Pharma Focus Asia - Issue 19

Issue 19 2013

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g n i g a n n o a i t M mina es a c i t t n c Co pra New

Regulation of Nanomedicines Possible challenges

Modularisation in Biologics Manufacturing Recent trends and developments

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Foreword

Drug Contamination A serious threat Contamination of drugs during manufacturing

substances, foreign products, particulate matter,

is not a new phenomenon. In today’s global

micro-organisms, endotoxins, drugs have to be

manufacturing landscape, it becomes even more

purified by dilution of contaminants or flushing

imperative the manufacturers have processes

contaminants.

in place to mitigate the risk of contamination.

The cover story in this issue by Alan Fisher,

Nevertheless, drug contamination has emerged

Contamination Control Specialist, Dycem USA

as a leading cause of recalls lately. According to

Limited, talks about how reducing costs and

the Medicines & Healthcare Products Regulatory

increasing output are affecting the risks involved

Agency in the United Kingdom, product contami-

in contamination and what associated risk phar-

nation is the second to third highest reason for

maceutical products and processes have. The

recalls in the UK in recent years.

article also covers what Risk Management Plans

In 2009, 84 Nigerian children were reported to have died after being given ‘My Pikin’, teething

have to be followed to prevent the contamination and cross-contamination problems.

syrup contaminated with diethylene glycol. In

Also in this issue we present articles on

November 2012 404 cases of fungal infection

regulation of nanomedicines by Rajneesh Kumar

occurred with 29 deaths due to contaminated

Gaur from Ministry of Science and Technology,

injectable medication in the New England

Government of India; Rajesh Nair and Manish

Compounding Center meningitis outbreak.

Gupta from Indegene, US write about reorgan-

The regulatory authorities need to re-examine

ising for the future; Brian D Smith, Pragmedic,

the approach to quality control. Companies

UK writes about the challenges facing pharma;

and regulatory bodies like World Health

and Jan Lilja and AsaGaasvik, KeyPlants AB

Organization (WHO) and the U.S. Food and

and ParAlmhem, ModWave LLC. write about the

Drug Administration (FDA) have to ensure

modularisation in biologics manufacturing.

that processes for detecting and controlling contamination and cross-contamination and risk management strategies are put in place at manufacturing facilities.

Process and equipment need to be designed to avoid or minimise risks of contamination.

Irrespective of contaminants like products /

Prasanthi Potluri Editor

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Content

COVER STORY

STRATEGY 5

Relative Valuation of Biotech Discovery Companies Optimising Risk-Return Ratios

Michael A Berry, Managing Director, Discovery Investing, US

11 Risk Management of Contamination Prevention or cure?

Alan Fisher, Contamination Control Specialist, Dycem USA Limited, USA

16 Regulation of Nanomedicines

Possible challenges

Rajneesh Kumar Gaur, Scientist ‘C’, Department of Biotechnology, Ministry of Science and Technology, New Delhi, India

22 Reorganising for the Future

Succeeding in the new pharmaceutical industry

Rajesh Nair, President, Indegene, India

Manish Gupta, CEO, Indegene, India

28 Whither Pharma?

Possible challenges

Brian D Smith, Managing Director, Pragmedic, UK

CLINICAL TRIALS 34 Getting the Most from your Outsourcing Partner

Executing more cost effective and successful clinical trials

Jim Murphy, President and Managing Director, Almac Clinical Technologies, US

MANUFACTURING 40 Flexible BioPharmaceutical Production Solutions

Scott Kaplan, Senior Director of Project Development, PharmaduleMorimatsu Inc., US

46 Modularisation in Biologics Manufacturing

Recent trends and developments

Jan Lilja, Director, Commercial Management, KeyPlants AB, Sweden

AsaGaasvik, Sr Design Engineer, KeyPlants AB, Sweden

ParAlmhem, ModWave LLC, US

54 BOOKS

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ISSUE - 19 2013

NETZSCH DELTAVITA®

Laboratory, Pilot Plant and Production Sized Machines

DELTAVITA® 15 - 300 DELTAVITA® 600

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Advisory Board

Editor Prasanthi Potluri 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

Art Director M A Hannan Product Managers Prabha Nandikanti Breiti Roger Khaja Ameeruddin Jeff Kenney Senior Product Associates Vineetha G Vinay Kumar M Ben Johnson Veronica Wilson Compliance Team P Bhavani Prasad P Shashikanth Sam Smith Steven Banks CRM Naveen M Subscriptions incharge Vijay Kumar Gaddam

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

IT Team T Krishna Deepak Yadav Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Founder, Center for Biopharmaceutical Operations University of California, Berkeley, USA

Rustom Mody Director, Quality and Strategic Research Intas Biopharmaceuticals Limited, India

Confederation of Indian Industry

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Sanjoy Ray Director, Technology Innovation Merck Research Laboratories, USA Sasikant Misra Management Consultant and Ex-Deputy Director CII, Drugs and Pharma Sector 4

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Š Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

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strategy

Relative Valuation of Biotech Discovery Companies Optimising Risk-Return Ratios In this article, the author describes that use of ‘computing with words’ technology in conjunction with Discovery Investing factor model is a new approach to separating likely winners from likely losers.

Michael A Berry, Managing Director, Discovery Investing, US

M

any investors believe biotech is all about growth. It’s not. In my view it is about discovery.

It's an analytical technique quite different, called 'Discovery Investing.' I've developed it through the last decade because neither the growth nor value styles fit the mold in risk / reward analysis in the life sciences (Biotech) segment.

But some of the advice relative to portfolio risk / reward analysis is generic.

If you want to invest in the biotech space, you must diversify risk exposures. With the expensive nature of preclinical and clinical trials, biotech micro caps tend to burn money quickly. So the investor must focus on multiple applications in the life sciences space, and understand that one cannot know everything about those applications. Diversification will cancel those risks of the unknown unknowns.

These are sometimes called the 'Black Swan' risks.

Another piece of advice is to understand the broad value determinants and significant risk factors characteristic of the biotech space. If as an analyst, you are interested in stem cells, for instance, find the literature and the top scientists, and get to know them. Many are univer-

sity professors and easy to contact. If the cancer space is of interest, read the literature. From personal experience, I know that tremendous strides have been made recently in treatment of the skin cancer called melanoma. You handle risk analysis by understanding the biotech space of interest.

Ideally, you must be invested in life science themes that interest you, and that you naturally are attracted to. That makes risk / reward decision-making so much easier.

Finally, zero in on public—and especially nonpublic—companies in your space of interest. I like to track companies that are not yet public and get to know the management. You reduce your risk of being diluted, as so often happens during the pre-clinical and clinical trial process.

Then, and only then, use our 10-point grid and the Discovery Scoreboard1 software to grade and rank your companies of interest on a relative reward / risk basis.

To analyse risk and reward potential at the same time we have developed a factor 1 www.discoveryboard.com

model that we believe actively considers a very large proportion of the risk /reward spectrum for biotech companies.

Discovery Investing refers to an investment discipline pioneered by Dr. Michael Berry and popularised over the past 10+ years in his Morning Notes newsletter2. The philosophy behind Discovery Investing is that substantial wealth can be created by identifying companies with significant potential for major 'discoveries,' such as new and valuable natural resources, unique technologies for solving major problems, or revolutionary products such as stem cell technology or a successful cancer therapy. We refer to such biotech companies as potential 'discovery companies.'

Most companies with discovery potential are micro / nano-caps (very small market capitalisation) that are well short of achieving the sort of predictable performance and liquidity associated with larger established biotech companies.

They often have little or no revenue and indeed may have no near-term prospects for earnings. The resulting uncertainty and lack of historical performance data renders useless most fundamental analysis methods, including price/earnings ratios www.pharmafocusasia.com

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and cash flow analysis. Furthermore, the market liquidity of many discovery companies is so low that so-called “technical analysis” of their stock price behaviour (using well-known indicators such as stochastics, moving averages, residual strength index and charting techniques) provides little insight into the company’s prospects.

Given these difficulties in traditional methods of evaluating discovery companies, investors have had to resort to alternative approaches, which being ad hoc in nature are quite inefficient.

They include for example the following methods: • Word of mouth discussions between colleagues • Individual / group visits with company management and inspections of company facilities and / or resource sites • Attendance at trade shows and investor conferences • Scrutiny of regulatory filings, press releases and participation in periodic conference calls and • Seading newsletter opinions and analyst reports (to the extent these are available, which may be very limited in the case of small-cap companies.).

A common characteristic of these methods is that they primarily involve subjective, qualitative judgments, based upon limited information that often is not widely available to the investing public. Such information is also inherently imprecise. Thus the investor is left with the daunting task of combining this

information in a rational manner into a normalised overall score for the company that can be ranked directly with the corresponding scores for other companies.

Investors also frequently desire to compare their own evaluations of a company with those of other investors.

This may allow them to identify contrarian investing opportunities where their evaluation of a company differs substantially from that of other investors, or perhaps consider investments where they lack adequate knowledge of the particular company to judge for themselves. The above evaluation methods generally do not lend themselves to taking advantage of the composite knowledge of a large group of investors.

These shortcomings demand an investment evaluation approach that: 1. Is easily useable by the public 2. Considers a full spectrum of discovery company attributes 3. Is capable of handling the imprecision of human judgments of these attributes in a mathematically principled manner 4. Aggregates the judgments of individual attributes, taking account of their relative importance 5. Accommodates attributes being mandatory, in the sense that a poor score in one of these results in a low overall score 6. Produces an overall score so that individual biotech company scores Final Company Score

can be compared directly and 7. Allows investors to exploit the ‘wisdom of the crowd’ to assist in their own evaluations.

Such an approach is useful not only for individual investors who manage their own accounts, but also provides a means for performing the ‘due diligence’ required of institutional investors who manage money in pension plans, mutual funds, hedge funds and other pooled investment funds.

These considerations led to the development of the Discovery Investing discipline, which revolves around scoring life science and biotech companies with respect to a ‘10-point grid’ of investment decision factors, as illustrated by the blue ovals in Figure 1.

These factors represent different subjective evaluation dimensions of a company’s status, prospects, and potential. In our experience, this set of factors encompasses most of the primary influences on discovery company prices. The discovery factors may be summarised as follows: • Management / Board: Competence, track record and execution ability in achieving goals of the business plan relative to completing clinical trials and monetising the Intellectual Property (IP) • World Class IP: Company assets, intellectual property and/or technologies should be exceptional in their field. Potential for an effective cancer therapy or effective stem cell treatment of chronic ischemia would be examples

Company Diversification

Percent Project Ownership

Importance/Mandatory Contrarianness of Assets

Investor Sentiment

Company's Stakeholder Relations

Financial Soundness/ Sustainability Dilution Management

Management Board

World Class Assets/IP/ Technology

Asset/ Technology Potential Immediacy

Figure 1 The 10-point grid for evaluating the discovery potential of companies

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Cycle and Catalyst Identification

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3-5 December 2013

Bombay Exhibition Centre, Mumbai, India This event is an excellent opportunity to keep abreast with new developments in the pharma industry.

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CPhI India is part of the largest and most comprehensive pharmaceutical industry event in South Asia. Focused on pharmaceutical ingredients, machinery, equipment, outsourcing and bio-solutions, this is your ultimate one stop pharma shop!

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strategy

of ‘world class’ potential • Asset / Technology Potential / Immediacy: Degree to which therapies / devices are ‘game changers,’ with immediate impact and breakthrough potential • Company Diversification: Manageable diversification across projects to reduce risk of singleproject failure • Cycle and Catalyst Identification: Identification with events that may signal price changes, such as milestone announcements, market / sector cycles, or behavioral bubbles in share prices. Price bubbles often occur in the biotech space • Contrariness of Assets: Significant under or over-valuation in the share price relative to current asset or technology value • Financial Soundness / Sustainability /Dilution Management: Market liquidity and access to capital market or other funding sources necessary to sustain development without undue dilution of existing shareholders.

Sustainability is perhaps one of the most important factors in the micro and small cap biotech world where running out of financing to continue testing is a perennial problem • Company’s Stakeholder Relationships: Quality of relationships with shareholders, bond holders, money managers, customers, suppliers and locals • Percent Project Ownership: Degree to which the company maintains control of its destiny throughout the value creation process. The determination of the control point where the discovery can be monetized for the optimal amount • Investor Sentimentor Behavioral Biases: Degree to which company’s prospects are well-regarded by its shareholder base.

The 10 factors obviously are of differing importance in one’s final evaluation of a biotech company, and indeed some of them may be considered ‘mandatory’ in the sense described above.

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The philosophy behind Discovery Investing is that substantial wealth can be created by identifying companies with significant potential for major ‘discoveries’, such as new and valuable natural resources, unique technologies for solving major problems, or revolutionary products such as stem cell technology or a successful cancer therapy.

In the earliest embodiments of discovery investing, each factor for a given company was assigned a scalar score on a 0-10 scale, and a simple factor importance-weighted average is calculated to provide an overall company score. However, a much more advanced, online tool known as Discovery Investing Scoreboard (DIS) is now available free to discovery investors.

DIS2 was born of a meeting between the author, one of whom (Berry) is a former professor of finance at the University of Virginia and the other (Rickard) a researcher in the field of computational intelligence.

DIS employs very recent advances in the field of ‘computing with words’ to enable users to score biotech companies using simple word inputs for both factor 2 DIS was launched in January of this year and is now available for subscribers at www.discoveryboard.com

scores and factor importance. Users may select the factors, out of the 10 discussed above, considered appropriate for scoring each company, and also may designate any of these factors as mandatory by checking a box.

The system translates these word inputs into internal mathematical representations that account for the inherent imprecision in these word inputs (since the same words can mean different things to different people). It then computes an aggregate company evaluation that reflects this imprecision, taking full account of the importance and mandatory designations for each factor. This overall evaluation is displayed as a ‘footprint of uncertainty’ that illustrates the imprecision in the final score. From this, an overall number score is computed that can be used for comparisons and ranking between companies.

One of the most powerful features of DIS is that our approach enables the compilation of “crowd scores” for individual factors and for the overall company scores, based upon the inputs of all users for a given company. Thus an individual user who is unsure of how to evaluate a particular factor can incorporate the crowd score for that factor (where other users have scored it) into their own scoring. Alternatively, users may browse the overall crowd scores of companies. This provides a unique and quantitative way to exploit the “wisdom of crowds” in making investment decisions.

The initial release of the DIS system is tailored to individual investors, who score companies with respect to the 10 factors described above. Subsequent releases of the product will provide much more sophisticated versions of the system for use by institutional portfolio managers, financial analysts and broker/dealers. The institutional version will provide access to perhaps the most detailed decision tree ever developed for discovery company evaluation.

DIS also will provide a data product to corporate sponsors who typically are themselves discovery companies, based upon the crowd scores computed from

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that could possibly generate greater wealth. Incubator companies are the risky because their IP is not yet as well developed. But such companies often do pay off in great wealth creation.

We have developed the software system to rank biotech companies using the Crowd. The question is: how smart is the Crowd when ranking biotech stocks? The Crowd is defined by the subset of interested investors who independently scored our universe of biotech companies, in our case using the Internet to gain a large number of disparate disconnected and independent Discovery Analysts. We use a new technique called word-scoring. This allows for scorers to deal better with their imprecise knowledge and uncertainty about various company factors.

As discussed above, there are ten factors to score for a company but users can use the Crowd score when they do not understand a particular factor or factors, or they can simply ignore a factor while focusing on the two or three factors they have specific knowledge on.

We have been building a data base for the past two years. Currently 2000 users have registered and they have scored almost 1000 companies from the Canadian, US, Hong Kong and Australian stock exchanges.

The other day we were talking about performance and the relative power of the system as a risk / reward analytic tool. Naturally we are anxious to test performance that is the correlation between the Crowd ranking for a given company and the forward-looking returns performance.

A u t h o r BIO

our database. Online tutorials for DIS are available on our web site under the ‘Learn’ menu.

