Earned Value Management An Approach For Effectively Managing Pipeline Value Proteomic Tools For The Study of Model Organisms

Earned Value Management
an approach for effectively

managing pipeline value
Proteomic Tools
for the Study of
Model Organisms
Patient recruitment
Are we looking in the
right place?
Compliance Enhancing
Drug Pack Design,
A Benefit for All
Summer 2009
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Contents
EDITORS NOTE
REGULATORY & MARKETPLACE
Earned Value Management; an approach for effectively
managing pipeline value
Life Sciences R&D organisations have made advancements in
managing the performance of their development projects and
portfolios, yet prioritisation, resource and budget allocation, and
the tracking of value creation remain hard to achieve. Other
industries, for example defence, manage project value using an
approach called earned value management (EVM). EVM allows
organisations to move away from tracking project performance
by comparing planned against actual expenditures and instead
provides decision-makers with accurate and reliable feedback
on cost and schedule performance throughout the lifecycle of
their project. This insight supports better planning and easier
intervention to support failing projects. This article by Christelle
Dujardin & Stuart Pavelin of KINAPSE argues that Life Sciences
R&D Organisations should adopt EVM, describes the benefits of
applying EVM at the project level, and explores the potential for
additional benefits at the portfolio level.
Quality Assurance Practices in Medical Information
Departments of Pharmaceutical Companies: An Indian
scenario
Quality Assurance (QA) has been described as a formal mechanism
for evaluating the quality of products and services and ensuring
that goals are established and assessed, and that solution are
proposed if goals are not met. QA also identifies problematic
procedures or practices that, if addressed, may lead to improved
productivity or reduced errors. This paper by Jeroze Dalal & Viraj
Suvarna reports on a Survey conducted on QA MI practices for
pharmaceutical industry-based medical information.

Scotlands Offering In Life Sciences
Life science in Scotland is thriving, and medical and scientific
discoveries, on a par with those of Sir Alexander Fleming, the
discoverer of penicillin, will not be confined to Scotlands past.
With eminent scientists such as Sir Philip Cohen and Professor Sir
Ian Wilmut continuing to innovate, together with such a strong life
science base, Scotland is perfectly placed to continue to contribute
to future world-changing discoveries. Rhona Allison, Senior
Director, Life Sciences, Scottish Enterprise take you on a tour of
this thriving enterprise.
ITI Life Sciences: Real Possibilities for Scotland
With more than 620 life science organisations and 31,000
employees, Scotland currently has one of the largest and fastest-
growing life science clusters in Europe. Renowned for its particular
expertise in oncology, cardiovascular disease, diabetes, central
nervous system diseases, virology, immunology, stem cells and
regenerative technology, over 70 per cent of Scotlands core
life science organisations focus on human healthcare. Eleanor
Mitchell, Managing Director of ITI Life Sciences, look into the future
for commercial opportunities in a number of areas including stem
cells, plant biotechnology and non-invasive medical devices.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 1 www.ipimedia.com
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EDITOR:
Dr. Patricia Lobo
Email: patricia.lobo@aol.com
DIRECTORS:
Martin Wright
Mark A. Barker
PUBLISHER:
Mark A. Barker
EDITORIAL ASSISTANT:
Linda Stewart
Email: Linda@ipimedia.com
BOOK MANAGER:
Anthony Stewart
Email: Anthony@ipimedia.com
BUSINESS DEVELOPMENT:
Marie Powell, Chris Harradine, Clive Baigent
Email: info@ipimedia.com
DESIGN DIRECTOR:
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All rights reserved. No part of this publication may be
reproduced, duplicated, stored in any retrieval system
or transmitted in any form by any means without prior
written permission of the Publishers.
The next issue of IPI will be published in autumn 2009
and quarterly thereafter.
ISSN No. International Pharmaceutical Industry
ISSN 1755-4578
The opinions and views expressed by the authors in
this magazine are not necessarily those of the Editor or
the Publisher. Please note that although care is taken
in preparation of this publication, the Editor and the
Publisher are not responsible for opinions, views and
inaccuracies in the articles. Great care is taken with
regards to artwork supplied, the Publisher cannot be
held responsible for any loss or damage incurred. This
publication is protected by copyright.
2009 PHARMA PUBLICATIONS
Contents
www.ipimedia.com 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Proteomic Tools for the Study of Model Organisms:
The use of model organisms for genetic research is as old as genetics
itself. In hindsight, the breeding of domesticated animals for traits
of interest can be seen as slow, imprecise genetic engineering.
Predictably, general investigation of this kind was slowed by the
tools available. It was not until the 1970s that DNA manipulation
allowed researchers to deliberately test hypothesis function by
altering linked genes. Damon Hostin of Strategic Diagnostics
INC. surveys the genomic tools have been developed and are
commercially available to researchers in the last few years.
Domainex: the very model of a modern classical
hybrid biopharmaco
In an exclusive interview with IPI, Dr Eddie Littler, CEO of Domainex,
reveals how the company is driving ahead with its discovery
pipeline and revenue generating service platform.
Affordable Innovation
Over the last decade India has achieved worldwide acclaim
by being the destination of choice for IT, financial services and
business process outsourcing. These same drivers are contributing
to the rise of R&D outsourcing in the life science industry. The
industry cannot sustain historical levels of growth and is facing huge
cost pressures. Low cost-based countries such as India provide an
affordable alternative to drive innovation. Chandra Rao, Executive
Director of Laxai discusses the nature of this relationship that will
move from a more transactional state, to a partnership status
yielding more value from the outsourcing relationship.
CLINICAL RESEARCH
Patient recruitment are we looking in the right
place?
There is an unusual contradiction in play within the clinical trials
process that suggests the more experienced the industry has
become in conducting clinical studies, and the more resources
investigative sites have dedicated to recruiting study volunteers,
the more difficult patient enrolment has become. This inverse
relationship between the practice and funding of clinical trials on
the one hand, and the numbers volunteering on the other, has
been well documented. Chris Cabell, Senior Vice President of
access to patients and sites, at Quintiles pose the question if we
are looking in the right place?
Global Training Initiative Challenges (An American
Perspective)
In the clinical trials industry, there is an urgent need to provide
accessible, affordable, and quality training for global clinical
research professionals. Two of the key stepping stones to a long-
term, successful clinical research career are access to initial training
and continuing education programmes. This allows the career-
minded individual to gain a foothold in the industry and continue
their professional growth. Gbolahan Fatuga & Chad Downey of
Calegio Clinical One Vision discusses the challenges for a young
Contract Research Organisation (CRO) to be able to provide
training for ambitious professional candidates internationally.
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Contents
IT & LOGISTICS
Controlled environment storage and stability storage
- the case for outsourcing
In the highly competitive world of drug development and with the
economy in its current dire state, there has never been a better
time to consider the merits of outsourcing your stability storage
requirements. Controlled Environment storage is a demanding
business. It presents many challenges including high costs,
management expertise and regulatory procedures. Patrick Jackson
of Vindon analyses that a companys decision to outsource will
very much depend on their current resources. It may suffice now,
but what of the future?
MANUFACTURING & PACKAGING:
MANUFACTURING
CMC Biologics Facing todays challenges in
biopharmaceuticals from early stage drug
development to commercial manufacturing
Dr. Patricia Lobo, Senior Consultant of Life Science Business
Solutions & Editor-in-Chief of International Pharmaceutical Industry
(IPI) speaks with Dr Bernard Chan, Chief Business Officer, Dr Mads
Laustsen, CEO of CMC Biologics, Copenhagen and Dr Gustavo
Mahler, President of CMC Icos, Seattle, on the changing dynamics
in the marketplace for manufacture of biopharmaceuticals and
CMC Biologics role as a leading contract bio - manufacturing
organisation.
Critical Considerations in the Development and
Production of Freeze-Dried Products
Freeze-drying (lyophilisation) is a widely used method for
dehydrating a vast range of materials, including pharmaceuticals,
vaccines, diagnostics, biological materials, whole organisms and
foodstuffs. Despite its increasingly wide usage, however, it is still
apparent that many regard freeze-drying as somewhat of an
art. In this article, Dr Kevin Ward from Biopharma Technology
Ltd. outlines some of the principles of the technology and how
scientists are now moving to using a rational, analytical approach
to help them be more successful and efficient in the development
and production of freeze-dried products.
MANUFACTURING & PACKAGING:
PACKAGING
Compliance Enhancing Drug Pack Design, a Benefit
for All
Increasing the effectiveness of adherence interventions might
have a far greater impact on the health of the population than any
improvement in specific medical treatment. Over the last decade
the pharmaceutical industry would have adopted pack design and
reminder features helping the patients to keep track of their drug
intake. Tassilo Korab of HCPC Europe evaluates some excellent
packages that were developed to assist the patient in his medicinal
therapy, and proves that the benefit of such patient centred design
outweighs the slightly higher cost by far.
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48
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keal ossibilities
in LiIe Sciences
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EDITORS LETTER
Dr Patricia Lobo, Senior
Consultant, Life Science
Business Solutions
Flu watch
By the time this issue of IPI reaches your
desk, many of our readers will be going
on their summer holidays and hoping
their travel will be uneventful, despite
the escalating number of swine flu cases
around the world. The most recent WHO
data, released on 18th June, showed
that swine flu had infected nearly 40,000
people around the world in 89 countries
and territories, causing 167 deaths since
late March.
It turns out that age and immune
system strength may not be factors with
this virus type A (H1N1), unlike SARS and
avian flu, where the problem is thought
to be not so much the virus itself, but how
the bodys immune system responds to it.
In past flu pandemics, young and healthy
adults were more likely to be affected
than the very young or elderly. This was
because they showed an overreaction of
their immune response, with respiratory-
system inflammation that was ultimately
fatal. A stronger immune system fighting
those infections triggered an overly
strong response and greater threat to
life. Antiviral medications such as Tamiflu
have been seen to be quite effective in
treating this swine flu. There were no
such medications in the 1918 pandemic,
although it should be noted that the
current swine flu outbreak has been, in
most countries, comparatively mild and
mostly affects a younger age group (the
under 60s).
Sanofi Pasteur, the vaccines division of
Sanofi-Aventis, produces about 40% of the
influenza vaccines distributed worldwide,
while in the US it produced more than
45% of the flu vaccines distributed for
the 2008/2009 influenza season. The
company has also developed the first
and only US-licensed avian influenza
vaccine for humans. In its response to
the new type A (H1N1) influenza strain,
Sanofi Pasteur is maintaining flexibility
with vaccine production. All of Sanofi
Pasteurs influenza vaccine facilities have
been designed and built so as to be able
to convert from seasonal flu vaccine
production to pandemic influenza
vaccine production.
Once production of type A (H1N1)
vaccine begins, Sanofi Pasteur will
reserve 10 per cent of its output for
the WHO as a donation in order to
help address the influenza pandemic in
developing countries. In the event that
Sanofi Pasteurs manufacturing facilities
become fully committed to the production
of pandemic vaccine, the company will
also supply this vaccine under a tiered-
pricing policy for developing countries.
Outsourcing drug discovery
There have been many changes in the
market for outsourced drug discovery
with increased off-shoring to India and
China. In this corner of the marketplace
there are broadly two classes of service
company in India (1) companies that
are engaged in the development of their
own products and are offering these
for licensing to third parties even at an
early stage, and are active in their own
discovery activities, and (2) CROs who
are engaged in contract research and/or
manufacturing services (CRAMS). Global
pharmaceutical companies increasingly
outsource early-stage drug discovery to
India and China. The trend is not just a
matter of cost, but by relocating these
functions to these countries it helps them
to access enormous emerging markets.
In this issue of IPI, Chandra Rao of Laxai,
a successfully growing full functional
service provider of R & D services in
India and USA, discusses the trends in
outsourcing R & D activities to India (see
page 36). Meanwhile, the UK still remains
an important place for innovation in the
drug discovery area (see interview with Dr
Eddie Littler, CEO of Domainex page
32).
On the 8th and 9th July, CPHI
Conferences is organising a conference
in Berlin on Market Opportunities
in Biologics Identifying strategic
direction and outsourcing requirements
for biopharmaceuticals. According to
market reports, revenues for biologic
drugs reached about $125bn in 2008.
Patents on most current biologics have
expired or will expire between 2009 and
2024. In addition, there is mounting
pressure from governments, insurers and
patients groups to reduce the costs of
pharmaceuticals. Biologic drugs - noted
as among some of the most expensive
medicines - are major targets for cost
savings. The complexity of biologic drugs
has retarded development of regulatory
frameworks for approval of biosimilars
in many countries. The EU was the first
major regulatory authority to adopt a
procedure allowing regulatory approval
of biosimilar medicines. The US awaits a
similar legal and regulatory framework.
Challenges facing the development of
biopharmaceuticals and their production
are discussed by CMC Biologics (page
48) and Biopharma Technology (page 52).
As always, we welcome your
contributions to IPI. Many thanks go to
the authors for their interesting articles.
Enjoy your summer holidays - and dont
forget to pack this issue of IPI!
Patricia Lobo, MSc, PhD
Managing Director & Senior Consultant
for Life Science Business Solutions (LSBS).
I have worked in the pharma sector for
over 30 years after graduating in Chemistry,
Microbiology and Biochemistry and
gaining an external PhD in Biochemical
Pharmacology and a business training
course. My industrial career in the UK led
from the QC department of a generics
CMO to the R&D department of GD
Searle (now Pfizer), followed by working as
a CRA with Stiefel Laboratories, as Senior
Clinical Research Scientist with Farmitalia
Carlo Erba (now Pfizer), Oncology
Business Unit Manager with Schering
Plough, and for nearly 17 years as a
Management Consultant for Technomark
and RSA Consulting Ltd. There I have
supported international Life Science
clients with assignments in manufacturing
, clinical research, development and
marketing, providing specialised advice
in drug development, outsourcing, due
diligence, including advice to corporate
finance and equity organisations on
M&As, JVs, alliances and investment. I
have published over 20 scientific articles,
organised a major conference and
exhibition in London and have set up a
database of Contract Manufacturers.
Email:
plobo@lifesciencebusinesssolutions.com
I um kur| M. Lck|,
In 2000, we specio|ised in t|e type ol l|ose I ond IIo C|inico| Studies w|ic|
ore critico| ond olten de|oy c|inico| deve|opment becouse ol dillicu|t recruitment
conditions. T|ese studies ore.
- lK studies in t|e torget popu|otion (e.g. 0nco|ogy lotients)
- lK studies in potient popu|otions used os p|ormoco|ogico| mode|s |i|e
potients wit| reno| ond |epotic impoirment
- lrool ol Concept studies in t|e torget popu|otion (p|ose IIo) to speed up
strotegic decisions in c|inico| deve|opment ol new medicino| products
Why ure these studies so difficu|t to performI
- No t|eropeutic benelit lor potients increose re|uctonce to porticipote in suc| o
study.T|erelore it is necessory to |ove o pone| ol suc| potients w|enever possib|e.
- Reproducib|e boundory conditions ore dillicu|t to oc|ieve in normo| |ospito|
settings. T|erelore our own c|inico| sites ore exc|usive|y used lor c|inico|
reseorc|.
I set up INNDPHAR to provide you with:
- lotient popu|otions w|ic| ore t|e most critico| ones to recruit lor p|ose I ond
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- lig| quo|ity services ol our own c|inico| cites specilico||y toi|ored lor t|ese
types ol c|inico| studies
- T|e service direct|y ond not t|roug| ony sub controctor
- 0wn potient pone|s, we perlorm t|ese studies lrequent|y
- lxpertise, os p|ose I ond IIo studies in t|ese types ol potients ore our core business
- We recruit potients in |uge po|yc|inics w|ic| cover potient doto lrom S0,000
potients or more eoc|. We cooperote wit| S !0 po|ic|inics, ond os o resu|t we
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Advertisement
REGULATORY & MARKETPLACE
Earned Value Management; an
approach for effectively managing
pipeline value
Simple numeric targets run counter
to a value creation approach
A traditional planning and budgeting
process has an annual cycle that involves
the preparation, negotiation, approval,
and monitoring of detailed plans and
budgets by department, business unit,
division, and group - all consolidated
into the master plan and budget for
the year ahead. The targets that are
agreed become commitments between
different organisational levels and are
treated as fixed performance contracts
against which managers performance
is evaluated and incentive bonuses often
paid. Actual performance is controlled
throughout the year with reports that
analyse variances against plan. Pressured
by fixed targets and performance
incentives, managers focus on making the
numbers instead of making a difference,
meeting set goals instead of maximising
potential. In pharmaceutical R&D,
managing performance by the numbers
can be associated with phenomena such
as the Year End Proof-of-Concept effect
i.e. in some companies, Research eager
to achieve its fixed target of handed-over
proof-of-concepts to Development may
push a molecule through to the next
stage gate in spite of lack of substantial
pre-clinical efficacy data. When the
managing by the number system is as
pervasive in organisations as it is today,
it influences the behaviour of managers
and employees in a way that is counter-
productive to strategic management.
Companies need to demonstrate and
track the value they generate
In many cases analysts place little value
on the development pipeline and almost
nothing on earlier projects; ca. 10% of a
pharmaceutical companys value resides
in its pipeline (although this percentage
would go up for Biotechnologies or other
R&D heavy companies). Demonstrating
the value of R&D has been lost in
detail, in fragmented information
and in surrogate measures. Todays
organisations and processes hinder our
ability to maximise value from our asset
base. Pharmaceutical companies have
done much to improve the planning and
execution of development programmes,
yet little in the way of value management
has been incorporated at this level.
Life Sciences R&D organisations need
a unifying measure and objective that
recognises the different businesses along
their R&D pipeline.
Value creation measures an
organisations ability to add value to
a project. Put simply, value creation
is the difference between the output
price and input price of an activity less
the incremental costs of that activity.
Each activity in the R&D value chain
should add expected value to an
asset or else cause its termination.
One of the objectives of project portfolio
management is to maximise the portfolio
value which includes identifying the
value drivers of each project, focusing
on key drivers, and tracking progress of
projects and the portfolio against value
targets. By measuring project progress
in an objective manner, Earned Value
Management (EVM) provides an effective
framework for tracking project and
portfolio value over time.
Earned Value tracks progress against
plan in a single indicator
Traditional cost analysis focuses on
the actual cost of the work that was
completed. Much progress has been
made to collect the actual costs through
the time charge and accounting systems
that exist on practically all projects. What
Earned Value brings is a measure of the
amount of work that has been done in
a unit of measure that is consistent and
comparable with costs. In other words,
it allows the comparison of apples
and apples by using the same unit of
measure for progress as for cost.
EVM began in high-tech industries
(defence, aerospace & engineering)
in the 1970s and is now the accepted
basis of project management in these
industries. EVM is a project management
technique used for measuring project
progress in an objective manner. It
combines measurements of technical
Figure 1: NPV Pipeline Products/Economic Capital (2002) (%) 1
Economic Capital is defined as total assets less non-operating assets,
less non-interest-bearing liabilities plus economic adjustments
Figure 2: The maturity of project management in different industries 2
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performance (i.e. accomplishment of
planned work), schedule performance
(i.e. behind/ahead of schedule), and cost
performance (i.e. under/over budget)
within a single integrated methodology.
When properly applied, EVM provides an
early warning of performance problems
and answers the question What did we
get for the money we spent?
As shown in Figure 2, pharmaceutical
R&Ds Portfolio, Project and Resource
Management (PPRM) capability lags
behind that of other R&D-intensive and
technologically-advanced industries.
In spring 2008, Kinapse conducted
a survey to help Life Sciences R&D
organisations to evaluate and compare
their PPRM maturity against that of
How is the US Government managing value?
Department of Defense (DoD) contractors are required to establish and maintain
earned value management under the ANSI-EIA-748-98 Standard 4.
In 1965, the U.S. Air Force acquisition managers defined 35 criteria which they
felt would capture the essence of Earned Value Management (EVM), and also satisfy
their need to oversee the work that was being performed for them by private industry.
Two years later, the Department of Defense (DoD) adopted these same criteria as
their Cost/Schedule Control Systems Criteria (C/SCSC). These 35 standards were
then consistently applied to all cost type and incentive type contracts for the next three
decades.
Then in 1996, after a rewrite of the 35 C/SCSC criteria by private industry, the
DoD accepted the rewriting/rewording of these criteria under a new title called the
Earned Value Management System (EVMS). The total number of criteria was reduced
to 32. The 32 criteria of the Earned Value standard are based on the principles of
sound enterprise management. These criteria cover the process categories, project
organisation, planning, updating, evaluating, forecasting and baseline control
required to effectively use Earned Value measures.
In June 1998, private industry in the form of the National Defense Industrial
Association (NDIA) took the defined criteria concept one step further and obtained
acceptance of the EVMS in the form of the American National Standards Institute,
termed the ANSI/EIA-748 Standard, which was adopted the same year by DoD.
Currently, DoD and NASA requires EVM on cost or incentive contracts, subcontracts,
and other agreements greater than $20 M.
their peers3. The survey indicates that
performance management aspects of
PPRM appear not to be managed as
critical elements of Life Sciences R&D
organisations PPRM strategy. Little in
the way of value management has been
incorporated at this level.
