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A SUPPLEMENT TO BIOPROCESS INTERNATIONAL
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March 2011 | Volume 9 | Supplement 1
Commercializing a New
Class of Biopharmaceuticals
MACS is a registered trademark of Miltenyi Biotec GmbH. Copyright 2011 Miltenyi Biotec GmbH. All rights reserved.
Enabling cells for therapy
macs-stemcells.com/ct
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t "EESFTTJOHBMMZPVSOFFETJOEFWFMPQNFOU
NBOVGBDUVSJOHBOEBOBMZTJT
Every cell therapy
process is unique.
....so is every
scale up solution.
NORTH AMERICA EUROPE ASIA PACIFIC
To nd out more call 866 969 3232, email info@invetech.com.au or visit www.invetech.com.au
Argos Therapeutics
An automated cellular and RNA processing system developed to manufacture
autologous immunotherapies to treat advanced kidney cancer (metastatic renal cell
carcinoma), B-cell chronic lymphocytic leukemia and HIV.
KBI Biopharma
kSep, a closed continuous centrifuge was developed to gently concentrate
capture and/or separate cells by providing a very low-shear and nourishing
environment.
Invetech is an innovative consulting and engineering service provider developing scale-up strategies, automated equipment and
consumables for the development and manufacture of biological products, including cell therapies. Combining a clients process knowledge
with Invetechs technology and automation expertise, systems are created to meet client specic requirements for quality, cost and scale-up.
Invetechs specialist capability across the full development journey, from idea to market, provides the condence needed to achieve a
successful commercial outcome.
Invetech. Successful cell therapy
commercialization solutions.
Developers of closed, automated solutions.
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2 BioProcess International MARCH 2011 SUPPLEMENT
VOLUME 9 SUPPLEMENT 1 MARCH 2011
From the Publisher and Editor . . . . . . . . . . . . . . . . . 3
PART 1: INTRODUCTION
Therapies of Tomorrow Require More Than
Factories from the Past . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
David James
PART 2: CLINICAL DEVELOPMENT, NEW PRODUCTS
Successful Commercialization Through Industry
Collaboration: An Interview with Robert Deans
of the International Society for Cellular Therapy.. . . . . . . .12
Maribel Rios
Opportunities in Regenerative Medicine:
The Global Industry and Market Trends . . . . . . . . . . . . . . . .14
R. Lee Buckler
Stem-CellBased Therapies: Whats in Development,
Implications for Bioprocessing . . . . . . . . . . . . . . . . . . . . . . . . .20
Robert Shaw
Technologies on the Cutting Edge . . . . . . . . . . . . . . . . . . . . . .26
Maribel Rios
PART 3: PROCESS AND PRODUCT DEVELOPMENT
Cell Therapy Bioprocessing: Integrating Process
and Product Development for the Next Generation
of Biotherapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Ralph Brandenberger, Scott Burger, Andrew Campbell,
Tim Fong, Erika Lapinskas, and Jon A. Rowley
Meeting the Challenges in Manufacturing
Autologous Cellular Therapies . . . . . . . . . . . . . . . . . . . . . . . . . .38
Tamara T. Monesmith
Industry Roundtable: Viewpoints on Processing,
Quality, and Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42
Maribel Rios
PART 4: BUSINESS ASPECTS
Addressing Business Models, Reimbursement,
and Cost of Goods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46
Dawn Driscoll
PART 5: INDUSTRY EDUCATION FOR THE FUTURE
Industry Educational Platforms Drive Commercialization
Objectives: An Interview with Tracie Lodie of the
International Society for Cellular Therapy . . . . . . . . . . . . . .50
Maribel Rios
Working Together for the Future: A Letter from the
Chair of the Alliance for Regenerative Medicine . . . . . . . .54
Gil Van Bokkelen
Cell Therapy Resources . . . . . . . . . . . . . . . . . . . . . . .56
ON THE COVER
Regenerative medicines
are in development for a
wide range of indications,
as seen in this design by
Yusef Ramelize and
Cheryl Scott using an image
from BioLife Solutions.
(WWW.BIOLIFESOLUTIONS.COM)
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MARCH 2011 BioProcess International 3 SUPPLEMENT
FROM THE PUBLISHER AND EDITOR
Building a Bridge to Commercial Success
The history of the biopharmaceutical industry is one of
continual invention and reinvention, of business models
that have adapted to weather uncertain product futures
and shifting economic fortunes. Some of us followed the
up-and-down (and often financially painful) progress of
monoclonal antibodies toward their eventual commercial
success a wealth of experience to draw from as other
classes of products make their way from laboratories and
onto the market.
The vast majority of regenerative medicines are still
produced at laboratory scale, with suppliers targeting the
current market: research hospitals and laboratories. These
therapies could transform our approach to healthcare
and have a profound effect on the biotechnology industry
as a whole. They have the potential to reap tremendous
commercial successes.
What has been lacking is a strategic bridge connecting
current lab-scale cell therapies to commercialization.
The core challenge faced by this market lies in securing
funding which in turn rests on the ability of
companies to present solid data to ensure and support
commercially viable processes. The days when business
plans were approved and money secured based on
exciting science and visionary stories (rather than
solid projections) are over. The economic downturn and
increased sophistication of potential investors have made
it harder for start-up companies to secure funding.
Funding is indeed available. But a company must
show a detailed business plan and corporate strategy
that express confidence in market opportunities, early
clinical successes, management transparency, and
disease amelioration as well as efficacy that compares
favorably with existing treatment modalities.
That is the purpose of this issue: To serve as an
educational bridge to help move cell therapies from
laboratory to commercial scales. BPI will therefore
continue to delve into the science, technology, and
business realities of regenerative medicine, a major part of
the biopharmaceutical industry that we support.
Hundreds of regenerative medicines are in
development, and a number of tissue therapies (regulated
for the most part as devices) are already doing well on
the market. The hoped-for tipping point may have been
reached in mid-2010 with the approval of Dendreons
Provenge cell therapy. That company continues to pave the
way by venturing into the reimbursement arena, helping to
educate regulators and policymakers, and clearing the path
for further innovative therapies. Companies poised on
the brink of commercial launch are leading by example to
show how business models for such therapies must diverge
from well-known protein/antibody models.
For regenerative medicine, cells themselves are the
product, and scale-out (rather than -up) is the task.
Commercial success for most such therapies cannot
rest on continuing to replicate the same manual cell
reprogramming processes over and over again. Few
if any of those processes are yet automated. One recent
example suggested that, to produce enough cells to treat
1,000 patients, you might need some 20 cleanrooms
with identical equipment and 100 staff. But to produce
enough of the same product to treat 10,000 patients, you
could need 200 cleanrooms with identical equipment
and 850 staff. Add to that the logistics involved in rapid
processing and shipment from and back to patients
of fragile and sometimes irreplaceable patient-specific
cells and an industry that initially looks familiar to
what we already know about bioprocessing becomes, at
commercial scale, something very very different.
So why is BPI publishing a cell therapy supplement?
First, we remind you of our tagline: Covering the whole
development process for the global biotechnology industry. BPI
focuses on the myriad processes of moving products from
discovery to production (not simply processing as a discrete
step). From the start weve looked at the entire scope
of the industry both CDER- and CBER-regulated
products waiting for a point at which the regenerative
industry is primed to go commercial.
Given the tremendous promise, the thought that
cell therapy companies might struggle to replicate the
hard-fought lessons of other industry segments is just
unacceptable. One essential task is to help educate
potential investors be they venture capitalists, private
investors, or pharmaceutical companies seeking to expand
their product portfolios through strategic partnering. Our
readers want to serve the needs of humanity; they are
passionate about the promise of eliminating the physical
and economic ravages of the most devastating diseases.
Without successful commercialization, however, ground-
breaking therapies cannot reach those who need them.
So we are delighted to introduce you to so many
dedicated people and the good work they are doing to
advance the future of healthcare. We are eager to help
this segment of the industry communicate with and
learn from the experiences of the others and thereby
help speed these life-saving products to the market.
And we are grateful to Bob Speziale and David James
of Invetech; Lee Buckler from the Cell Therapy Group;
and Jon Rowley of Lonza Walkersville the team who
encouraged us to develop this issue and advised us along
the way. We also thank Jane Arthurs, who introduced us
to the ISCT committees; the organizers of the Phaciliate
Cell and Gene Therapy Forum; and all the authors and
interviewees who assisted in putting this project together.
Brian Caine,
publisher
S. Anne
Montgomery,
editor in chief
4 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES INTRODUCTION
Therapies of Tomorrow Require
More Than Factories from the Past
by David James
L
ive cells are being
incorporated as active agents
and delivery vehicles for a
broad range of emerging
therapeutic strategies. Successful
commercialization of a cell therapy
requires more than proving its
safety and efficacy to regulators.
Ultimately a therapy must be
commercially viable, allowing
enough patients to be treated with
an adequate financial margin to
justify investment in it as a product.
Whether the cells used are
universal (allogeneic) or patient-
specific (autologous), it is unlikely
to be wholly one or the other that
will dominate (1).
Commercial viability of
conventional therapeutic products
rests on economies of scale.
Investment in plants, facilities, and
personnel can serve a significant
patient population with a defined
candidature profile for a given
therapy. Factories used to produce
high-volume products are based
around established, scalable processes
with batch-control and risk-
management strategies that focus on
monitoring product quality. A drug
manufacturer can change the
manufacturing process extensively
and analyze the finished product to
establish that it is the same (2).
By contrast, many emerging cell
therapies will serve relatively small
patient populations with
autologous therapies at the extreme,
requiring a discrete batch for each
patient. Furthermore, for biologics,
the product is the process. Because
the finished product cannot be fully
characterized in the laboratory,
manufacturers must ensure product
consistency, quality, and purity by
ensuring that the manufacturing
process remains substantially the
same over time (2). So attempts to
dedicate a conventional production
philosophy to producing small-batch
therapies involve huge investment in
cleanrooms and equipment that is
often dedicated to each single small
batch with robust segregation
policies and procedures (3). Facility
use is therefore poor, with extensive
change-over costs when equipment
is cleaned and prepared to switch to
the next product batch.
Processing technologies used
during cell therapy clinical trials are
typically based on manual laboratory
methods that are not optimized or
easily integrated for production.
Further, although many cell
therapies in development require
similar processes, in reality such
novel therapies often require equally
novel processing technologies.
Those processes also require
significant manual interaction by
highly trained, professional staff.
Bench-level cellular therapeutic
production in the preclinical stage
requires skilled and highly focused
personnel working for long hours in
cleanroom conditions.
If you watch a manual cellular
process, you will see many detailed
manual operations: transferring
f luids from vessel to vessel, taking
cell counts, controlled dilutions, and
so on (Photo 1). Even if those
cleanrooms are built and the staff
well trained, maintaining a level of
consistency and quality to satisfy
regulatory requirements and process
demands is challenging.
Consequently, many small-batch cell
therapies have manufacturing
processes that are not well suited to
a current good manufacturing
practice (CGMP) environment. The
cost of such therapies can be
prohibitive, and managing scale-up
to meet demand is a particularly
daunting proposition (Figure 1).
Autologous therapies appear to
hold the key to controlling
communicable disease transmission
and addressing the need for immune
suppression, both of which limit the
application of allogeneic cell
therapies. Despite those potential
Photo 1 WESTMEAD HOSPITAL WWW.SWAHS.HEALTH.NSW.
GOV.AU/WESTMEAD/INDEX.HTM
MARCH 2011 BioProcess International 5 SUPPLEMENT
benefits, high costs normally
associated with small-batch
manufacturing often compromise its
commercial viability and can be a
major disincentive to investors and
developers. Herein lies a conundrum
for many companies interested in
developing new cell therapies:
Traditional bioprocessing factories
are not appropriate for small-batch
processes. Consequently, many cell
therapies are developed using
technologies and procedures that are
inherently expensive and labor-
intensive and require a high degree
of skill, training, and management
to minimize deviations.
To develop alternative processes
that are scalable will typically require
significant investment over a
considerable period. To prevent
complications associated with
postapproval process changes, a new
process needs to be ready for use
before clinical trials are complete
well before it is certain that the
therapy will be approved for market.
Several cell therapy companies have
recognized the need to address this
issue. Accordingly some have invested
a proportion of funds allocated for
clinical trials to planning, developing,
and optimizing innovative,
customized solutions to their
manufacturing challenges.
THE ROLE OF QBD AND PAT
There is an obvious commercial
imperative for small-batch cell
therapies, but process changes cannot
be made without careful
consideration. Biological products can
be sensitive to very minor
manufacturing process changes. Even
relatively small process differences
can significantly affect the nature of
a finished product most
importantly, how it functions in a
patients body. When the process is
the product as would be the case
with industrialized production of
stem cells variability is the enemy
and must be reduced and controlled
as completely as possible (4).
Successful biological
manufacturing therefore addresses
scale-up, process comparability, and
process characterization. Because
cell therapy products cannot be fully
characterized in a laboratory,
manufacturers must ensure product
consistency, quality, and purity by
ensuring that their manufacturing
processes remain substantially the
same over time. So companies must
tightly control the source and nature
of their starting materials and
establish appropriate process
controls for each unique product
and/or manufacturing process.
Further complicating these
matters is the fact that during
research and early stage clinical
trials, most cell therapies and
associated process controls are
developed and produced for a
limited number of patients. They
use technologies that are readily
available rather than what will
ultimately be needed for
commercial-scale production.
Typically those are manual,
laboratory-scale technologies that
are not optimized for specific cells
or process needs.
Authors from Aastrom
Biosciences, Inc. (www.aastrom.com)
highlighted in 2008 the criticality of
batch failure for autologous therapies:
The risk that a process will fail to
yield a finished cell dose meeting
specifications must be extremely low,
whatever the reason. For PSCT,
manufacturing failure is not merely
an operational inefficiency issue;
Photo 2: Sterile connections
for a closed consumable
Photo 3: QC sample collection
for a closed consumable
Figure 1: Schematic representation of scale-up for a typical manual cell therapy process; as the
number of patients increases, so must the number of technicians to prepare their treatments
IND
10 patients
Phase 1
10 patients
Phase 2
20 patients
Phase 3
50 patients
Commercialization
100 patients 1,000 patients 10,000 patients
6 BioProcess International MARCH 2011 SUPPLEMENT
instead, it directly translates into a
failed patient treatment (5). By
adopting a quality by design (QbD)
approach to developing cell therapy
processes, we can identify and
address critical failure modes and
process parameters.
For example, one useful measure
of process risk is the number of sterile
connections that must be made
throughout cell therapy
manufacturing. In a typical manual
process, operators make multiple
sterile connections in a biological
safety cabinet (BSC) over several days
to add reagents, collect quality
control (QC) samples, and package a
final product. In one relatively simple
process we analyzed recently, we
counted 76 sterile connections, all of
which were performed manually.
Each connection carries an inherent
risk to the product. When patient
numbers are small, such risk is
theoretically manageable by skilled
operators using good standard
operating procedures (SOPs). But risk
to products is considerable in
commercial-scale production.
A natural consequence of the QbD
approach to redesigning such a process
would be to minimize the number of
manual sterile connections. In fact,
when this concept of minimizing sterile
connections is taken to the extreme, it
implies a process without any manual
sterile connections. It is therefore
hardly surprising that much innovation
in small-batch manufacturing for cell
therapies has revolved around using
presterilized closed consumables
(single-use technology).
Process analytical technology
(PAT) has been defined as a system
for designing, analyzing, and
controlling manufacturing through
timely measurements (that is, during
processing) of critical quality and
performance attributes of raw and
in-process materials and processes,
with the goal of ensuring final
product quality (7). This philosophy
for monitoring and controlling
product quality is independent of
batch size, and its implications can be
profound as those batch sizes reduce.
For example, consider QC for an
autologous therapy. Regulators are
likely to require that the same tests be
performed regardless of batch size.
Each QC sample must be a specific
volume to suit a given analytical
method. Due to economies of scale,
the volume of cells used for a large
batch and the subsequent cost of
performing QC tests are relatively
minor. However, for an autologous
therapy, such identical QC samples
are likely to represent a significant
proportion of the total cells available
and the total cost per patient.
Final-product release testing must
satisfy a difficult combination of
constraints. Such tests must be
rapid (for products with short
shelf-lives), relatively inexpensive
(because they must be performed
for every dose), limited in
necessary sample volume (to
prevent excessive loss of final
product), and able to test a
complex product composition. (5)
So for small batches, it is even
more important that we invest efforts
in characterizing processes so that we
understand precisely which
parameters need to be monitored,
controlled, and tested including
operating limits within which a
predictable outcome can be assured.
If we combine the need to take
samples for PAT and QC with the
objective to use closed consumable
processing, then we have a specific
small-batch requirement for which a
solution must be found. How do we
efficiently collect samples from the
right place, at the right time, without
affecting product sterility (Photo 2)?
CLOSED SYSTEMS
Segregation is the comprehensive,
verifiable isolation of an internal
process from external contamination
at all points in a processing system.
Figure 2: Typical elements of a closed and automated cell processing system
Disposable processing set
Intermediate patient-specifc
product
Reagents and bufers
Automated processing
platform in a Class C area
In-process quality control
sample processing
Patient-specifc product
output to incubation,
freezing, and so on
Batch record
Figure 3: Typical facility layout for closed and automated cell therapy manufacturing
Reagents Store
Consumables
Store
Reagents
Prep Suite
Incubation
Patient-Specifc
Materials Prep
Process Recovery
Suite
Processing
Room
Quality Control
Freezing
Waste
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8 BioProcess International MARCH 2011 SUPPLEMENT
All process equipment and materials
must be cleaned and sanitized or
sterilized between batches to prevent
contamination. Cleaning and
sanitization/sterilization processes
also need to be validated. Batch-to-
batch segregation represents a
challenge to all therapeutic
manufacturing processes. For small
batch sizes, however, the impact of
conventional cleaning and sanitizing
strategies on operating costs and
facility uptimes can be significant.
The bioprocess industry has
recently seen an emergence of
presterilized, closed-consumable kits
and associated equipment. These have
been used for achieving product
isolation in conventional cell culturing
processes. As closed-consumable
technology has matured and gained
acceptance, the same philosophy has
also been applied to several upstream
and downstream processes such as
closed, continuous centrifugation.
KBI Biopharma Inc.s (www.
kbibiopharma.com) kSep technology
is one recent example that illustrates
the potential of closed processing
and how scalability can be
addressed. The closed, continuous
centrifuge was developed to gently
concentrate, capture, and/or separate
cells by providing a very low-shear
and nourishing environment. The
kSep technology is being applied in
a single-use format to take
advantage of shorter cycle times,
fewer validation requirements, lower
processing costs, and minimal risk
from cross contamination.
Photo 4 shows two kSep variants
based on an identical core process
technology but capable of
significantly different throughput
rates. Using them, development
work can be performed at small
scale with confidence: If or when
larger-scale batches need to be
processed, a bioequivalent solution
will be available.
As mentioned, closed-consumable
kits enable us to address the risk of
contamination during manual
operations such as sterile connections.
Such kits are also effective for
ensuring batch-to-batch segregation.
For cell therapies, each process is
unique. They typically involve
collection and isolation, then culture,
expansion, and manipulation of cells
followed by harvesting, washing,
filtering, and concentrating them;
formulation and product filling,
storage, and transportation; and
finally administration to patients.
Assuming that a cell therapy process
can be designed so that it remains
closed throughout, implications on
cost and quality can be profound.
Because a closed consumable is sterile,
associated risk of contamination from
its environment can be considered
negligible. On that basis and
provided that a consumable remains
closed throughout the entire process
processing can be undertaken in
lower-grade cleanrooms. It also means
that different batches (provided that
they too are closed) can be
concurrently processed in the same
room. This could significantly reduce
the need to build and operate
expensive cleanrooms.
To realize the full potential for a
cell therapy using closed-
consumable processing therefore
requires a closed solution for every
manufacturing and QC step in the
process, and herein lies the
challenge. Although closed
processing solutions now exist for
some process steps, they are often
not ideally suited to the
manufacturing requirements of a
specific cell therapy and thus are
not readily integrated.
Reengineering a cell therapy process
to make it closed and satisfy all
requirements for a specific cell
therapy requires
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of the process and its critical
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capabilities of available technologies
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gaps and development of novel
solutions
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user-friendly, error-free process that
can be quickly and reproducibly
scaled to match demand (Photo 2)
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requirements for CGMP
manufacturing.
CLOSED AND AUTOMATED
CELL PROCESSING
How It Works: Cell therapy processes
including centrifugation, incubation,
media addition, cell selection, cell
washing, and final fill and finish can
be performed within closed
consumables (Figure 2). Machines
integrate and automate the processes
and replicate many qualitatively
controlled manual tasks. They also
provide consistent and operator-
independent quality. Because
processing is closed, automated
machines producing therapies for
different patients can be placed side-
by-side in a processing room, whereas
conventional open processing would
require a separate sterile environment
for each patients therapy.
Benefits delivered from an
automated, closed-cell processing
system would include significant
reduction in the cost of therapies
(typically 2590%) and the number of
operators required (typically >70%);
lowered dependence on skilled labor;
Photo 5: kSep closed continuous
centrifuge machines
Photo 4: Loading Argos Therapeuticss
automated RNA machine with a
closed consumable kit
MARCH 2011 BioProcess International 9 SUPPLEMENT
significant savings in capital
investment through better facility use
(typically 3050%); improved quality
and fewer quality events; and an
ability to more rapidly scale up and
scale out to match market demands.
An integrated cell therapy
manufacturing facility (Figure 3)
comprises a central processing room
containing several automated
machines that process multiple
patients and batches in parallel.
Around that are situated other
facilities and processes needed to
support those operations including,
supply, storage, and retrieval of input
and output materials including
reagents, disposable processing sets,
patient materials, finished products,
and waste; collection and processing
of QC samples for data capture and
process feedback; and a process
recovery suite. This allows use of
specialized facilities to be maximized
and enables rapid scale-up of
production to match demand.
SCALE UP OR SCALE OUT?
My company has been involved in
developing several automated systems
for both autologous and allogeneic
cell therapy processes. Despite
differences in the types of cells and
processes required to produce these
therapies, the scale-up challenges
they face are remarkably consistent.
Cost: Cell therapy batch sizes are
often small (especially for autologous
products), so applying conventional,
large-batch processing strategies is a
poor use of facilities. Large GTP/
GMP cleanroom facilities are
impressive and glamorous, but very
costly to build, and even more
expensive to operate (3). Dendreon
Corporation (www.dendreon.com),
which received US FDA approval for
its Provenge prostate cancer treatment
in 2010, specifically describes some
risks to scale-up:
The costs of expansion of our
facilities and investment in related
equipment has been and will
continue to be a very significant
expenditure for us during 2010
and 2011. In order to
commercialize Provenge, in the
event of licensure by the FDA, we
will need to hire and train a
significant number of employees
and comply with applicable
regulations for our facilities,
which are extensive. In addition
to the monetary costs of
expansion of our manufacturing
capabilities, the facilities
build-out requires significant time
and attention of our executive
management (6).
Automation: Most cell therapy
processes have been developed in a
laboratory. As a consequence, they are
manual and labor-intensive, and they
require a high degree of skill. This may
be logical and manageable during
research, but it would be considerably
more difficult for commercial-scale
production. Processing technologies
typically used during clinical trials
arent often optimized or easily
integrated for cell therapy production.
