Pharma Focus Asia - Issue 03

Marketing Strategy

RFID

Biopharma

Nanotechnology

Microsoft’s Digital Pharma

Issue 3 2006 £5.95 €8.00 $8.95 www.pharmafocusasia.com

Clinical Trials

Market in Japan Regulatory changes and the acceptance of foreign clinical data have fuelled growth of the clinical trial sector in Japan.

Lim Bee Koong Director Life Sciences – Clinical TNT Asia

Published by

In association with

R&D

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Manufacturing

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Lab Technology

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Foreword

T

he global pharmaceutical industry today is severely affected by a combination of adverse factors — fast depleting new drugs in the pipeline, mounting costs of developing new drugs, patent expiries of many a blockbuster of yesteryears, intense competition from generics, threat of counterfeits etc.

The tale of its woes is indeed endless. The Asian pharmaceutical industry, however, is a silver lining to this gloomy scenario.

The Asian pharmaceutical industry presents a two-fold opportunity to the troubled world of the global pharmaceutical industry. Increasingly prosperous Asian economies, with their billions of population, represent a huge untapped potential market for medicines. The Asian region has also emerged as a low-cost

Costa Rican National Chamber of Generic Products provides interesting tips on negotiating IPRs with the United States Trade Representative.

Mergers, partnerships and alliances with biotechs is the order of the day in the global pharmaceutical industry today. The R&D spotlight presents insights into the unfolding biopharmaceutical scenario with views from the industry’s thought leaders such as, Kiran Mazumdar-Shaw of Biocon, John Wong of Boston Consulting Group, Heather E Fraser of IBM and Prof. F M Scherer of Harvard University and Tom Newton of Visiongain.

Microsoft’s Rüediger Dorn presents how the software giant’s Digital Pharma Initiative can be strategically deployed to combat a multitude of adverse factors affecting the pharma industry today with the help of IT. Géraldine Andrieux, et al of Yole illustrate the role of Micro and Nanotechnologies in pharma. Bayer’s Martin Gerlach, et al explain how BaychroMAT represents an advancement over existing online analytical measurement platforms. Michael E. Swartz of Waters Corporation discusses how UPLC ensures increase in speed, resolution and sensitivity predicted for liquid chromatography. Avani F. Amin et al of Nirma University of Science & Technology describe how superdisintegrants are an economical alternative in the ODT segment.

The Asian pharmaceutical industry presents a two-fold opportunity to the troubled world of the global pharma industry. destination for outsourcing R&D and clinical trials, reducing the cost burden for the Big Pharma.

The cover story by Lim Bee Koong, Director, Life Sciences – Clinical, TNT Asia, analyses the huge opportunity in Japan’s clinical trials market, unleashed by recent reforms by the government. Nicholas P. Zemo, Accelovance discusses how small pharma can also benefit from the emerging market in China. Novo Nordisk’s Baoping Wang and Esper Boel share lessons learned by their company in setting up their R&D arm in China. Roche’s Lee E. Babiss distills insights into outsourcing preclinical as well as clinical R&D to China.

Meaghan Lynch of IMS, Australia, discusses how pharmacoeconomics, hitherto perceived as a hurdle can be turned into an effective marketing tool by developing patient-centric models that can be used to demonstrate the value of expensive drugs to physicians as well as patients. Ogilvy’s Joanne Fensome presents incisive analysis of the Asia Pacific market and marketing strategies to deal with it. Shailesh Gadre of ACNielsen ORG IMS profiles the behavior of the Asian consumer to help pharma marketers understand the change. Roman Macaya of

Praful R Naik of Bilcare Limited, emphasizes the need for innovations in the pharmaceutical packaging niche. Peter Harrop of IDTechEx provides an Asian perspective to the use of RFID technology in the pharmaceutical industry.

Rajeshwer Chigullapalli Chief Editor

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Contents Cover Story Growth in

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Japanese Clinical Trials

Case Study Challenges for R&D success in China Novo Nordisk’s experience

14

Baoping Wang, Research Director, Novo Nordisk (China) R&D Centre, China, Esper Boel, Vice President and Head of Biotechnology, Novo Nordisk R&D, Denmark

Outsourcing

Market

Outsourcing Preclinical and Clinical R&D to China

22

Regulatory changes and the acceptance of foreign clinical data have fuelled growth of the clinical trial sector in Japan.

Lee E. Babiss, Vice President, Preclinical Research and Development, Roche

Lim Bee Koong, Director, Life Sciences – Clinical, TNT Asia

IPRs Negotiating with the USTR

Regulatory Environment 19

Roman Macaya, Executive Director, Costa Rican National Chamber of Generic Products

Research & Development

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Clinical Trials China 43 Clinical Trial Strategies for Small Pharma

HeraldingaNewEra

Nicholas P. Zemo, Vice President, Business Development & Sales, Accelovance, Inc.

Biopharma convergence seems to be the panacea for pharma companies struggling with weak R&D productivity and biotech firms facing funding shortfalls.

Strategy Pharmaceutical Marketing Strategies for Asia Pacific

Biopharma Convergence

08

Feroz Zaheer and Rajeshwer Chigullapalli

Joanne Fensome, Regional Director of Healthcare, Asia Pacific, Ogilvy Public Relations Wordwide

Pharmacoeconomics Introducingpatient-centredmodels Patient-centred modelling and pharmacoeconomics can provide an innovative way to market drugs and penetrate barriers to access in both government-funded and private pay healthcare systems.

10

Manufacturing & Processing BaychroMAT® CellCount 27 A Platform for Online Analytical Measurements Martin Gerlach, Stefan Steigmiller, Hans Tups, Bayer Technology Services GmbH

Micro and Nanotechnologies From R&D to Drug Delivery Micro and nanotechnologies will have a high impact on the pharmaceutical industry making the way to personalised therapy for better treatment efficiency and fewer side effects.

Meaghan Lynch, Senior Economist, Health Economics and Outcomes Research, IMS Health, Australia

Understanding the Psyche of Asian Pharma21

Consumers Shailesh Gadre, Managing Director, ACNielsen ORG IMS

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Géraldine Andrieux, Clémence Labat, Barbara Pieters, Jean-Christophe Eloy, YOLE Développement

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Laboratory Technology & Equipment UltraPerformanceLiquid Chromatography(UPLC™)

Issue 3

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2006

Chief Editor Rajeshwer Chigullapalli

Pharma Editorial Team Feroz Zaheer, Ramya Narasimhan

Copy Editors Srinivas G Roopi Sreenivasa Rao Dasari

UPLC presents the possibility to extend and expand the utility of conventional HPLC, a widely used separation science.

Art Director M A Hannan

Design Narsingoji Raju

Project Coordinators Nathan Jones Suresh P

Michael E. Swartz, Principal Scientist, Waters Corporation

Chemicals & Raw materials 47

Superdisintegrants An economical alternative

Project Associates

Mark Spencer Sushanth G Harry Parker Hussain Khan Roma Chaudhuri

Circulation Manager S V Nageswara Rao

Circulation Executives Gagan Kumar Vallabhaneni Kevin Smith Kranti Kalidindi Managing Director Vijay Chintamaneni

Avani F. Amin, Tejal J. Shah, Reena Dua and Renuka Mishra

Department of Pharmaceutics, Institute of Pharmacy, Nirma University of Science & Technology

Director Sales & Marketing Ashok Ganguly

Packaging

Pharma Focus Asia is published by SPG Media Limited in association with IMS

Marketing Manager Ahmed Tariq

51

RFID in Pharma An Asian perspective Peter Harrop, Chairman, IDTechEx

Integration of Packaging Innovations 56 Praful R Naik, Chief Scientific Officer and Executive Director, Bilcare Limited

Information Technology

India Office

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Microsoft

Digital Pharma Initiative Digital Pharma will enable lifesciences organisations to improve operations and decision making across the entire industry value chain.

Rüediger Dorn, Director, Life Sciences Industry, Worldwide, Enterprise Partner Group, Microsoft Corporation

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Pharmaceutical Marketing Strategies for Asia Pacific Success in Asia will depend upon the ability of marketers to navigate the local environment with globally developed products.

increasingly influenced by many different groups and individuals with a stake in the choice of treatment.

The changing environment impacting treatment decisions Joanne Fensome, Regional Director of Healthcare, Asia Pacific, Ogilvy Public Relations Worldwide, Hong Kong

D

evelopment of meaningful and cohesive marketing strategies in Asia is one of the hottest topics in the pharmaceutical industry today.

Multinational pharmaceutical companies are increasingly looking to Asia to drive sales growth. Marketing is simultaneously recognised by the industry as vital for product success and derided by the media as the main reason for high drug prices.

Meanwhile regional and local market strategies are needed in an increasingly complex and ever changing marketplace to achieve results.

Asia’s market potential has been widely discussed. Nearly 4 billion people, coupled with economic growth, increasing affluence and a projected increase in chronic diseases offer an opportunity to boost revenues at a time when blockbuster drugs are nearing the end of their product lifecycle in the US and Europe.

Asia, however, is not without challenges. Multiple countries with different cultures, languages, socio-economic groups and regulatory/legal systems, mean strategies can only be regionalised to a certain extent, after which country-specific approaches are needed. Even within some countries disparities of affluence and education can be associated with different healthcare expectations. Success in Asia will depend upon the ability of marketers to navigate the local environment with globally developed products.

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From global to regional to local The pharmaceutical industry is globally driven. Diseases and epidemics are global and prescription products designed to treat them are necessarily researched and developed by central teams, although it should be noted that clinical trials are being carried out and the drugs themselves being manufactured in the region.

Global marketing teams are also tasked with developing the business plans and strategies that include marketing elements such as product proposition, branding and pricing parameters. Of the four marketing P’s (product, price, place and promotion), this essentially leaves local marketers with ‘Place and Promotion’ to strategise. But, pharmaceutical product distribution channels are generally consistent for all companies within each market so promotion is the avenue where marketers can truly have an impact in the local market setting.

Prescription-products promotion Promotional marketing strategies are impacted by factors such as product lifecycle stage, market position, disease area and competitive activity. The one constant factor is that physicians will ultimately have to write the prescription.

Physicians have therefore been the focus of most marketing campaigns. But, today, the environment in which physicians are operating is changing and they are

Payers, reimbursement decision-makers and governments can all impact treatment availability and patient access.

Nurses, pharmacists and other healthcare professionals can influence physician perceptions. Professional organisations developing treatment guidelines can influence best practice. Patient organisations can influence patients, governments and physicians. Retailers can interpret generic prescriptions and influence customers. Finally, patients, their families and caregivers, are becoming pro-actively involved in researching disease areas, learning about treatments and discussing options with their physicians.

This changing environment means that marketing strategies cannot just focus on physicians rather they need to address the broader group now influencing treatment decisions.

Marketing strategies for influencers Effectively navigating the influencer group needs in-depth, in-country market research. Each country’s healthcare system, legal and regulatory environment, culture and socio-economic differences will impact the influencer group. But research in the following areas will help to define, understand and target them effectively: Who are the influencers, what is their role and at what stage of the treatment decision process are they involved?

What motivates each group? Which information channels do they routinely use? How do they like to be talked to?

For example hypertension, morbidity and mortality may mean a lot to physicians,

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but to most influencers who are not medically trained high blood pressure may be more relevant.

Brands, not just drugs Pharmaceutical products are no longer just drugs — they are brands. Lipitor, Viagra, Prozac are all widely recognized pharmaceutical products that demonstrate the effectiveness of branding. Through a brand it is possible to communicate a promise, an essence, and aspiration. And, branding builds loyalty.

In most cases brands are created by the global team, but local market strategies must continue to build upon this promise by carrying the brand through all elements of the marketing mix.

Prescription products in the consumer world Prescription products are no longer the domain of physicians and healthcare professionals. Many who influence treatment decisions are not medically trained and prescription products must now be positioned within a wider consumer environment. This is, however, at odds with the legal restrictions around the promotion of products as consumer marketing and direct to consumer activities are still prohibited in much of the world – the US being the obvious exception.

The challenge is that prescriptionproduct information is already available to the general public in the majority of countries. This is mainly due to globalisation of the world’s media and accessibility of the Internet through which information from the US is shared. Availability of this information is not going to change, we can’t turn the clock back, but pharmaceutical companies can develop strategies that support educational initiatives by other organisations and ensure accurate information is in the public domain.

The power of the media Consumer media, such as newspapers, magazines, radio and television, reach millions of people throughout Asia on a daily basis and the media is increasingly interested in reporting on disease trends, drug developments and pharmaceutical company activities. With the increasing level of media interest, it is necessary to develop

both proactive and reactive media strategies to ensure that accurate information is reaching the right people at the right time.

Pharmaceutical companies can particularly play a role in educating journalists about diseases and treatment options. In Asia, there are fewer healthcare-specific journalists, but this does not make the media any less influential. This knowledge gap provides a real opportunity.

The Internet explosion One billion people use the Internet and Asia accounts for the largest percentage of these users - 36 percent. Without a doubt, the Internet is readily available, much used and a major source of healthcare information. Patients sitting anywhere in the world can find out about their disease and treatment options. Not all information, however, is equal. Many sites are inaccurate and it is prudent for companies to develop Internet strategies and alliances that direct patients and physicians to credible websites with accurate information. And, as if websites weren’t enough, blogging now adds another dimension to the online patient experience.

Patient empowerment Patient organisations are growing in number across Asia in many disease areas.

These groups represent patients’ interests in many ways, be it providing disease and treatment information to individuals or representing patient perspectives in the media, with governments or physicians.

These groups, however, need funding and this comes from a variety of sources, including the pharmaceutical industry.

As a minimum, companies should work with third party organisations to ensure that the information they are providing patients about treatment options is accurate. But, more effective partnerships can be developed when common areas of focus between company and organisation marketing strategies can be identified and co-sponsored programs conducted.

Back to the industry-physician relationships Against this backdrop of increasing influence, interference and awareness physicians still need to be in a position to treat patients

with the best available medical care. Ultimately, the prescription they write is their decision and unless that situation changes, physicians must remain at the heart of prescription-product marketing.

Marketing to physicians is not new, but the interaction and co-dependent relationship between industry and physicians is complicated, often criticised and has raised ethical concerns within the profession. But while physicians need new products to treat their patients and pharmaceutical companies are able to develop such products, the two groups will need to interact.

Pharmaceutical companies and physicians do interact frequently and in a number of ways – sales representative visits, medical conference attendance, research funding, speaker engagements and continued medical education (CME) funding, to name a few. These tactics, however, need to be part of an overall strategic approach that can be determined by gaining a greater understanding of physician attitudes, beliefs, needs, motivators, prescribing habits and preferred information channels through research.

Sales representatives will remain the most important vehicle for communicating with physicians - they are the face of the company and are able to provide individualised information that drives prescriptions. Much has been written about sales force effectiveness - too much to cover here - but marketing teams can support their representatives by implementing strategies that create an environment that removes potential prescribing barriers and surrounds physicians with positive product reinforcement.

In summary Marketing strategies will play an important role if Asia is to realise its potential. These strategies, however, should be tailored to the region and its countries. Moreover, they will need to encompass not only the physician audience but also increasingly the influencers who have the power to make or break a product. Finally, pharmaceutical companies will need to become experienced in navigating the consumer space with prescription products and ultimately turning pharmaceutical marketing into brand marketing.

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Pharmacoeconomics

Introducing patient-centred models Companies preparing for the implementation of pharmacoeconomic guidelines in Asia have an opportunity to use those resources for purposes other than justifying government reimbursement.

Meaghan Lynch, Senior Economist, Health Economics and Outcomes Research, IMS Health, Australia

M

any countries in the Asia Pacific region are both eagerly anticipating Korea’s implementation of pharmacoeconomic guidelines later this year, as well as remaining apprehensive. Governments are hoping that the reimbursement requirement will provide a framework that can be adopted to improve efficiency and contain pharmaceutical spending in Asian markets. Simultaneously, pharmaceutical companies are wary of the consequences.

Despite uncertainty as to where guidelines may appear next, many companies are taking a proactive approach and preparing for a future wave of pharmacoeconomic requirements in the region. They have started hiring health economists, looking at pharmacoeconomic models prepared by their global counterparts, and collecting local cost data to populate models. In addition, those that can demonstrate their drug’s “value-for-money” using pharmacoeconomics are voluntarily submitting data as part of their reimbursement application.

Pharmacoeconomics: Friend or foe?

