal
College of Surgeons in Ireland and a Fellow of
the Royal Society of Medicine. In addition,
Chris has a PhD in Biochemical Engineering
under the supervision of Prof Peter Dunnill
(UCL), leads the Stem Cell and Regenerative
Medicine Bioprocess Group at UCL (a team
of 20 researchers) and has a broad range of
expertise in commercial consultancy.
Furthermore, he has over 10 years
experience at boardroom level of running
technology companies.
Chris is also cofounder and co-organiser of
the London Regenerative Medicine Network,
Member of the Steering Committee for the
UK National Stem Cell Network and on the
Editorial Boards of the journals Regenerative
Medicine and Tissue Engineering.
39
Malcolm Rhodes is experienced in industry

bioprocess development, product
development, biomanufacturing
management, R&D management and
innovation management at Pfizer, Celltech
Biologics (now Lonza Biologics) and
Serologicals (now Millipore).
Malcolm Rhodes BSc, PhD

Mission Coordinator
Technical Director
bioProcessUK
14/15 Belgrave Square
London
SW1X 8PS
T 0131 440 6164
F 0131 440 2871
mrhodes@bioindustry.org
www.bioprocessuk.org
bioProcessUK is the Knowledge Transfer
Network (KTN) dedicated to advancing the UK
biopharmaceutical bioprocessing sector. KTNs
are a DTI business support product delivered
through the Technology Programme whose
purpose is to facilitate further investment in
science, engineering and technology with the
active participation of business and industry.
bioProcessUK is managed by the BioIndustry
Association (BIA).
As a KTN focused on advancing the UK
biopharmaceutical bioprocessing sector,
bioProcessUK does not directly own
technologies or develop products. Instead it
facilitates research by means of a
Bioprocessing Research Industry Club (BRIC),
and encourages knowledge dissemination
through technically orientated workshops and
an annual conference.
40
His role at bioProcessUK is to encourage

industry-academic collaboration and
knowledge transfer (in both directions) for
the UK biopharmaceutical industry, including
cell and tissue therapies. This includes BRIC
and DTIs Collaborative R&D for
bioprocessing research.
He is currently developing assistance for
academics and small and medium sized
enterprises (SMEs) on cell therapy regulatory
issues with the National Institute for
Biological Standards and Control (NIBSC), the
BIA Regulatory Affairs Advisory Committee
(RAAC) and Manufacturing Advisory
Committee (MAC) and the DTI sponsored
PAS for cell-based therapies, and is able to
coordinate input from these groups.
Malcolm has a BSc in chemistry and a PhD
in microbiology.
CELS runs a healthcare network in North East

England which holds relevant events and
provides guidance and advice to regional
companies. In addition it runs a medical device
design and testing service for regional SMEs.
It also runs an academic club called BioNEt
which has over 1,000 industrial and academic
members. This organisation runs frequent
events across a number of bioscience and
technology areas.
Philip Aldridge BSc, MSc, AMIChemE

Project Director
Centre of Excellence for Life Sciences
(CELS) Ltd
Bioscience Centre
International Centre for Life
Times Square
Newcastle upon Tyne
Tyne and Wear
NE1 4EP
T 0191 211 2574
F 0191 211 2561
philip.aldridge@celsatlife.com
www.celsatlife.com
The regional development agency (RDA) for
North East England, One NorthEast (ONE),
developed a Strategy for Success which
identified the academic strengths of the
region and aimed to exploit this expertise for
the regeneration of the regional economy. As
part of this strategy Centres of Excellence
were created in a number of S&T areas.
CELS resulted from the execution of this
strategy, and has the objective of growing the
healthcare economy of North East England.
In order to help companies, CELS uses its
knowledge of bioscience markets, regional
companies and the local academic base to
identify areas for commercial exploitation.
CELS also seeks to understand the routes to
market and the technologies required to
achieve commercialisation.
CELS acts as the commercial arm of the Life

Knowledge Park and the Institute for Stem
Cell Biology and Regenerative Medicine.
CELS is currently putting together a proposal
for a Biopharmaceutical Technology Centre
(BTC) which will be a national centre for
research, teaching and companies in the field
of biopharmaceutical bioprocessing
technology. CELS also runs life incubators in
the north east.
Philip Aldridge is a Project Director in CELS
responsible for growing the
biopharmaceutical sector of the economy in
the region. This involves helping existing
companies, helping ONE attract new
companies to the region and helping people
start new businesses in the field. The creation
of the BTC is part of this brief in that such a
centre will be of benefit to regional (and
national) companies in this field. Philip also
hosts inward investment missions to the
region with recent visits being from China
and Israel.
Philip has a BSc in cell biology and
biochemistry (York) and an MSc in
biochemical engineering (UCL). He is an
Associate Member of the Institution of
Chemical Engineers.
41
for high throughput screening, together with

sample management software.
Rosemary Drake BA, MA, DPhil

Director Business Development
The Automation Partnership (TAP) Ltd
York Way
Royston
Hertfordshire
SG8 5WY
T 01763 227 200
F 01763 227 201
rosemary.drake@automationpartnership.com
www.automationpartnership.com
TAP is a major provider of automated
equipment for the life science industries;
its customers include many of the top
20 pharmaceutical and biotechnology
companies. TAP is based near Cambridge,
England, and employs around 180 people.
TAP specialises in supplying automated
solutions to industrialised complex laboratory
processes, such as those involved in sample
management and screening for drug
discovery and high throughput biology. It
leads the world in design, development and
implementation of automated cell culture
systems, and has been supplying such
systems since 1989.
TAPs portfolio of automated systems for drug
discovery research includes HomeBase and
Solar for sample storage, BasePlate and
BasePlateXR for plate preparation and Asset
42
TAPs automated mammalian cell culture

systems include: Cellmate for roller bottle
processing for GMP applications, eg viral
vaccine and therapeutic protein production;
SelecT and CompacT for cell maintenance
and production of assay plates for drug
discovery screening; Cello for high throughput
clone generation and selection. Piccolo
enables high throughput, highly parallel
optimisation of protein expression in
microbes and eukaryotic hosts, for structural
biology studies.
TAPs key technologies include automation,
liquid handling, cell culture, sample/data
tracking and clean processing.
TAP has research programmes in low
temperature (-80oC) storage of biological
samples for the UK Biobank, and automating
bioprocess optimisation. It also has
collaborations with UCL and Loughborough
Universitys ReMedi project on regenerative
medicine.
Rosemary Drake is Director responsible for
Business Development at TAP. She leads a
team that evaluates new business
opportunities new products, markets or
licensing opportunities and develops new
concepts for novel automated systems. In her
current role Rosemary has been responsible
for originating a number of TAPs cell culture
systems including SelecT, Cello and Piccolo.
She has worked at TAP since the company
was founded.
Avecia is taking a lead role in a new partnership

to establish bioprocessing technology for
advanced tissue engineering. The work involves
creating cost-effective and scalable methods for
making ethically-derived adult stem cells for
therapeutic use, notably for wound healing. The
project aims to bring significant advances in the
development of new, fully functional skin tissue
to treat burns victims.
Bo Kara BSc, MSc