In a CGMP production environment
where the product is the process,
change is only possible under very strict
controls. Changing manual processes
into more efficient, automated
processes after regulatory approval is
often difficult, time-consuming, and
expensive. In fact, we have seen several
cases in which cell therapy companies
are committed to technology that
they know is suboptimal or, worse still,
no longer available.
A trained researchers mindset is
forever locked into the quest for
innovation and improvements as well
as the drive to act on new findings
in short to experiment. Minds
normally dedicated to investigating
unexplored elements at the forefront of
medicine would need to switch gears
to engage in operating a production
process that is reproducible, consistent,
and invariably repeatable. This
fundamental mismatch in mindset
would be a waste of talent and
training. Companies embarking on a
route to scale-up, unsurprisingly,
report worker dissatisfaction and
significant difficulties in recruitment
and retaining of staff.
Risk: The potential of cross
contamination and/or loss of patient
identity (chain of custody) for each
batch must be maintained at a zero
risk level as scale-out occurs (1).
Apart from the inherently high cost
of manual cell therapy processes, it is
therefore extremely difficult to
imagine how you could efficiently
scale up or scale out a manual process
without significant deviations. Up to
50% of batch failures are attributable
to operator error, and it is intuitive
that the increasing complexity of an
operation raises the likelihood of
errors occurring (1).
The primary strategy that
Invetech has applied to small-batch
processing is to create a new type of
factory in which manufacturing
processes are closed and the most
complex and vulnerable process
steps automated. With careful
design and a real-time quality
control system that detects
erroneous states before process
Figure 4: Typical development stages for cell therapies with closed, automated processing
IND
10 patients
Phase 1
10 patients
Phase 2
20 patients
Phase 3
50 patients
Commercialization
100 patients 1,000 patients 10,000 patients
Plan Develop, Prove
Roll Out
10 BioProcess International MARCH 2011 SUPPLEMENT
deviations are created, a
manufacturing process can thus be
created that achieves a commercially
viable cost of goods and eliminates
critical failure modes.
The system developed by Invetech
for Argos Therapeutics represents a
previously manual process that was
successfully redesigned based on the
guiding philosophy of closed-
consumable processing on an integrated
and automated production machine.
We developed an automated cellular
and RNA processing system to
manufacture autologous
immunotherapies for treating advanced
kidney cancer (metastatic renal cell
carcinoma), B-cell chronic lymphocytic
leukemia, and HIV infection. At the
heart of the automated process are
three standalone units: an RNA
processing subsystem (Photo 4) that
processes tumor homogenate into
amplified tumor RNA, with all steps
performed on a single patient sample
and taking place in a closed disposable
container; and two cellular units
designed to perform a series of cellular
and plasma processing steps to generate
a final product in functionally closed
disposable vessels.
The system removes complex and
vulnerable manual operations and
replaces them with automated
processing steps that can be
consistently reproduced. Each unit can
be validated and will perform precisely
the same function no matter where in
the world it is operating. This
substantially eliminates the most
significant contributor to variation:
operators. We now have a process that
can be scaled out to match demand by
installing additional, automated
machines in either the original facility
or in others that are located closer to
potential markets. By locking down
the process with automation and
closed consumables, we have also
significantly reduced the companys
reliance on hiring and training skilled
operators as well as the cost and time
required to establish dedicated
cleanrooms.
ROADMAP TO COMMERCIAL-
SCALE PRODUCTION
Cell therapy companies need to invest
in alternative technologies to ensure
that they can have commercially viable
products. However, it is also
important to recognize that funds are
typically precious during early stage
clinical trials. Until a therapy is
proven to be safe and efficacious, and
a reasonably mature process exists,
investment in highly customized
systems should be kept to a minimum.
But after phase 3 clinical trials using a
specific process are complete, changes
to that process can be extremely
difficult to make and will require
proof of bioequivalence or even
additional clinical trials.
Developing a customized CGMP
system will typically take two to four
years, depending on the complexity of
the process and the time it takes to
progress through development, clinical
trials, and capital raising. Invetechs
recommendation is to invest a
relatively small amount of effort and
money at phase 1 to identify the most
appropriate scale-up system and plan a
development strategy that includes
cost and timing (Figure 4). Another
primary objective of the feasibility and
planning stage is to identify core
technologies that can be used for
initial trials and subsequently scaled
up and integrated into a CGMP
commercial-scale production system.
Ideally, development of a
commercial production system should
commence during phase 1 or 2,
depending on the development time
scale and clinical trial schedule. At a
minimum, the key objective should
be to have a commercial-scale system
available during phase 3. This
ensures that those pivotal trials are
conducted using a process that is
equivalent to the commercial
production process, which prevents a
need to make expensive and time-
consuming postapproval changes.
Photo 6 shows one of the outputs
of such a feasibility study that my
company undertook for MolMed SpA
before commencement of phase 3
clinical trials for its TK therapy.
The product is an ex vivo cell therapy
to enable safe haematopoietic stem cell
transplants (HSCTs) from partially
compatible bone-marrow donors to
treat hematological malignancies,
particularly high-risk acute leukemia.
Debate will continue as to the
relative merits and likelihood of success
for allogeneic and autologous cell
therapies. Ultimately, the overall
commercial success of any such product
will depend on it being safe,
efficacious, cost-effective, and scalable.
It also needs to be affordable and
accessible to a substantial patient
population. For some companies,
allogeneic cell-based therapies are
attractive because they reflect the
current large-batch pharmaceutical
investment model and have been
supported on this basis. However, not
all allogeneic therapies would be
considered large-batch products. Many
autologous therapies could provide
significant therapeutic advantage.
At Invetech, we believe that for
the cell therapy industry to reach its
full potential, it must have
commercially viable small-batch
processing and ideally the ability
to deal with a batch size of one
(patient). Some cell therapy
Photo 6: A closed and automated system
from a feasibility study undertaken for the Italian
company MolMed SpA (www.molmed.com)
C
For the cell therapy
industry to reach its
full potential, it must
have commercially
viable small-batch
processing and
IDEALLY
the
ability to deal with a
batch size of one.
companies have already invested in
developing innovative closed,
automated systems for small-batch
cell therapy manufacturing. Those
systems have delivered significant
cost, quality, and scale-up benefits
over existing manual, cleanroom-
based processing strategies. They
have also provided valuable insight
into the industrys needs and
demonstrated what is possible.
Cell therapy no doubt is an
extremely exciting and rapidly
advancing field of medicine that
could have a significant impact on
how we treat a vast array of diseases.
To reach its full potential, however,
the technology will require more
than old-fashioned factories. Closed
and automated cell-processing
systems provide an opportunity to
change the paradigm and deliver
these therapies at a cost that was not
previously thought possible.
REFERENCES
1 Mason C, Dunhill P. Assessing the
Value of Autologous and Allogeneic Cells for
Regenerative Medicine. Regen. Med. 4(6)
2009: 835853; www.slv.vic.gov.au.
2 How Do Drugs and Biologics Differ?
Biotechnology Industry Organization:
Washington, DC, 2010; www.bio.org/
healthcare/followonbkg/DrugsVBiologics.asp.
3 Burger SR. Design, Operation and
Management of GTP/GMP Cell
Engineering Facilities. BFDA 2007
International Symposium on Regulation of
Human Cell- and Tissue-Based Products.
Taipei, Taiwan, 3 October 2007; www.ac-gt.
com/talks/Dec 2010.
4 Shaw R. Industrializing Stem Cell
Production. BioProcess Int. 8(9) 2010: 1015;
www.bioprocessintl.com/journal /2010/
October/Industrializing-Stem-Cell-
Production-303899.
5 Hampson B, Rowley J, Venturi N.
Manufacturing Patient-Specif ic Cell
Therapy Products. BioProcess Int. 6(8) 2008:
6072; www.bioprocessintl.com/
journal /2008/September/Manufacturing-
Patient-Specif ic-Cell-Therapy-
Products-183198.
6 Form 10-K Annual Report Pursuant to
Section 13 or 15(d)of the Securities Exchange
Act of 1934. Dendreon Corporation: Seattle,
WA, 31 December 2009; http://f iles.
shareholder.com/downloads/
DNDN/1125257529x0x420918/E230B7F2-
3912-4F73-AD30-9208DA7DBA53/
ar_2009.pdf.
7 CDER/CVM/ORA. PAT Guidance for
Industry: A Framework for Innovative
Pharmaceutical Development, Manufacturing,
and Quality Assurance. US Department
of Health and Human Services, Food and
Drug Administration: Rockville, MD,
September 2004.
FURTHER READING
Mason C, Hoare M. Regenerative
Medicine Bioprocessing: Building a
Conceptual Framework Based on
Early Studies. Tiss. Eng. 13(2) 2007;
www.slv.vic.gov.au Nov 2010.
C
David James is director of life science
and pharmaceutical manufacturing
innovation for Invetech Pty. Ltd., 495
Blackburn Road, Mount Waverley,
Victoria 3149, Australia; 61-3-9211-7742;
david.james@invetech.com.au,
www.invetech.com.au.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download a low-resolution PDF online
at www.bioprocessintl.com.
n
e
t
h
e
p
o
GE Healthcare
Life Sciences
GE, imagination at work and GE monogram are trademarks of General Electric Company.
WAVE Bioreactor and Ficoll-Paque are trademarks of GE Healthcare companies.
All third party trademarks are the property of their respective owners.
2011 General Electric Company All rights reserved. First published Feb 2011
GE Healthcare Bio-Sciences AB, Bjrkgatan 30, 751 84 Uppsala, Sweden
GE Healthcare at the ISCT Meeting in Rotterdam
May 23 25, 2011
Visit our booth for a demonstration of automated expansion of cells in suspension using
the WAVE Bioreactor

System 2/10
Also featuring
= Ficoll-Paque

PREMIUM products for preparation of mononuclear cells


= StemSource

900/MB

for adipose derived stem cell concentration
= AXP AutoXpress

Platform for cord blood processing


= Res-Q

60 BMC for bone marrow concentration


12 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES COMMERCIALIZATION
Successful Commercialization
Through Industry Collaboration
An Interview with Robert Deans of ISCT
by Maribel Rios
N
early a year ago, the
International Society for Cell
Therapies (ISCT) decided to
integrate industry into its
organization to build a stronger
platform for commercializing
therapies. Robert Deans, vice
president of regenerative medicine at
Athersys, was invited to serve as a
leader of ISCTs Industry Task Force,
which aimed to identify industry roles
in its organization. Within two
months, the task force invited industry
members and chartered a white paper
(1) that described how ISCT should
go forward. As a result, its
Commercialization committee was
formed.
Deans currently serves as
Commercialization committee chair,
with co-chairs Richard Maziarz
(Oregon Health and Science
University) and Francesco Lanza
(Hospital of Cremona, Italy). This
committee aims to set specific
benchmark objectives for the
relationship among industry,
academia, regulators, and ISCT
members this year. Along with ISCT,
it is also committed to forming an
Industry Community, an advisory
panel of industry representatives.
These two organizational units are set
up to foster industrys role in
commercializing cell therapies. The
committee is further organized into
four subcommittees, one of which is
Clinical Development and New
Product Introduction, chaired by
Deans. During a BPI interview, he
described the objectives of both and
provided his view on key questions.
BPI: What are the goals of the Clinical
Development and New Product
Introduction subcommittee?
RD: We focus on bringing global
regulatory agencies together with key
translational medicine opinion leaders
in academia and industry. In
workshops and focus groups, these
experts are tasked with identifying
commercialization hurdles in specific
therapeutic areas. These efforts
include identifying or setting
standards for cell characterization so
that investigators can distinguish
among competing or alternative cell
therapy products. They also include
evaluating current clinical trials and
clinical endpoints in trial designs so
that people can share lessons learned
from existing studies. The
subcommittee makes
recommendations to regulatory
agencies on standardized preclinical
models and clinical endpoints that are
best suited to evaluate the
effectiveness of cell therapy in these
new trials. And, most important, we
provide pharmaceutical companies and
healthcare companies with a risk
measurement for entry into this
therapeutic space.
BPI: What is needed to standardize
preclinical models and safety assessments
in certain disease areas?
RD: It involves committing to an
animal model with standardized
surgical or other procedures for
inducing disease; setting standards for
the number of animals in groups and
the types of controls that should be
run; and setting standards for
establishing a dose response in a cell
therapeutic so that you get a valid
interpretation of potency of a cell
population.
For example, probably three to six
groups are using adherent stem cells
like mesenchymal stem cells (MSC)
for treating stroke these are just
coming into the clinic. There are
many different rodent models, both
mouse and rat, available for testing
cells for their efficacy in treating
stroke, and they differ by degree of
damage and by type of behavioral
readout that is observed.
Investigators differ in how they
analyze tissue for safety or for
WWW.PHOTOS.COM
MARCH 2011 BioProcess International 13 SUPPLEMENT
physiological improvement. So one
task for ISCT through the new
products subcommittee meetings is
getting regulatory agencies to meet
academic thought leaders and industry
participants who are filings
investigational new drug applications
(INDs) to proceed clinically. The
subcommittee wants them to debate
and agree on the most effective animal
model to show a certain property.
This will encourage the FDA to start
to mandate a consistent standard in
testing a certain disease state, and
both academia and industry will be
aware in advance of expectations. As a
result, they can streamline their
development process.
BPI: How would you describe current
developments of cell therapies?
RD: Many new exciting cell
therapies have come forward and are
now entering either phase 2 or phase
3 pivotal commercialization trials.
Many of these are driven by
biotechnology companies that have
limited capital and are focused on
showing proof of mechanism for in
principle the effectiveness of a
therapy. But they lack the capital to go
through a pivotal approval trial, which
is a late-stage, very large clinical trial.
Because cell therapeutics have so many
properties in manufacturing and in
function that are different from drugs
or biologics, the pharmaceutical
industry and the healthcare industry
have been averse to investing in these
late-stage trials.
ISCT and the Commercialization
committee are trying to present a
scientific perspective and a regulatory
perspective to reduce the risk and
encourage investment. That is
probably one of the key endeavors of
the clinical development
subcommittee: to adopt an open-code
development philosophy. We are
encouraging industry members and
academics to make their trial design
and their trial data open for all to
share, and then use that to foster and
educate big pharma so that we can
reduce their risk to invest in these
trials. Were really trying to stimulate
both intellectual investment and
financial investment in later stage cell
therapy.
BPI: How is the committee conducting
the necessary risk analysis?
RD: We hold forums of 2050
participants who debate around those
topics. We structure a point
counterpoint type analysis and publish
the outcome in the appropriate
therapeutic society journal. Before
bringing this concept into ISCT, this
is something that we have been
involved with in the areas of stroke
and solid-organ transplant. It has been
quite successful.
BPI: Would you consider regulatory
issues in your list of potential roadblocks
or necessary areas of understanding?
RD: Yes we would, particularly with
heterogeneity in the global regulatory
environment. It is very important to
understand the regulatory
environment in different geographies
so that you can optimize your patient
accrual and trial design accordingly.
An extension to this relates to
understanding regional differences in
standard of care. Healthcare
management prior to and following
treatment is a significant variable in
outcome determination and may
confound clinical interpretations in a
global study. ISCT aims to bring
these issues forward as part of their
global initiative for commercialization.
BPI: What are some of the
misconceptions about cell therapies?
RD: There is still confusion in the
lay public between embryonic stem
cells and adult cell therapies. So it is
important to continue to educate about
cell strategies currently available. There
is also a big gap in knowledge around
development cost and product cost for a
cell therapy, and a very big gap in
anticipating the reimbursement
likelihood for some of these emerging
therapies. Industry doesnt know how
much the reimbursers the insurance
companies and the medical providers
are willing to pay for certain
therapies. And they are also not clear
on what it is truly going to cost in
terms of a manufacturing platform to
produce these therapies. That is a very
important aspect of cross-education
and trying to bring issues into an open
forum.
BPI: What is needed to for an efficient
manufacturing process?
RD: There is still quite a way to go,
both in the context of autologous cell
therapies and allogeneic cell therapies.
With autologous therapies, in part, its
the cost of production. A major
expense is individualized production
hardware and lot release testing. In
allogeneic cell therapy you can
generate many clinical products from
one manufacturing run. The same
cost for lot-release testing is averaged
out over all of the products, so your
overall costs decrease significantly.
That is one of the biggest issues for
the business model discrepancies
between autologous and allogeneic cell
therapies.
BPI: What is the Commercialization
committee working on right now?
RD: We just finished our first
workshop on cell therapy in peripheral
vascular disease (mid-January) with a
cardiovascular conference in New
York City. We had about 10 industry
representatives present and about an
equal number of key opinion leaders
as well. Our next workshop is going to
be on allogeneic bone marrow
transplant and managing graft-versus-
host disease. We have a venue but
have not made a public announcement
for this focus group yet. The event we
are having after that is on the use of
biomaterials in solid organ
transplantation, to be held at the
ISCT annual meeting in Rotterdam.
Our fourth workshop is planned to
focus on inflammatory bowel disease,
which is scheduled to be held in June
2011. All of these have a balance of
academic thought leaders, regulatory
agency representatives, and industry
participation.
REFERENCE
1 Deans R, et al. A Changing Time: The
International Society for Cellular Therapy
Embraces Its Industry Members. Cytotherapy
12, 2010: 853856.
C
Maribel Rios is managing editor of
BioProcess International, 1-646-957-8884,
mrios@bioprocessintl.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808,
ext. 154. Download a low-resolution PDF
at www.bioprocessintl.com.
14 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES COMMERCIALIZATION
Opportunities in
Regenerative Medicine
The Global Industry and Market Trends
by R. Lee Buckler
C
apitol Hill fly-in days (see the last
page of this issue) . . . A focus of
Google Ventures (www.google.
com/ventures) . . . A favored new
investment arena for GEs CEO Jeffrey
Immelt, the recently named head of
President Obamas economic recovery
advisory panel, and Life Technologies
Greg Lucier . . . Hardly a day skipped
without a major news publication
covering some exciting aspect of the science
. . . The provocative cover of Wired
magazines (www.wired.com/magazine)
November 2010 issue . . .
It all sounds like the stuff of a
major blockbuster industry, but that
was regenerative medicine (RM) in
2010. Some people may see this as
unfounded hype very divorced from
commercial reality; others view it as
warranted attention. The general
consensus is that a large gap remains
between the commercial promise and
reality of the cell therapy sector of
regenerative medicine. Given the
paucity of revenue, rarity of
profitability, relative scarcity of
venture capitalists interested in early
stage companies, and a general feeling
within the industry that were still
waiting for our first tranche of real
success stories, most believe that the
RM industry is still truly nascent. It is
probably not quite as nascent as many
might perceive, but its nowhere near
the powerhouse others might
understandably sense given all the
buzz. Here I present some metrics on
which you can base your own
judgment.
DEFINITIONS
Here I largely focus on cell therapies,
which I will simply define as
therapeutics that involve and include
live cells but not basic, hospital-based,
stem cell transplantation. Cell therapy
represents several existing and potential
business models with as yet little
industry precedent or consensus. They
are, however, easy enough to understand
conceptually. Focusing strictly on the
therapeutic side of the industry (rather
than companies offering devices, tools,
ancillary services, and so on), the
business models include
tDPNQBOJFTUIBUMPPLBMPUMJLF
traditional biopharmaceutical
organizations
tPUIFSTCBTFENPSFPODMJOJDBM
services than has heretofore been the
case for biopharma
tBOETUJMMPUIFSTUIBUNJHIUMPPLB
lot more like medical device
companies although they are
bringing innovative therapies to
market.
Cell therapy fits within the large
and even more diverse RM industry.
RM is typically described as having
four primary pillars: cells, devices,
biomaterials, and bioactive agents
(reagents, drugs, and biologics). Their
common goal is to replace, repair, or
regenerate human cells, tissues, or
organs in such a way as to restore or
establish normal functions. If cell
therapy is about delivering cells as
therapeutics, I often refer to RM as
being about affecting cells (including
whole tissues or organs) whether
through their delivery (cell therapy) or
their in vivo recruitment and/or
manipulation through molecular or
other means.
SOME INDUSTRY METRICS
Regenerative medicine is already
commercially available and entrenched
into several types of American and
Western European clinical practice:
tissue engineering (e.g., skin repair/
wound healing), orthopedics (e.g.,
spinal disc and joint cartilage repair),
diabetes (e.g., islet cell
transplantation), oncology/hematology
(e.g., stem cell transplants),
ophthalmics (e.g., limbal stem cell
deficiency, corneal disease, and so on),
and cosmetic/aesthetic (e.g. body
sculpting). Cell Therapy Group tracks
products that are commercially
available and in the development
pipeline (under clinical investigation
or the subject of late-stage preclinical
development). Our industry metrics
are limited to industry-sponsored
Apligraf bilayered skin is an established
regenerative medicine product from
Organogenesis, Inc. WWW.APLIGRAF.COM
MARCH 2011 BioProcess International 15 SUPPLEMENT
trials and may not accurately capture
products in early stage trials, where
industry sponsorship is less than
transparent.
What follows is based on CTGs
data. For another perspective, you can
view the presentations given at a
January 2011 regenerative medicine
briefing hosted by the Alliance for
Regenerative Medicine at the BioTech
Showcase during a JP Morgan
conference (www.alliancerm.org/
presentations.html).
Products: Some 275 therapeutic
companies with about 240 cell-based
therapies are currently on the market
or in some stage of clinical
development. These therapies can be
roughly broken down as follows: ~77
in phase 1, ~89 in phase 2, ~27 in
phase 3, and ~44 are commercial
(marketed in at least one country).
On the books, we are tracking
what we believe is a fairly accurate
total of 27 phase 3 or pivotal cell
therapy industry-sponsored products
in clinical trials: 15 autologous (58%),
three allogeneic, three allogeneic
autologous combinations, three
allogeneics with devices, one
allogeneic with gene modification, one
allogeneicautologous combination
with a drug, and one autologous with
gene modification. About half those
products are fresh in their final
formulation (predominately the
autologous ones). Seventeen of the 27
are being developed by companies
based in the United States, with the
remainder in Europe and Asia.
When you scrutinize that list for
typical signs of commercial life, only
10 of those trials can be considered
active by any measure. These can be
broken down as follows: six autologous
(5860%), two allogeneic, one
allogeneic with gene modification,
and one allogeneicautologous
combination with a drug. Six of these
are being developed by companies
based in the United States.
Industry-sponsored cell therapies in
phase 3 pivotal trials are almost 1:2
allogeneic over autologous products.
Industry-sponsored cell therapies in
all phases of clinical development are
roughly 1:1.5 allogeneic over
autologous products. Our early
analysis of late-stage preclinical
studies appears to suggest that the
ratio is reversed (~1.4:1), allogeneic
over autologous.
Only 3035% of currently
marketed therapies (~1316) have
required and received regulatory
approval. By contrast, we estimate that
~90% of therapies in development are
products that will require premarket
approval. Although ~70% of therapies
currently marketed were not required
to obtain regulatory approval when
they were brought to market (and may
still not now), this is not a statistical
trend expected to continue. It is an
artifact of a commercial environment
that existed in a relative regulatory
vacuum for these types of therapies
certainly a different regulatory
framework from what now exists.