We believe that DIS will evolve into the standard for the evaluation of risk reward analysis for biotech companies.

No other such tool is available to the investment community, and we believe users will gain a much deeper insight into their investment decisions through the use of DIS. We invite you to try it!

The Internet greatly facilitates all these tasks. It is an interactive research tool investors should take advantage of.

There are no excuses for not developing a relative risk / reward ranking for the companies of interest to you.

Furthermore as James Surowiecki points out, forcefully, in The Wisdom of Crowds: “Groups properly organized, with little or no conversing between group members - are very intelligent even in the face of extreme uncertainty and imprecision.”

A word of warning: In this space, investors must be prepared to take profits to manage risk intelligently. That, perhaps, is the more important aspect of wealth creation in the discovery space.

Because of our Discovery Investing philosophy and software, we are not afraid of microcap biotech stocks.

However, one of the important 10 discovery factors is sustainability. So we look carefully at a company's balance sheet, and its sources and use of funds through clinical trials, to ascertain howl the company can survive.

We also look for positive catalysts, and how near and likely they might be.

And does the management—if management is composed of scientists (so often this is the case and scientists are usually such poor managers), understand the more general management issues involved in taking a product to the market, or generating a monetising event.

In some markets you must weight your portfolio toward mature life sciences discovery companies, versus less well known incubator companies

Our methodology is as follows:

1. We take the DiS data base scoring as of May 15th 2012 2. There were 58 companies scored at that time (minimum 5 analyst scores) We sorted the 58 companies into 10 deciles of 6 companies each by rank. (Deciles 5 and 6 had 5 companies). Decile 1 held the highest scoring (most highly regarded) companies 3. We measured performance of these companies between May 15, 2012 and June 15 and between May 15 and July 15 4. We calculated equally-weighted returns for the top two deciles and the bottom two deciles of companies as ranked by the Crowd.

The results for 30 and 60 days were as follows:

30 days 60daysTSX 30TSX 60 Decile 1 (Highest rank)25.3% 13.2% .88%.96% Decile 2 (Next highest)16.2%9.2% …..

Decile 9 (Low Rank)-2.3%-11.1% Decile 10 (Lowest Ranks) 4.4%4.7% Although the sample size at the time was relatively small you can see how the ranking of the biotech stocks into deciles (10 per cent of the entire sample) using the risk / reward analysis and the Crowd’s wisdom seems to correctly produce excess returns in the lower deciles (decile 1 and decile 2).

This use of ‘computing with words’ technology in conjunction with our Discovery Investing factor model is a new approach to separating likely winners from likely losers in a portfolio context.

Michael Berry earned a Ph.D. from Arizona State University (quantitative analysis and investment finance). He testified to Congress on US natural resource policy surrounding domestic energy development in 2010. He recently served as Chairman for the Global Bio Fuel Conference held in San Francisco in December 2010. Currently he publishes Morning Notes by Michael A Berry.

The notes discuss geopolitical, technological and economic trends and their effect on capital markets. He serves as an independent director of Quaterra Resources.

Risk Management of Contamination Prevention or cure?

Contamination remains one of the major dangers to the integrity of pharmaceutical products. The risks associated with contamination are greatly increased through the current trends of reducing costs whilst increasing output.

Additional complications from outsourcing, nanotechnology and test methods are resulting in change, uncertainty and increased risks which need to be managed.

Alan Fisher, Contamination Control Specialist, Dycem USA Limited, USA

T

hese are very interesting, exciting and challenging times in the world of pharmaceutical products, companies and regulatory bodies. There is a very valid argument that the pharmaceutical industry has some vital decisions to make regarding its future, particularly with about outsourcing production and the introduction of new technologies. Recent trends in outsourcing pharmaceutical production to Contract Manufacturing Organisations, Nanotechnology, introduction of Rapid Methods of Microbiology and the

uncertainty of the ‘unknown’ means that life will be anything but quiet. It was Donald Rumsfeld who quoted “Reports that say something hasn’t happened are always interesting to me, because as we know there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns–the ones we don’t know we don’t know”. Contamination and Cross Contamination complicated by the factors of Contract Manufacturing,

Nanotechnology and developing methods of Microbiology take us into a new era where the ‘unknown unknowns’ are waiting to be known.

What is contamination and where does it come from?

Contamination, cross-contamination and its control has long been one of the main challenges in pharmaceutical production as nothing else is a greater liability to the health and safety of patients.

Contamination is when a substance has impurities in it that can cause harm to living things and is basically anything that can be harmful to the pharmaceutical process or product. Contamination is ‘dirt in the wrong place’ and anything affecting the integrity of a substance. The World Health Organisation (WHO) have for Good Manufacturing Practice (GMP) defined contamination for pharmaceutical products as ‘the undesired introduction of impurities of a chemical or microbial nature, or of foreign matter into or on to a starting material or intermediate during

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production , sampling, packaging, storage or transport’, and cross-contamination as ‘contamination of a starting material, intermediate product or finished product with another starting material or product during production’.

Contamination control requires an understanding of the microbial entry points and the various routes that can be taken to arrive where they are undesired.

The diagram shows some of the sources of environmental contamination in addition to which there are cleaning agents, active Ingredients, decomposition products and materials, synthetic intermediaries, excipients, other residues, unfiltered air, room air, machines, ancillary equipment, containers, packaging, and the main source people. People are the problem as often they are the only real source of micro-organisms, generating particles just by being there. The routes of contamination need to be identified as these contaminated particles have to be controlled.

Particulate contaminants

Contamination comes in the form of particles which is one of the smallest units of matter in the world. It is termed as a molecule (when it is made up of two or more non-metal atoms) or a compound (where two atoms are bonded together).

One of the major reasons contamination and particles are difficult to comprehend is the fact they are so small and in the majority of cases invisible to the naked eye. Particles are defined as bodies with definite physical boundaries in all direc-

tions with diameters ranging from 0.001 microns to 100 microns (where a micron is equal to one millionth of a meter). To put this in perspective the measurement of 25mm is equal to 25,400 microns and the eye of a typical needle is equal to 749 microns. The ability to see individual particles depends upon the eye itself, the quality of light, the background and the type of particle. In ambient air 99 per cent of all airborne particles by count are less than 1 micron in size. The typical eye cannot see below 30 microns.

The pharmaceutical industry, like many others has now become embraced in the world of Nanotechnology. This is the ability to manipulate particles/matter at the atomic and molecular level to create materials with very varied and new properties. The term Nano comes from the Ancient Greeks meaning ‘Dwarf’ and scientifically one Nanometer represents the size of one billionth of a meter. Again to try and picture this one Nanometer is 40,000 times smaller than the thickness of a human hair. This ability to work at such small scales promises much in such fields as drug delivery, gene therapy, research and clinical applications. In fact we have original drugs, generics, biosimilars and now nanosimilars!

Particles can be viable or non-viable and it is widely accepted that microorganisms live and move around on 0.5 micron to 5 micron particles. The motion and movement of particles is affected by the velocity of the fluid for examle air; the inertia of the particle; gravitational, electrical, magnetic forces; the viscous

drag and the collision with molecules, other particles or surfaces forming agglomerates. To put this in perspective and as an example five 1 micron particles colliding in the right conditions will form a five micron particle.

Particles are generated by everything and using vectors move about freely within our environments. Examples of vectors include air and other gases, water and other liquids, physical objects and of course people. People generate 80 per cent of particles; equipment only 15 per cent and the environment the remaining 5 per cent. In pharmaceutical manufacturing particles commonly found include: • Human/Animal hair • Synthetic fibres • Glass • Paint • Closures (stoppers) • Insects • Metals • Skin flakes • The environment Particulate matter proliferates in pharmaceutical manufacturing for a number of reasons. Manufacturing has so many stages with the product constantly in contact with process. There is process precipitation and the opportunity for chemical breakdown, aging and interaction with so many different materials. This leads to contamination and cross contamination from raw materials, containers, packaging, other materials, cleaning, storage, people and the environment.

Given all of this it is perhaps surprising that any pharmaceutical product gets to its destination, the patient, in the safe state it does. However, the foregoing establishes beyond doubt the risks to human health and safety that exist at every stage of manufacture and why a risk management policy in pharmaceutical facilities is so essential.

Risk management

Figure 1

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In today’s safety conscious and highly regulated / legislated society the term

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Contract manufacturing

The current financial pressures combined with

many other reasons such as concentrating on core competencies are encouraging the pharmaceutical industry to look to contract manufacturing because of benefits such as cost savings through the economies of scale amongst others.

With benefits comes risks and it is clear that no one organisation can afford a serious Health or Environment incident.

Manufacturing new and different drugs in the same rooms, using the same and similar equipment for multiple end-users brings with it hazards especially as the drugs themselves get more and more potent. In addition to potential quality risks comes a lack of control, compromising Intellectual Property rights, language and cultural concerns/differences, on time delivery issues, potential shortage of supplies and competition for priority of supply etc. The parties in these relationships will have to address and amend their Risk Management to cater for this change to include using tools such as Risk-MaPPing to prevent cross-contamination from whatever source. Their Risk Management Plans will have to be continually monitored and amended.

Nanotechnology

Let’s get back to the unknowns.

Pharmaceutical nanotechnology has already provided some very great Assess

Risk Management

Evaluate

‘risk management’ is surely familiar to every manager in every pharmaceutical organisation. An understanding of risk management and risk assessment is today becoming a pre-requisite for those working in quality control and quality assurance and those active in pharmaceutical and medical device production.

Quality risk assessment is a mandatory requirement.

Risk management is defined as ‘the forecasting and evaluation of financial risks together with the identification of procedures to avoid or minimise that impact’ (Oxford English Dictionary).

The European Medicines Agency through its document ICH Q9 ‘Quality Risk Management’ sets out in depth how Risk Management now plays such an important part in GMP to the extent that ICH9 was incorporated into Chapter 1 of the GMP Guide in July 2008.

All pharmaceutical products and processes have an associated risk which is why, and without exception, all the regulatory bodies now use a risk based approach. As early as 2002 the FDA announced their risk based approach and this has been followed by most, if not all, of the regulatory bodies worldwide.

Risk can be good or bad but there is little doubt that the use of the word ‘risk’ has negative undertones. This negativity extends to some future event that may or may not occur. There is a wealth of information and a whole professional industry associated with risk and its potential to become catastrophic and

Measure

Figure 2

most of the experienced analysts would agree that damage to human health and the environment are at the centre of risk management.

The risk management process often starts with a risk management plan which is drawn up by a risk management team.

The team should represent as wide a view as possible of the various operational functions within the organisation.

The process then moves through the following (not exhaustive) activities: Risk: Assessment; Identification; Analysis; Evaluation; Control; Reduction; Acceptance; Communication; and Review.

It can be argued that perhaps the most important aspect of any risk management is the risk review. Risk management is a continuing process and one that should never end. One thing in life that is certain is change and that small word says everything about what is, or should be done, to cope with and address change within a risk management plan.

Should the following questions be asked?:“ How do you know that your risk management methods are working or not?” “What are the consequences if they do not work?” It can be argued that the biggest single risk for any organisation is the risk that their risk management process doesn’t work!

This article does not propose to go into the plethora of models and tools that can be used within a Risk Management Process or Plan as such information is readily available from a number of sources and far more eminent authorities than the writer. It will instead look briefly into some of the risks associated with some of the challenges already highlighted.

Manage Figure 3

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Suggested simple solutions to aid prevention 1. Establish protocols 2. Limit access, establish strict rules of entry 3. Use and enforce barrier technology 4. Use best practice in the design and manufacture of the suites 5. Maintain positive air pressures in as many areas as possible 6. Maintain a disciplined cleaning regime 7. Restrict foreign materials in the production suites 8. Use filter technology Figure 4

Microbiology

Micro-organisms are responsible for much harm to the safety and integrity of pharmaceutical products. They are found by the millions in or on the environment, water, raw materials, containers and closures, equipment and not least people. Not all organisms are bad, but again the unknowns come into play as it is generally accepted by all in the industry that so little is known about them, how they communicate and just how many different species exist. To help protect the quality and integrity of pharmaceutical products we have testing methods which help us

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identify and deal with this contamination but as with all testing there are limitations. One of the major problems remains the time taken to identify if there is anything contaminating products and if so identifying them. Rapid Microbiological Methods are increasing in use as is Real Time Particle Counting but with them the uncertainty or risk that they have limitations and need development to provide even better solutions. Again Risk Management will include some testing and validation and again needs to be monitored, continuously improved and changed as the risks of this new technology are identified.

Prevention or Cure

It has already been mentioned that ‘people are the problem’, which raises another complex issue of Risk Behaviour. The terms ‘Contamination’ and ‘Risk’ are raised every day and are mentioned constantly in pharmaceutical production. ‘People being people’ invoke the human factors of familiarity and complacency. Historically where there has not been a problem why should there be one now. In order to be

A u t h o r BIO

benefits in diagnosis and treatment of disease. On the negative and risk side it has raised social, ethical, scientific and not least regulatory issues. There are some unanswered questions on health risks many of which appear to be carcinogenic/highly toxic. There are also environmental concerns and problems and uncertainty about the general safety of the science. The risks are extremely complex but will include amongst others, the release of nanoparticles into the environment; political risks regarding the impact on economic development of countries; intellectual property and business risks.

Any risk management plan or policy/ process relating to nanotechnology will involve a complex risk assessment and identification process needing to be flexible, dynamic, and scientific.

effective at reducing complacency and familiarity an understanding is needed how ‘At risk behaviour’ occurs.

So ‘is prevention better than cure’?

The rationale behind this saying is that it is better and cheaper to prevent problems before they occur. ‘Familiarity breeds contempt’ becoming accustomed to familiar things that you no longer value them. Colin Powell wrote “’If it ain’t broke don’t fix it’ is the slogan of the complacent, the arrogant or the scared. It is an excuse for inaction, a call to non-arms”.

“If particles are kept out of the critical areas in a production unit there is less risk of contaminated products being produced”.

“Prevention costs a lot less than the cure”, which is recalled product, waste, scrap, regulatory fines, suspension or ultimately closure.

Place contamination control flooring to prevent foot-borne, wheel-borne and air particles in gowning rooms, transfer air locks, warehousing to manufacturing.

References are available at www. pharmafocusasia.com

Alan is a Contamination Control Specialist who has been involved in working with and advising Pharmaceutical and Medical Device Manufacturers on controlling contamination preventing the risks associated with such contamination to their products. Alan has worked in Asia, Europe, USA and the UK where he serves on a number of ISO Working Committees and is an active Committee Member of the Pharmaceutical & Healthcare Sciences Society

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Regulation of Nanomedicines Possible challenges Regulation of nanomedicines is a challenge due to the lack of extensive scientific advancements, non-availability of expertise easily and customised detection tools and techniques in the field.

Rajneesh Kumar Gaur, Scientist ‘C’, Department of Biotechnology, Ministry of Science and Technology, New Delhi, India

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N

anomedicines refer to drugs, medical devices and health products developed using nanotechnology with the aim of diagnosing, monitoring and treating diseases at the molecular level. Nanomedicines can be used to achieve the same therapeutic effect at smaller doses than their conventional counterparts due to their nano size, which improves their solubility and bioavailability. Broadly, there are three types of nanomedicines namely nanocarriers for drug delivery, nanosuspensions and nanoparticles for bioimaging. Though nanomedicines possess tremendous potential in the treatment and diagnosis, in-spite there are concerns regarding their safety and

strategy

Currently, the world is divided regarding the regulatory framework for nanoproducts. One school insists on the formulation of a new regulatory process, while another school emphasises that the existing regulatory processes are robust enough to tackle the issues related to nanotechnology possibly with specifically desired modifications and amendments. It is certain that bridging the existing bifurcation regarding the regulation of nanoproducts including nanomedicines, demands at least deeper understanding of the underlying physiological processes such as Absorption, Distribution, Metabolism and Excretion (ADME) and the resulting implications.

toxicity? Therefore, regulatory framework or guidelines for nanotechnology products must be in place for extending the immense positive benefits of nanomedicines to the society.