Head of Expression and Cell Sciences
Avecia Ltd
PO Box 2
Belasis Avenue
Billingham
Cleveland
TS23 1YN
T 01642 364 448
F 01642 364 463
bo.kara@avecia.com
www.avecia.com
Avecia is a private biotechnology company
focused on the development and
manufacturing of innovative new
biotechnology based medicines.
Headquartered in Manchester (UK), it has two
main operating business units: DNA
Medicines based at Milford (MA, USA) and
Biologics based at Billingham (UK). The
company has recently established a vaccines
development capability through major
contracts with the US Government to develop
defence vaccines.
Partners in the approximately 1 million,

three-year project include: the Centre for
Stem Cell Discovery and Regenerative
Medicine at Durham University; the Blond
McIndoe Centre prominent in plastic and
reconstructive surgery; Smith & Nephew; and
CELS the healthcare-based economic
development agency. Avecia will bring to the
project its extensive expertise in the
development of robust, scalable, economic
and compliant bioprocesses.
Bo Kara has over 20 years expertise with ICI,
Zeneca, AstraZeneca and Avecia in designing
R&D programmes to develop scalable and
validatable manufacturing processes for
recombinant protein products. He is currently
Head of Expression and Cell Sciences at
Avecia, responsible for the Molecular
Biology/Gene Expression, Microbial
Fermentation and Mammalian Cell Culture
process development/scale-up groups, and is
Project Leader for the tissue engineering
project described above.
Bo is responsible for technology
development, definition and evaluation of
external new technology, and is a member of
the Avecia R&D management team.
Key activities include biotherapeutic process

invention, creation and optimisation from
microbial and mammalian cell based systems,
and GMP manufacturing of microbially
derived biotherapeutics: preclinical, Phase 1,
2, 3 and commercial manufacturing.
43
All the companys products are derived from

unmodified, human cells.
Mike Leek joined Intercytex in 2000 as
Commercial Director and has been VP
Operations since January 2005. He is
responsible for overseeing the manufacturing,
quality and facilities functions of the business.
Mike Leek PhD, MBA

Vice President Operations
Intercytex plc
Innovation House
Crewe Road
Manchester
M23 9QR
T 0161 904 4500
F 0161 904 4510
mleek@intercytex.com
www.intercytex.com
Intercytex is an emerging healthcare company
developing and commercialising cell therapy
products for the wound-care and aesthetic
medicine markets. It is using its proprietary
expertise in cell therapy to develop products
that harness the innate ability of human cells
to regenerate and repair the body.
Intercytex has four products in development:
ICX-PRO, designed to actively stimulate
repair in chronic wounds in Phase 3 trials
ICX-TRC, a hair regeneration product
about to commence Phase 2 trials
ICX-RHY, a facial rejuvenation product
in Phase 1 trials
ICX-SKN, being developed as a durable and
robust skin replacement due to start
Phase 1 trials during 2006
44
Mike has over 15 years experience in

commercial wound-care and cell therapy. Prior
to Intercytex he was with Smith & Nephew
Group Research running the tissue repair
programme, identifying and developing
products for the wound-care and orthopaedic
markets including a JV with Advanced Tissue
Sciences (ATS) in the development of
Dermagraft, a cell therapy wound-care product.
BioHealing of New York, and S&N continues

to develop cell-based therapies especially in
the area of repair of cartilage.
Nick Medcalf CChem, MRSC, CEng, FIChemE, MSc

Bioprocessing Manager,
Smith & Nephew Research Centre
Smith & Nephew plc
York Science Park
Heslington
York
YO10 5DF
T 01904 824 157
F 01904 824 004
nick.medcalf@smith-nephew.com
www.smith-nephew.com
The majority of S&Ns products at present are

implants for bone repair such as the Trigen
Fusion Nail and fixator systems for complex
fractures like the Taylor Spatial Frame. Soft
tissue repair is addressed through
management of infection with active silver
compounds like the burns treatment
Flamazine and nanocrystalline silver
antibacterial dressings. However, in the
engineering of tissue S&N has researched
the healing processes within cartilage and
has an innovation project in repair based on
chondroprogenitor cells. S&N also develops
novel bioresorbable materials for implants,
dressings and tissue scaffolds.
Nick Medcalf is responsible for the
management and operation of the clean-room
suite at the Smith & Nephew Research Centre.
A Chartered Chemist and Chartered Chemical
Engineer, Nick has a first degree in chemistry
and a Masters degree in bioprocessing.
Smith & Nephew (S&N) is a global healthcare

company with annual sales totalling around
1.4 billion. Although the headquarters is in
London the main manufacturing businesses are
in the USA. There are three global business
units representing the three main areas of
application: Endoscopy (Boston, MA),
Orthopaedics (Memphis, TN) and Wound
Management (Hull, UK). The Research Centre
at York (UK) is the home of the main R&D effort
for the Group and employs around 170 people.
S&N formed a JV with ATS in 2002 to bolster
its commitment to cell and tissue therapies.
S&N became the sales and distribution
partner for the products Dermagraft and
TransCyte both originating at the ATS
operation and comprising engineered tissue
for dermal repair. The operation and the two
products have since been sold to Advanced
45
Angels core competencies are in

fermentation and protein purification using
microbial and mammalian cell culture to
produce active biomolecules for use in
medicines and vaccines, as well as in stem
cell and cell therapy manufacture.
Angela Scott BSc

Head of Cell Culture Operations
Angel Biotechnology Holdings plc
44 Colbourne Crescent
Nelson Park
Cramlington
Northumberland
NE23 1WB
T 01670 591 920
F 01670 591 921
angela.scott@angelbio.com
www.angelbio.com
Angel is an AIM listed, UK-based, contract
biomanufacturing company offering process
development services, pre-GMP and cGMP
manufacturing to support biotechnology and
pharmaceutical companies worldwide. Angel
is able to provide development and
manufacturing support for production of
biologics working from laboratory scale to
development of a robust manufacturing
process. Services range from strain
development, through near GMP
manufacture of the small quantities needed
for preclinical studies to the high quality GMP
drug product needed for clinical trials and
beyond. Angel also has expertise in stem cell
and cell therapy manufacture.
Angel operates out of two sites, at
Cramlington near Newcastle upon Tyne and at
Pentlands Science Park near Edinburgh.
46
Angela Scott has a BSc in life sciences and

has over 24 years experience in cell culture.
She worked for the Imperial Cancer Research
Fund for 10 years on the derivation and
characterisation of human primary cells and
drug resistant animal cell lines. She then
worked for 10 years with Pharmaceutical
Proteins Ltd (PPL) on a variety of R&D
programmes focusing on pioneering work
within nuclear transfer in addition to stem
cells and large-scale protein production to
cGMP. Angela has also gained experience in
facilitating projects from development to
GMP production in her role as Development
Manager for Excell Biotech Ltd, and prior to
her current role she was retained as a Quality
Consultant for ESI International (Singapore).
Angela has responsibility for the cell culture
development team based in Cramlington and
is Head of Production for the MHRA approved
production facility based in Edinburgh.
Appendix C
TERMS OF REFERENCE
DTI the Government department that