For instance, marketed cell
therapies under EMA jurisdiction are
now in a transitional status. With the
exception of the ChondroCelect
cartilage repair product from Belgian
company TiGenix NV (www.tigenix.
com), none of these received EMEA
approval under the new advanced
therapy techniques and products
(ATMPs) regulatory framework. Even
previously state-approved cell
therapies that are currently available
commercially will have to be
confirmed either as falling within the
nonmedicinal classification (allowing
them to fall outside the new
regulation requiring marketing
approval) or be transitioned under the
ATMP regulatory framework. The
latter products will have to comply
with ATMP regulations no later than
30 December 2011 or 2012
(determined by an applicable ATMP
category). Market approval
applications (MAAs) with supporting
scientific, clinical, and manufacturing
data will have to be submitted for
those to continue on the market.
To date, the EMA has reviewed
seven ATMP MAAs thus far. One
was approved (the ChondroCelect
cartilage product by Tigenix, www.
tigenix.com), and another was still
under evaluation as of December
2010. I suspect the latter is the
Glybera gene therapy for lipoprotein
lipase deficiency by Amsterdam
Molecular Therapeutics (www.
amtbiopharma.com). The others were
rejected or withdrawn. I believe that
Ark Therapeutics (www.
arktherapeutics.com) Cerepro gene
therapy would be one of those rejected
but have no data or speculation as to
the others rejected or withdrawn.
Some have speculated that one of
those might have been Cellerix (www.
cellerix.com) beginning to file but
then withdrawing for Ontaril cell
therapy, which was in a phase 3 trial
to treat complex perianal fistulas not
associated with Crohns disease. But
we have seen no data to confirm or
deny that speculation.
About 80% (or ~35) of the nearly
four dozen marketed cell therapies
worldwide fall into one of two
categories: cartilage and skin (wound,
ulcer, and burn) repair. The Skin
Repair box lists marketed skin repair
cell therapies, for example. Here are
the cell therapies that are marketed,
sold, and provided in the United States:
A 2001 prcmarkct approval
application (PMA) for the Dermagraft
cryopreserved human fibroblast-
derived dermal substitute from
Advanced Biohealing, Inc. (www.abh.
com) was approved by the US FDAs
Center for Devices and Radiological
Health (CDRH).
SKIN REPAIR CELL THERAPIES
ON THE MARKET
Apligraf (Organogenesis, Inc.)
Bioseed-S (BioTissue Technologies,
GmbH)
CellSpray (Clinical Cell Culture)
Dermagraft (Advanced Biohealing, Inc)
EPIBASE (Laboratories Genevrier)
Epicel (Genzyme Biosurgery)
EpiDex (Modex Therapeutiques)
Hyalograft 3D (Fidia Avdanced
Biopolymers)
J-TEC artificial skin ChondroCelect
(TiGenix)
Laserskin (Fidia Advanced Biopolymers)
MySkin (York Pharma)
OrCel (Ortec International, Inc.)
PolyActive (HC Implants, BV)
TissueTech Autograft System: Laserskin
and Hyalograft 3D (Fidia Advanced
Biopolymers)
16 BioProcess International MARCH 2011 SUPPLEMENT
8ioTissuc, !nc. (www.biotissuc.
com) lilcd a 2003 510(k) prcmarkct
notilication ol intcnt to markct lor its
Prokcra dcvicc bascd on
cryoprcscrvcd amniotic mcmbranc
that was approvcd by thc CRH as a
class !! mcdical dcvicc.
Although thc originator company
Forticcll 8ioscicncc (www.
lorticcllbioscicncc.com) is rcccntly
bankrupt, its 2001 PMA lor rCcl
bilaycrcd ccllular matrix was approvcd
by thc US FA CRH.
Gcnzymc Corporation's (www.
gcnzymc.com) 2007 humanitarian
dcvicc cxcmption (H) application
lor piccl culturcd cpidcrmal
autogralts was approvcd by US FA
CRH. Thc company's 2007
biologics liccnsc application (8LA)
amcndmcnt lor its Carticcl kncc
cartilagc trcatmcnt was approvcd by
US FA's Ccntcr lor 8iologics
valuation and Rcscarch (C8R).
rganogcncsis, !nc. had a 2000
PMA approvcd by thc US FA
CRH lor Apligral woundhcaling
trcatmcnt.
!n 2010, cndrcon Corporation
(www.dcndrcon.com) rcccivcd 8LA
approval lrom C8R lor thc Provcngc
autologous ccllular immunothcrapy.
Somc pcoplc might includc thc
photophcrcsis systcm lrom Thcrakos,
!nc. (www.thcrakos.com) in that list
bccausc it dclivcrs a ccllbascd product
that is manipulatcd cx vivo likc thc
stcm ccll dcvicc lrom Cytori
Thcrapcutics (www.cytoritx.com).
Nonccllular RMs on thc markct
includc NcuroMcnd and NcuroMatrix
products lrom Collagcn Matrix !nc.
(www.collagcnmatrix.com), Hclitcnc
absorbablc librillar bovinc tcndon
collagcn, NcuraGcn and Ncurarap
collagcn ncrvc guidcs, TcnoGlidc and
!ntcgra crosslinkcd collagcnGAG
scallolds, !ntcgra mcshcd bilaycr
wound matrix and dcrmal
rcgcncration tcmplatcs, and MZA!K
and !ntcgra S collagcn and
Ctricalcium phosphatc scallolds, all
lrom !ntcgra Lilc Scicnccs (www.
intcgralilc.com), Unitc stabilizcd
cquinc dcccllularizcd pcricardial
biomatrix lrom Pcgasus 8iologics
(www.pcgasusbio.com), and AxoGcn
and A\ANC dcccllularizcd human
pcriphcral ncrvc products lrom
Axogcn, !nc. (www.axogcninc.com).
Companies and Revenue: Lcss than
20 ol ccll thcrapy companics arc
currcntly public. About a quartcr ol
thosc with a ccll thcrapy in clinical
dcvclopmcnt havc multiplc products in
clinical dcvclopmcnt. About 25 ol
companics arc still in thc prcclinical
stagc with thcir lcad product.
Most industry analysts agrcc that
thc RM markct surpasscd thc 81
billion mark in thcrapcutic salcs in
2007. Tablc 1 lists thc top tcn RM
products sortcd by cstimatcd
worldwidc rcvcnuc that ycar (1).
According to a 2008 rcport, only two
RM products gcncratcd morc than
8100,000,000 in rcvcnuc !nlusc by
Mcdtronic and Allodcrm by Lilcccll
and ncithcr has a ccllular
componcnt (1). nly onc ol thc top
livc products in thc scctor is composcd
ol cclls: Gcnzymc's Carticcl trcatmcnt
lor kncc cartilagc rcpair. Although
livc ol thc top 10 RM products arc
ccll bascd, thcy account lor a total ol
only ~8165,000,000 in annual
rcvcnuc. Togcthcr, thcy would not
qualily as a top 200 drug on thc
markct lor 2007.
8ascd on cstimatcs lrom thc
cumulativc numbcrs ol units
manulacturcd and paticnts trcatcd . . .
as wcll as lrom discussions with scnior
industry cxpcrts," a morc rcccnt rcport
valucs thc currcnt RM ccll thcrapy
markct at ~8100200 million pcr ycar
(2). 8y lar thc largcst contribution to
that comcs lrom thc Apligral skin
product. !n thc Unitcd Statcs, on
avcragc, oncc cvcry two minutcs
Monday through Friday, a paticnt is
trcatcd with it (2). And according to
Table 1: Worldwide top 10 regenerative medicine commercial products
Company
Brand
Name Product Type
Therapeutic
Area Indication Launch 2007 Revenue
20062007
Revenue
Growth
Advanced
Biohealing
Dermagraft Allogeneic neonatal
cells with matrix
Skin Diabetic skin ulcers 1997 ~$20,000,000 >10%
Cytori Celution Autologous cell-based
product
Soft Tissue
(adipose)
Reconstructive breast
surgery
2008 ~$10,000,000
~$12,000,000
NA
Genzyme Carticel Autologous cell-based
product
Cartilage Knee repair 1995 ~$83,000,000 ~30%
Integra Life
Science
Various Allogeneic accellular
matrix
Skin Skin repair and replacement 2001 ~$20,000,000
each
25%
LifeCell Alloderm Allogeneic accellular
matrix
Skin Skin replacement and
hernia repair
1994 $167,100,000 40%
Medtronic Infuse Growth factor with
matrix
Bone Spinal, orofacial, and open
tibial fractures
2002 ~$700,000,00 18%
Organogenesis Apligraf Allogeneic neonatal
cells with matrix
Skin Diabetic skin ulcers 1995 ~$30,000,000 >10%
Osiris/Nuvasive OS100001 Allogeneic cell-based
products
Bone Fracture repair 2005 $15,200,000 83%
RTI Spinal
implants
Allogeneic accellular
matrix
Bone Spinal fractures 1991 $11,100,000 17%
Stryker OP-1 Growth factor with
matrix
Bone Spine fusion and long-bone
fractures (humanitarian
device exemption)
2005 ~$80,000,000 60%
You can see it at INTERPHEX, Booth 1734.
18 BioProcess International MARCH 2011 SUPPLEMENT
Mason and Manzotti, an estimated
675,000 RM cell therapy units have
been manufactured as of 31 March
2010, with some 323,000 patients
treated by those same products over
the same period (2).
OBSERVATIONS AND QUESTIONS
Draw what conclusions you may from
the metrics listed here. There are
some trends worth noting and some
questions worth asking.
Pharmaceutical, biopharmaceutical,
life science, and healthcare companies
are investing heavily in strategy and
modestly/cautiously with their money
in regenerative medicine. However,
with a few exceptions (e.g., Genzyme
and Celgene Corporation, www.
celgene.com), biotherapeutics
companies are notably absent in these
ventures. Governments and
nongovernmental organization are
investing heavily. Strategic investors
(e.g., Google Ventures) have begun
participating in the sector. And
disciplines and companies outside the
industry are beginning to make larger
impacts on regenerative medicine: e.g.,
process engineers, mechanical
engineers, manufacturing
technologies, genomics, imaging
technology, cosmetics/aesthetics, and
so on. Despite evidence to date that
cell therapies are not (compared with
predecessor biotherapeutics) cheaper
or faster to develop, do not fail less in
development, and have yet to produce
profound clinical efficacy over
standard care, their promise to cure
conditions we currently treat only with
palliative care continues to engender
great enthusiasm.
Will our institutional, educational,
and commercial paradigms allow cell
therapy and regenerative medicine to
take advantage of the different world
in which they are being developed to
advance these therapies differently
than their predecessors? This is a
world of personal genomics (the $100
genome is on its way), bioinformatics,
personal connectivity and social
media, adaptive clinical trial designs,
personalized medicine (diagnostics,
biomarkers, theranostics), healthcare
reform, aging demographics, increased
heal insurance pressure, and workplace
virtualization obviating much need for
physical infrastructure. Can
companies afford not to adapt
traditional biotherapeutic development
paradigms, given the increasing
financial pressures they face and
constraints on the old blockbuster
model? How will medical tourism and
insurance incentives to drive
treatments off-shore affect the
industry? And what will be the
Xenotransplantation applies living cells, tissues, or organs from
one species to another, most familiarly from pigs to humans.
Before introduction of recombinant proteins in the 1980s,
porcine-derived insulin was the most common treatment for
diabetics. Researchers have extrapolated a cell therapy based
on the idea of implanting porcine pancreatic cells that make
insulin (www.dailymail.co.uk/sciencetech/article-1201672/
Experimental-diabetes-treatment-inject-humans-pig-cells.html).
The concept of cellular xenotransplantation faces many
challenges, including the potential for zoonotic disease
transmission or endogenous retroviruses and the fact that most
animals have shorter lifespans than humans, so their tissues age
at a different rate. Currently there arent many published cases
of success beyond preclinical reports.
Perhaps the greatest obstacle faced by any company choosing
to invest in cellular xenotransplantation would be public
perception. Even when cells are genetically engineered to
prevent immune-system rejection issues, and even if concerns
over zoonoses and aging were addressed, the very idea of
animal cells used in this way might be intolerable to most
people. And some 20th-century quackery may have set the
wrong stage, as well.
Dangerous Dealings: The first recorded attempt at cellular
therapy occurred in 1912 when German physicians attempted
to treat hypothyroid children with thyroid cells. An American
physician named John R. Brinkley began in 1917 to implant
men with tissue from the testicles of young goats, saying it
would help with impotence/infertility and cure a wide range of
ailments. Ultimately Brinkleys license to practice medicine was
revoked. In the 1930s, Dr. Paul Niehans, called by some the
father of cell therapy began offering rejuvenation therapy
(injecting animal cell suspensions) to those who could afford it
at his expensive clinic in Switzerland (www.quackwatch.
com/01QuackeryRelatedTopics/Cancer/cellular.html). That clinic
and others are still in business today.
In 1970 Wolfram Khnau, an associate of Niehans, began using
similar methods to treat cancer patients in Tijuana, Mexico. He
claims to have helped those with Downs syndrome, Alzheimers
disease, epilepsy, and HIVAIDS, among other conditions. And
now a naturopath named James L. Wilson is promoting
products made from bovine mesenchymal cells. He says they
can migrate to any tissue in need of repair. Wilson even
administers the cells under his patients tongues never mind
that the digestive systems primary function is to break down
cells, tissues, and proteins into their usable components, not
letting them migrate intact through the body. There is little
discussion, as well, about human immune systems identification
and elimination of foreign bodies such as cells from other
species injected into the bloodstream.
And then theres sicca cell treatment, also known as cell, dry cell,
or fetal cell therapy (www.ds-health.com/cell.htm). First given to
children with mental retardation in the 1950s, the product
consists of lyophilized cells from the organs of fetal cattle and
sheep. These animal cells are also said to magically migrate to
where they are needed. The potential adverse effects of such
injections are numerous: from anaphylaxis to prion disease.
The public should not confuse valid cellular therapies with all that
nonsense. Unfortunately, however, a lay person searching the
Internet for information about cellular therapies (whether xeno- or
allo- in nature) is just as likely to come across claims of the above
as they to find data from the latest GMP-backed clinical trial or
press release about an FDA approval. Charlatans like to adopt
scientific-sounding language, but instead of regulatory
compliance, they back up their claims with conspiracy theories
portraying themselves as victims of a medical industry smear job.
That makes it hard to counter their claims without seeming like
just the bullies theyre talking about. Its a fine line to walk, but
legitimate companies must take steps to separate themselves
from purveyors of modern-day snake-oils.
Cheryl Scott, senior technical editor
CELLULAR XENOTRANSPLANTATION
impacts of patient advocacy,
expectations, and sophistication over
the short and long term?
A CONFLUENCE OF EVIDENCE
Regenerative medicine and cell-based
therapies continue to engender bold
prognostications about how they could
revolutionize healthcare. These
predictions are increasingly coming
from people outside the sector, and
they are increasingly betting their
corporate strategies on the promise
coming true. I believe this is based not
only scientific data, but also progress
on the clinical, commercial, and
manufacturing fronts. Slowly this is all
enhancing the confidence of skeptics
regarding the eventual clinical and
commercial viability of this entirely
new class of medicines. I hope this
brief snapshot of the industrys current
status helps you better understand the
industry and assess your own
strategies regarding the regenerative
medicine sector.
REFERENCES
1 Smith DM. Successful Business Models
for Cell-Based Therapies. 2008 World Stem Cell
Report. Genetics Policy Institute: Wellington,
FL, 2008; 158162; www.celltherapygroup.
com/uploads/2008WSCRBUSINESS-
SuccessfulBusinessModelsforCell-
BasedTherapies.pdf.
2 Mason C, Manzotti E. Regenerative
Medicine Cell Therapies: Numbers of Units
Manufactured and Patients Treated Between
1998 and 2010. Regen. Med. 5(3) 2010: 307313.
FOR FURTHER READING
Buckler RL, Margolin R, Haecker SA.
Chapter 15: State of the Global Regenerative
Medicine Industry. The Delivery of Regenerative
Medicines and Their Impact on Heathcare.
Prescott C, Polak J, Eds. CRC Press (Taylor &
Francis Group): Boca Raton, FL, 2011.
Mason C, Dunnill P. The Strong Financial
Case for Regenerative Medicine and the Regen
Industry. Regen. Med. 3(3) 2008: 351363;
www.chrismason.com/general_publications/
assets/Mason_Dunnill_Financial.pdf.
Mason C, Dunnill P. A Brief Definition of
Regenerative Medicine. Reg. Med. 3(1) 2008:
15; www.chrismason.com/general_publications/
assets/Mason_Dunnill_Definition.pdf.
PAS 84:2008. BSI Regenerative Medicine
Glossary of Terms. BSI: London, UK, 2008.
Mason C. Regenerative Medicine 2.0.
Regen. Med. 2(1) 2007: 1118; http://
celltherapygroup.com/uploads/
RegenMed_2.0.pdf.
C
R. Lee Buckler is founder and managing
director of Cell Therapy Group and
RegenerativeMedicineJobs.com, as well as a
BPI editorial advisor; Suite 417, 103 East
Holly Street, Bellingham, WA; 1-778-278-
6311; lbuckler@celltherapygroup.com,
www.celltherapygroup.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download a low-resolution PDF online
at www.bioprocessintl.com.
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20 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES COMMERCIALIZATION
Stem-CellBased Therapies
Whats in Development, Implications for Bioprocessing
by Robert Shaw
A
recent review of therapeutics
in clinical development
revealed 68 stem cell-based
approaches (1). The majority
of those leverage a patients own
hematopoietic stem cells; others are
exploring use of mesenchymal, neural,
or embryonic stem cells. Here I
highlight new therapeutic applications
of stem cells and explore advances in
the areas of induced pluripotent stem
cells (iPS cells) and process-scale
production of stem cells. Both should
create new opportunities for stem cell-
based therapies.
TYPES OF STEM CELLS
Hematopoietic stem cell transplants
are routinely given to patients with
cancers and other disorders of the
blood and immune systems.
Autologous transplantation can
successfully reconstitute a patients
own bone marrow and immune system
after high-dose chemotherapy (as
described in the 50 Years box).
Allogeneic transplantation is used to
replace a patients defective marrow or
immune system.
Current trials are further exploring
uses of hematopoetic stem cells for
immune modulation, tissue
regeneration, and treatment of
hematologic cancers. For example, a
recent study at the University of
Indiana School of Medicine (www.
medicine.iu.edu) used genetically
modified hematopoetic stem cells to
target melanoma (2). Researchers
introduced a T-cell receptor gene
cloned from a melanoma patient into
the hematopoetic stem cells of mice
with metastatic melanoma. The potent
antitumor gene led to permanent
immune reconfiguration and a
complete remission of the cancer. A
phase 1 clinical trial using this
technique is expected to begin in
2011.
Mesenchymal stem cells are
multipotent stem cells that can
differentiate into a variety of cell types
including osteoblasts, chondrocytes,
and adipocytes. The properties of
these cells make them good candidates
for use in for tissue engineering.
When transplanted systemically, they
can migrate to sites of injury in
animals.
Launched in 2005, Nuvasives
(www.nuvasive.com) Osteocel cellular
bone matrix contains mesenchymal
stem cells and osteoprogenitor cells.
The product is used for the repair,
replacement and/or reconstruction of
bone defects.
Additional applications of
mesenchymal stem cells include
cardiovascular repair and treatment of
ischemic stroke (3, 4). A number of
studies have made use of mesenchymal
stem cells in treating acute myocardial
infarction with a patients own cells
injected directly into damaged cardiac
tissue (5).
Cardiac Stem Cells: Recent studies
suggest that stem cells may also be
able to replace damaged heart muscle
cells and establish new blood vessels
to supply them. In 2009, doctors at
Cedars-Sinai Heart Institute (www.
cedars-sinai.edu) in Los Angeles, CA,
completed the first such procedure.
Stem cells from a patients own heart
tissue were isolated and injected back
into that patients heart in an effort to
repair and regrow muscle damaged by
a heart attack. In the future, stem
cells may be dosed along with small
molecules to improve their homing
abilities and engraftment.
Neural stem cells are self-renewing,
multipotent cells that generate the
main nervous system phenotypes.
These cells are being evaluated for the
treatment of highly aggressive
glioblastomas at City of Hope
Medical Center (www.cityofhope.
org), also in Los Angeles. In late
2010, doctors injected neural stem
The American Type Culture Collection
recently introduced primary adipose-derived
mesenchymal stem cell growth solutions:
cells accompanied by optimized media for
functional biomarker expression; normal
morphology; and multipotent, lineage-
specific differentiation.
ATCC WWW.ATCC.COM
MARCH 2011 BioProcess International 21 SUPPLEMENT
cells with a special enzyme directly
into the brain of a patient. The stem
cells seek out and attach themselves to
cancerous cells. The patient then takes
a pill containing a nontoxic drug that
enters his or her brain. By interacting
with the enzyme in those stem cells,
the drug creates an active
chemotherapy.
The use of human embryonic stem
cells for therapeutic purposes has
taken hold more slowly. It was only in
October 2010 that doctors began the
first tests in patients, injecting stem
cellderived oligodendrocytes into a
paralyzed man (6). The study had
been initiated in 2009 but was halted
for seven months after safety concerns
arose from animal studies.
With their potential to yield all
possible cell types, embryonic stem
cells offer tremendous potential for
therapeutic applications. However,
safety, ethical, and regulatory concerns
as well as challenges in
manufacturing large quantities of
these cells have tempered
enthusiasm for them in the
commercial sector. Applications using
stem cells from a variety of sources
will continue to evolve (Table 1). In
parallel, new opportunities are arising
as a result of our ability to create stem
cells from differentiated adult cells.
INDUCED PLURIPOTENT STEM CELLS
Reprogramming adult somatic cells
into iPS cells has created tremendous
interest since they were first generated
from mouse and human fibroblasts
several years ago (7, 8). These
remarkable cells are similar to
embryonic stem cells in their ability to
differentiate into a wide range of cell
types, and they are now routinely
generated from adult cells.
Fibroblasts derived from a simple
skin biopsy are a common starting
point. For example, a researcher can
obtain fibroblasts from a patient with
Alzheimers disease or amyotrophic
lateral sclerosis (ALS) and reprogram
them into iPS cells. Those can then
be induced to differentiate into
neurons and other cell types that
might be affected in the disease.
The ability to revert somatic cells
to an embryonic state and
subsequently differentiate them into a
range of cell types offers a wealth of
opportunities for personalized
regenerative medicine and disease
research. Because iPS cells can be
generated from individuals with
different clinical phenotypes and
genotypes, they offer a strategic
advantage over embryonic stem cells
for use in patient-specific cell
replacement therapies.
A number of obstacles first must be
overcome before iPS cells can be used
for therapeutic purposes. Viral vectors
and transcription factors must be
removed from cells undergoing
manipulation. More robust and
consistent methods are needed to
direct and control differentiation into
the desired cell types.
Initial efforts to generate iPS cells
required simultaneous coinfection of
cells with four separate retroviral
expression vectors. Each vector carried
one transcription factor, which led to a
high number of genomic integrations.
Alternative approaches include use of
plasmids and nonintegrating
adenovirus vectors to deliver the
transcription factors. However, the
reprogramming efficiency (the rate at
which cells convert to pluripotency) of
the latter is far lower than that of the
former (9).
Generation of human and mouse
iPS cells now can be accomplished
using a single, excisable polycistronic
lentiviral vector that delivers all four
Yamanaka transcription factors: the
STEMCCA lentivirus
reprogramming kit from EMD
Millipore. Use of a single vector
significantly reduces the number of
viral integrations required. In some
cases, iPS clones with only a single
viral integrant can be isolated (10).
