Pharma Focus Asia Issue 21

Issue 21 2014 www.pharmafocusasia.com
Rethinking
Drug Discovery
Bioprinting
The patent landscape
The Six
Great
Shifts
Transforming the
pharma industry

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Foreword
to look for investing more in developing new
products. This would increase the number of
products serving the market while also meeting
unmet medical needs by reaching underserved
markets.
Succeeding in this new landscape will require
partnerships between pharmaceutical compa-nies,
governments and/or non-profit organisa-tions.
Further, pharmaceutical companies will
need to step outside their comfort zone and
develop partnerships with players from other
industries for better outcomes.
The cover story of this issue by Brian D
Smith from PragMedic, UK, provides an insight-ful
analysis of six great shifts transforming the
pharma industry. The article covers shifts in
value, network and information globally, along
with the systemic shift and trimorphic shift. Dr
Smith explores the implications of the six great
shifts and how selection pressures will impact
pharma strategies.
Prasanthi Potluri
Editor
w w w . p h a r m a f o c u s a s i a . c o m 1
Gearing up for
Post-Blockbuster Era
The golden era of blockbuster drugs is coming to
an end but there are reasons to believe that new
growth opportunities exist for pharma compa-nies
willing to adapt to the change. The FDA
approved 27 New Molecular Entities (NME) in
2013, and this number came down from 39 in
2012 and 30 in 2011. Twenty-eight first-of-a-kind
drugs were approved annually over the past five
years. A few more new drugs were reformulated,
incremental modifications or new indications
of existing drugs were also done.
According to Bain & Company, strong
pharma and biotech companies are restructuring
their organisations and planning to launch many
products simultaneously, rather than launching
one blockbuster every other year.
Switching to this model, known as ‘Pharma
3.0’, requires companies to adapt to new busi-ness
models. The traditional ‘Pharma 1.0’ model
concentrated on blockbuster drugs, where as
‘Pharma 2.0’ model focused on bringing more
product offerings to a global market. The next
phase of development, ‘Pharma 3.0,’ focuses
on service components. This model allows phar-maceutical
companies to target health benefits
per dollar spent, allowing companies to explore
a variety of new business models.
With the changing market dynamics, trans-formation
of technology, communications and
business, pharmaceutical companies need

Content
STRATEGY
05 Bioprinting
Robert W Esmond, Director, Biotechnology/Chemical Group,
Sterne, Kessler, Goldstein & Fox P.L.L.C., USA
11 Creating and Sustaining Cultural Change by
Focusing on Operational Excellence
ThomasFriedli, Managing Director TECTEM,
Vice Director Institute of Technology Management
NikolausLembke, Research Associate
ChristianMänder, Research Associate
University of St.Gallen, Switzerland
RESEARCH &
DEVELOPMENT
22 Rethinking Drug Discovery
Subhadra Dravida, Founder and CEO of Tran-Scell Biologics &
TranSTox BioApplications, India
Prabhat Arya, Department of Organic and Medicinal Chemistry,
Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad
Campus, India
Manufacturing
27 Validation Projects in China
Magnus Jahnsson, Director Regulatory Affairs,
Pharmadule Morimatsu, AB Sweden
Daniel Nilsson, Director GMP and Validation Services,
Pharmadule Morimatsu, China
Erik Östberg, Project Validation Manager,
Pharmadule Morimatsu, China
Information
technology
32 Quality by Design
A rapid and systemic approach for
pharmaceutical analysis
M V Narendra Kumar Talluri, Assistant Professor, Department
of Pharmaceutical Analysis, National Institute of Pharmaceutical
Education and Research, Hyderabad, India
white paper
38 Crippled by Cost? CMO Quo Vadis
Arun Ramesh, Senior Research Analyst, Beroe Inc., India
2 Pharma Focus Asia ISUE - 21 2014
11
27
COVER STORY
16 THE SIX
GREAT
SHIFTS
Transforming the
pharma industry
Brian D Smith, Managing Director,
PragMedic, UK

TOGETHER
WE WRITE
HISTORY
WITH
PEPTIDES
shop.bachem.com
Building on our heritage, we pioneer
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Alan S Louie
Research Director, Health Industry Insights
an IDC Company, USA
Christopher-Paul Milne
Associate Director, Tufts Center for the Study of
Drug Development, Tufts University, USA
Douglas Meyer
Senior Director, Aptuit Informatics Inc., USA
Frank A Jaeger
Director, New Business Development
Solvay Pharmaceuticals, Inc., USA
Georg C Terstappen
Chief Scientific Officer, Siena Biotech S.p.A., Italy
Kenneth I Kaitin
Director and Professor of Medicine, Tufts Center for the
Study of Drug Development, Tufts University, USA
Laurence Flint
Associate Director, Clinical Research
Schering-Plough Research Institute, USA
Neil J Campbell
CEO, Mosaigen Inc. and Partner
Endeavour Capital Asia Ltd., USA
Phil Kaminsky
Founder, Center for Biopharmaceutical Operations
University of California, Berkeley, USA
Rustom Mody
Director, Quality and Strategic Research
Intas Biopharmaceuticals Limited, India
Sanjoy Ray
Director, Technology Innovation
Merck Research Laboratories, USA
Editor
Prasanthi Potluri
Editorial Team
Grace Jones
Sasidhar Pilli
Art Director
M A Hannan
Product Manager
Jeff Kenney
Senior Product
Associates
Veronica Wilson
Ben Johnson
Circulation Team
Naveen M
Sam Smith
Steven Banks
Subscriptions
In-charge
Vijay Kumar Gaddam
IT Team
Krishna Deepak
James Victor
Head-Operations
S V Nageswara Rao
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strategy
Bioprinting
The bioprinting of tissues and organs has been big news
recently. However, the patenting of bioprinting techniques has
quietly been going on for years. This article will discuss the
patents covering the three process phases of bioprinting, the
exceptions to patent infringement for experimental uses, and the
prospects for further patenting and patent infringement lawsuits.
Robert W Esmond, Director, Biotechnology/Chemical Group, Sterne, Kessler, Goldstein & Fox P.L.L.C., USA
Additive manufacturing or 3D
printing, as known more widely,
is revolutionising the manufac-ture
and distribution of products. With
the expirations of the basic additive
manufacturing patents, anyone can
purchase an inexpensive printer and
replicate products. But these prod-ucts
are often protected by various
forms of intellectual property laws.

The widespread additive manufactur-ing
of products will pose many intel-lectual
property rights challenges similar
to those encountered by the recording
industry in the 2000s when widespread
copying of copyrighted music began.
Products made by additive
manufacturing may infringe intellectual
property rights as described in the table
below. The limitations on enforcing the
rights are also set forth (Table 1).
Products of commerce may be
protected by any one of these IP rights.
But the protection for bioprinted tissues
and organs is much more limited as
they are essentially utilitarian. While the
software and code used to manufacture
a bioprinted tissue or organ may be
protected by copyright, the tissue or
organ itself does not have a means for
expression, ornamental features, or
source of origin. In addition, trade
secret protection for a bioprinted tissue
or organ will provide little protection
in view of national regulations that
require the disclosure of the methods of
approved making biologics and medical
devices.
The best way to protect bioprinting
innovation is with utility patents.
While patents are expensive and time
consuming to obtain and difficult
to enforce, regulatory approval for
a bioprinted tissue or organ is very
expensive and time consuming. There
is little incentive to invest in obtaining
regulatory approval if the bioprinted
tissue or organ can be knocked off once
approved for marketing.
In order to determine what patents
might dominate the making, using and
selling of bioprinted tissues and organs,
we carried out a patent landscape search1.
The landscape search did not attempt
to cover all patents filed on additive
manufacturing techniques which are
thousands in number.
As shown in table 2 below, the most
frequent patent filers were located in
the United States.
1 Thanks to Rebecca Hammond, Ph.D., for participating
in the landscape search.
IP Right Nature of Right Limitations
Copyright Protects means of
expression of an idea.
Useful to protect
software, code, CAD
drawings, sculptures and
3D models. Easy and
cost-effective to obtain.
Statutory damages
are available in many
countries.
Protection does not
extend to the utilitarian
features of a product.
Difficult and expensive to
enforce in court.
Design patent Protects novel
ornamental features of a
product, i.e., the way an
article “looks.” Easy and
inexpensive to obtain.
Protection does not
enforce in court.
Trade Dress Protects the visual
appearance of a product
that indicates the source
of origin. No filings
required.
Protection does not
enforce in court.
Trademark Protects indication of
source of origin and
protects consumers
from being confused by
the origins of a product.
Easy and inexpensive to
obtain.
Protection is limited to
the mark and does not
features of the product.
enforce in court.
Trade Secret PProtects against
misappropriation of
secret information
about a product
maintained as a secret.
Such information may
include design plans,
software and code used
to make the product.
No filings required but
steps must be taken to
ensure secrecy of the
information.
Competitors can reverse
engineer the product and
method of manufacture.
Unless trade secret
misappropriated, there
is no protection once the
information is no longer
“secret.” Difficult and
expensive to enforce in
court.
Utility Patent Grants limited right
(generally 20 years) to
exclude others from
making, using and selling
claimed a product or
process.
Expensive and time
consuming to obtain.
enforce.
The Limitations On Enforcing The Rights
Table 1
strategy