Generally, the pharmaceutical industry

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views pharmacoeconomic requirements from two different perspectives. On the one hand, they are preferred over continuous price cuts as a more predictable and transparent method for governments to increase the efficiency of pharmaceutical spending. The opportunity to demonstrate “value-for-money” is also seen as advantageous.

On the other hand, pharmacoeconomics represents a “fourth hurdle” that companies must overcome in the reimbursement process.

While these two perspectives have global applications, pharmacoeconomics presents a further problem for companies in low and middle-income markets. The main dilemma associated with presenting the cost-effectiveness of modern drugs in the region is that the costs of local resources are considerably lower than in high-income countries and drugs are not considered to be cost-effective unless they are cost saving.

As illustrated above, the cost-effectiveness or “value-for-money” of a drug is usually assessed in relation to its impact on government reimbursement decisions.

However, opportunities to employ this

economic technique extend beyond government reimbursement.

Pharmacoeconomics: An evidence-based marketing tool Patient level economic modelling offers an opportunity to demonstrate “value-formoney” at the patient level. The information derived can be used to educate both physicians and patients as well as demonstrate to a patient the value of prescribing a more expensive drug.

Interactive models can be designed so that the user can input patient characteristics and, based on modelled data extrapolated from clinical trials, project expected outcomes for different treatment options.

Treating physicians can then use the model to demonstrate to the patient how treatment improves patient-specific outcomes such as the probability of relapse, hospital re-admission and return to work.

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Patient-centric models for resource allocation In publicly financed healthcare systems, such as Taiwan, prescribers are facing increasing pressure to contain costs.

In 2002, the Taiwan Bureau of National Health Insurance (BNHI) implemented global budgeting at the hospital level. Under Taiwan’s global budget system, hospitals receive lump sums from the BNHI to cover the cost of providing all medical services. While global budgets have successfully restrained the growth of expenditure, they have also limited the capacity of healthcare providers to embrace change in healthcare technology.

As a result, many hospitals are passing down budgetary pressure to the department and individual physician level. This practice has limited market access for new drugs since physicians, responsible for their own budgets, are reluctant to prescribe premium medications. Pharma-driven patient-centred interactive models can serve to support physician decision-making in resource allocation as well as identifying patients for whom the drug represents “value-for-money.” For example, a physician could determine for each individual patient whether the premium product would provide a greater reduction in health outcomes, such as relapse or hospital re-admission, than the alternative treatment in consideration of the patient’s current health status. By Out-of-pocket expenditure vs other healthcare expenditure

In % 100 80 60 40 20 0

China

India

Philippines

Government healthcare expenditure Other private healthcare expenditure Net out-of-pocket healthcare expenditure

prescribing a more expensive drug to those patients that the model identifies as having a greater risk reduction profile after treatment, the hospital can potentially reduce costs and reallocate those resources elsewhere.

Patient-centred models can be an important aid to help companies with premium products to break into markets where prescribers face increasing budgetary pressures.

Towards a more risk-informed patient

inclusion of productivity changes is contentious. By including productivity losses in a pharmacoeconomic model, an analyst assumes that a patient who is sick must forego employment during that period of illness. However, given a pool of unemployed labour, jobs may be filled by other members of the community and productivity changes may not be recognized at a societal level.

However, productivity is a patient relevant outcome. Demonstrating the potential change in productivity due to treatment translates into personal income for the individual patient and can be a strong incentive to reduce health risks by adhering to superior, albeit more costly, treatment regimens.

Several Asian countries provide minimal government financing in the area of healthcare. Consequently, the majority of patients in countries such as China, India and the Philippines must pay out-of-pocket for medical services and prescription drugs.

Patient-centred modelling and According to the WHO, pripharmacoeconomics can provide an vate healthcare expenditure in innovative way to market drugs and 2004 constituted 62.6 percent of total healthcare expenditure penetrate barriers to access in both in China, 75.7 percent in Ingovernment-funded and private pay dia and 57.3 percent in the healthcare systems.

Philippines. Net out-of-pocket spending in China, India and the Philippines was 86.7 percent, 97.0 percent and 77.3 percent of Pharmacoeconomics for total private healthcare expenditure, recompetitive advantage spectively.

Companies starting to prepare for the poFor many individuals in these countential wave of pharmacoeconomic requiretries, healthcare presents a significant fiments in Asia should embrace opportuninancial burden. The cost of premium drugs ties to utilise the technique in other areas to treat an underlying condition may lead of business, such as marketing. By develpatients to discontinue treatment regimens oping patient-centred models, companies if they are not well informed of the financan demonstrate to patients in private pay cial and health risks associated with forgomarkets both health and financial benefits ing treatment or non-compliance. of paying for more expensive treatments.

In these situations, an interactive modReducing the risk of productivity losses el can serve to help patients understand and more expensive hospitalization may how a treatment reduces health risks as well inform and incentivize patients to request as demonstrating that discontinuation of premium drugs and maintain treatment therapy will prove to be more expensive in regimens. In government-funded health the long run. The impact on indirect costs systems, patient-centred modelling can be can also be demonstrated to the patient. used to improve resource allocation deciIndirect costs and benefits are often sions at the prescriber level and help comsynonymous with productivity gains and panies break into markets that are facing losses. Productivity denotes the time paincreasing cost-containment pressure. tients or their families consume or free-up Patient-centred modelling and phardue to treatment and often is associated macoeconomics can provide an innovative with work time. Pharmacoeconomic modway to market drugs and penetrate barriers els designed for reimbursement applicato access in both government-funded and tions often take a societal perspective and private pay healthcare systems.

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Understanding the psyche of Asian pharma consumers The pharmaceutical industry needs to revisit its ‘doctorheavy’ marketing strategies to succeed in this continent.

Shailesh Gadre, Managing Director, ACNielsen ORG IMS, India

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hesaurus would use the words customer and consumer interchangeably but the pharmaceutical industry would probably not. For the pharmaceutical marketers, the customer is distinctly different from the consumer, wherein their customers are the doctors whose patients are the consumers. Traditionally, in many Asian countries, the ‘customers'’ influence, uniquely armed by their medical knowledge, has completely overshadowed the defenceless consumer dominance in decisions pertaining to the patient’s health.

Consumers in most Asian countries continue to remain vulnerable to varying degrees, subject to the level of illiteracy, accessibility to information, local infrastructure and insurance support by government and employers etc. Thanks to the challenges faced by the global pharmaceutical industry, Asia is getting the maximum attention and utmost importance. But Asian consumers exhibit a striking diversity in the power of their arms to fight the doctor's influence.

On a closer look, we can conveniently divide the Asian subcontinent into three tiers, with likes of Australia, New Zealand, Korea, Taiwan in top tier which are more westernised in approach and more developed on the fronts like education, information and infrastructure, while the lower tier has Philippines, Indonesia, Vietnam who score the lowest on these vulnerability criteria. India and China have recently broken loose from this lower tier, creating a middle tier of their

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and again as to what has led to the change in the patient behaviour, I remember one of the statements put forth by Henry Commager, “Change does not necessarily assure progress, but progress implacably requires change. Education is essential to change, for education creates both new wants and the ability to satisfy them.”

True to this adage, the mass of nouveau literate consumers growing at double-digit have increasingly become aware of themselves and their health, questioning the doctor’s dictate. The accessibility to information via the Internet, electronic and print media have enabled consumers to be more informed of the happenings across the world and keep themselves updated with the changing trends. The growth in the penetration of TV media estimated at more than 17% in India and the print media at 7%, further evidence the quick information spread. This could also be the reason for the growth in self–medication as well as the growing interest in the OTC markets.

Further, easy access to information and strong connectivity has boosted the knowledge levels of consumers. If we just observe the exponential growth in the penetration of the PCs from 0.7% in 1997 to 7.2% in 2003 (in India itself ), we can get an idea of the technological advancement further enhanced by the spread of internet.

Today, with a click of button, the consumers have all the information pertaining to the intricacies of ailment, options of medi-

own due to their quick alignment to the global standards and faster economic development. India and China are rated today as the most promising markets, thanks to the untapped potential existing here due to the large population and high mortality/ morbidity rates. The economic development and the acceptance of IPR in these countries make them attractive baits as they also offer a potential patient base with an increasing capacity to pay.

As the consumer today has become more demanding and better informed, could tomorrow's patient be any different? Armed with the awareness sword, the meek patient of yesterday is now questioning the doctor’s knowledge in the first place and has in fact, gone one step ahead and started adorning the doctor’s role in making the choice of the pill. So the pharmaceutical industry needs to revisit its ‘doctor-heavy’ marketing strategies, with a conspicuous absence of patient focus, to succeed in this continent. Further, the reimbursement scenario has also evolved in the Asian geographies with payer taking a more prominent role in choosing the right pill for patients.

India and China are rated today as the What has led to this difference? What is in most promising markets, on account this new consumer’s of the untapped potential existing here mind…? These are due to the large population and high some of the questions mortality/ morbidity rates. we need to answer.

As I plow over the question again

Events October 2006 cine available and avenues to get them.

With this knowledge force behind them, they refuse to blindly follow their doctors and question them till they are completely convinced. Further, the infrastructural development in terms of hospitals, public healthcare centres, has made the access easier; physical distance no longer remains an obstacle for access to medicine and knowledge.

Economic development has also been one of the primary triggers for the change.

In India, 80% of the times, patients pay from their own pocket for the drug expenditure. With the rising disposable income, patients are now ready to spend more on the medicines, but at the same time, since it is their own hard-earned money, they simply refuse to let go simply.

They seek value for their investments, increasingly weighing the options available, scientifically judging the worth behind each option. Hence, they now want to demand their returns on the investments made, and differentiate between a commodity and a brand.

So the patient is fast catching up with the demanding consumer. If I have to give a final word on the Asian pharma consumer, I would say, be ready to meet the wellinformed, techno-savvy, cost-conscious consumer and companies need to innovate much more to meet these needs.

BOOK Shelf Ethics and the Pharmaceutical Industry

Edited by: Michael A. Santoro, Thomas M. Gorrie Year of Publication: 2005 Pages: 520

10 – 12 October

1 – 3 December

Pharma R&D Partnering and Innovation India

The Convention on Pharmaceutical Ingredients (CPhI)

Renaissance Mumbai Hotel & Convention Centre, Mumbai, India

Goregaon (East), Mumbai, India

Organiser : IBC Life Sciences

Email

: cphi@cmpinformation.com

Website

: www.cphi-india.com

Email

: shubir.khattau@ibcasia.com.sg

Website : www.drugdisc.com/india/

November 2006 6 – 7 November Global PharmaBio Alliance 2006 The Leela Kempenski Kovalam, Kerala, India Organiser : Frost & Sullivan Email

: sunnikrishnan@frost.com

Website

: www.frost.com/pharma

7 – 10 November China-Pharm – 11th China International Pharmaceutical Industry Exhibition

For more, visit the Knowledge Bank section of www.pharmafocusasia.com

Organiser : CMP India and CMPi

January 2007 29-30 January BIO-Asia 2007 Tokyo, Japan Organiser : Biotechnology Industry Organization Email

: bioasia@bio.org

Website

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11 – 13 January Asia Pharma Expo 2007

Beijing, China

Dhaka, Bangladesh

Organiser : Messe Düsseldorf China Ltd

Organiser : Bangladesh Association of Pharmaceutical Industries, GPE Expo Pvt. Ltd.

Email

: chinapharmex@china.com

Website

: www.chinapharmex.com

Email

: bdass@bol-online.com, globaltouch@icenet.net

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: www.asiapharma.org

9 – 10 November XpoPharm 2006 aT Center, Seoul, Korea Organisers : Korea Pharmaceutical Traders Association (KPTA), CMP Media Korea Co Ltd Email

: xpochem@cmpmediakorea. com, yhchoi@kpta.or.kr

Website

: www.xpopharm.com

9 –12 November Mediphar Taipei 2006 (18th Taipei Int’l Show on Medical Equipment, Pharmaceuticals & Biotechnology)

February 2007 6 – 10 February CHeMTeCH + Pharma World Expo 2007 Mumbai, India Organiser : Chemtech Foundation Email

: a_afganullah@jasubhai.com

Website

: www.chemtech-online.com

March 2007

Taipei, Taiwan

6 – 8 March

Organiser : Taiwan External Trade Development Council, Formosan Medical Association

International Medical Equipment & Technology Exhibition

Email

Organiser : Top Repute Co. Limited

: mediphar@taitra.org.tw

Website : www.taipeitradeshows.com.tw

Description: Michael Santoro and Thomas Gorrie have compiled a series of essays that provide a fair, balanced, and insightful examination of an increasingly troubled relationship between the pharmaceutical industry and society.

December 2006

15-17 November INTERPHEX China 2006 Qingdao International Convention Center, China

Shanghai, China Email

: topreput@hkabc.net

Website

: www.toprepute.com.hk

April 2007 25 – 27 April

Organiser : Reed Sinopharm Exhibitions Co., Ltd.

RFID World Asia 2007

Email

: qinghua.wei@reedsinopharm. com

Organiser : Terrapinn Email

: elin.tan@terrapinn.com

Website

: www.interphexchina.com

Website

: www.terrapinn.com

SUNTEC Singapore, Singapore

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CASE STUDY

Challenges for R&D success in China

Novo Nordisk’s experience For pharma R&D success in China, the essence is to know how the local environment will support or pose challenges to the characteristics of an effective organisation.

Baoping Wang, Research Director, Novo Nordisk (China) R&D Centre, Beijing, China Esper Boel, Vice President and Head of Biotechnology, Novo Nordisk R&D, Denmark

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ovo Nordisk (NN) has pioneered R&D in China by setting up the first pharma R&D organisation in Beijing in late 2001. Over the past 5 years, the R&D centre has become a skilled biotechnology provider in core areas of expertise. Building on the past achievements in establishing technology platforms, the centre will now undertake the challenge to become a co-driver in novel drug target identification in selected areas.

Background NN is a mid-sized international pharmaceutical company headquartered in Denmark and is focused on establishing core businesses within diabetes, bleeding and growth disorders. In 2000, NN decided to extend its R&D activities into immunotherapy against cancer and inflammation. Accordingly, it became necessary to establish a stronger core competence in protein expression using E. coli as a host.

It was decided to establish this competence in China, i.e. establish Novo Nordisk (China) R&D (NNCR&D), for three main reasons: 1) support the NN business in China, 2) cost-effectiveness for a stateof-the-art biotechnology centre, and 3) identification of collaborative R&D opportunities in China.

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Development of NN China R&D (NNCR&D) The NNCR&D started operation in 2001 in an 800m2 facility designed for a staff of 30 employees. A project with high chance of success titled “Development of a new human growth hormone production process” was chosen as NNCR&D’s first project to help build the team with strong expertise in bacterial protein expression. Interacting with experienced colleagues from the HQ, the team succeeded in developing a new process enabling a 6-fold increase in hGH production, and a novel antibiotic-gene free E. coli selection system, which will be suitable for production of other proteins as well. Since then, NNCR&D has participated in more projects with excellent results. Due to the positive prospects of a long-term commitment to R&D efforts in Beijing, NNCR&D was relocated to a new 2300m2 facility designed for a staff of approx. 60 employees in the Zhongguancun Life Sciences Park in July 2004.

Challenges for biomedical R&D success in China Impact of the local environment on the R&D success in China The current pharmaceutical R&D environment in China is progressing with several

initiatives to move away from a fairly low starting point dominated mostly by in-experienced biomedical/industrial scientists.

First of all, although the Chinese culture is significantly different from that of the West, there is no major cultural barrier for success of a Western style R&D organisation in China, because Chinese employees are amenable to changes. Second, Chinese biomedical R&D environment in general does have a positive impact on the 10 characteristics: 1 Vision: a good vision can be well accepted 2 Clear goals: high expectations from upper management can be achieved 3 Workforce: people are motivated and hard working 4 Team work: good teams can be assembled to accomplish difficult tasks 5 Innovation: big pool of intelligent people 6 Strong management is a tradition of Chinese culture 7 Corporate culture: people can adopt to a positive culture 8 Values: good values are followed 9 Action: things happen fast in China 10 Finances: cost-effective compared to the West In the discussion below, we will not elaborate on these positive aspects, but focus on the challenges to the first 6 characteristics of an effective organisation. We think there is no major challenge to the last 4.