Regulatory scenario

So far, neither engineered nanoparticles nor the products and materials that contain them are subject to any special regulation regarding production, handling or labeling. Regulatory bodies such as the United States Environment Protection Agency (EPA) and US Food and Drug Administration (FDA) or the Health and Consumer Protection Directorate of the European Commission have taken initiatives to deal with the

potential risks posed by the nanoparticles. Berkeley, California is currently the only city in the United States to regulate nanotechnology through an Assembly Bill, 2006.

On the basis of ‘Nanotechnology Task Force’ report in 2007, the FDA issued its first draft guidance in June 2011 titled as ‘Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology: Draft Guidance for Industry’. Till date, FDA made available only the draft guidance documents but has not yet established specific formal regulatory guidelines for any nano-product. To promote nanotechnology, Government of India launched a Mission on Nano Science and Technology (i.e. Nano Mission) in May 2007 which is a successor of Nano Science and Technology Initiative (NSTI) of Department of Science and Technology (DST), 2001 but no guidelines are drafted for regulating nanoproducts in general.

Regulatory challenges

The nanomedicines either approved for marketing or under clinical trial are listed in Table 1. Currently under FDA, 591 clinical trials are going on for various liposomal preparations, which is just one type of a nanomedicine; while in India, the total number of nanomedicines

under clinical trial is 21. In India, nanomedicines are slowly appearing in the market, for example, Ranbaxy’s ‘Volini’ nanogel; therefore, regulatory guidelines are required to mitigate the hazardous outcome of any nanotechnology-based drug. The guideline preparation for nanomedicines is certainly not an easy task due to the lack of extensive and deep scientific knowledge as well as tools and techniques. There are few scientific and analytical concerns in the context of regulatory guideline for nanomedicines are discussed here.

Firstly, the definition of nanoproducts is not universally accepted and as a result, there is no homogenisation of the acceptable limit, for example, the US National Nanotechnology Initiative (NNI) launched in 2000 considers the dimension from 1-100nm. The U.K. Royal Society and Royal Academy of Engineering, 2004 proposed a range of 0.2-100nm. The ‘Friends of the Earth Australia’ recommend defining nanoparticles up to 300nm in size. The definition of nanoparticles is important as their size has proportionate increase in surface to volume ratio, admissible changes in physical, pharmacokinetic & pharmacodynamic properties, toxicity and biosafety level, direct or indirect environmental and ecosystem impact.

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Nanomedicines either approved for marketing or under clinical trial S. No.

Drug (Brand name)

Year of Approval/ Company

Indication(s)

INTERNATIONAL I. Approved 1.

PEGylated adenosine deaminase bovine enzyme (Adagen)

1990, Sigma-Tau Pharmaceutical

Severe combined immunodeficiency disease

2.

Styrene maleic anhydride-neocarzinostatin (SMANCS)

1993, Yamanouchi Japan

Hepatocellular carcinoma

3.

PEGylated L-asparaginase (Oncaspar)

1994, Sigma-Tau Pharmaceutical

Acute Lymphoblastic Leukemia

4.

Amphotericin B (Abelcet)

1995, Sigma-Tau Pharmaceutical

Fungal Infections

5.

PEGylated doxorubicin (Doxil/Caelyx)

1995, Johnson & Johnson/Scheering-Plough

Various Cancers

6.

Liposomal Daunorubicin (DaunoXome)

1996, Gilead Science Inc.

Advanced HIV-associated Kaposi’s sarcoma

7.

Glu, Tyr, Ala and Lys copolymer (Copaxone)

1996, Teva Pharmaceuticals

Multiple Sclerosis

8.

Liposomal Influenza Vaccine (Inflexal V)

1997, Crucell

Influenza

9.

Liposomal Cytarabine (DepoCyt)

1999, Pacira Pharmaceutcials

Lymphomatous meningitis

10.

Liposomal Verteporfrin (Visudyne)

2000, Novartis

Macular degeneration

11.

Polyamine (Renagel)

2000, Genzyme

Chronic Kidney Disease

12.

PEGylated interferon alpha-2b (PegIntron)

2001, Schering-Plough

Hepatitis C

13.

PEG and Filgrastim conjugate (Neulasta)

2002, Amgen

Chemotherapy induced Neutropenia

14.

Leuprolide acetate and PLGH polymer formulation (Eligard)

2002, Sanofi-Aventis

Advanced Prostate Cancer

15.

PEGylated hGH receptor antagonist (Somavert)

2003, Pfizer

Acromegaly

16.

Radioactive iodine tositumomab (131) BEXXAR

2003, Bexxar

CD20 positive follicular cancers, NHL refractory to rituximab

17.

PEGylated anti-VEGF aptamer (Macugen)

2004, eyetech Inc.

Neovascular age-related macular degeneration

18.

Liposomal morphine sulfate (DepoDur)

2004, EKR Therapeutics Inc.

Post-surgical pain

19.

Albumin based Paclitexel (Abraxane)

2005, Celgene Corporation

Breast Cancer

20.

PEGylated-epoetin beta (Mircera)

2007, Roche

Anemia associated with Chronic Kidney disease

21.

PEGylated Fab fragment of a humanized antiTNF-alpha antibody (Cimzia)

2008, UCB

Crohn’s disease, rheumatoid arthritis

22.

Muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) – (Mepact)

2009, IDM Pharma

Osteosarcoma

23.

Topical Diclofenac nano emulsion

2012, Pharmacos

Knee Pain

II. Under Clinical Trial

18

1.

Dendrimer gel (Viavgel)

StarPharma

HIV and Genital herpes

2.

Anti-R2 siRNA nanoparticle (CALAA-01)

Calando Pharmaceuticals

Various Solid Tumor Cancers

3.

Everolimus (XIENCE V)

Abott Vascular

Coronary Artery disease

4.

Actinium-225-labelled Humanized Anti-CD33 mAb HUM 195

Memorial Sloan-Kettering Cancer Center

Leukemia Myelodysplastic Syndrome

5.

Liposomal meglumine antimoniate (Glucantime)

Tehran University of Medical Sciences

Cutaneous Leishmaniasis

6.

TNF bound colloidal Gold

Natioanl Institute of Health clinical centre

Advanced Solid Tumors

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7.

Liposomal Lidocaine gel

University of Campinas, Brazil

Oral aneastheisa

8.

Liposomal Vincristine

Inex Pharmaceuticals

Soft Tissue Sarcoma, Lymphoma, Leukemia, Wilms' Tumor Osteosarcoma

9.

BLP25 Liposome Vaccine

Merck KGaA

Lung Neoplasms Carcinoma, Non-Small-Cell Lung

10.

Liposomal Cyclosporine

University of Maryland

Disorder Related to Lung Transplantation Bronchiolitis Obliterans Decreased Immunologic Activity Chronic Rejection of Lung Transplant

11.

Pegylated liposomes of Human Recombinant Factor VIII (Kogenate FS)

Recoly N.V

Haemophilia A

12.

Liposomal Irinotecan

Yakult Honsha Co., LTD

Cancer

13.

HL-009 Liposomal Gel

HanAll BioPharma Co., Ltd

Atopic Dermatitis

14.

Liposomal Recombinant Human Cu/ Zn-Superoxide Dismutase (Lipoxysan)

Apeiron Biologics

Radiation Induced Dermatitis

15.

Liposomal Amikacin (Arikace)

Insmed

Pulmonary Nontuberculous Mycobacterial Lung Disease, Cystic Fibrosis

16.

Liposomal TLK199

Telik

TNF bound colloidal Gold

17.

Liposomal c-raf antisense oligonucleotide (LErafAON)

Insys Therapeutics Inc

Neoplasms

18.

PEGylated liposomal Prednisolone sodium phosphate

Galapagos NV

Acute Exacerbation of Remitting Relapsing Multiple Sclerosis Clinically Isolated Syndrome

19.

Synthesized Peptide εPA-44 (Entecavir)

Chongqing Jiachen Biotechnology Ltd

Hepatitis B Vaccine

20.

Nanoliposomal CPT-11

University of California, San Francisco, USA

Glioblastoma, Gliosarcoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Mixed Oligoastrocytoma, Malignant Astrocytoma NOS

21.

Cystic fibrosis transmembrane conductance regulator

University of Alabama, Birmingham, USA

Cystic fibrosis

INDIA I.Approved 1.

Paclitexel

2007, Dabur

Advanced/Metastatic Breast Cancer, Non-smallcell lung and ovarian carcinomas

2.

Nano-peptide (Receptol)

2010, Biomix Network Ltd.

Antiviral (HIV/AIDS) and Immunomodulator agent

3.

Sirolimus (Supralimus-core)

2011, Sahajanand Medical Technologies

Coronary Artery Disease

II.Under Clinical Trials 1.

Docetexel

Sun Pharma

Advanced or metastatic Breast Cancer, locally advanced non-small cell lung cancer, hormone refractory metastatic prostate cancer

2.

Atropine Sulfate

Institute of Nuclear Medicine & Allied Sciences

Nerve Gas Poisoning

3.

Submicronic Salbutamol

Hypoxemic conditions associated or leading to pulmonary hypertension

4.

Silver Sulfadiazine

Burns

Source: Clinical Trials Registry, National Institute of Medical Statistics (Indian Council of Medical Research), India - Last accessed on 7th November’ 2012. A database of publicly and privately supported clinical studies developed by US National Institute of Health available at http://www.clinicaltrials.gov/ and last accessed on 26th November’ 2012.

Table 1

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The guideline preparation for nanomedicines is certainly not an easy task due to the lack of extensive and deep scientific knowledge as well as tools and techniques.

but will not be sufficient to probe the specific aspects such as counting and assessing the homogeneity of nanoparticles in a drug formulation especially nano-suspension, quantitative assessment related to the retention / excretion of both metallic and biological nanovehicles such as gold particles, carbon nanotubes and liposomes in human system and their risk assessment.

Fifth, nanomedicines pharmacokinetics have deviated from the normal course. As a result they are bioavailable for a sustained period, and, therefore, for such drugs the ‘over-the-counter’ approach may lead to potentially increased health hazard to the public.

Therefore, the regulatory bodies needs to assess whether the nanomedicines are allowed to market under the strict medical supervision or simply labeled as ‘Nano’. It is in fact not easy to reach either of these conclusions in the absence of availability of signifi-

A u t h o r BIO

Secondly, the issues related to the production of nanoparticles such as the infrastructure, training of human resource for handling the nano raw and manufactured materials, occupational hazards and associated health risks, quality control and their assessment in the absence of adequate technology for analysis.

Thirdly, the aspects related to the clinical usage of nanomedicines as they are supposed to deliver the drugs locally in high doses at a particular cellular site. This mechanism of drug delivery requires extensive safety data at least up to pre-clinical stage before market approval. The localised high drug dose might lead to wide arrange of possible adverse effects, which may be aggravated as a result of improper distribution and excretion of nanomedicines.

The localised high drug dose may lead to toxicity of a particular cell/organ type (lethal particularly in patients like diabetes and chronic kidney disease), or emergence of antibiotic resistant superbugs in case of antibiotics, hypersensitive reactions as a result of either interference of cellular processes due to retention of nano particulate metallic / nonmetallic vehicles or generation of antibodies against the antibodies used to direct a nanomedicine towards the target. Furthermore, due to the nano size of these medicines, they possess exceptional mobility quality; as a result, they may cross Blood Brain Barrier.

The unwanted presence of nanomedicines may compromise the ability of the brain either severely or for a long term. Also, as a result of their altered biochemical activity, they may bind either with key cellular protein(s) or unwanted molecules such as toxins, and resultantly, interfere with the protein action or enhance the toxic effect of toxins.

Fourthly, niche area of detection protocols and methodologies for nanomedicines needs to be encouraged. The existing methods may provide both the qualitative and quantitative data

cant toxicity, biosafety data analysis as well as their environmental risk assessment.

Lastly, delegation of responsibility to the appropriate group of government organisations is desired for formulating draft guidelines for nanomedicines through a wide array of consultative process involving various stakeholders such as sndustries, academia, clinicians and end users. Furthermore, there is immediate need for establishing world class regulatory laboratories and testing facilities at least at the federal level.

Simultaneously, risk assessment expertise in terms of personnel, guidelines and technical standards needs to be buildup.

Conclusion

Nanotechnology is highly inter-disciplinarily in nature, which requires a diverse set of stakeholders and their coordinated efforts. Limitations such as inadequate knowledge regarding nanoparticle behaviour, absence of standardised nomenclature, test methods, and characterisation of nanoparticles, shortage of trained personnel are some of reasons which are possibly hindering the process of determining primary jurisdiction for combination products, nanomedicine-specific safety protocol, ineffective control of nanoparticle and developing the framework or pathway for controlling the manufacturing processes, product quality and safety of nanomedicines.

Author’s Note: The views expressed are personal and has NO relation with official position in Department of Biotechnology, Ministry of Science & Technology, New Delhi, India.

Rajneesh Kumar Gaur has completed his doctorate in Structural biology from RWTH, Germany and having almost 8 years of experience in active science research. He is currently engaged in Planning, Co-ordination and International cooperation in Department of Biotechnology, Ministry of Science and Technology, New Delhi, India. He is interested in S&T policy matters.

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strategy

Reorganising for the Future Succeeding in the new pharmaceutical industry To survive, nay, thrive in the new market, pharmaceutical companies will have to fundamentally reorganise their entire business model. All things that were traditionally considered sacrosanct—R&D model, organisational design, pricing models and the much vaunted sales and marketing engine—will have to be reviewed.

Rajesh Nair, President Manish Gupta, CEO Indegene, India

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design, pricing models and the much vaunted sales and marketing engine— will have to be reviewed. One thing is for certain, companies that refuse to change or those that are not able to

do so fast enough will go the way of the dodo.

To understand some of the fundamental forces at play, a few are highlighted are and discussed below.

Commercial resources mlsallgned with stakeholder influence

Blinded company example 2008 data Total influence on Rx decision by stakeholder' Per cent Policy

"Based on Stakeholder Interviews and roundtables "Excluding rebates SOURCE. McKinsey & Co.,

T

he old pharmaceutical industry is dead: the one that was a fully integrated behemoth, with a R&D and commercial operation regularly launching blockbuster drugs for diseases that affects millions of people. The era of the ‘mad men’ in marketing and sales, strategizing with ad agencies on positioning, branding, and promotions is no more.

Today, blockbuster drugs are rarer than a snowflake in the Sahara.

Regulators have defanged marketers, growth is desperately being pursued in the emerging markets, licensing is preferred over in-house R&D efforts and M&A is preferred for responding to the pressures from the street.

To survive, nay, thrive in the new market, pharmaceutical companies will have to fundamentally reorganise their entire business model. All things that were traditionally considered sacrosanct—R&D model, organisational

10

Pharmacy

5

Payer

35

Patient

15

Provider

35

Total Commercial spend by Stak eholder''

Total Commercial FTEs assigned by stakeholder

Per cent 1

4

Per cent 0

1

0

6 1

11

93 84

strategy

A. The physician is no longer the primary decision maker

In most developed markets, the primacy of the physician as the ‘decision maker’ is changing. Published data (McKinsey, 2008)show that while the role of the physician has waned, that of the payer, patient and policy has increased. There is a gap in the industry structure, that is, commercial spending and headcount are still built for the old reality.

Impact: Pharmaceutical companies have to reorganise internal resources and spend to adapt to the new stakeholder structure.

B.Patients are becoming important stakeholders

Patient advocacy and pressure groups are already driving trial designs and regulatory fast-tracking in clinical trials on oncology and rare disorders. This will accelerate with further pricing pressures and politically driven decision making

Patients have more financial risk

50%

All Small Firms (3-199 Workers) All Large Firms (200 or More Workers) All Firms 40%

40%

35%

22%

21%

10%

18%

16% 10% 6%

0%

31% 27%

30% 20%

50% 46%

2006

22%

12% 8%

9%

2007

2008

13%

2009

17%

2010

2011

% of Covered workers with annual deductible > = $ 1,000 Source: Kaiser/HRET Survey of Employer-Sponsored Helth Benefits, 2006-2011

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on compulsory licensing to answer the clamour for accessible medications.