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strategy
Patent Filers
cell aggregates, each cell aggregate
comprising a plurality of living
cells; wherein the cell aggregates
are embedded in the at least one
layer of matrix in a non-random
predetermined pattern, the cell
aggregates having predetermined
positions in the pattern.
This patent appears to cover a tissue
or organ containing layers of matrix and a
plurality of living cell aggregates imbedded
in the layers of the matrix in predetermined
positions in a pattern. Thus, this patent
appears to cover all bioprinted tissues and
organs in the United States through its
expiration date in 2028.
B. US 8143055 ‘Self-assembling
multicellular bodies and methods of
producing a three-dimensional biologi-cal
structure using the same’ (Exp. Date
June 24, 2029)
Assignee: The Curators of the
University of Missouri (this patent may
also be licensed to Organovo, Inc.). It was
also filed in Australia, Canada, China,
European Patent Office, Japan and South
Korea. What is claimed is:
1. A three-dimensional structure
comprising: a plurality of multicel-lular
bodies, each multicellular body
comprising a plurality of living cells
cohered to one another; and a plural-ity
of discrete filler bodies, each filler
body comprising a biocompatible
material that resists migration and
ingrowth of cells from the multicel-lular
bodies into the filler bodies
and resists adherence of cells in the
multicellular bodies to the filler
bodies, wherein the multicellular
bodies and filler bodies are arranged
in a pattern in which each multi-cellular
body contacts at least one
other multicellular body or at least
one filler body.
This patent appears to cover bioprinted
tissues and organs containing patterned
discrete filler bodies that resist migration
and ingrowth of patterned multicellular
bodies containing living cells. Such filler
bodies may include sacrificial hydrogels
that form tubular engineered blood vessels
inside tissues and organs.
The search results were categorised
into a preprocessing or design phase,
production phase and post-production
maturation phase2.
Bioimaging + CAD + Blueprint

Bioink + Biopaper + Bioprinter

Maturogens + Biomonitoring
+ Bioreactor
The most important issued patents
in each category are described below3.
Pending applications are not included as
their issuance as patents is speculative.
2 See, Vladimir Mironov et al., Regenerative Medicine 3:
93-103 (2008).
3 For the complete search results, including pending appli-cations,
please contact the author at resmond@skgf.com.
I. Bioimaging + CAD + Blueprint
Patents
A. US 8579620 ‘Single-action three-dimensional
model printing methods’
(Exp. Date: May 30, 2031). What is
claimed is:
1. A system for printing a 3D
physical model from an image data
set, comprising:
a display component for display-ing
one or more printing templates;
and a single-action data process-ing
component that, in response
to a printing template selected by
a single action by a user, executes
the selected printing template to
take the image data set as input and
generates a geometric representation
for use as input to a 3D printer;
wherein the selected printing
template comprises predefined
instructions for processing the
image data set.
The owner of this patent is not
known. It was filed only in the United
States. This patent appears to cover a
system for 3D printing any product
from an image data set in response to
a printing template selected by a single
action by a user. The patent specifica-tion
makes clear that bioprinted organs
are contemplated: ‘FIG. 14 illustrates an
example of printing a physical model of
selected organs . . .’
II. Bioink + Biopaper + Bioprinter
Patents
A. US 8241905 ‘Self-assembling cell aggre-gates
and methods of making engineered
tissue using the same’ (Exp. Date Mar
11, 2028)
University of Missouri. This patent is
reportedly licensed to Organovo, Inc4.
It was filed only in the United States.
What is claimed is:
1. A three-dimensional layered
structure comprising: at least one
layer of a matrix; and a plurality of
4 See Organovo’s press release at http://ir.organovo.com/
news/press-releases/press-releases-details/2012/Organovo-
Announces-Two-Issued-Patents-First-Company-Patent-and-
Key-Founder-Patent1130104/.
Company/Institution
Organovo, Inc. (USA)
University of Missouri (USA)
Oganogenesis, Inc. (USA,
Switzerland)
Harvard Bioscience, Inc. (USA)
Tengion, Inc. (USA)
INSERM (France)
Nanyang Technological University
(Singapore)
Cornell Research Foundation, Inc.
(USA)
Clemson University (USA)
Wake Forest University Health
Sciences (USA)
Nscrypt, Inc. (USA)
Medical University of South
Carolina (USA)
Novatissue GmbH (Germany)
Table 2

C. GB2478801 ‘Multilayered
Vascular Tubes’ (Expiration date March
16, 2031).
Assignee: Organovo, Inc. It was also
filed in Canada, China, European Patent
Office, Israel, Japan, South Korea, Russia,
and United States. What is claimed is:
1. An engineered multilay-ered
vascular tube comprising an
outer layer of differentiated adult
fibroblasts, at least one inner layer
of differentiated adult smooth
muscle cells and differentiated
adult endothelial cells, and having
the following features: (a) a ratio of
endothelial cells to smooth muscle
cells of 1:99 to 45:55; (b) the engi-neered
multilayered vascular tube
is compliant; (c) the internal diam-eter
of the engineered multilayered
vascular tube is 6 mm or smaller;
(d) the length of the tube is up to
30 cm; and (e) the thickness of the
engineered multilayered vascular
tube is substantially uniform along
a region of the tube; provided that
strategy
the multilayered vascular tube in
non-innervated and free of any pre-formed
scaffold.
This patent describes in detail how the
engineered multilayered vascular tube is
made by laying manually elongate cellular
bodies and elongate bodies of gel matrix.
The patent also describes the use of a
bioprinter to make the same structure.
This patent appears to cover bioprinted
multilayered vascular tubes (e.g., tubular
engineered blood vessels) containing an
outer layer of differentiated adult fibrob-lasts
and at least one inner layer of differ-entiated
adult endothelial cells, with the
additional required elements (a)-(e).
D. US 8747880 ‘Engineered Biological
Nerve Graft, Fabrication and Application
Thereof ’ (Expiration date May 28,
2031).
University of Missouri (this patent may
also be licensed to Organovo, Inc.). It was
also filed in Australia, Canada, China,
European Patent Office, Israel, Japan and
Russia. What is claimed is:
1. A multicellular construct
consisting essentially of: a multi-cellular
region comprising: a plural-ity
of living cells cohered to one
another to form an elongate graft for
restoring neural connection between
the ends of a severed nerve; a plural-ity
of a cellular channels extending
axially through the multicellular
region; and wherein the multicel-lular
construct does not comprise
any scaffold material at the time of
implantation into a living organism
having a nervous system.
This patent covers a nerve graft that
may be made using bioprinting tech-niques.
E. US7051654 ‘Ink-Jet Printing
Of Viable Cells’ (Exp. Date May 22,
2024)
Assignee: Clemson University. This
was filed only in the United States. What
is claimed is:
36. A method for forming an
array of viable cells, said method
comprising:

supplying a cellular composi-tion
containing cells to at least one
printer head of an ink-jet printer,
said printer head defining an orifice
through which said cellular compo-sition
is capable of flowing;
forming one or more droplets
from said cellular composition;
flowing the droplets through
said orifice so that said cells are
printed onto a substrate; and depos-iting
a support compound onto said
substrate for supporting said cells,
said support compound forming a
gel after being deposited onto said
substrate.
This patent appears to cover a method
of preparing a bioprinted tissue or organ
by ink-jet printing a cellular composition
containing cells and forming a gel after
deposition.
F. US7625198 ‘Modular Fabrication
Systems And Methods’ (Exp. Date Aug.
10, 2025)
Assignee: Cornell University. This
patent was filed only in the United States.
What is claimed is:
An article fabrication system
comprising: a plurality of material
deposition tools containing one or
more materials useful in fabricat-ing
the article; a material deposition
device having a tool interface for
receiving said material deposition
tools, the tool interface of said mate-rial
deposition device being movable
in various paths . . . relative to a
substrate to dispense material . . . a
system controller operably connected
to said material deposition device .
. . and a tool rack comprising tool
mounts ....
This patent appears to cover an
ink jet printer that may be used for
bioprinting. The specification makes clear
that it may be configured for deposition
of a hydrogel with seeded cells.
II. Maturongens + Biomonitoring
+ Bioreactor
Only pending applications were found
on the post processing steps of bioprint-ing.
While patents are
expensive and time
consuming to obtain
and difficult to enforce,
regulatory approval
for a bioprinted tissue
or organ is very
expensive and time
consuming.
Thus, much patenting activity has
been ongoing. Some of the patents overlap
in coverage. For example, Missouri’s
US Patent 8132055 appears to cover a
bioprinted tissue or organ with filler bodies
that may be sacrificial hydrogels that will
form tubular engineered blood vessels.
And, Organovo’s GB2478801 claims an
engineered multilayered vascular tube with
certain types of cells and dimensions. The
engineered multilayered vascular tube
may also be made with a filler matrix or
sacrificial hydrogel that forms the tubular
structure.
A number of patent applications
were filed on the bioprinting device
itself, although only Cornell’s US Patent
7625198 has granted as a patent in the
United States.
There is room for additional
patentable innovations
While it may seem that it is too late
to start filing patent applications on
bioprinting innovations, there remains
room for further patentable improve-ments.
A number of researchers have
questioned whether it will be possible to
create a functioning bioprinted organ. For
example, Dr. Darryl D’Lima, a researcher
at the University of Manchester in Britain,
has been quoted as saying that “Nobody
who has any credibility claims they can
print organs, or believes in their heart
of hearts that will happen in the next 20
years5.” And, there have been reports
that Dr. Gabor Forgacs, inventor of the
Missouri patents and Scientific Founder
at Organovo, has questioned whether the
days of printing organs will ever come6.
In view of this skepticism, if one discov-ers
a method of bioprinting a functional
organ, the patenting of such a method
should be patentable.
Existing patent filings may not
impede commercialisation of
bioprinted organs
It will be many years before a functioning
bioprinted organ is made and approved by
regulatory authorities. In the meantime,
the basic patents may expire. Even if they
do not, many countries have an excep-tion
to patent infringement under what
is called the experimental use exception.
In the United States, the law provides
for an exception to patent infringement
when the patented item is tested for devel-opment
of information for submission
to the US Food and Drug administra-tion.
Thus, in many countries, one can
carry out clinical testing of a patented
bioprinted organ or tissue without fear
of patent infringement.
In conclusion, if the technical
challenges of making a bioprinted organ
are overcome, the future of bioprinted
organs will be very bright. And, the
patenting activity will continue.
5 http://www.nytimes.com/2013/08/20/science/next-out-of-
the-printer-living-tissue.html?pagewanted=all_r=1
6 See, http://www.fool.com/investing/general/2014/04/09/
organovo-holdings-inc-founder-we-may-not-print-org.aspx
Au t h o r BIO
Robert W Esmond's intellectual property law experience has
principally been in the biotechnology and chemical areas. His
legal experience includes counseling clients in various intellectual
property matters such as patentability investigations, validity
and infringement analyses, freedom to operate and FDA/ANDA
practice.
strategy