Vision and management team It is pivotal to have a vision for the R&D organisation in China. The vision determines the kind of organisation a company wants to set up: a service type technology provider or a driver in novel drug discovery. The vision is largely set by R&D management in the HQ. A competent local management team is necessary to drive the R&D team to work towards the vision. It

CASE STUDY

is a challenge in China to recruit managers with experience in global R&D because locally trained PhD scientists usually do not have the experience needed to fulfil such requirements. Thus, it is necessary in the initial phase to recruit key managers from the Western job market or to expatriate key managers from the HQ. Clear goals The Chinese culture values management’s recognition of a job well done, and another cultural influence is that people tend to wait for instructions.

Thus, if a goal approved by HQ management is easy to reach, a person might be satisfied and relaxed with the recognition of reaching the goal. Therefore, ambitious yet achievable annual goals defined by management can significantly improve the productivity and competence level of the R&D organisation.

Workforce: Talent recruitment and team building Talent recruitment can be difficult or easy depending on the mandate for the China R&D organisation. China has a huge pool of young talent in the category of technology providers that primarily requires clever hands and flexible minds to perform established protocols. Thus, it is very easy to recruit excellent associates at the bachelor and masters degree levels. However, if the mandate is novel drug discovery such as identification of novel drug targets or drug leads, a team of scientists with the relevant experience and capacity is needed: a deep understanding of disease biology and all practical issues associated with drug R&D. Such scientists cannot be trained during a short period, but usually require a PhD training plus years of international postdoc experience to reach their full potential.

At present, it is difficult to recruit such scientists among locally trained candidates due to lack of an international level innovative drug sector in China. Therefore, it is necessary to recruit such qualified candidates from the Western market.

However, it is a challenge to recruit scientists from the West to China. Many qualified scientists of Chinese origin would like to return to work in China, provided their quality of life is not significantly reduced. Such scientists usually are enjoying a good middle-class life in the West. Hence, it takes a dedicated effort to recruit quali-

fied candidates from the West to China.

Teamwork Novel drug development takes about 1014 years from idea to market, and teamwork is a must during every stage of R&D. However, teamwork is not a traditionally strong aspect of the Chinese culture, as there is a Chinese saying: “Individually Chinese are dragons, together they are worms.” People are motivated to do their outmost; however, the priority may be personal achievement rather than maximising team productivity. Teamwork also requires seamless communication not only within R&D organisation in China but also with colleagues in HQ. It is often a major task for the local management to support a strong teamwork spirit.

Innovation True innovation is not a strong aspect of the current pharma R&D climate in China. This is not due to lack of intelligent people, but rather related to a number of impairments in the R&D environment in China. Consequently, the average level of domestic PhD training in innovation is lower than that of the West due to insufficiencies in research funding, in number of high level PhD mentors, and in drug innovation experience. A brain drain to the West continues as many brightest graduates predominantly favour to be trained and stay in the West. Moreover, the locally trained PhD scientists may need to improve their competence to contribute to stimulating scientific oral communications with their counterparts from the West.

However, many Chinese scientists have made excellent careers in pharma R&D in the Western countries. Thus, an R&D organisation in China has the potential to become an excellent innovation organisation provided it: 1) Builds a strong and competent team through recruiting experienced scientists from the West combined with dedicated programs to train locally recruited scientists, and 2) Adopts the innovative environment of the West, including opportunities for scientists to attend global scientific meetings, and promote a climate for information exchange and for open and frank discussions addressing both successes and failures.

Strong management: Tough but fair The Chinese culture values fairness and an employee tends to evaluate his own value

through comparison to his peers, particularly regarding the fairness in income level. Ironically, the remuneration gaps between different job positions in China is larger than those in the West. This differentiation, considered necessary from the company’s point of view in order to recruit an appropriate blend of the best possible employees with the needed scientific background, poses an additional challenge to the management.

External factors The above discussions deal with the challenges within an organisation. There are also a number of external challenges. One challenge is to establish and maintain professional relationships with the local stake holders, such as government organisations and project collaborators, that may have different working styles compared to that of the R&D unit. Another major challenge is logistics on high-grade reagents and instruments which are currently largely imported to China. It takes weeks or months to obtain equipment and reagents. Pricing of major instruments and reagents may be higher than observed in the US and Europe. Technical support for equipment may be not as efficient as it should be.

These conditions will all undoubtedly be improved gradually in future.

Perspective The Chinese pharma market has grown at double digit rate during the last decade, and is expected to be the fifth largest market by 2010. Innovative drug R&D initiatives by domestic companies and global R&D organisations in China will likely become more and more active. The number of global Pharma R&D organisations in China is currently low: less than 10. However, the Pharma market and the global Pharma R&D organisations in China resemble the IT business in China. The Chinese domestic IT market was small 20 years ago, but has become a major global market today.

Almost all major global IT related companies have now set up one or more R&D organisations in China, and their businesses have grown from technology service centres to innovation centres for the global markets. The global pharma companies and their R&D organisations will be following the steps laid down by the IT sector to be successful in the years to come.

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r&D

Biopharma Convergence

Heralding a new era Feroz Zaheer and Rajeshwer Chigullapalli, Pharma Editorial Team

Biopharma convergence seems to be the panacea for pharma companies struggling with weak R&D productivity and biotech firms facing funding shortfalls.

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t might not have been in the wildest dreams of Genentech and HoffmanLaRoche Inc. that what they were about to do would be a harbinger for other biotech and pharma companies. The deal between the two firms in the year 1990 is considered as the pioneer of convergence between pharma and biotech. Genentech was facing an uncertain future when its sales hit at an all-time low. Even though the company had a very attractive product pipeline, it lacked the resources to maximize the pipeline’s value. Its stock price was down and fears of a hostile takeover were looming large. At this juncture Roche bought 60% of Genentech’s shares for $2.2 billion, while allowing Genentech to continue as an independent, publicly traded company. It was an equity investment that proved to be mutually beneficial for both the companies. In the subsequent years, the two firms have partnered with each other, with Roche commercializing Genentech’s products outside the US, among other things. And since then, many pharma and biotech firms followed suit. Of late, the trend has reached a new peak.

The global biopharmaceuticals market was estimated to be $64.3 billion in 2005

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and the pharma-biotech partnering deals were worth $15 billion. According to Frost & Sullivan, more than 1,500 alliances were formed from 1997 through 2002, and the contribution of licensed products to total sales is estimated to increase from 20% in 2002 to 40% in 2010. Some pharma companies are gearing up to reinvest around $100 billion in the biotech industry instead of channelling the money for their in-house R&D. The pharma industry reinvests an estimated 25% of its revenues in R&D, which is twice as much as other high tech industries viz. aerospace or IT. In biotech, the pharma industry found a way out.

The blockbuster model began fading and biopharma started gaining ground.

Pharmaceutical companies are either consolidating or forming strategic alliances with biotech companies to overcome the double whammy of R&D productivity woes and onslaught of blockbuster patent expiries resulting in weak product pipelines. The biotechs, in turn, are motivated by the marketing and financial prowess of the pharma companies.

What’s in it for me?

The global pharmaceutical industry is currently going through a difficult phase on account of three major issues i.e. increasing penetration of generics in developed markets, fewer new drug launches and drug safety issues. While New Molecular Entity (NME) approvals by the FDA have fallen since 1996 for pharma, biotech’s share of NMEs has been increasing since 1995. Of the total 21 NMEs approved by FDA in 2003, 12 belonged to biotech companies.

The pharma and biotech firms are now converging to leverage each other’s complementary core competencies. The pharma companies partner with biotech firms to

develop and / or market new drugs, or acquire biotechs to revive their research base and product pipelines. Heather E Fraser, Global Life Sciences Lead, IBM Institute for Business Value opines, “At the level of the body’s molecular pathways, drug companies are racing to put their R&D efforts to good use. But few will succeed on their own.” She further adds that from the perspective of large pharmaceutical companies, outsourcing R&D projects to smaller, innovative biotechs continues to be an important strategy.

Acquiring a biotech implies that the pharma company can add new products, product platforms and technologies which would be more economical than to start from the scratch. Biotech products are also more difficult to be reproduced by the competing generic companies because of the biologics involved. Tom Newton, Pharmaceutical Market Analyst, Visiongain, quotes the example of TEVA and says, “TEVA is actively seeking biotechs.

In 2004, it acquired Sicor, and more recently acquired a controlling interest in Tianjin Hualida Biotechnology, a Chinese biotech company.” Other recent instances of pharma companies acquiring biotechs are – Roche acquiring Antisoma, Pfizer acquiring Esperion Therapeutics, Novartis taking over Chiron and the acquisition of Scios by Johnson & Johnson (J&J). Wyeth too, has been actively forming partnerships and alliances with biotechnology companies. Says Cavan Redmond, Executive Vice President, Wyeth BioPharma, “If you take a look at Wyeth and biotechnology, especially our biotech group, about 80% of our revenues are with partnered companies.” Other companies like Pfizer and Merck are deriving at least 20% of their revenues from the biotech products, while it is a sizeable 70%, in the case of Roche.

r&D

GSK, Roche/Genentech and sanofi-aventis have the maximum number of biotech products in their total R&D pipeline - 35, 25 and 23, respectively. From an R&D perspective, Roche/Genentech, Amgen, Eli Lilly and Boehringer Ingelheim focus their R&D pipeline more towards biotech.

When a pharma firm partners with a biotech firm for the development and commercialization of a drug, it implies that the risks involved in the drug discovery process also get divided. It becomes more important to have partners to share the risks considering the high cost of developing a new drug. By 2010, the cost of turning a promising compound into a patentable drug (currently around $1 billion compared to $200 million in the last decade) is estimated to be an astounding $2 billion.

The pharmaceutical companies benefit the biotechs through their rich experience in developing drugs through trials. The unavailability of a strong IPO market for biotechs encourages the biotech founders and venture capitalists for a sell off, in order to realize returns on the investments made.

Says John Wong, Regional Chair, Asia Pacific, Boston Consulting Group, “For biotech companies, the real strategic issue is basically growth and sustainability.” Forming an alliance with a Big Pharma company also increases the value of the partnering biotech firm in the market. According to a study by the National Bureau of Economic Research based in USA, biotech firms in a partnership received substantially higher valuations from venture capitalists and from the public equity market.

The alliance formed between a pharma company and a biotech can have different structures. It can be a technology alliance like Celera Genomics’ alliance with LION bioscience AG, or a product alliance based on the strength of each partner in the areas of drug discovery, development, marketing etc. It could also be a manufacturing alliance or a marketing alliance wherein a drug developed by the biotech company is marketed by the pharma company.

For instance, Imclone has partnerd with Merck and Bristol-Myers Squibb (BMS) for developing cetuximab, an anti-cancer drug, where Merck and BMS have codevelopment and co-marketing rights for Imclone’s drug.

F M Scherer, Professor, Harvard University opines, “Biotechs have a large menu of interesting therapeutics. But it is hard for them to fund full-scale clinical trials; and they often lack the field sales organisations to market the approved NME.” As an example he quotes the history of Amgen’s epogen (red blood cell enhancer). Amgen carried epogen through clinical trials. It could build a marketing force to interact with the several hundred hemodyalisis centres. But it couldn’t reach the much larger number of hospitals where epogen could be used in cancer chemotherapy, and therefore licensed Johnson & Johnson to develop that and other markets.

The biopharma market The biopharmaceutical market has undergone rapid expansion since its emergence thirty years ago. The market is no longer confined to growth hormones, insulin and RBC stimulating agents. Innovative science, driven by the 2001 human genome project is accelerating the market into targeting a wide range of diseases from growth deficiency to arthritis to multiple sclerosis and orphan diseases such as Fabry’s disease.

The biopharma market was estimated to be worth $ 64.3 billion in the year 2005. The market comprises of 9 major therapeutic areas i.e. oncology, anti-infectives, vaccines and blood disorders, endocrine disorders, multiple sclerosis, enzyme deficiency disorders, arthritis and ophthalmics. By the year 2010, analysts expect that the market will represent 17% of all prescriptions compared to 12% in 2004.

The biotechnology sector is on an upsurge after several years of significant decline.

Global revenues rose from $23 billion in 2000 to more than $50 billion in 2005.

Almost 16% of products achieving blockbuster status in 2004 were biotech drugs1 and going by its current rate of transformation, the sector is expected to have an increased share in the blockbuster market.

With majority of the sales revolving around 10 companies, the biotech market is more concentrated than the pharma sector.

These top ten global biotech companies together are responsible for more than 80% of sales. The market leader, Amgen, alone, 1 According to IMS

contributed around 24% of total sales with six showing above-market growth. The top ten biotech products globally accounted for 43% of sales in 2004. Currently, the US is the leader of the biotech market and will continue to be for some more time.

Analysts expect that Japan and the EU will see a fall in the global market share, while the Asia-Pacific region will witness high levels of unprecedented growth.

The pharmaceutical market in Asia, especially China and India, is already witnessing consolidation on a large scale.

The pharma companies in the region are making efforts to make their presence felt globally. Big firms like Dr. Reddy’s and Ranbaxy are already into biotechnology in a big way. Asia is still in the process of catching up with the trend of biopharma convergence, and experts have their own opinions regarding the impact of this trend on the markets in Asia. John Wong says, “The biggest market in Asia – Japan - is still into traditional pharmaceuticals. And in India and China, the biological idea is not well defined. So it might be longer before convergence happens in Asia.” However, Kiran Mazumdar-Shaw, CMD, Biocon Limited opines, “As confidence in the expertise of Asian drug companies grows, we are likely to see more synergistic alliances between them and their Western counterparts in niche areas.”

Challenges In a biotech-pharma alliance one of the main challenges is whether the two companies can adjust to each other’s vastly different cultural environments. Biotech companies have an entrepreneurial culture while pharmaceutical companies have a big-business culture. According to IBM Institute for Business Value2, a change in the senior management at the pharma company was the biggest contributor to alliance failures.

Scherer avers, “I think innovation is likely to be more vigorous if different kinds of companies are kept separate at the discovery stage.” The partnering companies need to understand that the alliance is a necessary means of survival rather than a mere trend. Better understanding of each other’s expectations, commitment and trust are 2 IBM Institute for Business Value’s 2004 BioPartnering survey

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r&D

the deciding factors for the success or failure of an alliance.

Post merger, large biopharmaceutical companies may face the risk of a shifting demand in the marketplace, including a potential reduction of pricing power and an increasingly demanding customer base.

These companies will have to take significant business risks, related to the spiralling cost of gaining and preserving intellectual capital.

The road ahead The convergence of pharma and biotechnology gives rise to the question whether the traditional chemical formulation based drugs will see a downtrend. John Wong says, “Biologicals as a percentage of overall medicine are still small. So, may be the growth rate of chemical formulations segment won’t be as high but still there will be a lot of value there.” The development of new drugs through the conventional chemical-based technologies is increasingly getting more difficult and expensive.

Therefore, it is too early to decide if the

recent decline reflects a long-term downtrend or if it merely is a random fluctuation.

The biopharma convergence is expected to initiate the platform for new business models that will ultimately lead to greater deal making and an efficient blending of strategic interests and opportunities. Notes a white paper by Deloitte3, “To achieve success in an era of convergence, players need to be nimble about relationship structures and relationships in general, whether at the production, discovery, development or marketing level.”

Though biotech-pharma convergence is the current remedy adopted to meet pipeline woes and the increasing demand for biopharmaceuticals, this alone may not be sufficient to drive growth on a sustainable basis and companies need to increasingly analyze in-house R&D productivity and the innovation process. Experts feel 3 Convergence of Opportunities and Interests in Pharmaceuticals and Biotechnology

that convergence will gradually reach a point where difference between pharma and biotech processes and techniques will disappear. John Wong avers, “Over a period of time, the so called real big difference between a biotech and a pharma company will fade away.” It would not be wrong to say that the biotech sector is indeed maturing, however, it is still in the nascent stages. It would be too pre-mature to conclude that biotech would overtake pharma or would prove to be a major threat to it. It’s been thirty years since the biotech revolution began but the industry is yet to make significant aggregate profits. In fact, the industry in total has lost $100 billion since its creation in the 1970s. Therefore, only time would answer if this convergence results in a smooth integration of competencies or if both the industries emerge as major competitors to each other.

Find a Round Table discussion on Biopharma Convergence at the Knowledge Bank section of http://www.pharmafocusasia.com

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R e gulator y e nvironm e nt

IPRs

Negotiating with the USTR Should it be impossible to exclude the issue of intellectual property from a bilateral negotiation with the USTR, much care should be taken in setting the terms of negotiation.