A prime example is the US where the Accountable Care Act is a direct response to pressures from patients (voters).

While countries like India have been facing these pressures for years [drug price control order (DPCO), process patents, etc.], countries like the UK (NHS) and US (employer driven) have seen patient contribution to healthcare expenditures (through taxes or direct payment) moving towards unsustainable levels.

Impact: Patient centricity will have to move from a marketing phase to a coherent approach to manage and serve patient demands.

C. Multichannel promotions and social media are the future of meaningful engagement with customers

Across the world and across all age and demographic segments, internet penetration, smart device usage and social media participation is increasing. Healthcare will not be an exception to this transformation and will manifest changes in the way patients search for health information, get opinions for their diagnoses and how physicians make treatment decisions.

The nature of interactions and relationships will change with text messaging, virtual portals and telehealth becoming more mainstream. To reach physicians and other care providers, companies will have to go beyond just the sales force and focus on multichannel tools and initiatives.

Impact: Physical and virtual tools will be used to meaningfully engage customers. This will need a wholesale change from the current ‘headcount’ model.

D. Pharma growth markets are shifting

While the developed markets are likely to grow in low single digits, the emerging markets will continue to grow at 10 per

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cent or more for the next 5 to 10 years.

For example, the largest global market, that is, the US will grow between 2 per cent and 4 per cent while Latin America is projected to grow at more than 12 per cent and India at 15 per cent or more.

Impact: Companies will have to decide what to centralise and what to localise. Reuse, cross-leverage and standardisation will become key mantras.

Local infrastructure and flexibility will become critical in decision making.

E. The traditional R&D model has failed

Regulatory sensitivity to adverse events, me-too claims and time and cost of clinical trials have killed numerous products that may have passed muster in the past.

In addition, a slew of late-stage failures have put pressure on senior management to justify internal R&D productivity to a sceptical marketplace. The chang-

ing nature of the discovery process, complex and multifactorial nature of target diseases, coalescence of large data, ‘–omics’ technologies, niche marketing and the need to integrate market as well as clinical view during the discovery and development processes call out for a transformation of the insular ‘everything made in-house' R&D culture.

Impact: Efficiency and effectiveness may lie in more open-source and network-based approaches.

Now that we have had a glimpse of the tidal forces at play, what do all of the above trends portend for the new pharmaceutical industry? What are some of the key changes that are needed now?

A few key structural and strategic initiatives—most of which are in various stages of ‘initial consideration’ to ‘feverish execution’ across leading pharmaceutical and life science organisations—are highlighted below.

The new consummer

The new HCP

87%

75%

Percent Own A Smart Phone

Us Physiciansown An Apple Device

85%

30%

Use Social Media For Health

Hcps Use Smartphones For Professional Use

strategy

1. Globalisation and organisational redesign (centralisation vs. localisation)

The competing issues of ‘growth’ in emerging markets vs. ‘contraction’ in developed markets mean that existing service structures will have to be reorganised to cater to the new growth drivers.

The traditional notion of central headquarters trying to ‘help out’ the emerging markets when possible is simply not effective, especially because they become large markets by themselves and need to be empowered to be nimble. In contrast, there is a need to drive a change in organisational mind-set, culture and capabilities to drive big shifts in areas like hybrid sales and marketing models and patient enablement. Consequently, there are initiatives to restructure functions like R&D, regulatory and safety, medical affairs, sales and marketing and other country-operating structures as well as create new structures. Some of the key questions raised include: • What roles/functions can be centralised and aggregated and efficiencies can be scale derived?

• What roles/functions need to stay decentralised?

• What should be the global organisational structure? Monolithic or split into logical business units like established products, new/emerging drugs and speciality products?

• Shared services and centres of excellence (CoEs) across emerging markets—how are these different from those in developed markets?

• What shared services need to be created to build new capabilities in the organisation and how do they partner with country units?

• What change management processes need to be implemented?

2.Externalisation and outsourcing (fixed vs. variable costs)

Given the cost pressures, the traditional ‘in-house’ model is undergoing a significant change in the developed markets, with transformational initiatives such

Regulators have defanged marketers, growth is desperately being pursued in the emerging markets, licensing is preferred over in-house R&D efforts and M&A is preferred for responding to the pressures from the street.

as reduction in force, variabilisation of costs and sharing of ramp-up/rampdown risks with service partners. New structures being tested include outsourcing and offshoring, risk-sharing models for R&D and marketing, cloud service models, software as a service and centralised platforms and technologies.

All these initiatives essentially focus on converting traditional fixed costs to variable and shifting internal risks across multiple external partners and making use of prevalent industry best practices in a cost-efficient way. A key decision, especially in the context of sales and marketing, will be when to use global partners and when or where to empower country units to work with local partners.

The benefits of local empowerment and agility will have to be examined against issues like risk of noncompliance and overall organisational cost.

3.Hybrid sales models (multichannel marketing)

Over the past 4 years, more than 40,000 pharma sales jobs have been eliminated in the US market alone. At the same time, the challenge is exactly the opposite in the emerging markets, where there is tremendous scarcity of trained

representative along with 20 per cent to 30 per cent sales force turnover. In addition, the regulatory pressures are increasing across the world, resulting in issues of promotional compliance, standardisation of message and return on investment (RoI).

Migration from ‘physical sales calls’ to a hybrid model where sales force is augmented with multiple channels, which may include teleservices, e-mails, eDetailing/video detailing and online portals, is a smart response to the demise of the traditional model. This new multichannel marketing (MCM) model requires a centralised ‘platform’ to integrate data from multiple activities, run appropriate targeted campaigns and analytics to ensure RoI. This calls for a shift in mindset from looking at MCM as just another version of a ‘digital’ campaign to strategically approaching it as building a new sales and marketing infrastructure for the future. This sales and marketing infrastructure will build new capabilities and partner with country units and brand teams to drive change.

4.Patient enablement

The product portfolio for many pharmaceutical companies is increasingly shifting towards rare and orphan indications, biologics and speciality products.

In every one of these cases, the role of patient advocates, patient motivation and patient enablement is critical. Even in the case of chronic indications, the importance of patient adherence and compliance is a significant factor to drive clinical outcomes as well as reduce revenue leakages. Going beyond coupons and vouchers, new social media tools, multichannel engagement approaches and behavioural modelling need to be incorporated into the existing sales and marketing infrastructure.

5.New R&D models (closed vs. open networks)

Today’s R&D models are focusing on building open or semi-open virtual networks. There are more collaboration,

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strategy

A. Example 1: TransCelerate Biopharma TransCelerate is a consortium of 10 leading biopharma companies that are driving a collaborative initiative aimed at improving the drug development process.

The major players, including Pfizer, GSK, Sanofi, Roche and J&J, are collaborating on clinical trial and development issues like data standards, risk monitoring, site qualification and training and ensuring access to comparator drugs. Given the

challenges in terms of trial delays, longer approval timelines and late-stage failures, the premium on openness, externalisation of R&D efforts and collaboration between competitors will lead to more experiments in the future.

B. Example 2: stand up to cancer Stand Up To Cancer is a groundbreaking initiative by entertainment industry professionals to find cures for cancer. This model up-ends the traditional funding and research model by identifying and funding ‘dream teams’ to focus on specific cancers.

The focus is on team/collaborative approach, large grant sizes, frequent expert reviews and aggressive time bound agenda.

The initial scepticism of the scientific and pharmaceutical establishment is morphing into acceptance as the early results are beginning to arrive.Several pharmaceutical companies are starting to partner with Stand Up To cancer.

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The above examples throw a spotlight on the changes underway and some of the responses from stakeholders. The next section highlights how we at Indegeneare is partnering with global pharmaceutical and device companies to help solve these transformational challenges.

strategy

How Indegene is partnering to solve the challenges and help build the “new pharmaceutical industry” A. Driving productivity and efficiency

Indegene has been one of the pioneers in setting up hybrid global delivery models and infrastructure to deliver high value services to the pharmaceutical industry across R&D, regulatory and safety, medical and commercial functions. Leveraging a team of more than 1000 scientific, technology, analytics and communication experts across multiple delivery centres in North America, India and China, Indegene has today one of the most sophisticated infrastructures and systems to take care of pharmaceutical regulatory, compliance, data and process issues while helping clients reduce costs and drive efficiency by more than 50 per cent.

To take this initiative to the next level of sophistication, Indegene has developed a unique business innovation–Extended Enterprise Model—that works hand-in-glove with clients to build mirror image functional service organisations across multiple locations.

The Extended Enterprises, including Extended Medical, Extended Analytics and Extended Commercial Enterprises, comprise interlocking elements, including cross-functional skills, software platforms and tools, process and training models and ability to deliver outcomes across a ‘value-chain’ rather than across a single process.

B. Driving revenues via new commercial models

With the recent acquisition of Aptilon to the portfolio, Indegene today has the leading global MCM infrastructure to deliver sales and marketing solutions across the US, EU and Emerging Markets. This cutting-edge infrastruc-

ture includes proprietary ‘cross-channel hub’ platforms, call centres with telerepresentatives, e-mail, SMS, eDetail and video detail solutions, recruitment tools, analytics frameworks, content, digital factories and operational support to help clients launch new products across multiple markets, augment sales force efforts to enhance uptake curves and deal with loss of exclusivity (LoE) issues.

Indegene has been successfully working with both central ‘digital’ organisations and brands/therapy areas to increase the reach, improve the quality of interactions, increase the efficiency and optimise the cost. The business impact has been successfully measured across multiple dimensions, including campaign level issues like touch points, prescriptions and multi-device access metrics as well as business elements like integration efficiencies, lower time to market, operational flexibility and overall business outcomes.

C. Leveraging technology platforms

Indegene believes that integrating technology platforms with service to deliver business outcomes is a key requirement for next-generation service partners. Towards this vision, Indegene has built a portfolio of proprietary IP platforms that help solve fundamental

A u t h o r BIO

risk sharing and funding models. The case studies below highlight 2 two examples of the new models being explored.

issues across R&D, regulatory, medical affairs and commercial organisations.

These include: TrialPedia: A patented clinical trial benchmarking and claim-space analysis platform with more than 200,000 clinical trials, 30+ granular search parameters and a host of analytic tools.

IndegeneConnect+ DAMS:A pharma industry-focused proprietary workflow and digital asset management platform to handle regulatory and compliance issues for digital factories, offshore production and in-house program management.

MedHost and iLearn: Enterprise learning and development platforms to help drive change in management, enhance time to market and ensure regulatory compliance.

Phynyx, Optimax and ChannelHQ: MCM infrastructure platforms that help connect multiple channels, drive campaigns and provide integrated analytics and reporting.

To conclude, it is clear that the transformational challenges faced by the pharmaceutical industry call for a fundamental Change in organisational design, cost structures, commercial strategy and service tactics are required for pharma industry’s transformational challenges.

More openness, partnerships, collaborations and a flexible approach will separate the winners from the losers.

In a career spanning over 20 years, Rajesh has been one of the leading global experts in the transformation of commercialization and marketing initiatives within the pharmaceutical industry. He has been at the forefront of evolving strategies for globalization of scientific services related to the industry and defining the paradigms for improving the efficiency and effectiveness of sales and marketing activities.Rajesh is a physician with 3 years of clinical experience. He also holds an MBA from the Indian Institute of Management (IIM), Ahmedabad.

Manish has more than 15 years of experience with expertise in organizational strategy, financial management, HR systems and processes and managing operations. He has pioneered the application of robust and scalable operational processes to the domain of pharmaceutical commercialization and scientific services.

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strategy

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Whither Pharma?

Possible challenges

The pharmaceutical industry is a complex adaptive system whose past is explained and future predicted by evolutionary science. New research into this area predicts the speciation of pharma business models. For industry CEOs, this implies difficult choices about which part of the industry habitat to occupy and how to guide the evolution of their company’s business model.

Brian D Smith, Managing Director, Pragmedic, UK

T

o predict the future of pharma, we need a powerful tool and fortunately, in evolutionary theory, we have what philosopher Daniel Dennett called the best idea ever. First used to understand the complexity of life, evolution is now used by management scientists to explain and predict many other complex adaptive systems, including whole industries. Evolutionary economics equates business models with species and the changing natural environment with variations in the market context. With

valuable clarity, it accounts for the history of our industry and allows us to predict the future of pharma.

The application of evolutionary theory begins by understanding that the pharmaceutical industry is not simply evolving; it is co-evolving with its scientific and sociological environments.

In the latter, demographics, globalisation and the attitudes of governments, patients and investors are among the many factors that are re-shaping who pharma’s customers are and how they

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strategy

define value. For most of the past 100 years, pharma’s customers have been governments and insurance providers in the so-called “developed world”, who defined value as the best clinical outcome.

A dramatic shift towards value defined as the best health-economic outcome is already visible, but that is only the start of the change to be expected. As demand outstrips what governments can pay for, organisational payers will retreat into providing a core service. Above and below state and employer provision, individuals will purchase their own healthcare. When the new rich use their wealth to prolong and enhance their lives and mass consumers sacrifice consumer goods to co-pay and self-medicate, the pharmaceutical industry will have three customer habitats of significant importance. In each habitat, value will be defined in a different way and it will no longer be sufficient to operate one business model.

Similarly, pharma’s market will also be fragmented by the co-evolving technological environment. The most obvious biological science trends, such as genomics and systems biology, will make possible fantastic new therapies.

But other, non-biological sciences will be just as important. Nanotechnology and the spread of information technology to are just two examples of non-pharmacological technological change that will reshape the way healthcare value is created and delivered. And beneath these headlines will be the application of technology to how pharmaceutical companies work, allowing them to restructure and become hyper-efficient. This will lead to a three-way polarisation of the way pharma companies create value. New science will remain a value creator for the industry, but it will also become possible to create value by tailoring healthcare to the patient and by reducing the costs of

treatment to a tiny fraction of today’s prices. Scientific innovation, personalisation and low-cost business models each exist today, of course, but they will evolve far beyond current ideas and, compared to today’s models, will have a more equal balance between prevention and cure.

The next step in understanding the evolution of pharma’s business models is to grasp that its new habitats are formed at the intersections of sociological and technological change. Customers’ new ways of defining value will combine with novel ways of creating value, creating a new landscape of market habitats.

Evolutionary theory predicts a complex landscape will emerge with no fewer than eleven fitness peaks, analogous to ecological niches, and three troughs, analogous to evolutionary dead-end s(see Figure 1).This fragmentation of the business environment has huge implications for the industry’s structure, the first of which

Figure 1: Fop fitness landscape

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New business models The first class of new business model that can be seen emerging, labelled ‘Genii’ in the research, will take technological capabilities to new extremes, combining pharmacological, materials and information technology to provide therapies of science-fiction-like power. But they will be small by today’s standards, dominating only the limited habitats where wealthy individuals pay for themselves or governments are forced to pay for politically-sensitive patients. The Genii firms’ huge profit margins will reflect the very risky nature of their business model and their survival will depend on radical innovation.

The next most familiar model will be the 'Monster Imitator’ firms. Superficially similar to today’s generic companies, they will make today’s generics look small, inefficient and costly. For these firms, survival will depend on fast following, massive scale and ruthless efficiency.

As a result, only a handful of global firms will dominate this off-patent market habitat and small firms will have little chance here. States and other payers will buy most of their drugs from these firms but at tiny margins in a tender-based market that will be much more commoditised than any part of today’s market.