EVM provides the insight Management
needs to take effective project
decisions
Companies manage shareholder
expectation by providing guidance on
future performance, and it is against
shareholder expectation that company
performance is measured. The objective
of corporate strategy is to deliver value
to shareholders by prioritising projects
against strategic objectives, and it is
portfolio management that implements
corporate strategy to meet shareholder
expectations. However, portfolio
management also helps to develop
corporate strategy, and as such plays a
pivotal role in providing guidance on
future company performance.
Most companies use the traditional
expected net present value (eNPV) metric
in determining the financial value of their
development compounds in light of the
substantial technical and market-based
uncertainty inherent in pharmaceutical
R&D. Figure 3 indicates the principles of
an eNPV calculation.
Project valuations as part of
evaluations can be in some companies
the responsibility of the portfolio
management department and are
traditionally part of an annual/semi-
annual portfolio review process. As
the development process and market/
sales expectations are characterised by
uncertainty, individual project eNPVs are
inevitably subject to constant change.
Progress to market and incremental
R&D expenses affect the value of
individual projects, the portfolio and the
company. Until now R&D life sciences
leadership has not been well supported
in understanding project performance.
Most organisations have access to lots
of data:
Projects and studies have milestone-
based plans
Templates or benchmarks for
expected cycle times exist for projects
and studies
Likely external spend (direct project
costs) on projects and studies are
estimated
Resource allocation algorithms give a
view of likely internal costs by function
Costs can be related to effort and time
taken to move between milestones
Systems for gathering actual costs and
relating them to projects and studies are
in place.
The challenge organisations face is
finding a way to synthesise the above
Figure 3: Project eNPV
PoS = Probability of Success
ePV = Expected Present Values
Progress to market
and incremental R&D
expenses affect the
value of individual
projects, the portfolio
and the company.
the limits of common variance for their
projects. If CPI and/or SPI far exceed 1.0
or are well below 1.0 this may indicate
other problems in the project and may
not simply be due to the existence of
opportunities or unmanaged planning
and resourcing issues. Typically, if actual
performance is much greater or much
lower than expected or planned, this
could indicate poor planning or incorrect
scoping when setting up the initial
baseline plan. Baseline re-planning effort
should be considered 5. Plotting the
trend of CPI and SPI over time against
such thresholds can also give useful
information to indicate whether the risk
process applied is being effective in
addressing uncertainty and managing
project performance.
EVM may be pushed beyond project-
level usage to support decision-
making at the portfolio level
The EVM technique has the potential to
be pushed beyond the current state-of-
the-art application at project level and be
applied at the portfolio level. We advocate
the use of the Portfolio Performance Index
(PPI) to measure the performance of the
portfolio in terms of value.
If PPI<1, the actual portfolio
performance is behind the planned
performance. The portfolio is not on
Figure 4: Project eNPV (size of the bubble) plotted against CPI and SPI at the
time of portfolio review (Baseline)
Figure 5: Project eNPV (size of the bubble) plotted against CPI and SPI at
Baseline + n Month
Since EVM performance indices (CPI,
SPI) measure deviation from plan, they
can be used to indicate whether the risk
process is being effective in addressing
uncertainty and controlling its effects on
project performance.

A. High SPI but low CPI. The project
is overspent and ahead of schedule,
requiring focused attention to cost risk,
with the possibility of spending additional
time to address this. In such instances,
the Project Manager should be ready to
answer key questions to help decision-
makers/stakeholders to interpret the EVM
indices adequately e.g. has the project
consumed resources that were essential
for other projects?
B. Both CPI and SPI are greater than 1.
The project is underspent and ahead of
schedule, creating opportunities to be
captured e.g. consider re-distributing
resources across the portfolio, conduct
project lessons learned and identify best
project practices, etc. In such instances,
the Project Manager should expect
questions like has the overall quality of
the project been compromised to achieve
early, under-budget delivery?
C. Both CPI and SPI are lower than 1.
The project is overspent and behind
schedule, requiring aggressive action to
address threats.
D. High CPI but low SPI. The project
is underspent and behind schedule,
requiring attention to be paid to
addressing schedule risk, and cost trade-
offs to be considered. In such instances,
the Project Manager should be ready
to answer questions such as is the lack
of resources responsible for the project
delay?
The key to using EVM indices as
indicators is to determine appropriate
threshold values by reviewing historical
trend data for CPI and SPI and identifying
Figure 6: Relationship between the values of EVM indices and risk
incurred (5)
data into meaningful knowledge.
In a volatile environment, life sciences
R&D executives track and assess the risk
incurred on the overall portfolio value
by applying EVM. Project performance
can be assessed by plotting an individual
projects eNPV against their respective
Cost Performance Index (CPI) and
Schedule Performance Index (SPI). The
SPI provides an objective measure of
schedule progress by calculating the ratio
of work physically performed versus work
scheduled based on approved budget.
The CPI provides an objective measure
of cost progress by calculating the ratio
of work physically performed versus the
actual cost incurred in accomplishing the
work based on approved budget.
This can help to visually track and
identify those higher-value projects
hindered by poor performance and/or
cost efficiency factors and define the
necessary corrective actions to mitigate
the risk on the portfolio value.
track to deliver its planned value.
If PPI>1, the actual portfolio
performance is ahead of planned
performance. The portfolio is offering
additional opportunities to deliver greater
value than originally planned.
The PPI index answers the question
Will the portfolio deliver the
expected value?
While plotting the eNPV for each project
against their CPI and SPI informs on
variations in their respective project value,
monitoring the PPI over time informs on
variations in the overall portfolio value.
Clearly some variation of the PPI is to be
expected as projects unfold, but if a trend
develops and crosses the threshold of
common acceptable variance, action
should be considered to mitigate the risk.
Equally, if an upward or downward PPI
trend can inform on the risk incurred in
the overall portfolio value, a stable PPI
trend does not necessarily imply that the
portfolio is in the same shape as it was at
the baseline point. The overall portfolio
value may remain roughly the same
over time while the individual project
values vary but balance themselves out.
Therefore, the PPI is a valuable indicator
if used in combination with the eNPV for
each project plotted against their CPI
and SPI.
By defining appropriate CPI and SPI
threshold values based on historical data,
organisations can measure their portfolio
value management effectiveness. For
instance, if an organisation were to establish
0.95 as being the lowest CPI and SPI
threshold values and 1.05 as the highest
values, then the PPI performance lower
bound would be set at 0.90 [PPI lower
bound = CPI lower bound (0.95) *SPI
lower bound (0.95)] and upper bound
at 1.10 [PPI upper bound = CPI upper
bound (1.05) *SPI upper bound (1.05)].
Figure 7 illustrates an example of time
point interpretation of the PPI value and
potential risk-mitigation actions undertaken.
How to implement EVM
Implementing EVM is well worth the
effort. Although the EVM technique
has the potential to be applied at the
portfolio level, before such benefits can
be experienced the foundation of the
EVM technique needs to be solidly in
place at project level. Project Managers
and stakeholders must be first armed
with the Earned Value information so that
the current status of a project, the rates
Figure 9: Integrated Earned Value Process
Figure 8: Project Earned Value Process
Figure 7: Portfolio Performance Index (PPI) over time
challenge is to track project performance
across the entire portfolio in a timely
and effective manner. This will help R&D
executives to demonstrate that they will
deliver the planned pipeline value to give
stakeholders confidence that todays
business decisions will deliver growth
and profitability goals, leading to higher
yield R&D investments. However, since
the portfolio review is traditionally a
(semi-)annual exercise, the difficulty of
tracking variation to the expected value
of projects that are subject to constant
project planning changes is used as an
excuse not to do so. The EVM technique
applied at portfolio level can enable
holistic performance tracking of the
portfolio, monitoring of portfolio value
over time and identification of trends
which can support effective risk-mitigation
planning and implementation. Ultimately,
this delivers to R&D executives the ability
to credibly and responsively redirect the
activities of their portfolio and easily
communicate the value gained through
doing so.
Appendix - Managing Projects Using
Earned Value Measures
1. EVM consists of the following
primary and derived data elements
Primary Measures
Planned Value (BCWS) is the cost of the
work that is scheduled to be done in a
certain time period if everything goes
exactly to plan. For example, if you have
a two-day task that is scheduled to cost
$50 per day, the Budgeted Cost of Work
Scheduled (BCWS) for that task after the
first day is $50; after the second day, it is
$100. This measure tells you how much
should have been spent up to a certain
date according to your plan.
Actual Cost (ACWP) is the total
costs actually incurred and recorded in
accomplishing work performed during a
given time period for a schedule activity.
Earned Value (BCWP) is the budgeted
cost of the work that has been done
up to a certain point. This tells you
how much the work you have actually
done up to a certain date should have
cost, if the costs went according
to plan. If this number is less than BCWS,
it means that work is being done slower
than planned.
Derived/Calculated Measures
From the three primary measures it is
possible to derive measures that can be
of variances, and once significantly into
the project the end budget compared
to the original estimate, can be
accurately predicted.
Further benefits can also be gained
from implementing EVM by pushing
the techniques beyond current project-
level usage through further seamless
integration with the operational portfolio
review cycle. This enables holistic
performance tracking of the portfolio,
monitoring of portfolio value over time
and identification of trends which can
support effective risk-mitigation planning
and implementation.
Comparing planned against actual
expenditures does not inform project
performance but EVM truly does.
However, tracking and reporting actual
cost incurred in accomplishing the work
performed at the activity/project level
remains a challenging issue among life
sciences R&D organisations. One place
to start applying the EVM technique is
co-development projects because they
typically are more closely tracked and
greater information is often available.
Conclusion
Although pharmaceutical companies
understand value at the portfolio level, the
processes that they have adopted hinder
their ability to maximise value from the
asset base. Pressured by fixed targets and
performance incentives, managers focus
on making the numbers and meeting set
goals instead of maximising potential.
Life sciences R&D organisations
need a unifying measure and objectives
that recognise the different businesses
Figure 10: Earned Value Chart
supporting their R&D pipeline. Yet the
pharmaceutical industry has done little in
the way in embedding it in their project
management culture, while in the defense
industry, the US Government manages for
value by demanding of the Department
of Defense (DoD) contractors that they
maintain Earned Value Management
under the ANSI-EIA-748-98 Standard.
Life sciences R&D organisations should
move away from informing project
performance by comparing planned
against actual expenditures and
embrace EVM as the unifying measure
that truly provides project managers
and decision-makers with accurate and
reliable feedback on cost and schedule
performance throughout the life cycle of
their project.
As demonstrated in this Kinapse
White Paper, the techniques of EVM
can be pushed beyond current project-
level usage and applied at the portfolio
level. Portfolio managements common
Although
pharmaceutical
companies
understand value at
the portfolio level,
the processes that
they have adopted
hinder their ability to
maximise value from
the asset base.
The planned schedule efficiency factor
representing the relationship between
the earned value and the initial planned
schedule.
SPI = BCWP/BCWS. A SPI 1 is
good. SPI < 1 suggests actual work is
falling behind the planned schedule.
Budget at Completion (BAC). Sum
total of the time-phased budgets.
BAC= BCWS
Estimate to Complete (ETC). A
calculated value, in dollars or hours that
represents the cost of work required to
complete remaining project tasks.
ETC = BAC BCWP
Estimate at Completion (EAC). A
calculated value, in dollars or hours that
represents the projected total final costs
of work when completed.
EAC = ACWP + ETC
Please note that in Microsoft Project
2007, EAC is calculated as EAC =
ACWP + (BAC - BCWP) / CPI
Figure 13: Time-phased spend plan against actual as of 31 December 2009
Figure 14: Cumulative planned budget against cumulative actual costs and earned value
used to accurately assess the status of the
project and predict its future state.
Cost Variance (CV). The numerical
difference between the Earned Value
(BCWP) and the actual cost (ACWP).
CV = BCWP ACWP.
If CV value is positive, the project is
currently under budget.
Schedule Variance (SV). An indicator
of how much a programme is ahead of
or behind schedule.
SV = BCWP BCWS.
If SV value is positive, the project is
currently ahead of schedule.
Cost Performance Index (CPI).
The cost efficiency factor representing
the relationship between the actual cost
expended and the earned value.
CPI = BCWP/ACWP.
A CPI 1 suggests a relatively
efficient cost factor, while a CPI < 1 may
be cause for concern.
Schedule Performance Index (SPI).
Figure 11: Time-phased spend plan before project start
Figure 12: Cumluative planned budget against cumulative actual costs
2. An EVM Case Study - EVM truly
informs project performance
An example of project tracking that does
not include Earned Value performance
management is presented below. This
project has been planned in detail,
including a time-phased spend plan
for all elements of work. The project is
planned to start on 01 July 2008 and
has a planned total budget of $315 M
(BAC), and a total estimated duration of
6.5 years to submission. The planned
estimated cost for each development
phase is indicated to the right of the
activity bar.
Figure 12 shows the cumulative
planned budget for this project as a
function of time (the blue line, labelled
BCWS). It also shows the cumulative
actual cost of the project (red line)
through Q4 2009. It appears that this
project was under budget from Q3 2008
to Q4 2009. How should management
react to this information? What is missing
from this chart is an understanding of
how much work has been accomplished
during the period compared to the
planned performance.
How should management react to
this information? A method is needed
to measure technical performance
objectively and quantitatively and
inform on decision-making. That is
what EVM accomplishes.
As of 31 December 2009, the Project
Manager reports an actual total spent of
$54.5 M.
Phase 1 was completed with a three-
month delay and for an actual total spent
of $40 M.
As a consequence, the start of
Phase 2 has been delayed and as of the
status date 12% of this activity has been
completed. The actual spent to date is of
$14.5 M.
The actual cost for each development
phase is indicated to the right of the
activity bar.
Is this project on time and budget?
We have calculated for this project the
primary and derived EVM measures.
Although Figure 12 suggests that this
project is under budget at the end of
Q4 2009, the project has actually
overspent $1.7 M (CV) for the work that
has been accomplished since the start of
the project. This project is also behind
schedule (SPI<1).
3. Detailed calculation of Earned Value measures used in the case study
Legend:
Data Input: Data known by the Project Manager
Data Output: Calculated Earned Value Measures
For more information please visit www.
kinapse.com or email info@kinapse.com.
References
Kearney, A.T. 2003. The 2002 Value
Creation Index: A Prescription for
Pharmaceutical Health article). [Online]
Available at:
http://jobfunctions.bnet.com/abstract.
aspx?docid=59352 [Accessed July 2007].
Terence J., Cooke-Davies, A. and
Arzymanowc, A. 2002. The maturity
of project management in different
industries: An investigation into variations
between project management models.
[Online] Available at:http://cs.joensuu.
fi/pages/tenhunen/projhall/pm-maturity.
pdf [Accessed July 2007].
Kinapse. 2008. Portfolio, Project and
Christelle Dujardin
is a Manager
at Kinapse. She
consults with global
pharmaceutical
companies in
Portfolio, Project
and Resource Management, Peformance
Management and Organisational Design.
Resource Management (PPRM) Survey:
Analysis of Responses
National Defense Industrial Association
(NDIA). 2005. National Defense Industrial
Association (NDIA) Program Management
Systems Committee (PMSC) ANSI/
EIA-748-A Standard for Earned Value
Management Systems Intent Guide.
[Online]
Available at: http://ocio.os.doc.gov/s/
groups/public/@doc/@os/@ocio/@
oi tpp/documents/content/prod01_
002424.pdf [Accessed July 2007].
Hillson, D. 2004. Earned Value
Management and Risk Management: A
Practical Synergy [Online]
Available at:
http://www.risk-doctor.com/pdf-files/cev-
b1004.pdf [Accessed July 2007].
Stuart Pavelin is
a Vice President
at Kinapse and
leads the companys
Asset Value
Consulting practice.

Quality Assurance Practices in Medical
Information Departments of Pharmaceutical
Companies: An Indian scenario
Scientific information on new drug
therapies is increasingly becoming
available. Easy access to high quality and
reliable information is the key to enabling
the customer to understand drugs better
and to make the right choices when
prescribing. In recent years there has
been a growing recognition of the need
to improve the quality, availability and
accessibility of medical information.
This is being driven by a number of
stakeholders, namely physicians,
patients, regulatory authorities and the
pharmaceutical industry. The medical
information team in a pharmaceutical
set-up is responsible for collecting,
storing, retrieving, evaluating and sharing
this information with the customers, both
internal and external. As the volume of
data and medical information inquiries
increase, the effectiveness of the entire
response procedure can be tested and
the potential for errors increased.
Medical information services have
been described as a resource for providing
rapid, accurate, and concise information
about drugs. With the enormous amount
of information available today, it is difficult
for healthcare professionals to assimilate
all of the information that they need to
practice medicine effectively. Historically
the responsibility for storing, retrieving
and evaluating data was delegated to
drug information services in academic
or institutional facilities. However the
pharmaceutical industry has realised
its responsibility to maintain a product
information database and to disseminate
this information as requested.
Quality Assurance (QA) has been
described as a formal mechanism
for evaluating the quality of products
and services and ensuring that goals
are established and assessed, and
that solutions are proposed if goals
are not met.1 It is a method that
ensures standards are established and
maintained, in addition to identifying
solutions for standards that are not up
to the mark. Formal QA programs are
common in many areas of healthcare and
the pharmaceutical industry. However
there are very few QA programs focused
on building and maintaining quality in
medical information that is provided by
the pharmaceutical industry.
QA practices utilised by medical
information departments generally include
a review of response times, turnaround
times, standards and styles of written
responses, database tracking the queries
and responses and having QA meetings.2
The quality assurance practices reported
used in industry medical information
departments to date primarily involve
peer evaluation and user satisfaction
surveys. Quality assurance can identify
strengths and areas of improvement
in the medical information process.
Conducting internal QA reviews can help
ensure that a department is minimising
legal/regulatory risk as well as complying
with its own policies & procedures.
It has been said that obtaining
complete, accurate, practical and
timely responses from pharmaceutical
companies can be challenging.3 Often,
the scope of questions received by
medical information departments is
broad, with topics ranging from storage to
clinical application. Responding to these
questions requires a wide knowledge of
general science and clinical medicine.
Additionally, medical information
specialists may be needed to respond to
inquiries spanning a variety of therapeutic
areas. In addition to the challenges
of a wide array of questions, medical
information professionals must be acutely
careful to ensure that the information
provided to the healthcare professional
or to the consumers (patients) is
scientifically accurate and fairly balanced
with regard to the available information.
Because the pharmaceutical industry is
highly regulated, responses must meet
regulatory and legal requirements for the
provision of information from industry.4
Comparative claims are among the most
sensitive topics handled by the industry-
based drug information practitioners.
The FDA has been clear that comparative
claims must be based on well-controlled
randomised clinical studies. The responses
should be written while keeping in mind
that the audience may also include the
competitors medical, regulatory, and
legal departments and the FDA.2
There are a number of reasons to
perform QA. Reducing legal liability is one
concern for the development of ongoing,
prospective, quantitative and objective
measurement of the drug information
department. The QA process can also
increase the likelihood of consistency
among different personnel. Other reasons
for performing QA include identifying any
errors that may have occurred and using
these findings for teaching purposes. QA
also identifies problematic procedures
or practices that, if addressed, may lead
to improved productivity or reduced
errors.5,6
Materials & Methods:
A simple questionnaire was developed
on the lines of the survey conducted by
Genentech. This includes questions about
the medical information department,
response documents, vendors, corporate
partners and one question about other
QA practices.
QA Practices at Pfizer India:
The medical information function
addresses the medical information
needs of internal and external customers
by providing evaluated and formatted
information of a medical, scientific or
technical nature on Pfizer products and
programmes, its competitors and related
areas. The function actively interfaces with
other business units to ensure the quality
applicability and availability of medical
information resources. Responding
to medical information queries is an
essential component of the job of medical
There are a number
of reasons to
perform QA.
advisor in any pharmaceutical company.
In Pfizer, this is a core competency that
has, over the years, been honed to near
perfection.
Very often, one is asked to compare
the Pfizer product with that of the
competitor. It is here that Pfizer excels with
its fair evaluations. Customers respect
the company for providing unbiased
and scientifically accurate information.
Sometimes, there are situations when the
questions are based on interest that is not
purely academic or is a form of complaint
and can have legal implications. Such
cases demand that responses are carefully
worded and are not promotional in any
sense. When it is required to enclose full
text articles as references, Pfizer corporate
policy is followed. According to this,
all copyrighted material is restricted to
personal use within Pfizer and is not to be
reproduced in any form or redistributed to
any persons outside Pfizer. Feedback is an
important tool in striving for excellence.
Query response time and Customer
Feedback Score are parameters on which
we assess and benchmark ourselves. For
all medical information, peer evaluation
is a part of the quality assurance process.
In addition, medical information is
sampled and reviewed for content, style,
and response time.
Future Direction
The QA programme at Pfizer India was
re-evaluated based on departmental
changes. A need for a medical information
QA process was perceived. In addition,
the QA processes are expected to identify
areas of improvement, education and
efficiency. For example, during the QA
process, identification of a customer
interest in a certain topic may prompt the
department to develop a new medical
response document or ensure that the
current response document addresses the
needs of the customer.
Overall, a robust QA program
implementation will reap the following
benefits:
Enhance the image of the company
as a source (provider) of accurate,
balanced, concise, data-driven, evaluated
and formatted information.
Can flag training concerns or the
need to send a write-up to the field force
on a particular issue if some particular
information is repeatedly asked for.
Evaluate the existing strategies and serve
as a source of business intelligence.