Creating and Sustaining
Cultural Change by Focusing
on Operational Excellence
Over the past decade, the impor-tance
of Operational Excellence
(OPEX) in the pharmaceutical
industry has grown significantly. A mere
copy and paste from successful auto-motive
excellence programmes does not
work for the pharmaceutical structural
requirements in the long run (Friedli
et al., 2013). This has been realised by
most of the pharma companies in the
past ten years while working their way
with individual roadmaps. Accordingly
Lean, along with Six Sigma has grown in
prominence with their principles, meth-odologies
and tools supporting OPEX
initiatives (Friedli et al., 2010, p.220).
Although highly standardised programmes
of Operational Excellence (OPEX) have been
implemented in almost every globally operating
pharmaceutical company, the success of OPEX
initiatives differs considerably. This article presents,
based on the St.Gallen OPEX understanding, an
overview of the factors that enable a sustainable
OPEX culture and OPEX implementation.
ThomasFriedli, Managing Director TECTEM,
Vice Director Institute of Technology Management
NikolausLembke, Research Associate
ChristianMänder, Research Associate
University of St.Gallen, Switzerland
strategy

However, the evolution of OPEX in the
pharma industry showed that the path-way
to OPEX is more than just about
applying tools. As each OPEX initia-tive
is shaped by a company’s culture,
they tend to vary to a large extent with
no universal recipe. But based on the
research and project experiences of the
Institute of Technology Management of
the University of St.Gallen, Switzerland
(ITEM-HSG) some common guidelines
and procedures are identified.
A definition of operational
excellence
Modern approaches to OPEX have
evolved from the understanding of Lean
Production and are generally regarded as
part of continuous, corporate improve-ment
concepts (Friedli Schuh, 2012).
However, OPEX programmes cannot
be viewed as standalone or as a set of
new methods and tools as they comprise
and rely on several already established
manufacturing concepts (Friedli et al.,
2010). Operational excellence is about
the continuous pursuit of improvement
of a production plant in all dimensions.
Improvement is measured by balanced
performance metrics comprising effi-ciency
and effectiveness, thus providing a
correlative basis for improvement evalu-ation
(Friedli et al. 2013, p.24).
The philosophy of OPEX can
be traced back to research results on
excellence by Drucker (1971), Peters
and Waterman (1982), Hayes and
Wheelwright (1985), and Schonberger
(1986), complemented by a long history
of Japanese manufacturing concepts
strongly linked to the Toyota Production
System, which was first published by
Sugimori (1977). In 2004, the ITEM-HSG
started its activities in the field
of pharmaceutical manufacturing
to better understand OPEX and its
implementation level in the industry.
Based on the work of Cua et al. (2001)
the ITEM-HSG developed a framework
for the structured discussion of OPEX in
a pharmaceutical context – the so called
St.Gallen Operational Excellence Model
(see Figure1) was established.
The St.Gallen Operational Excellence Model (Friedli et al. 2013)
On the highest level of abstraction,
this model can be divided into two larger
sub-systems: a technical and a social
sub-system.
The technical sub-system comprises
of Lean practices like Total Productive
Maintenance (TPM), Total Quality
Management (TQM), and Just-in-Time
(JIT). Most of these major operations
management principles usually aim at
a certain area of concern (such as low
equipment availability, low quality, high
inventories); companies implement them
in order to address exactly these issues.
Based on the first benchmarking results
the ITEM-HSG structured these three
sub-elements in a logical sequence in
their implementation, namely: first
TPM, second TQM and third JIT.
Without TPM, the goals of TQM cannot
be achieved, as there can be no stable
process based on unstable equipment.
The mastering of TPM and TQM are
prerequisites to be able to take out waste
without facing the danger that the whole
underlying system starts to crash. (Friedli
et al., 2013, p.17)
Second, there is a ‘social’ sub-system,
the so called Effective Management
System (EMS) which takes up the
quest for an operational characterisation
of management quality and work
organisation. This second system focuses
on supporting and encouraging people to
continuously improve processes. (Friedli
et al., 2013, p.20)
Standardisation and visual
management cannot be clearly related
to either TPM, TQM or JIT. We call
them basic elements because they can
be regarded as basic prerequisites for
successfully implementing the whole
technical sub-system in operations and
administration. As Imai (1986) explained
in his book on continuous improvement,
it is impossible to improve any process
before it has been standardised, and thus
stabilised. Visual management provides
the workforce with updated information
on process and performance data which
assists the deployment of TPM, TQM,
and JIT principles. (Friedli et al., 2013,
p.20)
OPEX in the pharmaceutical
industry - a status-quo
The St.Gallen OPEX benchmarking
assesses a set of production-specific KPIs
that are closely linked to the technical
sub-system (comprising TPM, TQM and
JIT), as well as the social sub-system;
Totally 50 operational KPIs are collected
and analysed. A look at the results of the
past 10 years shows an improvement in
Figure1:
strategy

Extract On OPEX And EMS Performance In The Pharmaceutical Industry From 2003 To 2013
(Friedli et al 2013)
performance of the global pharmaceuti-cal
industry in terms of both effective-ness
and efficiency (Friedli et al. 2013).
Figure 2 indicates an extract of the
benchmarking. From a TPM perspective
the major advancement is the increased
awareness of the relationship between
good maintenance and good quality. In
the TQM section, a positive develop-ment
of the Complaint Rate Customer
can be shown. It has decreased from 1
per cent in 2003 to 0.57 per cent in
2012. The Rejected Batches score (given
as percentage of all batches produced)
stayed at 0.75 per cent from 2003 to
2012. Looking at JIT performance, the
median score reveals a change in Raw
Material Turns i.e., from 4 turns per year
in 2003 to 5.35 turns per year in 2012.
Companies are increasingly trying to
deliver a demand-oriented JIT instead
of a stock-oriented approach. In the
St.Gallen OPEX benchmarking (EMS
way of thinking. Schein (1985) defines
organisational culture as a set of arte-facts
(visible behaviour), values (rules,
standards), and assumptions (invisible,
unconscious) that are shared by members
of an organisation. Creating and sustain-ing
an organisational OPEX culture is
a key challenge for the leadership team.
Leadership characterised by a participative
leadership style is essential to establish a
high level of collaboration. Continuous
improvement, the main philosophy of
OPEX programmes requires shared tasks,
empowerment, and teamwork with clear
rules. Thereby it needs to be ensured
that decisions are made at the lowest
possible organisational level. Thus, the
more individuals become involved in
the decision-making process, the more
variety and more ideas will be created.
Further initiating a cultural change is
mainly driven by activities designed and
coordinated from corporate level. During
sub-system) absenteeism and fluctua-tion
are used as measures of employee
satisfaction. Absenteeism, measured as
the percentage of the total working time
an employee is absent, decreased from
4 per cent in 2003 to 3.3 per cent in
2012. Fluctuation, however, increased
by about 50 per cent from 5 per cent in
2003 to 7.5 per cent in 2012. (Friedli
et al., 2013)
How to create an OPEX culture
The success of an OPEX program
depends, to a greater extent on lead-ership
and behavioural skills than on
technical skills (Friedli et al., 2010,
p.202). Managers often think ‘Changing
Culture’ leads to ‘Changes in the Work’,
but in fact it is backwards and culture
is more an outcome than an input.
‘Changing the Work’ leads to ‘Change
in the Culture’ as OPEX is a new way of
leading, new way of working, and new
Total Productive Maintenance (TPM)
Comparison of the Benchmark Results from 2003 and 2012(medians)
2003 2012
Performance
Overall Equipment Effectiveness (OEE)
2003 36%
2012 55%
Figure 2:
+53%
Unplanned Maintenance
2003 25%
2012 18% -30%
Total Quality Management (TQM)
2003 2012
Performance
Rejected Batches
2003
0.75%
2012 0.75%
0%
Complaint Rate Supplier
2003 1.0%
2012 2.0%
+100%
Complaint Rate Customer
2003 1.00%
2012 0.57% -43%
Just-in-Time (JIT)
2003 2012
Performance
Raw Material Turns
2003 4
2012 5
+100%
Finished Goods Turns
2003
9
2012 7
-22%
Service Level
2003 95%
2012 97%
+3%
Effective Management System (EMS)
2003 2012
Absenteeism
2003
7.5%
4.0%
2012 3.3%
+50%
-19%
Fluctuation
2003 5.0%
2012
Training Days
3.0 days
7.7 days
2003
2012
+157%
Unskilled Employees
2003
2012 4%
10%
-60%
Performance
strategy