Most recent efforts to reprogram
human somatic cells to iPS cells
involve synthetic mRNAs encoding
the four Yamanaka factors, which
eliminates problems associated with
genomic integration and insertional
mutagenesis (11).
A second barrier to realizing the
full potential of iPS cells is the need
for robust in vitro protocols for
directing their differentiation into cell
types of interest. Identifying the right
cocktail of media conditions,
supplements, and growth factors that
successfully and reproducibly drive iPS
cells toward a desired lineage is a
time-consuming, iterative exercise. A
carefully choreographed series of
signals must be recreated to guide cells
down a chosen pathway. This labor-
intensive work has already been
performed for a number of cell types.
Kits and media containing an
optimized set of factors necessary to
differentiate stem cells to a chosen
lineage are commercially available for
generating neurons, oligodendrocytes,
mesenchymal cells and osteocytes.
Understanding the
microenvironment that iPS derivative
cells may face when they are
transplanted back into a patients body
is also critical to the success of cell
replacement therapies. Aileen
Anderson and her team at the
University of California at Irvine
(www.anatomy.uci.edu/anderson.html)
are exploring whether neurons derived
from fetal neural stem cells, embryonic
stem cells, and iPS cells can be used to
mediate repair in spinal cord injuries.
Our focus right now is to
understand what the role of the
inflammatory microenvironment will
Table 1: Progression of stem-cellbased therapies
~2010 ~2015 ~2020 and Beyond
HSC Used today for
hematological
cancers
Purified cell populations
and broader applications,
including cardiovascular
May be dosed along with small
molecules to improve their
engraftment and homing
ESC/iPS Toxicity testing Model systems of disease
for drug discovery and
research
ES and/or iPS cellderived
therapies for diseases such as
Type 2 diabetes
MSC/NSC Osteocel product
(marketed)
Broader applications
including Crohns and
cardiovascular disease
Therapies based on MSC factors
HSC = hematopoietic stem cells; ESC = embryonic stem cells; iPS = induced pluripotent stem cells;
MSC = mesenchymal stem cells; NSC = neural stem cells
22 BioProcess International MARCH 2011 SUPPLEMENT
be in dictating how a cell population
responds after transplantation, she
describes. Were studying how cells
from these different populations are
going to be influenced after
transplantation in terms of their fate,
their migration, and how the
environment they see is going to
signal back to those cells.
Andersons laboratory is exploring a
range of factors that will affect the
ability of a cell transplant to mediate
repair including the timing and
location of transplant, the impact of
different immunosuppressants, and the
original source of the cells whether
they are fetal-derived neurons,
embryonic stem cells, or iPS cells.
TOOLS FOR DISCOVERY
Disease-specific iPS-derivative cells
are being used for disease modeling
and to support small molecule drug
discovery and development. Uses
include facilitating target discovery,
screening lead compounds, and
improving toxicity evaluation and
metabolic profiling (Figure 1).
Disease Modeling: For decades,
researchers have relied on animal
models, immortalized cell lines, or
short-lived primary cultures to dissect
the mechanisms and pathogenesis of
diseases. Genetic manipulations
including overexpression, knock-
down, knock-out, and knock-in
strategies are often used with animal
models in an attempt to replicate
genetic patterns linked to specific
disease phenotypes.
Differentiated cells derived from
iPS cells have the potential to
transcend the inherent limitations of
existing disease model systems. Cells
derived from patient-specific iPS cells
could provide a more relevant model
system. Their properties more closely
resemble a patients system, and they
dont require genetic manipulation.
Diseases that arise from single
base mutations or deletions are
certainly well-suited for modeling
with iPS technology, notes Gustavo
Mostoslavsky, codirector of the Boston
University Center for Regenerative
Medicine (www.bumc.bu.edu/
stemcells). But more complex diseases
and those that do not have robust
animal models also have the potential
to be modeled using iPS cells.
Mostoslavskys laboratory is
generating intestinal epithelial cells
from iPS cells to study disorders such
as irritable bowel and Crohns
diseases. Recent studies have shown
a role for macrophages in Crohns
disease, describes Mostoslavsky.
Another paper showed triggering of
the disease by a virus when a
particular gene mutation is present in
mice (12).
The lab is developing a human
model system of intestinal epithelial
cells and macrophages derived from
Crohns patients by way of iPS cells
and will ultimately compare those
with the same cell types from disease-
free individuals. The virus suspected
of playing a role in Crohns can then
be introduced into both systems.
Chad Cowans laboratory at the
Harvard Stem Cell Institute (www.
hsci.harvard.edu) is using iPS cells to
support studies of obesity and
metabolic disorders. Although his lab
can easily obtain fat cells from
patients, those cells cant be cultured
over the long term. We can keep the
fat cells alive for a short period, but
that only allows us to do a one-time
endpoint assay. It doesnt allow us to
tease out the complexities of what
might be going wrong in a patient
with a metabolic disorder. The ability
to make patient-specific fat cells from
iPS cells completely changes the
game.
With iPS cells, the lab can conduct
dozens of assays to identify differences
in fat cells from a person with a
metabolic disorder such as type 2
diabetes versus an unaffected
individual. The ability to take a single
genotype and potentially make any
tissues that might be involved in a
metabolic disorder such as
pancreatic beta cells, hepatocytes, or
hypothalamus cells can lead to a
powerful disease model.
Drug Screening: Using iPS-
derivative cells, potential therapeutics
can be screened against a large
number of patient-specific cells before
initiating clinical trials. Variation in
the response to drugs by cells of
patients with genetic differences can
guide targeted selection of patients for
enrollment in clinical trials, resulting
in studies that are smaller and more
likely to be successful.
James Ellis, senior scientist at the
Hospital for Sick Children in Toronto
(www.sickkids.ca/Research/Ellis-lab)
and scientific codirector of the
Ontario Human iPS Cell Facility
(www.ontarioips.ca), is interested in
drug screening applications for cystic
fibrosis. He readily sees the value in
the derivation of lung cells from iPS
cells.
Obtaining lung cells from a
patient with cystic fibrosis is really
only possible when theyve undergone
a lung transplant. But one
consequence of the disease is that
patients have dramatic lung infections,
so its very difficult to establish
primary cell lines. Even if you did,
those will have a limited ability to be
passaged. You may not be able to
make enough cells to complete or
verify your screen.
Figure 1: Potential uses for iPS cells include target identification, screening, ADME/toxicity testing,
and therapy
Target
Identifcation,
Validation
Primary
Screening
Secondary
Screening
Lead
Optimization
Preclinical
Studies
Clinical
Trials
(Phase 14)
ADME (Toxicity)
Cellular Models
Therapeutic Applications
Replenishment therapy
Disease treatment
SC-derived hepatocytes, cardiomyocytes,
and neurons for toxicity testing
Cells from multiple donors for genetic
diversity (e.g., metabolism diferences)
iPS or ESC-derived cells from healthy
donors for HT/high-content screening
(efcacy, mechanism of action, potency)
Disease models from iPS
cells for target ID and
efcacy screening
Tomorrows Process Today
Your Cell Therapy Partner
Superior Tissue Acquisition
Therapeutic Custom Media
Closed System Disposables
Visionary Upstream Development
Expert BioAssay Services
Quality Commercial Facilities
For more information, please contact your
Lonza Sales Representative or visit www.lonza.com/celltherapy
At Lonza, the next step of innovation is in your hands.
Pictured above is a fnal cell therapy product ready for clinical trials.
24 BioProcess International MARCH 2011 SUPPLEMENT
Through use of iPS cells, the Ellis
laboratory plans to generate large
numbers of cells from a range of
patients. Genomic patterns can then
be cross-referenced to drug screening
results. You can then compare one
patient with others and maybe start to
make predictions as to which drugs
are going to work in which patients.
Investigative Toxicity: Differentiation
and expansion of human iPS cells into
functional hepatocytes for use in
investigative toxicity studies could
overcome the shortcomings of primary
hepatocytes and immortalized cell lines.
Use of iPS-derived hepatocytes (and
other cell types commonly used for
toxicity studies) offers a number of
important advantages to investigative
toxicity studies including
availability ol a consistcnt sourcc
of cells that more closely match in vivo
phenotype and physiology
climination ol rcliancc on
sporadically available donor sources
rcduction in usc ol animal modcls
and animal tissue
a morc standardizcd, rcproduciblc
process for toxicity testing
improvcd prcdictivc capabilitics ol
early toxicity studies for less frequent
late-stage attrition of drugs.
More efficient and predictive
toxicity studies enabled by iPS-derived
cells can be expected to reduce
development costs associated with the
late-stage failure of drug candidates.
Identifying those candidates with
toxicity concerns earlier in discovery
can improve the safety and
ultimately the success of clinical
trials.
LARGE-SCALE PRODUCTION
As demand for stem cells in both drug
discovery and therapeutic applications
grows, effectively translating their
promise into reality will require large-
scale industrialized production
under tightly controlled conditions.
Achieving that while meeting rigorous
quality and regulatory standards will
depend on further progress in cell
culture and scale-up, characterization,
enrichment, purification, and process
control to safely and cost-effectively
deliver a consistent and reproducible
supply of cells.
In both autologous and allogeneic
therapies, cells are harvested from
donors or the patients themselves,
grown to sufficient quantities, and
then retuned. Cell replacement
therapies derived from embryonic
stem cells or iPS cells present a more
challenging bioengineering and
manufacturing feat. Techniques used
by the pharmaceutical industry for
50 YEARS OF SUCCESS IN STEM CELL THERAPY
Just as blood transfusions can be considered the first human cell therapies, we can
think of bone marrow transplants (used to treat certain cancers and blood disorders)
as the first stem cell therapies. Multipotent stem cells in bone marrow give rise to
blood cells replacing cancerous white cells in leukemia patients, for example. A
patients own bone marrow (and its stem cells) is killed by chemotherapy and/or
radiation, then replaced with some from a healthy, matching donor. In successful
transplants, injected stem cells migrate to a patients bone marrow to begin
producing new, healthy blood cells. (Unlike the animal-cellbased quackery
described elsewhere in this special issue, these human cells from carefully selected
donors really can perform the migration that purveyors of fake cell therapies claim
without so much risk of immune response.)
An early leader in bone marrow transplants and consequently, stem cell research
is the Fred Hutchison Cancer Research Center (www.fhcrc.org) in Seattle, WA,
founded in 1972. Pioneering work of E. Donnall Thomas in bone-marrow
transplantation at the center led to a 1990 Nobel Prize in medicine, by which time his
once-radical ideas had made FHCRC the recognized leader in the field. Early bone-
marrow transplants in the 1950s involved only identical twins, and the first successful
nontwin sibling procedure was conducted in 1968. An unrelated transplant first
succeeded in 1973, and FHCRC was the site of the first such transplant to treat
leukemia shortly thereafter.
An NIH-funded FHCRC institutional self-analysis of transplant-patient outcomes
reported in fall of 2010 on a decade of refinements in marrow and stem cell
transplantation for treating blood cancers at FHCRC. The study compared transplant-
patient outcomes in the mid-1990s with those a decade later. Results showed a 60%
reduction in the risk of death within 200 days of transplant and a 41% reduction in
the risk of overall mortality.
Everything we looked at improved a decade after the initial analysis, said George
McDonald, MD. He and his colleagues reviewed the outcomes of 1,418 transplant
patients who received peripheral-blood stem cells or bone marrow from unrelated
donors between 1993 and 1997 and compared those with 1,148 patients who had
the same procedures between 2003 and 2007. Malignancies treated included forms
of leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome.
Estimated one-year overall survival rates for both groups were 55% and 70%,
respectively, with statistically significant declines in the risks of severe graft-versus-
host-disease; infections caused by viruses, bacteria, and fungi; and complications
caused by damage to the lungs, kidneys, and liver.
Several improvements in clinical practices improved risk and outcomes. For example,
use of donor peripheral blood hematopoietic cells instead of bone marrow provided
for faster engraftment and return of immunity. Donor matching for unrelated
patients had also improved over time.
This research and the improved outcomes are the result of a team approach to one
of the most complex procedures in medicine, McDonald said in a press release,
crediting medical oncologists; transplantation biologists; specialists in infectious
disease, pulmonary and critical care medicine, nephrology, gastroenterology, and
hepatology; as well as nurses and support staff. These data show clearly that our
collective efforts have improved the chances of long-term survival for our patients.
The National Bone Marrow Donor Registry was federally funded in 1986, and in 1987
the first donor match was made. In 1988, the name was changed to the National
Marrow Donor Registry (NMDP), and it now includes a network of donor registries in
30 countries. The database contains more than 5.5 million donors, facilitating some
200 transplants every month.
Cheryl Scott, senior technical editor
MARCH 2011 BioProcess International 25 SUPPLEMENT
manufacturing protein-based drugs
must evolve or in some cases be
completely reengineered to
support the manufacture of cell-
based therapeutics. I contributed a
review of related challenges and
advances to the October 2010 issue
of BioProcess International (13).
Stem cells represent seemingly
limitless clinical applications. Yet
along with this great promise come
numerous challenges. Taking full
advantage of the unique properties
of these cells will require advances
in our knowledge of their inner
workings as well as development
of new approaches to their large-
scale production.
REFERENCES
1 McKernan R, McNeish J, Smith D.
Pharmas Developing Interest in Stem Cells.
Cell Stem Cell 6, 2010: 517520.
2 Ha SP, et al. Transplantation of Mouse
HSCs Genetically Modified to Express a
CD4-Restricted TCR Results in Long-Term
Immunity that Destroys Tumors and Initiates
Spontaneous Autoimmunity. J. Clin.
Investigation 120(12) 2010: 42734288.
3 Psaltis PJ, et al. Concise Review:
Mesenchymal Stromal Cells: Potential for
Cardiovascular Repair. Stem Cells 26(9) 2008:
22012210.
4 Doeppner TR, Hermann DM.
Mesenchymal Stem Cells in the Treatment of
Ischemic Stroke: Progress and Possibilities.
Stem Cells Cloning 3, 2010: 157163.
5 Martin-Rendon E, et al. Autologous
Bone Marrow Stem Cells to Treat Acute
Myocardial Infarction: A Systematic Review.
Euro. Heart J. 29, 2008: 18071818.
6 Strauss S. Geron Trial Resumes but
Standards for Stem Cell Trials Remain Elusive.
Nature Biotechnol. 28, 2010: 989899.
7 Takahashi K, Yamanaka S. Induction of
Pluripotent Stem Cells from Mouse Embryonic
and Adult Fibroblast Cultures By Defined
Factors. Cell 126, 2006: 633676.
8 Takahashi K, et al. Induction of
Pluripotent Stem Sells from Adult Human
Fibroblasts By Defined Factors. Cell 131(5)
2007: 834835.
9 Baker M. Integration-Free iPS Cells.
Nature Reports Stem Cells, 16 October 2008.
10 Sommer CA, et al. Excision of
Reprogramming Transgenes Improves
Differentiation Potential of iPS Cells
Generated with a Single Excisable Vector. Stem
Cells 28(1) 2010: 6474.
11 Warren L, et al. Highly Efficient
Reprogramming to Pluripotency and Directed
Differentiation of Human Cells with Synthetic
Modified mRNA. Cell Stem Cell 2010: in press.
12 Cadwell K, et al. Virus Plus
Susceptibility Gene Interaction Determines
Crohns Disease Gene Atg16L1 Phenotypes in
Intestine. Cell 25 June 2010.
13 Shaw R. Industrializing Stem Cell
Production. BioProcess Int. 8(9) 2010: 1015.
C
Robert Shaw is commercial director of the
stem cell initiative at Merck Millipore, 290
Concord Road, Billerica, MA 01821; 1-781-
533-2511; robert_shaw@millipore.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download a low-resolution PDF online
at www.bioprocessintl.com.
A VETERINARY SUCCESS STORY
Formed in 2002, Vet-Stem Inc. (www.vet-stem.com) is the first company to offer
regenerative medicine to veterinarians (1). In 2003, the company introduced the first
veterinary stem cell service in the United States. Its technology has been used to
treat tendon, ligament, and joint injuries in more than 3,000 horses and more than
1,000 dogs. Under cofounders Robert Harman, DVM, MPVM, and Michael Dale, the
company holds exclusive worldwide licenses to adipose regenerative cell technology
from the University of Pittsburgh (through its licensee, Artecel Inc., www.artecel.com),
the University of California, and Hawaiian company Tissue Genesis, Inc. (www.
tissuegenesis.com). Vet-Stems own pending patents cover uses and methods of
procurement and delivery of related cells in veterinary and human medicine.
Adult fat has a high progenitor cell concentration available in quantities that can
supply a therapeutic dose without cell culture. Thats why Vet-Stem uses regenerative
cells extracted from adipose (fat) tissue, which is readily available and highly
metabolic. Adult stem cells used for joint disease and tendon and ligament injuries
are taken from an animals fat reserves, isolated from surgically removed fat at a
company laboratory, then in 48 hours returned to the veterinarian, who injects them
into an arthritic joint, tendon, or ligament, where they accelerate and optimize the
animals innate natural healing process. Adult stem cells produce growth factors and
stimulate resident cells to become more active, reduce proinflammatory mediators
and increase antiinflammatory mediators in the tissue, and home in directly to
injured tissue.
This puts stem cell therapy into the present day instead of a future theoretical
concept, said Harman in a press release, Now there are new and effective treatment
options for injuries that in the past would have ended the career or usefulness of a
horse.
Last fall, the company announced its lifetime donation of stem cell treatments to
treat the war injuries of Lex, a canine commemorative Purple Heart recipient who
was a Marine Corps bomb-sniffing dog stationed in Fallujah, Iraq. The dog survived a
rocket-propelled grenade blast in March 2007 that left him severely injured and took
the life of his handler, Corporal Dustin J. Lee. Since that time, Lex has struggled with
several problems related to his injuries, including chronic arthritis. His vet, Dr. Lee
Morgan, made Vet-Stem aware of the case. About half the dogs treated with stem cell
therapy need to be retreated within two years. The company stores more than 18,000
doses of stem cells for thousands of animals and can create more using stem cell
culture technology.
We are pleased to be a part of this great effort and to do our small part in providing
comfort to Lex and the Lee family, said Harman in a press release, and we appreciate
Dr. Lee Morgans contribution and discounted services. Dr. Morgan noted, This is one
of the most important patients I have seen in 14 years of practice. I was surprised to
see how quickly Lex responded to the stem cell therapy.
Reference
1 Young RR. Executive Summary: 20102020 Analysis and Market Forecasts. 5th Annual
Stem Cell Summit, 16 February 2010, New York, NY.
Cheryl Scott, senior technical editor
26 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES COMMERCIALIZATION
Technologies on the Cutting Edge
Perspectives on Making Cell Therapies Work
by Maribel Rios
O
n the brink of bringing
exciting new therapies to
commercialization, cell
therapy developers are taking
notice of how other companies are
addressing processing and technical
challenges. Here, leaders from
Dendreon, Advanced BioHealing, and
Pluristem describe their current cell
therapy programs. And two
organizations the Alliance for
Regenerative Medicine (ARM) and
McLaughlinRotman Center for
Global Health provide details on
the promises of regenerative medicine.
CELLULAR IMMUNOTHERAPY
Dendreons Provenge (sipuleucel-T)
cell therapy induces an immune
response to aid in treating existing
prostate cancers. The US Food and
Drug Administration (FDA) classifies
it as an autologous cellular
immunotherapy, although the
company also uses the term active
immunotherapy to distinguish it from a
preventative immunotherapy such as a
vaccine. Dave Urdal, chief scientific
officer at Dendreon (www.Dendreon.
com), explains its processing.
BPI: How does time to manufacture
become a critical factor?
DU: Key raw materials that go into
a dose of sipuleucel-T therapy come
from a patients blood. The final
product is live cells, never frozen, so
its shelf life is much shorter than that
of a recombinant protein. Antigen-
loaded activated cells must be infused
into a patient within 18 hours from
the time we complete cell harvest.
BPI: What is involved in the
processing?
DU: First, we isolate white blood
cells from a patients blood using
apheresis. The white blood cell
fraction is collected and sent to a
Dendreon manufacturing facility. At
our facility, we remove residual red
blood cells and granulocytes from the
preparation using buoyant density
centrifugation. We isolate antigen-
presenting cells (APCs) and culture
them in a recombinant antigen
(Figure 1). That cell fraction is placed
in culture with defined media made of
a genetically engineered recombinant
protein composed of the prostate
antigen linked to a cytokine known as
granulocyte-macrophage colony-
stimulating factor (PAP-GM-CSF).
Those cells with that antigen are then
cultured for about 40 hours. During
culture, the GM-CSF portion
activates the APCs within that
mixture of cells. Those cells take up
antigen and load up the surface of the
APCs with peptide epitopes that
educate the T cell compartment of
the immune system.
BPI: How do you ensure cell quality?
DU: Key operating steps include
maintaining cells in the right type of
growth media and at the right
conditions to ensure they remain
viable and have ideal characteristics.
We use procedures similar to those of
stem cell transplantation, in which
hemapoeitic stem cells are isolated
from bone marrow or peripheral
blood. We manipulate cells in culture
using centrifugation. Those are
common steps used in conventional
biologics manufacturing, but our work
is done under conditions that
minimize cell damage.
Weve worked out assays to help us
verify the process was taking place for
each dose. We have a very specific
Figure 1: Mode of action for Dendreons Provenge immunotherapy
PAP-GM-CSF
antigen
combines with
resting APC
APC takes
up the
PAP-GM-CSF
PAP-GM-CSF is
processed and
presented on the
surface of the APC
PAP-GM-CSFloaded
APCs are now the
active component
of Provenge
Prostatic acid phosphatase (PAP) an antigen
expressed in more than 95% of prostate cancers
Granulocyte-macrophage colony-stimulating
factor (GM-CSF) an immune-cell activator
MARCH 2011 BioProcess International 27 SUPPLEMENT
potency assay to show that cells are
activated for each patient. Each dose
meets prespecified quality release
criteria before the lot is released for
infusion into the patient. We use a
straightforward approach of assessing
cell viability in preparations, and we
enumerate the cells. So we monitor a
number of those types of properties on
every batch before release.
BPI: What is next for Dendreon?
DM: The success has validated our
approach of using autologous APCs in
ways that will be useful for treating
other cancers. We have filed an
investigational new drug application
(IND) for another antigen for targeting
HER-2 positive tumors. The next
clinical testing is in patients with
invasive bladder cancer. We have other
target antigens that are in preclinical
stages of development that would allow
us to address treating colon cancer, renal
cell carcinoma, and other malignancies.
DERMAL HEALING
Relaunched in 2007, Advanced
BioHealings (ABHs) Dermagraft
therapy is a dermal substitute used to
treat diabetic foot ulcers. Kathy
McGee, senior vice president of
operations at ABH, provides an
overview of its processing and safety
testing.
BPI: What is Dermagraft?
KM: Dermagraft is a cryopreserved
human fibroblast-derived dermal
substitute; it is comprised of fibroblasts,
extracellular matrix, and a
bioabsorbable scaffold. The final
product is an approximately 2-inch
3-inch piece of dermal tissue, approved
by the US Food and Drug
Administration for the treatment of
diabetic foot ulcers.
BPI: What is the source of ABH cells?