Roman Macaya, Executive Director, Costa Rican National Chamber of Generic Products, Costa Rica

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egotiating Intellectual Property Rights (IPRs) with the United States Trade Representative (USTR) is somewhat like negotiating a banana with a hungry 300 kilogram gorilla: you can try it, but you are not going to get too far. The USTR will use the full weight of its power to determine the market access that the negotiating partner will have in the United States, the largest market in the world for just about anything, in order to obtain painful concessions. Therefore, the best strategy is not to negotiate.

The USTR adopts this strategy when it comes to discussing agricultural subsidies by simply stating that this issue is only to be discussed in the World Trade Organisation (WTO). This ensures that nothing will happen, at least for many decades. By eliminating farm subsidies from the scope of the negotiation, the USTR also ensures that it will not have to ‘pay’ a significant bargaining chip in order to keep its subsidies. Certain countries, such as Brazil, have adopted this strategy with intellectual property rights by stating that they will not negotiate IPRs unless farm subsidies are also within the scope of the negotiation. This essentially stalled the Free Trade Agreement of the Americas (FTAA), which then prompted the United States to seek bilateral negotiations on its own terms with countries that have less conviction on the issue of intellectual property.

Should it be impossible to exclude the

issue of intellectual property from a bilateral negotiation with the USTR, much care should be taken in setting the negotiating terms. A negotiation based on valid arguments should be a basic criterion, although one should not assume that this will actually be practiced during the negotiation, as we will see further ahead. A second premise should be that the intellectual property terms sought would not exceed the US law (this condition assumes it has not been possible to keep the terms within TRIPS guidelines). Third, the negotiating text should be publicly accessible by the civil society. Negotiating parties usually try to keep the negotiating draft confidential, under the premise that revealing the text compromises some secret negotiating strategy. However, an open text puts pressure on the non-US negotiating party to demonstrate concrete results from the negotiation, not just an acceptance of the original US proposal. Finally, for the non-US party, a non-agreement must also be an acceptable outcome in order to avoid the common trap of believing that there has to be an agreement, regardless of the terms. This final condition requires political willpower and clarity of negotiation objectives. If the objectives have not been met, there should be no agreement.

US - plus terms It is clear that the USTR seeks “TRIPSPlus” terms to strengthen the monopoly

power of the multinational pharmaceutical and agrochemical companies through bilateral trade agreements since the US has been unable to impose these terms in multilateral negotiations. However, what is surprising is that the USTR imposes terms that go beyond even US law. This occurs because the trade advisory committees called ISAC-3 and ITAC-15, respectfully, define the USTR’s position on chemical products and intellectual property. The US exports a policy on intellectual property that is not balanced by the diversity of interests that exists within the United States.

The result is that in almost all bilateral Free Trade Agreements, the USTR has imposed all the IPR protection clauses, but left out the clauses that attempt to balance property rights with the greater social good.

For example: Patent extensions The USTR attempts to impose patent extensions beyond the twenty-year period for administrative delays in the issuance of the patent, or the approval of a pharmaceutical product, with no upper limit on those extensions. Patent legislation in the United States allows for patent extensions for excessive delays in patent issuance or product registration, but such patent extensions cannot exceed five years and under no circumstances can the exclusive rights granted by a patent exceed fourteen years from the date of product registration with the Food and Drug Administration. The USTR does not include such limitations in their proposal.

Patent-registration “linkage” The USTR introduces the obligation of the regulatory authorities to prevent the registration and marketing of a generic pharmaceutical when a patent that covers the product exists. This provision converts the health authorities into “patent police”.

However, this is not how the regulatory authorities of the United States and Europe

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R e gulator y e nvironm e nt

work. In the US and Europe, the FDA and EMEA, respectively, notify a patent owner of a registration submission of a product covered by such a patent. Only active ingredient patents apply. Given that roughly half of all patent invalidation proceedings in the US that reach a verdict result in the patent being revoked1, the mentioned provision adopts an exaggerated presumption of validity of patents and will result in the creation of gratuitous drug monopolies, besides placing the legal responsibility and cost of defending private patent rights on the State rather than the patent owner.

Exclusive use of test data One of the key barriers to generic competition in both pharmaceutical and agrochemical products is not the production of such products, but the registration of these products. Since both types of products are highly regulated substances and require registration prior to commercialization, any barrier to registration of generic products constitutes an effective barrier to the competition of generics.

This is the reason for “exclusive use” of test data being pushed so aggressively by the pharmaceutical and agrochemical lobbies. The TRIPS agreement only mandated the protection of undisclosed information (Article 39.3 of TRIPS does not require the protection of disclosed information) against unfair competition, as described in the Paris Convention. According to the Paris Convention, gaining a competitive advantage per se is not considered dishonest unless it is illegal. The USTR also attempts to eliminate the condition that information be “undisclosed” in order for protection to apply. In addition, the USTR pretends to grant exclusive use of test data, which will guarantee drug monopolies for at least five years and ten years from the date of registration in the respective country for drugs and agrochemicals, respectively.

Questionable arguments The USTR does not always give adequate reasons as to why it wishes to impose new rules. The reasons given usually have to do 1 Empirical evidence of the Validity of Litigated Patents, Mark A. Lemley & John Allison, 26 AIPLA Quarterly Bulletin 185 (1998).

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with protecting the creative effort of inventors. However, it is always a good idea to question the reasons given, because sometimes they are absolutely wrong.

For example, during the negotiations of the Free Trade Agreement between Central America, the Dominican Republic and the United States (CAFTA-DR), the USTR required 5 years of test data protection for pharmaceuticals, and 10 year for test data related to agrochemicals.

The trade group representing the generic agrochemical manufacturers of Costa Rica requested an explanation from the Costa Rican negotiators as to why agrochemicals deserved twice as long of a protection period as pharmaceuticals. Since they did not have an answer (nor had they bothered to question this), they made a request for an explanation from the USTR. After about four months, the USTR came back with the following answer to this simple question:

While pharmaceuticals require tests in patients, agrochemicals require tests in plants, animals and the environment, thus making this data more complex and costly to generate [thus justifying greater protection].

This statement is unfounded for two reasons. First, IPRs are there to protect innovation, not investments. The above statement justifies greater protection on the basis of a greater investment, which would logically mean that the more expensive it is to develop an innovation, the greater its protection should be. This is not the foundation of an intellectual property system since it does not consider the greater profits these innovations can also generate during the protection period. Second, the statement is completely false. Two industry studies, cited or financed by the multinational agrochemical and pharmaceutical lobbies, contradict the statement.

A study funded by CropLife concluded that developing a New Chemical Entity (NCE) in the agrochemical industry costs an average of US$184 million and takes

on average 9.1 years2, while a study often cited by PhRMA states that a NCE in the pharmaceutical industry costs on average US$897 million and takes 10-15 years.

This is exactly the opposite of the USTR’s statement. However, when these studies were presented to the USTR, there was no change of position, nor any new arguments. It became a simple imposition of arbitrary protection terms. Therefore, impositions of terms based on arbitrary or contradictory arguments should be ruled out at the very beginning of the negotiation, when negotiating rules are discussed.

Not all FTAs are equal Finally, one should not conclude that there is nothing one can do when facing the USTR in a negotiation. After all, not all Free Trade Agreements (FTAs) are signed under the same terms. For example, there are variations in recent FTAs signed by the USTR in terms relating to the definition of ‘new product’, when the clock starts on the data protection term, whether there is a ‘waiting period’ available for the original product to seek registration in the country after the first registration, exclusion of patentable material, etc.

Therefore, before starting a negotiation, it is crucial to study the terms agreed to in previous FTAs on a variety of issues in order to attempt to negotiate an optimal and acceptable outcome. Some FTAs are truly different from the rest. The following is the entire “chapter” (really a paragraph) in the Israel-US FTA. This FTA is the result of a clear position of the State of Israel, and demonstrates that not all FTAs are equal.

Article 14 Intellectual Property The Parties reaffirm their obligations under bilateral and multilateral agreements relating to intellectual property rights, including industrial property rights, in effect between the Parties. Accordingly, nationals and companies of each Party shall continue to be accorded national and most favoured nation treatment with respect to obtaining, maintaining and enforcing patents of invention, with respect to obtaining and enforcing copyrights, and with respect to rights in trademarks, service marks, trade names, trade labels, and industrial property of all kinds.3 2 Phillips McDougall, A Consultancy Study for Crop Life America and the European Crop Protection Association, April 2003 (www.cropdecisions.com).

3 www.mac.doc.gov/tcc/data/commerce_html/TCC_ Documents/IsraelFreeTrade.html

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outsourcing

Outsourcing preclinical and clinical R&D to China In the coming years, China will become an important player in local and global healthcare, from both provider and utilisation perspectives.

Lee E. Babiss, Vice President, Preclinical Research and Development, Roche, USA

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n 1968, the noted singer/songwriter Bob Dylan penned the hit song, “The Times They Are a Changin.” However, in his wildest dreams, I am sure that Dylan could not have imagined how prophetic his words were with regard to China.

China has emerged from the shadows of isolation to become a world economic power with a staggering growth rate (8% per annum for the past five years)1 that will soon eclipse the likes of France and England. Low-cost manufacturing and the availability of inexpensive and abundant labour have fuelled this growth. However, in order to sustain such growth and become a significant global economic power, the Chinese Government recognizes that future growth will only be achieved by investing in Research & Development (R&D).

China’s pharmaceutical market, including ethical and over-the-counter (OTC) drugs, already ranks in the top ten.2 Furthermore, it has been suggested that this sector will rise to $24 billion by 2010 – making it the fifth-largest market worldwide (Leonard, D. Wellspring of Knowledge, 1998, Harvard University School Press). Projecting further into the future and considering that along with economic growth and prosperity ensue the

1 PWC, China: Prescription for Growth, 2004, Part I 2 BCG, A Game Plan for China, Rising to the Productivity Challenge in Biopharma R&D, Dec., 2005

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unwanted emergence of late onset chronic diseases, such as diabetes, arthritis and cardiovascular disorders, some theorize that by the middle of the century drug sales in China will outstrip those in every other country.

Unlike many developing nations, science education is strong and extensive in China. A UNESCO report on global education revealed that China has the largest number of college students in the world and produces approximately 300,000 students with graduate degrees each year, (Burrill&Company, Greater China Group 2005), a large portion of which are in life sciences. Clearly, more scientists are needed to fuel innovation and it is commendable that these talented young scientists are eager to enter the workforce and learn about the process of discovering medicines.

All of the above, coupled with a global pharmaceutical industry, which is suffering from increasingly higher costs to fuel their R&D engines and lower than expected productivity, suggest that investing in emerging markets, such as China, makes sense.

Investing = Value R&D investments by multinational pharmaceutical companies come in three flavours. The first and most advanced is simple fee-for-service outsourcing. Today many Contract Research Organisation (CRO)-based chemistry and pharmacology

companies are emerging in China. Most were founded by Western-trained Chinese scientists, who returned to develop their business models. These models involve value-creation, which can be driven by cost-efficiencies passed on to the partner, coupled with high quality and timely output. Overall, this approach has had mixed success as most CRO-based relationships are not motivated primarily by cost savings. Rather, it is the quality of the work and the timeliness of delivery that drives long-term relationships. Consequently, the jury is still out for some CROs in China.

Nevertheless, they are quick to learn and adapt and are now striving to improve the quality of their services.

More recently, some multinational CROs are looking to China to establish facilities with similar business models. Their understanding of the needs of pharmaceutical and biotech companies, coupled with their know-how of global regulatory environments, will make them important players in the market. In addition, these companies have begun to recognise additional growth drivers that will develop in the coming years. These include gaining access to a highly-trained and motivated workforce, the growth of biotech, pharmaceutical and clinical research centres, as well as an environment that allows freedom of operation in the area of safety pharmacology, and an overall trend in offshoring. However, the potential growth of the multinational CRO sector in China will be challenged by rapid increase in operating costs, owing to the overall increase in affluence. A prime example has emerged during the past three years, as the cost for hiring Master’s level synthetic organic chemists in Shanghai almost doubled.

The second type of outsourcing will come from relationships between multinational pharmaceutical companies and biotechs, and emerging biotechs in China, which is being fuelled by Chinese

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scientists returning to market, with prior drug discovery experience and a focus on collaborative innovation. Today, the biotech sector is funded largely by private investors, local venture capital firms (VC) and the government. Similar to CROs, this sector provides both cost-efficiencies for the partner, along with novel approaches for discovering new medicines. While the talent is there and the entrepreneurial spirit is high, many of the emerging biotechs are under-funded. Unreasonable pressure is also being placed on these companies to provide a rapid return on investment.

However, this dichotomy is not healthy and could, therefore, pose a serious threat to future growth. Clearly, this sector will grow, once U.S. and Western European VCs enter the market, driving the creation of more and better-funded start-ups, with reasonable business models.

The third outsourcing model will occur via a long-term investment in R&D by multinational pharmaceutical companies in the market. Roche, a pioneer among these firms, agrees with the Chinese Government that growth is driven by investing in R&D, which led us to create the first wholly owned R&D centre in China. This important commitment to both business and science in the Chinese market could not have occurred without strong support from the Pudong and Shanghai governments and a mutual understanding of the value-proposition. This was evident in 2004 by the visit of Vice Mayor Zhou Yu Peng during the opening ceremony of the Roche Shanghai R&D Centre.

Our initial focus in Shanghai is on medicinal chemistry to support lead generation and lead optimization, which we envision evolving to include all of the functions necessary to drive compounds into the clinic.

Specific emphasis will then be on developing differentiated medicines that address diseases, which are prevalent in China and the Pacific Rim. These include Influenza, Severe Acute Respiratory Syndrome (SARS), Nasopharyngeal Cancer, Hepatocellular Carcinoma and Hepatitis B. Supplemented by the existing clinical development team and collaborations throughout the country supporting genetic/genomic efforts aimed at target discovery and lead generation, Roche now has a true innovation network in China, with the R&D Centre as its hub.

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China’s changing business environment While there are many issues that Roche addressed before investing in China, one that remains key is protection of intellectual property rights. It is encouraging that since 1985, Chinese patent law has undergone two revisions that better define the legal framework concerning the application, evaluation and approval process for patents, as well as enforcement.

Today, Chinese patent law complies with WTO/TRIPS requirements and since the Chinese government is now investing considerable funds in support of drug discovery, there is a strong interest to assure IPR protection going forward. As a result of the increase in both local and global support of the emerging biotech industry, intellectual property continues to be a major factor to consider for all innovation-based domestic and multinational companies. Clearly, the direction the government has taken, to address this key issue, has led to greater investments in innovative healthcare.

On the pharmaceutical development front, medical care in China at times outstrips its Western counterparts. Hospitals and their networks are the backbone of the Chinese healthcare system and these hospitals are modernizing and focusing on developing preclinical/clinical trial capabilities that meet international standards.

They enjoy a huge patient flow. On average, a doctor in China will see two-to-three times as many patients per day as in Western countries. The Beijing Tumor Hospital has more than 1,400 beds with a bed turnover rate of more than 100%.

However, the efficiency gained from this with regard to patient recruitment for drug development programs is counterbalanced by lengthy procedures required for approval and review of clinical trial designs, which makes China less desirable than other markets for conducting international clinical trials. On the brighter side, the government is now turning its attention to this issue and it is hoped that changes in the regulatory practices will likely emerge. In the meantime, not all is lost, and based on our long-term view, Roche is currently conducting about 23 clinical trials in China.

China emphasises the development of infrastructure to support the development

of novel medicines, which includes building new high-tech parks clustered with biotech companies, hospitals and university institutes throughout the country. One example is Zhangjiang Hi Tech Park in Shanghai, which offers multinational companies an environment that fosters talent recruitment and close cooperation between inter-related healthcare organisations.

Outlook Clearly, China will become an important player in local and global healthcare from both provider and utilisation perspectives.

The market and the people cannot and should not be ignored and both outsourcing and insourcing will be major growth drivers. When the transition from feefor-service to innovative drug discovery emerges in the coming years, medicines from China will have a major impact on patients suffering with diseases around the world.

At Roche, our goal is to help drive that growth in China via collaboration and to provide our medicines and diagnostic products to healthcare providers and patients.

BOOK Shelf Outsourcing R&D in the Pharmaceutical Industry

Edited by: Bianca Paichau Year of Publication: 2005 Pages: 192 Description: This book examines the strategic aspects of outsourcing in relation to the firm. It provides a holistic view of the outsourcing process, starting with conceptualization, through to implementation and management of the process. Although the book is based on a case study of the pharmaceutical industry, the general principles derived from the Strategic Sourcing Model are generic in nature and the model can be applied to instances of outsourcing in other industries.