As the medical information group
begins implementing QA processes,
there are multiple factors that need to be
considered:
Size & workload of the department
Available resources
Formal SOP/policy and procedures
for QA
Utility of QA results
Regulatory compliance
Review of QA practices
Corporate environment
The size of the department may determine
the number of QA practices that are
practical and required to meet the
departments standards. Additionally, the
workload and the resources available to
conduct QA may play a factor in which
QA practice is deemed necessary for
a group to maintain standards. Does
the group need to have a QA person
to support them? If so, how much time
should be devoted to QA?
The development of a formal SOP or
policy and procedure for the departments
QA process should be documented and
readily available. Having the key processes
documented allows for consistency
among the groups and can be employed
as a valuable teaching tool.
How the group uses the QA results
can dictate what QA practice the group
implements. A satisfaction survey can be
used if the group wants to document good
customer service. Having external groups
review medical response documents may
provide an opportunity for recognition of
the quality of work the group performs.
Another consideration is whether
the tracking database, as well as any
departmental processes, would be in
the scope of a regulatory audit. If this
is a consideration, conducting QA
may ensure good medical information
practices and quality work to comply
with regulations and prevent a cause for
concern during an audit.
A routine review of the QA practices/
processes any group uses should be
considered. This activity will help ensure
current medical information processes
are adequate and appropriate.
Lastly, the corporate environment
may be a consideration. How does the
company view QA? Is it viewed as Big
Brother is watching to catch errors and
punish offenders, or as a process to
ensure consistency and quality services?
At Pfizer India, it is the latter!
Results of the survey
Quality assurance practices in medical information departments in Indian
pharmaceutical industry
Of the eight responses that have been
received from medical directors of
multinational companies operating in
India the following may be gleaned: four
do not have separate medical information
departments and presumably the medical
advisors/product physicians in the medical
affairs department handle the medical
information queries. They get on average
88 medical information queries every
month, ranging from as low as 10 to as
high as 200. These queries are more often
received via email (~ 57% on an average,
ranging from as low as 20% to as high
as 92%). Paper-based queries come next
(on average, 27%, ranging from as low
as 1% to as high as 70-80%), followed
by queries received via telephone/fax/
SMS (on average, 20% ranging from as
low as 1% to as high as 70%). Five of
the eight companies maintain a system
of standard replies to commonly asked
medical information queries, and all
eight maintain electronic databases of the
queries received and replied to, mostly
in a simple Excel sheet form (5/8). Six
of the companies surveyed reported that
they do log in telephonic queries into their
database. A quality review of the medical
information function is done in six of the
eight companies medical departments but
every reply is not routed through a review
system before sent out to the doctor. None
of the companies outsource their medical
information services and none engage
vendors to send reprints to doctors.
Most did mention that the MI function
was perceived as useful to very useful
by both internal and external customers
(even unsolicited feedback), enhances the
high science image of the customer and
company, creates a good rapport with
key opinion leaders and key accounts,
increases doctor confidence and improves
patient management, which indirectly
results in increased product usage. Only
one company had an MI function related
to a disease management program, while
four have a co-marketing/co-promotion
agreement involving the shared use of MI
resources. Only one company mentioned
that they have an SOP on their medical
information practices.
The quality assurance practices in
the medical information survey that
was replied to by eight multinational
companies operating in India did reveal
that there are differences in the way
medical information is conducted in those
companies vis a vis Pfizer. Key differences
were in terms of the fact that we do not
have a separate medical information
department while four of the companies
surveyed did have such a separate
function, indicating the importance of MI
to the business. The number of queries
received per month was comparable, but
Pfizer India does respond to more queries
than a number of these companies. Some
companies have switched to an electronic
system (simple Excel-based format) but
most still have a paper-based system. But
even among those who have an electronic
system, none have a Documentum-based
system. Five companies (among the eight
surveyed; eight did not respond before
the cutoff date of April 15, 2007) do
have a system of standard replies, and
while we do have an excellent repository
it is time we also moved towards a system
of standard replies which makes it easier
for medical information officers who may
List of pharmaceutical companies surveyed
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Jean Philippe Pin, Director of
Research CNRS, Department of
Molecular Pharmacology, University of
Montpelier
Oliver Nayler, Director, Head Molecular
Biology, Actelion
Meet, benchmark and
discuss with over 35
industry speakers incIuding:
Stephen Douglas, Director, Discovery
Translational Medicine, Wyeth
Sandra Siehler, Research Investigator II,
Center for Proteomic Chemistry, Novartis
Institutes for BioMedical Research
Gebhard Schertler, Senior Scientist and
Group Leader Structural Studies MRC Lab
of Molecular Biology, Cambridge
Rochdi Bouhelal, Research Investigator,
Centre for Proteomic Chemistry, Novartis
Udo Lange, Neuroscience Research,
Medicinal Chemistry, Abbott
Stephen Brough, Principal Scientist,
GlaxoSmithKline
Thomas Ryckmans, Senior Principle
Scientist, Pfizer PGRD Sandwich
Gary Tresadern, Senior Scientist, Molecular
Informatics, Johnson & Johnson PRD
Steve Garland, Group Leader Lead
Generation, GSK
Stephen Hill, Director, Institute of Cell
Signalling, University of Nottingham
Wolfgang Fecke, Unit Head Bimolecular
Screening, Siena Biotech
Martin Lohse, Institute of Pharmacology and
Toxicology, University of Wurzburg
MEDIA SPONSORS
For more information about the conference programme or to enquire about
sponsorship and speaking opportunities please email
info@oxfordgIobaI.co.uk or call +44(0) 1865 304925 and quote "GPCR09HEX"
not necessarily be medically qualified.
A quality assurance system does exist
in some companies like Pfizer, but in
most cases a query reply is not reviewed
before being sent out. In Pfizer India,
when a medical advisor joins, the first
few queries are reviewed and modified
so that he/she gets a firm understanding
of the nuances of replying to medical
information queries the Pfizer way before
being given independent charge. Also,
the MI replies are reviewed at random
from time to time by the senior manager,
medical affairs and/or the senior medical
advisor to provide on-the-job coaching
and encouragement. Vendors are not
engaged by these companies, while we
do have a system of paying selected
vendors for reprints if we need to provide
them specifically to external customers,
thus being compliant with copyright
requirements. The MI function is universally
helpful to the companies just as it is with
Pfizer India. The feedback from internal
and external customers validates this
perception, as does the survey conducted
among key opinion or thought leaders
benchmarking our MI function with that
of the top companies (both Indian and
foreign multinational) in the country. Pfizer
India did share its MI function resource
with our co-promotion partner, Sanofi,
when Daxid (sertraline) was co-promoted,
and Pfizer India does have patient
assistance programs as well as a disease
management program through which
medical information queries are relayed
to the medical affairs department.
References
1.McLean A, Winchell JR. New QA guidelines
raise new questions. Health Care 1984:26(1):20-21.
2. Graves DA, Baker RP. The core curriculum for medical
information professionals practicing in the
pharmaceutical industry. Drug Inf J.2000; 34:995-1008
3.Colvin CL. Understanding the resources and
organization of an industry-based information
service. Am J Hosp Pharm. 1990; 47:1989-1990
4.Salter FJ, Kramer PF, Palmer-Shevlin NL.
Pharmaceutical industry medical information
departments: regulatory and legal perils and
pitfalls. Drug Inf J. 2000:341009-1015.
5.Hileman SJ et al. Industry based medical
information : benchmarking survey of quality
assurance practices. Drug Inf J. 2005; 39:35-42.
6.Fung, Stacey M. Quality Assurance Practices
for Pharmaceutical Industry-based Drug
Information Departments: A Review & Case Study.
Drug Inf J.2004.
Jeroze Dalal is one of
the most versatile and
experienced clinical
research professionals
in India today having
worked in several
multinational pharma-
ceutical companies
and CROs like
SmithKline Beecham, AstraZeneca, Pfizer and
Quintiles. She is a post-graduate in Chemistry
and has conducted research in leprosy and
malnutrition at aleading hospital in Mumbai.
She is currently pursuing her PhD in General
Management. Presently, she heads Clinical
Operations at GlaxoSmithKline, India. Email:
jeroze.j.dalal@gsk.com
Dr. Viraj Suvarna is
the Head of Medical
Affairs and Research
Specialists (MARS),
within the Medical
and Research Division
at Pfizer. He provides
Medical interface with
government, NGOs, academia, and medical
associations. The Medical Research Specialists
facilitate investigator-initiated research
projects, unrestricted educational grants and
medical relationship management. His team
designs local studies, including outcomes
research, epidemiology, bio-equivalence,
non-interventional, comparative, and in vitro
studies, and provides medical support to the
first ever Cardiovascular Disease Management
Program in India (Healthy Heart).
Email: Viraj.Suvarna@Pfizer.com
Scotlandss Offering in Life Sciences
For a relatively small country, with a
population of just 5 million people,
Scotland punches well above its weight
in its contribution to life sciences around
the world. Scotland has a strong history
of developing life-changing medical
and scientific advances, such as the
discoveries of insulin and penicillin in
the twentieth century. More recently
the cloning of Dolly the sheep and
ReNeurons ground-breaking stem cell
trial for stroke patients evidences a few
of the headline advances emerging from
Scotland.
These discoveries will continue thanks to
the proactive strategy to nurture, grow
and develop life sciences in Scotland.
The need to work in collaboration in the
creation of an idea, to early stage drug
discovery, medical technologies, clinical
research and diagnostics is paramount.
Many individuals and organisations
feed into that process to strengthen the
offering and create this enviable Scottish
hub.
Last January, the Scottish Government
published the Scottish Life Sciences
Strategy 2008 Achieving Critical
Mass, which identifies the next steps
the life sciences community will take to
ensure Scotland maximises its return
from market opportunities.
By investing in all aspects of drug
development and focusing on where
most value can be added, the industry
continues to attract the greatest minds
from around the world to work in this
field. Coupled with the investment in
technology and innovation, Scotland is
successfully converting scientific discovery
into commercial products which are
sought around the world.
Underpinning the competitiveness
and the strategy to grow life sciences is
the collaborative nature of Scotlands
companies, academic institutions,
the health service and the Scottish
Government.
In June 2009, the Scottish Academic
Health Sciences Collaboration (SAHSC)
was launched to bring together the
combined talents of associated university
medical schools in Aberdeen, Dundee,
Edinburgh and Glasgow, and the NHS
Boards. The SAHSC places Scotland at
the forefront of turning the latest scientific
research into real health benefits for
patients, and puts Scotland in a strong
position to win increased international
health research funding and create
stronger collaborative links with industry.
ITI Life Sciences, a government-
sponsored innovation fund, invested
9.3m in an international research
venture to mine the Ubiquitin Proteasome
System (UPS) for the next class of novel
targets to treat inflammation, infectious
disease, and cancer. The Universities
of Glasgow and Strathclyde, alongside
life sciences company Millipore, will
accelerate the work already ongoing at
the University of Edinburgh and Mount
Sinai Hospital in Toronto.
In parallel, Sir Philip Cohen is setting
up a Protein Ubiquitination Unit in the
Scottish Institute for Cell Signaling at
the University of Dundee. The unit
will build a critical mass of leading
scientists carrying out research into the
ubiquitin system.
The Division of Signal Transduction
Therapy (DSTT), a collaboration founded
ten years ago between AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline,
Merck KGaA and Pfizer, involves 13
research teams based at the University
of Dundee. DSTT is accelerating the
development of improved drugs to treat
diseases such as cancer, diabetes
and rheumatoid arthritis. The 34m
project is widely regarded as an excellent
model of academia and industry
working together.
More medical research is conducted
per capita in Scotland than anywhere else
in Europe. All 14 universities in Scotland
are involved in medical technology
research, with 57,000 students currently
studying life science-related subjects.
Over 52 university and research facilities
fuel the community in Scotland and
provide access to over 17,000 research
staff. Research links are particularly
strong with Europe, Korea, Japan and
the United States of America.
This thriving life sciences sector
contributes over 3bn to the Scottish
economy. Foreign investment plays a
significant part, with hundreds of life
sciences jobs created as a result of
international firms such as Johnston &
Johnston, GlaxoSmithKline and Quintiles
recognising the value that being based in
Scotland can have for their business.
Scotland attracts around 300m of
research funding each year. For every
7 million invested by the Scottish
Government, an additional 18 million
is leveraged by private firms in life
sciences. Currently, over 750m of
Edinburgh BioQuarter - artists impression.
A major force in Scotlands
life science industry
Central Scotland is home to more than 360
life science-related companies, 9 world class
universities and several highly respected research
institutes. Together, they provide employment for
over 24,000 individuals.
Continued investment in industry and state-of-the-art
research facilities provides a conducive environment
that allows experts in related fields to work closely
together. World class expertise in areas such as
the cardiovascular system, leukaemia, oncology,
veterinary medicine, stem cell research, immunology,
bioinformatics, medical devices and more, underpins
a wealth of exciting translational research and
technology convergence.
Vibrant, innovative and competitive central
Scotlands life science community continually rises
to the challenge.
Nexxus promotes and supports research
excellence, innovation and knowledge transfer
within the life science community in central
Scotland.
The website provides information on life science
related events in Scotland and worldwide plus
comprehensive information on central Scotlands
life science research and news, its companies and
institutions, and general information on living and
working in the area.
Sign up now for regular communications, free
networking events and to keep up with whats
new in central Scotlands life science industry.
East office: +44 (0)131 200 6411
West office: +44 (0)141 330 5381
Website: www.nexxusscotland.com
Email: info@nexxusscotland.com
Nexxus is funded by a number of organisations including the European
Regional Development Fund see website for more details.
private and public sector funding is going
into projects across Scotland.
This integration of public and private
sector interest is harnessed by Scottish
Enterprise, the Scottish Governments
economic agency tasked with working
with companies to help them improve
efficiencies, access finance and exploit
new markets.
Scotland is internationally renowned
for its excellence in scientific research
and development, particularly in the
areas of oncology, cardiovascular
disease, diabetes, central nervous system
diseases, virology, immunology, stem
cells and regenerative technology.
In addition to its strength in research
and development, Scotland boasts
a significant manufacturing multi-
national medical technology presence
in diagnostics, wound care, implants,
disposables, ophthalmic and imaging.
The country is home to one of the
most successful and rapidly growing
life science clusters in Europe, with over
620 companies creating jobs for 31,000
people. This is evidenced by the presence
of some of the worlds leading medical
pioneers:
GlaxoSmithKline (GSK) represents the
most considerable investment of any
pharmaceutical company into Scotland.
With over 1,200 employees in Scotland,
GSK have continued to invest in their two
Scottish sites manufacturing antibiotics
and antiviral medicines for the treatment
of HIB, flu and malaria.
ProStrakan is a rapidly growing
speciality pharmaceutical company
gaining an international reputation for the
development and commercialisation of
prescription medicines for the treatment of
unmet therapeutic needs. The company
markets a range of products through its
commercial operations in the UK,
US, Germany, France, Spain, Sweden
and BeNeLux.
In 2007, Scottish company Touch Bionics
launched the worlds first commercially
available multi-articulating bionic hand,
the i-LIMB Hand, reinforcing Scotlands
worldwide reputation as a driver of
medical innovation and literally changing
the quality of life for thousands of people
across the globe.
Collaborative working has also generated
significant advances for life science R&D.
Edinburgh, Scotlands capital city, is home
to the Edinburgh BioQuarter, a 600m
public and private sector collaboration
which is unique in the UK. It is the only
location to offer a large state-of-the-
art teaching hospital, the University of
Edinburghs world-renowned medical
school and bespoke biomedical research
and development facilities all on one
site. The 100-acre site brings together
public healthcare, academic research
and extensive commercial laboratory
space to accelerate translational
medicine and facilitate large-scale Life
Science collaborations. The campus is
set to attract internationally renowned
companies and expertise from Scotland
and overseas and create 6,500 jobs.
Edinburgh is a major centre for
genomics and bioinformatics research,
with world-class capabilities at the
University of Edinburgh, Roslin Institute
and the Scottish Centre for Regenerative
Medicine (SCRM).
The SCRM at the University of
Edinburgh covers the full spectrum of
stem cell research. The Centre positions
the UK at the forefront of international
translational stem cell science and brings
together world-leading groups who have
a proven track record in clinical stem cell
research and therapy.
The Translational Medicine Research
Collaboration is a world-leading network
of clinical and scientific excellence.
Developed by Wyeth and the four
major clinical academic centres at
the Universities of Aberdeen, Dundee,
Edinburgh and Glasgow and the NHS in
Scotland, the TMRC will see more than
50million injected into clinical research
over the next five years to:
Establish a state-of-the-art laboratory
methodology and technology to lead
an international centre for translational
medicine and development of
biomarkers.
Develop and coordinate clinical trials
aimed at obtaining samples from clearly-
defined disease populations.
Link with the Scottish Clinical Research
Network to manage streamlined ethical
approvals, data collation and statistical
analysis of results.
Coordinate research activities on the
samples collected.
The Scottish life sciences sector will
continue to excel in research capability
and the transmission to commercially
available products around the world.
Historically the sector has focused on
healthcare, however looking to the future,
there are significant opportunities for
Scotlands expertise and capabilities to
be applied to add value to the industrial,
marine, environment and veterinary
biotechnology sectors.
Life sciences in Scotland is thriving,
and medical and scientific discoveries,
on a par with those of Sir Alexander
Fleming, the discoverer of penicillin, will
not be confined to Scotlands past. With
eminent scientists such as Sir Philip Cohen
and Professor Sir Ian Wilmut continuing
to innovate, together with such a strong
life science base, Scotland is perfectly
placed to continue to contribute to future
world-changing discoveries.
Rhona Allison,
Senior Director, Life
Sciences, Scottish
Enterprise. With 18
years experience
in the Life Science
industry, Rhona has
responsibility for setting and delivering
Scottish Enterprises Life Science strategy
to support sustainable economic growth
and development of the Life Sciences
sector in Scotland.
Email: investment@scotent.co.uk
ITI Life Sciences:
Real Possibilities for Scotland
At ITI Life Sciences were committed
to making brilliant ideas commercial
reality. Generated as part of ITI Scotland
in 2003 by Scottish Enterprise and with
the support of the Scottish Government,
ITI Life Sciences leads the nation in
delivering market-driven commercial
business opportunities in life sciences.
Together with our two co-ITIs, ITI Energy
and ITI Techmedia, ITI Life Sciences is
committed to ITI Scotlands core values
of investment in trailblazing Research &
Development (R&D) programmes and
the funding of market-driven innovation
for Scotland. We are 100% commercially
focused and committed to positioning
Scotland as an important world centre
for the creation and marketing of new
intellectual assets.
Our purpose
Our extensive research of global markets
identifies future commercial opportunities
and drives the formation of innovative
R&D programmes. These programmes
design, develop and deliver platform
technologies and enable the formation
of new products and services to address
emerging market opportunities.
The result is a portfolio of commercially
valuable, cutting-edge intellectual assets.
These are owned and exploited by ITI for
the benefit of the Scottish economy by
licensing to new and existing organisations
and stimulating the formation of start-up
and spin-out companies.
Life sciences in Scotland
With more than 620 life science
organisations and 31,000 employees,
Scotland currently has one of the largest
and fastest-growing life science clusters
in Europe. Renowned for its particular
expertise in oncology, cardiovascular
disease, diabetes, central nervous system
diseases, virology, immunology, stem
cells and regenerative technology, over
70 per cent of Scotlands core life science
organisations focus on human healthcare.
Possible explanations for the Scottish life
sciences pre-eminence include its rich
talent base, an unprecedented historical
scientific legacy and in particular its
internationally-renowned universities.
Scotland has 57 universities and research
institutes working in life sciences. With
17,000 research staff, they employ
11.6 per cent of the UK total. Each year,
Scotlands universities and research
institutes attract 410 million funding.
In real terms, this means Scottish life
sciences receives 13 per cent of total
UK funding, for just 9 per cent of the UK
population.
In 2005, 20 per cent of Europes life
science initial public offerings (IPOs) were
Scottish, with recent successful Scottish
IPOs including ProStrakan, IDMoS and
Optos. Cyclacel was founded in Scotland
in 1996, and is the first and only
European spinout to raise more than
$100 million. Or as the Financial Times
Group put it, Scotland is one of the best
places to do business in Europe.
Our experience & partners
The people behind ITI Life Sciences come
largely from the commercial sector, and
we pride ourselves on our impressive
business pedigrees. By supporting the
transition from the groundbreaking idea
to the development of the commercial
application, we cover the ground where
few investors dare to tread, and where
few SMEs can venture because they lack
the internal resources. At ITI Scotland
we make it our business to de-risk the
commercialisation process through our
programmes. We undertake the market
analysis, commission the research and
handle the intellectual asset management,
drawing on expertise from our advisory
boards and extensive networks.
To make innovative ideas a commercial
reality, ITI works in partnership with a
range of respected strategic partners
from across the business spectrum. We
form close ties with scientists, researchers,
IP and patent specialists, market analysts
and corporate financiers.
Taking innovation to the marketplace
The ultimate aim of ITI Life Sciences is to
stimulate Scottish business by licensing
our technologies to existing organisations
or promoting new company formation.
Our R&D process has proved a valuable
tool in business growth. Our commercial
partners are often involved with the
R&D programmes before licensing the
resulting Intellectual Property (IP), and
range from entrepreneurs and small
businesses to large corporates and global
multinationals.