KM: The fibroblast cell line used in
the manufacture of Dermagraft was
derived from a single newborn
foreskin tissue, which was qualified in
1993 when the product was owned by
Advanced Tissue Sciences. From the
donor tissue we isolated the fibroblast
cells the cells that make up the
dermal layer of skin to create a
master cell bank and then expanded
the cells to generate a working cell
bank. The same cell line has been
used in the manufacture of
Dermagraft since the product was
initially launched in 2001, and is fully
qualified under the Center for
Biologics Evaluation and Researchs
Points to Consider.
BPI: What are the processing stages?
KM: The Dermagraft
manufacturing process begins when
fibroblast cells are removed from the
working cell bank. Our daily routine
includes thawing cells from the
working cell bank and expanding
them further to grow enough cells to
seed onto our final product. We begin
with a starting point of about 1
million cells and over a period of
about four weeks, expand and grow
the cells in roller bottles to result in
approximately 1 billion cells to begin
producing our final product.
The cell expansion process is in a
monolayer. As we start our growth
process, we harvest the cells and feed
them onto a three-dimensional
bioabsorbable mesh scaffold that will
break down in the body when
implanted into the patients wound.
When the cells are introduced onto
the scaffold, we maintain the
environment to closely resemble as
much as possible the conditions they
would see in the human body. We
maintain the pH and temperature and
add the nutrients and various
concentrations of nonessential amino
acids and growth factors that the cells
need to form a healthy dermal tissue
For 2.53 weeks, we allow the cells to
grow in a closed system, which
becomes part of the products final
configuration. Part of the final
packaging is placed into a foil pouch
and then into a cardboard box,
labeled, and frozen to 70 C. The
tissue is frozen using a cryo-
preservative, which helps protect the
cells during freezing and thawing
BPI: What testing is done to ensure
the final product is safe and efficacious?
KM: Before releasing the product,
we extensively test for efficacy and
safety per predetermined and approved
specifications. There is a therapeutic
range and safety profile that the
product must meet before its release to
ensure the product has not been
compromised during processing. Our
safety profile ensures our product is
safe for a host of patients; we have no
history of patients experiencing
rejection issues. Further, there is no
pigmentation, so it doesnt matter
which patient gets the product.
BPI: How is sterility ensured?
KM: Our cells and all of our
starting materials are considered
sterile, and all of our processing
components are disposable. We use
preassembled, irratiated bioreactor
pouches to which we aseptically add
the cells. The product is grown in the
pouch, which also serves as its final
packaging configuration (Photo 1).
ALLOGENEIC ADULT STEM CELLS
FOR PERSONALIZED THERAPY
Pluristem Therapeutics (www.
pluristem.com) uses adult stromal cells
derived from donor placenta to
produce cellular drug factories.
Although the company does not yet
have a product on the market, the
potential for its technology to treat a
variety of diseases and indications is
drawing interest. Zami Aberman,
CEO, describes how the cells are
processed and discusses plans for
further clinical trials.
BPI: How can Pluristems adult stem
cell therapies be used in treatment?
ZA: Our cells act as tiny (20-m
cell size) drug manufacturers. We are
using adult stem cells as sophisticated
drug delivery vehicles. When cells are
injected into a patients body, they
receive biomechanical signals from the
patient and start to produce a
specified drug as the patient needs it.
The problem of over- or under-dosing
is prevented because delivery is based
on a patients individual
Photo 1: Advanced BioHealings Dermagraft
therapy is grown in a presterilized pouch
that also serves as its final packaging
28 BioProcess International MARCH 2011 SUPPLEMENT
biomechanical signals that direct the
quantity needed. So the treatment
becomes a personalized therapy.
BPI: How is processing conducted?
ZA: We start with a donors
consent. We take blood samples from
a mother to ensure she does not carry
biocontaminants. After the placenta
arrives at our facility, we keep it for
three weeks. During that time we
check for potential contamination. We
extract cells, clean them, and grow
them in two-dimensional Petri dishes
to rid them of all immunological
ingredients. Only then do we culture
them in our unique bioreactor
technology, harvest them, and
cyropreserve them. They are kept for
one year, and during that time they
are sent to a hospital or other facility,
where they are thawed and injected.
Our process produces high
quantities of cells with batch-to-batch
consistency. Because the final product
does not require a match, we can
produce it at one location and ship it
around the world. From one placenta
we can treat about 10,000 patients for
a variety of indications.
BPI: What therapeutic areas are you
targeting, and what is the progress in
those areas?
ZA: Weve completed phases 1 and
2, proving safety and defining the
dose for the next study, which will
start during the first half of 2011. The
first clinical study is treating patients
with critical limb ischemeia (CLI),
which is related to peripheral arterial
disease (PAD). CLI patients have pain
or nonhealed ulcers on their feet.
We have followed both FDA and
European Medicines Agency (EMA)
guidelines. We conducted phase 1 and
2 studies under FDA and under EMA
approval. Phase 1 was conducted using
1-L bioreactors, but now we are
approaching 5-L bioreactors, and at
marketing we will use 1520 L
bioreactors.
REGENERATIVE MEDICINE
The Alliance for Regenerative
Medicine (ARM) was established in
2010 as a group of companies and
other institutions that aimed to draw
attention to the progress being made
in regenerative medicine (RM), new
stem cell therapies, and tissue
engineering. According to ARM
chairman Gil van Bokkelen, the group
also provides industry with a voice,
particularly in Washington, DC.
BPI: What are ARMs objectives?
GVB: Were focused on policies that
relate to legislation introduced at the
end of the last congress that was
designed to promote some aspects that
are important to ARM specifically,
achieving legislative clarity around the
DickeyWicker amendment. We are
also promoting funding and trying to
create incentives for investment into
the RM area. On the regulatory side,
we are working with the FDA so that
we can establish clearer standards for
McLaughlinRotman Center for Global
Health (in association with the University
of Toronto) recently conducted a study on
regenerative medicine (RM) in Brazil (1).
Dominique McMahon (researcher, PhD
student) conducted face-to-face
interviews with 50 RM experts, including
researchers, policy analysts, funders,
companies, and regulators for that study.
BPI: What are the main therapeutic areas of
Brazils regenerative medicine industry?
DM: One main driver of RM in Brazil has
been the need for new technologies and
new products to address local health
challenges. There has been a shift of
Brazils health profile toward chronic
disease because of economic growth that
led to changes in diet and lifestyle, and
due to decreasing burdens of infectious
and parasitic disease. In the 1930s, ~50%
of all deaths were related to infectious and
parasitic disease; in 2005 it dropped to 5%.
Cardiovascular disease has increased
threefold since the 1930s and is currently
the cause of about 32% of all mortality.
Clinical research continues in cardiology,
orthopedics, diabetes, and neurology. In
addition, one treatment in clinical trials is
for Chagas disease, which is a local tropical
disease that can cause serious heart
problems if left untreated. Brazil has
conducted several clinical trials using stem
cell treatments and had one of the largest
stem cell trials in the world for
cardiomyopathies. Brazil has also
developed a treatment for diabetes
mellitus which when tested in a small
group of patients, allowed long-term
insulin independence, and a promising
stem cell treatment for stroke.
BPI: What are the stengths in Brazils
program?
DM: Our study found that Brazil is doing
quite well in RM work, but it is an
emerging sector. Some of the economic,
regulatory, and policy events have been
very supportive. For example, the growing
strength of the economy has made
possible investments in biotech (which are
considered higher risk and which require
significant infrastructure). Recent laws that
support human embryonic stem cell
research, and the innovation law which
helps develop linkages between
universities and industry are important.
But the field has moved forward because
of clear government support and the need
to develop solutions to local health
problems.
BPI: What are areas of improvement?
DM: If this sector is to do well, it must
have consistent financing. It is very
difficult to find private funding in Brazil;
grants are almost entirely from public
sources. Researchers are often on very
short-term grants, which forces them to
define their research agendas with short-
term goals.
Other major barriers to developing RM
products in Brazil include the cost and
delays of material importation.
Researchers claim it can sometimes take
up to a year for them to receive items they
have ordered. More collaboration between
firms, researchers, and clinicians may also
help the development of RM therapies.
BPI: How would you describe Brazils
regulatory environment?
DM: Brazil has a strong regulatory
environment. The equivalent to US FDA is
ANVISA (National Health Surveillance
Agency), the main drug regulatory group.
Stem cell therapies are not considered
drugs, but ANVISA does oversee all of the
laboratory facilities that generate cells for
clinical use. The Ministry of Health
oversees clinical trials and is responsible
for approving RM therapies. The other
main regulatory body is CONEP
(Coordinator, National Ethical Committee),
which oversees ethics. All stem cell clinical
trials must gain national ethics approval
from the CONEP board.
Reference
1 McMahon D, et al. Regenerative
Medicine in Brazil: Small but Innovative.
Regen. Med. 5(6) 2010: 863876.
BRAZILS REGENERATIVE MEDICINE INDUSTRY
MARCH 2011 BioProcess International 29 SUPPLEMENT
companies that are developing new
therapies. Investors dont like
uncertainty, so having clear regulatory
standards that enable companies to
operate efficiently and cost effectively
is very important. Companies need to
do that while bearing in mind the
primary goal, which is to protect
patient safety. So we think working
directly with the FDA and learning
from them but also working to
educate them in terms in exciting new
technologies.
BPI: Is ARM working toward
educating the general public about the
possibilities of regenerative medicine?
GVB: That is another important
objective. ARM is involved in
educating the media and the general
public so that they can understand
these new technologies. I think a lot
of people intuitively understand the
potential for regenerative medicine
and what new therapies might mean
in healthcare. I also think there is a
very high degree of comfort among
people in the public about the
potential for stem cell medicine and
regenerative medicine technology.
One of the facts were trying to convey
through multiple different forums and
other efforts is that regenerative medicine
really has transformation potential in the
sense that its one of the few areas where
we can both dramatically improve the
clinical outcomes in high-need areas
while simultaneously shifting the cost
curve in the right direction.
BPI: Is ARM addressing questions
about the safety of RM products?
GVB: Many of these technologies are
associated with an outstanding safety
profile. If you look at the history of drug
development, the odds of developing a
small-molecule therapeutic historically
have been about 1 in 20 or 1 in 10 at best.
But in many instances, you are developing
small molecules that dont normally exist
in the body they are synthetic
constructs. However, if you look at the
success rate of biologics that haven
developed during the past couple of
decades, the success rate is actually
substantially higher than that, so the odds
of developing a biologic have been more
than 20% that is from the time you
start clinical development. One reason for
that is that many of these therapeutics
have a good safety profile they are
substances that normally exist in the
human body. Thats the differentiating
factor. With respect to stem cells, many
therapies being developed are based on
what ordinarily exists in the body. We are
just harnessing the power of specific cell
populations, turning them into a
pharmaceutical-grade product, and
applying them in a way that makes sense
to speed recovery and healing. So the
emerging safety profile is something that
a lot of people view as being very exciting.
And now what they are looking for is
evidence of efficacy or therapeutic
effectiveness in a range of areas that make
the case in a compelling way. But that
evidence is starting to emerge across
various studies.
C
Maribel Rios is managing editor of
BioProcess International, 646-957-8884;
mrios@bioprocessintl.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808,
ext. 154. Download a low-resolution PDF
at www.bioprocessintl.com.
Gil Van Bokkelen, director of the Alliance
for Regenerative Medicine, describes an
example of how regenerative medicine
can help in tissue healing.
When most people think about RM, they
tend to think first about inserting a new
organ or inserting new tissue to replace
something that has been lost. Although,
there are certainly some exciting
possibilities in that regard, the application
of RM is a lot broader than that. Certain
cell types can home to sites of tissue
damage, inflammation, and injury. In
many instances these therapies could be
administered locally, injecting them near
or right into the site of damage, or
administered intravenously, where the
cells will respond to various signals in the
body and go where they are needed. The
cells express multiple types of proteins or
factors that can promote or accelerate
healing and tissue repair shifting a
bodys healing response in the right
direction, for example by reducing
inflammatory damage, and promoting
formation of new blood vessels.
RM has the potential to address a wide
range of unmet medical needs. For
example, one area that illustrates the
potential of these new therapies would be
in the area of treating patients that have
suffered an ischemic stroke. In the United
States every year there are ~800,000
people that suffer a stroke, of which ~85%
are caused by a clot or a blockage in an
artery (~2 million people if you include
Europe and Japan). Unfortunately, if you
suffer an ischemic stroke, you only have
about a three-hour window to get to a
doctor to get treated with the only drug
that is currently available to a stroke victim
(tPA, Genentech). If you cant get to the
doctor in that three-hour time frame, you
are not supposed to receive treatment
with tPA because by that point it could
actually do more harm than good. So as a
practical consequence, ~95% of the
people that have an ischemic stroke are
not treated with tPA because they cant
get to a doctor in time. Essentially these
patients receive palliative care, which
ranges from physical therapy to extended
hospitalization or even permanent
institutionalization.
The average cost of care for a stroke
victim is in the hundreds of thousands of
dollars. For those that cant afford or dont
have access to long-term institutional care,
a family member will have to care for
them, and in many instances people live
with a dramatically reduced quality of life.
Its a huge cost for our healthcare system
about $73 billion a year just for stroke,
according to American Heart Association.
And the numbers are expected to
skyrocket in the years ahead given the
aging population.
Several companies are focusing on adult-
derived stem cells that can be
administered to stroke victims. Preclinical
research from studies has shown that in
some instances, stem cell therapy not only
reduces or corrects a lot of the damage
from stroke, but it can lead to a nearly
complete recovery. Moreover, evidence
suggests some stem cell therapies can be
administered several days or even a week
(or possibly longer) after a stroke has
occurred and generate those results.
Imagine what that might mean for those
who have suffered from a stroke. That
could change the landscape of stroke
medicine as we know it.
REGENERATIVE MEDICINE: ADDRESSING UNMET MEDICAL NEEDS
30 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES TECHNOLOGY
Cell Therapy Bioprocessing
Integrating Process and Product Development
for the Next Generation of Biotherapeutics
by Ralph Brandenberger, Scott Burger, Andrew Campbell,
Tim Fong, Erika Lapinskas, and Jon A. Rowley
T
he past 15 years have seen
approval and commercialization
of the first cell-based
therapeutics, including cartilage
repair products; tissue-engineered
skin; and the first personalized,
cellular immunotherapy for cancer.
Those successes are outnumbered,
however, by all too common product
failures. Notable failures can be
attributed to commercial concerns such
as high cost of goods (CoGs) and
technical hurdles such as inadequate
characterization, high process
variability, and loss of product efficacy
when manufacturing is scaled up (1).
Arguably, the root cause of those
commercial and clinical failures is a
lack of sophistication in developing
living cell-based drugs with all the
verifiable consistency of any other
drug class. Many early cell therapy
companies lacked drug development
expertise and pursued products that
were not feasible commercialization
candidates. Some companies, unable
to continue with iterative development
and further characterization, instead
relied on insufficient understanding of
their products and ineffective process
development, which impaired critical
product characteristics and likely set
the stage for clinical failure (1).
For cell therapy products to achieve
the manufacturing success of
biopharmaceuticals, there must be
communication and cooperation
among three groups of people:
tDFMMQSPDFTTJOHQSPGFTTJPOBMT
typically working in academic centers
that collectively process hundreds of
cell products for transplantation every
month
tDFMMCJPMPHJTUTXIPIBWFBTUSPOH
foundation in product development
and cell characterization (as it relates
to therapeutic efficacy of cell-based
drugs) and can help identify and
quantify quality parameters and
product specifications
tCJPQSPDFTTFOHJOFFSTXJUIUIF
engineering discipline required to
create scalable and robust
manufacturing processes (2) that will
maintain the critical quality
parameters of living cell products
while minimizing manufacturing costs
inherently expensive products.
Only with a cross-functional
approach that encompasses those
skill-sets will it be possible to achieve
an integrated approach to product and
process development that can lead to
clinical and commercial success.
The Process and Product
Development (PPD) subcommittee of
the International Society of Cell
Therapy (ISCT) is a group of industry
and academic cell therapy
professionals aiming to help establish
MARCH 2011 BioProcess International 31 SUPPLEMENT
and communicate best practices for
integrating the process and product
development aspects of cell-based
therapeutic development. Its work will
include establishing and sharing best
practices in establishing specifications
for identity, potency, purity, and safety
of cell-based therapeutics as well as
development of commercially viable
bioprocesses to manufacture these
products to specifications. These
efforts will include driving
standardization when possible, sharing
best practices within the industry, and
helping position early stage, academic-
based therapies for potential
commercialization.
Cell therapy manufacturing is
poised to benefit from know-how and
technical innovation that the protein
bioprocessing field has driven over the
past 20 years (3). Production, storage,
and delivery of living cell-based
pharmaceuticals presents several
unique challenges. Novel, innovative
technologies and strategies will be
required to bring cell therapies to
commercial success.
MAJOR DIFFERENCES BETWEEN
THERAPEUTIC CELLS AND PROTEINS
In just a couple decades, the
commercialization of monoclonal
antibodies and other therapeutic
proteins led to the growth of a
multibillion-dollar industry. A great
deal of effort has been applied to the
establishment of methods for efficient
product scale-up and cost reduction of
manufacturing processes (4). In
addition, a tightly controlled
regulatory policy that includes
sterility, purity, and quality of raw
materials (animal-originfree, and so
on) guidelines has been adopted for
manufacturing biotherapeutic
molecules. The cell therapy industry
has generally been slow to adopt such
practices because of specific
(sometimes prohibitive) differences
between the two product categories.
Recombinant monoclonal
antibodies and other therapeutic
proteins are generally secreted by
genetically engineered cell lines into
their culture medium and then can be
highly purified, sterilized, and
concentrated under well-defined and
regulated conditions. By contrast, the
product of a cell therapy is the cell
itself. That presents a challenge: The
end product must be harvested
efficiently and cannot be terminally
sterilized. Additionally, many cell
types currently are not amenable to
cell culture systems that exclude
animal serum or other animal-origin
materials. Further development of
serum-free culture systems will be
necessary to reach the level of
regulatory compliance that is required
in the therapeutic protein market.
A major difference between the
protein and cell industries is the
source of their cells. Many
recombinant proteins are produced
from selected clones of mammalian
cells that are fully characterized,
tested, consistent, and stable. Most
cell therapies are derived from primary
cells isolated directly from tissues that
have limited expansion potential. Such
cells cannot be selected for optimal
performance characteristics, and
donor-to-donor variability leads to
substantial variability among
processes. Scalable production
platforms, process validations, and
quality control release thus remain as
daunting challenges.
PROCESSING LABORATORIES
IN ACADEMIA
Most clinical cell therapy laboratories
at academic medical centers have
grown far beyond their origins in
processing bone marrow to support
blood and marrow transplant
programs. They have become
powerful resources in development of
novel cell-based products. Academic
cell processing laboratories commonly
serve a range of clinical programs and
are closely linked to their academic
investigators. Their staffs have
developed a valuable breadth of
knowledge as well as cutting-edge
processing techniques and
characterization methods (Photo 1).
The most active laboratories produce
hundreds (in some cases, thousands)
of cell therapy products each year. To
date, it is estimated that tens of
thousands more doses of living cells
have been processed in academic
laboratories than have been
manufactured in all of industry, which
represents a remarkable level of
experience.
Focusing on phases 1 and 2, such
laboratories represent an early stage in
the development pipeline. Technology
transfer, characterization, and process
development activities in an academic
processing laboratory thus have great
impact on later stages of clinical
development and commercialization.
It is neither practical nor necessary for
an academic cell therapy laboratory to
develop commercial-scale
manufacturing or testing. It is,
however, essential that early stage
development work in such laboratories
enable rather than impede subsequent
commercialization.
To give cell therapy products the
greatest chance of success, academic
cell therapy laboratory staffs must
understand the needs of their industry
counterparts further along the
development pathway. It is always
useful to begin with the end in mind,
which can be thought of as
establishing a target product profile
while in early clinical development.
Early stage process development
should focus on defining and
optimizing a reproducible
manufacturing process and
establishing a characterization profile
that can support product release and
subsequent development. Raw
materials should be selected and
qualified to simplify sourcing and
regulatory compliance at later stages of
development and commercialization.
In the next decade, commercialization
of cellular therapies will force most
manufacturing from academic
laboratories to industry. Leveraging
the knowledge of those centers will be
important to minimizing wheel
reinvention.
COMPARING AUTOLOGOUS AND
ALLOGENEIC PRODUCT MANUFACTURE
There are two main manufacturing
process paradigms in cellular therapy:
patient-specific/autologous and
universal-donor/allogeneic products
(Figure 1). Historically, most cell
therapy products have been patient-
specific due to a need for immunologic
compatibility. Many cell therapy
32 BioProcess International MARCH 2011 SUPPLEMENT
products in clinical development
today, however, are based on cell types
that do not give rise to an immune
response. Such allogeneic unmatched
cell therapies could be more
pharmaceutical-like off-the-shelf
products.
Unmatched allogeneic donor
products are amenable to bulk
manufacturing, and their production
often can take advantage of some
aspects of bioprocess technology.
Manufacturing commonly involves
establishing and qualifying
cryopreserved master and working cell
banks, then producing large lots of
product for release testing. As in
biopharmaceutical manufacturing, the
process is scaled up during clinical
development, and release testing may
be performed on lots that represent
hundreds or thousands of product
doses. The main challenges in
allogeneic manufacturing are
maintaining a cell products critical
quality parameters while scaling up its
manufacture (stressing cell
characterization, as discussed below),
and controlling the cost of goods
(CoGs) for these inherently expensive
products. Although labor and facilities
are the greatest component of CoGs
for allogeneic cell therapy products
during clinical development, it is
expected that culture medium and
supplements will be the largest part
during commercial-scale
manufacturing.
Production of autologous, patient-
specific cell therapy products are not
amenable to a scale-up approach, so
their bioprocesses will be scaled out
for commercial manufacturing. To
achieve efficiencies of scale, high-
throughput production by parallel
processing of multiple, separate
products in automated, functionally
closed systems should be widely
adopted (5, 6). Functionally closed
process technology provides product
and process isolation, maintaining
each product entirely within its own
separate, presterilized, disposable
processing set. Such systems are
highly amenable to automation and
associated with extremely low rates of
contamination, and they typically
improve product yield.
Because each product represents a
unique donor, autologous and patient-
specific products have the greatest
potential for variability, which is a
major challenge. Logistics present a
challenge as well in that
manufacturing each product involves
obtaining living cellular raw material.
Because patient-specific products are
manufactured as one lot per patient,
release testing often accounts for the
bulk of their CoGs. Despite all these
challenges and costs, multiple patient-
specific, autologous cell therapy
products are on the market or in
clinical development today. They
generally target applications of major
unmet medical need.
CELL CHARACTERIZATION
AND POTENCY ANALYSIS
Cell-based products present unique
characterization challenges. Producers
of small-molecule and recombinant
biologic drugs use defined
manufacturing and purification
processes that yield relatively
homogeneous final products with little
lot-to-lot variation. Characterization of
purity and identity for such drugs can
be directly related to several measurable
physical traits such as molecular
weight, chemical structure, and purity.
Drug potency is often correlated with
and measured by specific biochemical
or cell-based assays in vitro. However,
most methods used to characterize the
purity and potency of traditional drugs
are not suitable for testing cell-based
products.
Figure 1: Allogeneic processes generally include strategically placed cell banks and large lots of
patient doses. In autologous/patient-specific processing, every lot manufactured is meant to treat
only a single patient, and in some cases much of the product is lost to product release testing.