While the ‘Genii’ and the ‘Monster Imitator’ will trace their DNA directly back to today’s research based and generic firms, the five remaining models will evolve from the cross-breeding of capabilities from both pharma and non-pharma companies. The ‘health-concierge’ model will, for example, resemble a cross between today’s private wealth-management companies and a pharmaceutical company. Focussing tightly on the wealthy, it will offer health maintenance as well as therapy. For the less wealthy, states and other payers will pay some firms, the ‘Lifestyle Managers’, to prevent disease and, when this fails, pay other firms to manage the chronically ill, a new form of 'Disease Manager’ very different from its 1980s version. In addition, a shoal of firms will evolve to extract new value from old therapies by reformulation or redesign. These “Value Pickers” will be the carrion of industry and, in pharma markets as well as in biology, this will be a very successful approach. For those populations that payers cannot or will

not pay for, a new model will arise, that will have traces of DNA from retailing, pharma, OTC, nutraceuticals and the fitness industry. These firms, the ‘Trust Managers’, will supply branded generics and prophylactic products along with services. Their distinctive characteristic will be their ability to build and maintain the trust of the patient who will be their customer.

There are two other characteristics of these future pharma species that will be quite different from today’s firms. The first is their differentiating capabilities, which will be much more polarised than at present. The innovative capabilities of the Genii will be so much greater than the other pharma firms as to be incomparable. Similarly, the low-cost efficiency of the Monster Imitators will mean their pricing will not be comparable to other pharma firms that seek to add value in some way. And the different customer-management capabilities of the other models will each be so distinctive and so specifically-adapted to their habitat that they will co-exist in adjacent but different market niches.

The second characteristic of future pharma firms that will surprise an observer used to today’s companies will be their structure. The outsourcing we see today will go to extremes and business units will become smaller, more specialised but more networked. If the biological analogy of today’s firms is a higher mammal, with its multiple interrelated physiological systems and processes within one organism, then tomorrow’s pharma company will be more like a lichen. This symbiote of simple, separate but inextricably connected organisms is a good analogy for what the outsourced, disintegrated pharma company structure of the future will look like.

This evolutionary process means that the pharma CEOs have, in essence, three decisions to make. Firstly, in which of the future market habitats should my firm attempt to operate? Secondly, what capabilities and structures will we need to develop in order to adapt to that habitat?

Finally, how can we adapt faster and more effectively than our competitors? Those three questions will be addressed in the final section of this article.

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New habitat

New species of business model

Core state provision and limited choice

The monster imitator - Adequate therapies sold extremely cheaply

Lazarus & Narcissus, pressured state and advance state provision

The genii – Fantastic, very expensive, relatively small volume therapies

Get well, stay well

The trust manager –Trustworthy, non-innovative branded therapies sold to the masses

Chronic cost containment

The disease manager -Chronic conditions managed efficiently

Mass prophylaxis

The lifestyle manager- Prevention and maintenance for the masses

Wealthy well

The health concierge – Wellness and treatment for the wealthy

Value pockets

The value picker – Value-added reformulation of old ideas Table 1

is that the industry’s three major business models – generics, big pharma and speciality pharma – have no place in the new world and firms clinging to these old business models are volunteers for extinction. However, extinction will be accompanied by the rise of new pharma business models as firms adapt and specialise to fit the new ecological niches, (see Table 1).

CEO decisions

The first, most fundamental decision facing pharma CEOs concerns which habitat to occupy and thus which business model to guide the company towards. Unlike biological organisms, executives can consciously guide the evolution of their company, but it is

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fraught with three inherent dangers to which many companies will fall victim: • Indecision: Because each business model is very different and requires capabilities specific to its habitat, the seven models are, largely, mutually exclusive. For example, firms that attempt the hyper-efficiency of a Monster Imitator model at the same time as the Discovery Excellence of the Genii model will, inevitably, find themselves straddling the two strategies and competitively compromised in both • Ego: Research suggests that the Genii business model, with its scientific prestige, is the default choice for most of today’s companies. Yet

this is a relatively small habitat and likely to be extremely crowded. A more rational, successful leader will discount ego and consider carefully which of the seven models fits closest with their firm’s current capabilities and organisational culture • Self-knowledge: To make the right choice of habitat and model depends on understanding objectively what the strengths of the organisation truly are. For example, firms may perceive themselves to have strengths in discovery when their true strength lies in the trust their corporate brand has acquired over decades. A firm that truly understands its strengths would therefore make different and much better choices than a firm that is deluding itself.

The second CEO decision concerns what new capabilities the new business model implies. Research shows that the new capabilities needed by the pharma company of the future fall into three categories: • Core capabilities are those needed just to operate in a market; they confer no advantage but lack of them means certain failure. In the future of pharma, these will include negotiating complex regulatory and market access problems and managing the perceptions of a cynical, media-led public. But they will also include understanding increasingly complex customer networks of payer, prescribers and patients and, compared to today, developing frugal business processes • Distinctive capabilities are those that will allow firms to compete and, importantly, they are different for each of the seven business models.

The value-picker model, for example will have to excel at spotting niche opportunities. The lifestyle manager, by contrast, will need to develop complex, integrated value propositions rather than simple products • Dynamic capabilities are those that enable change in the organisation and

strategy

borrow “industry best practice’ from other pharma companies, believing the industry to be special or unique. This is the corporate equivalent of incest and it simply re-circulates the same old practices. To achieve a rich, varied injection of new practices, pharma will need to learn how to import ideas from many other sectors and break its habit of corporate incest.

This article attempts to summarise the extensive, radical findings of a very large scale research project into the future of the pharmaceutical industry.

A u t h o r BIO

as such are the most precious and problematic. They will include practices that allow firms to create market insight, build on that insight to create strong strategies and to execute them via complex alliance networks.

The third, and perhaps most difficult, question for CEOs to address is how to develop these new capabilities faster than the competition. Evolutionary theory suggests three important factors will determine the speed at which firms will evolve. Firstly, the capabilities needed will be very different from today; second, the practices needed will vary greatly between business models; and finally, many of these practices will not come from pharma industry but from other sectors. These three factors have important implications for how the most successful firms will acquire their new practices. For example, almost always pharma’s instinct is to

Modern ideas of evolutionary economics predict a complex, fragmented market landscape that will drive the evolution of several new business models and the extinction of the ones we’re familiar with. That prediction of speciation and extinction both identifies and guides the decisions that need to be made by the industry’s leaders. If they make and implement the right decisions, the pharmaceutical industry will continue to contribute hugely to our society. If they fail, both our society and the industry will be much the worse for it.

Brian D Smith is Adjunct Professor at SDA Bocconi, Italy and Visiting Research Fellow at the Open University Business School, UK. After a 20 year career as a research chemist then marketer in the pharmaceutical and medical technology sectors, he has spent the past 15 years researching competitive strategy in markets where the customer is the healthcare system. He works with many of the industry’s global leaders and he is editor of the Journal of Medical Marketing. He has published almost 300 papers and books, the most recent of which, the Future of Pharma, is the basis of this article. He welcomes comments and questions at brian.smith@pragmedic.com

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Clinical trials

Getting the Most from your Outsourcing Partner Executing more cost effective and successful clinical trials This article discusses globalisation trends, outlines the benefits of strategic partnerships and outsourcing, and shows how to overcome the challenges associated with clinical trial management on a global scale.

Jim Murphy, President and Managing Director, Almac Clinical Technologies, US

M

ultinational biopharmaceutical companies abandoned the practice of performing all of their Research & Development (R&D) functions in house years ago, but the drivers behind the decision to outsource are changing. While the need to reduce fixed costs remains a primary reason for big pharma's dependence on outsourcing partners, a recent study found that improving quality and speeding time to market were actually cited more often as motivators. This is accompanied by the growing trend for companies to develop strategic relationships with vendors who can demonstrate excellence in a range of closely related drug development services such as those that support patient and clinical supply management.

When companies practice strategic outsourcing and work closely with a select few vendors, producing cost savings is a baseline requirement. The real value— and what companies should expect from such long-term relationships—comes in process and technology innovations that lead to competitive advantage. By virtue of their wide experience across sponsor companies and deep functional

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Clinical trials

specialisation, the best service providers have actually developed greater expertise in their particular niche than sponsor companies. This should translate into transformative advances that improve quality and speed time to market.

But this begs the question: how can the relationship be nurtured to provide this expected value? Here we offer insight into current outsourcing trends for managing patients and clinical supplies during drug development and share advice on how to ensure that strategic outsourcing yields optimal results.

Outsourcing options

One of the basic questions that companies must answer when developing their R&D outsourcing strategy is whether it is best to consolidate services with a vendor offering ‘one-stop shopping’ or to work directly with a select few vendors offering specialised services. (Working with a long list of preferred providers responsible for each distinct drug development task has long since proven too costly and unwieldy to be a viable option.)

In theory, of course, there are advantages to working with a solesource vendor—chief among them is the convenience factor. However, sponsor companies taking this approach must be sensitive to the fact that in such a complex industry, it is unrealistic for any single supplier to ‘do it all well’—just as it was difficult for pharmacos themselves to excel in every aspect of R&D before they began outsourcing. Neither will a provider that attempts to be master of all domains have the management focus or ability to invest in each niche to deliver excellence consistently.

One way around this is for the primary vendor (such as a CRO) to subcontract with specialty providers (such as those offering patient and supply chain management) who can work effectively with them and integrate services. While this is a workable model, it does not give sponsors with high study volumes the

Outsourcing in Asia In general, the growth in strategic outsourcing in R&D has paralleled the global expansion of trials. As the market for new drugs has grown considerably in emerging markets and as the challenge of patient recruitment has intensified over the past decade, sponsor firms have naturally expanded the geographic reach of their trials. This is especially evident in Asia. The overall R&D market in Asia's top seven countries totaled US$5.3 billion in 2011 and is forecasted to reach US$17.3 billion by the end of 2018. Asia now accounts for 15 percent of all of the world's clinical trials (up from 11.6 per cent in 2011.)

Rather than invest in the extensive human and physical infrastructure required to establish and maintain a global drug development footprint, it's common for companies to contract with global par tners that can supplement resources in major drug development centers and provide local capabilities in emerging, highly specialised trial markets. In Asia, the use of services provided by clinical research organizations (CROs) such as site selection, patient recruiting, site monitoring, and data management is virtually universal. Until recently, large biopharmaceutical companies have tended to maintain their own supply distribution capabilities in the region, although this practice is shifting.

maximum opportunity for continuous improvement and value creation.

Another option is to adopt a "best-of-breed" model in which the sponsor contracts directly with a small network of specialised providers that are leaders in their respective areas and capable of collaborating effectively to meet the sponsor's goals. This does not mean that one should have to turn to separate vendors for every individual responsibility involved in setting up and running a clinical trial; market leaders have integrated their services within their areas of expertise, limiting the number of players required.

This best-of-breed approach, when orchestrated properly, capitalises on the focused core competencies and nimbleness of each contributor, yet

results in an integrated solution. The challenge, of course, is in governing the relationships with all parties efficiently and effectively.

Keys to success

A recent assessment of strategic partnerships between sponsors and R&D vendors has revealed a mixed degree of success to date. According to a 2012 survey by the Avoca Group, one fifth (22 percent) of pharmacos have discontinued their strategic agreements with outsourcing partners due to poor performance, and 40 percent admitted that expectations for operational efficiencies were being met only some of the time.

We surmise that the reasons for these results are that not all vendors are equally capable across all tasks in all regions and

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When the future is uncertain and the going is tough

Choose very carefully Pharmaceutical-Tech.com is the online platform of choice for pharma decision makers seeking to create fruitful partnerships and stay abreast of the day-to-day developments in the pharmaceutical industry.

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Protech Pharmaservices Corporation 00886 2 2657 7777 contact@ppccro.com www.ppccro.com PRTM 0081 3.5326.9090 infojp@prtm.com www.prtm.com Radpharm Scientific 0061 2 6251 6533 www.radpharm.com.au Recon Machine Tools Pvt. Ltd. 0091 22 26875931 sales@reconmachine.com www.reconmachine.com Romaco AG info@romaco.com www.romaco.com Royal Artist 0091 22 28320800 response@royalartist.com www.royalartist.com S.Zhaveri Pharmakem Pvt Ltd 0091 22 66 60 7756 / 57 vikas@szhaveri.net www.szhaveri.com Saeplast 00354 460 5000 saeplast@saeplast.is www.saeplast.com Samex 0091 261 2590950 / 25934203 info@samexoverseas.com mehul_jhaveri@hotmail.com www.samexoverseas.com Santapet Polymers Limited 0091 22 2342 0381 info@santapetpolymers.com www.santapetpolymers.com Saz Boilers 0091 20 26970840 saz@vsnl.com www.sazboilers.com Servotex Engineers 0091 22 28454982 servotex_engineers@yahoo.com www.indiamart.com / servotexengineers Shakti Pharmatech Pvt. Ltd. 0091 2717 250405 sales@shaktipharmatech.com. www.shaktipharmatech.com Shiv Shakti Process Equipment Pvt. Ltd. 0091 22 26768480 office@shivshaktiequipments.com www.shivshaktiequipments.com Sigpack Systems AG 0041 52 674 65 00 www.sigpack.com Skan AG 0041 61 485 44 44 info@skan.ch www.skan.ch Speciality Meditech Pvt. Ltd 0091 141 5105136 speciality_meditech@yahoo.com www.indiamart.com Spectrum Pharmatech Consultants Pvt. Ltd. 0091 22 25977000 hemant.lokare@spectrumpharmatech.com www.spectrumpharmatech.com Srinidhi Engineers 0091 22 28497424 / 32964483 srinidhirk@gmail.com www.srinidhiengineers.com Stamfag Punching Tools 0041 44 914 35 35 info@stamfag.ch www.stamfag.ch Starcom Mediavest Group 00971 4 4276435 Samar.jalil@dubai.starcomworldwide.com www.smvgroup.com

Sujyot Engineering 0091 79 25856044 / 26639686 info@boxstrappingmachine.com www.boxstrappingmachine.com Superlite Lighting Co. Pvt. Ltd 0091 22 26852822 info@superliteindia.com www.superliteindia.com Swami Vessels Pvt. Ltd 0091 257 2211294 / 2211447 response@swamivessels.com www.swamivessels.com Syngene International Pvt. Ltd. 0091 80 2808 2808 / 2783 2169 arun.nataraj@biocon.com www.biocon.com Trebing & Himstedt Prozessautomation GMBH & Co 0049 385 39572-0 sinkmann@t-h.de www.t-h.de Turchette Advertising Agency 001 73 227 8080 rsiciliano@turchette.com www.turchette.com Tyagi Air-Wave Equipments Pvt. Ltd 0091 120 2820548 / 2829333 tyagiairwave@yahoo.co.in www.airwaveindia.com UBM India Pvt Ltd 0091 22 66122600 bhaskar-chivukula@ubm.com www.ubm.com Uma Brothers 0091 22 25004510 / 25004579 umabros@vsnl.com www.umabrothers.com UPM-Kymmene India Pvt. Ltd. 0091 22 2767 0031 Santosh.Kumar@upmraflatac.com www.upmraflatac.com Vertis Biotechnologie AG 0049 8161 141 12 11 www.vertis-biotech.com Wintech Pharmachem Equipments Pvt. Ltd. 0091 250 2456495 winpharma@vsnl.net www.wintechpharmachem.com WLE Technology Sdn Bhd 0060 3-7845 0598 / 0798 enquiry@wengloong.com www.wengloong.com Yogesh Pharma Machinery Pvt. Ltd. 0091 79 40233800 to 804 bizypmpl@gmail.com www.pharmaequip.in Zenithmedia GmbH (Siemens) 0049 89 71 05 18 0 Henning.Kittner@zenithmediamuenchen.de www.zenithmediamuenchen.de

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Clinical trials

that the need to adjust capacity rapidly has introduced quality-related challenges for some vendors. So, how can this track record be improved?

Choosing the right partners is, of course, essential. To qualify as an integrated services outsourcing partner, a firm needs to demonstrate that it has the experience, expertise, and scale to consistently deliver quality results with the necessary speed. Vendors should bring deep domain expertise, insight into regional norms, and a complete understanding of applicable regulatory and safety issues, since errors, or even a learning curve, cannot be tolerated.