Our track record
Five years into ITI Scotlands initial ten-
year model, we have committed over
150 million in funding and launched
27 programmes. Eleven of these
programmes are complete, eight of them
reaching a close during the financial year
2007/08, and 16 are at various stages
of development. Further programmes
are planned for launch once diligence
activities are completed.
On top of these achievements 112
patents have been filed to date and this
has led to new market applications and
commercial potential being developed
from the IP. In addition, 17 commercial
licensing deals have been signed with
commercial partners, both new start-ups
and existing companies, based on the
intellectual assets developed by the ITI
programmes.
The business benefits of engaging
with ITI Life Sciences
Cellartis: R&D provider and commercial
partner for ITI Life Sciences Stem Cell
Technologies Programme
ITI Life Sciences called upon the
experience of Cellartis, the largest
provider of ethically derived human
embryonic stem cells in Europe, when
setting up the 9.5 million Stem Cell
Technologies Programme. To deliver its
part of the programme, Cellartis has
moved into a state of the art R&D and
manufacturing facility in Dundee.
Earlier this year ITI Life Sciences signed
a licensing agreement with Cellartis,
granting them a worldwide licence to
further develop and commercialise specific
assets, generated from ITIs Programme.
This marked ITI Life Sciences seventh
licensing agreement and the fifteenth for
ITI Scotland.
The technology being licensed
was developed as part of an ongoing
three-year ITI programme, launched in
January 2007, to develop an automated
process for producing large volumes of
high-quality, ethically-derived human
embryonic (hES) stem cell lines (i.e. cells
with the potential to become any type of
cell). This technology has the potential of
driving unprecedented innovation in drug
discovery and regenerative medicine
today and in the future.
Cellartis and the other research
providers Universities of Dundee,
Glasgow and Heriot-Watt devoted their
considerable shared expertise to identifying
a major market need, which can now be
filled by this groundbreaking technology.
At a time of significant economic pressure,
when many pharmaceutical investment
companies are looking for better return
on investment, the research income this
technology will generate is particularly
welcome.
According to Mats Lundwall, CEO of
Cellartis AB, We are very proud of our
involvement in ITIs Stem Cell Technology
Programme. Our participation in the
programme has been a strong catalyst
for our growth, and we look forward
to delivering more success together in
Scotland.
Cardiac Biomarkers
IMI: Measurable multi-platform success
with ITI Life Sciences
Cardiovascular disease is a major cause
of ill health in Scotland. It is also an
acknowledged area of strong expertise
for the Scottish life sciences community.
In February 2005, ITI Life Sciences
committed 30 million to a three-year
R&D programme to develop new near-
patient and home-use diagnostic tests.
Through its market and technology
analysis foresighting activity, ITI Life
Sciences could identify increasing use of
near-patient tests by clinicians and patients
for the diagnosis and management of
chronic conditions. Offering benefits to
both healthcare providers and patients,
testing at home allows patients to monitor
their disease and manage their condition
more effectively. The global market for
near-patient testing is estimated to be
currently worth US$3.3 billion and is
growing at around approximately 8% per
annum.
To deliver the programme, ITI Life
Sciences attracted US-based Inverness
Medical Innovations (IMI) to set up a new
research, development and manufacturing
company in Stirling, Scotland. The new
company, Stirling Medical Innovations
(SMI), will use novel biomarkers with
next-generation technologies to develop
accurate, rapid, easy to use, near-patient
diagnostic tests.
Over the next three years IMI invested
37.5 million in the R&D programme
and, following successful completion, a
further 30 million in manufacturing and
the commercialisation of new products.
SMI released a handheld medical device
to monitor blood clotting at home called
SmartCheck in the European market,
using technology developed during this
programme.
With the programme now at its
conclusion ITI Life Sciences is now
progressing to the next stage by examining
potential exploitation of the technology in
the veterinary market. SMI will continue
with the development of the technology
and will look to produce relevant
technology in the human healthcare
market. Meticulous foresighting and a
multi-platform approach to emerging
technology is a key feature in ITI Life
Sciences success story to date.
The challenges ahead
At ITI we are keenly aware of the need
to maximise business opportunities for
Scotland in challenging economic times.
We recently announced that we would
be integrating with Scottish Enterprise.
We believe this will bring substantial
benefits for the Scottish economy.
The amalgamation will maximise cost
efficiency and provide an even stronger
focus on the commercial end-game.
The integration will also offer significant
advantages for our partners already
benefiting from the support, advice and
partnerships of ITI. They will soon gain
an even broader range of advantages
through Scottish Enterprise.
Our programmes
Commissioning and managing R&D
programmes for ultimate commercial
success is at the heart of ITI Life Sciences
activities.
To date we have commissioned six
programmes:
Two are in the research phase:
Stem Cell Technologies
9.5 million programme to develop novel
technologies and automated processes
to produce high-quality human stem cells
as tools for pharmaceutical research.
Ubiquitin Proteasome System
9.3 million programme to identify
and confirm the association of specific
E3 ligases in the UPS with cancer,
inflammatory disease and infectious
disease, and develop cell and biochemical
assays.
Four have completed the research
phase:
Text Mining
5.3 million Text Mining Programme
to develop powerful new information
extraction tools using Natural Language
Processing.
Cardiac Biomarkers
30 million to develop near-patient and
home-use diagnostic tests based on novel
biomarker technologies.
Transgenic Screening and Safety Models
5.5 million programme to develop new
predictive safety models for early drug
development.
3D Fluorescence Lifetime Cell-
based Assays
Programme to develop fluorescence
lifetime cell-based pharmaceutical
screening instrumentation and cell-based
assays.
Become part of the ITI success story
We are always happy to discuss your
cutting edge ideas in energy, life sciences
and digital media and communications
technology. Contact us and take the first
valuable step in maximising the potential of
your concept. We are also actively seeking
commercial partners to collaborate with
us and take groundbreaking innovation
to the marketplace. So if you have
interests in commercialising any of these
technologies, we want to hear from you.
You can also now become a member
of ITI Scotland free of charge. Membership
entitles your company to download our
foresighting reports from our websites.
The foresighting reports look into the
future for commercial opportunities in
a number of areas including stem cells,
plant biotechnology and non-invasive
medical devices.
For further information about ITI and
any of our programmes and to sign up
for membership visit www.itilifesciences.
com.
Eleanor Mitchell
is the Managing
Director of ITI Life
Sciences, set up in
2003 by Scottish
Enterprise to
leverage Scotlands
research excellence in life sciences to
generate new technologies that address
future global market opportunities.
This is achieved by identifying and
commissioning early stage R&D
programmes based on assessing future
market needs and developing the
required technology assets. They also
identify appropriate commercial partners
to exploit these assets globally.
Email: enquiries@itilifesciences.com
Your research is too important to be left to others!
www.bmglabtech.com
Proteomic Tools for the Study of
Model Organisms
The use of model organisms for genetic
research is as old as genetics itself. In
hindsight, the breeding of domesticated
animals for traits of interest can be seen
as slow, imprecise genetic engineering.
Even as Mendels pea plant experiments
demonstrating the patterns of heredity
were rediscovered in the early 19th
century, embryology researchers in
Germany were searching for ways
to trace organism development from
a single cell. Imagine attempting to
understand developmental biology
without the grounding of genetics or
molecular biology. The major leap
in progressing these fields was the
research of Thomas Hunt Morgan at
Columbia University in New York. As
a developmental biologist, Morgans
early work focused on the manipulation
of embryo cells in Drosophila, but soon
patterns emerged that hinted at biology
far more powerful and fundamental
then cell manipulation and physical
morphology-linked mutations. Through
the many generations of fruit flies Morgan
bred, natural germ-line mutations began
to appear. The classic example is that
of the white-eyed mutants and, although
biologic mutations were common in
the cabinet of curiosities that were early
natural history museums, these white eyes
were inheritable and only manifested in
females. The ability to assign this genetic
element to a specific chromosome was
a breakthrough, and Morgan progressed
forward in many fields throughout his
career - launching a new generation of
researchers.
Predictably, general investigation
of this kind was slowed by the tools
available. It was not until the 1970s that
DNA manipulation allowed researchers
to deliberately test hypothesis function by
altering linked genes. From forced single
gene mutations, dramatic morphologic
changes were created through Edward
Lewis research at Caltech. These
experiments showed how single gene
manipulations yielded flies with two sets
of wings, and legs where antenna should
be - pointing to a set of master genes
that governed specific mechanisms
of development. This work applied
to disease research yielded statistical
tools such as linkage analysis to link
traits with genes, and with new DNA
manipulation tools, disease models could
be envisioned. When the Drosophila
melanogaster genome was published in
Science in 1999 by Celera Genomics, the
blueprint for the fly was made available,
allowing scientists to apply new tools to
the genome data (Reference 1).
A similar story can be told for a number
of model organisms: Caenorhabditis
elegans, a nematode worm; zebrafish
(Danio rerio); and the African clawed frog,
Xenopus laevis, used in developmental
biology because of its large embryos and
ease of physical and pharmacological
manipulation. Much interest surrounds
zebrafish, a freshwater fish that has a
nearly transparent body during early
development, which provides unique
visual access to the animals internal
anatomy. They are also used to study
development, toxicology, gene function
and roles of signalling pathways. On
a larger scale, Rhesus macaque, being
93% homologous to the human genome,
is used for studies on infectious disease,
drug ADMET (Adsorption, Distribution,
Metabolism, Excretion and Toxicity),
and neural cognition. With complete
genomes and powerful bioinformatic
tools, the aforementioned organisms
are of particular interest. C. elegans,
Drosophila and zebrafish in particular
are extensively used in functional and
comparative genomics. There are
many more organisms used in modern
drug discovery that due to specific
breeding, development, behaviour and
homology of systems are used for specific
studies; not to be ignored, however, are
the common models of mice, rats,
and yeast.
To support this progress, genomic
tools have been developed and are
commercially available to researchers
in the last few years. Sequence-
specific expression microarrays and
RNA knockdown libraries/morpholino
reagents are continually emerging.
Following the progression seen with
biological and drug development tools
in the past, tools for the study of model
organism proteomics are scarce. While
expression of genes in these organisms
is common, visualising the proteins in
action is not an easy feat. Proteomic
tools, such as antibodies, follow genomic
tools both in the progression of research
and in commercialisation. Despite claims
of catalogue reagents that there is cross-
reactivity across species, more often than
not, the performance outside of human
samples fails to deliver useful information.
This is typically due to aligning a 15
amino acid peptide antigen sequence
to other organisms and making the
assumption of cross-reactivity. Peptide
antigens typically deliver Western blot
results well, but for assays demanding
antibodies against conformational
epitopes, the available reagents fall short.
To bridge this unmet need researchers
have sought custom antibody reagents
to complete their studies. Initiating a
custom antibody project traditionally
demanded a physical antigen such as
purified or recombinant protein. In the
workflow of model organism research,
purified protein typically is not available.
Also, the production of small peptides as
antigens limits the assay possibilities to
those of linear epitopes.
Strategic Diagnostics (SDI) is the
leader in the production of model
organism antibodies through its
Genomic Antibody Technology (GAT)
(Reference 2). In 2008, SDI produced
over 400 custom projects against these
rapidly emerging organisms. Using a
highly optimised genetic immunisation
platform, researchers need only to
provide accession numbers in order to
receive purified antibody in 90 days.
The ease of use and economic benefits
of outsourcing the entire workflow of
custom antibody generation allow
the researchers to focus on their core
discovery activities and not be distracted
by laborious protein production. One
major relationship for SDI is in supporting
the National Human Genome Research
Institutes model-organism ENCODE
(modENCODE) Project. The project is
DRUG DISCOVERY DEVELOPMENT & DELIVERY
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working to identify and characterise DNA
sequence elements and proteins that
control genome activity in the C. elegans
and Drosophila genomes. These two
model organism species represent the most
advanced models for the understanding
of the corresponding human regulatory
proteins. The works focus is on proteins
that regulate chromosomal functions such
as transcription, DNA replication and
repair, recombination and chromosome
segregation (Figure 1).
Another application for SDIs platform
is work done with the University of
Oregon and Louisiana State University
Health Science Center in New Orleans
(LSUHSC), involving the supply of
antibodies for the study of Usher
Syndrome. The antibodies are being
used in the researchers unique zebrafish
and mouse model systems of the disease,
which causes progressive blindness and
deafness. The comparative data of the
morpholino knockdown to wild type
revealed key protein dynamics (Figure
2). Working with the University of the
Sciences in Philadelphia, SDI produced
antibodies against Drosophila proteins
for the study of photoreceptors in retinal
neurogenesis (Figure 3) (Reference 3).
Perhaps the most dramatic example
illustrating the need for a specific reagent
is on SIV infectivity studies to model HIV
infection dynamics in Rhesus macaque.
In flow cytometry, anti-human CD40
antibodies produced non-specific
data even though the gene was 93%
homologous to that of the macaque.
The production of an antibody through
GAT to a 100aa stretch of macaque
sequence led to the development of a
highly specific reagent (Figure 4).
The common thread throughout these
and other experiences is that due to
a lack of premade reagents, there is a
critical need for model organism-specific
antibodies to profile protein dynamics.
Traditional development techniques in
generating physical antigens hamper
discovery in functional genomics, as
these non-core activities are fraught with
difficulty and uncertainty. Addressing
these issues, Strategic Diagnostics GAT
technology and extensive experience
in this field positions the company as a
key partner in progressing these rapidly
evolving fields. In the future, there will
hopefully be proteomic tools as extensive
as genomic tools to support this research,
but in the interim, the custom generation
of antibodies needs to be simple, robust,
and cost-effective.
References
1. The Genome Sequence of Drosophila
melanogaster, Venter et al. Science 24 March
2000: Vol. 287. no. 5461, pp. 2185 2195
2. High-level generation of polyclonal antibodies
by genetic immunization, Chambers, R. &
Johnston, S., Nature Biotechnology 2003 Sep;
21(9):1088-92
3. Identification of novel regulators of atonal
expression in the developing Drosophila
retina, Melicharek, D., Shah, A., DiStefano, G.,
Gangemi, A.J., Orapallo, A., Vrailas-Mortimer,
A.D., and Marenda, D.R. (2008). Genetics 180:
2095-2110
Figure 1
Figure 3
Figure 2
Figure 4
SDI DAMON
HOSTIN STRATEGIC
DIAGNOSTIC
Damon Hostin, Sr.
Director of Market
Development,
Strategic Diagnostics
oversees Strategic
Diagnostics portfolio of antibody and
immunotool products. His experience in
antibody technology, genomics, oncology and
radiotherapy serves as a platform for his role
in the companys offerings and pursuit of novel
products. Hostin served as Director of Scientific
Operations for GenVis Labs, a genetic analysis
laboratory,and Manager of Research and
Development, Actinium Pharmaceuticals, where
he managed platform applications and strategic
alliances for the development of antibody
therapeutics, and pre-clinical programme
management. Email: dhostin@sdix.com
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Strategies for the formulation of poorly soluble compounds
and polymorph drugs based on polyelectrolyte carriers
The main challenge in the administration of
poorly soluble drugs is to design oral formulations
displaying a relevant bioavailability and to
develop injectable systems for the parenteral
application with minimised toxicity and high drug
loading. The LBL-Technology offers a strategy
for enhancing the kinetic of dissolution of BCS
class II drugs based on the presentation of the
drug in the form of nanoparticles stabilised with
layers of polyelectrolyte complexes (Fig. 1).
In this way, nanosuspensions of drug
substances with impaired water solubility can be
produced displaying a particle size distribution in
the nanometre range, modified surface charge
and high drug concentrations (Fig. 2). These
drug delivery systems are especially attractive
for their low aggregation in further galenic steps
in the development of solid dosage forms and
for their fast dissolution profiles.
There is a broad range of polycationic and
polyanionic pharmaceutical excipients which
build complexes by means of their electrostatic
interaction. Polyelectrolyte complexes are
amorphous carriers, which, depending on the
production method and composition, present
different rheological and plastic behaviours,
mechanical properties and degrees of
porosity (Fig. 3). These polyelectrolyte matrices
are optimal scaffolds for the precipitation
of polymorph drugs in the most preferred
amorphous state (Fig. 4). These compositions,
besides stabilising the drug in the amorphous
state, also have the additional role of being
appropriate filler excipients for solid dosage
form development. Polyelectrolyte complexes
loaded with drugs can be produced in the
form of sponge-like supramolecular structures
presenting an amorphous nature and with
improved rheological properties, stability,
solubility and later bioavailability.
Figure. 1: CLSM
(confocal laser scanning
microscopy) of a
nanosuspension of a BCS
class II drug stabilised
with polyelectrolyte
layer (left); detailed
representation of the
particle surface (below)
Figure. 2: Particle size distribution of a
nanosuspension formulated via LBL Technology (above)
Figure. 3: Polarised
microscopy of a sponge-
like polyelectrolyte
complex (left)
Figure. 4: X-ray powder diffraction (XRPD) of a control
polymorph drug in the crystalline state (grey), a drug-free
sponge-like polyelectrolyte carrier control (black) and
different formulations thereof displaying the drug stabilised
in the most preferred amorphous state (red, blue, green).
Maria Gonzalez Ferreiro,
MSc Pharmacy,
PhD Pharmaceutical
Technology (Freie Universitaet
Berlin, Germany). She is the
Head of Pharmaceutical
Development at Capsulution
Pharma AG in Berlin.
Email: info@capsulution.com
Domainex: The very model of a
modern classical hybrid biopharmaco
Domainex forges ahead with research
and in developing platforms that facilitate
drug discovery and development.
In an exclusive interview with Dr Eddy Littler,
CEO of Domainex, IPIs Editor-in-Chief,
Patricia Lobo, lifts the lid of a progressive,
forward-looking biopharmaco.
Domainex Ltd is not just a drug discovery
company that leverages its novel
combination of structural biology and
medicinal chemistry for developing
small-molecules, specifically with activity
against key nucleotide triphosphate
(NTP) dependent protein targets
DomaiNTaP its also a key services
player that bridges from the academic to
the industrial domains.
PL: It would be interesting to learn about
the life history of Domainex and how
your organisation evolved as a modern
biopharma company.
EL: Domainex today is a very different
company from what it was a few
years ago when it consisted of two
companies. Both companies were spun
out of UCL in London. NCE Discovery,
offering sophisticated computational
and medicinal chemistry and the other,
Domainex, a novel technology to express
challenging genes.
About three years ago, both sets of
shareholders decided to merge the two
companies for two reasons:
1. While both companies had a service
component, the idea of bringing together
chemistry and biology would provide
a critical mass, offering biology and
chemistry services to clients.
2. Bringing the companies together and
subsequently raising some investment
would enable the organisation to run its
own drug discovery programme.
The two companies merged in May
2007. At that stage I joined the company,
taking on the role of CEO at Domainex
part-time and became full time around
June 2008. After my arrival, we set about
attracting more investment.
The model that we are running is what
we call a classical hybrid model. The
services part of the business covers all
the overheads, while the investment is
targeted at the in-house pipeline.
What we have done since June 2008
is to consolidate the business at one
site, going from strength to strength. The
move went extraordinarily well as our
downtime was only three days, without
disruption to project work.
We also tackled a key skills gap in the
company by recruiting a very experienced
scientist, and the associated specialist
equipment, for running the assays both
for clients and our internal projects.
PL: How many people are employed in
the merged company?
EL: Initially, there were three biologists
in London and about 15 people in
Cambridge.
Currently we have about 25 staff about
three quarters of the research staff are
chemists and one quarter biologists.
Last year the theme was of
consolidation, bringing together the
pieces of the organisation, physically
bringing together the staff and equipment
and, this year, really using these assets to
move the business forward, improving
our services and establishing our internal
pipeline.
The intention is to grow the business
only according to business need. We
have no great ambition to build a huge
organisation for its own sake. When we
have the need to support client contracts
or for some additional skills will we
increase our head count. We provided
a good platform last year. So from early
2009, we started to move the business
forward. We ended last year on a real
up note with a major contract to provide
chemistry services for a Wellcome Trust
SDDI award obtained by St. Georges
Medical School.
PL: Would you like to say something
about collaboration?
EL: We form collaborations to push
forward either our services or our
internal pipeline. For example, earlier
this year, we announced a collaboration
with Breakthrough Breast Cancer at the
Institute of Cancer Research in London
based around two targets in breast
cancer. Breakthrough is a pre-eminent,
charity funded organisation with about
70 scientists at the Institute of Cancer
Research, right next door to the Royal
Marsden Hospital in South Kensington,
London. What Breakthrough brings
in research in breast cancer is second
to none - worldwide. They really are a
fabulous group. They are working on all
aspects of breast cancer from concept
right through to clinical trials. They have
immense biology know-how. They also
have a track record in drug discovery
and identified one of the targets in our
collaboration as being potentially very
important in breast cancer. There is a
really nice fit between Domainex and
Breakthrough. This collaboration is well
and truly in operation. Hopefully, in the
next few months, this will show some
quite exciting advances.
PL: What about the drug discovery
pipeline?
EL: Domainex has constructed its own
pipeline of drug discovery projects. We
chose a number of well-validated, but
challenging, targets that we can unlock
with our Combinational Domain Hunting
(CDH) and LeadBuilder technologies,
thereby delivering lead series through
structure-based drug design.