Master Cell Bank
Lot Tested
Working Cell Banks
Lot Tested
Patient Doses
Lot Tested
C
e
l
l

E
x
p
a
n
s
i
o
n
C
e
l
l

E
x
p
a
n
s
i
o
n
o
r

P
u
r
i
f
c
a
t
i
o
n
Testing
Patient or Donor
Cell Ampule or Dose Submitted for Testing
Allogeneic = Universal Donor
Autologous = Patient Specifc
Figure 2: Challenges to scale up/out for a typical cell therapy manufacturing process
MCB
WCB
Tissue
Acquisition
Primary Cell
Isolation
Cell Culture Harvest
Volume
Reduction
Washing
Formulate
and Fill
Cryo-
preservation
Storage and
Inventory
Testing and
Release
Shipping
Logistics
End User
(Handling,
Delivery)
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34 BioProcess International MARCH 2011 SUPPLEMENT
One major challenge to the cell
therapy industry is to develop
characterization and potency
specifications for products with
considerable inherent variability
particularly for autologous, patient-
specific products. Cell-based products
are often derived from donor or
patient tissues that contain many cell
types. Depending on the stringency of
methods used in cell isolation, final
products can contain several other cell
types in addition to the therapeutic
cells of interest. Donor- or patient-
based variations in tissue composition
add to variability in the final cell
product purity and yield. Even
products derived from cell lines (e.g.,
hES or iPS cells) may contain several
cell types. Such products require some
level of differentiation and expansion,
and no current protocol is 100%
efficient, so manufacturing produces a
mix of undifferentiated or partially
differentiated cells in the final cell
products.
The most commonly used
technology for characterizing cell
therapeutics is fluorescence-activated
flow cytometry. Multicolor flow
analysis allows phenotypic
determination of antigens on the
surface of a cell. If an appropriate
reagent cocktail is used, then both the
identity and purity of a final cell
product can be determined using a
single assay. Gene expression array
analysis is increasingly being used, as
well. More established analytical
technologies such as automated cell
counting and enzyme-linked
immunosorbent assays (ELISAs) play
major roles too. Assay validation,
including developing robust reference
standards, will have to be addressed as
cell therapy products come to market.
Like with traditional drugs,
potency assays must be established for
each cell-based product before phase 3
clinical trials. However, the
mechanism of action for many such
drugs is either multifaceted or
currently unknown. Developing
potency assays for cell products is
fraught with ambiguity. FDA
guidance suggests including a matrix
of assays including gene expression
profiles, cytokine secretion, or in vitro
cell-based assays showing biological
activity such as target cell lysis,
inhibition of target cell proliferation,
or pluripotent differentiation potential
(7). With the large variety of potential
cell products under development, the
challenge will be to develop assays
that are reliable, reproducible with low
variance, inexpensive, simple, and
rapid, with appropriate reference
standards that also have relevance
to the intended clinical activity.
COMMON UPSTREAM
PROCESSING PLATFORMS
With a wide variety of potential tissue
sources (e.g., blood, bone marrow,
cord blood, placenta, adipose and
other adult tissues, fetal tissue,
embryonic stem cell lines, induced
pluripotent cells), an important step in
the cell therapy manufacturing process
is initial isolation or enrichment of a
cell population of interest from the
tissue source. Several commercial
systems are already in use for bulk
enrichment and have attributes that
facilitate compliance with current
good manufacturing practice (CGMP)
guidelines. Examples include the
CliniMACs system from Miltenyi
Biotec (www.miltenyibiotec.com), the
Sepax system from BioSafe SA (www.
biosafe.ch), and the Elutra system
from CaridianBCT Inc. (www.
caridianbct.com). For processes that
require highly defined cell
subpopulations, fluorescence-activated
cell sorting (FACS) may have
applications, but it presents some
complications and limitations (8).
Unfortunately, no single cell-sorting
instrument platform yet offers a
complete, CGMP-compliant system
for cell therapy use. However, leaders
in the field are pushing forward and
adapting current platforms for clinical
cell sorting. A challenge for cell
product manufacturers will be to find
an isolation process that is cost-
efficient, easy to use, and CGMP
compliant and that can provide a
cell population of the required yield
and purity.
Culture processes for expansion
and/or differentiation of final cell
products (either allogeneic or
autologous) are based on current cell
culture technology and are ripe for
innovations specific to cell therapy
application. In general, cells for
therapeutic applications are either
grown in nonadherent suspension or
adherently through traditional two-
dimensional (2D) culture. Many cells,
such as hematopoietic stem cells
(HSCs) and T cells, can be grown in
nonadherent suspension culture. That
can involve relatively large-scale
bioreactors such as bag-based and
traditional stirred-tank vessels.
Through such means, large numbers
of cells can be generated with a
relatively small footprint and under
tightly controlled conditions.
Other cell types, such as
mesenchymal stromal cells (MSCs) (9)
from various tissues, are traditionally
grown adherently on tissue-culture
treated surfaces. Large-scale
expansion of these cell types requires
much surface area using traditional
2D methods. Multilayered flasks have
been developed to reduce the
laboratory footprint per square-
centimeter of culture surface.
Examples include the CellCube and
CellSTACK systems from Corning
Inc. (www.corning.com) and Cell
Factory system from Nunc A/S (www.
nuncbrand.com). But to reach
sufficient cell numbers for commercial
lot sizes (~10
10
10
12
cells), large clean
rooms (or even whole buildings) would
have to be filled with incubators of
flasks. Next-generation adherent
culture platforms are under
development specifically for cell
therapy applications, including
bioreactors, hyper-density stacked
vessels, microcarrier-based cultures,
and induced-suspension adaptation
growth methods for primary adherent
cell types. As the amount of tissue
culture surface area per lot increases,
the enzymatic harvest and
downstream processing of hundreds to
thousands of liters of cells will be a
new and challenging process
bottleneck.
COMMON DOWNSTREAM
PROCESSING PLATFORMS
Current downstream processing
methods for cells use common
laboratory equipment for
36 BioProcess International MARCH 2011 SUPPLEMENT
concentrating, washing (clarifying),
and formulating them before
packaging and storage. Transition to
closed, scalable systems will be
important to scale-up/out that will be
required for commercial production
(10). Many culture processes are still at
relatively small scale (1- to 10-L
harvest), but some midstage allogeneic
processes can reach 2030 L in scale.
Cell concentration and washing are
currently performed using open
centrifugation tubes (500 mL) or
performed using blood processing
equipment.
Recently, bioprocessing
technologies such as tangential-flow
filtration and continuous or
counterflow centrifugation have been
adapted for maintaining very high cell
viabilities and important biological
functions of living products. Cell
therapy is benefiting greatly by the
move of bioprocess suppliers toward
ready-to-use, sterile, single-use
systems, but focused development
effort specifically for cell therapy
applications is greatly needed. The
transition to scalable technologies for
processing cells will be central to cell
therapy success. As processes scale up
to 100-L and even 1,000-L harvests,
open centrifugation and blood
processing equipment will be unable
to accommodate such volumes.
Fill and finish processing of
therapeutic cell formulations is also in
need of standardization. Patient-
specific processes typically involve
small volumes that are manipulated in
biological safety cabinets or through
closed bags, tubing sets, and sterile
welders. Automation of such processes
(5, 6) including automated logistics
and tracking will ultimately be
required because single facilities will
be processing, releasing, and shipping
hundreds of lots per day. Most
allogeneic and autologous products are
still being filled in blood bags, which
are appropriate for small lot sizes.
However, as allogeneics increase to
hundreds or thousands of doses per
lot, a switch to pharmaceutical vials
and off-the-shelf filling lines is
anticipated (10, 11). Large-scale
cryopreservation and cold-chain
management and logistics will be an
engineering challenge as the industry
moves forward.
UNIQUE CHALLENGES
FOR HESC PROCESSING
Therapeutic application of human
embryonic stem cells (hESCs) offers
promising opportunities for addressing
diseases using unprecedented stategies.
This type of allogeneic process comes
with unique challenges, however.
These cells can proliferate indefinitely
in culture and differentiate into
lineage-restricted cells of all three
primary germ types (ectoderm,
mesoderm, and endoderm). That
ability of hESCs to proliferate
indefinitely allows for large,
characterized, CGMP-compliant cell
banks of undifferentiated hESCs to be
manufactured and tested. Cells from
those banks are thawed and expanded
to create large quantities of
undifferentiated hESCs, from which
differentiation cultures are initiated.
Differentiation culture processes
are designed to send hESCs down
specific differentiation pathways
through chemical signals from their
culture microenvironment (e.g.,
soluble signals in their media or
insoluble signaling from an adhesion
matrix) until a therapeutic cell
population of interest is produced.
During differentiation, the cells
typically pass through several
developmental stages and require
many media changes with different
formulations. Because of these
complex processes, differentiation
protocols are only now being
developed that are sufficiently robust
and reproducible to support
therapeutics manufacture.
Currently hESCs are cultured in
2D adherent systems on animal-
derived surfaces. Unlike many
adherent cultures, they are grown as
colonies of tightly clustered cells
(Photo 2). Cellcell adhesion is
important in chromosome stability,
and cells are in many cases passaged as
colonies using mechanical methods to
remove them from surfaces. The
passaging technique limits expansion
in multilayered vessels.
Technology development in the
emerging field of hESC bioprocessing
has focused on addressing technical
and raw-material challenges. For
example, several defined surfaces
including peptides and purified
recombinant proteins have been
identified recently that support
undifferentiated expansion and
differentiation of hESCs (1215),
which marks an important step toward
animal-originfree cultures.
Nonmechanical methods for
harvesting such cultures from flasks,
while maintaining the hESCs in
colony form, will make multilayer
vessel expansion a possibility. Proof-
of-concept work has used suspension
culture on either microcarriers or as
cell aggregates in suspension, which
would enable scalable bioreactor
production (2). Establishing
comparability of such scaled processes
will be critical, which emphasizes the
importance of analytical methods for
cell characterization and potency.
Because hESC production remains at
relatively small scales, little work has
been performed on scalable
downstream processing systems for
their postculture manipulation. Cell
separation technologies for reducing
cellular impurities in final products
may need to be developed and scaled,
as well.
THE FUTURE OF
CELL THERAPY BIOPROCESSING
Two decades ago, biotherapeutic yields
were beginning to reach 100 mg/L,
and todays 10 g/L yields would have
been almost unimaginable. Cell
therapy bioprocessing is still in its
early stages, and innovation focused
on addressing specific challenges will
bring similar advances. To succeed,
commercial success of at least a few
late-stage products currently in
development will be needed to fund
development of next-generation tools
and technologies for this field.
The Process and Product
Development subcommittee of ISCT
is working within the precompetitive
space of this field; driving home the
importance of integrating product and
process development; and stressing the
importance of cell characterization,
process reproducibility, and
standardization. Our end goal is a
sustainable industry based on robust,
scalable processes that are developed
to maintain the critical quality
parameters and important biological
functions of this new class of living-
cell products to address many diseases
that currently are untreatable, all at
reasonable manufacturing costs (3).
REFERENCES
1 Burger SR. Manufacturing Cell
Therapy Products: Models, Methods, and
Process Development. Cell Therapy
Manufacturing: Stem Cell and Immunotherapies,
London, UK, December 2010. Informa Life
Sciences: London, UK.
2 Kirouac D, Zandstra P. The Systematic
Production of Cells for Cell Therapies. Cell
Stem Cell 9 October 2008: 369381.
3 Mason C, Hoare M. Regenerative
Medicine Bioprocessing: The Need to Learn
from the Experience of Other Fields. Regen.
Med. 1(5) 2006: 615623.
4 Birch JR, Racher AJ. Antibody
Production. Adv. Drug Del. Rev. 58, 2006:
671685.
5 Fitzpatrik I. Cellular Therapy Success
Through Integrated Automation. BioProcess Int.
6(9) 2008: S32S37.
6 Hampson B, Rowley JA, Venturi N.
Manufacturing Patient-Specific Cell Therapy
Products. BioProcess Int. 6(8) 2008: 6072.
7 CBER. Draft Guidance for Industry:
Potency Tests for Cellular and Gene Therapy
Products. US Food and Drug Administration:
Rockville, MD, October 2008; www.fda.gov/
downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/
Guidances/CellularandGeneTherapy/
ucm078687.pdf
8 McIntyre C, Flyg B, Fong TC.
Fluorescence-Activated Cell Sorting for
CGMP Processing of Therapeutic Cells.
BioProcess Int. 8(6) 2010: 4453.
9 Dominici M, et al. Minimal Criteria for
Defining Multipotent Mesenchymal Stromal
Cells: The International Society for Cellular
Therapy Position Statement. Cytother. 8(4)
2006: 315317.
10 Rowley JA. Developing Cell Therapy
Biomanufacturing Processes. Chem. Eng. Progr.
(SBE Stem Cell Engineering Supplement)
November 2010: 5055.
11 Woods EJ, et al. Container System for
Enabling Commercial Production of
Cryopreserved Cell Therapy Products. Regen.
Med. 5(4) 2010: 659667.
12 Melkoumian Z, et al. Synthetic
Peptide-Acrylate Surfaces for Long-Term Self-
Renewal and Cardiomyocyte Differentiation of
Human Embryonic Stem Cells. Nat. Biotechnol.
28(6) 2010: 606610.
13 Rodin S, et al. Long-Term Self-
Renewal of Human Pluripotent Stem Cells on
Human Recombinant Laminin-511. Nat.
Biotechnol. 28(6) 2010: 611615.
14 Villa-Diaz LG, et al. Synthetic Polymer
Coatings for Long-Term Growth of Human
Embryonic Stem Cells. Nat. Biotechnol. 28(6)
2010: 581583.
15 Klim JR, et al. A Defined
Glycosaminoglycan-Binding Substratum for
Human Pluripotent Stem Cells. Nat. Meth.
7(12) 2010: 989994.
C
Ralph Brandenberger is director of
process sciences at Geron Corporation;
Scott Burger is principal at Advanced Cell
and Gene Therapy, LLC; Andrew Campbell
is a senior staff scientist for Life
Technologies; Tim Fong is technical
director for cell therapy at BD Biosciences;
Erika Lapinskas is in business
development at Sartorius-Stedim; and
corresponding author Jon A. Rowley is
director of cell therapy research and process
development services at Lonza Walkersville,
Inc., 8830 Biggs Ford Road, Walkersville, MD
21793-0127; 1-301-898-7025 x2620; jon.
rowley@lonza.com; www.lonza.com.
All are members of the Process and Product
Development subcommittee of ISCT.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download a low-resolution PDF online
at www.bioprocessintl.com.
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38 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES TECHNOLOGY
Meeting the Challenges in
Manufacturing Autologous
Cellular Therapies
by Tamara T. Monesmith
P
ersonalized medicine is a
promising new approach to
disease treatment. The
ultimate in personalized
medicine is a cellular therapy
manufactured specifically for an
individual patient using his or her own
cells. But this autologous approach to
generating immunotherapies has
unique manufacturing challenges.
Each patient receives an individual
product batch, which needs to be
manufactured, tested, and released. So
thousands to tens of thousands of
batches could be made for each
indication every year. Given the
personalized nature of these therapies,
the production scale remains the same
for each batch. Thus, scale-up is not
required; scale-out is key for meeting
the demands of autologous cell-
therapy manufacturing.
MANUFACTURING METHODS
Generating autologous cellular
therapies can take several approaches.
In general, all involve obtaining
autologous cells from a patient by
procedures performed at a hospital or
blood center. Depending on the
therapy, those cells are either
transferred to a local laboratory for
further processing or shipped to a
central processing facility. This
starting material has limited stability,
requiring immediate processing upon
receipt. For proliferating cells, the
desired cell type for a given therapy is
typically expanded in cell culture. If
the cells are terminally differentiated
(nonproliferating), then cells for the
therapy are typically generated by
isolating precursor cells for the desired
type and culturing them with
appropriate cytokines for
differentiation into the desired cell
type.
During cellular processing, an
antigen may be added to elicit a
desired immune response. This may
be a defined antigen (the same for
every patient and process) that can be
produced using traditional large-scale
methods. For example, Dendreon
Corporation uses a defined-antigen
approach in making its Provenge
(sipuleucel-T) prostate cancer
treatment, which received the first and
only FDA approval to date for an
autologous cellular therapy in April
2010. The antigen for Provenge is a
recombinant fusion protein comprising
granulocyte macrophagecolony
stimulating factor (GM-CSF)
crosslinked to the prostate antigen
prostatic acid phosphotase (PAP).
This recombinant fusion protein
(PAP-GM-CSF) is manufactured at
large scale to provide material for
multiple batches of product.
Other manufacturing approaches
use an autologous antigen from each
patients tumor for oncology
treatment or from a given virus for
treating infectious diseases. They
generate completely autologous
cellular therapies tailored to each
individuals disease. This enables
adaptation of methods from one
indication to another without the
need to identify defined antigens for
each indication. However, it also
increases the complexity of the
manufacturing process because an
antigen needs to be processed and
tested for each patient and combined
with that patients own cells.
There are different methods for
processing autologous antigens. The
simplest method is to use tumor lysate,
which requires relatively minimal
processing, essentially a
homogenization step. That provides a
Photo 1: Argoss prototype device for amplified
RNA processing was developed with the
Australian company Invetech Pty. Ltd.
patients cells directly with the proteins expressed by his or
her tumor as antigens during cellular processing to generate
the immunotherapy. Alternatively, tumor lysate can be
processed to isolate total RNA, enabling cells of interest to
express and process it for the immunotherapy. This can be
taken a step further by amplifying the mRNA in the
isolated total RNA. Although that requires the most effort
in terms of antigen processing, a relatively small amount of
tumor is required to generate sufficient mRNA for multiple
doses (or even multiple batches) of the cellular therapy.
Following cellular processing, the resulting cellular
therapy may be either directly infused (so one
manufacturing run generates one dose for the patient) or
cryogenically preserved (in multiple doses). Once
cryogenically preserved, each individual dose for a patient
is then delivered using liquid nitrogen dry shippers before
administration.
In early phase clinical trials, the manufacturing of
cellular therapies generally uses manual processing methods
transferred from research laboratories. Semiautomated
commercial equipment options are available for the
isolating precursor cells. Some instruments use antibody-
coated beadbased methods (e.g., the CliniMACS cell
separation system from Miltenyi Biotec, www.
miltenyibiotec.com) for isolating precursor cells. Another is
based on elutriation, also known as counterflow
centrifugation (the Elutra cell separation system from
CaridianBCT Inc., www.caridianbct.com). Some
companies have developed their own proprietary methods
for isolating precursor cells. Examples include a tangential-
flow filtration method developed by Northwest
Biotherapeutics, Inc. (www.nwbio.com) and a cell
separation device used by Dendreon.
Options abound for the initial isolation of precursor
cells. But little automated commercial equipment is
available to address either the remaining cellular processing
steps or the more complex antigen processing steps. Some
companies are working to develop cellular therapy enabling
devices, such as Miltenyis CliniMACS Prodigy system.
But a need remains for automated equipment that can
handle the complexity of autologous therapy processing and
enable scale-out for larger clinical trials and
commercialization. Therefore, Argos Therapeutics initiated
development of its own automated system to address these
manufacturing challenges.
The key to scale-out for autologous cellular therapies is
using functionally closed, single-use technologies and
automation for processing. Such disposables minimize
cleaning requirements between batches which is critical
for turnover of equipment and eliminate concerns
regarding cross contamination. Automation provides
consistency and efficiency in processing using disposables.
A CUSTOM DESIGN
Argoss Arcelis platform generates monocyte-derived
dendritic-cell products in clinical development for
oncology and infectious disease. The technology uses
amplified RNA from a patients tumor sample as an
Ccscd SysLcns rcn Ccrnng
ln Ihe race Io bring new drugs, Iherapies and vaccines Io markeI, researchers
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40 BioProcess International MARCH 2011 SUPPLEMENT
products in clinical development for
oncology and infectious disease. The
technology uses amplified RNA from
a patients tumor sample as an
antigen (Figure 1). In collaboration
with Invetech Pty. Ltd. (www.
invetech.com.au), Argos is developing
automated equipment that uses
functionally closed disposables to
enable commercial manufacturing.
White blood cells obtained from
patients through leukapheresis are
shipped to the Argos central
manufacturing facility for processing.
Isolation of monocytes (the precursor
cells used to generate dendritic cells)
is performed using a functionally
closed disposable and the existing
semiautomated Elutra cell separation
system. Two additional devices are in
development to perform the
remaining cellular processing steps:
media-exchange steps required to
prepare the cells for culture,
electroporation (the process used to
introduce antigen RNA into cells),
and formulation and fill of the drug
product. Because the drug product
formulation uses each patients own
plasma as an excipient, one device
processes the plasma, which is
collected during leukapheresis, and
prepares it for use in the final
formulation of the cellular therapy.
Patient material never comes into
contact with the equipment, only the
disposable, which prevents cross
contamination and minimizes
cleaning between processes. The use
of tube sealers and tube welders
enables movement (removal or
addition) of bags or reagents as
required. For example, when culture
bags are filled with the appropriate
cells, media, and cytokines, they are
removed using a tube sealer to be
incubated for the required five days.
When cells need harvesting, those
culture bags are attached to the
appropriate disposable using a tube
welder. Methods are in place to verify
that the appropriate patients cells
will be welded onto the disposable.
Similar methods verify that the
correct tubes are being welded before
welding is enabled for all reagents
and in-processing materials.
Argos and Invetech designed a
third prototype device (Photo 1) to
process tumor homogenates to isolate
and amplify RNA inside a
functionally closed disposable
container. This single-use technology
has been uniquely designed to ensure
that equipment does not come into
contact with patient material (Figure
2). Again, this eliminates concerns
for cross contamination between
processes. It also eliminates the need
for cleaning validation, which would
be extremely challenging because the
product generated during this process
is amplified nucleic acid.
The disposable containment
consists of a rigid tray incorporating
a PCR plate for nucleic acid
amplification. It also contains
washing and elution stations for
isolation and purification steps. A
disposable pump head is
incorporated to generate a closed-
loop vacuum for isolation and
purification using silica columns. An
incorporated reagent rack can be
cooled to ensure reagent stability.
All necessary reagents are foil-sealed
until required for processing. There
are tip racks to hold new and used
pipette tips for all liquid transfers. A
f lexible barrier top with an
incorporated pipette head is sealed
onto the rigid tray. The barrier
allows a pipette head to access all
areas inside the tray: tip racks,
reagent racks, PCR plate, and
washing/elution stations.
The device contains analytical
equipment needed to determine
concentration of the nucleic acid,
with spectrophotometric cuvettes
incorporated in the rigid tray for
such testing. Volumetric cuvettes are
designed to enable determination of
the volume of resulting nucleic acid
solutions generated to calculate
yields and volumes required for
concentration normalization. The
thermal cycler lid moves through the
side of the disposable through a
rolling boot, enabling it to move in
and out to cover the PCR plate
during incubations and allowing
pipette access for transfers to and
from the plate. Overall, this
equipment and disposable design
provides a fully automated method
for RNA isolation and amplification
from tumor homogenate in a single-
Figure 2: Argoss single-use technology for functionally closed processing of amplified RNA
Flexible barrier to allow
robot arm movement
Disposable vacuum
pump head
Pipette head attached
to robot arm
Thermal cycler lid inside
thermal cycler boot
Sealed tubing for aliquots
Figure 1: Argoss Arcelis platform for generating monocyte-derived dendritic cell therapies
Clinical Site Argos Therapeutics
Small amount of
tumor/pathogen
Leukapheresis
Intradermal injection
Cryoshipper
Total RNA
Amplifed RNA
Monocytes
Mature Dendritic Cell
Vial and Freeze
Mature, Electroporated
Dendritic Cell
use format. This is critical for
meeting the demands of commercial
manufacturing for Argos
Therapeutics.