the first stage of implementation, corpo-rate
support is absolutely essential. An
obtrusive communication of the benefits
and need for continuous improvement
inside the organisation is key aspect for
the OPEX leader. Besides this, the execu-tion
of activities with a visible benefit and
sense for employees as well as the credible
behaviour is mandatory to successfully
and sustainably manage OPEX.
Underlying values have a strong
influence on the behaviour of employees,
as values define how they behave,
regardless of the situation and context
(Modig Ahlström, 2012). Learning
experiences of the organisational
members, especially those at site level,
influence these values and consequently
the sustainable success of OPEX. Besides
corporate commitment, it is also
essential to gain the site management‘s
commitment for the deployment of
OPEX in order to sustain cultural
change at site level. This commitment
should go beyond formal agreements
and include the active involvement
of the site leadership (Friedli et al.,
2010, p.203). A common approach
designed at a corporate level needs to
be tailored for each site’s specific needs
to a certain level. In a research project
with a leading pharma company, the
St.Gallen OPEX team developed an
‘OPEX Implementation Reference
Model’ which comprises eight categories
of influencing institutional and process-related
factors (Figure 3). In each of these
subcategories, practices were identified
that supported or hampered a sustainable
implementation. (Friedli et al., 2010,
p.205)
The category of ‘Organisational
Inertia‘ describes the degree to which a
site is capable of adopting new practices
and initiatives, i.e. of changing current
or past practices and ways of working
and thinking. An organisation‘s ‘culture‘
is the sum of its past and current
assumptions, experiences, philosophy and
values, and is expressed in its self-image,
inner workings, interactions with its
stakeholders and future expectations. This
addresses differences in the availability
OPEX Implementation Reference Model (Friedli et al 2010. p.204)
of highly professionalised corporate
support, the connection between site
objectives as defined in the vision and
mission statement and OPEX objectives,
as well as the visible engagement of
corporate support people. ‘Management
commitment’ means that the high level
executives at site level directly participate
in and pay attention to OPEX activities.
The category of ‘organisational structure’
deals with the organisational integration
of OPEX and available resources. The
category of ‘people’ describes the level of
general understanding of OPEX across
the organisation as well as engagement
and training of shop floor employees.
The category of ‘implementation process’
focuses on the degree of standardisation
in dealing with OPEX projects from idea
selection to knowledge management. The
more an initiative becomes a regular part
of organisational activities the more
standardisation can streamline activities.
‘Integration’ describes the process of
attaining close and seamless coordination
between departments, groups, systems
and other corporate initiatives. (Friedli
et al. 2013, p.206ff )
Enabling factors
During the research and project work
of the ITEM-HSG OPEX team over
the past ten years it has become clear
that patterns of OPEX programmes
feature some common elements. The
OPEX programmes of Pfizer, Novartis,
Roche, Genentech and Merck Serono
show that what matters most is structure
and, in most cases a corporate support
function, adequate training method-ologies,
tools and activities. One of
the most differentiating factors when
comparing OPEX initiatives from one
organisation to another is the way they
are embedded into the respective global
and local organisations. Having the right
OPEX organisation in place unlocks the
potential of OPEX due to designing,
executing, coordinating, enabling, and
communicating functions in order to
create structures to get the right infor-mation
at the right time to the right
people. An OPEX training programme
is essential for the sensitisation in OPEX
of the employees at different hierarchi-cal
levels as well as of course providing
the necessary knowledge in principles,
methods, and tools. Furthermore it is
necessary to establish a common OPEX
language at corporate management level
and production sites. A change in the
culture cannot happen without the use
of OPEX tools and the execution of
OPEX activities. As already indicated,
a change in the way of working leads
to a change in the culture. ‘You cannot
create a culture without first introduc-ing
tools. Culture doesn’t just evolve.
You need to handle the practical world
using concrete tools and projects. The
Figure 3
strategy

strategy
cultural element gradually grows as a
layer on top of the tools if you continu-ously
emphasize the thoughts behind
the tools.’ Andrew Finnegan from Novo
Nordisk (Friedli et al. 2013, p.135)
Summary
Today most pharmaceutical manufactur-ers
apply selected approaches, princi-ples
and methods as well as tools from
OPEX in order to increase efficiency.
Operational Excellence (OPEX) as a
continuous pursuit of improvements
in all dimensions leads to changes in
existing working environments. Changes
in the work environment in the long
term lead to changes in the culture. A
culture of Operational Excellence is not
a bunch of written rules by the manage-ment
team; it is the decision by the
organisation to commit to go beyond
the ordinariness and not being satis-fied
with the current status-quo. The
major driver on a cultural level is the
promotion of OPEX with all its aspects
and the increased effort in training. As
each OPEX initiative is shaped by an
individual company’s culture, OPEX
initiatives can vary to a large extent
and it is the task of the OPEX leaders
to balance the initiative (Friedli et al.,
2013, p.114). An organisation with an
OPEX culture provides personal and
professional satisfaction for the employ-ees
about what they do and gives the
company some kind of legitimisation
and purpose, thereby motivating its
members to make a contribution in view
of achieving superior goals (Friedli et
al., 2010, p.206).
Literature
Cua K. O., McKone K. E., Schroeder R.
G. (2001). Relationships between imple-mentation
of TQM, JIT, and TPM and
manufacturing performance. Journal of
Operations Management, Vol. 19(2),
pp. 675–694.
Drucker P.F. (1971). What we can learn
from Japanese management. Harvard
Business Review, Vol. 49 No. 2, pp.
110-22.
Friedli T., Basu P.B., Gronauer T.,
Restoring Our Competitive Edge:
Competing Through Manufacturing.
Wiley, New York.
Imai M. (1986) Kaizen: The Key to
Japan's Competitive Success. Random
House, New York.
Modig N., Ahlström P. (2012). This is
lean. Resolving the efficiency paradox.
Rheologica Publishing, Stockholm.
Peters, T.J. and Waterman, R.H.
(1982), In Search of Excellence –
Lessons from America’s Best-Run
Companies, HarperCollins Publishers,
London.
Schein, E. H. (1985). Organizational
culture and leadership: A dynamic view.
Jossey-Bass, San Francisco, CA.
Schonberger R.J., (1986). Japanese
Manufacturing Techniques. The Free
Press, New York.
Sugimori Y., Kusunoki K., Cho F.,
Uchikawa S. (1977). Toyota Production
System and Kanban system: materiali-zation
of just-in-time and respect-for-human
system. International Journal of
Production Research, Vol. 15 (6), pp.
553–564.
Operational
excellence is about
the continuous
pursuit of
improvement of a
production plant in
all dimensions.
Werani J. (2010). The pathway to
operational excellence in the pharma-ceutical
internal criteria. Editio Cantor Verlag,
Aulendorf.
Friedli T. Basu P.B., Bellm D.,Werani J.
(2013). Leading pharmaceutical opera-tional
and cases. Springer,Berlin, Heidelberg.
Friedli, T., Schuh, G. (2012).
Wettbewerbsfähigkeit der Produktion
an Hochlohnstandorten. 2. Auflage,
Springer Verlag, Berlin, Heidelberg.
Hayes R.H., Wheelwright S.C., (1985).
Au t h o r BIO
industry - Overcoming the
excellence - Outstanding practices
Thomas Friedli leads a team of 14 researchers and is lecturer in
Business Administration. His main research focus is the management
of industrial enterprises with a focus on production management.
He is editor and author of several books, with his latest book
‘Leading Pharmaceutical Operational Excellence’.
Nikolaus Lembke concentrates on the challenges of manufacturing
companies with a focus on the pharmaceutical industry and the
implementation of operational excellence. Nikolaus graduated in
technology management as mechanical engineer at the University
of Stuttgart (Germany), complemented with a stay at the Nanyang
Technological University (Singapore).
Christian Maender concentrates on the challenges faced by
the pharmaceutical industry. His focus is on the management of
operational excellence programs. Christian graduated in mechanical
engineering with a focus on production techniques at the Karlsruhe
Institute of Technology (Germany).

strategy
Cover Story
THE SIX
GREAT
SHIFTS
Transforming the
pharma industry
Anyone involved with the life sciences sector can
see how changes in technology, demographics
and health economics are driving the industry.
But these are merely symptoms; beneath
them lie six great shifts that are transforming
the industry and - determine which business
models will survive and which will die.
Brian D Smith, Managing Director, PragMedic, UK