PL: and the technology skills?
EL: Basically, we have built up three
platform technologies with common
themes. Lets start with chemistry. The first
technology is called LeadBuilder.
1. LeadBuilder
LeadBuilder is the proprietary lead
generation platform that has been
developed by Domainex to provide
unusually rapid and cost-effective access
to high-quality hits. It is a virtual screening
approach to drug discovery for hit
identification and lead optimisation. Its
a very pragmatic tool. We have operated
this for over two years as a service for
many clients. It is a very effective tool.
The underlying concept is that there are
several million compounds and variables.
However, most of these compounds have
certain issues. They are either not readily
available or they are not freely available
from a supplier.
This technology integrates our state-
of-the-art capability in three key areas:
compound collection design and
selection; protein modelling; and virtual
screening.
Within LeadBuilder we have a
virtual compound library (NICE) of
commercially available compounds that
have been carefully selected to meet all
of our criteria for an ideal screening hit,
so that they have several potential points
of interaction with a target protein; very
favourable molecular properties; and a
good predicted ADME-Tox profile. We
use powerful virtual screening methods
to analyse our NICE set of compounds
so that we can develop from knowledge
of the target protein, or known ligands.
Hits, compounds of high quality, are
identified by selecting what is absolutely
relevant to the target protein from a
universe of diverse, relatively cheap and
commercially available compounds,
whilst saving the time and expense
needed to build a large screening
collection. LeadBuilder hits are designed
to be well-suited to rapid modification,
in order to develop all the characteristics
required of a candidate drug, including
a strong patent position.
Many of these compounds have
technical problems of toxicity, maybe
chemical structures that are not good
as a starting point for drug discovery.
What we have done is to analyse a set of
compound for their required properties
and brought down the number from
millions of compounds to 250,000.
This is our starting point for using
different approaches to interrogate the
set and to come up with a smaller, more
tailored set for the client. Typically, the
client is interested in the capacity to screen,
compounds, according to their budget.
The aim is to derive a set from about 500
to a few thousand compounds that are
targeted towards the clients target. In
effect they are fired and screened until
hits are found, statistically in the region
of 1 - 10%. The advantage is that hits
from this NICE set represent a very good
starting point for drug discovery.
2. Medicinal Chemistry
Design and synthesis from hits to
candidate drugs
Our chemists have many years of
experience in creating drug candidates
from hits. Domainex will design a
medicinal chemistry programme taking
into account all the relevant factors
including biological activity, drug-
likeness, likelihood of toxicology, and
patentability.
A combination of thoughtful design
with one-at-a-time synthesis and
preparation of intelligently designed
arrays of compounds is integral to the
way Domainex works. It speeds up the
provision of high-quality development
candidates.
Key elements in the medicinal
chemistry strategy will include:
Experimental Design techniques to
plan the synthesis of sets of analogues
that will thoroughly explore structure-
activity relationships
Arrays of analogues that explore several
areas of the molecule simultaneously
Protein-ligand structural information
(when available) into the library design
Pharmacophore hypotheses are used
to drive our design process.
Calculated physicochemical parameters
into the design of compounds
Absorption, distribution, metabolism
and excretion (ADME) properties of
compounds are considered throughout
lead development.
With this, our second platform
technology, we take the initial hits and
using these hits we will then do hit
to lead optimisation. This is a mix of
computational chemistry and medicinal
chemistry that we run in-house. We
integrate these two a lot better than
other organisations. Trevor Perrior and
I independently came to very strong
opinions about that. Its very important
to have medicinal chemistry and
computational chemistry working in an
integrated way, side by side.
Its worth mentioning that using this
approach our clients currently have three
compounds identified from our work in
clinical trials. We will have taken a project
for clients right from the very beginning,
from hit finding through to candidate
selection.
The third and final platform technology
is Combinational Domain Hunting CDH,
protein expression for difficult target genes.
3. Combinational Domain Hunting
Combinational Domain Hunting (CDH)
identifies segments of a target gene
that express in high yield protein
constructs, which are correctly folded,
stable, and soluble. The main elements
of the CDH technology are:
Design of a synthetic gene, optimised
for expression in E.coli.
Random fragmentation of the gene
using our patented method.
Cloning of the tagged gene fragments
into E.coli.
Expression of a library of protein
constructs, and screening of these for the
desired characteristics.
Confirmation of the desired functionality
in hit fragments.
CDH is protected by granted
European patent EP1442134, and has
been allowed in Japan with further US
and worldwide patents pending.
Recent developments to CDH have
allowed us to significantly increase our
throughput by prosecuting groups of
targets as cassettes. This multiplexed-
mode of CDH can allow us to offer clients
special terms for multi-target deals.
Domainex is also using this increased
capacity to work through a gallery of
CDH targets over the next year or so.
Most of the gallery targets are proteins
that are known to be difficult to work
with, but have good disease validation.
Commercial deals around gallery targets
can be developed with customers on an
exclusive or non-exclusive basis.
That approach looks at targets which
are known by biopharma companies
and considered to be attractive, but
they have had a technical problem
in approaching expression that may
prevent the development of a good assay
or could be preventing the derivation of
decent crystal structure or both.
This lack of an assay or crystal structure
means that people cannot target at all
even though they like to or if they have
worked on a target they tend to end up
with some technical problems in cul-de-
sacs or blind alleys, which are difficult for
them to approach: and structure would
solve that problem.
We offer this as a service mode. The
first is a bespoke mode. A client can
come to us saying they have a target,
but cant get a structure, or they have a
structure, but is very poor but amenable
to a CDH approach to the problem.
The other mode is the gallery that
we are working through. We are aware
of many of these challenging targets,
where we are producing these clones
and making then available on a non-
exclusive basis.
We are happy to work in either of
these two modes.
The way that CDH works is based upon a
principle that crystallographers have been
aware for many years, that on numerous
occasions a full length protein will not
respond appropriately. Accordingly,
you take a domain/region approach
which will behave much better. Thats
the approach crystallographers have
used in order to generate structures over
a long period of time, while molecular
biologists used to try and get proteins to
express, perhaps generated by proteolysis
or cloning.
Theres an issue in that the way these
groups tackle is empirical or guess work
it gives a rough idea as to which region
to try, but with no precision at all. You try
a few ideas and either you are lucky and
they work, or you are not. You could just
keep going on and on. What we have
done is to develop a technology that in
essence evaluates all the potential start
and finish points of these constructs at the
same time, not making these constructs
in a serial manner but in parallel, in
one experiment. We make very large
libraries of constructs: minimum 20,000
independent constructs to 100,000 in
some cases. We make those at the same
time and we then screen these libraries
for clones that E. coli can express. We
have a good level of expression and a
lack of aggregation. We have run this
now for 35 or so clients, with very high
success rates.
PL: Who are the other key people at
Domainex?
EL: Our Chairman is Keith Powell, a
Biotech executive with more than 25
years experience, with Zeneca in the UK
Dr Trevor Perrior, Research Director of Domainex
Chemists at work - Domainex Laboratory
X-ray crystal structure of a kinase
and Maxygen in the USA and a leading
influence on the companys strategy. The
scientists of Domainex are a team of high
international standing in the fields of
molecular and structural biology, led by
Professor Laurence Pearl, CSO, a founder
of Domainex and on the Board. Laurence
is Professor of Crystallography and leads
the work at ICR on the structural biology of
DNA repair including Hsp90, a program
now licensed to Novartis. Our research
director is Dr Trevor Perrior, with over
twenty years experience as a medicinal
chemist with Celltech, Zeneca and others.
Trevor joined NCE Discovery in 2005, as
CSO, and when NCE Discovery merged
with Domainex he became Research
Director of the enlarged company.
PL: Where do you see Domainex in the
next five years?
EL: We underwent a period of
consolidation, last year. We are now in
the process of really driving the business
forward. I would anticipate that in the next
12 to 18 months we will take at least one,
or possibly two, of our internal projects
from a pre-clinical model through to
proof of concept,
In taking the company forward, our
pipeline will broaden with more targets,
with some organic growth, bringing
in some more skills that currently we
dont have in the organisation. We are
cost conscious and if it makes sense
to outsource our work then thats
the approach we will take. In fact,
this is already an integral part of our
approach.
I strongly believe that business models,
similar to that of Domainex, are among
the ways that biotechs will evolve: away
from cash burning dinosaurs to lean
and nimble mammals which are better
adapted to the financial environment that
we have around us. However, as usual in
evolution, time will tell.
Dr Eddy Littler,
Chief Executive
Officer of Domainex
Eddy began his
research career at
the University of
Leeds working with
Ken Powell. After postdoctoral research
at McMaster University in Canada and
the Paterson Institute for Cancer Research
in Manchester he joined the Wellcome
Research Laboratories where he became
Head of the Gene Targets Group and
became Head of Antiviral Research at
GlaxoWellcome. Eddy is a member of
the SAB of Tibotec and a member of the
Infection and Immunity Board and the
Translational Research Group at the MRC.
Email: Eddy.Littler@domainex.co.uk
Affordable Innovation
Introduction
The pharmaceutical industry is facing
unprecedented challenges over the next
decade:
The industry faces a very steep cliff
face. Products to the value of US$125bn
will be wiped off the profit and loss
statements in the Pharma industry.
R&D costs are ballooning while the
number of NCEs approved remains low.
Typically it takes approximately 76,000
scientists to produce approximately 75
NDAs per year, or around 1000 scientists
to make one NDA; the total duration of
the drug development cycle is well over
ten years.
A number of companies have a high
degree of exposure to patent expiries.
The threat of losing a significant
proportion from the revenue line, while
facing increased costs, is compelling
the industry to look at outsourcing core
processes in R&D to low cost-based
countries such as India.
India life science outsourcing
Over the last decade India has achieved
worldwide acclaim by being the destination
of choice for IT, financial services and
business process outsourcing. These
same drivers are contributing to the rise
of R&D outsourcing in the life science
industry. There are a number of factors
driving this:
No language barrier science
throughout the world is taught
predominantly in English, the main
medium of language teaching in India
Robust IT infrastructure for secure and
reliable data exchange
A large and talented pool of scientists;
India is projected to have a surplus
working population of well over 40m,
while the rest of the world is in decline
as a result of the ageing population.
There are six times the number of trained
chemists in India compared to the USA
Key scientists and management are
often trained in the west
Cost advantage of the Indian
workforce
A shift towards affording greater
patent protection having signed up to the
TRIPS agreement
Currently chemical synthesis-based
services can be sourced from mg to
multi-kg / pilot scale. Chemistry seems
to be the most sought after service by
Pharma companies. Although a number
of factors are involved in the decision,
one of the main issues is probably the
relative ease with which deliverables
can be monitored for an off-shore site
quantity synthesised, chemical structure,
purity. Typical services offered are:
Synthesis of molecules from the
patent literature
Synthesis of building blocks for
chemical libraries
Synthesis of intermediates for ongoing
projects
Re-synthesis of molecules for ongoing
projects
Scale-up of synthesis of molecules for
in vivo studies and preclinical studies
Synthesis of molecules identified
through virtual screening experiments.
Increasingly companies are offering
value additions such as computational
modelling and pre-clinical ADMET
services. Certain providers also offer
more than straightforward synthesis of a
range of molecules, including:
Lead optimisation performed auto-
nomously with reduced management
time from the client
Primary biological testing of
molecules, thus reducing the time needed
for shipping samples
Lead generation through in-silica
technologies / platforms and subsequent
synthesis of the hits.
So far the majority of projects are
modelled around two main contractual
arrangements a fee for service model
or a fee for each full time equivalent
(FTE). The former is the primary choice
for some clients and is most successful
where projects can be well defined and
can be delivered within a predefined
time scale at an agreed level of quality;
the latter is the primary choice where
the exact nature of the work may not be
known beforehand, such as in medicinal
chemistry. Typically the fully loaded cost
per FTE in India can be a fraction of the
cost in the USA or Europe.
For the latter there are many methods
of working:
Pricing can be exclusive or inclusive of
raw materials with a capitation formula
being applied
Contracts may include a initial pre-
training period at the clients side if the
technical nature of the project makes it
necessary
Projects can range from pure technical
delivery to more creative projects where
the clinical research organisation (CRO)
is expected to furnish insight and provide
creative input computational modelling,
lead optimisation, process research.
Increasingly many companies are
looking at more sophisticated models
of engagement, and are moving from
a transactional nature to more of a
partnership model either through risk-
reward sharing or the Build-Operate-
Transfer model (BOT). An example
is the collaborative research project
between Merck & Co. (US) and
Advinus Therapeutics.
With the BOT model, a service
provider builds a dedicated facility,
and is responsible for all operational
tasks hiring, local approvals for site
development (which in India can be
onerous and a lengthy process if one is
unfamiliar with it), day-to-day operations.
A good example of this is the GVK site
developed exclusively for Wyeth.
Decision-making process in
outsourcing
An important ingredient of successful
outsourcing relationships can be split
into key stages facilitating a holistic view
of the outsourcing strategy:
1. Make or buy decision
2. Separate non-core and core
activities
3. Select a partner
4. Ongoing management of the
outsourcing relationship
5. Evaluate performance
6. Forge a strong partnership
working model
7. Organisational learning.
Many of the stages above are well-
Advinus and Merck will work together to
develop clinically validated drug candidates
for metabolic disorders, with Merck retaining
the right to advance the most promising of
these candidates into late-stage clinical trials.
Under the terms of the agreement, Advinus
will receive an upfront payment and could
potentially receive milestone payments of up
to US$74.5 million for each target included in
the collaboration. Advinus is also eligible for
royalties on the sales of any products that result
from the collaboration. The collaboration will
begin with two target programs, and could
expand to include others over time.
This collaboration provides an avenue
for Advinus to gain access to cutting-edge
technologies from Merck while leveraging
its India-based discovery and development
capabilities, said Dr. Rashmi Barbhaiya,
CEO and Managing Director of Advinus.
Importantly, this agreement also reflects
Indias emerging role in bringing innovative
and life-saving drugs to market with speed
and cost-effectiveness.
Merv Turner, Ph.D., Senior Vice President,
Worldwide Licensing and External Research
at Merck, noted that Merck is looking
forward to establishing its first research-based
collaboration in India with Advinus. This
agreement furthers our strategy of building
global alliances and our commitment to
discovering and developing innovative
medicines for metabolic disorders, a growing
public health issue, Dr. Turner added
Advinus Press Release
documented in outsourcing literature,
however as the outsourcing relationships
are morphing into more value-added
sophisticated models, the ability to
choose the right partner is becoming
more and more significant. There are
many attributes one can look for based
around key categories. PJB Publications
research suggests that the following
attributes contribute towards successful
partnerships:
Cost mechanisms should be put in
place which allow variable costs to be
monitored; there should be no surprises
at the period of review
Financial health backing for the
CRO should be sound and should have
enough resources to survive at least over
the time of the project being outsourced
Resources equipment available,
infrastructure (both existing and planned);
does the supplier have the capacity to
scale up
Competencies qualifications and
skills of the management and delivery
staff at the provider
Quality systems are in place for
monitoring quality on a regular basis
Track record is outsourcing core
to the suppliers business, how long have
they been in this line of business
Interviews key to a successful
relationship is to ensure there is rapport
Flexibility what scope of change to
the original contract is possible from the
service providers perspective.
Conclusions
The industry cannot sustain historical
levels of growth and is facing huge cost
pressures. Low cost-based countries such
as India provide an affordable alternative
to drive innovation. The nature of this
relationship will move from a more
transactional state, to a partnership status
yielding more value from the outsourcing
relationship.
Chandra Rao has worked in the
Pharmaceutical Industry in a number of
roles. He has been part of Integration
teams during Mergers and acquisitions
(Pfizer/Pharmacia); has been head of
Strategic and Operational Planning,
has led policy development working
with Governments and alliance partners
across Europe. He has advised Private
Equity groups on healthcare transactions
and in turnaround projects. Currently he
is an Executive Director at Laxai.
Email: chandra@laxai.com
CLINICAL RESEARCH
Patient recruitment :
are we looking in the right place?
There is an unusual contradiction in
play within the clinical trials process
that suggests the more experienced
the industry has become in conducting
clinical studies, and the more resources
investigative sites have dedicated to
recruiting study volunteers, the more
difficult patient enrolment has become.
This inverse relationship between the
practice and funding of clinical trials
on the one hand, and the numbers
volunteering on the other, has been well
documented. But are we looking in the
right place?
A recent Datamonitor report suggests
that around 90% of clinical trials are
delayed because of patient recruitment
problems, and this is particularly acute
in large studies such as those involving
cardiovascular or central nervous system
disorders. At the same time, sponsors
and investigative sites report spending
more money, and dedicating more time,
to recruiting study volunteers.
Recruitment problems
There are of course valid reasons for
recruitment difficulties. The focus of drug
development has shifted to oncology and
CNS where patient numbers are low and
in terms of the chronic diseases, the clinical
endpoints have become more complex
to measure. The patient populations are
more targeted; trials have got bigger
as regulators require more data from
sponsors; and protocol designs have
become more complex and demanding
on investigative site personnel and study
participants. Indeed, a study conducted
in 2007 by the Tufts Centre for the Study
of Drug Development found the growing
difficulty of protocol execution led to a
75% drop in enrolment rates between the
periods 1999-2002 and 2003-2006.
At the same time, there has been
significant reporting on drug safety which
may cause uncertainty and affect study
enrolment. Yet, despite such difficulties,
there is evidence to suggest a willingness
to participate among the public at large.
Large surveys of the general public
have shown that around two-thirds of
Europeans and 82% of North Americans
would consider participating in a clinical
trial. While these figures of course belie
the actual numbers that enrol in practice
just 6% of Europeans and 10% of
North Americans they offer the industry
significant opportunity to improve on
current enrolment rates.
Numerous initiatives have been
implemented to reach these potential
volunteers, ranging from newspaper, TV
and internet campaigns to the modern
media approach of video footage and
DVDs. But one area that has received
less attention, but is nevertheless essential
to successful start-up, is a thorough
understanding and documentation of the
route by which patients receive treatment
the so-called patient pathway. And it
is this simple route to patients that is so
often undervalued.
Focusing on the patient pathway
If mapped correctly, the patient pathway
can reflect treatment variations between
clinics and individual clinicians, identify
the different custodians of patients during
treatment, and provide a consistent,
structured template across all stages in the
study, highlighting how to identify patients
that meet the protocol requirements.
Indeed, by applying more rigour to
understanding where the patient comes
from, within each country, within each
clinic, and in each disease area where
they go within the hospital or healthcare
setting, who speaks to them, who treats
them, and the treatments and care they
receive, clinical staff are better equipped
to access the appropriate patients in an
effective and timely manner.
Figures for study enrolment times are
testament to the fact that the traditional,
What is required
is a new, more
considered approach
to identifying the
right patients
based on data-
driven performance
metrics and focused
planning processes.
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ad hoc system of identifying study patients
using traditional communication networks
is no longer optimal. What is required is
a new, more considered approach to
identifying the right patients based on
data-driven performance metrics and
focused planning processes.
This more formalised approach needs
to be adopted for every disease. It involves
mapping the therapeutic area treatment
pathway (TTP) using current best-practice
guidelines, recommendations and
internal libraries of data. The resulting
decision tree for disease management
then becomes the template for mapping
the actual patient pathway for specific
conditions, even as they move across
different disciplines and speciality areas.
At this point, the protocol specific
pathway can be overlaid onto it,
providing a tool for informed discussion
between the clinical research associate
(CRA) and the doctor at the feasibility
stage in much the same way a detailing
aid might be used by a medical sales
representative. This data-driven map
can be utilised and refined through each
stage of the study, from feasibility, through
start-up, to monitoring of the recruitment
and treatment phase.
Given the changes taking place within
the industry, adopting this more rigorous,
formalised, standardised approach to
the patient pathway is now essential.
Negotiating the complexities
The clinical trial sector has evolved into
a highly regulated industry, performing
multi-centre, multi-country, randomised
studies under stringent conditions.
Similarly, the quality of patient care and
treatment has increased and is becoming
more standardised - leading to better
outcomes data and higher expectations.
But the different interpretations of
these standards within every healthcare
system, from country to country, clinic to
clinic, and site to site, have added levels
of complexity that make it increasingly
difficult to identify target study patients
within the healthcare system.
At the same time, more complex
study protocols with multiple endpoints,
and patients with combination medical
conditions are required. Patients with
conditions that fit the study criteria often
follow a treatment pathway that involves
experts from multi-disciplinary healthcare
teams, rather than being referred to a
single specialist. This can confound the
window of opportunity for their possible
recruitment into the study, creating an
extra challenge in deploying a successful
patient recruitment strategy.
Moreover, the role of the CRA has
also changed in a way that facilitates a
new approach to patient recruitment.
The CRA is no longer a process,
detail-oriented scientist concentrating on
the core areas of monitoring. CRAs are
taking on more of a customer relationship
management role, and with it a growing
understanding for patient enrolment
which was once the sole domain of the
An effectively
mapped patient
pathway will
contribute to the
successful execution
of a clinical trial.
Christopher Cabell,
MD, MHS, FACC
is the Senior Vice
President of Global
Access to Patients.