MORE CHALLENGES
In addition to the need for automated
processing equipment, other critical
considerations come
up when processing autologous cellular
therapies on a commercial scale. The
need to process the patients cellular
samples immediately upon receipt of
them makes knowing when a therapy
is prescribed and scheduling of their
collection critical. If an antigen is
autologous as well, then companies
must ensure that material is received,
processed, and ready to be
incorporated into cellular processing.
Given the unique traceability
requirements for autologous cellular
therapies, mechanisms to ensure that
multiple patient product streams are
combined correctly and that the
correct product is delivered to each
patient are essential. The
extraordinarily high number of
batches being tested and released for
commercialization needs to be
addressed. The complexity of process
scheduling, traceability, and release
issues for autologous cellular therapies
requires a well-designed
manufacturing execution system to
manage those activities and enable
electronic batch records with release
by exception. For the promise of
personalized cellular therapies to be
fully realized, effective methods need
to be developed that will address all
these challenges and complexities of
their manufacture.
FOR FURTHER READING
Goldman B, DeFrancesco L. The Cancer
Vaccine Roller Coaster. Nat. Biotechnol. 27(2)
2009.
Nicolette C, et al. Dendritic Cells for
Active Immunotherapy: Optimizing Design
and Manufacture in Order to Develop
Commercially and Clinically Viable Products.
Vaccine 25, 2007: B48B60.
Whiteside TL. Evaluation of Dendritic
Cell Products Generated for Human Therapy
and Post-Treatment Immune Monitoring.
BioPharm Int. 21(3) 2008: 4267.
Miesowicz f. Dendritic-Cell Based
Therapies. Genetic Eng. News 27(20) 2007:
4446.
Finke LH, et al. Lessons from
Randomized Phase III Studies with Active
Cancer Immunotherapies: Outcomes from the
2006 Meeting of the Cancer Vaccine
Consortium (CVC). Vaccine 25S (2007): B97
B109
Osada T, et al. Dendritic Cell-Based
Immunotherapy. Int. Rev. Immunol. 25, 2006:
377413.
Hoos A, et al. A Clinical Development
Paradigm for Cancer Vaccines and Related
Biologics. J. Immunother. 30(1) 2007: 115.
Kantoff PW, et al. Sipuleucel-T
Immunotherapy for Castration-Resistant
Prostate Cancer. N. Engl. J. Med. 363, 2010:
411422.
Fitzpatrick I. Cellular Therapy Success
Through Integrated Automation. BioProcess Int.
6(9) 2008: S32S37.
Rios M. Flexible Manufacturing. BioProcess
Int. 8(5) 2010: 3446.
C
Tamara T. Monesmith is director of
manufacturing and process development at
Argos Therapeutics, 4233 Technology Drive,
Durham, NC 27704; 1-919-287-6321, fax 1-919-
287-6301; tmonesmith@argostherapeutics.
com, www.argostherapeutics.com.
To order reprints of this article, contact
Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download a low-resolution PDF online
at www.bioprocessintl.com.
42 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES COMMERCIALIZATION
Industry Roundtable
Viewpoints on Processing, Quality, and Regulations
by Maribel Rios
W
ith one eye on
commercialization and the
other on monitoring every-
day challenges, cell therapy
manufacturers are asking critical
questions about process efficiency,
ensuring quality, and satisfying
regulatory demands. In this virtual
roundtable discussion (participants
were asked questions separately), cell
therapy industry representatives
answer key questions in hopes of
broadening understanding about this
new class of biopharmaceuticals.
Participants in this roundtable are
Timothy Fong, PhD (director cell
therapy, Becton Dickinson
Biosciences), Annemarie Moseley,
PhD, MD (CEO, Repair
Technologies), Firman Ghouze
(director of cell therapy, GE
Healthcare), Aby Mathew, PhD
(senior vice president and chief
technology officer, BioLife Solutions),
and Robert Deans (vice president of
regenerative medicine at Athersys and
ISCT committee chairman).
PROCESSING
BPI: How does the processing of
therapeutic cells differ from that for
traditional biologics?
Fong: Cells are rather fragile, so
techniques used for purifying small
molecules or biologics are too harsh,
because they are mostly physical
methods of isolation with potentially
extreme non-physiological conditions.
Many cell processing protocols use a
combination of traditional cell culture
methods and techniques used in
peripheral or cord blood banking such
as elutriation. When I think about cell
therapy processing, I think more about
antibody-based separation methods.
There are two main types: magnetic-
beadcoupled antibody reagents and
flow-activated cell sorting (FACS).
However, as of today no FACS systems
are what I would consider to be
completely compliant with current
good manufacturing practice (CGMP).
So cell processing companies need to
jump through some additional hoops in
terms of process development and
validation to comply with regulatory
aspects of cell CGMP processing.
Moseley: If the cells are frozen, they
need special handling, and you need to
pay attention to the timing of
therapies. Under biotechnology
conditions cells cannot survive or they
are modified. Cell therapy processing
reactors are different, and there are no
ultracentrifuges. Currently there is not
even a good way to reduce volume from
a large cell collection. So there is a lot
of room for manufacturing
improvements all likely to come
after the first product is approved.
Ghouze: Some manufacturers use
tangential flow filtration (TFF), in
which the cells arent rammed against a
filter membrane. Many facilities that
develop cells either have discrete closed
systems to process these cells, or they
have a large CGMP-type laboratory
that works with cells.
Fong: One of the current major
needs in processing and isolating cells
in general is the development of better
closed systems in which we can isolate,
grow, activate, and expand them. The
technology is emerging, but we dont
have a lot of choices in hand to
facilitate that.
Moseley: Manufacturing is still very
people-dependent. It requires a lot of
oversight and very intense
manipulation by personnel, as opposed
to robotics and automation in
biopharmaceutical processing. Scale-up
and logistics are still in their infancy.
Its much like the antibody industry, in
which initially no one could do it, so
companies had to hire contractors.
Now everyone is making antibodies
in-house. I think that is eventually
where we are going to see this field
moving.
BPI: What equipment is used to
manufacture cell therapies?
Moseley: Most companies have
customized processes, so there are no
standardized bioreactors, for example.
Cells used in antibody production have
been manipulated to the point where
they can be in suspension, but most
Human mesenchymal stem cells
preserved for three days with
HypoThermosol FRS media from BioLife
Solutions WWW.BIOLIFESOLUTIONS.COM
MARCH 2011 BioProcess International 43 SUPPLEMENT
adult stem cells like being attached to a
surface. Designs using many tubes or
beads have been tried, but right now
there are only a few containers that
have a lot of surface area. The primary
of those are Cell Factories (Nunc,
ThermoScientific, www.nuncbrand.
com). They resemble a lot of tissue
flasks glued together. Those designs
have not addressed scale-up. They are
simple because so far there hasnt been
much demand for them. As demand
increases, the industry will need a cell
reactor. But right now, there arent
enough companies with products in the
intermediate phases, so they are having
to adapt their collection systems and
centrifugation steps.
BPI: How will scale-up become an issue
as products progress to commercialization?
Ghouze: Getting cells of the
required quality in a scalable manner
will be a challenge. Companies can
successfully process them at a scale for
small clinical studies (trials with 1020
patients). But if some of those cell
therapies progress in the way industry
hopes, and if clinical trials progress
well, then companies will need scalable
solutions from a CGMP facility to
enable really widespread distribution.
Moseley: Each Cell Factory system
has a few liters of volume media in it
that must be centrifuged to collect the
cells, which is a problem at scale-up.
Currently there are no large-scale
systems for handling that much media.
So researchers have been trying to
figure out different ways to speed up
the process of centrifugation before
cells are diluted in freezing media. All
the centrifuge systems used to collect
the antibodies off of the reactors are
way too harsh for the cells because
antibodies are so much smaller. The
process of getting massive volumes of
cells and combining them is not
automated, and companies have been
trying to figure out ways to do that
efficiently. There are some real
opportunities for process development,
automation, and new devices. Its just a
question of what is going to trigger that
work. A lot will depend on market
need and whether many companies will
be doing that part of the process
themselves or whether it will be done
through a contract services provider.
BPI: Cryopreservation is an important
processing step for some cell therapies.
What techniques are currently used?
Mathew: Techniques are usually
separated between the standard
cryopreservation methods (used by
most) of traditional ice management
home-brew freeze cocktails or the
newer class of intracellular like complex
formulations; and then to a lesser
degree vitrification. Certainly,
controlled-rate freezers have allowed
programming and greater manipulation
of freezing rates throughout a
cryopreservation protocol, but even
isopropanol freezing containers have
made it easier for folks to have more
consistency in their cryopreservation
protocol.
BPI: What tests are used to ensure cells
are viable after cryopreservation?
Mathew: All biologics are normally
maintained under normothermic
conditions either within the body or as
part of cell culture conditions.
However, once cells are removed from
normothermic conditions, changes
occur in their metabolism and cellular
integrity. If these changes are
reversible, then cells can recover
appropriately upon return to normal
conditions. If the stresses of these
changes build up too much, the cell is
negatively influenced to undergo active
pathways of breakdown (such as
apoptosis) or passive pathways of
breakdown (such as necrosis).
Tests used to ensure viability
(and/or functionality) are varied and
debatable regarding appropriateness.
For cell therapy, viability is often
assessed immediately postthaw by
simple live/dead assays that may not
indicate the true, long-term viability of
BPI: What is your understanding of FDA
requirements for assays and testing?
Moseley: The FDA requires the same
global release criteria in terms of sterility,
potency identity, and so forth as for
antibodies. Assays to date have been
based on the identity of the cells as stem
cells, and potency assays have varied
based on the indication and whether a
company chooses to focus on indication
potency or potency as to stem cellness.
The same types of toxicity testing apply,
although biodistribution is different and
duration of the studies has been longer
in some cases, making preclinical studies
more costly.
BPI: What is your understanding about
guidelines for operator safety?
Fong: Peripheral and cord blood banks
primarily use closed cell-processing
systems. A Class 10,000 room is perfectly
acceptable for those types of systems.
Other processes such as FACS cell
isolation are not closed systems. My
current understanding is that a Class
10,000 room or equivalent is probably
required in addition to some sort of
biosafety cabinet for flow instruments.
Obviously, a major concern is operator
safety because flow sorters are not
closed systems, and most of them have
some level of aerosolization. As far as
handling of large numbers of cells
before, during, and after cell
manipulation, a lot of the systems that
cell therapy developers are using today
have been co-opted from the blood
banking industry. So suppliers need to
think how they can develop more
specific closed systems for all the
different types of cells stem cells,
adherent cells, suspension cells that
companies will be wanting to grow for
future cell therapies.
A lot of developers have become very
familiar with the guidance for cord blood
banking, tissue processing guidelines,
and biologics manufacturing guidelines,
particularly when it concerns
manufacturing reagents. Take antibody-
based separation methods, for example.
If you look through the FDA guidelines
for cell therapy, it refers back to
manufacturing guidelines for therapeutic
monoclonal antibodies. So in a sense,
even though your antibody reagent is
really part of your process for isolating
your cells, manufacturing to guidelines is
essentially equivalent to a therapeutical
monoclonal antibody. Having said that, I
believe that most regulatory agencies are
flexible, and theyre looking at each IND
application and cell manufacturing
process case by case to determine
whether the level of CGMP compliance is
acceptable for that particular application.
As far as I can tell, in general, FDA and
EMA are trying to follow similar
guidelines. One issue unique to Europe is
that in addition to EMA regulations, you
have national and regional regulations
that can add another layer of complexity.
REGULATIONS AND SAFETY
44 BioProcess International MARCH 2011 SUPPLEMENT
the cells due to the phenomenon of
preservation induced, delayed onset
cell death.
During cell therapy product
characterization and manufacture, it
would behoove a manufacturer to
validate the efficacy of its preservation
methods with multiple viability,
potency/functionality, and stability
assays. For broad application to many
cell types, you can use tests such as
live/dead assays that can be assessed
with a fluorescent plate reader or flow
cytometer. Metabolic assays and
membrane integrity tests are another
method of assessing cell health.
Furthermore, analysis of the -omics
(e.g., genomics, proteomics,
metabolomics) allows for in-depth
characterization of a cell product. And
these assessments should be performed
on the cell product at multiple stages in
the stability intervals to better
understand the limitations of the
overall system of manufacturing,
banking, and/or transport, and clinical
delivery application. An optimized
biopreservation system would allow
clinical and commercial development of
cell and tissue products with the
greatest clinical efficacy, lowest
manufacturing costs, and greatest
stability to enable worldwide
distribution.
The biggest disparity is that there is
the academic/basic science
perspective to cryopreservation and a
process development view.
Academically, each cell/tissue type has
its own characteristics of water content,
membrane permeability, size, sensitivity
to stress, and so forth. However, from a
process perspective you do not want to
have to use a custom process and
custom solution for each cell type. A
cell therapy company that invests a lot
into its specific cells (such as custom
growth media) may be okay with a
custom freeze process if all it is
working on is that cell type. But if you
are a cell supplier, or a pharmaceutical
toxicity group that might be
concurrently working on CHO cells,
hepatocytes, or iPS cardiomyocytes,
then no one will want to have to use a
separate cryopreservation process for
each of these cell models. Cell therapy
groups do not want to invest more time
and resources than needed into
optimizing freeze media or cooling
rates, so cryopreservation methods that
support a streamlined, consistent, and
effective process will enable them to
achieve their goals sooner rather than
later.
BPI: Are there concerns about safety and
quality?
Moseley: Preclinical and safety
issues mostly refer to embryonic stem
cells. What you need to do to
demonstrate safety for the adult stem
cells has become almost routine now
with the FDA because probably up to
10 companies or more and many
protocols (over 50 already) have gone
through the FDA on this area. So that
is not so much an issue, but every
embryonic program will have its own
issues and programs.
Fong: One major misconception is
that cell therapy is a brand new field. If
you define cell therapy as using cells to
try to treat a medical condition, the
actual history goes back over 100 years
with blood transfusions and almost 60
years with bone marrow transplant.
However, what is new is the type of
cells and the sources of cells that we are
using. New developments are our
greater understanding of stem cells and
mature cells such as T cells and other
lymphocyte populations. We have a
better understanding of their
phenotypes, a better methodology of
isolating them to greater homogeneity,
and a greater understanding of how
cells act in normal physiology as well as
in disease. So now we can begin to
manipulate them and use them in our
favor to treat disease. That goes hand
in hand with improvements in cell
characterization and isolation.
Ghouze: Because bone marrow
transplantation has been around for a
long time, cell therapies based on bone
marrow cells have quite a robust quality
control (QC) process. There are various
techniques people can use to define
whether the cells used with
engraftment have a high likelihood of
success, for example. There is a drive
toward standardization, for QC
technologies to define what makes a
cell effective and safe. The industry is
currently moving in that direction, but
there is still some ways to go in that
area. The mechanism is poorly
understood in some instances. Having
said that, people will use existing
technologies such as flow cytometry,
but it must be scalable.
Robert Deans: There will always be
different perspectives on safety. With
the development of new and more
sensitive safety testing, tools, and
procedures, there is always going to be
a need to further educate and
reevaluate. But I dont see the adult cell
therapeutic space as being considered
highly risky at this point. Regulatory
agencies are encouraging development
and supporting trials in this area; and
there has been a very good safety track
record, especially in the case of
mesenchymal stem cells (MSCs). I
think there are now more than 5,000
patients who have been treated with
MSCs. So I dont see it as a safety
issue; I see it as a matter of education.
Potency assays are a very hot topic.
This relates to how cells are
characterized either phenotypically or
functionally, which in turn relates to
their biological performance. Part of
the issue also involves the intellectual
property that protects many cell
therapeutics. Investment and
development in this space is also going
to be driven around intellectual
property boundaries. We have an
insufficient hold on quantitatively
measuring potency and then comparing
potency among alternative but related
cell types. That is a very big area for
scientific and technology development,
and its one of the topics that is very
important for open debate so that
potential financial investors have an
opportunity to hear scientists make an
opinion on assays that they trust and
information they would require before
making a decision.
C
Maribel Rios is managing editor of
BioProcess International, 1-646-957-8884,
mrios@bioprocessintl.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808,
ext. 154. Download a low-resolution PDF
at www.bioprocessintl.com.
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CELL THERAPI ES BUSINESS
Addressing Business Models,
Reimbursement, and Cost of Goods
by Dawn Driscoll
T
he early ISCT organization
provided a powerful forum for
sharing solutions, developing
standards, and moving the
emerging concepts in cell therapy
forward as the field grew up and out of
academia. Currently, the ISCT
organization is uniquely positioned to
facilitate sharing of best practices,
standards, and strategies across the for-
profit cell therapy industry through its
Commercialization committee.
The Business Models,
Reimbursement and CoGS (cost of
goods sold) subcommittee of the ISCT
Commercialization committee was
formed to address several key business
topics with direct impact on the
industrys ability to develop, register,
and ultimately market cell therapies
successfully. The subcommittee aims
to define the issues as well as examine
successful approaches and solutions
companies have used, with a goal of
sharing best practices and strategies.
Activities in the United States, the
European Union, Japan, and China
will be evaluated, as well as in other
Asia-Pacific countries such as
Singapore and Australia. Although the
latter are smaller markets, they have
very well developed and advanced cell
therapy infrastructures and regulatory
environments.
CELL THERAPY BUSINESS MODELS
The business aspects of developing
and successfully marketing cell
therapies are genuinely complicated
but becoming better defined as the
field progresses.
An ideal cell therapy product
business model fits well with a
companys overall business plan and
integrates all relevant aspects of the
product throughout its lifecycle. Many
companies are currently wrestling with
overall go/no-go investment decisions
for cell therapy programs. Taking into
account all of a technologys
components can help determine the
appropriate manufacturing approach
and help determine whether that
technology can be a good fit within a
companys portfolio, and therefore a
solid investment.
As conventional wisdom has it, if a
technology is autologous, then its
primary emphasis will be on a service
model, whereas an allogeneic products
model is akin to a pharmaceutical,
long-termstorage model. However,
only taking allo- or auto- into
account is not sufficient for building
an appropriate business model for a
cell therapy.
All cell therapy business models are
dictated primarily by the technology:
e.g., the specific cell type, source
tissue and manufacturing process,
route of administration, and the
medical condition for which the
product will be used. Beyond that,
however, is the need to consider a
products market, including all current
and forthcoming competition; the
practice of medicine for that
indication; and flow of product,
patients, and money through the
overall system.
After those factors have been
considered, a company can build a
fully integrated forecast of production
(for example, the number of products
per month) for the entire lifecycle
(phase 13, launch, growth, and
maturity). This forecast will quantify
the needs for GMP manufacturing,
show when those needs occur, and
therefore help make the difficult rent
or buy (deciding between contract
manufacturing and internal
production) decision. Here is a
suggested pathway for mapping out an
overall model.
First, consider your product
technology, which encompasses the
following questions.
Source Tissue/Cells: Common or
rare? Hardy or delicate? Immunogenic
or not?
Production Process: Simple or
complex? Public or proprietary? Cheap
or expensive? Bedside, local, or remote?
Packaging: Single or multiple doses?
Fresh or frozen?
Based on your technologys
characteristics, next build a sales
forecast that incorporates
a rcgulatory stratcgy, with timing
and target content for each filing (e.g.,
it is not sufficient to write File an
IND; map out laboratory, clinical,
and other data that each filing must
contain to schedule what must be
gathered at each point)
a manulacturing/proccss
development and scale-up plan,
including a plan for transitioning to
commercial GMP scale-up
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a CoGS cstimatc, providing costs
lor cach stcpup in GMPncss"
a clinical dcvclopmcnt plan,
including a cost cstimatc, cxpcctcd
timing and gcographics in which trials
will bc conductcd, and dcscription ol
thc spccilic 1' and 2' cndpoints to
dcmonstratc salcty, cllicacy, and
rcimbursibility," bccausc thcsc all
dctcrminc thc product prolilc
a markct ovcrvicw, including a
dcscription ol how thc condition is
currcntly trcatcd, thc major
compctitivc thrcats, and a projcctcd
dcscription ol thc markct at launch.
Finally, combining thosc product
tcchnology dctails with thc lorccast
will hclp dctcrminc thc overall
appropriate business model lor a
product. Although traditional modcls
arc scrvicc (c.g., surgcry), dcvicc (c.g.,
bcdsidc proccssing), and ollthcshcll
(bankcd or shcllstablc product), ccll
thcrapics will cross ovcr into multiplc
modcls. All modcls prcscnt advantagcs
and disadvantagcs, but undcrstanding
thc lull aspccts ol thc product, its
manulacturing, and uptakc lorccast
and ovcrall markct will hclp dctcrminc
whcthcr thc product is a good portlolio
lit an important milcstonc.
REIMBURSEMENT
Reimbursement is a word that many
pcoplc in thc ccll thcrapy
commcrcialization world drcad
irrationally. At this point in ccll
thcrapics' toddlcrhood," thc costs lor
most linal ccll thcrapy products arc
rclativcly high, whcrcas rcimburscmcnt
lor thosc products is likcly to bc
constraincd. !n many countrics, thcrc
is a nccd (and rcgulatcd rcquircmcnt)
to incorporatc cconomic, costbcnclit
aspccts into clinical trials. That is,
conccpts ol qualityollilc (QoL)
bcnclit (bcyond clinical outcomcs) and
impact on ovcrall costs to thc
hcalthcarc systcm must bc considcrcd.
8clorc you can dclinc rcimburscmcnt
potcntial, you must lully undcrstand
your product's prcdictcd usc in tcrms
ol its cxact mcdical coding and
undcrstand thc lull rangc ol compcting
thcrapics in that codc and thcir
associatcd costs to paycrs.
Many dcvclopcrs locus only on thc
rcquircmcnts to gct a ccll thcrapy
through rcgulatory approval and
liccnscd lor salc. Liccnsurc, howcvcr,
is only thc bcginning. !n countrics
such as thc Unitcd Statcs, whcrc thc
govcrnmcnt is not thc primary or solc
paycr lor mcdicincs, a product's
approval lor salc is not ticd in any way
to its rcimburscmcnt status. Howcvcr,
actual clinical usc and uptakc ol thc
product is complctcly dcpcndcnt on
having achicvcd a rcimbursablc"
status lrom multiplc kcy paycrs such
as Mcdicarc and largc privatc insurcrs.
That said, in many countrics whcrc
thc govcrnmcnt is thc primary paycr
lor mcdicincs, liccnsurc and
rcimburscmcnt arc ticd closcly
togcthcr. !n thc Unitcd Kingdom, lor
cxamplc, approval ol ncw mcdicincs
cntails an cconomic justilication lor
thc mcdicinc and an asscssmcnt ol its
ovcrall impact to thc national hcalth
budgct.
Vith cithcr typc ol paycr systcm,
clinical trials should includc cndpoints
that addrcss conccpts thc paycrs will
bc cvaluating whcn considcring
whcthcr or not to pay lor thc thcrapy.