champions UK business sponsors companies
to Gain first hand knowledge of technology
development in the world. To this end the DTI
Global Watch Service kindly sponsored
bioProcessUK, the UK Knowledge Transfer
Network (KTN) for biopharmaceutical
bioprocessing, to organise a small team of
delegates to visit the West Coast of the USA to
investigate the cell and tissue therapeutic area.
Mission overview
The purpose of this mission was to explore
the state of cell and tissue therapeutic
development and production on the West
Coast of the USA currently the dominant
country developing cell and tissue products.
In November 2005, bioProcessUK ran a
workshop on the bioprocessing of Novel
Cell and Tissue Therapeutics to debate the
complex issues that must be addressed in
the commercialisation of cell therapies.
Bioprocessing experts from academia and
industry discussed measures to support
the translation of academic research
through to industry and foster the
development of scalable, reproducible and
GMP standard systems for manufacturing
cell therapy products.
One of the recommendations from the
bioProcessUK workshop report was that
bioProcessUK/DTI Global Watch Service
should sponsor a mission to the USA to
pinpoint the key opportunities since it was felt
that the US stem cell and regenerative
medicine companies were far more advanced
with respect to their UK counterparts. Thus
by examining and reporting back to the UK on
examples of where innovation, translation and
technology exploitation has been successful

in the USA, all the UK stakeholders could
potentially capitalise on advanced cell and
tissue therapy opportunities more efficiently
and rapidly.
The mission team was charged to carefully
consider a cross section of R&D subject
areas for cell and tissue therapies. The team
was briefed to examine a number of core
issues related to how scientific discoveries in
the area can be translated into routine clinical
practice and the successful business models
that can enable this to happen.
High level aims
The key fact-finding objectives of the
mission included:
To identify technologies for minimising the
cost of goods
To find technologies for making products
more effective
To develop understanding of how these
technologies can successfully be brought
to market
To gain better understanding of US market
needs including both regulatory and quality
requirements
Overall, the mission teams brief was to
consider the complete range of issues which
affect successful commercialisation of
advanced cell and tissue therapies. The
subsequent report describes how the US
companies perceive key commercial,
technical and regulatory issues. It concludes
with an analysis of the strategic implications
for the UK and recommendations for action.
47
Appendix D
COMPANY VISITS
Advanced BioHealing Inc

10933 North Torrey Pines Road
La Jolla
CA 92037
Advanced Cell Technology Inc

1201 Harbor Bay Parkway
Suite 120
Alameda
CA 94502
www.advancedbiohealing.com
www.advancedcell.com
Kevin Rakin
CEO
David Eisenbud
Executive VP
Advanced BioHealing Inc is a speciality
biotechnology company focused on the
development and marketing of cell based and
tissue engineered products for wound care. It
is a privately held, New York based company
with two FDA approved products: Dermagraft
and TransCyte. Its development pipeline also
includes a next-generation bioengineered
wound therapy for which an Investigational
Device Exemption (IDE) application has been
submitted to FDA.
In 2006, Advanced BioHealing purchased the
manufacturing and marketing rights to
Dermagraft (human fibroblast-derived dermal
substitute) and Transcyte (a human fibroblastderived temporary skin substitute) from
Smith & Nephew. Advanced BioHealing is on
target to return Dermagraft to the market in
2007 following manufacturing improvements
at the companys La Jolla, California facility.
48
William M Caldwell IV
Chairman and CEO
Michael D West
President and CSO
Advanced Cell Technology Inc is a
biotechnology company applying human
ES cell technology in the emerging field
of regenerative medicine. It operates
facilities in Alameda, California and
Worcester, Massachusetts.
The company owns or licenses over 300
patents and patent applications related to the
field of stem cell therapy, nuclear transfer
which allows the production of stem cells
genetically matched to the patient, and a
reduced complexity library of stem cells for
acute clinical applications. It believes its IP
represents one of the strongest portfolios in
the field.
The company is focused on being the first to
commercialise the most profitable
applications of regenerative medicine.
California Institute for Regenerative

Medicine (CIRM)
210 King Street
San Francisco
CA 94107
Cellerant Therapeutics Inc

1531 Industrial Road
San Carlos
CA 94070
www.cellerant.com
www.cirm.ca.gov
Zach W Hall
President
Robert Klein
Chairman, Independent Citizens Oversight
Committee
CIRM is a state agency established through
the passage of Proposition 71, the California
Stem Cell Research and Cures Initiative. The
statewide ballot measure, which provided
$3 billion (~1.5 billion) in funding for stem
cell research at Californian universities and
research institutions was approved by
California voters in November 2004 and called
for the establishment of a new state agency
to make grants and provide loans for stem
cell research, research facilities and other vital
research opportunities.
CIRM will function using bond proceeds to
fund basic and applied biomedical research
focused on developing diagnostics and
therapies and on other vital research
opportunities that will lead to life-saving
medical treatments. All proposals are peerreviewed to support the most promising
scientific research. Research grants are made
only to California-based research institutions.
Bruce Cohen
President and CEO
Cellerant Therapeutics Inc is a clinical stage
biotechnology company with a portfolio of
products based on the regulation of the
human haematopoietic (blood-forming)
system. The company focuses on curative
therapies for seriously ill patients.
Currently Cellerant has three major products
under development, including pure
haematopoietic stem cells (CLT-001) for
therapeutic applications in cancer, genetic
blood disorders and autoimmune diseases. It
is also developing a novel, cell based
medicine (myeloid progenitors/CLT-008) as a
treatment for chemotherapy and radiationinduced neutropenia (abnormally low levels of
a particular white blood cell) as well as for
acute radiation syndrome.
The company is also applying its considerable
expertise in haematopoietic biology to identify
novel drug targets and therapeutic antibodies
aimed at cancer stem cells.
CIRM is overseen by an Independent

Citizens Oversight Committee (ICOC). The 29
ICOC members are public officials, appointed
on the basis of their experience earned in
Californias leading public universities, nonprofit academic and research institutions,
patient advocacy groups and the
biotechnology industry.
49
Cerco Medical LLC

2180 Palou Avenue
San Francisco
CA 94124
Cognate BioServices Inc

709 East Evelyn Avenue
Sunnyvale
CA 94086
www.isletmedical.com
www.cognatebioservices.com
Scott R King
President
Alan K Smith
President and COO
Cerco Medical LLCs mission is to develop

cellular-based therapies to treat common
diseases through the application of its
proprietary encapsulation technology. The
companys implantable thin-sheet devices
make cell therapy potentially possible without
the requirement for toxic immune
suppression therapy.
Cognate BioServices Inc is a value-added

provider of development and cGMP
manufacturing services to companies
developing a variety of cell therapy
technologies. It is a fully integrated company
with highly experienced technical staff and
management team, along with fully validated
cGMP manufacturing facilities on both Coasts
and state-of-the-art R&D laboratories. It also
has the ability to rapidly advance technology
from early research stages through preclinical
and process development, cGMP
manufacturing and scale-up, regulatory
submission and into the clinic.
Cerclos sole current focus is an implantable

bio-artificial pancreas device to treat diabetes
called the Islet Sheet. The company is
carrying out preclinical studies of this alginatebased technology in animal models of
diabetes and anticipates clinical trials within
the next two years.
50
Cognate fills a unique role in supporting

development of cell-based therapeutics and
has substantial experience in the successful
development of cell-based therapeutic
products that have been introduced into
human clinical trials through IND applications
to the FDA. Members of Cognates staff have
played a material role in the development of
16 successful stem cell and cellular product
IND applications.
Cytori Therapeutics Inc