As such, Dr. Cabell
leads Quintiles
focus on addressing the increasingly
critical challenge of recruiting patients
and developing a more efficient site
infrastructure. Prior to joining Quintiles,
Dr. Cabell was on faculty at Duke
University School of Medicine and
the Duke Clinical Research Institute in
Durham, NC where he was Director
of the Echocardiography Core Lab,
Associate Director of the ECG Core
Laboratory, Co-Chair of the Cardiac
Safety Research Consortium and Director
of the International Collaboration on
Endocarditis.
Email: christopher.cabell@quintiles.com
investigator.
Those companies that have access to
sophisticated patient databases and other
information sources will have a better
understanding of where the target study
patients are in the system. By providing
CRAs with a data-driven map of the
patient pathway, this should minimise
the risks of miscommunication between
the CRA and the investigator. Any false
optimism on the part of the investigator
in meeting study inclusion criteria will
therefore be dealt with at the feasibility
stage, before the project is delayed or
derailed, as has happened on so many
occasions in the past.
An effectively mapped patient pathway
will contribute to the successful execution
of a clinical trial. The increased level of
sophistication helps to overcome the
unique set of challenges in recruiting
patients.
A study specific pathway
Essentially, what the mapping process
boils down to is a series of questions,
at the heart of which is: where do the
patients come from? Who will be treating
them and how does the protocol compare
to the standard of care at their particular
clinic, to identify where patients may be
lost from the trials?
By leveraging any previous work on
treatment pathways within the company,
these patient maps can become
transformational tools for delivering
recruitment results at various delivery
points within the project lifecycle. And
they can build into a sophisticated library
of therapeutic area treatment, and
protocol specific pathways.
These libraries will not be built
overnight. They are highly process-
oriented, and the volume of work required
to map every disease, in every therapeutic
area, across multi-cultural international
borders, is no small challenge. It may
necessitate a change in the way some
CRAs work with investigator sites. And
it certainly requires accurate feasibility
and site selection in order to have the
conversation that will identify whether
a site actually has the number of target
patients they say they do. But when this
mapping is done correctly it will result
in more timely patient enrolment by
ensuring much earlier identification of the
right investigators, with the right patients,
for the right study.
20 23 October 2009
Hyatt Regency
Boston, United States
2 practical workshops
Pre-conference workshop 20 Oct
Strategies to identify and mitigate
risk in rst in man clinical trials
Post-conference workshop 23 Oct
Biomarkers hype or true value?
Improve decision making in early clinical trials
The 2nd annual Exploratory Clinical Development World Americas is the premier
event for exploratory and phase I professionals to discuss strategy and solutions to
bottlenecks in early development.
2nd annual event
One year on from the excellently received inaugural event, we bring you a packed
agenda, larger speaker panel, more sessions and wider reaching content. You
will hear from industry thoughts leaders from Pzer, GlaxoSmithKline, Novartis,
AstraZeneca, Merck & Co., Wyeth, Bristol Meyers Squibb, Eli Lilly & Co., Schering
Plough, Millennium: The Takeda Oncology Company, Abbott, Genentech, Lundbeck,
SuperGen, Emergent Biosolutions, The Critical Path Initiative and the FDA who will
provide you with discussion, summary and knowledge of the best current practices
that will help you drive compounds through phase I proving proof of concept.
Produced by: Sponsors:
www.healthnetworkcommunications.com/2009/explorusa
Exploratory Clinical
Development World
Americas 2009
3 easy ways to register
Tel: + 44 (0) 207 608 7039
Fax: + 44 (0) 207 608 7050
Online: www.
healthnetworkcommunications.
com/2009/explorusa
MKG code: IPI
Global Training Initiative Challenges
- An American Perspective
In the clinical trials industry, there is
an urgent need to provide accessible,
affordable, and quality training for global
clinical research professionals. Two of
the key stepping stones to a long-term,
successful clinical research career are
access to initial training and continuing
education programmes. This allows
the career-minded individual to gain
a foothold in the industry and continue
their professional growth. It can be a
challenging job for a young Contract
Research Organisation (CRO) to be
able to provide training for ambitious
professional candidates internationally.
This type of training program must be
adaptive as well as informative. It must
combine the inherent cultural differences,
such as language and regional dialects,
with effective transmission of educational
information, as well as allowing for
evaluation of the knowledge acquired by
the participants. Unlike more established
companies, a small CRO has budgetary
concerns that necessitate creativity to
circumvent financial constraints. This
results in the need to take advantage
of the more affordable choices of
communication mediums such as
conventional landline conference calls,
free VOIP software or a combination of
both. Each of these more cost-effective
ways of communication carries its own
merits and unique challenges.
As a regional employee of a small
CRO (Caligeo Clinical, Atlanta, GA), I
have had the opportunity to participate in
these types of programmes. The merits
and challenges of trans-continental
training methods are quickly recognisable.
Use of one of the various landline
teleconferencing services has proven an
ideal solution. Freeconferencecall.com
is one such service that provides trainers
and trainees with the ability to connect
with little or no service interruption and
excellent audio quality. This modality
coupled with appropriate software,
such as Microsoft PowerPoint for
example, results in an almost seamless
virtual classroom. This allows smaller
companies to provide professional
development for their employees at more
than one location simultaneously in a
cost-effective way. More challenges arise,
however, when that virtual classroom
expands to include participants from
across the ocean.
As an American who has worked
with international partners on several
projects, I have been privy to many of
the frustrations experienced by them.
The task of connecting trainers and
trainees in the United States is fairly
painless, but difficulties result when
expanded to international regions,
particularly in developing countries.
There are also inherent challenges in
the provision of training for clinical
trials performed according to Food and
Drug Administration (FDA) standards. It
requires detailed planning that takes into
account the differences in educational
backgrounds and limited technological
knowledge that sometimes impede access
for the international user. Additionally,
while VOIP and videoconferencing
technologies such as Skype and Windows
NetMeeting provide good service for
a modest financial investment, certain
regions of the globe still experience
inconsistent internet connectivity and
electrical power instability.
Participation in and implementation
of successful international training
relationships requires flexibility in the
management of cultural differences.
Differences in such customs as
appropriate e-mail etiquette, reasonable
hours of telephone communication and
business etiquette standards between
opposite sexes are just some of the
issues that can arise. You must choose
your battles wisely and put aside your
personal preferences and individual
tastes to concentrate on a win-win
outcome for all your interactions. This
takes patience on all sides. However,
development of good international
interpersonal skills can be even more
valuable and rewarding than the latest
technological communication advances.
The world is becoming a smaller and
smaller place and everyone must realise
that they cannot always have it their
way, but by working together as a
team we can help the world become
a better place.
So, to conclude, there is an urgent
need to provide accessible and
affordable high quality training for clinical
research professionals globally. And as
small CROs, such as Caligeo Clinical,
grow to compete with other, larger
research companies, one of their major
strengths will be their ability to provide
training and continuing education
programmes to clinical professionals
who seek to gain new skills or maximise
their existing expertise. By making
the most of current communication
technologies and emphasising the
importance of international interpersonal
communication skills and techniques,
these young companies will quickly grow
to be industry leaders.
Chad L. Downey is
a Clinical Research
Consultant for
Caligeo Clinical, an
international Clinical
Research Organization
(CRO) based in
suburb of Atlanta, GA
with key objectives
of promoting clinical trials throughout
Africa and the Caribbean as well as among
underrepresented population in the USA.
Downey received his B.S. in Electrical
Engineering from North Carolina State
University in Raleigh, NC. In addition, he
is an active member of the Caligeo Clinical
OneVision and Caligeo Clinical Trials
Initiatives (CCTI). Email: marahclinical@
gmail.com
Gbolahan Fatuga is
the founder of Caligeo
Clinical OneVision,
an international
non-profit Clinical
Research Organisation
(CRO) with the
primary objective of
promoting clinical
trials throughout Africa and the Caribbean.
Fatuga received his M.Sc. in Drug Regulatory
Affairs and Health Policies from Massachusetts
College of Pharmacy and Health Science,
and his B.Sc degree in Neuroscience from
Brown University. He is an active member of
the International Faculty Advisory Board for
the Association of Good Clinical Practices
in Nigeria (AGCPN) and a member of the
Nigerian Association of Pharmacists and
Pharmaceutical Scientists in the Americas
(NAPPSA). Email: gfatuga@gmail.com
Analytical Biochemical Laboratory BV (ABL BV) is an independent contract
laboratory and a central laboratory serving (multicentre) clinical trials for
pharmaceutical and biotechnological companies. ABL is a laboratory that
operates world-wide, supporting clinical trials and pre-clinical drug development
studies (PK-PD-and safety samples).
ABL is subdivided into two departments
Bio Analytical Services
Focuses on the analysis of samples derived from pre-clinical and clinical studies.
Available techniques include:
LC-MS/ MS
GC-MS
GC-FI D, NDP and ECD
HPLC with UV, fluorescence and electrochemical detection
Immunochemistry (RIA, EIA, FIA)
Clinical chemistry
Hematology
Contact: Mr. E. Oosting MSc, technical director
E-mail : eoosting@abl .nl
Clinical Trial Services
Offers support services for the conduct of multi -site clinical trials ranging from
sample logistics and source verification to data and project management.
Contact: Mr. H.J. Trip, manager CTS
E-mail : hjtrip@abl .nl
By combining these two activities, ABL is able to optimize the overall efficiency,
quality and data integrity while saving costs and time. We operate under a set
of strict protocols and procedures to ensure transparency whilst not affecting
the capability to adapt to the requirements and needs of the individual client.
Analytical Biochemical Laboratory BV
W.A. Scholtenstraat 7
P.O. Box 232, 9400 AE Assen
The Netherlands
Telephone +31 (0) 592 34 42 11
Fax: +31 (0) 592 34 44 25
www.abl .nl
Analytical Biochemical Laboratory BV
Clinical Research Organization
IT & LOGISTICS
Controlled environment storage and
stability storage :
the case for outsourcing
In the highly competitive world of drug
development and with the economy
in its current dire state, there has never
been a better time to consider the merits
of outsourcing your stability storage
requirements.
Just ask yourself a few crucial questions.
Can you justify, or even afford, the costs
associated with setting up your own
facilities and investing in the necessary
equipment? Have you got the time and
experienced manpower to attempt an in-
house solution? Do you possess the skills
to manage the increasingly technical
aspects of stability storage? Are you able
to cope with the sea of regulatory control
that is so pivotal to the success of your
project?
It could be a potential minefield for
your organisation, so why not take the
easy option? Increasingly companies are
commissioning a Preferred Outsourcing
Partner (POP) to help them through
the maze of equipment, technologies,
controls and procedures.
Costs
So first, lets consider the kind of outlay
involved with a typical stability storage
trial. By its very nature, the process may
need a large investment in custom-
built premises. Floor space comes at a
premium and much of the equipment
needed has a large footprint. So why
incur the cost of an in-house option
when you could be relying on an off-site
resource?
Premises and facilities
Any storage facility should be capable of
accommodating bulk products. Vindon
Scientific cited this as one of their main
reasons for moving to more spacious
premises last September. They reacted
to ever-increasing client demands and
instantly increased their storage capacity
by 600%.
Vindon now boasts more than two
million cubic litres of environmentally
controlled storage space, with a suite that
can house 2000 cubic metres of product.
A typical room could cost anywhere
between 30,000 - 150,000 to set
up, and with separate rooms needed for
different environmental conditions, you
can see how costs could escalate.
All this expertise does of course come
at a price, usually levied as a standard
monthly or annual fee, but you should
not expect to pay extra charges for set-
up, transactions or removing samples.
Youll find that your POP will offer a
simple cost-effective arrangement for
a very precise and intricately managed
service.
With the new building at the prestigious
Kingsway Business Park in Rochdale,
Vindon is one storage resource that is
ideally suited to meet the demands of the
largest pharmaceutical organisations in
the UK and Europe.
Equipment
Your POP should offer you the use of
reliable and well-maintained equipment,
plus the assurance of trained and
qualified operatives, with the necessary
systems in place for a foolproof service.
By far the most significant outlay is for
cabinets and chambers. Walk-in stability
rooms and chambers should always be
available, with additional chambers to
be called upon for specific requirements
such as retained samples, secondary
storage, and storage of quarantine
samples, freeze/thaw testing and aerosol
testing.
These rooms and chambers should
be very versatile. They should be able
to cater for a multitude of purposes
including stability storage, commercial
environmental testing, fingerprint
development, corrosion testing, UV
testing, environmental stress screening,
shock testing, temperature and humidity
testing and photostability.
Any cGMP facility should incorporate
chambers and rooms that have
been mapped and validated for
pharmaceutical stability storage and
BioTech storage. These temperature and
humidity controlled rooms and chambers
can be tailored to suit individual customer
requirements as well as shelf life studies,
intermediate testing and accelerated
testing per ICH Q1A (R2).

Well-designed rooms
Its the norm for controlled environment
rooms to be built and validated to
provide climatic conditions specified
in ICH guidelines. This should include
equipment to allow for simulating
conditions for all four climatic zones for
long-term, intermediate and accelerated
testing.
Ambient temperature and unique
conditions should also be available,
regardless of the size of product.
Designing and building controlled
environment rooms and a chamber is a
skill that is developed over many years.
Your POP should have the ability to
design rooms that are built and validated
using the most modern techniques.
Unique airflow technology systems should
also be incorporated, in order to deliver
definitive environmental conditions.
Reliable stability testing
The assessment of drug substance stability
is a vital and essential aspect of the
development of pharmaceutical products.
Stability testing is capable of providing
information on how environmental
factors such as temperature, humidity
and light affect their quality over a period
of time. Data derived from a stability
study enables recommended storage
conditions, retest intervals and shelf life
to be established.
Your POP should have a
comprehensive range of conditions
CREDIT CRUNCH... ENERGY COSTS. . .
I NTEREST RATES. . . I NFLATI ON. . .
CASH FLOW...
STABILITYSTORAGEsULTRALOWTEMPERATURESTORAGEsCRYOGENICSTORAGE
Vindon Scientific Limited
John Boyd Dunlop Drive, Kingsway Business Park, Rochdale, OL16 4NG
Tel: +44 (0)1706 716710 Fax: +44 (0)1706 716740
Email: patj@vindon.co.uk Internet: www.vindon.co.uk
SCIENTIFIC
Vindon
CO.UK
In todays atmosphere of financial turmoil, its a relief to know that theres one company that can
be more than just a fair-weather friend. Vindon Scientific have up to 2000m
3
of stability storage
with ICH and bespoke conditions, ultra-low temperature storage at -80C and cryogenic storage at
temperatures down to -196C.
Theres never been a better time to choose a proven service, rather than incurring the capital cost
of purchasing your own controlled environment equipment. Take the safe option. Contact Patrick
Jackson at Vindon today on 01706 716710 or email patj@vindon.co.uk and let us keep a weather
eye open for your controlled environment storage needs.
Weathering the storm
including ICH photostability Option
1 and Option 2 studies, as well as the
capacity for customising.
A good storage resource should offer
all these services:
Long-term stability testing
Intermediate stability testing
Accelerated stability testing
Tailored stability testing
Forced degradation studies
Stability testing of APIs
Stability of Clinical Trial Material (CTM)
Biopharmaceutical stability
Registration stability
Conditions
The POP must be able to provide unique
conditions, as there are many instances
where drugs and drug-related products
need to be stress tested at conditions
outside ICH guidelines. Any independent
storage facility should offer conditions
specifically suited to your product. It
should meet the needs of companies
that require off-site stability storage,
redundant stability storage, short-term
growth needs, backup storage, or long-
term stability storage conditioning.
Biopharmaceuticals, for instance, are
particularly sensitive to environmental
factors, making strict storage conditions
necessary for the maintenance of
biological activity and product integrity.
The choice of temperature for the
storage of biological, medical and
pharmaceutical materials is dependent
upon the sample to be stored. Vindon
offers customers the option of storing
materials under controlled ICH and non-
ICH conditions in a purpose-designed
storage suite. This unique service provides
an extremely cost-effective solution for
controlled environmental storage at
temperatures ranging from minus 196C
to plus 60C and relative humidities from
10% to 95%.
Pure DNA will exist for long periods
at 4C in buffer solution. For long-term
storage DNA is stored at minus 40C,
while proteins are better stored at minus
80C and stem cells are stored at
temperatures from minus 150C to minus
196C. A comprehensive cryobank will
provide a solution for these and almost
all other storage applications.
Cryogenics
Cutting edge cell technology means
there is an ever-increasing need for
cryogenics in todays controlled storage
world. Cryopreservation is a process
where cell (biology) or whole biological
tissues are preserved by cooling to low
sub-zero temperatures, such as (typically)
77K or minus 196C (the boiling
point of liquid nitrogen). At these low
temperatures, any biological activity,
including the biochemical reactions that
would lead to cell death, is effectively
stopped. However, when vitrification
solutions are not used, the cell (biology)
being preserved is often damaged due
to freezing during the approach to
low temperatures or warming to room
temperature. These factors are further
proof that it makes economic sense for
pharmaceutical and related industries to
adopt an outsourcing partnership for their
complex cryobiological programmes.
Your POP needs to provide a full
range of services to store and manage
biological materials at any given
temperature. From bar-coding frozen
vials through to relocating your entire
repository, the quality policy should be
reinforced by a positive commitment to
your needs. This starts with an assurance
that samples are stored in a high security
facility with convenient access.
Storing samples safely
The storage of cells at temperatures
below minus 150C is necessary to
preserve materials unaltered. This is the
point at which biological activity ceases.
Although mechanical devices can be
used to maintain temperatures below
this level, they can be noisy and they
also generate heat. They also require
liquid nitrogen backup to avert disaster
should the electricity supply be disrupted
or the freezer fail. Liquid nitrogen is
the most logical choice for storage
at temperatures below minus 130C.
But there are risks associated with its
use. To ensure there can be no cross-
contamination with the stored samples, it
is generally recommended that materials
are stored in the vapour phase above the
actual nitrogen, where temperatures are
in the region of minus 150C down to
minus 178C.
Industry experts believe that the use of
dry-store freezers, specifically designed
as vapour phase storage systems, offers
exceptional sample security. A slight
positive pressure in the sample chamber
will circulate out any pathogens. And
operator safety is ensured because the
storage area is completely free of liquid
nitrogen, which is housed in a jacket
surrounding the chamber. Temperature
performance to minus 190C can be
achieved, well below the level required
to keep materials in first-class condition.
An efficient cryobank should provide
a management solution for short-term,
medium term and long-term temperature
controlled storage. It should incorporate
secure storage and real-time tracking of
the stored samples and all safety issues
should be in strict accordance with the
latest regulations. It is also essential
that your POP has the staff and systems
to offer foolproof biological storage
conditions. A purpose-built state-of-the-
art biorepository should accommodate
biological samples, culture collections,
microbial, viral seed stocks, DNA and
bone marrow, as well as all-important
stem cells and cord stem cells.
Stem cell technology
Stem cells are found in most, if not all,
multi-cellular living organisms. They differ
from other kinds of cells in the body in
that they are all capable of dividing and
renewing themselves for long periods.
Being non-dedicated and with the ability
to differentiate, they can become an
ongoing source of cells that make up
critical tissues and organs. There are
two broad categories of stem cells -
adult stem cells (also known as somatic
stem cells) and embryonic stem cells.
Adult stem cells are now routinely used
to treat life-threatening conditions and
have the potential to treat many more
illnesses in the future. Stem cells also
have possibilities for new regenerative
therapies and can be used in research
for the development of new drugs.
Now commonly used in bone marrow
repair, stem cells can be sourced from
the bone marrow itself, peripheral blood
and, most recently, umbilical cord blood.
Stem cells from umbilical cord blood
(hematopoietic stem cells) have to date
been used to repair bone marrow in over
2000 patients. New sources of stem cells
from adipose tissue (fat), childrens milk
teeth and even hair are regularly being
identified.
Cord blood storage
The first cord blood transplant was
performed in 1988 to treat a five year old
patient with Fanconis Anemia, a fatal
blood disorder. Since that first successful
operation, more than 10,000 further cord
blood transplants have been carried out
to treat a wide variety of disorders and
diseases, including cancers and inherited
conditions.
In the USA, cord blood has become
the most frequent source of stem cells for
transplantation in children. Along with
ongoing research to improve the use
of cord blood in stem cell transplants, a
significant amount of research is being
conducted to explore the application
of cord blood in fields including the
treatment of brain injury, cerebral palsy,
type 1 diabetes, heart disease and critical
limb ischemia.
It is estimated that by the year 2015,
there will be up to 10,000 cord blood
transplants worldwide per year, using
banked cord blood. A vital aspect of
this programme will be to develop
repositories for the storage of cells to
guarantee continued successes in this
exciting arena.
Long-term storage
There are some finely tuned methods
of preserving biological materials by
freezing and storing them at ultra-low
temperatures. The provision of long-term
preservation of biologics, reagents and
specimens is often required, together
with a secure facility for samples and
laboratory research materials. Ideally this
should cater for anything from a single
box of samples, up to virtually any volume
for the duration of any research project,
and be capable of storing millions of
samples, vials or tube racks. Vindons
new cryobank satisfies all these criteria.
Validation
A comprehensive storage facility should
have full regulatory compliance to
guarantee the integrity of customer
samples. Vindons new premises, for
example, have been built with the latest
equipment, so that customers can be
assured that the facility is technically fit for
purpose, meets the highest standards of
environmental control and includes built-
in redundancy and emergency backup.