To contribute to the success of a strategic outsourcing arrangement, providers must also be willing to commit to a long-term relationship, immersing themselves in the sponsor's business to understand it with an insider's perspective. They must also have sufficient scale and breadth to support global trials, while also being flexible enough to adapt to changing requirements. These relationships generally involve large volumes of work that often prove to be overwhelming for boutique firms. Outsourcing partners in this model must also be open to working collaboratively with other parties in the mix.

And specifically in patient and supply management, vendors should understand the flow of work and data throughout the trial process to ensure that systems feed one another in real time, giving the sponsor maximum control and transparency into key performance indicators.

Strategic focus

One of the primary objectives of a strategic outsourcing relationship is to collaborate on engineering out costs. This should not be confused with treating every aspect of the outsourced service as a commodity in an attempt to push down unit costs. Doing so undermines the

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Vendor selection

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Efficiencies gained via: Strategic focus Relationship governance

• Service integration • Trial planning • Supply chain management Figure 1

Caption: Tangible benefits accrue when working with outsourcing partners that bring sufficient global scale and adequate breadth to integrate services across multiple functions in the trial process.

whole premise of strategic outsourcing as a means to identify process and technology improvements that yield a competitive advantage.

Finding the breakthroughs that deliver business value necessitates that a sponsor spend time on managing and continually refining its support services.

A strategic outsourcing relationship will only live up to its full potential when there is alignment of strategic goals, active engagement from both sides of the relationship, openness to process evolution, and controlled experimentation.

Relationship governance

How the relationship between the sponsor and its outsourcing partner(s) is governed is a critical factor in ensuring that the relationship transcends tactical execution and truly addresses more strategic goals.

Companies must follow a disciplined process that entails: • Articulating the vision of the ideal future state and the strategic goals for the relationship • Establishing each party's remit, negotiating Service-Level Agreements (SLAs), and establishing metrics to evaluate quality • Developing annual strategic objectives for both parties in the relationship. The goals must extend beyond SLA targets,

which are generally very operational, and target key areas where there is the highest level of interdependency in the work flow • Determining how decisions will be made and information communicated, specifying how both organisations’ technologies and processes will be integrated, and deciding how intellectual property will be protected • Overseeing the partnership at operational, management, and executive levels through a governance body that sets policies and addresses issues as they arise.

Clearly, all parties need to invest in the partnership, committing the necessary resources to keep it thriving over the long haul. The goal is to maintain a win-win relationship that results in higher quality and faster drug development at a reduced cost.

Efficiencies from outsourcing patient and supply management

Providers of services for managing patients and the product supply chain, when working as strategic outsourcers to sponsors, are able to realize efficiencies in three fundamental ways: service integration, thoughtful trial planning, and comprehensive supply chain management.

Clinical trials

Forward-thinking firms have invested in the facilities, staff, and technologies to be able to integrate their services in a logical way and deliver them seamlessly to clients. A single company, with an integrated delivery model, can provide aspects of blinded supply manufacturing, packaging and labeling, analytical testing, storage and depot services, and worldwide distribution and logistics, as well as the interactive technologies that power patient enrollment, randomisation, and drug assignment.

There is a significant interdependency between clinical supply management services and the interactive response technologies (IVR/IWR) that are used to connect those clinical supplies with sites and patients. This is most pronounced during the study start-up process with activities such as forecasting supplies, blinded labeling, pooling products, selecting resupply models, and defining the workflow for managing drug returns.

Having these services integrated through one vendor that is strong in each of these areas offers many benefits: • Sponsor or CRO staff do not need to serve as mediators overseeing tactical communication and planning details between individual vendors during the study start-up phase • It is faster and easier to forecast product demand pre-study and mid-study when the latest patient enrollment data and an inventory of medication throughout the supply chain are visible in one system. This results in fewer shipments, translating into reduced costs • Supply volumes can be easily adjusted should enrollment trends differ significantly from assumptions or if other factors such as protocol amendments lead to regional or global supply shortages. It becomes much easier to manage resupplies for a particular label type or region, adjust the depot strategy from a country-specific to a regional distribution center, or to execute

just-in-time labeling operations in support of product pooling or expiry management • The integrated systems produce an end-to-end audit trail of the study drug, from packaging all the way to the return and destruction of supplies.

Trial planning

Sponsors are increasingly engaging suppliers in the planning process for clinical trials—often beginning with protocol development. Outsourcing partners can provide advice on study design, randomization, and blinding as well as help forecast when drug products will actually be needed during the course of the trial.

Forecasting product demand is particularly important in large, Phase III studies. Upfront forecasting allows sponsors to coordinate packaging, labeling, and shipping with patient enrollment progress and treatment stages.

This enables them to manage production runs, determine dispensing units and kit sizes, ensure that products are available when needed, and reduce waste from over-production. Suppliers that also offer patient management applications can synchronize current information on patient status with forecasting software for real-time adjustments to demand forecasts.

Supply chain management

Supply chain firms are also instrumental in helping sponsors manage drug inventory and minimise shipping costs throughout the life of the trial.

Experienced professionals armed with real-time supply and demand data—

A u t h o r BIO

Service integration

available only when patient management systems are integrated with supply chain systems—can proactively make recommendations on depot locations, shipping routes, and resupply strategies.

Such careful management not only saves money, but spares sites from having to store excess drug product and diagnostic kits in their facilities.

A supply chain outsourcing partner can also effectively deploy drug pooling strategies to reduce the amount of blinded supply that must be produced, and to expedite product distribution.

When common inventory is held in a drug depot, IVR/IWR technology and secondary labeling specialists must work in unison to ensure supplies are labeled for the correct protocols, shipped to the correct sites, and assigned to the to correct patients.

Partnering for better results

Strategic outsourcing, whereby sponsors develop trusted and long-lasting relationships with select, key providers, can help biopharmaceutical companies meet their strategic R&D goals—particularly in emerging markets. One key to success is to rely on outsourcing partners that have sufficient scale to operate globally and sufficient breadth to integrate services across multiple functions in the trial process. The ideal supplier brings a niche domain expertise that complements the competencies of the sponsor and other providers in the mix. A formal governance structure helps guide collaboration and ensures that the relationship continues to offer transformative innovations that benefit the sponsor.

References are available at www.pharmafocusasia.com

Jim Murphy is President & Managing Director of Almac Clinical Technologies, a role he has held since 2006. He also leads Asia Pacific operations for The Almac Group, overseeing the company’s strategic expansion in the region. Since joining the company in 1999, Murphy has held several senior leadership positions in Operations, Business Development, and Marketing. He holds a Bachelor’s degree in Biochemistry and a Masters in Molecular Biology, both from the University of California at Santa Barbara, US.

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Manufacturing

Flexible BioPharmaceutical Production Solutions

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Manufacturing

The article will identify the challenges to getting a new biomanufacturing facility through design, construction, and start-up in a timely manner-Balancing the financial risks of committing to a capital project too early with those associated with not getting a treatment to market to help patients. I will present a solution, leveraging the advantages of single-use process equipment and modular design and fabrication, to streamline the delivery process while enhancing predictability and mitigating risk.

Scott Kaplan, Senior Director of Project Development, Pharmadule Morimatsu Inc. US

A

s with all technologies today, the advancements within the life sciences industry are accelerating beyond what any of us have experienced in the past. Every facet of our industry, from early drug discovery and development, through human trials and commercial manufacturing, are evolving at a rate that was unthinkable a decade ago. What was considered cutting edge innovation and accepted to be the future of biotech production just 10-15 years ago is now antiquated and thought to be unusable and ready to be shipped off to the local museum as an exhibit to show what was happening in the Biotech Stone Age. The focus of this article is to trace a history of manufacturing innovation over the last 15-20 years. Starting from a point in time when many biologics were being approved and companies were frantically attempting to accelerate the timeline for getting additional capacity on-line to meet patient demands, through a period of overcapacity and product rejection, this article will examine how we arrived at today’s drive to downsize and decentralise production. The approach to meeting demand for the manufacturing of new products is balanced by a need to create flexible manufacturing so that new products and process platforms can

easily replace the equipment that is no longer needed.

While biological based treatments have existed in the pharmaceutical industry since the first experiments with Penicillin nearly a hundred years ago, it has been much more recent that research has increasingly turned toward living organisms for treatment of disease rather than the traditional reliance on chemical synthesis for most cures. Over the last 30 years, more and more investment has been diverted from the small molecule to biotech research. This has led to the explosion of new products that have become available to diagnose and treat as well as prevent many diseases that previously had no treatments.

The production of these new biopharmaceutical products is significantly different and more complicated than a chemical synthesis. The equipment used is different. Instead of reactors, blenders and compression equipment, there was much more control required with fermenters and bioreactors, centrifuges, columns and filters and the final dosage forms were mostly temperature sensitive liquids that required aseptic conditions for filling.

The new and more complex processes also brought dramatic changes to the facility requirements. The targets of

the initial new biological treatments were wide spread diseases with large patient populations. When these treatments were successful in gaining regulatory approval, the combination of the price for the treatment and quantity of annual doses made them blockbuster drugs. To satisfy demand, so that every patient that needed the treatment could have access, large facilities were built driven singularly by ‘speed to market’.

There were a number of characteristics that these early biopharmaceutical production facilities shared: • Designed to manufacture a single product • Large production capacity with multiple (up to 6) trains of large (up to 20,000 liter) bioreactors • All hard piping with no portable or disposable equipment • CIP/SIP required throughout the process between batches • Customised processes and stainless steel equipment • Some open processing driving the facility design to the use of clean rooms for downstream processing.

The timeline for getting one of these facilities from concept through validation was in excess of 60 months and project costs ranged from US$250million to more than US$1 billion. The price was not a deterrent in building a new facility because the firms that owned the rights to the approved product had exclusivity for an undetermined period of time. While exclusivity for a chemical entity lasts for 17 years before facing generic competition, there was no approval process for the generic equivalent of a biopharmaceutical. Once the product was approved, it had an unlimited period to generate exclusive revenues.

One problem that did exist, however, was the timeline to get additional capacity. If a company waited for an approval to begin building a new facility, they could potentially be unable to keep up with patient demand for the treatment and lose years of revenue until gaining licensure for the commercial capacity.

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Manufacturing

During this time there was very little excess bio-manufacturing capacity that could be contracted while completing a new facility. This led some companies that were in development or the clinical trial period for a promising new treatment to take a chance and start building one of these traditional facilities early to ensure that once a product gained approval, they would have ample production capabilities to meet the commercial market requirements. Unfortunately for some, their products did not survive in trials and they were left with capacity for a product that was not approved.

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Some companies benefitted from this new unused capacity. The companies with the facilities began offering to contract out the excess production and companies with approved products now had a place to manufacture until they could bring their own production on-line. Another factor that provided excess capacity was process improvement. Through improvement to equipment and controls, along with enhancements to the robustness of cell culture lines and feed strategies, the yield per batch was improving, providing product with higher titers .Finally, as biotech research expanded, more diseases

were targeted with smaller patient populations requiring less annual production.

There were a number of other factors that were influencing facility designs: • Schedule was no longer the only success driver for a project. With available capacity, a decision was needed regarding whether to build or contract, and a big part of that decision was the risk associated with capital commitment • With more products and less annual consumption, the single product facility model with low equipment utilisation was being challenged. To justify a large capital commitment, a facility needed

Manufacturing

the capability to manufacture multiple products, either simultaneously or through rapid change over • Both the reliability and availability of disposable components were improving. From some early 10 liter to 100 liter bags, the technology has grown to provide complete trains utilising 2000 liter single-use bioreactors straight through harvest, purification and final dosage filling.

• The model for product distribution was also changing. Instead of one central production plant there were drivers for replicating facilities in multiple global locations. Some of these drivers included:

o Governments requiring production in-country for country o Maintaining production even if issues arise in one location o Tax benefits in locations like Ireland and Singapore • With a pathway to biosimilars approved by regulators, the unlimited competition-free revenue stream for a product was threatened. The company that was losing patent protection needed the ability to retrofit space for a different product or new process platform. The biosimilar company would now need a streamlined project delivery to enter the market • Smaller batch sizes were a better fit for the single-use process trains while helping to mitigate risk from losing an expensive batch and minimising waste • Along with the new equipment came standard designs that, with a small amount of customisation, could satisfy most production requirements • With improvements to healthcare in emerging countries, these locations have become a target for expanding the market for these biopharmaceutical treatments. With little experience building these highly complex facilities, new project delivery methods for these locations were required.

Over time, these factors have led from the traditional large volume single product facilities to what is today referred to as the Facility of the Future or Production of the Future. Many companies, including architectural and engineering firms, original equipment manufacturers and consumable component providers are promoting facility designs that incorporate most or all of the characteristics listed above. The remainder of this article will focus on one such design. Pharmadule Morimatsu, which was introduced at the Biotech Concept Facility in 2012 and since then has been providing designs and project delivery services to many of the largest and most dynamic biopharmaceutical companies in the industry.

There were several characteristics that were drivers in the facility design: • Standard processing platform that could be customized based upon product requirements • Open selection of equipment and component-no sole sourcing • Fixed price for design, delivery, assembly and qualification • Delivery, from concept through qualification in 12 months • Operational in any global location • Expandable as market demand increases or production requirements change • Re-locatable if production was need at a different site.

The key to providing the level of flexibility required in today’s bioprocessing market is modularisation. By leveraging the quality and streamlined schedule derived from modular delivery, the Biotech Concept Facility, has succeeded in providing a low capital alternative for bringing production in-house. The use of facility modules maximises the adaptability to any local conditions. Entire functional modules can be added or removed based upon the availability of utilities, admin and warehouse space or the need for additional product expansion.

The standard facility includes the following functional areas: • Dispensary • Media prep, buffer prep, inoculum prep • Cell culture • Pre-viral purification • Post viral purification • Bulk filling While there are standard sizes for these areas, the equipment is chosen based upon the end-user preference and production requirements. During the design,

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Manufacturing

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als for clinical trials and easily be reconfigured to meet launch and commercial product demand. It has been designed to operate as a multi-product facility, either simultaneously utilizing two trains for two separate products or campaigning with quick change-over between product runs.

The facility flexibility extends beyond the process area itself. As described above, the modular facility can form an addition to an existing manufacturing building, utilising existing utilities, and other support services. The design, however, A u t h o r BIO

the equipment, both for the process and support systems and utilities, is specified and the layout is developed to be able to deliver everything in the Pharmadule facility modules. The modules are fabricated in a clean assembly environment and any non-portable equipment is installed in the final location within the facility.

This allows for Factory Acceptance Testing of an entire production plant to ensure proper operations before shipment to the project site.

The maximum use of disposable components has been an important factor in optimising the delivery time and capital cost. This has also helped to eliminate most of the expensive clean utilities use for CIP and SIP of stainless steel equipment. The standard is designed to operate using SUBs from 500 liter up to 2 trains at 2000 liters each. This provides a facility that can efficiently manufacture materi-

has been extended to include any utilities the process requires, both plant and clean utilities as well as QC labs, warehouse and administrative space. The design can also provide an aseptic suite for downstream final dosage filling. This provides a turnkey solution for biopharmaceutical production that can operate in any global location.

This modular biotech production facility has all of the features found in a conventionally constructed plant. It is a two-story structure with the lower level for process and the upper level used for any utilities and piping distribution. Total area would be just over 4300 square meters.

There are several aspects of the project delivery that are unique to the modular technology. Since a standard approach is used to fabricate and assemble the modules, there is a lower resource loading required of the end user.

Expansion is also different for a modular facility. In the case of this standard biotech design, the areas for expansion have already been integrated into the base facility design to ensure good unidirectional flows throughout the expanded facility as well as segregation as required. Expansion also takes place independent of the operation of the plant. Since modules are fabricated off-site, there is no interruption to on-going operations, so the product can be manufactured and distributed throughout the plant expansion.

There are many ways to produce biopharmaceutical treatments. While every process is unique and every end user has acceptable guidelines, there are certain standards that can be utilise to provide an off-the-shelf flexible facility that meets the requirements today and can grow to satisfy future demands.