3020 Callan Road
San Diego
CA 92121
Geron Corp
230 Constitution Drive
Menlo Park
CA 94025
www.cytoritx.com
www.geron.com
Christopher J Calhoun
CEO and Vice-Chairman
Thomas B Okarma
President, CEO and a Director
Cytori Therapeutics Inc is discovering and

developing proprietary, cell-based therapeutics
utilising adult stem cells derived from adipose
(fat) tissue. The companys investigational
therapies target cardiovascular disease, spine
and orthopaedic conditions, gastrointestinal
disorders and new approaches for aesthetic
and reconstructive surgery.
Incorporated in the state of Delaware in 1990,

Geron Corp has been in business since 1992.
The companys headquarters and main
facilities are located in Menlo Park, California.
It also has a subsidiary in Edinburgh, Scotland.
To facilitate the processing and surgical

delivery of adipose stem cells, Cytori is
developing its proprietary Celution System to
process and concentrate a patients own
stem cells in approximately one hour. This
system will dramatically improve the speed at
which personalised (autologous), cell-based
therapies can be delivered to patients.
Geron is a biopharmaceutical company

developing and commercialising three groups
of products:
Therapeutic products for oncology that
target telomerase
Pharmaceuticals that activate telomerase
in tissues impacted by senescence, injury
or degenerative disease
Cell-based therapies derived from its
human ES cell platform for applications in
multiple chronic diseases
51
Primogenix Inc
1640 Marengo Street
Suite 702
Los Angeles
CA 90033
Progenitor Cell Therapy LLC

21 Main Street
Court Plaza South
East Wing, Suite 304
Hackensack
NJ 07601
www.primogenix.com
www.progenitorcelltherapy.com
Robin Wesselschmidt
CEO
Primogenix Inc was founded in 2003 with the
purpose of providing investigators around the
world with access to high quality mouse ES
cells derived from standard research strains
as well as transgenic and knockout models.
Leveraging 15 years experience in ES cell
technology, Primogenix is applying proven
expertise to help result-driven researchers
achieve their project goals faster and at lower
cost. It provides the highest quality mouse
ES cell lines, expertise and consulting
services to accelerate research projects.
Robert A Preti
President and CSO
Progenitor Cell Therapy LLC is a client-based
cell therapy services company that supports
the development and commercialisation of
cellular therapies. It provides cGMP-compliant
cell manufacturing and consulting services
that address regulatory, financial, technical,
process and quality system strategies.
Services include a full spectrum of support
related to process and product development,
validation, due diligence evaluations, tissue
collection, processing and storage, product
manufacturing, distribution and transportation.
The companys products and services include:
52
Stem cell isolation and validation

Differentiation
Electroporation
Mouse chimera production
Progenitor currently serves its global client

base from its two facilities in Hackensack
(New Jersey) and Mountain View (California).
Proteus Venture Partners

8 Redberry Ridge
Portola Valley
CA 94028
StemCells Inc
3155 Porter Drive
Palo Alto
CA 94304-1213
www.proteusvp.com
www.stemcellsinc.com
Gregory Bonfiglio
MD and Partner
Martin McGlynn
President and CEO
Proteus Venture Partners is a team of

experienced investment and operations
professionals who came together to establish
a regenerative medicine fund The Proteus
Fund. The team has aligned itself with key
players in academia, industry and government.
The Proteus Advisory Board represents the
top leaders of stem cell and regenerative
medicine research, thus assimilating the
thought leaders of this sector.
StemCells Inc is focused on the discovery

and development of stem cell therapeutics
that will form the basis of therapies to
support or replace cells that have been
damaged or lost through disease, injury or
genetic defect. Initially it is focusing on such
conditions in the central nervous system
(CNS), liver and pancreas.
The Proteus Fund is a $150 million

(~77 million) fund focusing on cell therapies,
tissue engineering, tools and devices and
aesthetic medicines. It plans to invest in
companies across a broad range of
development, from early stage companies
seeking their first institutional round of
financing, to small-cap public companies
seeking private investment in public equity
(PIPE) financing. Its investment focus is not
limited by geography; for example, it expects
to make a number of investments in the UK,
Canada, Israel and other centres of
excellence outside the USA.
The company is a world leader in the

discovery and development of human neural
stem cell technology using cells derived from
adult (ie non-embryonic) brain tissue. It uses
a proprietary process to isolate, purify and
expand rare candidate stem cells found in
adult human tissue. To date, it has discovered
the human neural stem cell as well as a
population of rare candidate stem cells found
in human liver and pancreas.
StemCells has over 40 issued US patents,
plus foreign equivalents to some 14 of its US
patents and applications, for a total of over
170 individual patents worldwide.
53
Synthasome Inc
3030 Bunker Hill Street
Suite 308
San Diego
CA 92109
Theregen Corp
225 Bush Street, 16th Floor
San Francisco
CA 94105
www.theregeninc.com
www.synthasome.com
Anthony Ratcliffe
President and CEO
Synthasome Inc is a biotechnology company
developing products for regenerative
medicine, primarily for musculoskeletal
applications, using tissue-engineering
technologies. The company has a product
pipeline, NIH-funded projects, and patents
have been submitted.
The first products are those that can be
brought to market relatively quickly and with
modest investment. The revenues from these
early products will then be used to drive the
future R&D programme.
The overall objective of Synthasome is
to develop products that meet previously
unmet clinical needs in reparative
medicine using tissue engineering
technology within a financially profitable
and independent organisation.
54
Michael Siani-Rose
President
Theregen Corp (formerly Iken Tissue
Therapeutics) is a regenerative medicine
company that develops cell-based therapies
for patients with cardiovascular and vascular
disease. It has worldwide exclusive rights to
research, manufacture, develop and
commercialise its lead product Anginera for
cardiovascular and peripheral vascular
disease applications.
Currently the company is conducting a
Phase 1 human clinical safety trial for
Anginera, a cell-based epicardial therapy. In
preclinical studies, Anginera has been shown
in animal models to have the potential to
induce remodelling and angiogenesis (new
blood vessel formation) in the ischemic heart,
leading to functional changes that may
benefit patients with heart failure.
VistaGen Therapeutics Inc