Every piece of equipment also has an
individual preventative maintenance
schedule.
Constant monitoring is normally
performed with a paperless data logging
system that, ideally, should also be
compliant with the requirements of the
US Code of Federal Regulations. An
ultra-low temperature storage facility
of minus 70C to minus 85C can be
tailored to the needs of biotechnology,
pharmaceutical and agrochemicals
companies, including veterinary industries
and academic institutes.
Expertise in sample management
underpins the secure storage of samples
and should include constant monitoring
of the storage conditions, the ability
to track and retrieve samples to GLP
standards and full traceability in highly
regulated environments.
Validation must be carried out
regularly to ensure that an environmental
room, cabinet or cryogenic freezer is
capable of accurate and repeatable
performance. Ideally a combination of
United Kingdom Accreditation Service
(UKAS) calibration probes and state-of-
the-art data acquisition systems should
be used to ensure that temperature and
humidity levels are monitored at all times
to incorporate an identifiable audit trail.
Reliable sample tracking
Managing hundreds of thousands of
samples for different companies, with
dissimilar protocols, requires an efficient
sample tracking system to ensure that
they are all handled properly - essential
for a well-run facility. When samples
are outsourced properly, identification
of each sample or batch of samples
is needed to prevent confusion when
removing them from chambers. Samples
should be clearly labelled, typically with
quantity, storage conditions, product
name, product code, lot number and date
of manufacture. Reliable software can
also make a significant difference when
tracking pull dates, sample locations and
quantities. Its important to comply with
regulations for audit trails and security
compliance in order to meet inspection
regulations.
A comprehensive information
management system is at the heart
of all storage solutions. The inventory
management solution should enable
the user to record all data associated
with the samples including location,
temperature and humidity, as well as
recording all user-defined information.
Every sample handled by Vindon is given
a unique barcode label and is recorded
on the system. This significantly simplifies
handling, tracking and processing.
Supplementary information relating to
individual samples in terms of movement
within the facility, time and duration
of storage vessel openings and who
accessed the vessel is also available as
part of a comprehensive audit trail. All
staff should be fully accountable and
provide a service that complies with
regulatory requirements.
As part of an ongoing commitment to
provide businesses with secure secondary
storage or disaster recovery, your POP
should also offer an established disaster
management capability for stored
product as an added insurance.
Clear-cut advantages
Controlled Environment storage is
a demanding business. It presents
many challenges including high costs,
management expertise and regulatory
procedures. Your decision to outsource
will very much depend on your own
companys current resources. It may
suffice now, but what of the future?
For qualified and knowledgeable
staff who always keep abreast of topical
developments, for unique conditions
with state-of-the-art facilities to match,
outsourcing has to be the logical
outcome.
Patrick Jackson
Patrick, a qualified
engineer, was
recruited in 2005.
He has over thirty
years experience in
project management
and business development. His
responsibilities include development of
new markets in the UK and overseas,
ongoing sales, client liaison, marketing,
negotiating and overseeing commercial
and technical agreements, as well as
general day-to-day management.
Email: Patrick@vindon.co.uk
MANUFACTURING & PACKAGING : MANUFACTURING
Facing todays challenges in
biopharmaceuticals from early stage
drug development to commercial
manufacturing
Dr. Patricia Lobo, Senior Consultant of
Life Science Business Solutions & Editor-
in-Chief of International Pharmaceutical
Industry (IPI) speaks with Dr Bernard Chan,
Chief Business Officer, Dr Mads Laustsen,
CEO of CMC Biologics, Copenhagen
and Dr Gustavo Mahler, President of
CMC ICOS Biologics, Seattle, on the
changing dynamics in the marketplace
for manufacture of biopharmaceuticals
and CMCs role as a leading contract
biomanufacturing organisation.
PL: Tell me about CMC - how or where
did it start, what is the main focus of the
business, types of customer, services
offered, size of the organisation etc.
CMC:
CMC is eight years old, and it was
started in 2001 in Copenhagen, Denmark.
A group of entrepreneurs, mostly
bringing their experience of industrial
biopharmaceuticals manufacture from
Novo Nordisk, founded a Contract
Manufacturing Organisation (CMO)
to service the biologicals market. With
know-how, determination and passion,
these people found the means and the
money to construct a manufacturing
facility that from the outset was purpose-
built as a CMO.
Since that time, the quality designed
into the facility has ensured successful
European licensing, and the facility holds
a licence to manufacture both clinical
and commercial biological products.
A key milestone for CMC was the
acquisition of its facility in Seattle in
2007, which was owned at the time
by Eli Lilly. Critical to this expansion
was the acquisition and retention of an
experienced bio manufacturing team that
brought a long history of manufacturing
excellence.
Our focus is biologicals contract
development and manufacturing services
from DNA through to commercial supply.
To optimally service its clients, CMC is a
pure-play CMO, i.e. it does not have
own products, and thereby no conflicts of
interests between customers and in-house
developments, which is a downside to
other mixed-model CMOs.
Focus:
o CMC operates with an
international focus (English as company
language, multi-cultural workforce,
facilities in EU and US and an international
client base).
o CMC is proud of being a
one-stop-shop in both cell culture and
microbial-based manufacture with
abilities to help the client throughout the
whole development from the early DNA /
cell line development work until market.
o CMC has based its developments
on best in class technologies combined
with industrial experience and approved
flexible facilities supported with compliant
quality systems.
The CMC organisation is today
approaching 400 employees, with about
60% of the staff at its Danish site and
40% at its US site.
Our customers range from small,
virtual biotech to large pharma.
Customers are truly global, spanning US,
EU, Japan and Australia.
PL: Could you say a few words about
the changing face of biopharmaceuticals
with particular reference to contract
services?
CMC:
With the current global economic
climate, companies developing
biopharmaceuticals are reviewing
their pipelines and the commitment to
outsource to contract suppliers (CROs,
CMOs, CALs) is more protracted.
But biopharmaceuticals remain the
favoured future growth area for many
pharma companies, and outsourcing is
very much on the agenda as a means to
reduce overheads at this time.
The difficulty is that contract suppliers
are also struggling, and some are not
surviving. In the biologics CMO world,
recent examples of exits include Xoma
and QSV. They wont be the last. These
CMOs have been hurt in two ways:
(1) customer products suffer the usual
attrition, normally due to failure in meeting
clinical end-points, and late-phase
failures in particular leave a big hole in
the CMOs schedule; (2) the downturn
has affected customer confidence in
committing to capacity reservations, and
upfront fees which are commonly high
for biologicals manufacture have been
driven down, causing cash-flow crises for
some CMOs.
So the choice for pharma and biotech
is shrinking, at a time when some would
prefer to outsource.
CMOs like CMC Biologics have
a growing and more mature client
base, and a track record to deliver on
commitments ensures repeat business
which is critical in such turbulent times.
The prospect of the Far East
becoming a major player in the
biologics CMO business remains only
a prospect, and the know-how needed
0DQXIDFWXULQJ 0HGLFLQHV
.your outsourcing partner of choice
Manufacturing biological Active
Pharmaceutical Ingredients has many
challenges. Choosing your manufacturer
may not be the biggest challenge, but
your choice could be the difference
between success or failure.
CMC Biologics can help make your
choice easier. Who else can offer a
uniqueness that combines:
Mammalian and microbial platforms, and
Solutions from DNA to commercial supply, and
Biomanufacturing in both US and Europe, and
Independent ownership: no in-house conflicts
With facilities in Copenhagen and Seattle,
and production scales ranging from
100L to 3000L, our is likely to fit
your needs.
But it's our people, their know-how
and our passion for delivering
medicines, that makes us
a top-tier solutions provider.
www.cmcbio.com
CMC Biologics A/S
Vandtaarnsvej 83
DK-2860 Soeberg
Copenhagen
Denmark
+45 7020 9470
CMC ICOS Biologics Inc
22021 20th Avenue SE
Bothell
WA 98021
USA
+1 425 485 1900
for bio processing development and bio
manufacturing is still heavily weighted
to US and European talent. Hence we
still observe significant interest from
Far East drug developers who choose
CMC Biologics for the provision of such
services.
PL: Give examples of the business
environment, the types of product driving
demand and the ways in which you see
bio-outsourcing evolving in 5-10 years.
CMC:
The current economic downturn
is impacting the pharmaceutical and
biotechnology industry, perhaps more so
than one might have expected.
Nevertheless, drug developers that
have been holding back over the last
12 months, reviewing their pipelines or
conserving their cash, are now appearing
to be moving out of the gloom. Drugs
still need developing, and stalling
programmes may help to alleviate short-
term cash-flow concerns, but ultimately
companies need to commit and move
forward.
With the consolidation that has
happened during the global recession,
outsourcing of biologicals manufacture
has become a more favourable option.
The dilemma for drug developers is that
some biological CMOs have recently
exited (Biovitrum, Apptec, Xoma and
QSV Biologics are examples).
Fortunately there are a number of
CMOs such as CMC that have raised
their heads above the declining pool,
with a better reputation for quality of
service and technical prowess.
Over the coming years, we expect to
see more of the smaller CMOs exiting,
and only a few like CMC making grounds
on the two biggest suppliers. Such growth
for the few will likely come from the
current movement of large pharma into
the biologics space, and the continued
preference of the outsourcing model.
PL: How would the challenges faced by
your potential customers in developing
the bio manufacturing strategy fit in the
scheme of things?
CMC:
The first challenge for customers is
taking the make or buy decision. Many
have already made that decision when
they come to talk to us, but not all (some
have the option of in-house capacity).
At CMC Biologics, we can offer
a number of compelling reasons for
choosing an outsourcing model:
o The repertoire of protein-based
drugs that CMC Biologics has been
exposed to over the years provides a
greater depth of bio processing and bio
manufacturing know-how, which many
companies lack. This facilitates getting
things right first time, and more successful
trouble-shooting when technical issues
arise;
o With a large proportion of
drugs being antibodies, CMC Biologics
can fast-track the development pathway
by using standardised platforms and
tried-and-tested approaches to achieve
regulatory compliance and approval at
each gateway of the development life
cycle;
o As a customers product
progresses towards commercial approval,
a strategy needs to be developed to
ensure appropriate manufacturing
scale. CMC Biologics offers a variety of
scales of operation, enabling a route for
scale-up. Future growth for particular
high-demand products is catered for
with expansion potential at both our
sites in Seattle and Copenhagen. Many
customers are only able to handle small
scale clinical supplies, and some only
handle large scale commercial supply.
Additionally we offer a number
of options for leveraging on strategic
alliances. For example, customers can
implement a bio manufacturing strategy
that ensures reserved capacity over
a longer period of time at a reduced
financial risk, while the progress of
any particular drug candidate remains
uncertain. Alternatively, customers may be
looking for future scale-up expansion on
a joint risk-sharing basis with a contractor
such as CMC Biologics, who remain in a
position to place such a customer at the
highest of priorities.
PL: Where is CMC currently positioned?
Is CMC more or less focused on
processes or products? How does this
compare with the competitors?
CMC:
There can be no disputing that the
biggest revenue generators in the
biologicals CMO business are Lonza and
Boehringer Ingelheim. They are probably
also the most recognised names in the
market.
CMC Biologics has progressed rapidly
over just a short number of years to hold
a position in the next tier, competing with
only a small pool of other CMOs as well
as the two top companies.
This has been achieved by focusing
on two key success factors: quality and
process (and manufacturing) know-how.
Where other CMOs have pinned their
cards to a specific cell-line, or their own
drug development products, or more
recently diversifying into new ventures
such as in-house biosimilars, CMC
Biologics has built its reputation and
brand around the fundamentals of the
chemistry, manufacturing and controls
requirements. We believe this is ultimately
what customers need, and our name
speaks to that belief and commitment.
PL: How would you assess the
costs of process development in bio-
manufacturing, for example which are the
most costly or labour-intensive aspects?
Our expansion into the US in 2007
with the acquisition of our Seattle facility
was an important milestone towards
establishing a global presence.
Our vision sees us rising to the number
three CMO in our market, measured
in terms of revenues, market reach and
brand recognition.
We believe we will get there by
achieving our mission of enabling our
customers to realise the potential of their
biopharmaceuticals by contract process
development and manufacture.
is only true if the process issues have
been properly addressed by this stage.
Otherwise the biggest cost becomes the
lost opportunity, as a poorly developed
process hinders regulatory filing and
possibly supply of pivotal studies.
PL: To what extent would you say
analytical services in support of
bioprocess development are important?
CMC:
Analytical is absolutely critical.
Bioprocess development cannot happen
without the right analytical tools. This
applies equally to manufacturing.
The difficult part is integrating the
analytics and the bioprocess efforts. This
requires not just having the analytical
tools, but knowing when and how to
apply them, and discerning what the
analytical data is telling you, such that
the right decisions can be made to further
the development of the process.
Analytics are needed for release
testing, in-process testing, stability,
characterisation, comparability and
a host of other activities essential for
developing a robust bioprocess.
At CMC Biologics, we recognise the
pivotal role played by strong analytics,
and our analytical capabilities, in terms
of equipment and people, are among
our strongest assets and differentiators.
PL: What is CMCs vision?
CMC:
CMCs vision is to be a world market
leader in biopharmaceutical contract
services in terms of quality, know-how
and timeliness.
CMC:
Development of a bio-manufacturing
process is a challenge, and overcoming
challenges costs money. Drug developers
that undertake in-house process
development often do not realise what it
will take and how much they will need to
spend.
In the early stages of the development
pathway, designing a manufacturing
process to deliver non-clinical or initial
clinical material is relatively inexpensive
per se. But most companies are fortunate
if they have one new biological entity
to move into development per annum,
so the overhead of maintaining unused
process development laboratories and
scientists can be significant. Outsourcing
to a CMO can be highly cost-effective in
real terms, because CMOs have multiple
projects to work on and running costs are
spread.
Its in the later stages of the
development pathway that drug
developers often underestimate the
process development cost. With
increasing manufacturing experience,
including scale-up to the commercial
process, there is almost always a need to
undertake further process development.
And the cost of such work, especially the
analytical characterisation and testing,
can be very high.
At CMC our philosophy is to try to
avoid the amount of later stage process
development by investing earlier in the
manufacturability of the drug. Working
with so many types of products and having
a history of challenging biologicals, we
are better equipped to foresee potential
issues to deliver a workable process that
can be locked earlier.
As products move through Phase III
clinical, costs to validate the process and
analytical methods, produce the required
consistency batches and preparations
for commercial launch, far outweigh
the process development costs. But this
Dr Bernard Chan,
Chief Business Officer.
Responsible for Business
Development at CMC,
Bernard has 20 years
experience developing
and commercializing
biotechnology drugs. Previous senior
management positions were with Celltech,
UCB and Xceleron. A PhD molecular biologist.
Mads Laustsen,
Chief Executive Officer.
CEO and Co-founder
of CMC, Mads has
over 20 years experience
in the biologics industry.
Previous positions were
with Novo, Zymogenetics and Novozymes. A
biochemical engineer.
Dr Gustavo Mahler,
President. President
of CMCs US division,
Gustavo has 15 years
experience in the
industry, 14 years with
Bayer in manufacturing
and management. A PhD in biochemistry.
cmcinfo@cmcbio.com
Critical Considerations in the
Development and Production of
Freeze-Dried Products
Synopsis
Freeze-drying (lyophilisation) is a widely
used process for dehydrating a vast range
of materials, including pharmaceuticals,
vaccines, diagnostics, biological
materials, whole organisms and
foodstuffs. Dr Kevin Ward from freeze-
drying specialists Biopharma Technology
Ltd. in Winchester (UK) outlines some
of the principles of the technology and
how scientists are now moving to using
a rational, analytical approach to help
them be more successful and efficient
in the development and production of
freeze-dried products.
Introduction
Lyophilisation has been used on an
industrial scale for many decades to
increase the shelf-life of a wide range
of materials and is now well established
throughout many industries and applied
to many products and specimens,
including pharmaceuticals, vaccines,
diagnostics, biological materials, body
tissue, foodstuffs, whole organisms and
even whole animals. Despite its wide
and increasing usage, it is apparent that
many industries, scientists and process
operators still regard the technology
as somewhat of an art, and possibly to
a greater extent in the pharmaceutical
industry than elsewhere. It is easy to see
why this myth persists after all, it is a
complex process in terms of the physics,
while pharmaceutical-grade freeze-dryers
are themselves often sophisticated pieces
of machinery, built to operate as a freezer,
a vacuum vessel and an autoclave (for
sterilisation), with complex and secure
control systems, safety features and data
readouts. Further to this, materials that
are freeze-dried are often composed
of multiple ingredients, which may give
variable and unpredictable freezing and
drying behaviour. There are several
variables to consider as part of the
lyophilisation process, many of which are
interdependent.
For new products that are developed
with a view to lyophilisation, it is now
becoming more widely recognised
that the formulation process and the
lyophilisation cycle development process
may be carried out at the laboratory
scale, with scale-up and technology
transfer issues taken account of during
this early development stage. How
might this be achieved? One of the most
important factors to understand is how
each product will respond to the various
stages of the process, with arguably the
most stressful stages of the process (from
the point of view of the product) being
freezing and sublimation. This article
describes some of the basic features of
the lyophilisation process and how the
development of analytical procedures
such as freeze-drying microscopy (FDM),
thermal analysis and electrical impedance
analysis are allowing formulation
and process development to be
approached on an integrated, scientific
basis.
How does Lyophilisation work?
The process works by initially freezing
a material, then removing the solvent
(typically water, as shall be considered
here) under vacuum. The main drying
step-primary drying, involves the removal
of ice from the frozen material, mainly by
sublimation (i.e. a direct phase change
from ice to vapour without passing
through the liquid state). However,
not all the water molecules in the
starting material may form part of the
ice structure, but instead will remain
as individual or clusters of molecules,
termed unfrozen water (e.g. within
salt crystals, in the hydration shells of
proteins, or otherwise associated within
the structure). As such, these molecules
will not sublime, but some of them may
be removed (intentionally or otherwise)
by evaporation and desorption.
Further secondary drying involves the
removal of such unfrozen water, with a
view to enhancing the shelf-life of the
final product.
Minimising processing defects in
freeze-dried products
Different materials freeze in different
ways, depending on a number of factors,
including the nature of the individual
components and their effect on each other,
the speed of cooling and the cleanliness
of the material (e.g. filtered solutions
will often have different ice formation
patterns to unfiltered solutions). It is the
behaviour of the solutes themselves that
is particularly important in freeze-drying,
since once the ice is removed during the
sublimation process, it is these solutes
that will become the dried product.
Few materials will crystallise in such
a predictable manner as, for example,
sodium chloride, which adopts what
is termed eutectic behaviour (i.e. it
freezes at the same temperature and
the same concentration irrespective of
the initial concentration). Therefore,
although reducing the temperature to
just below 0C should be sufficient to
convert the freezable water to ice in
such a solution (and indeed it may look
frozen to the naked eye), the spaces
within the ice crystal structure will be
occupied by a eutectic liquid, which
will boil under vacuum. To achieve full
solidity, the solution must be cooled to
below its eutectic temperature (Teu), so
that the eutectic liquid solidifies fully and
is maintained in this state throughout the
drying process.
Most materials that are currently
freeze-dried are non-crystalline, so will
solidify to give an amorphous glass
containing regions of unfrozen water. This
is typically much more difficult to remove
than the water in a frozen eutectic system,
since it requires not only sublimation, but
also higher levels of evaporation and
desorption than would be necessary
compared to those required in a eutectic
material. In contrast to eutectic materials,
solutions containing solely amorphous
components will not contain a eutectic
liquid between the ice crystals; instead,
they will comprise a glassy structure which
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changes from being flexible to rigid
at their characteristic glass transition
temperature (Tg).
To initiate the sublimation process,
once fully solidified, a vacuum is applied
to the material. The subliming vapour is
then condensed and trapped as ice on
the product condenser (vapour trap),
which is held at a lower temperature than
the drying material. During this stage the
control of product temperature is possible
by adopting an appropriate combination
of temperature and pressure conditions
within the drying chamber. Heat input is
required to provide sufficient energy to the
drying material to convert ice to vapour
(approximately 2,800 Joules for every
1 gram of ice), yet it is also important
not to provide more energy to the
material than it is able to lose through
sublimation, otherwise the temperature
of the material will rise, which will lead
to physical defects in the final product if
a crystalline material rises above Teu or
an amorphous material rises above its
collapse temperature (Tc), which will be
at or some way above Tg. The collapse
temperature may be defined as the
temperature at which the material softens
to the point of undergoing viscous flow, a
phenomenon that may be closely linked
with unacceptable product appearance,
incomplete drying, poor stability and
difficulty in reconstitution.
Determining eutectic, collapse
temperatures and glass transition
Collapse temperatures can really only be
identified using freeze-drying microscopy
(FDM), since the collapse event only
occurs in a material that is subjected
to freeze-drying and therefore can only
be determined under freeze-drying
conditions. A freeze-drying microscope
is essentially a micro-freeze-dryer
that allows the intrinsic freeze-drying
characteristics of a small volume of
material (around 2l) to be identified.