An cxamplc ol this would bc to
include a validated quality-of-life
questionnaire to the case report forms.
A good QoL survey will address not
only clinical-type questions (e.g., such
as those referring to pain), but also
general everyday-life questions about a
patients ability to care for himself,
drive, and return to work.
Building the case for adequate
reimbursement based on a therapys
clinical and social benefits as part of
the clinical trials is crucial. It is also
crucial for the developer of a cell
therapy to understand fully the costs
of making its product. Although this
may not be considered a primary
rationale for payers to agree to a
certain price point, it can provide
good secondary rationale. It is also
critical for the understanding of the
potential areas of savings and for
building out the long-term business
plans for the product.
COST OF GOODS SOLD
A therapys long-term financial
outlook begins with the above
concepts and assesses the products
costs to understand the impact to
business. Certain cost drivers can be
identified as likely to be lowered either
through technology improvements
such as automation or through
economies of scale. Understanding all
cost drivers allows developers to
identify areas for savings.
Common critical questions include
Vhat inllucnccs cconomics ol
scale in cell therapies autologous or
allogeneic?
How can costs bc drivcn down:
Vhcn is thc right timc to start
thinking about automation?
Howcvcr, it is oltcn thc
unanticipated costs of cell therapies
that drive the profitability down
substantially. Companies need to be
prepared for the high cost of
biologistics, maintenance of (and
documentation of) chain of command
throughout the entire process, and the
potentially staggering cost of long term
follow up of patients treated in clinical
trials. A corollary to that is the high
cost of obtaining clinical trial
insurance/underwriting for trials that
will entail very long-term patient follow
ups, as do most gene therapy trials.
IMPORTANCE OF AN
INTEGRATED BUSINESS MODEL
In conclusion, companies can address
the difficult go/no-go investment
decisions for cell therapy programs, by
building an integrated business model,
including in the model realistic and
thorough estimates for both
anticipated reimbursement and CoGS.
This can be developed to map out a
full development and sales pathway for
cell therapy products and provide a
clear picture of the products fit within
a companys structure.
C
Dawn Driscoll, MBA, PhD, is chair of ISCTs
Business Models, Reimbursement, and CoGS
subcommittee as well as principal of
DCi Biotech Inc., 1-215-847-0777 or 61-4-
8734-3292; ddriscoll@dci-biotech.com;
www.dci-biotech.com.
For Further Reading
For more discussion on the topics raised
here, see Building from the Ground Up by
S. Anne Montgomery in the accompanying
March 2011 issue of BioProcess International.
17
th
ANNUAL
MEETING
ISCT
50 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES EDUCATION
Industry Educational Platforms
Drive Commercialization Objectives
An Interview with Tracie Lodie of ISCT
by Maribel Rios
W
ithin the International
Society for Cellular
Therapys (ISCTs)
Industry Commercialization
committee, Tracey Lodie, director of
immunology and stem cell biology at
Genzyme, chairs the Industry
Education subcommittee, which was
established in May 2010. In an
interview with BPI, she described the
subcommittees objectives and how
they tie into the manufacturing,
testing, and commercialization
challenges for cellular therapies.
REDUCING THE RISK
ISCT is working toward becoming an
informational hub, acting as a resource
to de-risk cell therapy and get products
to market. We work together in four
subgroups: process/product
development, clinical development/new
product introduction, business models/
reimbursement/COG, and industry
education. We seek to aid in developing
business models from early discovery to
pre-clinical research through to clinical
development. The goal of the education
committee is to evaluate how the
industry is addressing these needs,
discovering where we find overlap with
other societies, and bringing this
information to those in the clinical
field and at the research bench.
A new goal this year for us is to
select certain disease indications that
ISCT members and cell therapy
experts felt were good areas to focus
on. There is a significant amount of
preclinical data and early clinical data
for certain disease areas. We want to
hold discussion forums that focus on
these areas with expert key opinion
leaders, including medical scientists
and regulatory experts. We want to
identify and address the holes in
technology and push the technology
forward in particular indications.
Once this information is available we
will disseminate it trough public
channels at ISCT.
The education committees goal is
not to promote a specific company; we
do not give out proprietary
information. We have assembled a
core group of people who want to
advance cell therapies before they
want to advance a particular product
for their company, realizing that one
persons success allows people to
piggyback on those regulatory and
clinical successes and even move on to
different indications.
INDUSTRY CHALLENGES
Analytics: As with any company, the
main challenge for those working in
cell therapy is determining how to
manufacture product that will get
regulatory approval. In general, the
field needs to improve on cell
characterization and identification to
ensure from lot to lot that what you are
developing is actually the same
product. Its very different from an
antibody or small molecule for which
you can do standard quality assurance/
quality control analysis. Its a cell, and
there are going to be varying degrees of
differences from batch to batch simply
because of normal biologic growth.
The field is still advancing and in
need of developing additional potency
assays to discern these slight variances
from lot to lot in vitro testing to
translating into clinical efficacy. If you
had a reagent that hit a single target, I
would be able to tell you the
concentration that is the maximum
dose. But with a cell therapy, there are
always areas of gray. That is the
challenge in the field. As a committee,
we are reaching out to others in the
field and other societies to tackle these
issues and get the information out
publicly to the point that regulatory
agencies will adopt it. That is the goal.
Right now there has been such a risk
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that many companies have been going into indications where
the treatment may be the last effort or the treatment is very
specific. For example, embryonic stem cells (hES) are being
tested in the clinic in a very specific spinal cord injury
population. So you either eliminate risk by going into a
narrow subset of a population or by going into a population
where its end-stage.
Manufacturing: Its much more expensive to manufacture
a cell therapy because of all the components that go into it,
including media, serum, lab space, tissue culture space, and
delivery. Its not something standard can fit in a vial and store
at room temperature or lyophilized and reconstituted. There
are going to be cost-based challenges to manufacturing. For
most in big pharma, it will not be sufficient to just transfer the
know-how to get a product approved, it must be profitable. A
process may be scalable and reproducible, but it might not be
the most cost efficient and needs to be more refined. Thats
where ISCT wants to come in with industry education
information that will help companies get more refined and
scalable processes, learning from what has been experienced
from phase 3 to approval.
Clinical Trials: Cell therapies undergo the same phases of
clinical development as protein biologics. You still need to
show efficacy, primary pharmacokinetics (PK) and
pharmacodynamics (PD), animal studies, and so forth before
getting into the clinic. But the challenge lies in the PK and
PD of a cell therapy because it is distributed throughout the
body and may or may not be incorporated into the tissue that
should be treated. This is very different from an antibody or
small molecule that has a certain half life. A cell therapy
provides unique challenges based on the cells multifaceted
mode of action.
Biotech has taken on diseases that are difficult to tackle,
and cell therapies have their own niche where other
therapeutics have failed. This means clinical trials are
difficult. Cells are usually added on top of an existing
standard of care, so the number of patients has to be larger in
order to get a significant outcome. If its a refractory or
relapsing population, then the trial is more challenging from
the outset. For example, in treatments for graft-versus-host-
disease (GVHD), adult mesenchymal stem cells have gone in
to either assist with bone marrow transplant reconstitution or
to actually cure steroid refractory resistant GVHD.
Adult mesenchymal stem cells have a dramatic safety
profile and have shown efficacy in phase 2 clinical trials, but
the field is still waiting the first approval due to the need for
a conclusive phase 3 trial. Even though big pharma considers
GVHD a risky indication with difficult patient populations
and the larger trial size needed due to its multiorgan nature,
a success comes with a big reward. The ultimate goal is an
approved product to treat this unmet medical need.
ISCT wants to get thought leaders in the field to
identify bottlenecks in that development. As an information
hub, we can improve this and get big pharma involved. The
more big pharma is involved, the more know-how there is
for getting therapies into the clinic and toward approval that
is profitable. That is the lofty goal.
Improving Business Models: Cell therapy companies are
trying to determine how to make the hurdle toward end-
Technologies Include:
Cell Therapies
Chemicals & Raw Materials
Clinical Trial Services
Contract Services
Downstream Processing
Economic Development & Site Selection
Equipment and Laboratory Products
Expression Systems/Upstream Processing
Information Technology
stage manufacturing, get more cell
therapies to the clinic, and improve
their business models to make it
profitable. That was an issue for
Genzyme with our autologous cell
products. They were scaled up and
processed and delivered to the patient,
but the infrastructure was such that in
order make it profitable, we would
need to treat many more patients than
we were able to treat using an
autologous therapy. The therapy
worked and was very efficacious, but it
was never very profitable.
The business model is very
different for allogeneic cell therapies.
The cost of goods needs to be
improved in terms of scalability,
where you can remove fetal bovine
serum and you can remove certain
scale-up steps as well as certain
intermediaries such as freezing to
have it fine tuned. That is really
where the field needs to improve.
Intellectual Property: When you
make a recombinant protein, you make it
from one source, but a lot of these cells
can come from several sources. What
makes the IP challenging is the different
cell-surface markers for the cells that
come from different organs. And the
question that arises from a patent
examiner is: Is this cell functionally
different? People may not know the
answer to that because the potency
assays are not refined enough to answer
that. That is where the difficultly arises.
These are the challenges that lay ahead
for cell therapy.
CURRENT PROJECTS
The task ISCT has set for themselves is
to provide industry information and to
link experts in the field to assist them to
find the best indication to trial a cell
therapy. ISCT wants to be a hub for
information for scientific data, from both
preclinical and clinical trials, and to have
access to key opinion leaders in certain
indications. ISCTs goal is to have the
information and the experts and link the
two. Currently we are working on
coordinating a two-day forum on
inflammatory bowel disease to get
industry, biotech, and regulatory
representatives. The industry community
is working on putting together plenary
sessions for the ISCT annual meeting.
And we will work on an announcement
of that for the ISCT website.
And we are in the process of
linking ISCT with other societies,
(with hopes to be completed by the end
of the year) through web and face-to-
face meetings. The plan is to have two-
day forums twice a year of these
investigator meetings in topics that the
industry community and other ISCT
members have deemed important, and
then publish the results of those forums
by webinar and ISCT website to get
the information out and readily
available to ISCT members.
C
Maribel Rios is managing editor of
BioProcess International, 1-646-957-8884;
mrios@bioprocessintl.com.
To order reprints of this article,
contact Carmelita Garland (carmelitag@
fosterprinting.com) at 1-800-382-0808, ext.
154. Download an electronic copy
at www.bioprocessintl.com.
22nd ESACT 2011 Vienna
Since its foundation in 1976, ESACT meetings with their joint trade exhibition have developed into
one of the two major events in the area of animal cell culture technology, building on a tradition
of combining both basic science and its use and transfer into industrial technology. Attended by
participants both from academia and industry, ESACT meetings are ideal venues for creating solu-
tions to problems by trying to understand the cell and its functioning while introducing the technical
solutions available both from research institutions and commercial providers. This years motto
Cell Based Technologies
highlights the importance of the cell as the central tool for all technologies and applications covered
in the scientic program. The Scientic and Organising Committees cordially invite you to this event
and look forward to meeting old friends, to introducing newcomers to the area of animal cell technol-
ogy and to lively interactions and discussions on the newest hot topics in the eld.
Nicole Borth Hermann Katinger
8 Visit WWW.ESACT2011.COM
For more detailed information on:
the program and scientic sessions q
interesting speakers at this event q
numerous Workshops introducing new q
techniques and discussing current
scientic challenges
the highlights of the social program q
the historic venue q
and travel information q
54 BioProcess International MARCH 2011 SUPPLEMENT
CELL THERAPI ES EDUCATION
Working Together for the Future
How One Industry Group Is Helping to Shape Policy
and Perspectives on Regenerative Medicine
by Gil Van Bokkelen
M
ost individuals who choose
to pursue a career in
healthcare would say they
do so because they are
driven by a fundamental desire to
help people. If you ask people why
they decided to work in the field of
regenerative medicine, many will tell
you its because they believe it is the
most exciting area of medical
research and that it holds the greatest
potential to transform medicine as we
know it. The transformational
potential of stem cells and
regenerative medicine is intuitively
obvious to most people whether or
not they have a scientific or technical
background. If we can effectively
harness the power and potential of
regenerative medicine technology, we
can truly transform the way medicine
is practiced in many areas.
Conventional medical approaches
are highly successful in many areas,
but unfortunately they cannot
effectively address problems and
challenges that many patients face
when dealing with the consequences
of a stroke, heart disease, progressive
medical conditions, autoimmune
disease, or trauma. In many situations,
current therapeutic and clinical
approaches are limited to being largely
palliative; they cannot alter the
underlying cause of a disease or repair
damage that has already occurred.
The best they can do is to partially
mitigate the consequences of the
damage, perhaps slow further
deterioration, and make a patient more
comfortable. The impact on quality of
life for such patients and their families
is enormous, as is the cost of care.
Successful development of novel
stem cell and regenerative medicine
therapies could genuinely improve the
lives of millions of patients who
currently have little or no hope. From
a US national healthcare perspective,
regenerative medicine technologies
have the potential to shift both the
cost curve and the current limits on
clinical outcomes in the right
direction simultaneously. Imagine
what it could mean to develop safer
and more cost-effective therapies for
conditions that are both life-altering
and hugely expensive to treat, those
that will become ever more prevalent
in an aging population. If we are
successful in dealing with just a few of
these problems, the impact will be
dramatic.
The Alliance for Regenerative
Medicine brings together leading
clinical and research institutions,
foundations, companies, patient
advocacy organizations, and other
groups committed to making the
promise of regenerative medicine a
reality. Our common goal is to make
the collective vision of transforming
medicine a reality and accelerate that
process by working together and
focusing on the following objectives:
t&EVDBUJOHQPMJDZNBLFSTPOUIF
potential of regenerative medicine
technology and approaches in all its
forms by illustrating how these
technologies can improve clinical
outcomes and reduce healthcare costs
t"EWPDBUJOHGPSEFWFMPQNFOUBOE
implementation of policies that will
incentivize investment to accelerate
the development of new therapies
while maximizing use of available
resources through creation of more
effective publicprivate collaborations
t8PSLJOHXJUIUIF64'%"BOE
other regulatory agencies to establish
clear standards and policies that will
ensure patient safety while creating a
clear regulatory development path that
can lead to safer and more effective
medicines
t1BSUOFSJOHXJUIQBUJFOUBEWPDBDZ
groups and others to help educate the
media and the general public on the
power and promise of stem cells and
regenerative medicine
t8PSLJOHXJUIUIF64/BUJPOBM
Institutes of Health to ensure robust
Teamwork: human embryonic stem (hES)
cell colony on a mouse embryonic fibroblast
feeder layer PUBLIC DOMAIN IMAGE
MARCH 2011 BioProcess International 55 SUPPLEMENT
funding resources for innovation and
clinical translation across various
disciplines contributing to regenerative
medicine research.
Those are challenging objectives
that will require sustained effort over
time. By working together, we can
improve the world around us through
technological leadership, effective
policy making, focused investment,
and teamwork.
In September 2010, ARM held its
first International Legislative Fly-In
Day to meet with members of the US
Congress and their staff as well as
members of the UK parliament, to
educate policy makers on important
work in regenerative medicine, and to
illustrate how emerging technologies
can improve clinical care and reduce
long-term healthcare costs, both of
which are priorities worldwide. This
day coincided with introduction of the
Regenerative Medicine Promotion Act
by representatives Diana DeGette
(D-CO) and Michael Castle (R-DE)
(1). Although the bill did not become
law, it was just the first step in the
process, and Im optimistic about the
impact we can have if we continue to
work together. These are efforts
everyone can be part of, whether by
directly supporting ARM or
volunteering time and effort to
advocate for polices that promote the
development of new regenerative
medicines. Im honored to work with
so many dedicated individuals who are
part of the Alliance and to have the
opportunity to serve as chair as we
work together to change medicine for
the better.
REFERENCES
1 Castle M, DeGette D. HR 6173:
Regenerative Medicine Promotion Act of 2010.
111th US Congress, 20092010; www.govtrack.
us/congress/bill.xpd?bill=h111-6173.
C
Dr. Gil Van Bokkelen is chairman of the
Alliance for Regenerative Medicine (2099
Pennsylvania Avenue NW, Washington, DC
20006; www.alliancerm.org) and chairman
and CEO of Athersys Inc. 3201 Carnegie
Avenue, Cleveland, OH 44115-2634; 1-216-
431-9900, fax 1-216-361-9495; www.
athersys.com/Home/tabid/36/Default.aspx.
SCIENCE FICTION/SCIENCE FACT
For my five-volume novel series, Racing History, I envisioned a future in which (among
other things)
- longevlty treatments help those who can afford them lead actlve, healthy llves well
into their hundreds
- whole organs and llmbs can be cloned and reconstructed from a few cells (agaln, for
a prlce)
- stem-cell-based "Kwlk-Heal wound-repalr gel and nanomedlclnes are as cheap and
easy to use as bandages and over-the-counter medlcatlons
- gene theraples help space travelers overcome cell damage from radlatlon exposure
- genetlc englneerlng has produced human-anlmal hybrlds who face troubles wlth
clvll rlghts, rampant cancers, and elaborate fertlllty lssues
- and a bloenglneered vlrus helps the "good guys defeat a seemlngly lnvulnerable
alien enemy.
Coverlng the blotechnology lndustry ln my day [ob has clearly lnfluenced the sclence
flctlon | wrlte ln my spare tlme! As an author, |'m partlcularly lnterested ln the soclal
consequences of technologlcal advancement: wlll cost lssues exacerbate class
dlvlslons and even lead to real class warfare! wlll whole new specles remaln the
property of thelr developers! wlll our technologles outpace our ablllty to control
them! Although Racing History ls set some 200 years ln the future, |'ve been surprlsed
to see how much of what | thought of as futurlstlc has come to pass [ust slnce | was
wrltlng the flrst draft a decade ago. And | do see some soclologlcal questlons already
presentlng themselves.
Relatively small events today can have far-reaching effects in the future (another
theme of my flctlon). Por example, the argument between Nlcola Tesla and Thomas
Edison regarding alternating and direct current ultimately determined what our
modern electrlcal grlds look llke and how they operate. Pestrlctlons placed by George
w. 8ush's admlnlstratlon on embryonlc stem cell research encouraged surprlslng
advances ln the lnducement of plurlpotency. Pobotlcs technologles have contrlbuted
much to labor dlfflcultles when a factory formerly employlng hundreds can now
functlon wlth mere dozens of workers. And a cell llne that early ploneers [ust
happened to be worklng wlth already (and know pretty well) Chlnese hamster
ovary cells became the prlmary work-horse mammallan expresslon system of the
proteln blopharmaceutlcal lndustry.
Currently hundreds (maybe thousands) of regeneratlve medlclne concepts are ln
varlous stages of development by laboratorles all over the world. what fractlon of
those wlll flnd thelr way to eventual market success, what products wlll change the
world, and how! wlll some cause unforeseen problems! whlch managers can be
trusted to lead thelr companles to an ethlcal as well as profltable future! How do we
ldentlfy now the small rlpples that wlll make blg waves as tlme goes by! These are
some of the questlons faced by lnvestors, patlents, physlclans, and pollcymakers
looklng at any promlslng new technology. Cell theraples and regeneratlve medlclnes
are no exceptlon.
The sclence ls no longer flctlon and the future ls lnevltable. 8ut as we you
bulld that future, remember that there are no stupld questlons. There are, however,
unlnformed and mlslnformed people who are ready to offer plenty of wrong answers,
some of whlch may be detrlmental to both your lndustry and even soclety as a whole.
Meetlngs llke APM's fly-ln day are as lmportant to regeneratlve medlclne today as the
now-legendary Asllomar conference was to blotechnology ln general almost 40 years
ago. Thelr outcomes wlll be as vltal to the lndustry's future as manufacturlng
methods, tralnlng for all people lnvolved, and money to pay for lt all. |ndeed, they
may well determlne where all those come from and where they go.
Cheryl Scott, senior technical editor
BSK WWW.SXC.HU
Cell Therapy Resources
EVENTS
International Conference on Stem
Cell Research: 2526 April 2011,
Penang, Malaysia; www.stemcellconf.org
World Stem Cells for Drug
Developers Summit: 2728 April
2011, Boston, MA; http://stemcells-
drugdevelopment.com
World Stem Cells and Regenerative
Medicine Conference: 911 May
2011, London, UK; www.terrapinn.
com/2011/stemcells
17th ISCT Annual Meeting: 1821
May 2011, Rotterdam, The
Netherlands; www.celltherapysociety.
org/index.php/meetings-events/isct-
2011-annual-meeting
Stem Cells Europe: 2021 July
2011, Edinburgh, Scotland; www.
selectbiosciences.com/conferences/
SCE2009/index.aspx
MSC2011. Innovations in Cell-
Based Regenerative Therapies: 2224
August 2011, Cleveland, OH; www.
msc2011.net
Phacilitates Asian Cell and Gene
Therapy Forum: 1921 September
2011, Singapore; www.phacilitate.
co.uk/pages/singapore_cgt/index.html
IIRs Regenerative Medicine and
Stem Cell Partnering Summit: 2123
September, Boston, MA
World Stem Cell Summit: 35
October 2011, Pasadena, CA; www.
worldstemcellsummit.com
OTHER ORGANIZATIONS
Many of these organizations hold
annual meetings and other events. Find
more information on their websites.
The Alliance for Regenerative
Medicine (www.alliancerm.org)
educates key policy makers about the
potential of regenerative medicine and
advocates for favorable public policies.
The American Society of Gene and
Cell Therapy (www.asgct.org) is a
professional organization of
researchers, clinicians, and others
dedicated to the understanding,
development, and application of
genetic and cellular therapies and the
promotion of professional and public
education in the field.
The Cell Transplant Society (www.
tts.org/index.php?option=com_content
&view=article&id=71&Itemid=55) is
an international collegial association
of scientists with background/interest
in the field of cellular transplantation.
It promotes research and collaboration
on pancreatic islets, bone marrow,
endothelial, epidermal, myoblast,
neural, and stem cells.
The European Society of Gene and
Cell Therapy (www.esgct.eu) promotes
basic and clinical research in gene
therapy, cell therapy, and genetic
vaccines by facilitating education, the
exchange of information and technology,
and by serving as a professional adviser
to stakeholder communities and
regulatory bodies in Europe.
The International Society for Cell
and Gene Therapy of Cancer (www.
iscgt.net) fosters camaraderie and
scientific collaboration among scientists
and clinicians around the world in cell
and gene therapies of cancer.
The Regenerative Medicine
Foundation (www.
regenerativemedicinefoundation.org)
seeks to advance new treatments and
therapies based on tissue engineering
and regenerative medicine.
GLOSSARIES
http://stemcells.nih.gov/info/
glossary.asp
www.celltherapysociety.org/index.
php?page=glossary
www.cancercenter.com/stem-cell/
stem-cell-glossary.cfm
MORE INFORMATION
Cell Therapy News (www.
celltherapynews.com) is a free, weekly
e-newsletter and website portal
dedicated to cell therapy, stem cells,
gene therapy, cord blood, and
regenerative medicine.
Invitrogens Cell Therapy Central
Online Community: http://
cellnetwork.community.invitrogen.
com/community/celltherapycentral
The National Institutes of Health
Resource for Stem Cell Research:
http://stemcells.nih.gov/index.asp.
C
I N D E X O F
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