For more, visit the Knowledge Bank section of www.pharmafocusasia.com

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BaychroMATÂŽ CellCount A platform for online analytical measurements

Fully automated control of fermentation processes on the basis of cell count is now possible in a production environment for the first time.

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iotechnology will continue to experience above-average growth in the coming years. The primary reasons for this are the increasing content of biotechnological active substances (red biotechnology) in drug products, and regenerative fuels such as bioethanol or biodiesel (white biotechnology), which have become commercially attractive in light of the high price of oil. Driven by the growing pressure for greater efficiency, process analytical technology is widely used in the production of standard chemicals, in petrochemistry and the polymers industry.

In biotechnological applications, however, online process analysis is currently restricted to a limited number of measurement methods for standard parameters such as pH, conductivity, dO2 or turbidity. In the future, novel analytical measurement systems will be able to monitor additional parameters online, including cell count and protein concentrations. BaychroMATÂŽ CellCount, the technology platform introduced by Bayer Technology Services, is one step towards this future.

Even today, the production of chemi-

Hans Tups, Head, Competence Center, Process Analyzer Technologies, Technology Management Life Sciences, Bayer group Martin Gerlach, Head, BTS-department, Process Analyzer Technology, Bayer Group Stefan Steigmiller, Head, Process Analyzer Technology, Technology Management Life Sciences, Bayer group, Germany

cal and pharmaceutical products often includes manual sampling so that reaction progress can be investigated by means of laboratory analysis. Because it often takes several hours or even days before a complete analysis report is available, the laboratory values obtained cannot be used for controlling a process. What is needed in these times of increasing competition is material concentrations in near real-time so that utilisation of capacity and product quality can be economically optimised.

This was realised some time ago in classic chemistry and the polymer industry with the implementation of innovative process analytical technology (PAT). Using spectroscopic and chromatographic measuring techniques, concentrations can be monitored round the clock and used for the targeted control of processes. Maximising yields demands comprehensive knowledge of the process, i.e. one has to know which critical parameters influence the process and how changing a parameter affects the overall process. This includes not only knowledge of physical parameters such as temperature and pressure, but also the change over time

of material compositions.

PAT currently plays rather a minor role in biotechnology. Although physical parameters of fermentation processes, including temperature, pH, optical density, CO2 and oxygen pressure, are measured inline, i.e. directly in the process, there is generally no online determination of individual material components or the precise, near-time determination of the cell count, which is essential for the control of fermentation. One reason is that previously only a few reliable inline sensors (e.g. for glucose or ethanol) were available for determining the material composition directly in the fermenter, thus material analysis required that samples are removed from the fermenter. Sampling was frequently performed only once per day to minimise the risk of fermenter contamination.

Another reason that many companies in the pharmaceutical industry have chosen not to embrace the optimisation potential of PAT is the costly and time-consuming revalidation of their approved, registered production processes. In late 2002, the FDA launched a PAT initiative to

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encourage a paradigm change in the pharmaceutical and biotechnology industries.

One objective is to understand the influence of critical process parameters on the quality of the drug product and thus better understand the process. The critical parameters of many bioprocesses have not yet been completely identified. Otherwise, a producer would be able to explain what influence individual components (sugar, salts, vitamins, serum) have on his process.

Why are auxiliary components formed, and why do they occur in different concentrations in different runs? Or can someone explain why it is necessary, despite constant process conditions, to interrupt fermentation in a continuous fermentation process to guarantee consistent product quality?

In the case of a fermentation process, the critical parameters, which also include material concentrations and the cell count, must be identified and continuously monitored if these questions are to be answered.

Technical implementation requires the complete automation of sampling, sample transport and sample analysis. In the past,

employees had to transport the sample from the fermenter to the analytical device, breaking the automation chain. The BaychroMAT® technology platform from Bayer Technology Services GmbH solves this problem. With the development of BaychroMAT® CellCount for fermentation processes, a prototype which was presented at the Interkama and ACHEMA trade fairs in spring 2006, a fully-automated, online analysis system for fermentation control is now available for the first time.

In spring 2006 BaychroMAT® CellCount went public at Interkama fair in Hannover, Germany.

Reliable, sterile sampling and the extraction of minimal sample volumes were made possible by the development of a novel, fully automated valve with minimal dead space installed in a standard DN 25 nozzle. The transport of the cell-bearing medium has been optimised to minimise shearing and cell losses, even with sensitive cell lines. After each sample is taken, the sampling valve and transport line can be cleaned with sterile steam and flushing

liquids such that the system meets all CIP requirements. The samples are conditioned in an integrated sample preparation module then automatically made available to one or more analytical devices. In addition to the cell counter (Cedex® from innovatis AG) integrated into BaychroMAT® CellCount, biochromatography systems or enzymatic bioanalysers can also be operated online with BaychroMAT®.

The MOAB software controls every component of the BaychroMAT® CellCount and uses multiple sensor systems to monitor sampling and ensure reliable operation. The platform can be connected to all common process control systems (analog and digital) via ARTS, the integrated analyser result transfer software.

Thanks to the combination of these two software packages in conjunction with innovative sampling and the proven functions of the BaychroMAT® platform, fully automated control of fermentation processes on the basis of the cell count is now possible in a production environment for the first time.

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Micro and Nanotechnologies From R&D to drug delivery Micro and nanotechnologies will have a high impact on the pharmaceutical industry making the way to personalised therapy for better treatment efficiency and fewer side effects.

Géraldine Andrieux, Life Sciences Project Manager, Yole Développement, Clémence Labat, Senior Analyst, Yole Développement, Barbara Pieters, Market Analyst, Materials & Instrumentation, Yole Développement Jean Christophe Eloy, Managing Director, Yole Développement, France

M

icro and nanotechnologies will support pharmaceutical companies in their development strategy by providing solutions to: • Discover new drug candidates and therapeutic pathways • Reduce new therapies development time • Facilitate drugs launching with adapted delivery systems • Provide better treatment performances • Extend pharmaceutical products lifecycle thanks to innovative delivery systems.

This article gives an overview of micro and nanotechnologies and the way they impact the pharmaceutical industry using product and development case studies.

Introduction to micro and nanotechnologies Microtechnologies are related to micro manufacturing processes leading to miniaturized devices. It involves specific material and process technologies like micromachining or etching of layers staked for structuration with lithography techniques.

First developed for automotive and IT applications, microsystems technologies are today a main miniaturisation approach for Life Science applications.

Nanotechnologies are techniques allowing to synthesize, transform, measure,

manipulate and assemble objects whose dimensions are less than or around 100 nanometers (nm) in order to work out special properties or functions like new mechanical, optical, electrical, magnetic, chemical and biological properties. Microtechnologies have first led to miniaturised solutions whose performances are today enhanced by nanotechnologies.

The impact of micro and nanotechnologies on drug discovery Microtechnologies have shown their high added value in supporting pharmaceutical R&D efforts, in improving the drug discovery process results, in proposing new and faster analysis possibilities while notably reducing the analysis cost.

Microtechnologies offer the advantages of miniaturisation to: - reduce cost by lowering sample volume and reagents used - enable faster analysis - enable high parallelisation - enable multiplex analysis - provide with higher accuracy Miniaturised microtiter plate up to 1536 wells in combination with microdispensing systems (nl range up to pl) are examples of solutions provided in such objectives.

Other good examples are microarrays,

microsystems with tailored surface properties (figure-1). They offer a high parallelisation of analysis, leading to higher throughput and enhanced efficiency. They are the key solution to manage the high complexity level linked to molecular biology.

This first microarray based on microtechnologies has successfully reached the market and is now becoming a gold standard in drug discovery both in academic and industrial research labs. It is produced

by Affymetrix (US) with a process allowing the synthesis of nucleic acid probes on a glass wafer subFigure 1: GE Healthcare strate.

Some limits still CodeLink Microarray remain especially in terms of sensitivity and reproducibility.

Going a level forward, nanotechnologies are now entering the field to provide solutions for new biochips generation.

While microtechnologies indeed bring the advantage of miniaturisation, nanotechnologies offer new physical, chemical and biological properties of materials at the nano scale: • Nanocoatings further expand microarrays applications by allowing the attachement of a broad range of probes • Nanotechnologies provide new surface to increase the biochips' sensitivity.

• Nanotechnologies make it possible to analyse interactions directly at the molecule level with sensors relying on conformational changes in biomolecules (figure 2)

Microfluidic technology also improves drug discovery and development.

LabChip 3000 from Caliper Life Sciences (US) is a good example of microfluidics

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Figure-2: Xenon Biosensor

device. Recently Caliper Life Science announced that 12 of the top 15 pharmaceutical companies actively use Caliper systems in their discovery efforts, including AstraZeneca, Novartis and Vertex Pharmaceuticals.

Microtechnologies thus help scientists better predict which compounds will be successful drug candidates.

Microtechnologies for process intensification

Micro and nanotechnologies in drug delivery

Another emerging trend is to use microtechnologies in a production device integrating mixing and production reaction.

Micro Reaction Technology (MRT) has the following advantages: - help process intensification by reducing the size of the plant, the amount of reagents and catalyst, enhancing the speed of reaction and heat exchanges.

- higher chemical efficiency, leading to higher yield obtained at lower temperatures and with less catalyst.

- set up of new processes and new chemical pathways. It will lead to the synthesis of new molecules that were previously not achievable.

MRT also will enable to reduce the cost of the manufacturing, which is a major advantage in a competitive environment.

Top pharmaceutical companies are already assessing microreaction technologies.

Micro and nanotechnologies are also showing a very high potential in drug delivery.

Areas of high value addition are: • Facilitate drug launching with an adapted delivery system • Provides better treatment performances • Work in a non-invasive way • Be as small and compact as possible to be easily implanted in the body or portable for emergency tools • Extend pharmaceutical products lifecycle thanks to innovative delivery systems.

Those miniaturization techniques have thus proven their added value in therapy through new generation medical devices.

The commercialised product Respimat® Soft Mist™ Inhaler of Boehringer Ingelheim microParts for asthma or chronic obstructive pulmonary disease (COPD) treatment is a good example. Such device increases lung deposition by reducing side effects.

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Many developments are running in this field especially for implantable intelligent delivery systems with an actuation mode, allowing drug dispense with a specific dosing. For example ChipRX Inc (US) is working on the development of a Self Regulating Responsive Therapeutic System (figure 3).

Future nanoparticles will act as the most suitable drug targeting system by providing treatment at the molecular level.

They provide controlled drug release, reduce side effects, and make possible to deliver new drugs candidates not adapted to conventional delivery solutions.

Conclusion Micro and nanotechnologies provide solutions to drive innovation in the next therapies strategies both from a molecule and delivery strategy perspective.

In the future, micro and nanotechnologies will make the bridge between diagnosis and treatment. Such bridge is named “theranostics”.

Micro and nanotechnologies will thus have a high impact on the pharmaceutical industry making the way to personalised therapy for better treatment efficiency and fewer side effects.

In 2004, Boehringer Ingelheim ac-

quired microParts, a MEMS contract manufacturer illustrating the attractiveness of microtechnology for pharmaceutical companies. Other pharmaceutical companies are today actively investigating those technologies through the setting up of collaborations with technology providers. Indeed many competencies have been developed worldwide by start ups, SMEs and major players of the microtechnologies industry to provide attractive solutions.

Micro and nanotechnologies are a powerful way for the pharmaceutical industry to strengthen its innovation strategy.

References Data extracted from Yole Développement reports: LifeScienceIC, EMMA, NanoSEE Yole Développement is the market research consulting company in the micro and nanotechnologies field providing marketing, technology and strategic analysis for business development.

For more information please visit our website: www.yole.fr

Figure 3: ChipRX Self Regulating Responsive Therapeutic System

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Ultra Performance Liquid Chromatography (UPLC™) UPLC presents the possibility to extend and expand the utility of conventional HPLC, a widely used separation science.

Michael E. Swartz, Principal Scientist, Waters Corporation

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igh performance liquid chromatography (HPLC) has proven to be the predominant analytical technology used in laboratories worldwide during the past 30-plus years.

One of the primary drivers for the growth and continued use of HPLC has been the evolution of the packing materials used to effect the separation. An underlying principle of HPLC dictates that as column packing particle size decreases, efficiency and thus resolution also increases. As particle size decreases to less than 2.5µm, not only is there a significant gain in efficiency but also the efficiency doesn’t diminish at increased linear velocities or flow rates as dictated by the common van Deemter equation. By using smaller particles, speed and peak capacity (number of peaks resolved per unit time) can be extended to new limits, termed Ultra Performance LC™, or UPLC™. With UPLC, it is now possible to take full advantage of chromatographic principles to run separations on shorter columns, and/or higher flow rates for increased speed, with superior resolution and sensitivity.

Chemistry of small particles The design and development of sub-2µm particles is a significant challenge, and researchers have been active in this area for some time to capitalize on their advantages. Although high efficiency nonporous 1.5 µm particles are commercially

available, they suffer from poor loading capacity and retention due to low surface area. To maintain retention and capacity similar to HPLC, UPLC uses a novel porous particle that can withstand high pressures. Silica based particles have good mechanical strength, but can suffer from a number of disadvantages, which include a limited pH range and tailing of basic analytes. Polymeric columns can overcome pH limitations, but they have their own issues, including low efficiencies and limited capacities.

In 2000, Waters introduced XTerra™ particle technology, a first-generation hybrid chemistry that took advantage of the best of both the silica and polymeric column worlds. XTerra columns are mechanically strong, with high efficiency, and operate over an extended pH range. They are produced using a classical sol-gel synthesis that incorporates carbon in the form of methyl groups. But in order to provide the kind of enhanced mechanical stability UPLC required, a second generation bridged ethane hybrid (BEH) technology was developed, called ACQUITY UPLC BEH technology. ACQUITY UPLC BEH 1.7µm particles derive their enhanced mechanical stability by bridging the methyl groups in the silica matrix, resulting in a column packing that can stand up to the rigors of both high pressure and high pH. Packing a 1.7µm particle in reproducible and rugged columns was also a

challenge that needed to be overcome, however. A smoother interior surface for the column hardware, and re-designing the end frits to retain the small particles and resist clogging were necessary. Packed bed uniformity is also critical, especially if shorter columns are to maintain resolution while accomplishing the goal of faster separations. All ACQUITY UPLC BEH columns also include eCord™ microchip technology that captures the manufacturing information for each column, including the quality control tests and certificates of analysis. When used in the Waters ACQUITY UPLC System, the eCord database can also be updated with real time method information, such as the number of injections, or pressure information, to maintain a complete column history.

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Capitalising on smaller particles Instrument technology also had to keep pace, to take advantage of the increased speed, superior resolution and sensitivity afforded by smaller particles. Standard HPLC technology simply doesn’t have the horsepower to take full advantage of sub2µm particles. A completely new system design with advanced technology in the pump, auto sampler, detector, data system, and service diagnostics was required. The ACQUITY UPLC System has been holistically designed for low system and dwell volume to take full advantage of low dispersion and small particle technology.

Achieving small particle, high peak capacity separations requires a greater pressure range than that achievable by today’s HPLC instrumentation. The calculated pressure drop at the optimum flow rate for maximum efficiency across a 15cm long column packed with 1.7µm particles is about 15,000psi. Therefore a pump capable of delivering solvent smoothly and reproducibly at these pressures that can

compensate for solvent compressibility, and operate in both the gradient and isocratic separation modes is required.

Sample introduction is also critical.

Conventional injection valves, either automated or manual, are not designed and hardened to work at extreme pressure. To protect the column from experiencing extreme pressure fluctuations, the injection process must be relatively pulse-free. The swept volume of the device also needs to be minimal to reduce potential band spreading. A fast injection cycle time is needed to fully capitalise on the speed afforded by UPLC, which in turn requires a high sample capacity. Low volume injections with minimal carryover are also required to realise the increased sensitivity benefits.

With 1.7µm particles, half-height peak widths of less than one second are obtained, posing significant challenges for the detector. In order to accurately and reproducibly integrate an analyte peak, the detector sampling rate must be high enough to capture enough data points across the peak. In addition, the detector cell must

have minimal dispersion (volume) to preserve separation efficiency. Conceptually, the sensitivity increase for UPLC detection should be 2-3 times higher than HPLC separations, depending on the detection technique. MS detection is significantly enhanced by UPLC; increased peak concentrations with reduced chromatographic dispersion at lower flow rates (no flow splitting) promotes increased source ionization efficiencies.