Glass transitions have been
traditionally determined by thermal
analysis. However, the thermal change in
a frozen material when cooled or warmed
through Tg can be subtle and difficult
to determine; therefore, alternative
methods such as electrical resistance
or impedance analysis may be used in
conjunction with thermal methods, in
order to provide a more complete picture
of frozen state behaviour, including
identification of temperatures at which
frozen solutes undergo relaxation and
mobility changes.
Used in combination, thermal
analysis, electrical impedance (or
resistance) analysis and FDM provide
a comprehensive means of formulation
characterisation in terms of frozen state-
and freeze-drying- behaviour and critical
temperatures, from which it is possible
to determine whether a material is
practically freeze-dryable without further
refinement of the formulation, and to
begin the design and development of a
lyophilisation cycle for a given product.
In addition to the information taken from
such methods, further factors such as the
product container type and dimensions,
fill depth (or volume), solute density and
level of particulate content should be
taken into consideration.
Many real formulations contain a
mixture of crystallising and amorphous
components, which can make for
complex behaviour and heterogeneity
in the final product, sometimes with the
amorphous and crystalline components
forming separate phases within the
frozen structure. In terms of minimising
visible product defects, arguably the most
prudent approach when freeze-drying
such materials is to maintain the product
temperature below the lowest critical
temperature of the identified solute
phases (so Teu for a crystalline phase or
Tg / Tc for an amorphous phase).
In an efficient and safe product
lyophilisation cycle, a safety margin is
often adopted, whereby the product
temperature is maintained at some
temperature below that of its critical
temperature typically between 3C
and 7C below its critical temperature,
depending on the perceived intra- and
inter- batch variability upon scale-up.
During cycle development, product
temperature is often measured by
inserting thermocouples or resistance
thermometers into samples of product
in the freeze-dryer, which provide an
indication of what the product itself is
experiencing during the process. This
information can then be used to refine
processing conditions in the subsequent
freeze-drying cycle, or indeed in the
present cycle if the control system allows
parameters to be changed.
Once the sublimation process is
complete, the final part of the process
(secondary drying) involves removal of
the unfrozen water in order to achieve
the target moisture content identified to
provide sufficient shelf stability under the
expected storage conditions. Care must
be taken with heat-sensitive materials
such as biologically active proteins, which
may undergo undesirable reactions
(e.g. degradation) or interactions (e.g.
aggregation) if inappropriate conditions
are employed even towards the end of
the freeze-drying process.
A more reliably acceptable final product
Generally, one looks for the final
freeze-dried product to fulfil a number
of set criteria, including maintenance
of activity, good reconstitution
characteristics, cosmetic acceptability
, appropriate moisture content and
good shelf stability. Due to the complex
interrelationship between the numerous
product and process variables, some
developmental work may be required
to achieve these criteria. The advent
of new technologies, particularly FDM,
thermal analysis and more recently
electrical impedance (Zsin) analysis,
together with more sophisticated and
flexible control systems on research scale
freeze-dryers, is enabling such work to
be approached on a more rational basis
by allowing a greater understanding of
how products respond to freezing and
drying, enabling development scientists
to rapidly refine conditions accordingly,
without the need for months of trial and
error experimentation.
Dr Kevin Ward is
presently the Director
of Research and
Development at BTL
and is responsible
for the day-to-
day running of the
company. Following a degree in Applied
Chemistry, he was awarded his Ph.D.
for studies in pharmaceutical freeze-
drying, focusing on the use of protective
agents in formulations of proteins and
liposomes for drug and vaccine delivery.
Kevin worked in the pharmaceutical
industry and as a Research Fellow in
vaccine development before joining BTL
in March 2000. He continues to publish
in the field and regularly lectures on the
freeze-drying process itself, as well as on
analytical and product-related issues.
Email: KWard@biopharma.co.uk
PACKAGING
Compliance Enhancing Drug Pack
Design : A Benefit for All
User-friendly packaging of drugs is a
low-cost way of increasing compliance
with (antimalarial) drug therapy said
the World Health Organisation Infectious
Disease Report published ten years ago
(1) and it went on by stating: A simple
packet of fast acting drugs made widely
available to parents together with
training to recognize malaria symptoms
could save the lives of many children
with severe malaria.
What this report said about the
treatment of malaria is just as true for
most other diseases and is not restricted
to the third world. A wide range, in fact
almost all therapies and their success
depend on the continuity of the drug
consumption, starting with antibiotics
where the problem of discontinuity in
adherence is particularly dangerous and
expensive. Patient compliance/adherence
is the prerequisite for an economic and
efficient way of curing illnesses or of
improving the general level of human
health. Yet compliance is not the rule
but the exception. Non-compliance is
an issue to individuals whos condition
may worsen or who even may die if they
fail to medicate correctly. It is however,
just as much a concern for the public
as non-compliance leads to losses in
productivity and increased expenses for
modern medication, for better and more
efficient drugs. It has to be added that the
subsequent cost for non-compliance is
not only that of the wasted medicines but
is compounded by the cost of emergency
and acute intervention when medication
is not taken.
According to P. Rudd (2) Hypertension
and in particular the treatment with Beta-
blockers requires a compliance rate
of more than 80 % in order to lower
the blood pressure permanently. In
addition medication holidays from beta
blockers can provoke a sudden crisis as
a result of the so called rebound effect
leading to cardial infarctions, strokes
or other life threatening events. The
WHO report: Adherence to Long-term
Therapies Evidence for Action (3) states
that despite the availability of effective
treatment, over half the patients being
treated for hypertension drop out of
care entirely within a year of diagnosis,
and of those who remain under medical
supervision, only about 50% take at least
80% of their prescribed medications.
The report says: Because of poor
adherence to anti-hypertensive treatment,
approximately 75% of patients with a
diagnosis of hypertension do not achieve
optimum blood-pressure control.
In other words: if a therapy is either
not or insufficiently successful, it is not
necessarily the medication that fails but
non-compliance has to be taken into
consideration as a cause of the failure.
The minimal rate of compliance to ensure
therapeutical success, however varies
from medication to medication and from
disease to disease.
Current methods of improving
medication adherence for health
problems are mostly complex, labour-
intensive, and not reliably effective.
Medication reminder packaging
which incorporates a date or time for a
medication to be taken in the packaging,
can act as a reminder system to improve
adherence. A study, titled Reminder
packaging for improving adherence to
self-administered long-term medications
carried out by Heneghan CJ, Glasziou P,
Perera R (Cochrane database) suggests
that Reminder packaging may help
people take long-term medications.
People often miss taking prescribed
medication, because of forgetfulness,
changing medication schedules or busy
lifestyles. It is estimated that between
40% and 60% of people do not take
medication as prescribed, which can lead
to worse health outcomes. Packaging of
medications with reminder systems for
the day and/or time of the week is an
attempt to help people take long-term
medications. (4) The right way of drug
packaging helps compliance.
A WHO review investigating whether
fixed-dose combination pills or unit-of-
use packaging improve adherence?
concludes that: overall, the evidence
suggests that fixed-dose combination
pills and unit-of-use packaging are likely
to improve adherence...(5)
And an investigation into the question
regarding the Impact of Medication
Packaging on Adherence and Treatment
Outcomes in Older Ambulatory Patients
carried our by Philip J. Schneider; John
E. Murphy; Craig A. Pedersen at the
Ambulatory care clinics at Ohio State
University Medical Center, Columbus;
University of Arizona Health Science
Center, Tucson; and Riverside Methodist
Hospital Family Medicine Clinic,
Columbus, Ohio, from July 1, 2002,
to December 31, 2004 concludes:
Providing medications in a package that
identifies the day each dose is intended
to be taken and provides information
about proper self-administration can
improve adherence to treatment regimen
and treatment outcomes in elderly
patients being treated for hypertension.
Incorporation of this durable strategy
could also lead to improvements in
medication-related outcomes in elderly
patients with other chronic diseases.
Considering the potential effect of the
new Medicare prescription benefit on the
U.S. health care system, further research
into the benefits of durable strategies
in various patient groups on health
and economic outcomes is important.
Because benefits have already been
demonstrated with adherence-aiding
packaging, such packaging should be
made increasingly available for long-term
medications. Better packaging may be
used for medications as a way to create
an improved system of care that results in
better adherence to treatment regimens
and enhanced treatment outcomes.
28-29th September 2009, Midland Hotel, Manchester, UK
China is at the forefront of the increasing trend to use so-called emerging markets where clinical
trials can cost substantially less than those in Western countries.
However, the decision to outsource clinical trials to China requires an understanding of the
scientic and regulatory procedures in China and a thorough knowledge of the implications
involved.
KEY TOPICS TO BE ADDRESSED:
Assessing the real value of incorporating China into a multinational clinical trials strategy
Strategic and regulatory considerations before conducting clinical trials in China
Considerations involved in designing the China component of the trial to position the drug for eventual
China market approval
The China SFDA has been working more closely with regulatory bodies and industry leaders to improve
processes and approval times. Is this still an obstacle and what changes have been made?
What are the concerns for small and medium pharma and biotech companies conducting clinical trials in
China without operations in the country?
OUR EXPERT PANEL OF SPEAKERS INCLUDES:
Dr. Xunting Zeng Ph.D General Manager, InCROMChina
Ying Luo, Ph.D - Chairman and CEO, Shanghai Genomics, Inc, Chairman and CEO, GNI Ltd
Prof. Leung Ping Cheng, Director of the Institute of Chinese Medicine, Chinese University of Hong Kong
Zheng Qin Yin MD& PhD - Professor and Director of Southwest Eye Hospital
Senior representative from SFDA
Dr. Yiding Xing Director of Pharmacovigilance, Excel PharmaStudies Inc
Dr. Frank Lu Director of Bioinformatics, Excel PharmaStudies Inc
The congress provides an opportunity to learn rst-hand how to outsource preclinical and clinical trials to
China and to meet and network with over 20 Chinese CROs and Hospitals actively involved in conducting
preclinical and clinical trials.
REGISTER BEFORE 14TH AUGUST AND SAVE 305 PER DELEGATE
For more information about registration or to enquire
about sponsorship and speaking opportunities please go
to www.globalengage.co.uk
Alternatively, please contact Steve Hambrook,
Conference Director, at steve@globalengage.co.uk
The China Clinical Trials
Outsourcing Congress
pharma companies who jointly market
their products in ZacPac benefit from
a significantly increased market share
over those they had when their related
medicines were marketed independently
in traditional packs.
The following graph (7) shows that
the duration of the treatment has strong
influence on the compliance rate.
With the shift of demographics
towards a worldwide older population
and with the advances in modern
medical treatment chronic diseases
are affecting an increasingly higher
percentage of people than ever before.
People live more and more on their own
and cannot rely on the help of family
members with their medicinal regimen
when they fall ill. Life styles in the
modern and industrialised world are not
necessarily contributing to better health
conditions and long-term therapies are
required to cure diseases that are often
the direct result of too high calorie intake
and too little exercise. And many of the
conditions occurring at a later stage in
life are non symptomatic and require
long term therapies. Non-compliance
is especially problematic in chronic
diseases that are not associated with
any symptoms and in diseases in which
the symptoms occur erratically. These
people need help with their medication,
help that to some extent can be provided
by cleverly designed drug packs which
take into account that older patients
have lesser capabilities to access their
drugs and to keep track of their intake.
Calender packs like the one of ZacPac or
other electronic reminder devices which
are now available at reasonable costs
(like the one incorporated in Stora Ensos
DDSi), allows the patient to communicate
with a central data base, thus allowing
the practitioner to see the compliance
pattern and to intervene. These were
designed exactly for that purpose: to
assist patients in their endeavours to stay
compliant.
Increasing the effectiveness of
adherence interventions might have a
far greater impact on the health of the
population than any improvement in
specific medical treatment. (6)
All this is not new and one would
expect that over the last decade the
pharmaceutical industry would have
adopted pack design and reminder
features helping the patients to keep
track of their drug intake. The few scarce
examples of excellent packages that were
developed to assist the patient in his
medicinal therapy prove that the benefit
of such patient centred design outweighs
the slightly higher cost by far. One of
the finer examples of such design is a
combination therapy for the treatment
of helicobacter pylori, composed by
two antibiotics from Abbott and a
proton pump inhibitor from Nycomed,
former Altana. The pack was designed
by DesignConnection a company
specialised in packaging design for the
pharmaceutical industry concentrating on
the need of a high level of compliance to
achieve the desired result in this case:
the eradication of helicobacter pylori. The
two graphs below show the difference in
compliance between the traditional form
of medication in three separate packs
with no reminder features and the new
ZacPac.
Although this specific treatment is one
for a condition with severe symptoms
and designed for a short period of
time the difference in compliance is
significant. And the result are much
better outcomes. This in turn convinced
the practitioners after the introduction
of ZacPac in Germany to prescribe this
therapy as it does the better job. The two
Scenario 2: Use of a Combination Package for
PPI, AB1 and AB2
Scenario 1: Use of 3 Distinct Packages for PPI,
AB1 and AB2 in Parallel
Stora Ensos Pharma DDSi Pack
Tassilo Korab
holds MSc in health-
care Manage-
ment. He started
his career as an
International Sales
Manager, and has
been in the packaging industry for
more than 25 years. Focusing on
patient compliance, standards and
regulations for child resistant packaging
and the war against counterfeits.
Co-founder of HCPC Europe, Tassilo
Korab is the MD of TKM HandelsgmbH,
Austria. Email: tassilo@korab.at
References
1. World Health Organisation Infectious disease
report. Publication Code: WHO CDS99.1, 1999
2. Rudd P. : Compliance with antihypertensive
therapy: a shifting paradigm. Cardiological
Rev. 1994
3. WHO Report. Adherence to long-term
therapies: evidence for action. 2003
4. http://www.cochrane.orgreviewsenab005025
.html
5. http://www.scielosp.org/scielo.php?script=
sciarttext&pid=S0042-96862004001200010
&lng=e&nrm=iso&tlng=e
6. Haynes R.B. et al.: Interventions for helping
patients follow prescriptions for medications.
Cochrane Database of Systematic Reviews.
2001
7. Heuer H.O., Heuer S., Lenneke K.,: Compliance
in der Arzneitherapie. Wissenschaftliche
Verlagsgesellschaft mbH. Stuttgart 1999
8. The Report by The Task Force for Compliance
November 1993 Revised April 1994
HCPC-Europes
Conference 2009
Compliance Drug Packaging
the Prescription for Success
ACCOMMODATION
Ramada Plaza Basel
Messeplatz 12
CH-4058 Basel
www.ramada-treff.ch/basel
CONFERENCE VENUE
FHNW-Hochschule fr Life Sciences
Mattenstrasse 22
CH-4058 Basel
www.fhnw.ch/lifesciences
UPatient compliance is a key factor
for healthcare cost containment
and for therapeutical success.
UListen to top speakers from
leading European universities,
the pharmaceutical industry,
experts in public health and
patient compliance and represen-
tatives of patient organisations.
ULearn how drug packaging can
improve patient compliance.
UUnderstand how improved
patient compliance can contribute
to the success of your business.
UHear how more thoughtful drug
packaging design helps to
improve cost effectiveness in
healthcare.
UGet an insight into the work
of package design and its
contribution to patient safety.
UMeet key opinion leaders
and decision makers in the
pharmaceutical and packaging
industries and in the world of
healthcare economics.
NOVEMBER 10
TH
2009
FHNW- HOCHSCHULE FR LI FE SCI ENCES, BASEL
Or contact:
HCPC-Europe
A-1090 Vienna
Liechtensteinstrasse 46a/10
Tel.: +43-1-890 34 45
Fax: +43-1-890 34 45 05
E-mail: hcpc-europe@tkm.co.at
WWW.HCPC-EUROPE.ORG PLEASE FIND THE REGISTRATION FORMS HERE
ACCUBRAILLE by BOBST: The
efficient way to emboss Braille dots
BOBST GROUP is the worldwide leading
supplier of equipment and services to
packaging manufacturers in the folding
carton, corrugated board and flexible
materials industries. Founded in 1890
and based in Lausanne, Switzerland,
BOBST has always focused on products
that meet current markets requirements.
Developments are numerous in the
folding carton industry as equipment has
to be more and more versatile. In addition
to the high levels of sophistication of the
boxes to be diecut and folded, development
continues in the addition of value to
the box (embossing, hot foil stamping,
holograms, Braille embossing, etc).
A module named ACCUBRAILLE is
among BOBSTs developments. It took
18 months of R&D work by a team of
five people to design an in-line solution
to BOBSTs exacting quality standards.
Integrated in a machine that folds and
glues cartons, it embosses Braille dots.
Compared to the Braille embossing of
the cartons at the cutting and creasing
stage, this solution brings advantages,
which enable the converters to cope in
a highly efficient manner in line with the
European regulation on pharmaceutical
packages.
Various production challenges
Braille embossing creates production
challenges. When applied at the stage of
diecutting, it introduces costs caused by
the constraint to buy as many embossing
tools as there are cartons on a printed
sheet. Consequently, users felt that it
would be more cost-efficient to apply
Braille at the last part of the entire process,
the folder-gluer, where the cartons are
taken one by one. The ACCUBRAILLE
module removes the need to emboss on
the diecutter and brings several benefits:
the preparation of the diecutter is
faster (no setup of embossing tools),
the stops of the diecutter are fewer
(less cleaning of embossing tools),
fewer challenges on the folder-gluer
since the boxes are embossed in the
section following its feeder, and therefore
improved run-ability of the gluer as the
module is mounted after the feeder (no
blanks stuck together),
the setup of tools takes less than
five minutes; no additional staffing is
required.
It brings with it the possibility of
applying embossing very close to the
cut or creased edges and, therefore,
more interesting design possibilities. It
functions at normal production speed for
pharmaceutical boxes (75,000 boxes/
hour). BOBST has developed an option
to improve productivity to a level of up to
100,000 boxes/hour. The system works
according to the Marburg Medium
standard, with a maximum of four lines,
and handles materials ranging from 200
to 500 gsm.
It was introduced in March 2007
when 170 persons, all pharmaceutical
packaging producers, from all over
Europe visited BOBST. Live demonstrations
showed a BOBST folder-gluer
incorporating the ACCUBRAILLE module
working with a CARTONPACK GT end
of the line packing solution integrating
the optional full speed sampling device,
a unit especially suited to products that
require inspection checks.
BOBST SA/A. Thompson/A. Michel/June
2nd, 2009.
Accubraille 2: Embossing of Braille dots.
Accubraille 1: Embossing as protection
against counterfeiting
Braille embossing
creates production
challenges.
B O B S T G R O U P . C O M
ACCUBRAILLE
Delivered by Express
Braille
Getting Braille onto cartons has never been faster than with
ACCUBRAILLE and a BOBST folder-gluer. Taking just minutes to set,
ACCUBRAILLE needs only a single low-cost tool, and keeps pace with
your gluer even at 100,000 boxes an hour. But, if that isnt enough,
ACCUBRAILLE can also be used on any of the four carton panels, right
up to creases or edges, and Braille embossing on your folder-gluer
instead of your diecutter means an end to dot denition drift over the
length of the run.
ACCUBRAILLE: Revolutionary Braille embossing.
www.cphi.com | www.icsexpo.com | www.p-mec.com | www.bioph-online.com
Unrivalled networking
opportunities at the worlds
leading pharmaceutical event
CPhI Worldwide, ICSE, P-MEC & BioPh
13 - 15 October 2009, Feria de Madrid, Spain
CPhI Worldwide, now in its 20th year, consistently draws
thousands of key decision makers and executives from the
pharmaceutical and ne chemical industry. This truly is the
foremost event where intelligence gathers, offering a host of
networking opportunities to support your business needs.
ICSE has been bringing outsourcing solutions to CPhI since
its introduction in 2000. In 2009, it continues to be the
international platform for companies providing a wide diversity
of outsourcing services including clinical trials, contract research,
contract packaging, logistic and analytical services.
Held alongside CPhI and ICSE, P-MEC connects hundreds of
sellers of pharmaceutical machinery and equipment to thousands
of blue-chip buyers and speciers. Addressing every aspect of
processing and manufacturing, this premier event highlights
the latest knowledge and the newest trends.
Completing this quartet of industry-leading events is BioPh.
This brand-new event brings together companies and
organisations dealing with new and innovative bio-solutions
and treatment methods for pharma. BioPh will help your
business make the right connections in biopharma.
Make sure you dont miss this unique event.
Visit the websites below, email cphi@ubm.com
or call +31 346 559 444 to nd out more.
News Page
Gteborg World Leader in Biomaterials
The city of Gteborg, on the west coast of Sweden, boasts one of
Europes finest clusters for life science and biomedicine. As the site
of numerous breakthroughs in research and development within
medicine, the city has become a leading cluster in biomaterials and
cell therapy. The key to Gteborgs strength is its combination of
high-calibre academic research capabilities and a well-established
industrial base.
Strong Research Tradition
Gteborg has an excellent record of achievement within the
biomedical field. Among its pioneers are Prof Arvid Carlsson, who was
BMG LABTECHs new PHERAstar FS
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the ultimate multidetection microplate reader for high throughput
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awarded the Nobel Prize in 2000 for his research into dopamine, Prof
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Strong Life Science Industry
There are some 170 companies and over 8,000 employees in life
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The China Clinical Trials
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The Gteborg region has a strong research tradition
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The Gteborg region has also a very strong life
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Earned Value Management An Approach For Effectively Managing Pipeline Value Proteomic Tools For The Study of Model Organisms

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Earned Value Management

an approach for effectively

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