Global Watch USA 2006 Report
Global Watch USA 2006 Report
Global Watch USA 2006 Report
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
CONTENTS
EXECUTIVE SUMMARY
EXECUTIVE SUMMARY
FOREWORD
INTRODUCTION AND
OBJECTIVES
2.1
2.2
2.3
2.4
6
14
16
23
27
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
FOREWORD
Exhibit 1.1 Mouse embryonic fibroblast cells (MEFs) are presently used as feeder cells for culturing embryonic
stem cells (Primogenix Inc)
2.1
2.2
2.3
2.4
2.1.1
Manufacturing overview
Cell bank
Primary
expansion:
multiple stages
Tissue
sample
Enrichment of
desired cell
fraction
Production
stage: roller
bottles or cell
factories
Expansion
Bulk cell
product
Translation strategies
Raw materials
2.1.5
Minimal manipulation
manufacturing
2.1.6
Commercial manufacturing
11
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
Adoption of automation
Distribution
2.2.1
Overview
Cryopreservation
Shipping
Local production
2.3.1
Overview
2.3.2
2.3.3
Asepsis
Manufacturing equipment
The product
19
Delivery
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
Commercialisation
Therapeutic companies
23
2.4.3
2.4.2
Tools companies
Contract manufacturing
organisations (CMOs)
26
3.1
3.2
3.3
3.1
3.1.2
3.1.1
28
Importance of bioprocessing
3.2
3.3.3
33
4.1
Conclusions
Recommendations
36
Appendix A
ACKNOWLEDGMENTS
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
38
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
41
43
Appendix C
TERMS OF REFERENCE
47
Appendix D
COMPANY VISITS
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.
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.
49
www.isletmedical.com
www.cognatebioservices.com
Scott R King
President
Alan K Smith
President and COO
50
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
51
Primogenix Inc
1640 Marengo Street
Suite 702
Los Angeles
CA 90033
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.
52
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
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.
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.
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.
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
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.
ICOC
Independent Citizens Oversight Committee
(CIRM, San Francisco, CA, USA)
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
pluripotent stem cell
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
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
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
pluripotent stem cell
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.
UCL
University College London (UK)
UK
United Kingdom
UKSCI
UK Stem Cell Initiative (DH, London)
undifferentiated
Not having changed to become a specialised
cell type.
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
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
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
66
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
2.2
2.3
2.4
12
3.1
27
3.2
29
4.1
35
68
69
70
71
72
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First published in December 2006 by Pera on behalf of the Department of Trade and Industry
Crown copyright 2006
URN 06/2092