1450 Rollins Road
Burlingame
CA 94010
www.vistagen-inc.com
H Ralph Snodgrass
President, CEO and Director
VistaGen Therapeutics Inc is a
biopharmaceutical company developing
breakthrough drugs for disorders of the
CNS and diabetes. Its lead drug candidate
AV-101 targets two large CNS markets:
epilepsy and neuropathic pain. The companys
key R&D partnership applies its clinically
predictive in-vitro ES cell technologies to
discover and develop a new generation of
drug candidates for diabetes and other
metabolic syndrome diseases.
VistaGen is developing an internal pipeline of
products to provide late-stage product
opportunities for large pharmaceutical
companies by advancing new generation drug
candidates through Phase 2 clinical trials and
pursuing partnerships to complete Phase 3
development and commercialisation.
55
Appendix E
GLOSSARY
~
approximately
~
approximately equal to
anchorage dependent
A characteristic of cells which will not thrive
unless attached to a biocompatible surface
true of most human cells from connective
tissue or organs.
pound sterling $1.94 (Nov 06)
API
active pharmaceutical ingredient
$
US dollar 0.52 (Nov 06)
ATP
adenosine triphosphate
510(k)
A route to product registration in the USA
available for products for which substantial
equivalence in mode of action can be shown to
a product already on the market (the so-called
predicate device).
ATS
Advanced Tissue Sciences (USA)
adipose
Based upon the fatty components of soft
connective tissue.
adult stem cell
An undifferentiated cell found in a
differentiated tissue that can renew itself and
(with certain limitations) differentiate to yield
all the specialised cell types of the tissue
from which it originated.
AIM
Alternative Investment Market (London Stock
Exchange, UK)
allogeneic
A process or therapy in which tissue or cells
are removed from a patient and used to
create a therapeutic product which is then
used for a number of different patients.
AMIChemE
Associate Member of the Institution of
Chemical Engineers (UK)
56
autologous
A process or therapy in which tissue or cells
are removed from a patient and after
processing are returned to the same patient.
autologous transplant
Transplanted tissue derived from the intended
recipient of the transplant. Such a transplant
helps avoid complications of immune rejection.
BBSRC
Biotechnology and Biological Sciences
Research Council (UK)
BIA
BioIndustry Association (UK)
BIGT
Bioscience Innovation and Growth Team (UK)
bone marrow
The soft, living tissue that fills most bone
cavities and contains haematopoietic stem
cells, from which all red and white blood cells
evolve. The bone marrow also contains
mesenchymal stem cells that a number of
cell types are derived from, including
chondrocytes, which produce cartilage.
bone marrow cell

Refers to both haematopoietic and
mesenchymal (stromal) cells.
bone marrow transplantation
Autologous bone marrow transplantation is a
process in which a patients healthy bone
marrow is withdrawn and preserved, then
injected back into the patient to restore the
production of healthy blood and immune
cells by the bone marrow. This strategy is
often used in patients with certain types of
cancer who have undergone radiation
therapy or chemotherapy that destroys the
bone marrow cells.
BRIC
Bioprocessing Research Industry Club (UK)
BS
Bachelor of Surgery
BSc
Bachelor of Science
BSI
British Standards Institution (London)
BTC
Biopharmaceutical Technology Centre (UK)
CE marking
The initials CE do not stand for any specific
words but are a declaration by the manufacturer
that their product meets the requirements of
the applicable European Directive(s).
CEO
Chief Executive Officer
cGMP
current Good Manufacturing Practice
chondrocytes
Cartilage cells which produce and maintain
the articulating surfaces of skeletal joints.
CIRM
California Institute for Regenerative Medicine
(San Francisco)
CMO
contract manufacturing organisation
CNS
central nervous system
CoG
cost of goods
COO
Chief Operating Officer
degrees Celsius
CA
California (state, USA)
CSO
Chief Scientific Officer
CCP
critical control point
cytokines
A generic term for a large variety of
regulatory proteins produced and secreted by
cells and used to communicate with other
cells. One class of cytokines is the
interleukins, which act as intercellular
mediators during the generation of an
immune response.
CELS
Centre of Excellence for Life Sciences
(Newcastle upon Tyne, UK)
DARPA
Defense Advanced Research Projects Agency
(USA)
CASE
Cooperative Award in Science and
Engineering (UK)
57
DH
Department of Health (UK)
EU
European Union
differentiation
The process of maturation of stem cells into
specialised cell types of the body.
ex vivo
Outside the living body.
DMSO
dimethylsulphoxide
DNA
deoxyribonucleic acid a chemical found
primarily in the nucleus of cells. DNA carries
the instructions for making all the structures
and materials the body needs to function.
DTI
Department of Trade and Industry (UK)
embryo
In humans, the developing organism from the
time of fertilisation until the end of the eighth
week of gestation, when it becomes known
as a foetus.
embryonic stem (ES) cells
Primitive (undifferentiated) cells from the
embryo that have the potential to become a
wide variety of specialised cell types.
EMEA
European Medicines Agency (London, UK)
EngD
Engineering Doctorate
epithelium
The layer of cells forming the epidermis of the
skin. These cells serve the general functions
of protection, absorption and secretion.
EPSRC
Engineering and Physical Sciences Research
Council (UK)
ES
embryonic stem (cell)
58
extracellular matrix
The microenvironment next to a cell that
allows for structural support, orientation, and
connections for cell-to-cell interactions and
formation of connective tissues.
F
fax
FACS
fluorescence-activated cell sorting
FDA
Food and Drug Administration (USA)
feeder cell layer
Cells that are utilised in co-culture to maintain
pluripotent stem cells. Cells usually consist of
mouse embryonic fibroblasts.
fibroblasts
Cells that give rise to connective tissue.
fluorescence-activated cell sorting (FACS)
A technique that can separate and analyse
cells, which are labelled with fluorochromeconjugated antibody, by their fluorescence
and light scattering patterns.
foetal calf serum
A type of culture medium often used in the
culture of stem cells. It provides a number of
growth factors.
FRCS
Fellow of the Royal College of Surgeons (UK)
ft2
square foot = 0.0929 m2
Good Laboratory Practice (GLP)

Regulations, codes and guidelines for
laboratories conducting non-clinical studies.
This includes toxicology and pharmacology
studies in animals.
hybridoma
A hybrid cell produced by the fusion of an
antibody-producing cell and a multiple myeloma
cell. The cell has the capability to produce a
continuous supply of identical antibodies.
Good Manufacturing Practice (GMP)

Set of regulations, codes and guidelines for
the manufacture of drugs (known as
medicinal products in Europe), medical
devices, diagnostic products, food products
and active pharmaceutical ingredients.
ICOC
Independent Citizens Oversight Committee
(CIRM, San Francisco, CA, USA)
Good Tissue Practice (GTP)

Regulations, codes and guidelines for the
manufacture of cell-based therapeutic products.
haematopoiesis
Generation of blood cells, mainly in the
bone marrow.
haematopoietic stem cell (HSC)
A stem cell from which all red and white
blood cells evolve.
hepatic
Relating to the liver.
hepatocyte
Liver cell.
hES cell
human embryonic stem cell a type of
pluripotent stem cell
HFEA
Human Fertilisation and Embryology Authority
(London, UK)
HSC
haematopoietic stem cell
HTA
Human Tissue Authority (London, UK)
hUMP
human universal myeloid progenitor (cell)
IDE
Investigational Device Exemption (application)
(FDA, USA)
immunofluorescence
The detection of antibodies by using special
proteins labelled with fluorescein. When
present, the specific organism or antibody is
observed as a fluorescent material when
examined microscopically while illuminated
with a fluorescent light source.
immunogenic
Relating to or producing an immune response.
immunohistochemistry
Examination of tissues through specific
immunostaining techniques.
IND
Investigational New Drug (application)
(FDA, USA)
in vitro
Literally, in glass; in a laboratory dish or test
tube; an artificial environment.
in vitro fertilisation (IVF)
An assisted reproduction technique in which
fertilisation is accomplished outside the body.
in vivo
In the living subject.
IP
intellectual property
59
IPR
intellectual property right(s)
IRB
Institutional Review Board (USA)
IVF
in vitro fertilisation
JV
joint venture
keratinocytes
Cells that synthesise keratin and are found in
the skin, hair, and nails.
mES cell
mouse embryonic stem cell a type of
mesenchymal stem cells (MSCs)
Stem cells found in bone marrow. A number
of cell types come from mesenchymal stem
cells, including chondrocytes, osteocytes and
adipocytes which produce cartilage, bone and
fat respectively.
MHRA
Medicines and Healthcare Products
Regulatory Agency (London, UK)
m2
square metre
minimal manipulation
That amount of handling and processing
which, in the view of the regulatory
authorities, is insufficient to produce a
significant change in the behaviour of cells
before they are used therapeutically.
MA
Massachusetts (state, USA)
monoclonal
From a single cell.
MAb
monoclonal antibody
monoclonal antibody (MAb)