Scott Kaplan is the Senior Director of Project Development for PharmaduleMorimatsu Inc. responsible for clients in North and South America. Supporting the Pharmaceutical Industry since mid-1980s, Scott has experience working with process equipment manufacturers as well as complete project integration including all phases of design, construction and start-up support. Scott began working with Pharmadule in 2004.

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45

Manufacturing

Modularisation in Biologics Manufacturing

Recent trends and developments The inherent risk in establishing Biopharmaceutical production (product, process, timeline, capacity, regulatory and location) can be significantly mitigated by using a modular and standardised approach. Utilising a combination of standardisation, modularisation and use of modern process solutions such as single use equipment offers significant advantages over traditional design and construction.

Jan Lilja, Director, Commercial Management, KeyPlants AB, Sweden AsaGaasvik, Sr Design Engineer, KeyPlants AB, Sweden ParAlmhem, ModWave LLC, US

D

esign, construction and installation of complete modular production facilities for pharmaceuticals and biopharmaceuticals have in recent years been widely accepted.

According to Gilroy and Martini ‘modular construction’ of a pharmaceutical manufacturing facility refers to construction of all or part of a new or renovated facility built at a remote location, transported to the owner´s address and re-assembled on site. Modules consist of structural frames that are fit out with all mechanical, electrical and plumbing architectural elements – complete with all fixed process equipment. Modularisation considerably increases productivity, which is probably one of the most unpredictable aspects of a construction project. Besides bad weather conditions, conventional on-site construction labour productivity is plagued by high turn-over, changes, inexperienced contractor´s workers, and the challenges of working out of position. In a modular facility project typically over 80per cent of all installations are performed and qualified in the supplier’s workshop instead leaving 20per cent or lest to be performed in the field.

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The pioneer in the construction of modular pharmaceutical facilities was Pharmadule AB, a Swedish company that is out of business since February 2011. Companies that offer modular facility construction include Biologics Modular, G-Con, Jacobs Engineering and Key Plants. Some traditional bioprocess equipment suppliers, e.g.

GE Healthcare Life Sciences, Sartorius Stedim Biotech and Merck Millipore have begun to offer fully equipped modules for specific process steps.

Key Plants has developed an innovative approach to modular facility design and construction that is flexible, and cost efficient, while allowing for use of process equipment from any supplier. This design provides greater flexibility in the layout and design of both upstream and downstream process areas. Modules can be installed and operated within an existing building or as a separate modular building as long as a suitable power source is available.

Current trends Market developments are increasing the demand for modular solutions, at the same time as technical advancements in pharmaceutical and biopharmaceutical processing are making modular alternatives even more feasible. These market and technical trends include (but are not limited to): • Increasing pressure to significantly reduce the time and cost to build manufacturing capacity– “How can we build in half the time, at half the cost, without compromising quality?”

• Needs/demands for local production in many markets that previously did not have this capacity or the necessary competences to build and sustain it • Increased capabilities and use of single use technologies in biopharmaceutical production – for drug substance as well as for formulation and filling • Developments in processes for OSD manufacturing, including continuous processing.

Manufacturing

Introduction to the new generation facilities

In a recent discussion on next-generation manufacturing facilities, an author argued that bio-manufacturing facilities can be divided into process, facility, and infrastructure components. Each plays a significant role in the success of a manufacturing enterprise. A failure or weakness in either will lead to poor product quality and/or inefficient manufacturing.

Improvements in manufacturing technologies and advancements in single use systems have clearly transformed bioprocesses. Hand-in-hand with those process improvements comes modular construction, which will become more and more common because modular alternatives can have smaller footprints than traditional facilities and be deployed rapidly in locations where clean-room and piping expertise may not be readily available.

Combined, modular technology and single-use technologies can reduce investment and operating costs, as well as the financial risk of building new biopharmaceutical manufacturing facilities.

Smaller, greener and more flexible facilities of the future that look to new technology solutions may also enable a key industry transition from fixed to variable cost structures to structures that follow demand. Defining and understanding the business drivers, uncertainties, and risks associated with building and operating bio-manufacturing facilities is a key first step in the development of future generation manufacturing facilities.

Success of future facility design must be measured in terms of utilisation, flexibility, and efficiency while providing a platform that supports and facilitates the operational excellence required to reliably produce high quality product, while meeting an ever-evolving set of regulatory compliance guidance. As the industry looks to make the transition from current state to the future model, new enabling technologies can provide manufacturing platforms that meet the

goals of being flexible with low capital unit operations changeovers, efficient movement to new markets, and a scaleout approach with smaller increments of capacity from highly productive processes to meet lower demand markets.

Operational excellence is the fundamental driver for producing high quality product and efficiently meeting all necessary regulatory requirements. The following questions could be the starting point for identifying the best facility options to satisfy product quality, operational excellence and regulatory compliance: • Does the facility provide an optimum environment (not to small not too large) to execute the process steps • Based on the manufacturing requirements, does the facility incorporate and support optimal segregation strategies for separating the products and processes manufactured in the facility • Does the facility design facilitate the use of existing and future advanced process control technologies • Is the process train designed for reliable operation given the operational design basis • Does the facility meet current as well as likely future technology challenges in the Quality Target Product Profile

established and thus will it be able to meet future regulatory expectations • How can the impact of uncertainties and risks be minimised?

In order to answer these questions, a novel design platform was developed for biologics production. Several criteria were identified as essential in order to come up with the right answers, such as a modular design, utilisation of singleuse equipment, build on a well-known bio-process, and risk-based level of segregation.

A flexible layout is of importance especially for sites working with combinations of products, product classes, and host-cell types. The important issue is how we can combine single-use and stainless steel technologies to provide the most productive, cost-effective and regulatory risk-optimised process in a faster and more predictable way.

Basis for a standard design platform

The standardised drug substance manufacturing suite´s configurable modules have adequate space based on a MAb process on the basis of a CHO cell line and bioreactor train 1x 50 litre – 1x 200 litre – 1x 1000 litre, The downstream process consists of preparation of equipment, buffer preparation of

A platform layout was developed utilising six functional modules

Figure 1 Standard Platform Functional modules: material staging and dispensing, media and buffer preparation and storage, and upstream and downstream processing, along with sufficient space for all support functions and appropriate airlocks and corridors.

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Manufacturing

Risk acceptance profile buffer solutions, tangential filtration and concentration of the uterine culture fluid, and subsequent depth filtration of the concentrate, affinity chromatography, cation-exchange chromatography, anion exchange chromatography, concentrating tangential diafiltration and viral inactivation of the concentrated MAb obtaining the active pharmaceutical ingredient (API),formulation and sterile filtration of the API followed byaseptic filling in vials.

The estimated productivity of the cell line 4-6 g MAb from 1 liter of culture.

The total loss initially estimated in the upstream and downstream process is 70 per cent. The API has a concentration of monoclonal antibody (MAb) 10 mg / mL, titer concentration 5g. Annual output from 80 kg Mab, annual output approximately 50 batches(300 working days, batch duration 18 days including change-over time), 16,000 vials per batch, filled in 10 ml vials (100 mg/vial).Filled during three shifts.

The utilisation of single-use equipment is optimised for the process. This can be adjusted to the end user’s needs, and the level of stain less steel equipment increased to meet each application.

The standard facility is equipped with single use seed and production bioreactors. In addition all media and buffers were prepared using single use systems consisting of powder transfer bags, disposable bags with a disposable internal agitator, external mixing system, weighing station, and a disposable path (pump, tubing, filters, etc.) for transfer of the prepared media or buffer into a disposable bag system for storage. When necessary, buffers are prepared in concentrated solutions to accommodate the transport in disposable bags at a maximum volume of 500 L, which is a typical volume limitation for transport within the facility. In-line dilution skids were utilised at point of use for the concentrated buffers. Media is prepared at the start of each production batch. Similarly, buffers are prepared in advance and stored within the facility until used. A new batch of media or

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Figure 2

buffer is prepared for each production batch. For each of the chromatography steps included in the purification process, 630 mm diameter columns packed to 200 mm bed heights are used, with each column being used for multiple cycles per batch. For the Protein A affinity column, five cycles per batch is required.

For the cation exchange column, three cycles per batch is used and for the anion exchange column, two cycles per batch is assumed. CIP/SIP for column packing is included.

Important to consider is the level of segregation based on regulatory requirements, product, closed/contained processing steps and user corporate standards.

Starting from an open design, it is possible to increase the segregation level by adding walls and airlocks, e.g. to divide cultivation and initial purification areas into two rooms. Also the media and buffer preparation and hold works in the same way. In order to choose the appropriate level for a certain product/ multi-product facility and the risk for cross-contamination or contamination from adventitious agents is to use a riskbased approach. Rios makes the same conclusion at a recent conference “One well-recognised challenge in multiproduct facilities is minimising or eliminating cross contamination. For that, industry and regulatory experts have advised

manufacturers to take a risk-based approach. Such strategy can prove beneficial in flexible layouts in sites working with combinations of products, product classes, and host-cell types.”.

To further ensure segregation within the facility, the design includes multiple air handlers located on an upper level. The level of segregation is based on a risk assessment and includes the following: • Separate air handling zones • Segregated pre- and post viral processing • Closed process where possible (grade D) • Live organism containing areas separated from other areas • Open processing areas (seed lab, final purification and bulk filling) separate and in grade C (also with bio-safety cabinets) • Increased segregation in cell cultivation and purification areas possible with easy to erect clean-room panels according to product and risk (BSL, cross-contamination etc.).

ICH Q9 II.4: QRM for facilities, equipment and utilities recommend the use of a Risk Acceptance Profile (Figure 2). EMA 5.19 EU GMP Guide states that cross contamination should be avoided by appropriate technical or organisational measures.

Manufacturing

Modular Bio Solutions,MAb Facility Standard Modular Bio Solution

Figure 3

In addition, separate processing areas are provided for downstream processing operations pre- and post-virus removal by nan-ofiltration. Wherever possible, fully closed and contained processing is used, generally within a Grade D environmental classification. Open processing areas, such as those required for innoculum preparation, final purification, and bulk filling are designed to be Grade C with specific open operations being performed in suitable bio-safety cabinets with laminar air flow.

The facility also includes suitable staging areas for raw materials, consumables, and equipment and appropriate locker rooms and airlocks for personnel changing and entry and exit from the facility. Media and buffer preparation areas are located in the centre of the facility to allow the most possible adjacencies to processing areas. Wherever possible, buffers are stored in closed containers in controlled but unclassified space to minimise the environmental burden and lower the overall HVAC requirements for the facility. The result of the design of the layout within the product processing area is a general U-shape design for the product flow being unidirectional from one end of the facility to the other. The facility includes a thorough and optimised equipment positioning in order to minimise the tubing or piping needed for product and material transfer.The tubing components are delivered gamma irradiated and can be connected by tube welding. The layout has one single access point for all production personnel and

one exit point. Included in the bulk drug substance area are also functionality such as Storages for raw material, consumables and equipment. The buffer and media preparation is centralised in order to minimise the adjacencies between the media hold bags and the process equipment respectively. In order to maximise the ease of transporting the different bags the largest hold bag is 500L. There is also included an in-line dilution skid for the buffer preparation for the Protein A Chromatography step to even further reduce the amounts of buffer that needs to be prepared and stored. In the Grade C area for Final Purification, an Aseptic Filling (Crystal® closed, pre-sterilised vial technology) L1 Robot Line has been placed, to meet a filling capacity of up to 600 vials/hour. Typical batch size around 5,000 vials, on a single shift basis.

The standard MAb manufacturing facility (Figure 3) has a total floor area of 1208 m2, including the mechanical space on the second floor.With the 1,000 liter bioreactor train, the process area is less than 740m2.The time schedule to build the facility is less than 12 months for the standard layout. The price for the ‘plug-and-play’ two storey facility described is estimated to be well in line with conventional clean-room installation. The facility may be connected to an existing building as well as being used in an indoor concept and built in an already existing building or a rapidly constructed shell.

In-door modules (Figure4) can be placed on a concrete slab in a building with pipe-racks and connections installed under, over or parallel to the modular process facility. HVAC and utility systems (mechanical areas) can be placed over or next to the modular building. An outdoor(Figure 5) modular building can be placed on foundation of concrete-pillars, a slab or on top of basement or building.

The main difference is the façade/roof system for the out-door building, which is insulated and weather proofed.

Clean-rooms are constructed utilising an integrated panel system for walls, ceilings, doors, windows etc. Walkable ceilings create mezzanine space with

In-door facility

Figure 4

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Manufacturing

Out-door facility

Figure 5

The modular cost advantage–time is money

One key advantage of modular construction for biopharmaceutical facilities is the off-site construction of modules.

The benefits of this approach include enhanced quality control, reduced waste, reduced impact on current operations, and simplified site logistics. Transferring labour hours away from the construction site also reduces risk and overall cost for a facility construction project. Building multiple modular elements in parallel without,for example, weather impact, can

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reduce the construction schedule for a facility project by 50per cent. The ability to leverage factory acceptance testing (FAT) at a module construction facility will often significantly shorten the time for start-up and commissioning of a new facility. Once modules are delivered to the construction site, they are assembled into the complete facility so that final testing and qualification can be completed.

Jamesonhas discussed in detail the cost benefits of the Modular Facility Technology. Comparisons of project cost components were discussed to help potential users of this technology gain

Jan Lilja has over 28 years experience from Management in Lifescience companies in Europe/Asia/USA. Established Life-Science companies in 10 countries including 6 Asian J/Vs. Lilja has 10 years experience in Pharmadule (modular project execution turn-key) as Director responsible for biotech &pharma sales in Pharmerging Markets and previously Asia, strategic business planning, feasibility studies for pharma/med-tech start-ups, multinational strategic analysis and project co-ordination.

A u t h o r BIO

service access above the clean-rooms for AHUs and other utilities such as piping, electrical and ductwork distribution. It may also be used for electrical rooms and clean utility generation. Support systems (electrical, piping, HVAC, etc.) will have the main distribution in the mezzanine. Each pre-fabricated module will have distribution integrated in the module with only one hook up point for the support systems. This will create minimal hook-up installation and each module will work as a plug and play unit.

Utilities have access points into process rooms either with ceiling panels lowered into the process room or integrated wall panels. Other systems included aredata communication – ethernet, grounding system, telecommunication, security system, air lock interlocks, fire alarm, etc. Sprinklers and alarm systems are installed according to local codes and requirements. Functional modules can be designed to incorporate any kind of process with automation as an integrated solution.

a better understanding of cost allocations and expected differences between a modular approach and a conventionally executed project. While this example indicated an initial 9per cent cost premium for the modular concept at the conceptual design phase, the risks involved with a conceptual design were quantified, which in turn shows that the modular approach is actually in the range of5per cent more cost effective. This comparison does not include consideration for the potential loss of sales revenue due to delays in market launch (every day of lost sales revenue will be substantial considering a per dose price of certain MAb products of around US$ 1,000).

With the new standardized modular concepts, also the first cost of a modular alternative is typically competitive to conventional design and construction.

Adding the lower risk in the project, and the shorter time to market, a modular project many times offers a significantly higher Net Present Value.

References are available at www.pharmafocusasia.com

Asa has over seventeen (17) years’ of experience working for the pharmaceutical and processindustry. She has focused on studies and projects involving process design, capacity planning, building design, site planning, estimating etc. Åsa possesses deep knowledge in process design in different processes for both pharmaceutical and process industry regarding various substances including containment and hazardous substances. Åsa also presents twelve (12) years of experience working with layouts for both conventional and modular facilities to accommodate good material and personal flow in process GMP facilities including SVP, OSD, API etc,.

ParAlmhem is the President of ModWave LLC, a solutions provider to the Pharmaceutical, Biopharmaceutical, Food and Process Industries, and of ModularPartners, a leading supplier of modular solutions to the Life Science Industries.Prior to his current engagements, Mr.Almhem was President of Pharmadule, Inc., the U.S. entity of Pharmadule AB of Sweden who was the pioneer supplier of high-techmodular production facilities to the Pharmaceutical and Biotech industries.