The ACQUITY UPLC System consists of a binary solvent manager, sample manager (including the column heater), detector, and optional sample organiser.

The binary solvent manager uses two individual serial flow pumps to deliver a parallel binary gradient. There are built-in solvent select valves to choose from up to four solvents. There is a 15,000psi pressure limit (about 1000 bar) to take full advantage of the sub-2µm particles. The sample manager also incorporates several technology advancements. Low dispersion is maintained through the injection process using pressure assisted sample introduction, and

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Figure 1: Comparison of HPLC and UPLC for the separation of a ginger root extract. HPLC conditions: Column: 2.1 by 100mm 5.0µm prototype ACQUITY BEH C18 at 28°C. A 25-96%B linear gradient over 10 minutes, at a flow rate of 1.0 mL/min was used. Mobile phase A was water, and B was acetonitrile. UV detection @ 230nm, 10µL injection.

UPLC conditions: Column: 2.1 by 100mm 1.7µm ACQUITY BEH C18 at 28°C. A 50-100%B linear gradient from 1.4 to 3.7 minutes, followed by a hold until 6.0 minutes, at a flow rate of 0.3mL/min was used. Mobile phase A was water and B was acetonitrile. UV detection @ 230nm, 5µL injection.

Figure 2: UPLC Separation of Seven Coumarins Illustrating Fast Method Development. Column: 2.1 by 30mm 1.7µm ACQUITY UPLC BEH C18 @ 35°C. A 20-40%B linear gradient over 1.0 minute, at a flow rate of 0.86mL/min was used.

Mobile phase A was 0.1% formic acid, B was acetonitrile. UV detection @ 254nm and 40 pts/ sec. Peaks are in order: 7-hydroxycoumarin-glucuronide, 7-hydroxycoumarin, 4-hydroxycoumarin, coumarin, 7-methoxycoumarin, 7-ethoxycoumarin, and 4ethoxycoumarin.

a series of pressures transducers facilitate self-monitoring and diagnostics. It uses needle-in-needle sampling for improved ruggedness and a needle calibration sensor increases accuracy. Injection cycle time is 25 seconds without a wash and 60 sec with a dual wash used to further decrease carry over. A variety of microtiter plate formats (deep well, mid height, or vials) can also be accommodated in a thermostatically controlled environment. Using the optional

sample organiser, the sample manager can inject from up to 22 microtiter plates. The sample manager also controls the column heater. Column temperatures up to 65°C can be attained. A “pivot out” design allows the column outlet to be placed in closer proximity to the source inlet of an MS detector to minimise sample dispersion.

The tunable UV/Visible detector includes new electronics and firmware to support Ethernet communications at the high data rates necessary for UPLC detection. Conventional absorbance-based optical detectors are concentration sensitive detectors, and for UPLC use the flow cell volume would have to be reduced in standard UV/Visible detectors to maintain concentration and signal. Smaller volume conventional flow cells would also reduce the path length upon which the signal strength depends according to Beer’s Law. And worse: a reduction in cross-section means the light path is reduced, and transmission drops, increasing noise. Therefore, if a conventional HPLC flow cell were used, UPLC sensitivity would be compromised.

The ACQUITY Tunable UV/Visible detector cell consists of a light guided flow cell equivalent to an optical fibre. Light is efficiently transferred down the flow cell in an internal reflectance mode that still maintains a 10mm flow cell path length with a volume of only 500mL. Tubing and connections in the system are efficiently routed to maintain low dispersion and to take advantage of leak detectors that interact with the software to alert the user to potential problems.

Finally, the ACQUITY UPLC System is the first instrument of its type to incorporate Intelligent Device Management technology - a type of technology that has been successfully implemented in highly regulated, maximum-security medical devices and medical records environments. Called Connections INSIGHT, this technology continuously monitors instrument operation, securely collects information about instrument conditions and then encrypts and transmits it to secure proxy servers at Waters or to pre-designated authorised service technicians within a client organisation whenever preventive maintenance is required or a system fault is encountered.

In doing so, preventive maintenance pro-

cedures can be scheduled before the scientist is even aware of the need for them.

Applications Chromatographers are used to making compromises; and one of the most common scenarios involves sacrificing resolution for speed. In addition, for complex samples like natural product extracts, added resolution can provide more information in the form of additional peaks. Figure 1 shows an HPLC versus UPLC separation comparison of a ginger root extract sample where both speed and resolution are improved. Chemometric modelling software (DryLab, Rheodyne Corp.) was used to model and redevelop the separation and transfer it to the ACQUITY UPLC System and BEH chemistry..

Faster separations can lead to higher throughput and time savings when running multiple samples. But a significant amount of time can also be consumed in developing the method in the first place.

Faster, higher resolution UPLC separations can cut method development time from days, to hours, or even minutes. Figure 2 is an example of an UPLC separation of several closely related coumarins and a metabolite that was developed in under an hour; including UPLC scouting runs for gradient optimisation, and individual runs for elution order identification. These runs were performed in a fraction of the time that would be necessary by conventional HPLC, resulting in significant time savings in the method development laboratory.

Conclusion At a time when many scientists have reached separation barriers pushing the limits of conventional HPLC, UPLC presents the possibility to extend and expand the utility of this widely used separation science. New ACQUITY UPLC technology in chemistry and instrumentation provides more information per unit of work as UPLC begins to fulfill the promise of increased speed, resolution and sensitivity predicted for liquid chromatography.

Acknowledgments:

The author would like to acknowledge the contributions of the ACQUITY program team at Waters, particularly Michael Jones, and Andy Aubin for their contributions to this manuscript.

ACQUITY UPLC, UPLC, eCord, XTerra, and Ultra Performance LC are trademarks of Waters Corporation.

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Cover Story

Growth in

Japanese Clinical Trials Market

Regulatory changes and the acceptance of foreign clinical data have fuelled growth of the clinical trial sector in Japan.

Lim Bee Koong, Director, Life Sciences – Clinical, TNT Asia

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he clinical trials environment in Japan has changed dramatically over the last eight years. In particular, changes in the Pharmaceutical Affairs Law (PAL) have allowed the acceptance of foreign clinical data and fuelled the growth of the clinical trial sector in the country.

There is an increased need for businesses involved in clinical trials to take heed of the rapidly changing environment to capitalise on its growth.

Background to pharmaceutical administration In 2004, the Japanese government introduced new initiatives and expanded old ones to promote fundamental reforms in the country and drafted its “Basic Policies for Economic and Fiscal Policy Management and Structural Reform 2004.” The primary objective was to establish a foundation for economic growth amid a declining population and a changing international environment that was becoming increasingly globalised, competitive and yet, inter-dependent.

These policies clearly underscored the government’s commitment to reform the social welfare system through gradual decentralisation and deregulation while ensuring continued health, safety and

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C ov e r S tor y

general well being of the Japanese society.

The medical and healthcare sectors were, and still are, expected to have significant effects on the overall economy from the standpoint of expanding the country’s industrial base and improving the quality of life. As such, the life sciences industry underwent significant changes.

As healthcare is becoming more and more of a government issue with populations experiencing longer life spans, there is an increased need for medical facilities and medication to be readily available and accessible to all. Due to previous stringent drug registration rules, the Japanese population has been unable to access 25 per cent of the world’s newest and most advanced drugs. To counter this, as well as promote more efficient management and enhanced services in the medical industry, much deregulation is taking place in Japan. Perhaps the most significant reform has been the recent revision in the Pharmaceutical Affairs Law, which transferred about 350 drug items to the quasi-drug category, and approved their retail sales at convenience stores and other general retail stores.

These revisions, which took effect in April 2004, have made it easier for international firms to market pharmaceuticals in Japan by simplifying the approval process for importing and manufacturing pharmaceuticals. Essentially, as the Japanese government relaxed its rules on research data requirements for drug registration, data from countries such as Korea and Taiwan can now be accepted. Also, Japanese companies, which are more open to outsourcing research to international laboratories, can now do so with ease.

As a result, the pharmaceutical and biotechnology market in Japan has experienced significant growth in the last couple of years. The clinical trial market, once estimated to be worth more than US$27 million in 2004, is now expected to grow almost seven fold to US$180 million by 2010. Similarly, the broader biotech industry in Japan is predicted to be worth US$350 billion by 2010. In addition, more than any market in Asia, the Japanese life sciences market is expected to grow nine per cent year-on-year.

A significant portion of this growth has come from international Contract Research Organisations (CROs), which have set up branches in Japan. With the regulatory changes, pharmaceutical companies are able to take advantage of CROs based in other countries to increase flexibility and efficiency as well as to lower the overall costs of research and development.

The rule change benefits the industry as a whole and is a key opportunity for businesses involved in the biotech sector in Japan, including businesses involved in the transportation of clinical trial material, such as TNT.

The need for clinical trial logistics The complexities of managing clinical trial logistics in Japan and the rest of Asia have spawned the entry of global, full service logistics providers, such as TNT1, into the pharmaceutical logistics industry.

Many pharmaceutical companies and central laboratories have turned to these

With the increased globalisation of drug development, companies will have to introduce new drugs into every market simultaneously and rapidly, Japan included.

specialist logistics providers as they offer an immediate and reliable solution to clinical trial logistics’ needs and enable pharmaceutical companies to focus on their core competencies.

1 To support the growth of the clinical trials sector and meet the logistical needs in the region, TNT launched ‘Clinical Express’, a suite of logistics services for the clinical trial logistics market in April 2004. Targeted at pharmaceutical companies, central laboratories and CROs engaged in clinical research and drug development, Clinical Express offers two distinct levels of services – ‘Clinical Express Exclusive’, the global door-to-door service for diagnostic specimens under frozen conditions, and ‘Clinical Express Network’ for ambient diagnostic specimens. Apart from providing customers with a full suite of customised services, TNT also offers cost advantages by consolidating shipments. Customers can also be confident in the service as TNT seeks to ensure that staff members constantly upgrade their skill sets, and are always kept up-to-date with the most current knowledge of health, safety and customs regulations.

In clinical trials, diagnostic specimens such as blood samples are both time and temperature sensitive. To maintain the accuracy of the test specimens, they need to be kept within specific temperature ranges, and tested within 72 hours of collection.

The typical temperature ranges required for such samples include: ambient (room temperature), refrigerated (2-80C), and frozen (below –200C).

Furthermore, when test samples need to be transported overseas via airfreight, their movement is subject to regulation by the International Air Transport Association (IATA), which has stringent requirements for packaging, documentation and regulatory declarations. Inaccurate labelling or packaging can result in customs delays for days and render the test samples invalid.

The future of clinical trials market in Japan It is still too early to analyse the results of the deregulation, as it is still a complex process. In fact, despite introducing the revisions in early 2004, full-scale implementation of the revised Pharmaceutical Affairs Law entailing the introduction of the manufacturing and sales approval system; the classification of medical equipment according to risk levels; the introduction of designated third-party certification organisations and the expansion of post-marketing safety measures, was only enacted last year.

The sector also faces a number of challenges. Despite the rapid expansion of pharmaceutical and clinical trial market, there is a need to provide more trained researchers and technologists in Japan to provide the relevant professional and technical expertise.

While some countries in the region are already showing promising signs of changes in regulations, it will take some time before Japan and the rest keep pace with the industry’s global standards. With the increased globalisation of drug development, companies will have to introduce new drugs into every market simultaneously and rapidly, Japan included. Global communication and the use of common clinical data will also further increase.

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China

Clinical trial strategies for small pharma Utilising a company that is based in China and understands both ICH GCP and China SFDA GCP requirements is very important for ensuring clinical trial integrity and success.

Nicholas P. Zemo, Vice President, Business Development & Sales, Accelovance, China.

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ffshoring clinical research is becoming more prevalent as the biopharmaceutical industry seeks to address the escalating time and cost for drug development. Implementing such a strategy in China presents three key opportunities: availability of patients, favourable cost structure, and the world’s fastest growing pharmaceutical market.

These opportunities are so compelling that large pharmaceutical companies feel they cannot afford NOT to be there and many have been investing in infrastructure in China for years. However, smaller companies typically do not have the internal resources (capital, personnel, capacity, or time) necessary to take advantage of these opportunities. Armed with knowledge of the processes and challenges associated with clinical trials, there are strategies smaller companies can undertake to realize the benefits of conducting trials in China.

The time for the regulatory review and approval of clinical trial application process poses a major consideration when deciding whether or not to conduct a trial in China. It typically takes approximately ten months for the China State Food and Drug Administration (SFDA) to approve clinical trial applications. Depending on the study’s enrolment period and/or the ability to submit an application early, this

has considerable impact on what types of trials benefit the most by being conducted in China. It should be noted that the ability to recruit patients in China faster than any other region in the world might offset the initial regulatory delay. The lengthy approval process is a significant concern and the China SFDA is working closely with global industry leaders and regulatory bodies to improve its processes. There is optimism that in the near future the approval process will become more favourable; however, for the present time, it poses a considerable obstacle and must be evaluated.

Another regulatory consideration is that the China SFDA typically requires some existing clinical data and/or long-term toxicology data before approving a clinical trial application. This precludes doing first-in-man Phase I studies at the IND stage.

While planning regulatory strategy, companies should consider designing the China component of the trial to position the drug for eventual China market approval. China’s pharmaceutical market is currently ranked seventh in the world and is projected to be fifth by the year 2010 and second by 2020 with revenues experiencing continued double-digit growth. This is an opportunity that could bring tremendous

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value in terms of potential revenue. New revenue streams, particularly for small companies, may enable the companies to reinvest and expand their existing portfolio. Designing a trial with this intent not only enhances the value of the trial itself, it also eliminates associated ethical issues and scepticism about conducting the trial without the intent of making the drug available to the Chinese population.

The strategy to conduct later stage clinical trials for difficult to enrol indications with long enrolment periods could provide significant value to the sponsor.

For many of these indications and therapeutic areas, the ability to recruit patients in China and complete enrolment is much faster than in the west. Several small, USbased biotech and pharma companies have pursued China to access and recruit patients faster and more cost effectively than western locations. The results have been impressive; randomising twice as many patients in one-half the time of the originally scheduled enrolment period (regulatory approval time not withstanding).

Maintaining ICH GCP quality and ethical compliance are the key industry concerns for conducting global trials in China. The confidence level around quality is rising quickly as indicated by the increasing number of FDA IND products being tested in China. To ensure quality compliance, clinical trials are currently only conducted in hospitals that are China SFDA GCP certified. Despite this government involvement and approval, there is

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still a concern with western companies that a gap exists between SFDA GCP and ICH GCP standards.

Companies need to carefully select their development partners and address quality concerns to ensure that the gap is filled for acceptance by the FDA and studies are conducted under ICH GCP guidelines.

China poses cultural, language and logistical challenges that must be addressed for any venture to succeed. Understanding the Chinese culture is critical in all aspects from establishing strong business relationships to ensure the patients, investigators, and research staff understand, adhere to, and execute the trials according to ICH GCP without bias. A comprehensive understanding of the culture from a social, economic and government perspective also helps to maximise the roles of hospitals, doctors, monitors, the government and local partners. The Chinese language presents a communication barrier, making it essential to have proper translation and interpretation to define goals and clarify expectations of all parties. For the small pharma and biotech company conducting clinical trials in China without operations in the country, logistics are of great concern. Logistics can be challenging with long distances between labs, dealing with different time zones and working with unfamiliar customs requirements. General travel costs and their frequency must also be factored into the business decision and emphasise the need for a qualified partner located in China to maintain control over timelines and budgets.

For smaller companies without resources in China, it is important to work with an organisation that can address the challenges mentioned and help capitalise on the opportunity and minimize risk.

Utilising a company that is based in China and understands both ICH GCP and China SFDA GCP requirements is very important for ensuring clinical trial integrity and success. Additionally, this partner should help the sponsor by bringing a

thorough understanding of both Chinese and Western cultures and languages to ensure that trials are processed and executed with efficiency. Partnering with Chinese biopharmaceutical companies is a strategy for funding both clinical trials and commercialisation activities. Such a business arrangement allows companies to overcome capital and resource limitations and is embraced by the Chinese as a way to capitalise on the opportunity to add late stage candidates or approved drugs to their portfolios.

China offers tremendous opportunities relative to the availability of patients, lowcost clinical trials, and potential revenue.