strategy
BOX
1
Many languages have an
equivalent to the expression
“Seeing the forest for the
trees”, meaning the ability to discern the
big picture from little details. That ability
is important in life but especially true for
leaders of life sciences sector. Every day we
are bombarded with news of innovative
technology, tighter regulation and new
approaches to controlling healthcare
spending. The challenge is to see how these
myriad factors are combining to shape
the sector. Only by doing so do industry
leaders stand any hope of preparing for
the future. My work uses evolutionary
science to enable this necessary foresight.
In this article, I’ll talk a little about the
basic ideas behind my research before
moving onto the findings. I’ll conclude
by suggesting some practical implications
that you may like to act on.
Organisms and organisations
All good science is based on a well-supported
theory; an explanation of
how the world works. Germ theory,
atomic theory and gravity, for example,
are all good explanations that help us
understand and manage the world
around us. To understand a sector as
complicated as life sciences, we need a
very good theory and luckily we have
one; evolution by natural selection.
Darwin’s profound insight was first used
to explain the profusion of species on
our planet, but, in more recent years,
has been used to explain the behaviour
of industries. This is possible because
biological and economic systems are both
examples of complex, adaptive systems.
That is, they are both large collections
of many different entities that interact
with and adapt to each other. Whether
we are trying to understand organisms
or organisations, the basic science is the
same.
Complex, adaptive systems are
characterised by non-linear behaviour;
it’s practically impossible to predict what
will happen in the long run. Instead,
we can observe how the countless,
seemingly random interactions result
gradually in patterns of behaviour.
We call these emergent properties.
The flocking behaviour of birds is an
emergent property as are traffic jams.
In my research, I consider how many
different components of the life sciences
sector combine to create emergent
properties and what these properties
imply for the competitive strategies of
companies operating in this sector.
From the complex adaptive system
of the life sciences sector, six important
properties emerge: three from the
industry’s social environment, three from
its technological context. Each one is a
shift from the way the world used to be
to how it is transforming. And each shift
creates an evolutionary selection pressure
that favours some business models and
discriminates against others. That’s why
understanding these pressures and their
implications is for the sector’s business
leaders. In the following sections, I’ll
describe the shifts, their origins and the
selection pressures they create.
1. The great value shift
The great value shift (see BOX 1) is a
fundamental change both in how value
is defined and who defines it. It is also
about an increase in the heterogene-ity
of value definition. It arises from
the interaction of a number of separate
social factors: demographics, healthcare
inflation, rising expectations and disease
patterns, amongst others.
The great value shift creates a
selection pressure in favour of business
models that can understand what multi-dimensional,
customer-perceived value
is and create that context-specific value
through its combination of product,
services and pricing. At the same
time, the value shift creates a selection
pressure against business models that
continue to understand value only in
terms of clinical outcomes as defined
by healthcare professionals and value-creation
only in terms of products.
2. The global shift
The global shift (see BOX 2) is a wide-reaching
change in what customers
want and where they are. Importantly,
it includes not just globalisation of
demand but also fragmentation of
customer needs to accommodate many
non-clinical factors such as aesthetics
and convenience. It creates multiple,
diverse global segments within any
disease or therapy area. It arises from
the interaction of trade internation-alisation,
multinational corporations,
increasing global wealth and subse-quent
maturation and fragmentation
of customer needs.
The global shift applies a selection
pressure in favour of business models
that can understand the heterogeneity of
their market and use that understanding
to select which parts to focus upon and
deliver value to those targeted customers
on a global basis. At the same time, the
value shift creates a selection pressure
against business models that continue
A shift in the definition of the value of treatments, interventions and
associated products and services from a relatively simple and ubiq-uitous
definition of value as improved clinical outcome, as defined by
healthcare professionals, to a much more complex, context-specific
definition of value defined in terms of clinical, economic and other
factors by some combination of healthcare professionals, payers
and patients or their proxies

BOX
2
A shift in the demand pattern for treatments, interventions and associ-ated
products and services from one which is geographically focussed
on western economies and in which demand heterogeneity is limited
and based mostly on differing clinical requirements, to one in which
demand has a global geographic spread and is very heterogeneous
along multiple dimensions of clinical requirements, payer prefer-ences
and patient needs, both clinical and otherwise.
to view market heterogeneity only
in clinical terms are unable to focus
their resources appropriately and
cannot deliver customer-specific value
globally.
3. The network shift
The network shift (see BOX 3) is a
profound change in the way firms and
other organisations structure themselves.
It involves two factors: a reduction in
the scope of what firms do within their
own organisation and strengthening of
their relationships with other organisa-tions.
In essence, it is a shift from big
firms to networked organisations that
are more complex, more fluid and less
well defined than we are used to. It arises
from the combination of changes in
capital markets, changes in transaction
costs within and between companies,
the specialisation of corporate capabili-ties
and the increasing need to manage
business risk.
The network shift applies a selection
pressure in favour of business models
that can build and manage dynamic,
symbiotic networks of different
organisational entities and use that
structure to create better returns, better
manage risk or some combination of
the two across any part of the value
chain. At the same time, the network
shift creates a selection pressure against
business models that persist in unicentric
structures that fail to optimise returns
and risk across the value chain.
The systeomic shift
The systeomic shift (see BOX 4) is a shift
of great consequence in the science and
technology of the sector. It represents a
move from a 19th century, Oslerian para-digm
of medicine to a systems approach
that seeks to support the efforts of indi-viduals
to maintain their own wellbe-ing.
It is based on enabling technologies,
such as gene sequencing, biomarkers and
synthetic biology. These enable bioin-formatics
which in turn enables systems
biology and so systems medicine.
The systeomic shift applies a selection
pressure in favour of business models that
can translate system medicine into an
improvement of returns or a reduction
risk at any point in the value chain.
Conversely, it creates a selection pressure
against business models that remain on
a reductionist, hierarchical, population
based understanding of disease or injury
and the ways we manage them.
strategy
The information shift
The information shift (see BOX 5) is
much more than the expansion of infor-mation
technology. It is an inflection
point in what information we collect,
from where and how we manipulate
and apply it. Importantly, it influences
not only how we discover and develop
drugs, devices and other medical tech-nologies
but also how we produce prod-ucts,
deliver services and understand our
customers’ needs. It is based upon plat-form
technologies such as biosensors and
improved chips, memories and batter-ies.
These enable connectivity, wearable
technology and artificial intelligence.
Alongside this sit new capabilities in
making sense of large-scale data.
The information shift applies
a selection pressure in favour of
business models that use information
to improve returns or reduce risk,
whether that is in RD, Operations
or Sales and Marketing. The obverse
is that the information shift creates
a selection pressure against business
models that remain based on the use of
information in a small-scale, fragmented,
unidirectional and deductive manner.
The trimorphic shift
The trimorphic shift (see BOX 6) is
a three way polarisation in the way
that companies focus their resources.
In essence, it involves research-based
firms becoming even more innovative,
low-cost firms becoming incredibly lean
and efficient and customer-centric firms
becoming excellent at tailoring their
BOX
3
A shift in the focus of economic activity from organisations with
predominant centres and well-defined, stable boundaries and scope
to one in which the focus of economic activity is polycentric networks
with fluid, ill-defined boundaries and scope.

strategy
Elephants and Antelopes co-exist but
use different approaches. In the same
way, how companies use IT or systems
medicine or create value differs, whilst
still adapting to, the selection pressures
implied by the shifts.
And the take home? First, recognise
these great shifts and don’t become too
focussed on individual factors in the
BOX
6
A shift in our approach to
understanding, perceiv-ing
and managing the
continuum of mental and
physical health, illness
and injury from one that
is essentially reactive,
population-based and
hierarchical to one that
is proactive, personalised
and participatory.
value propositions to segments of one.
It arises from advances in supply chain
architectures, research and development
technologies and sales and marketing
methodologies. Alongside this sits
the polarisation and specialisation of
corporate cultures in line with their
business model.
The trimorphic shift applies a
selection pressure in favour of busi-ness
models that focus on creating value
by either product excellence, operational
excellence or customer intimacy and
by targeting the parts of the global
market that will respond to such an
offer Similarly, the trimorphic shift will
apply a selection pressure against firms
that do not focus their resources and
adopt a strategy that “straddles” across
the three approaches. Such firms, who
may have good products, efficient opera-tions
and effective sales and market-ing
processes will find themselves at a
BOX
4
disadvantage to those more focussed
firms with either excellent products,
hyper-efficient operations and the ability
to identify and satisfy very small and
specific customer segments.
Shifting your company
The implications of the 6 great shifts
are fundamental and real. In simple
terms, firms will only survive if they
BOX
5
A shift in the collection,
storage, use and commu-nication
of information
from small-scale, frag-mented,
unidirectional
and deductive to large-scale,
integrated, perva-sive
and inductive.
adapt to the selection pressures created
by the shifts. But these pressures are
huge and often work against each other,
just like the need to be big and fast on
the African savannah. In practice, this
means that firms must and will evolve
into their chosen market habitats and in
the process become ever more special-ised.
Roche, for example, is evolving into
an outcome-oriented, research hyper-intensive
firm, as recent acquisitions
show. Medtronic is pushing towards a
customer-intimate firm in which prod-uct
development complements rather
than leads its strategy. And Mylan is
specialising into a hyper-efficient cost
leader. Many other firms are evolving
into networked entities, keeping only
their differentiating activities in house.
How they respond to the six shifts varies
according to their chosen habitat: Au t h o r BIO
Brian D Smith is a world-recognised authority on competitive
strategy in the pharmaceutical and medical technology sectors.
He researches the evolution of the sector at the University of
Hertfordshire, UK and SDA Bocconi, Italy. He welcomes comments
and questions on brian.smith@pragmedic.com.
A shift in our approach to
understanding, perceiving
and managing the contin-uum
of mental and physi-cal
health, illness and injury
from one that is essentially
reactive, population-based
and hierarchical to one that
is proactive, personalised
and participatory.
market. Second, understand that these
shifts are inexorable and that you can
only adapt to them, not stop them.
Third, use the selection pressures as
guides, allowing them to shape your
choice of markets, strategies and
structures. As someone once wisely
said: It’s easy to lead a market – just
work out where it’s going and get in
front.