Almhem holds a Master of Science Degree in Applied Physics and Electrical Engineering from Linköping University, Sweden.

Nanomilling for Pharmaceutical APIs

The NETZSCH DELTAVITA® Mill Raj Mukherjee, NETZSCH Premier Technologies, LLC., Exton, PA/USA

More than 90 per cent of drugs approved since 1995 have poor solubility, poor permeability, or both. Drug performance can be improved by reducing the particle size and at the same time increasing the specific surface area of the Active Pharmaceutical Ingredients (API). Therefore, however an API is administered – in tablet, capsule, powder, or liquid form – small particle sizes offer exciting advantages for pharmaceuticals. Known benefits include improved dissolution rate, increased bioavailability and higher activity, leading to lower dosages and a lower risk of side effects for the patient. Reducing drug particles to nano-size increases their surface area, and subsequent solubility dramatically.

The NETZSCH DELTAVITA® mill has been specially designed to efficiently increase solubility

of APIs, thereby enhancing their efficacy. Through the efficient use of energy, high flow-rate, multiplepass grinding strategy, DELTAVITA® mills achieve excellent repeatability as well as homogeneous dispersion. DELTAVITA® mills are fast, extremely versatile and designed to produce a very narrow range of ultra fine particles in a homogeneous formulation. Specific energy reductions of up to 30 per cent can be realised.

With the DELTAVITA®, users can achieve consistent particle size distributions below 100 nanometers to increase surface area, solubility, and bioavailability. Nanometer-scale particles provide many advantages. Gene and vaccine delivery becomes more targeted, as well as the development of particles which cross the blood brain barrier. Nanoparticles can enhance the properties of time release molecules, and nanoreceptors can be added to drug surfaces to release drugs exactly where needed.

As for different models, the DELTAVITA® 15-300 is designed with growth and flexibility in mind with several available and interchangeable chamber sizes in stainless steel and ceramic construction. The laboratory series sizes range from 15 to 300 ml chamber volumes. The pilot series is the DELTAVITA® 600 which offers 600 ml chamber volume. In the production series, NETZSCH offers models from 2,000 to 60,000 ml. DELTAVITA® systems are available in portable and permanently mounted-through-wall installations. Each machine is designed specifically for your process requirements.

Advertorial www.pharmafocusasia.com

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BioAsia

Innovation to drive the agenda from Feb 17, 2014 Innovations are the need of the hour across the world as today's innovations hold a promise of better tomorrow. The world today is demanding cutting-edge innovations in Life sciences that promise to push boundaries as Bio-business holds immense opportunities.

With the increasing disease burden, growing need for more efficient and affordable healthcare solutions, innovation holds the key and will drive the global life sciences economy in the coming years. The 11th edition of the unparalleled industry platform, the BioAsia will open with this most cogent theme – ‘Innovate.

Evolve’ and will bring together the global leaders to deliberate on the path breaking innovations in the sector, not just in terms of the innovative products but also the models to cut down R&D cost while increasing efficiencies, innovative financing models, and offer excellent opportunity for new business ideas.

Global innovation landscape: In any advanced economy - economic growth is inextricably linked to the capability for innovation. It has been established that low labour costs alone cannot sustain economic growth in a country, and there is a need for continual evolvement to sustain growth.

Exploitation of enabling technologies, convergence among core technologies, and R&D funding and incentivizing are propellers that will shape the innovation landscape globally.

The innovation landscape in Life Sciences has been marked by the emergence of clusters.

Geographically close groups of allied companies and associated institutions in a particular field, connected by common technologies and skills comprise ‘Clusters of innovation’. These are known to harness innovation by facilitating active exchange of ideas and capability amongst various stakeholders – companies, academia, research institutes and governments.

These clusters further promote collaboration and enable companies to capitalise on external R&D. Leveraging technology and analytics is another

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important component of innovation. Adoption of innovative approaches in R&D, including modeling, simulation and other statistical analysis tools is a key to progressive set-up. MNCs are increasingly investing in tools and conceptsthat simplify challenges that arise on a daily basis in R&D set-ups – to ensure coordination and harness innovation.

India–where are we?

The Indian growth story in the Life Sciences space has been remarkable with pharmaceuticals expected to reach an estimated US$54 billion by 2020. Inspite of varied challenges that MNCs have encountered like the DPCO, 2013 which seeks to reduce the price of 348 drugs and a series of patent and data exclusivity rulings in the favour of compulsory licensing, the industry has managed to witness a continual growth trajectory. Fuelled primarily by exports and the generic industry – pharmaceuticals in India has seen positive growth both in terms of value and volume.

However the lure of the Para-IV landscape will decline in all probability coupled with the reduction in the number of mega patent expiries – eventually diminishing the generic opportunity. Indian companies therefore must build innovative strategies to combat the lack of exclusive opportunities and build a sustainable business model.

Indian companies will need to target focused R&D in the field to emerge as an innovation hub.Innovating with product portfolios is being witnessed increasingly in the Indian context. There has been a gradual trend of companies targeting their energy towards niche segments and products with higher level of complexity and technology. Companies are also exploring biosimilars.

India currently holds 3 per cent of the global market after China and South Korea in the biosimilars segment. The global opportunity in the area is estimated at US$5 billion by 2015. Indian companies should look at further building capabilities in

Building a science-business bridge: In order to enable a Science-Business Bridge, BioAsia 2014 will bring together a trans-disciplinary environment for driving innovation in life science industry through a new initiative – Technology Conferences.

With the aim of sowing the seeds for leveraging technology trends for business relationships, the platform will help channelize the technology in the development relay across the world through co-development opportunities. The event will focus on helping the innovators / scientists building capabilities to break the ‘Resistors’ in the product development cycle for

BioAsia 2014 Attractions

this domain. Innovation also encompasses widening scope of therapeutic areas and looking to address emerging needs. Areas such a sports medicine, geriatric medicines, neutraceuticalsetc are all boons of an increasingly aware populace whose demand needs to be met.

Another very important facet as India emerges as an innovation hub is drug delivery systems. Focus on delivery system-based products may emerge is an important area of growth.

Innovation is largely driven and incentivised by investments and funding. Globally – there is ample evidence of MNCs investing in new high value research platforms and delivery systems. Some of the Fortune 500 pharma companies have floated internal VC wings to invest in these areas - Merck Ventures and Novartis Venture Fund are key examples of such ventures. Indian companies could look at replicating this model to upgrade their research output.

In a nutshell, the focus of the BioAsia 2014 would be to establish the importance and means to achieve sustainability by capitalising on innovation. The sessions would focus on identifying key areas of growth and how innovation could reshape the existing landscape to make India an innovation hub.Over the ten editions, BioAsia has built up a formidable reputation for bringing together the entire universe of lifesciences face-to-face to discuss, analyse, showcase, explore and connect strengths, trends and perspectives in order to extendthe visible horizons in thought, possibility and innovation. However, merely understanding the challenge from a global perspective and through global participation is not the goal of this dynamic platform. To that end, it is both incisive and all invasive, inviting the participation of who's who of this industry, be it countries, pharmaceutical giants, regulatory authorities, thought-leaders, research scholars, trade experts and every other stakeholder of this industry.

1500+ Participants 1000+ Business Meetings 650+ Corporates 60+ Global Thought Leaders 3 Day Networking Conference 1 agenda INNOVATE. EVOLVE

smooth flow of technology and collaborations.

Focus of the technology conferences will be on key growth areas for India and perhaps Asia, including the Medical Electronics and Devices, Bio-Energy, Bio-Informatics, Regenerative Medicine, Bio-Therapeutics, Drug Discovery and Personalized Medicine. While the technology conferences at BioAsia has been structured to focus on the R&D Value Chain approach, the sessions will focus on New Platform Technologies for cross leveraging, Relay Linked opportunities in development and application oriented content tuning.

Mr. Shakthi Nagappan, CEO, BioAsia said, “BioAsia has always been about coming together to discuss the most relevant and futuristic trends around Lifesciences. Exclusive and interesting topics pertaining to the need of the changing times have been discussed at this forum in the past. This year BioAsia takes another leap by bringing Innovation at the center stage of discussion”.

Life Science is an innovation intense industry.

Traditionally, the Indian perhaps Asian life sciences businesses are centered around existing / established markets for their clearly defined products or services leaving very little space for experimentation, which to a great extent can be attributed to low risk appetite investor climate. However, the situation is changing and there is an increasing awareness that innovation is essential for sustenance and growth, even within established businesses. Hence, we are confident that the global business leaders, with demonstrated innovative capabilities coming together at BioAsia 2014 will add significant impetus to the India’s innovation path” “BioAsia is playing an important role in mobilizing investments into the biotechnology arena of the country. It has emerged as a prominent platform for facilitating investments, exploring technology opportunities as well as research and innovations for the sector. Dept of Biotechnology is extremely happy to support this global event that has culminated into more wholisticdiscussion, debate and decision-making giving the much needed momentum to the growth of the biotech industry” Mr. SreeshanRaghavan, Joint Secretary, Department of Biotechnology, Government of India Advertorial www.pharmafocusasia.com

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BOOKS

Pharmaceutical Outsourcing: Discovery and Preclinical Services Authors: George Karam, Bo Parfet, Jeffery Smith, Stacy Pritt, Harris Brotman, Robin Allgren, Gerald Yakatan, William Avrin, Oliver Klotzsche, Jayashree Srinivasan, R. Stephen Porter Anu Acharya, and Christopher Peterson Kevin Lustig Year of Publishing: 2011 No. of Pages: 276 Description: Pharmaceutical Outsourcing: Discovery and Preclinical Services is the first in a series on pharmaceutical outsourcing. This first book is written for all practitioners in the pharmaceutical and biotech world and is about managing projects in drug discovery and preclinical development. The purpose envisioned by the authors and editors is to provide an understanding of how outsourcing works from the perspective of sponsor, internal customer, service provider, outsourcing service marketplace, principal investigator, project leader, and consultant. The authors of this book and the companies they represent hail from the Americas, Europe, Asia, and Australia, underscoring the fact that drug discovery is an international effort.

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Creating a Lean R&D System: Lean Principles and Approaches for Pharmaceutical and Research-Based Organizations

Drugs for Life: How Pharmaceutical Companies Define Our Health

Author: Terence M Barnhart

No. of Pages: 280

Year of Publishing: 2012

Description: In Drugs for Life, Joseph Dumit considers how our burgeoning consumption of medicine and cost of healthcare not only came to be, but also came to be taken for granted.

For several years, Dumit attended pharmaceutical industry conferences; spoke with marketers, researchers, doctors, and patients; and surveyed the industry's literature regarding strategies to expand markets for prescription drugs. He concluded that underlying the continual growth in medications, disease categories, costs, and insecurity is a relatively new perception of ourselves as inherently ill and in need of chronic treatment.

Drugs for Life challenges our understanding of health, risks, facts, and clinical trials, the very concepts used by pharmaceutical companies to grow markets to the point where almost no one can imagine a life without prescription drugs.

No. of Pages: 267 Description: Creating a Lean R&D System: Lean Principles and Approaches for Pharmaceutical and Research-Based Organizations lays out the logic of why Lean implementation isn’t strictly for manufacturing and describes why it can be just as effective in R&D organizations. Terence Barnhart, former senior director of continuous improvement at Pfizer R&D, describes the theoretical and physical underpinnings of creating a Lean transformation in any R&D organization, as exemplified by the Lean transformation initiated within the R&D division of a global pharmaceutical company.

Author: Joseph Dumit Year of Publishing: 2012

Pharma's Prescription: How the Right Technology Can Save the Pharmaceutical Business

Therapeutic antibody engineering: Current and future advances driving the strongest growth area in the pharmaceutical industry

No. of Pages: 224 Description: The pharmaceutical industry needs a shot in the arm – and not a moment too soon. The executive suite is mired in a bygone era, a time when extensive, wellfunded pharmaceutical R&D produced blockbuster drugs, kept everything in-house and reaped the financial rewards. But that way of working needs to change. Executives now need to know what the technologists in their companies are doing in order to survive the next decade. Written for those new to industry, as well as for experienced professionals or specialists looking to expand their knowledge, this book is a mustread for business executives and information technologists alike.

Pharma’s Prescription bridges the knowledge gap between current business practices and the most valuable technologies today. This book is filled with practical, reallife examples from industry and is a straightforward guide for all pharmaceutical and information technology executives who need to improve their businesses.

Authors: Brian Smith Year of Publishing: 2011 No. of Pages: 212

Author: Kamal Biswas Year of Publishing: 2013

The Future of Pharma

Authors: William Strohl, Lila Strohl Year of Publishing: 2012 No. of Pages: 696 Description: The field of antibody engineering has become a vital and integral part of making new, improved next generation therapeutic monoclonal antibodies, of which there are currently more than 300 in clinical trials across several therapeutic areas.

This book examines all aspects of engineering monoclonal antibodies to make them more competitive and looks at ways that the various genetic engineering approaches will affect candidates of the future. The authors go beyond the standard engineering issues (ADCC, CDC, half life engineering, etc.) that are covered by most books and delve into structure function relationships that will help to evolve new antibody structures beyond those already in clinical trials.

Chapters discuss how current and future genetic engineering of cell lines will pave the way for much higher productivity, allowing for an overall decrease in cost of goods.

Description: "The Future of Pharma" examines the causes of the industry's potential decline and offers a convincing and rigorous analysis of the options open to it. What emerges is a landscape defined, on the one hand, by the changing marketplace of mass-market consumers, institutional healthcare systems and wealthy individuals; and on the other by the alternate sources of commercial value - innovative therapies; superefficient processes, supply chains and operations; and closer customer relations and increasingly tailored health services. The challenges to the pharmaceutical industry now and in the medium and long-term are very significant. Brian Smith's highly readable research findings are a wake up call and a first-step forward for anyone concerned with the future of the industry; whether executive, customer, policymaker or investor.

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Products&Services

Company........................................................ Page No. STRATEGY Bio-Asia.........................................................21, 52 & 53 India Lab Expo............................................................ 15 Priorclave Limited....................................................... 33 UBM India Pvt Ltd....................................................... 07 UPS............................................................................IFC RESEARCH & DEVELOPMENT INC Research.......................................................... OBC MANUFACTURING BOSCH...................................................................... IBC Fluid-Bag..................................................................... 09 NETZSCH.............................................................. 03, 51

SuppliersGuide

Priorclave Limited....................................................... 33

Company........................................................ Page No. Bio-Asia..........................................................21, 52 & 53 www.bioasia.in BOSCH....................................................................... IBC www.boschpackaging.com Fluid-Bag...................................................................... 09 www.fluid-bag.com INC Rearch................................................................OBC www.incresearch.com India Lab Expo............................................................. 15 www.indialabexpo.com NETZSCH............................................................... 03, 51 www.netzsch.com Priorclave Limited.........................................................33 www.priorclave.co.uk

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link.

1.IFC: Inside Front Cover 2.IBC: Inside Back Cove 3.OBC: Outside Back Cover

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UBM India Pvt Ltd........................................................ 07 www.cphi-india.com UPS.............................................................................IFC www.ups.com

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schwarzspringer

Processed and packaged as promised. Bosch.

Processing equipment and packaging machinery from Bosch achieve the agreed performance. Day after day. Year after year. GMP-compliant systems ensure the required pharmaceutical product quality. Simple validation, cleaning and sterilization processes and low maintenance requirements increase production efficiency. Experienced employees with extensive know-how guarantee professional service worldwide. Learn more at www.boschpackaging.com

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am caring

It’s not always easy to put patients at ease, so I try to really take an interest in their point of view, their concerns, letting them know I’m there for them.

As a site investigator I like having that same level of support from my CRO. Because sometimes I need to know there’s someone there for me too.

am INC Research

iam.incresearch.com

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