Smaller companies should realise that they can benefit as well, despite limited resources. To implement the appropriate strategy, the real opportunity must be identified and executed in a high quality manner. Resources and capital can be made available to fund these strategies through partnering with Chinese biopharmaceutical companies. In the end, this opportunity is great for the small biotech and pharma companies and China, which benefits from the availability of these drugs into their healthcare system.

BOOK Shelf Clinical Trials of Drugs and Biopharmaceuticals

Edited by: Chi-Jen Lee, Lucia H., Christopher L. Wu, Benjamin R. Lee, Mei-Ling Chen Year of Publication: 2005 Pages: 520 Description: This book provides an overview of current procedures and major issues involved in drug and biopharmaceutical development.

The book examines critical biochemical and pharmaceutical considerations for trials conducted during each phase of clinical development.

For more, visit the Knowledge Bank section of www.pharmafocusasia.com

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Superdisintegrants An economical alternative Orally disintegrating tablets are an emerging trend in formulation, gaining popularity due to ease of administration and better patient compliance for geriatric and pediatric patients.

Avani F. Amin, Assistant Professor & HOD, Department of Pharmaceutics, Institute of Pharmacy, Nirma University of Science & Technology, Tejal J. Shah, Reena Dua and Renuka Mishra, Department of Pharmaceutics, Institute of Pharmacy, Nirma University of Science & Technology, India

temperature limits its use to thermostable compounds only. Direct compression on the other hand represents the simplest and most cost-effective technique for the tablet manufacturing. This technique is useful for preparation of ODT because of the availability of improved excipients especially the superdisintegrants. The article cites the various types of superdisintegrants with their characteristics, mechanism of disintegration and their applications in the formulation of ODT.

Superdisintegrants

O

rally disintegrating tablets (ODT) are an innovative technology which disintegrates rapidly, usually in a matter of seconds, without the need for water, providing optimal convenience to the patient. Conventional tablets and capsules pose difficulty for swallowing in patient groups such as elderly, children, and patients mentally retarded, uncooperative, nauseated, or on reduced liquid intake diets. To fulfil the above needs, formulators have devoted considerable efforts for developing ODT. Researchers have formulated ODT for various categories of drugs, which are used for therapy in which rapid peak plasma concentration is required to achieve desired pharmacological response. These include neuroleptics, cardiovascular agents, analgesics, anti-allergic and drugs for erectile dysfunction.

The performance of an ODT depends on the technology used in its manufacture.

The disintegrating property of the tablet is attributable to a quick ingress of water into the tablet matrix, which creates porous structure and results in rapid disintegration. Hence, the basic approaches to develop ODT include maximising the porous structure of the tablet matrix, incorporating the appropriate disintegrating agent

and using highly water-soluble excipients in the formulation. Techniques, which have been used by various researchers to prepare ODT include Freeze-Drying, Tablet Moulding, Spray Drying, Sublimation, Direct Compression, Cotton Candy Process and Mass-Extrusion, however most of these techniques are patented.

Freeze drying is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve rapidly. However, the major disadvantages of this technique are that it is expensive, time consuming and fragile, which makes conventional packaging unsuitable for these products. Tablet moulding technology employs water-soluble ingredients for the rapid disintegration, but the tablets are less compact with low mechanical strength. Spray Drying and Mass Extrusion techniques also produce highly porous powders but require sophisticated instrumentation and the process is governed by a large number of variables. Sublimation produces a porous structure in the tablet matrix by use of volatile ingredients but it requires their complete removal since the remains are a matter of concern. The cotton candy process uses the candyfloss technique, however the high processing

Disintegrating agents are substances routinely included in the tablet formulations to aid in the break up of the compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet matrix. In recent years, several newer agents have been developed known as “Superdisintegrants�.

These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. On contact with water the superdisintegrants either swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs. The commonly available superdisintegrants along with their commercial trade names are briefly described herewith.

Modified starches Sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch. It is effective at a concentration of 2-8%. It can take up more than 20 times its weight in water and the resulting high swelling capacity combined with rapid uptake of water accounts for its high disintegration rate and efficiency. It is available in

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various grades i.e. Type A, B and C, which differ in pH, viscosity and sodium content.

Other special grades are available which are prepared with different solvents and thus the product has a low moisture (<2%) and solvent content (<1%), thereby being useful for improving the stability of certain drugs.

Modified celluloses Carboxymethylcellulose and its derivative (Croscarmellose Sodium) Cross-linked sodium carboxymethylcellulose is a white, free flowing powder with high absorption capacity. It has a high swelling capacity and thus provides rapid disintegration and drug dissolution at lower levels. It also has an outstanding water wicking capability and its cross-linked chemical structure creates an insoluble hydrophilic, highly absorbent material resulting in excellent swelling properties. Its recommended concentration is 0.5–2.0%, which can be used up to 5.0% L-HPC (Low substituted Hydroxy propyl cellulose) It is insoluble in water, swells rapidly and is used in the range of 1-5%. The grades LH11 and LH-21 exhibit the greatest degree of swelling.

Cross-linked polyvinylpyrrolidone It is a completely water insoluble polymer.

It rapidly disperses and swells in water but does not gel even after prolonged exposure.

The rate of swelling is highest among all the superdisintegrants and is effective at 1-3%.

It acts by wicking, swelling and possibly some deformation recovery. The polymer has a small particle size distribution that imparts a smooth mouth feel to dissolve quickly. Varieties of grades are available commercially as per their particle size in order to achieve a uniform dispersion for direct compression with the formulation.

Soy polysaccharide It is a natural super disintegrant that does not contain any starch or sugar so can be used in nutritional products.

Cross-linked alginic acid It is insoluble in water and disintegrates by swelling or wicking action. It is a hydrophilic colloidal substance, which has high sorption capacity. It is also available as salts of sodium and potassium.

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Gellan gum It is an anionic polysaccharide of linear tetrasaccharides, derived from Pseudomonas elodea having good superdisintegrant property similar to the modified starch and celluloses.

Xanthan gum Xanthan Gum derived form Xanthomonas campestris is official in USP with high hydrophilicity and low gelling tendency. It has low water solubility and extensive swelling properties for faster disintegration.

Calcium Silicate It is a highly porous, lightweight superdis-

and researchers are experimenting with modified natural products, like formalincasein, chitin, chitosan, polymerized agar acrylamide, xylan, smecta, key-jo-clay, crosslinked carboxymethylguar and modified tapioca starch.

Studies have suggested that the water insoluble superdisintegrants show better disintegration property than the slightly water soluble agents, since they do not have a tendency to swell. Superdisintegrants that tend to swell show slight retardation of the disintegration property due to formation of viscous barrier. There is no particular upper limit regarding the amount of superdisintegrant as long as the mechanical

List of superdisintegrants with commercially available brands Type of polymer

Commercially available brands & their varieties

Sodium Starch Glycolate

PRIMOGEL®, EXPLOTAB®, TABLO®, VIVASTAR®P, VIVASTAR® PSF

Cross-linked Sodium

AC-DI-SOL®, NYMCEL ZSD 16®, NYMCE ZSX®,

Carboxymethylcellulose

PRIMELLOSE®, VIVASOL®, SOLUTAB®, NS 300® (free acid type), ECG 505(calcium chelate type)

L-HPC

LH-11, LH-21

Cross-linked Polyvinyl- pyrrolidone

CROSSPOVIDON M®, POLYPLASDONE XL 10®, KOLLIDON CL®

Soy Polysaccharide

EMCOSOY®

Cross-linked Alginic Acid

SATIALGINE®

Gellan Gum

KELCOGEL®

Xanthan Gum

GRINDSTED®, XANTHAN SM®, KELTROL® CG, XANTURAL®

Ion Exchange Resins

INDION 414®

integrant, which acts by wicking action. Its optimum concentration range is 20-40% Ion exchange resins The INDION 414 has been used as a superdisintegrant for ODT. It is chemically cross-linked polyacrylic, with a functional group of – COO – and the standard ionic form is K+. It has a high water uptake capacity.

Others Although there are many superdisintegrants, which show superior disintegration, the search for newer disintegrants is ongoing

properties of the tablet are compatible with its intended use. The superdisintegrant may be used alone or in combination with other superdisintegrants. Commercially available superdisintegrants are listed in the table given below.

Thus, an overview of various types of superdisintegrants which are available have been discussed. The ease of availability of these agents and the simplicity in the direct compression process suggest that their use would be a more economic alternative in the preparation of ODT than the sophisticated and patented techniques.

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RFID in Pharma

An Asian perspective

RFID is performing functions relevant to pharmaceutical distribution and administration.

Peter Harrop, Chairman, IDTechEx, UK

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of service, security and cost control. The FID in healthcare is a small part US Food and Drug Administration FDA of the global RFID market today, recommends RFID on pharmaceuticals but it is growing rapidly to beat item level but for anti-counterfeiting. come a US$2.1 billion business by the end The FDA is dissatisfied with the limited of 2006. A large part of this will be the tagprogress on this. Pfizer's Viagra, Glaxoging of pharmaceuticals for many purposes, SmithKline's Trizivir and few other brands including RFID-enabled smart packaging are tagged so far, so the FDA may make it that records usage data such as when each a legal requirement by 2007. tablet was removed. These ‘patient compliEast Asian pharmaceutical suppliance monitoring’ blisterpacks and plastic ers must respond to these requirements bottles of tablets make the results of drug when exporting to the US and there is trials more trustworthy because they show also the possibility of local legislation and which patients fail to follow instructions.

Some of these packages prompt the patient when to take the pills and even give a graph of how well East Asian healthcare facilities are the patient performed in pill takincreasingly seen as innovators in using ing over the last week. Patients RFID in healthcare. welcome this information and try to do better. Some of the packages have electronic self-adjusting mandates mimicking the US practice but use by dates that respond to heating of the not in the near future. In addition, RFID contents. As prices come down, such smart is performing functions relevant to pharpackages will even appear in the home, but maceutical distribution and administrathat is a long way off. Let us look at what is tion, including RFID health cards given to happening now. patients with health record, dosage, adverse In the USA, Wal-Mart has a phased reactions and so on recorded on them and program of requiring suppliers, including RFID wristbands linked electronically to pharmaceutical companies, to RFID label RFID tagged drugs for error prevention. all pallets and cases it receives. In addiSome of the wristbands give position from a tion, Wal-Mart has a program requiring distance. They are Real Time Locating SysRFID tags to be fitted to Class 2 prescriptems RTLS. Some of the tagged drugs will tion drugs, such as painkillers and other be used on smart shelves and in smart cabiprescription narcotics, at item level. That nets that provide instant stocktakes and proincludes blisterpacks and small plastic botvide alerts when errors are about to occur. tles of medication. This is for improvement

Pretide Technology CEO Sharon Chen reports success in selling RFID systems to hospitals at around US$100,000 per initial system installed. Pretide Technology is a subsidiary of Pretide Holdings, headquartered in Hong Kong. Its Taiwan office operates as an independent enterprise handling Asian customers. These customers are mostly from Taiwan, Hong Kong and China. About 70% of the staff at Pretide Technology are R&D engineers and managers.

According to Chen, “Our company goal is to double our revenues and number of employees each year. We see real opportunities to achieve this here in Asia. Currently about 70% of Wal-Mart vendors are Asian companies. We think they could potentially be the second wave of our customers. We anticipate that mid-size companies and even small businesses in Asia will generate significantly more RFID users over the next few years. Regarding the US and Europe, mostly big customers are expected to deploy RFID solutions in the near-term. This is why I would predict compound annual growth at the 50-60% level, for the whole industry, during the next three to five years.”

From India, Ranbaxy Pharmaceuticals sells its brand and generic pharmaceuticals and active ingredients in over 100 countries. In 2004, it announced that it would be implementing an RFID tracking system to enable it to meet Wal-Mart’s RFID mandate for its Class 2 pharmaceutical suppliers. The system integrator that it uses, Acsis, is also providing pharmaceutical tracking systems for several of the world’s leading pharmaceutical companies to enable them to comply with Wal-Mart’s mandates as well as working for Wal-Mart itself.

Smart health cards are sometimes contactless i.e. RFID and therefore capable of

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working when wet and without need of a slot to sense them. By contrast, a conventional smart card has to be inserted in a slot the right way up and the right way round and it may be necessary to wipe the gold contacts to get it to work satisfactorily.

In Taiwan, 24 million people are benefiting from the world’s first Java-based smart health card project, with cards from Giesecke & Devrient. Taiwan’s National Health Insurance regime expects annual cost reductions equivalent to $220 million from the introduction of the smart card based health system.

“Ubiquitous Sensor Networks” (USN) are based on large numbers of small electronic devices that sense. They include RFID labels that record sensed data such as the time-temperature profile of blood in transit and storage – something beginning to be done in Europe and the USA. The more general concept of USN had field tests in South Korea in 2005. The National Computerisation Agency (NCA) selected what it called “application services models”. They included what was called

“u-hospital” which involved blood and anti-cancer agent management. KMI Co Ltd., created the RFID system and NCA established the technical and commercial feasibility of managing blood and anticancer agents in order to minimise medical accidents.

Mismatching patients to their care can involve giving the wrong medication.

Yet, in most healthcare facilities, there is no patient identification technology to prevent wrong administration of pharmaceuticals. Handwritten wristbands have problems such as: • 8.6% of them contain incorrect data • 5.7% are illegible to some degree • They usually cannot be read without disturbing the patient Barcoded wristbands are not much better so RFID is increasingly used, particularly since many versions can be updated with information at a distance even through obstructions such as bedclothes.

This solution involves tracking the patients at every stage of their treatment.

Catholic Medical Center - KangNam St.

Mary’s Hospital in Seoul, South Korea is using AeroScout parasitic Wi-Fi RFID tags and software with its Cisco wireless infrastructure to improve overall operational and patient flow in the 850-bed facility by “radio fingerprinting”, knowing location by a wristband sensing WiFi emitters. Hospital staff say that the resulting automatic patient recognition, real-time location and alert capabilities will help smooth traffic through the entire process and enhance delivery of patient services including pharmaceuticals, decreasing waiting periods for both staff and patients and reducing the chance of errors.

From May 2003 Alexandra Hospital, the only public hospital in Singapore not to be touched by the SARS outbreak, tested the new Hospital Management Tracking System in its accident and emergency department. The National University Hospital started a trial for its staff and this was then extended to cover patients and visitors. All patients, visitors and staff who enter areas in the two hospitals where the trials are being conducted must provide their

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name and contact information at the registration counter, so they can be contacted later, if necessary. They are then given an active (with battery) RFID card.

Hospital employees have also been given these cards. The active devices supplied

by DSTA of Singapore continually transmit RFID signals at 433 MHz to readers placed around the facilities. The emergency department at Alexandra Hospital is divided into several zones. A receiver has been installed in the ceiling of each zone.

The SARS virus incubates in 10 days, so the system was set up to store information about visitors for 21 days. This ensured that information about all the contacts, a probable SARS patient had within the hospital, remains available well after the incubation period. The information, which is confidential, is deleted from the system after 21 days.

DSTA worked with ST Electronics, a unit of Singapore’s ST Engineering. ST created the software that enables the system to track in real-time when a person enters or leaves a certain zone. It formulated

back-end software that allows staff to query the database for information. Hospital staff access the application through a portal on the hospital’s intranet. If a patient is suspected of having SARS, staff can run an immediate check to find out who has had contact with him/her, in which zone and at what time.

Alexandra Hospital handles about 250 emergency cases a day, with each patient allowed one visitor. There are also 36 doctors and nurses working in the department and the system has adequately tracked the movements and contacts of more than 500 people per day. So far, there have been no SARS cases, so the system has not been needed to trace back contacts.

The Tung Yuan hospital in China has also been tagging staff and patients as a measure against SARS and this is the basis of another case study on the IDTechEx RFID Knowledgebase of over 2000 cases of RFID in action in 75 countries. 156 of these studies are in healthcare, a sector where RFID adoption is now proving particularly rapid. See www.RFIDbase.com

There has also been work in Taiwan on patient and drug tagging. Indeed, Bangkok Hospital, one of the biggest hospitals in Thailand, has completed a pilot project on RFID technology and now plans a roll-out in 2006, then expanding it to 13 hospitals in its group in Bangkok and provinces countrywide within three years.

It is expected that patients will be issued RFID-based wristbands that store basic information about the patients such as name, sex, age, the drugs they have received and the dosages that need to be administered.

Parasitic Wi-Fi RFID has been chosen.

In summary, RFID is already widely used in pharma related applications across East Asia. Many of the suppliers of these RFID systems come from Europe and the USA but East Asian suppliers of RFID into healthcare applications are rapidly increasing in their number and capability.