India inc aims for pharma
dominance by 2020
Innovation Technology to steer 2014
edition of CPhI/ P-MEC India
• Preceded by 2nd Annual India Pharma Awards
2014
• CPhI India Technical Seminar on industry
trends challenges
• +28000 Pharma professionals from
+95 countries expected to attend
UBM India, today announced the event highlights of
CPhI India, which is co-located with P-MEC India,
ICSE India BioPh and slated for 2nd-4th December
2014 at the Bombay Exhibition Centre in Mumbai,
India. The three days industry event, wherein key
players of the pharmaceutical sector, worldwide,
will congregate to connect, share and ideate, will be
preceded by the India Pharma Awards, scheduled
for 1st December 2014 at the Westin Hotel, Mumbai.
P-MEC India, co-located with CPhI India and in its
8th year, provides the industry with an international
platform to showcase pharmaceutical equipment,
machinery and technology to a forum of decision
makers from across the world. Additionally, ICSE
India has rapidly gained a positive reputation in the
market by offering direct access to the outsourcing
and contract services sector which is one of the fast-est
growing segments within the Indian pharmaceuti-cal
industry.
At CPhI India 2014, UBM will also release India
Pharma Report, conducted with the help of research
partner Global Business Reports. The report, in addi-tion
to an overview of trends and analysis from key
industry players, will explore new growth areas emerg-ing
across the country and feature a robust analysis
of the Indian pharma market.
Mr. Joji George, Managing Director, UBM India
said “Against the backdrop of India constantly seek-ing
to match and surpass western quality standards
while maintaining lower manufacturing costs, at UBM,
our objective for CPhI 2014 is to help elevate India as
the global pharmaceutical destination by showcasing
the unique positioning of the Indian pharma market
and provide an optimum investment platform amidst
its global counterparts.”
2nd India Pharma Awards, 2014 1st
December 2014, Westin Garden City,
Mumbai.
Recognizing leading
innovators across 9
categories, the India
Pharma Awards initiated
by UBM India acknowledge
innovation and excellence in
the Indian Pharmaceutical
Industry, thus creating an
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RESEARCH DEVELOPMENT
The quest to undertake biological targets that are
based on the regulation of signalling pathways
is challenging the classical thinking in the drug
discovery arena. Historically, the complexity of the
biological system was underestimated! It is now well-accepted
that compared to old biological targets
that were focused on single gene or gene products,
we need to undertake targets that are derived
from complex and dynamic signaling pathways.
Subhadra Dravida, Founder and CEO of Tran-Scell Biologics TranSTox BioApplications, India
Prabhat Arya, Department of Organic and Medicinal Chemistry, Dr. Reddy's Institute of Life
Sciences (DRILS), University of Hyderabad Campus, India
Drug discovery is a tough busi-ness!
At the same time, it is
the domain that provides an
opportunity to improve the quality of
human health and allows recovering from
the suffering due to various biological
disorders.
In the past decades, we have witnessed
a major limitation in creating the next-generation
drugs despite a significant
boost in the financial spending for
research and development. After the
completion of the human genome project,
we were guaranteed a plethora of novel
Rethinking
Drug Discovery

Drug Discovery – A Paradigm
Shift
Pre-genomic era
Regulation and
de-regulation of
signaling
pathway-based
research
Pre-genomic era
Single, isolated
biological
targets, such as
enzymes
biological targets with the hope of
producing novel drugs with fewer side
effects. The genomics research has made
us appreciate the high level complexity
of our biological system and at the same
time, it challenges the classical thinking
in the drug discovery arena.
1.0 Classical drug discovery
approach: the pre-genomic era
Over the decades, the biomedical drug
discovery community’s efforts were
focused on a single gene and the gene
product, such as isolated enzymes, for
example: kinases and phosphatases (See
Figure 1). During this course of drug
discovery, serious efforts were made to
obtain the 3D structural information
of a given enzyme; this was then heav-ily
guided by extensive computational
studies leading to the design of novel
small molecules serving to kick-start the
drug discovery programme. In this age,
for example, the challenge is to discover
novel small molecule that has the poten-tial
to hit only one i.e. the desired kinases
or phosphatases. The post-genomic era
taught us that this is not going to be an
easy undertaking, keeping in mind that
human genome encodes more than 600
kinases and ~250 phosphatases.
2.0 The post-genomic era
The completion of the human genome
that resulted in the indication of nearly
30,000 genes promised a flood of targets
to be further undertaken in drug discov-ery
(see Figures 2 and 3). Although highly
useful, the information at gene level is
not easy to translate to functional protein
complexes that are the key to various cell
signalling events. Moreover, this infor-mation
also does not lead to any post-secondary
modifications that proteins
undergo, such as glycosylation and ubiq-uitination
etc., and, their effects on the
signalling functions. In fact significant
progress made in genomics and proteom-ics
research has brought us to the doors
of a high degree of complexity that lies
in our biological system. Furthermore,
it also challenges us to develop new
research models for understanding the
complexity of gene functions, such as
the Protein-Protein Interaction (PPI)
networks (commonly known as the
signalling pathways) that are central to
various cell functions in normal as well
as disease states. The moment we accept
the fact that, proteins do not function
in isolation and that they are a part of
highly complex network machinery, sets
new challenges to examine their role(s)
Historical Drug Discovery!
Figure 1
Biological Target
Structural Information
Structure-Guided
Small Molecule Discovery
• Biased Approach
• Need for new research models
small molecule
binder
• Well-defined
• Compact
• Deep pocket
Figure 2
in the drug discovery arena. Why is this
case? The pathways that involve multiple
protein-protein interactions are highly
complex and dynamic. In many cases,
even though, we as a community have
been successful to obtain the structural
information of a given protein-protein
interaction, their participation is much
more complex (for example, multi-protein
complexes), and often leads to a limited
information capture for the design of
small molecules with desired biological
effects.
3.0 Biological targets: signaling
pathways-based approach
The earlier approaches focused on
enzymes (such as kinases and phos-phatases)
and relied heavily upon the
structural information of a given isolated
target which would then aid in the design
and synthesis of small molecules. With a
few exceptions, in most cases, the organic
synthesis and medicinal chemistry efforts
led to producing heterocyclic compounds
and small molecules that are rich in the
sp2 character. The growing desire to
undertake biological targets that are
focused on protein-protein interactions
and on the de-regulation of dynamic sign-aling
pathways is changing our thought
process for the choice of small molecules
serving as a good starting point to devel-oping
the drug discovery research path.
Unlike the deep and well-defined pock-ets
that enzymes do offer, in general,
PPIs involve a shallow, large surface area

Going-in for Pathways!
Figure 3
with extensive hydrophobic interactions
(see Figure 4). Over the years, bioactive
natural products have shown an excellent
track record as modulators of PPIs, and,
in most cases, this is achieved through
allosteric sites rather than functioning at
the PP-interface. Despite much progress
that has been made towards obtaining
structural information of a given PPI, due
to the nature of these interactions that
are generally a part of complex multi-meric
protein complex, cell-based screens
remain the choice to search for novel
small molecules.
The drive to embrace the signal-ling
pathway-based approach is the
hallmark in the modern drug discovery
arena! And, this need is also seriously
questioning our classical approaches
to accessing small molecules that were
biased towards simple, flat, heterocyclic
compounds. A million dollar question in
this game, heavily relies on high quality
functional cell-based (or commonly called
as phenotype or pathway-centric) screen-
ing which is the choice of discovering
small molecules required in the program.
Traditionally, small molecule toolbox
small molecule binder
Need for a new thinking!
• map large surface area
• shallow surface
• combination of several weak
interactions
• extended hydrophobic interactions
• possible hot spots
Figure 4
within the pharma setting contains
compounds that are more biased towards
enzymes than on PPIs and pathways. In
Enzymes Vs Protein-Protein Interactions

most cases, these compounds also lack
the general features that are commonly
found on bioactive natural products,
such as 3D architectures, and, rich in
chiral display of functional groups etc,
functioning on pathways.
4.0 Translational chemical biology:
need for new collaborative working
models!
There are two prime reasons to explore
new research models in drug discovery (see
Figure 5), and these are: (i) as discussed
above, the traditional pharma collection
of small molecules contains compounds
that lack the features commonly found
in bioactive natural products that are
known to function as the modulators of
PPIs and signalling pathways; and, (ii)
in general, most pharma expertise resides
in the classical drug discovery approaches
with a focus on kinases, phosphatases
and other enzymes. The development of
a phenotype or pathway-based screen-ing
program is still in its infancy within
most or several pharma groups. With an
in-depth look at the current limitations
covering both points within the pharma
community, it is becoming apparent that
these bottlenecks can be taken care-of
by working closely with the academic
groups. Outlined below are some of the
advantages that would allow taking care
of these two short-comings.
The need for a good starting point
as the functional small molecule is the
crest of the chemical challenges. The
growing interest in undertaking PPI
or pathway-based targets is challenging
the organic synthesis and medicinal
chemistry community to develop novel
approaches that allow a rapid generation
of small molecules inspired by bioac-tive
natural products or hybrid natural
products. The goal here is to build the
next generation chemical toolboxes
with compounds that have 3D shapes,
present sufficient molecular complexity
from the medicinal chemistry point of
view and are more close to a wide variety
of bioactive natural products. To meet
these challenges, the academic commu-nity
has developed several path forward
Translational Chemical Biology Model
approaches, and, some these include:
Diversity-Oriented Synthesis (DOS),
Biology-Oriented Synthesis (BIOS) and
Functional-Oriented Synthesis (FOS).
In all these approaches, the long-term
goal is to access a new generation of small
molecules that are obtained through
the inspiration from bioactive natural
products. Because these new synthesis
efforts are highly demanding in the meth-odology
development, and, at present,
mainly practiced in academic labs,
building collaborative working models
with the relevant academic community
is not surprising. So is the case for the
phenotypic or pathway-based cellular
screening. From the past several years’
observations, it is now clear that several
academic labs across the globe have estab-lished
an outstanding expertise in this
domain that requires working on very
high risk projects involving identifica-tion
and understanding the nature of
the biological targets. One of the key
features of the translational chemical
biology model is that it allows obtain-ing
a thorough understanding of the
biological target by an extensive use of
biophysics tools, such as, protein NMR,
X-Ray, SPR etc.
Exploring some of these demanding
and high risk research areas by working
closely with the academic community,
it is indeed possible to develop next
generation path forward approaches
within the drug discovery arena. Cities
such as Boston, San Diego, Montreal and
Toronto have shown tremendous advan-tages
in embracing these new research
models. Specifically, Boston leads the way
in embracing new research models (for
example, Research at the Broad Institute
of Harvard and MIT) and, in building a
new research culture that has strong roots
in academia and the pharma sector. A
recent contribution of US$650 million
as the philanthropic donation to Broad
is the true testimony. It would be nice to
Figure 5
Organic Synthesis
Novel Chemical Toolbox
Natural Products
Natural Product-inspired
Hybrid Natural Products
Cell Signaling Biology
(Biological Questions/
Novel Assays)
Cellular Assays
Zebrafish Assays
Other Organisms
Biophysics and
Structural Biology
SPR
Protein NMR
Computational Tools