An exceptionally pure and specific antibody
derived from hybridoma cells. Because each of
the clones is derived from a single B cell, all of
the antibody molecules it makes are identical.
KTN
Knowledge Transfer Network (UK)
MAC
Manufacturing Advisory Committee (BIA, UK)
MB
Bachelor of Medicine
MBA
Master of Business Administration
MCB
master cell bank
MD
Managing Director
MEF
mouse embryonic fibroblast cell MEFs are
used as feeder cells when culturing
embryonic stem cells
60
morphology
The shape and structural make up of a cell,
tissue or organism.
MRC
Medical Research Council (UK)
MSc
Master of Science
MSC
mesenchymal stem cell
MTT
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H
tetrazolium bromide
multipotent stem cells

Stem cells that have the capability of
developing cells of multiple germ layers.
NASDAQ
National Association of Securities Dealers
Automatic Quotation System (USA)
NCTA
National Clinical Trials Agency (UK)
neuron
A nerve cell, the structural and functional unit
of the nervous system.
NHS
National Health Service (UK)
NIBSC
National Institute for Biological Standards and
Control (Potters Bar, UK)
NICE
National Institute for Health and Clinical
Excellence (London, UK)
NIH
National Institutes of Health (USA)
NJ
New Jersey (state, USA)
NSF
National Science Foundation (USA)
OEM
original equipment manufacturer a company
that makes products or components which
are used in products sold by another company
often called a value-added reseller (VAR)
ONE
One NorthEast (RDA HQ: Newcastle upon
Tyne, UK)
OTC
over the counter
PAS
Publicly Available Specification
passage
A single cycle of cell isolation, expansion
and recovery.
PAT
Process Analytical Technolog(y)/(ies)
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PhD
Doctor of Philosophy
phenotype
The observable set of biological and physical
characteristics of a cell that is the result of its
genetic identity under the influence of a given
set of environmental conditions.
PIPE
private investment in public equity
A single stem cell that has the capability of
developing cells of all germ layers (endoderm,
ectoderm, and mesoderm).
PPL
Pharmaceutical Proteins Ltd (UK)
precursor cells
In foetal or adult tissues, these are partly
differentiated cells that divide and give rise
to differentiated cells. Also known as
progenitor cells.
Process Analytical Technology (PAT)
A system for designing, analysing, and
controlling manufacturing through timely
measurements (ie during processing) of
critical quality and performance attributes of
raw and in-process materials and processes
with the goal of ensuring final product quality.
61
process validation
Establishing documented evidence that a
process or system, when operated within
established parameters, can perform
effectively and reproducibly to produce a
medicinal product meeting its predetermined
specifications and quality attributes.
progenitor cells
In foetal or adult tissues, these are partly
differentiated cells that divide and give rise
to differentiated cells. Also known as
precursor cells.
Proposition 71 (Prop 71)
The California Stem Cell Research and Cures
Act of 2004. Stem cell research funding
bonds to establish and maintain the California
Institute for Regenerative Medicine (CIRM) in
order to regulate stem cell research and
provide funding, through grants and loans, for
such research and research facilities.
QP
quality procedure
quality assurance (QA)
Programme for the systematic monitoring
and evaluation of the various steps of
production to maintain standards of quality of
a product.
quality control (QC)
Process or set of processes or measures
used to maintain proper standards to assure
the quality of a product.
S&N
Smith & Nephew (UK/USA)
S&T
science and technology
SCNT
somatic cell nuclear transfer
SME
small or medium sized enterprise
somatic cell
Any cell of a plant or animal other than a
germ cell or germ cell precursor.
somatic cell nuclear transfer (SCNT)
The transfer of a cell nucleus from a somatic
cell into an egg from which the nucleus has
been removed.
stem cell
A cell that has the ability to divide for
indefinite periods in culture and to give rise to
specialised cells.
stromal cell
A non-blood cell that is derived from blood
organs, such as bone marrow or foetal liver,
which is capable of supporting growth of
blood cells in vitro. Stromal cells that make
this matrix within the bone marrow are also
derived from mesenchymal stem cells.
T
telephone
R&D
research and development
TAP
The Automation Partnership (Royston, UK)
RAAC
Regulatory Affairs Advisory Committee
(BIA, UK)
telomerase
An enzyme that is composed of a catalytic
protein component and an RNA template and
that synthesises DNA at the ends of
chromosomes and confers replicative
immortality to cells.
RDA
regional development agency (UK)
RNA
ribonucleic acid
62
telomere
The end of a chromosome, associated with a
characteristic DNA sequence that is
replicated in a special way. A telomere
counteracts the tendency of the chromosome
to shorten with each round of replication.
US(A)
United States (of America)
teratoma
A tumour composed of tissues from the
three embryonic germ layers. Usually found
in ovary and testis. Produced experimentally
in animals by injecting pluripotent stem cells,
in order to determine the stem cells abilities
to differentiate into various types of tissue.
VP
Vice President
tissue culture
Growth of tissue in vitro on an artificial
medium for experimental research.
vascular
Composed of, or having to do with,
blood vessels.
WARF patents
Primate Embryonic Stem Cells (US patents
5,843,780, 6,200,806 and 7,029,913) James
Thomson (Wisconsin Alumni Research
Foundation), December 1998.
WFI
water for injection
TN
Tennessee (state, USA)
The above glossary is adapted from:
totipotent
Having unlimited replication capability. The
totipotent cells of the very early embryo have
the capacity to differentiate into extra embryonic
membranes and tissues, the embryo, and all
post-embryonic tissues and organs.
National Institutes of Health Glossary

and Terms section of the Stem Cell
Information website
http://stemcells.nih.gov/info/glossary.asp
UCL
University College London (UK)
Process Analytical Technology (PAT) Initiative

Center for Drug Evaluation and Research
(CDER), FDA
www.fda.gov/Cder/OPS/PAT.htm#Introduction
UK
United Kingdom
UKSCI
UK Stem Cell Initiative (DH, London)
Publicly Available Specification (PAS) 83

Guidance on codes of practice, standardised
methods and regulations for cell-based
therapeutics, from basic research to clinical
application (DTI in collaboration with BSI)
http://eshop.bsi-global.com/
ProductListing.aspx?cat=PAS+83
undifferentiated
Not having changed to become a specialised
cell type.
UK Stem Cell Initiative Report, November

2005
www.advisorybodies.doh.gov.uk/uksci/index.htm
UKSCF
UK Stem Cell Foundation
unipotent
Refers to a cell that can only develop in a
specific way to produce a certain end result.
63
Appendix F
SOURCES OF INFORMATION
Reports
2003
1998
Human Tissue Engineered Products Todays

Markets and Future Prospects IPTS/EU JRS
October 2003
http://ec.europa.eu/enterprise/pharmaceuticals/
advtherapies/docs/ipts21000en.pdf
Primate Embryonic Stem Cells (US Patents

5,843,780, 6,200,806 and 7,029,913) WARF
patent James Thomson (Wisconsin Alumni
Research Foundation) filed January 1996
first issued December 1998
http://patft.uspto.gov/netacgi/nphParser?Sect1=PTO2&Sect2=HITOFF&p=1&u
=%2Fnetahtml%2FPTO%2Fsearchbool.html&r=1&f=G&l=50&co1=AND&d=PTX
T&s1=5843780.PN.&OS=PN/5843780&RS=P
N/5843780
2001
Stem Cells: Scientific Progress and Future
Research Directions US Department of
Health and Human Services June 2001
http://stemcells.nih.gov/info/scireport/2001
report.htm
Stem Cell Research The Royal Society
June 2001
www.royalsoc.ac.uk/displaypagedoc.asp?id=1
1473
2002
Tissue Engineering Research WTEC Panel
Report International Technology Research
Institute January 2002
www.wtec.org/loyola/te/final
Stem Cell Research Report House of Lords
February 2002
www.parliament.the-stationery-office.co.uk/
pa/ld200102/ldselect/ldstem/83/8301.htm
64
2004
Cellular Therapy: Potential Treatment for Heart
Disease US FDA June 2004
www.fda.gov/cber/genetherapy/celltherapy
heart.htm
Regulating Stem Cell Therapies
Parliamentary Office of Science and
Technology June 2004
www.parliament.uk/documents/upload/POST
pn221.pdf
Stem cell mission to China, Singapore and
South Korea Report DTI Global Watch
Mission September 2004
www.oti.globalwatchonline.com/online_pdfs/
36206MR.pdf
Proposition 71 The California Stem Cell
Research and Cures Act of 2004 Approved
November 2004
www.cirm.ca.gov/prop71/pdf/prop71.pdf
2005
2020: A New Vision A Future for
Regenerative Medicine US Department of
Health and Human Services January 2005
http://www.hhs.gov/reference/
FutureofRegenerativeMedicine.pdf
Guidelines for Human Embryonic Stem Cell

Research National Academy of Sciences
April 2005 (Advance Copy)
http://www.nap.edu/catalog/11278.html
Human Tissue Engineering and Beyond:
Proposal for a Community Regulatory
Framework on Advanced Therapies
European Commission Initiative May 2005
advtherapies/docs/draftregulationadvancedtherapies-2005-may-04.pdf
Global Commercialisation of UK Stem Cell
Research UK Trade & Investment June
2005
http://www.fco.gov.uk/Files/kfile/UKTI%20stem
%20cell%20presentation2,0.pdf
Advanced Therapies: Tissue Engineering, Cell
Therapy and Gene Therapy Proposal
European Commission Initiative November
2005
advtherapies/docs/com_2005_567_en.pdf
Human Tissue-Engineered Products: Potential
Socio-Economic Impacts of a New European
Regulatory Framework for Authorisation,
Supervision and Vigilance IPTS/EU JRS
November 2005
www.jrc.es/home/pages/detail.cfm?prs=1338
UK Stem Cell Initiative Report and
Recommendations UKSCI November
2005
UK Stem Cell Initiative Report and
Recommendations UK Government
Response December 2005
2006
Stem Cell Research CRS Report for
Congress January 2006
www.usembassy.it/pdf/other/RL31015.pdf
Concept Paper on Guideline for Human CellBased Medicinal Products European
Medicines Agency (EMEA) January 2006
www.emea.europa.eu/pdfs/human/cpwp/323
77405en.pdf
Umbilical Cord Blood Banking Opinion Paper
Royal College of Obstetricians and
Gynaecologists June 2006
www.rcog.org.uk/index.asp?PageID=545
Regenerative Medicine 2006 US
Department of Health and Human Services
August 2006
http://stemcells.nih.gov/info/scireport/2006
report.htm
Turning Stem Cells into Cures DRAFT
Scientific Strategic Plan California Institute
for Regenerative Medicine (CIRM) October
2006
www.cirm.ca.gov/meetings/pdf/2006/10/Strat_
Plan_100406.pdf
PAS 83 Guidance on codes of practice,
standardised methods and regulations for
cell-based therapeutics, from basic research
to clinical application (DTI in collaboration with
BSI)
http://eshop.bsi-global.com/ProductListing.asp
x?cat=PAS+83
Useful websites
European Medicines Agency (EMEA)
Emerging Therapies and Technologies
www.emea.europa.eu/htms/human/itf/
itfguide.htm
British Standards Institution (BSI)
Regenerative Medicine information
www.bsi-global.com/Regenerative
Medicine/index.xalter
65
California Institute for Regenerative Medicine

(CIRM)
www.cirm.ca.gov
International Society for Stem Cell Research

(ISSCR)
www.isscr.org
EU Initiative: Advanced Therapies: Tissue

Engineering, Cell Therapy and Gene Therapy
advtherapies/index.htm
London Regenerative Medicine Network

www.lrmn.com
Medicines and Healthcare Products

Regulatory Agency (MHRA) Regulation of
Tissue Engineering
www.mhra.gov.uk/home/idcplg?IdcService=S
S_GET_PAGE&nodeId=207
UK Department of Health UK Stem Cell
Initiative (UKSCI)
UK Department of Health/Medical Research
Council online clinical trials guide
www.ct-toolkit.ac.uk
UK Human Fertilisation and Embryology
Authority (HFEA)
www.hfea.gov.uk
Scottish Stem Cell Network (SSCN)

www.sscn.co.uk/Home.aspx
Tissue Engineering & Regenerative Medicine
International Society (TERMIS)
www.termis.org
UK National Stem Cell Network
www.uknscn.org
Journals
Regenerative Medicine
www.futuremedicine.com/loi/rme
Tissue Engineering
www.liebertpub.com/publication.aspx?pub_id
=56
Useful publications
UK Human Tissue Authority (HTA)

www.hta.gov.uk
UK Stem Cell Bank
www.ukstemcellbank.org.uk
US Food and Drug Administration (FDA)
Center for Biologics Evaluation and Research
(CBER) Tissue Section
www.fda.gov/cber/tiss.htm
Networks
BRITE Net British Tissue Engineering
Network
www.briten.org
East of England Stem Cell Network
www.eescn.org.uk
66
Coecke S, Balls M, Bowe G et al. European

Centre for the Validation of Alternative
Methods (ECVAM) Guidance on Good Cell
Culture Practice (GCCP): A Report of the
Second ECVAM Task Force on Good Cell
Culture Practice. ATLA 33:261287 (2005)
http://ecvam.jrc.it/publication/GCCPtaskforce
report2.pdf
Corrigan O, Liddell K, McMillan J et al.
Ethical, Legal and Social Issues in Stem Cell
Research and Therapy: A briefing paper from
Cambridge Genetics Knowledge Park (2005)
www.eescn.org.uk/pdfs/elsi_paper.pdf
Dutton R L and Fox J S. Robotic Processing in