Emerging Direction In Cancer Research
Opinion
Tackling the cancer stem cells -
what challenges do they pose?
See:
Nat. Rev. Drug Disc. July 2014
Figure 6
Why understanding
and selective killing
of cancer stem cells
is important?
see efforts like this in a country like India,
who are aspiring to be a powerhouse in
building ‘knowledge-based economy’.
5.0 Embracing New Directions: An
Example in Cancer Research
In this section, we outline an example of
a translational chemical biology model
and its utilisation in embracing a new
direction in cancer research (see Figure
6). In addition to the toxicity issues, one
of the major problems with cancer drugs
is their inability to control the growth/
re-birth of cancer cells over a period of
time. In the past several years, it has
been shown that there is potential to
overcome this problem if we are able to
design small molecules that are highly
selective in killing Cancer Stem Cells
(CSCs). The lack of an ability to kill
CSCs by most anti-cancer drugs leads
to cancer cells formation and this then
leads to metastasis. Until very recently,
it has been shown that it is possible to
identify novel small molecules that are
highly effective as selective killers and
these compounds in combination with
the traditional anti-cancer drugs appear
to be a promising path-forward approach.
Once again, through developing novel
cancer stem cells-based phenotype screens
either in cells or in zebrafish combined
with a novel chemical toolbox having
natural product-inspired and hybrid
natural products provides an excellent
opportunity to practice working with
Au t h o r BIO
new models to reach highly unique drug
candidates that may prove to be more
effective than the traditional anti-cancer
drugs.
6.0 Summary
As we have seen for the past several
years, the current practice of drug
discovery seems to be a losing battle
and not much has come out to benefit
the society that is desperately looking
for next generation effective medicines
at an affordable cost. We are hoping
that through embracing some of these
new research working models and build-ing
like-minded teams that are a nice
blend of skill-sets from academia and
pharma sector would allow reaching
the objectives that are not possible
to be achieved with classical working
models. A challenging task is to build
teams to undertake high-risk research
programmes, and, this requires a deeper
understanding of the need of so called
‘collective competence’. Only time will
tell, whether, climbing this mountain
would lead to a productive path that
the patient community would benefit
from, and this remains to be seen in
days ahead!
All references are available at www.
pharmafocusasia.com
A Scientist by profession, Subhadra Dravida led global stem cell
research and commercialization initiatives in regenerative medicine
and drug discovery domains for over 12 years. She holds over
two dozen patents in the field of regenerative medicine and has
significant expertise in converting promising research into business
opportunities.
PhD (1985) from the University of Delhi and PDFs at Cambridge and
McGill, Prabhat worked at the National Research Council (NRC) of
Canada for nearly 20 years; and also, had a short stint at the Ontario
Institute for Cancer Research (OICR) to help build the medicinal
chemistry program.

Manufacturing
Validation Projects
in China
This article is a firsthand account of the experiences of Pharmadule in guiding
leading Chinese manufacturers through facility investment projects aimed at
compliance with Chinese, US and EU GMP requirements. These manufacturers have
been among the first in the world to fully embrace the work procedures outlined in
ICH Q8, Q9 and Q10. Implementing these guidelines in large organisations would
be a challenge with any global market, but it turns out that the Chinese market
offers both advantages and cultural disadvantages when managing change.
Magnus Jahnsson, Director Regulatory Affairs, Pharmadule Morimatsu, AB Sweden
Daniel Nilsson, Director GMP and Validation Services, Pharmadule Morimatsu, China
Erik Östberg, Project Validation Manager, Pharmadule Morimatsu, China
Between 1997 and 2000 Pharmadule
built a number of pharmaceutical
manufacturing facilities in China
for both domestic manufacturers and
multi-national pharmaceutical compa-nies,
including Eli Lilly and AstraZeneca.
The multi-national companies required
GMP compliance and validation services
comparable to the level that exist today.
The facilities delivered for Chinese manu-facturers
would comply with international
GMP requirements; but it became evident
at that time that the Chinese GMP regula-tion
was immature in comparison with the
EU regulations and guidelines. In 2011,
all of this changed when China launched
the new GMP regulations which elevated
the requirements to a level equivalent
with international cGMPs.
At about the same time, Pharmadule
refocused the strategy towards the
Chinese market and has since then

Manufacturing
a decade or more to fully implement in a
multi-national pharmaceutical company
in the EU or the US are accomplished
in a matter of months.
In recent assignments completed by
Pharmadule in the Chinese market, the
philosophy described by international
regulators in ICH Q8 – Pharmaceutical
Development, Q9 – Quality Risk
Management and Q10 – Pharmaceutical
Quality System have been seamlessly
integrated with the concepts of Process
Validation as described in the FDA
Process Validation Guidance from 2010
and ASTM E2500 - Standard Guide for
Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment.
Other international standards have also
been taken into consideration in order
to create a state-of-the-art Validation
Master Plan. This Validation Master
Plan governs the entire product and
process life cycle (as shown in Figure1)
and is used to manage all of the phases
of an investment project. The main steps
of this plan combine to form a control
strategy allowing an unbroken chain of
traceable verifications all the way from
the product attributes (e.g., shelf life)
via Quality by Design activities in the
Process Design and scale-up, through
design and qualification, all the way
to process validation. This level of
traceability is rare even with established
international companies.
Implementing a new QA culture and
a new paradigm for process validation
has of course not been an altogether
easy task. There have been a number of
obstacles, some obvious, some less so.
But there have also been circumstances
in China that enabled the shift.
Key observations
It was a positive surprise to find that
the degree of process understanding
was very high among engineers,
comparable or even exceeding western
expectations. This can probably be
attributed to the effectiveness of the
Chinese education system. However,
this process understanding was rarely
fully leveraged into the process
design and the GMP documentation.
With the right tools and training,
process understanding could easily
be transcribed into Critical Quality
Attributes, Critical Process Parameters
and ultimately risk-based control
strategies. Defining these boundaries
and limits for the process in Quality
by Design work has been both efficient
and accurate. Quality by Design also
facilitated, and eliminated unnecessary
aspects of Technology Transfer, since
Process Design departments, Operations
and QA worked closely together. An
impediment that could slow down
changes is that within the Chinese
culture, there traditionally is no
challenge to authority. This puts a cap
on the capability of innovative thinking
and creative solutions. Corporate culture
in China rarely encourages coworkers to
take risks and explore new solutions. In
fact, many companies punish employees
that take risks and fail, with public
shaming and fines. It is, therefore,
important to note that, in contrast to
the engineers, operators in the facilities
do not have the same level of training
as their western counterparts and will
not take own initiatives. They normally
only speak Chinese and will, for the
reasons stated above, follow the SOPs
they are given very rigorously. When
training operators, this must be taken
into account.
Turning process understanding
and Quality by Design into User
Requirement Specifications is a
challenge that is not unique to Chinese
manufacturers. International companies
also regularly fail in this area. The
sheer number of process engineers,
support from management, detailed
instructions and a flexible approach
to change, allowed rewriting of the
URSs to enable traceability of critical
parameters and aspects. Revamping
the URSs has consequently been easier
than expected. This is a key activity
in providing the foundation both for
procurement and for the rest of the
validation activities (In the new draft
been carrying out Validation, Quality
Management Systems, GMP compliance
improvement, and design projects in
China. Compared to the projects in
the late 1990s, assignments recently
undertaken required Pharmadule
to consider a number of significant
changes in the Chinese marketplace
when designing a modernised approach
for project execution in China and other
emerging markets.
One major difference is that while
European and American pharma
manufacturers typically have a QA/
QC-force amounting to up to 40
per cent of the production staff, the
Chinese companies we have encountered
have very small QA/QC-departments,
mainly focusing on QC and batch
release testing. Quality is typically
tested and validated into the products
and processes. Interestingly enough,
these immature QA and QC practices
partially enable the transition to modern
validation planning and execution.
The reason is that, in contrast to
the multi-national pharmaceutical
companies Pharmadule has worked
with, over the last 25 years, Chinese
companies do not have bureaucratic and
over-compliant Quality Management
Systems and validation frameworks.
Rather, they could be characterised
as non-compliant with EU or US
regulations. This is of course a concern
when it comes to the current level of
Quality Assurance expertise. However,
our Chinese clients have been very open
to embracing new ideas and knowledge,
allowing them to evolve faster than any
other market where Pharmadule has
worked in the past. Organisations offer
little resistance to change, provided they
understand the benefits and the details
of the new approaches. Consequently,
implementation of new business
processes can be much quicker than
in Europe and the US.
When a new facility is being
built, it provides the manufacturer
an opportunity to completely change
the approach to Quality Assurance and
validation. Changes that would take half

Pharmadule Life Cycle Model
Quality Assurance
Operations
Pre-validation Quality
Risk Management
Regulatory Filing ICH CTD
Module3 / CMC
Engineering Design
Construction
Good Engineering Practice
testing / verification
GMP-compliant Qualification
Figure 1
Manufacturing

Annex 15 to the EU GMP guidelines,
URSs are specifically highlighted as part
of the validation process). In China
there is an additional challenge that
increases the importance of URSs.
Traditional Chinese vendor
management pushes all the responsibility
for design, commissioning and
qualification — up until at least
Operational Qualification — on the
equipment vendors. Audits and contract
management have not been common
practices. On the contrary, maintaining
good relationships between business
parties is considered so important
that relationships sometimes supersede
written agreements. If the supplier is to
play a big part in the qualification, as is
the intention (such as in ASTM E2500)
then the supplier must initially undergo
an audit to ensure that they are able to
provide risk-based documentation, next
get a URS that allows them to write
risk-based documentation and finally
communicate during the design phase to
ensure an understanding and alignment
with the risk-based principles needed.
This has been and will be an area that
needs attention from the validation
team.
As a project moves closer to the
next step in the life cycle, Process
Validation (referred to as Process
Performance Qualification in the
latest FDA guideline), the state of the
Quality Management System becomes
much more important. This represents
both a practical and cultural change
for the Chinese pharma manufacturing
industry. Quality Management Systems
have traditionally been focusing on how
to achieve the product specification in
accordance with GMP and Pharmacopeia
by extensive end testing of products
and intermediates. Process Validation
has frequently consisted of three
batches, tested in accordance with the
product specification as defined in the
registration file. There is no scientific
basis for specifying the number of
validation batches to three, and while
this practice may still be acceptable in
the EU, there is a movement in the US
Implementing a new
QA culture and a new
paradigm for process
validation has of
course not been an
altogether easy task.
But there have also
been circumstances
in China that enabled
the shift.
Currently the industry in China is
waiting to see how the Chinese FDA
will interpret and enforce the new GMPs
from 2011. This may seem to be long
overdue since now over three years have
passed since the regulation was launched,
but the CFDA recognised that the new
requirements were setting a completely
new standard for the industry and gave
a grace period until January 2014. This
year a large number of sterile and aseptic
manufacturers are being inspected by
the authorities. It has been recognised
that while central CFDA has been very
strict in their interpretation, China is
an enormous country and it will take
time for the new interpretations to
trickle down to the provincial CFDA
inspectorates. Therefore, the industry
is still awaiting the outcome of local
inspections. This gridlock will probably
remain for the rest of 2014 and well
into 2015. If the CFDA is enforcing
the new GMP as vigorously as they
have announced, there will surely be an
increasing demand for new equipment
and facilities, but the main demand will
be new well-documented and improved
Quality Management Systems.
Many of the leading manufacturers
are not waiting for the results of the first
real CFDA new GMP audits, but have
instead chosen to aim for compliance
with EU GMPs for their current project
portfolio. This might even be the case for
projects without objectives of exporting
to the EU, but is rather done to be able
to set up strict quality objectives for
their projects.
Conclusions
Our recent experience suggests that
leading Chinese manufacturers not only
have adopted the Quality by Design
approach, but that they also fully
appreciate the regulatory implications
as well as the business drivers in
implementing enhanced process
understanding.
In applying Quality by Design and
Risk and Science-based approaches,
the Chinese are in some regards better
equipped to manage the changes of the
on to a more science-based approach.
Extended testing i.e extra tests outside
the product specification to obtain
an even more robust verification, an
expected practice in the EU and US
has not been the normal practice in
China either.
One of the main advantages of risk
and science-based validation is that it
provides a control strategy based on
residual risk after process design and
equipment qualification. This control
strategy is an input for the Design of
Experiments for process validation
batches that provides a scientific
rationale for the number of batches and
defines the extended testing needed.
Control strategies also help define
appropriate programmes for continuous
process performance monitoring i.e.
Continued Process Verification. In
order to achieve this goal there is a
need to implement a Pharmaceutical
Quality System including a number
of elements that traditionally
have not been prioritised. Change
Management, Deviation Management,
Supplier Management, Continual
Improvements and Product Quality
Reviews are examples of activities that
need to be implemented not just in the
documentation, but also in practice.
This is a major cultural change for most
Chinese pharma manufacturers.
Manufacturing

Manufacturing
organisations that this brings, due to
the lack of quality history. Since there
is a lack of understanding regarding the
extent to which the new CFDA GMP
will be enforced, and the similarities on
paper between EU and the new Chinese
GMPs, many leading manufacturers aim
for compliance with EU GMP in current
projects. While the industry as a whole is
still behind EU and the US in terms of
cGMP compliance, the gap is decreasing,
and it is decreasing rapidly. In a not too
distant future, Chinese manufacturers
are likely to catch up and even surpass
EU and US manufacturers both in terms
of compliance and quality performance.
However, China still has issues with
management, leadership, innovation
and creativity that are slowing the pace
of the development down for the time
being. Changing this probably presents a
bigger challenge than implementing new
industry regulations and guidelines.
Au t h o r BIO
Magnus Jahnsson has more than twenty years’ experience from the
pharmaceutical field, both from the industry and from regulatory
authorities. He has worked extensively in the fields of RD,
manufacturing, QA and regulatory affairs and has held positions
with AstraZeneca, European Medicines Agency and Pharmadule.
Daniel Nilsson has more than 15 years experience from the (bio)
pharmaceutical industry spanning all different areas of validation
and QA work, and management consulting, for multi-national and
Chinese manufacturers. He lives in China since 2012. Daniel holds a
Master’s degree in Chemical Engineering from the Royal Institute of
Technology in Stockholm.
Erik Östberg has 8 years of experience from the Life Science
industry and has worked for many multi-national manufacturers.
He is specialised in management of complex validation projects.
Erik lives in Shanghai since 2011. He holds a Master’s degree in
Biochemical Engineering from Chalmers University of Technology
in Gothenburg, Sweden.
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Pharma Focus Asia April 2014 - Approved LO.indd 1 20/03/2014 08:47:54

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Quality by Design
A rapid and systemic approach
for pharmaceutical analysis
The article presents a novel approach to applying Quality by Design (QbD)
principles to the development of analytical methods. Common critical parameters
in HPLC - gradient time, temperature, pH of the aqueous eluent, and stationary
phase - are evaluated within the Quality by Design framework. It is useful for
the robust analytical method development and Design Space optimisation.
M V Narendra Kumar Talluri, Assistant Professor, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education
and Research, Hyderabad, India

The first step is to define the intended
purpose of the analytical method. This has
been called the Analytical Target Profile
(ATP). The ATP is the set of criteria
that defines at what level the analytes
are measured; and accuracy or precision
of method in which matrix analytes are
estimated or over what concentrated
range. After the identification of ATPs,
proper analytical techniques are selected
based on the defined ATPs, for example,
for impurity/stability profiling of drug,
HPLC is more reliable technique other
than GC or UV techniques. The method
under development will then follow a
risk assessment which is the 3rd step in
method development. All parameters,
starting from sample preparation to
end of the method (data analysis) are
studied during risk assessment. Parameters
which have more influence on critical
quality attribute (CQAs) are found out
to construct the design space. CQAs
are the responses that are measured
to judge the quality of the developed
analytical methods, for example, total
analysis time, peak tailing, lower limit of
detection or quantification, resolution of
critical pairs, precision of the analytical
method which are the critical quality
attributes for chromatographic methods.
Quality by design (QbD) is defined
in ICH Q8 (R1) guidelines
as ‘a systematic approach to
pharmaceutical development starting with
pre-defined objectives with an emphasis
on product and process understanding
control’. Within the pharmaceutical
industry there is increasing discussion
about the principles of QbD analytical
methods. For many years, analysts used
to develop a method based on trial and
error approach. With this traditional
approach, many unexpected results are
observed during the stage of validation
in chromatographic methods (HPLC/
GC etc) including the disappearance
of a few peaks or appearance of new
peaks creating a need to go back from
starting of the method development steps.
This approach is very tedious and time
consuming and it cannot give robust
results. This can be avoided by applying
Quality by design (QbD) approach. The
degradants (impurities) can be separated
(or quantified) using chromatographic
techniques which can be tuned by many
variables and all these variables can be
optimised by QbD.
QbD has been initiated since 2002
and in Jan-2013 was fully adopted in
the pharmaceutical industry through
several regulatory initiatives such as FDA’s
cGMP for the 21st Century (Figure 1),
and the new regulatory documents, ICH
Q8, Q9 and Q10. Initiation of QbD
concept by regulatory authorities has
sparked several publications in this area.
In QbD approach, many statistical tools
are involved like Design of Experiment
(DoE), Multivariate Analysis and six
sigma methodologies. Since last decade
the number of publications increased
every year based on the experimental
design in chromatography.
Quality by Design steps for
analytical method development
To begin the development of a QbD
acquiescent analytical method and finally
reach the definition of its Design Space
(DS), a total of four steps need to be
completed as illustrated in figure 2.
History Of Quality By Design implementation process
FDA launched
new concepts
such as QbD,
design space
Guidance
on process
validation
Full
Implentation of
Qbd January
2013
PAT
Initiatives-recurrent
theme as QbD
cGMP for the
21st Century:
A Risk based
Approach by
FDA
FDA issued
guidance
clarifies the
QbD approach
to processing
human drugs
Figure 1
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