Barrier-Isolator Environments: A Life Cycle
Cost Approach. Pharmaceutical Engineering
26:1-8 (2006)
www.ispe.org/galleries/e-letter-files/06SODutton-SPP.pdf
Harris N, Munro C and Patel B. New guidance
on codes of practice, standardized methods
and regulations for cell-based therapeutics.
Regenerative Medicine 1:705-707 (2006)
www.futuremedicine.com/doi/abs/10.2217/17
460751.1.5.705
Lidell K and Wallace S. Emerging Regulatory
Issues for Human Stem Cell Medicine.
Genomics, Society and Policy 1:54-73 (2005)
www.lancs.ac.uk/fss/journals/gsp/docs/volume
1number1/klswgspvol1no12005.pdf
Winickoff D E. Governing stem cell research
in California and the USA: towards a social
infrastructure. Trends in Biotechnology
24:390-394 (2006)
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd
=Retrieve&db=PubMed&list_uids=16843559
&dopt=Citation
67
Appendix G
LIST OF EXHIBITS
Exhibit
Page
Caption
1.1
Mouse embryonic fibroblast cells (MEFs) are presently used as feeder cells
for culturing embryonic stem cells (Primogenix Inc)
2.1
Good Manufacturing Practice (GMP) cell therapy production incubator

loading (Cognate BioServices Inc)
2.2
GMP cell therapy production incubator checking (Cognate BioServices Inc)
2.3
Overview of typical cell product manufacturing systems
2.4
12
GMP cell therapy production cell harvesting (Cognate BioServices Inc)
3.1
27
GMP cell therapy production cell splitting and seeding (Cognate

BioServices Inc)
3.2
29
GMP cell therapy production cryopreservation (Cognate BioServices Inc)
4.1
35
A possible UK 2016 scenario
68
69
70
71
Other DTI products that help UK businesses acquire and

exploit new technologies
Grant for Research and Development
is available through the nine English Regional
Development Agencies. The Grant for Research
and Development provides funds for individuals
and SMEs to research and develop technologically
innovative products and processes. The grant is
only available in England (the Devolved
Administrations have their own initiatives).
www.dti.gov.uk/r-d/
The Small Firms Loan Guarantee is a UKwide, Government-backed scheme that provides
guarantees on loans for start-ups and young
businesses with viable business propositions.
www.dti.gov.uk/sflg/pdfs/sflg_booklet.pdf
Knowledge Transfer Partnerships enable
private and public sector research organisations
to apply their research knowledge to important
business problems. Specific technology transfer
projects are managed, over a period of one to
three years, in partnership with a university,
college or research organisation that has
expertise relevant to your business.
www.ktponline.org.uk/
Knowledge Transfer Networks aim to improve
the UKs innovation performance through a single
national over-arching network in a specific field of
technology or business application. A KTN aims
to encourage active participation of all networks
currently operating in the field and to establish
connections with networks in other fields that
have common interest.
www.dti.gov.uk/ktn/
72
Collaborative Research and Development

helps industry and research communities work
together on R&D projects in strategically
important areas of science, engineering and
technology, from which successful new products,
processes and services can emerge.
www.dti.gov.uk/crd/
Access to Best Business Practice is available
through the Business Link network. This initiative
aims to ensure UK business has access to best
business practice information for improved
performance.
www.dti.gov.uk/bestpractice/
Support to Implement Best Business Practice
offers practical, tailored support for small and
medium-sized businesses to implement best
practice business improvements.
www.dti.gov.uk/implementbestpractice/
Finance to Encourage Investment in Selected
Areas of England is designed to support
businesses looking at the possibility of investing
in a designated Assisted Area but needing
financial help to realise their plans, normally in
the form of a grant or occasionally a loan.
www.dti.gov.uk/regionalinvestment/
The DTI Global Watch Service provides support dedicated

to helping UK businesses improve their competitiveness
by identifying and accessing innovative technologies and
practices from overseas.
Global Watch Information
Global Watch Online a unique internetenabled service delivering immediate and
innovative support to UK companies in the
form of fast-breaking worldwide business and
technology information. The website provides
unique coverage of UK, European and
international research plus business
initiatives, collaborative programmes and
funding sources.
Visit: www.globalwatchservice.com
Global Watch magazine distributed free

with a circulation of over 50,000, this monthly
magazine features news of overseas
groundbreaking technology, innovation and
management best practice to UK companies
and business intermediaries.
Contact:
subscriptions@globalwatchservice.com
Global Watch Missions enabling teams of

UK experts to investigate innovation and its
implementation at first hand. The technology
focused missions allow UK sectors and
individual organisations to gain international
insights to guide their own strategies for
success.
Contact:
missions@globalwatchservice.com
Global Watch Technology Partnering
providing free, flexible and direct assistance
from international technology specialists to
raise awareness of, and provide access to,
technology and collaborative opportunities
overseas. Delivered to UK companies by a
network of 23 International Technology
Promoters, with some 8,000 current
contacts, providing support ranging from
information and referrals to more in-depth
assistance with licensing arrangements and
technology transfer.
Contact: itp@globalwatchservice.com
For further information on the Global Watch
Service please visit
www.globalwatchservice.com
Printed in the UK on recycled paper with 75% de-inked post-consumer waste content
First published in December 2006 by Pera on behalf of the Department of Trade and Industry
Crown copyright 2006
URN 06/2092

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GLOBAL WATCH MISSION REPORT

Advanced cell and tissue

Global Watch Missions

Cover image: Fibroblasts labelled for actin (red), microtubules

Advanced cell and

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

INFORMATION FROM COMPANY

Manufacturing and automation

STRATEGIC IMPLICATIONS FOR

3.1 The state of the Californian industry 27

This report describes the outcomes from a

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

The UK faces major challenges in the field of

The focus of the visit was Californian

In 2004 a Department of Trade and Industry

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

INTRODUCTION AND OBJECTIVES

This document describes conclusions of a

in the future NHS with the public sector as a

The activity of the largest companies visited

A rapid increase in the old age

Regenerative medicine has the potential to

The field of regenerative medicine addresses

An acceleration in the pace of innovation

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

Current research suggests that progress can

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

INFORMATION FROM COMPANY VISITS

Manufacturing and automation

PBMCs) achieve blockbuster status, a

This chapter addresses the technical,

Manufacturing and automation

Generally the primary systems being used to

Exhibit 2.1 Good Manufacturing Practice (GMP) cell

A small number of companies visited were

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

Scale of operation was primarily driven by the

following process optimisation during clinical

With all of the manufacturing systems

Bulk cell product

Bulk cell product

Exhibit 2.3 Overview of typical cell product manufacturing systems

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

could be beneficial there were concerns that

In-house manufacturing versus

All the companies visited during the mission

allogeneic cell therapy products. Their

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

significant shelf-life constraints. Shipment of

Distinct approaches to identify stem cell

population required. By using high speed cell

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

Getting involvement of a quality function early

A vital process factor being addressed by

have no specific endotoxin removal step.

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

An alternative, if not unique, manufacturing

Only two of the companies were in later

ADVANCED CELL AND TISSUE THERAPIES A MISSION TO THE USA

Consequently, a number of operational

There are significant process challenges

Generally the companies visited were using

Exhibit 2.4 GMP cell therapy production cell

All the companies visited recognised that