East Asian healthcare facilities are increasingly seen as innovators in using RFID in healthcare.

For more read “RFID in Healthcare 2006-2016” at www.idtechex.com

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Integration of

Packaging Innovations The earlier understanding that packaging is not consumed by the end-user, therefore it need not be considered an integral part of the drug, is fast fading off.

Praful R Naik, Chief Scientific Officer, Bilcare Limited, India

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he role of packaging in Pharmaceuticals has taken an incremental leap in terms of its critical importance as an integral part of a medicine.

The earlier understanding that packaging is not consumed by the end-user, therefore it need not be considered an integral part of the drug, is fast fading off. Many challenges, issues and concerns faced by the global pharmaceutical sector have fuelled this paradigm shift.

The healthy growth in the global pharmaceutical sector has also led to the express desire for having SMART packaging with additional enhanced features, which could fulfill the requirements of an active integrated packaging.

I have my own doubts of attributing this phenomenon to the innovations in drug discovery or NDDS reaching newer heights. My personal viewpoint is that an increased awareness amongst both the producers and the end-users of drugs along with the newer challenges, faced by the pharma industry is the main cause of an enhanced attention towards packaging.

However, I fail to understand why packaging has not yet come under the same regulatory purview, especially for those materials coming in direct contact with the drug products. With longer shelf life being the key objective of the pharma producers for every drug developed and manufactured by them, it necessitates the need

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for better understanding of the possible adverse impact of the packaging materials remaining in direct contact with the medicines, sometimes for durations as long as 60 months. The adverse impact not having immediate fatalistic implications may also be to an extent responsible for the pharma packaging not getting encompassed under the pharma regulatory ambit leading to the huge gap in GMP where the drug is at one end of stringent regulations and the packaging materials produced for these drugs at the other, with virtually no regulations, except for a few universal guidelines which are merely declared or assumed with superficial audits or sometimes even without any audits or inspections.

The better understanding of materials and components through specialised research provided by some leading packaging component manufacturers has resulted in a much higher awareness of the pharmaceutical sector with respect to packaging on a whole and about the critical positive role played by plastics in providing value added packaging components and systems.

This is quite evident by the extraordinary growth of plastics in the manufacture of packaging components for pharmaceutical use. The globalisation effect is compelling the pharmaceutical sector in revisiting their existing packaging systems and methods and changing them into better and innovatively packed medications which are

globally compatible and acceptable.

The ever increasing pressure of pharmaceutical sector on the packaging industry to become more novel and effective , is catalysing the change in the R&D thought processes of the packaging industry, propelling it into research and utilising its indepth understanding of material sciences for creating new, innovative products and also orienting its research and development on four key driving forces – Functionality, Time, Price and Global availability.

The pharmaceutical manufacturing operations are governed by a quality code of conduct, the Current Good Manufacturing Practices (cGMP). The cGMP in pharmaceutical operations are further governed by the Drug regulatory agencies of the respective countries, which monitor and enforce stringent guidelines on the pharmaceutical industries for ensuring the quality, efficacy and safety of the drugs being manufactured. Unfortunately, the same code of conduct applicable to the pharmaceutical industry does not get extended to the packaging industry manufacturing these components.

There is a need to address these significant gaps. The most plausible way could be continual yet focused and successfully applicable innovations.

Key issues Today, the global pharmaceutical industry faces numerous critical challenges: • Scientific packaging for providing adequate protection to the drugs for retaining their efficacy and potency throughout their shelf life.

• Abuse/Accidental misuse of drugs • Counterfeit drugs • User-friendly packaging systems • Branding strategy • Effective management of clinical supplies for global clinical trials • Speed of clinical trials • Medication compliance

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packaging

The pharmaceutical sector has a very strong base in molecule and formulation research, resulting in development of highly effective new drugs for a varied spectrum of dreaded diseases. However, there is absence of same level of expertise with respect to packaging of these developed drugs, which results in grossly inadequate protection against highly varied environmental conditions across the globe, subsequently resulting in huge losses of drugs across the globe due to loss of their efficacy profile over a period of time. This situation is primarily due to inability to understand the optimum packaging requirement for a specific medicine. Secondly, the pharmaceutical sector does not necessarily have the right knowledge of the functional uniqueness/limitations of currently available and used packaging materials as well as their mechanical and chemical properties leading to unscientific and speculative usage. This rather blind way of selection of a specific packaging component results in aberrant observations due to adverse affect

of the environmental conditions. Apart from these concerns, the pharma industry is also continually challenged for incorporating innovative solutions on counterfeits, brand differentiation and identity, effective communication to consumers, enhanced compliance and speed-to-market for new drugs.

Counterfeit is one of the most critical challenges faced by pharma industry.

Advancements in Information Technology has created another easier avenue for proliferation of counterfeits and spurious drugs. Internet pharmacies are the latest trend for fast and uncontrolled access to almost any drug. The use of conventional packaging along with sophistications in printing technology is making it easier to create a counterfeit. As our Chairman, Mohan Bhandari says, â&#x20AC;&#x153;It has become easier to produce counterfeit drugs than counterfeit currency leading to lesser spend and higher profits.â&#x20AC;? This underscores the need for packaging industry to be as research oriented as their users in the pharma sector are.

And moreover, the innovations should be viable and application oriented, focused to address the challenges of the pharma sector.

This is crucial as challenges of every sector are unique to itself and only a focused approach would churn continual innovations with successful applications capabilities.

Parallelly, the so called pharma packaging industry struggles to meet the expectations of the pharma industry, be it cost, complexities in requirements, small volumes or instantaneous delivery expectations, and hence tends to keep its hands in multiple sectors resulting in commoditising the otherwise scientific packaging requirements. Very few packaging companies in the world are capable of ploughing back some portion of their turnover into research. This creates a vicious cycle of mediocrity in the output of packaging industry, which further results in the produce getting confined to their domestic markets. Also, the research usually gets confined to companies making the raw materials for packaging industry and this research does not have

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packaging

much value addition for the pharmaceutical sector, as its consumption is relatively negligible compared to other sectors.

End-to-end solutions There is considerable progress being made by companies like Bilcare, focused on providing total value proposition to the global pharmaceutical sector in making packaging evolve from a functional tool to an integrated part of the drug product. This is what leads to the need of research in the field of packaging as such divergent expectations can be only met with innovations.

Also, packaging does play the most crucial role in providing the solutions because it is the packaging, which is first seen by the end-user, and which can communicate everything about the drug it holds within itself. There have been quite a few classical examples of success based on packaging in pharmaceuticals. Bilcare has contributed several innovations having successful applications leading to addressing the divergent expectations of the pharma industry. The need is to create a focused approach to-

wards development of packaging solutions exclusively for pharma products.

A few new technologies have been researched and developed but have not really been successfully adopted by the pharma industry. The prime reason may be because the Pharma industry is looking at conventional ways of cost cutting and not at total effective costing. Pharma Industry becomes more satisfied on the cost per kg concept without realising that they are losing more on an overall basis. Other area is the development of technology, which would identify the optimum packaging system on an enhanced speed to enable avoidance of multiple studies during the stability programs. Bilcare, for instance, was successful in developing a novel patented technology during its past 10 years of research, which has the capability to identify the sensitivity of any formulation using a 30-day evaluation program and establish scientifically, the most suitable and optimum packaging system for that product based on several key packaging dependent parameters.

Such unique technologies imply immense

value proposition to the global healthcare and life science industry to ensure complete integration of the packaging system to the drug product it encases and also the viability of total effective costing model.

Partnering has been found to be the most effective alternative to integrate innovations on both sides. Partnering research initiatives is increasingly gaining momentum to address the current and future key concerns, be it speed-to-market, counterfeits, enhanced stability of the product coupled with increased shelf life, brand differentiation and identity, enhanced compliance, comprehensive support for global clinical trials or packaging innovations.

Focused, research-based companies like Bilcare have taken significant strides to partner with the global pharmaceutical sector in addressing the crucial limitations and concerns through research pathway churning continual value-added innovations in the form of products and services.

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information t e chnolog y

Microsoft

Digital Pharma Initiative Digital Pharma will enable lifesciences organisations to improve operations and decision making across the entire industry value chain.

Rüediger Dorn, Director, Life Sciences Industry, Worldwide, Enterprise Partner Group, Microsoft Corporation, Germany

T

oday, life sciences companies around the world find themselves at difficult crossroads. While research and development (R&D) spending continues to grow, drugs that actually make it to market are mired in a decadelong decline. The reasons are numerous and complex. Driven by more stringent government mandates aimed at protecting consumer safety and information privacy, and an emerging focus on chronic diseases such as Alzheimer’s and obesity, drug development processes are longer and more

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expensive than ever before.

Meanwhile, patent expirations and the quest to achieve greater R&D efficiency have given rise to high levels of merger and acquisition activity. A rapidly aging and increasingly cost-conscious consumer population demands access to less expensive therapies. At the same time, the life sciences industry faces widespread pressure from health plans and government regulators to control prices. Promotional spending is also an issue, as the number of sales representatives has doubled in the past eight years, while the number of physicians has grown by only 15%.

However, the future also holds huge opportunities. Increasing prosperity in the emerging markets, particularly in Asia, creates new areas to increase top-line revenue.

In parallel, scientific progress in biotechnology and the understanding of the biology inside a human body allows researchers to identify and develop entirely new com-

pounds with higher efficacy and safety.

To meet the challenges and exploit the opportunities, pharmaceutical companies must find new ways to reduce costs, streamline research, and market their products more effectively. Today, two critical imperatives provide the essential starting point for responding to this challenging business environment. These imperatives are: • Speed to insight, which encompasses the ability to integrate disconnected data sources and facilitate collaboration in order to drive faster and more accurate insights that speed decision-making processes.

• Value for cost, which entails the ability to extract greater benefit from existing investments, and realize an even higher return on new investments.

To help life sciences companies fulfil these two imperatives Microsoft has developed Digital Pharma. Microsoft® Digital Pharma provides a practical vision and solutions framework for using new technological innovations to better integrate systems and information. Designed to enable seamless collaboration between pharmaceutical industry professionals, customers, and business partners, Digital Pharma will enable life sciences organisations to improve operations and decision making across the entire industry value chain from drug discovery through marketing and sales.

Microsoft Digital Pharma overview Pharmaceutical companies enjoy an incredible wealth of highly skilled information workers. But they are burdened by information infrastructures that were built on a complex mix of proprietary applications and systems, and assembled applicationby-application over the course of many years. While these infrastructures have

information t e chnolog y

served as the foundation for remarkable innovations during the past few decades, now they hamper the flow of information from person to person and between organisations, adding significantly to the cost of new product development and limiting the potential for innovation.

Microsoft Digital Pharma provides a solutions framework for bridging the gap between people and applications. So, pharmaceutical professionals can collaborate seamlessly no matter where they are located, and access information quickly no matter where it is stored.

Designed specifically to ensure that pharmaceutical companies can quickly and easily implement next-generation solutions that add new business capabilities on top of existing technology investments, Digital Pharma enables pharmaceutical companies to realise speed to insight and value for cost, all across their business value chain.

Based on proven Microsoft technologies, Digital Pharma delivers tangible benefits that have a positive impact across the entire pharmaceutical organisation and empowers researchers to focus on a new generation of innovations. Those benefits include: • Reduced complexity: Microsoft technologies enable solutions that are easy to learn, easy to integrate, and simple to deploy and manage.

• Improved productivity: Solutions based on the Digital Pharma framework help information workers communicate and collaborate easily so they can make better-informed decisions more quickly.

• Integrated innovation: Based on industry standards, Microsoft technologies connect people and systems, and provide a robust platform for adopting future innovations.

• Value: Digital Pharma ensures a higher return on technology investments through the price advantages of the Microsoft Windows® platform, the ability to use commodity hardware, and a comprehensive set of rapid application development tools.

In emerging economies new pharmaceutical companies are rapidly growing, for which Microsoft value can be even greater. These companies typically do not have to carry the burden of huge legacy applications and can enjoy the ‘green field’

approach based on today’s IT solutions.

Microsoft solutions can help to keep complexity to a minimum, and pharma companies can build a culture that is geared at global collaboration and leverage of information technology across the entire enterprise.

The Microsoft Technology Foundation for Digital Pharma Digital Pharma utilises proven technologies to provide a comprehensive framework for creating solutions that enable pharmaceutical companies to fulfil the critical imperative to enhance speed to insight and improve value for cost.

Digital Pharma utilises the Microsoft’s .NET Framework—which offers superior interoperability and integration capabilities—in combination with industry standards-based software to provide a robust infrastructure that helps pharmaceutical companies focus on solving business issues rather than dealing with complex integration and software implementation challenges.

To deliver the agility that pharmaceutical companies need to thrive in today’s demanding and fast-changing business world, Digital Pharma utilises Web services and Services Oriented Architecture (SOA) principles.

Targeting discovery, development, manufacturing and supply chain, and sales and marketing, the Services Oriented Architecture serves as a blueprint that enables Microsoft technology partners to develop software and hardware solutions that help life sciences organisations solve real-world business issues. It also provides a standards-based foundation for interoperability between Microsoft solutions and legacy systems, ensuring that pharmaceutical companies can extend the value of their existing technology investments.

Implementing Digital Pharma Pharmaceutical companies face the difficult task of striking the proper balance between the need to take advantage of innovation and the need to minimise the risks and dislocations that are inevitable whenever new technologies are introduced.

The good news for pharmaceutical companies that want to transform operations in order to achieve speed to insight

and value for cost is that their current technology provides the foundation needed to take the next step. And today, the standards that define the specifications for these new capabilities—including Health Level 7 (HL7) and the Clinical Data Interchange Standards Consortium (CDISC)—are maturing.

Digital Pharma is designed to enable pharmaceutical companies to build on current systems and utilise existing and emerging industry standards so they can pursue an incremental approach to technology investment that balances the benefits of each solution against critical issues such as cost, potential for disruption, and impact on existing systems. This incremental approach ensures that each solution delivers benefits that are carefully matched to strategic needs, comes with a manageable price tag, and delivers a rapid return on investment.

Future vision for lifesciences Microsoft Digital Pharma opens the door to integrated innovation that provides greater value at less cost. However, Digital Pharma is not launched as a one-off undertaking, but as a journey into the future.

Building on a history of innovation and excellence in software development and a strong commitment to collaboration and integration, Microsoft is working closely with technology leaders and many of the industry’s most forward-looking companies to create a new generation of solutions that will drive unequalled value for pharmaceutical companies. Digital Pharma partners have access to pre-release versions of the upcoming products Windows Vista, Office 2007 and BizTalk Server 2006. Recently, Microsoft has launched an alliance of leading software companies to join forces to develop the next generation of BioInformatics tools. Microsoft collaborates with thought leaders to pave the way for RFID adoption in the pharmaceutical industry. Its recent Origami ultra mobile device has been welcomed by pharmaceutical companies as an ideal tool to further boost sales force effectiveness. These examples illustrate how dedicated Microsoft is to continue investments into the pharmaceutical sector that help software partners to deliver new innovations to further accelerate speed to insight and increase value for cost for the lifesciences industry.

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Products & Services Company

Page No.

Chemicals & Raw materials A Choksey Chemical Industries Chemische Werke Hommel GmbH & Co. KG CPhI India Kores (India) Limited Novasep SAS Prachi Pharmaceuticals Pvt. Ltd. Radpharm Scientific SPR Pharma

Clinical Trials Chemische Werke Hommel GmbH & Co. KG Notox

45 42

Drug Delivery Bang & Olufsen Medicom Scilla Biotechnologies (P) Limited

21 34

49

Drug Discovery & Development Chemische Werke Hommel GmbH & Co. KG Novasep SAS Radpharm Scientific Syngene

45 45 IFC 38 2,3 30 46

45 38 30 OBC

Laboratory Technology & Equipment 57 High Class Art Intl Novasep SAS 38 Profile Solutions 26

Company

Page No.

Radpharm Scientific Saeplast hf

30 61

Manufacturing & Processing A Choksey Chemical Industries Ascent Solly Chem Pvt Ltd. Celogen Pharma Chemische Werke Hommel GmbH & Co. KG Gujarat Liqui Pharmacaps Pvt Ltd. Health Protection Agency Kanha Biogenetic Laboratories Kores (India) Limited Lomapharm M. B. Sugars & Pharmaceuticals Ltd. Prachi Pharmaceuticals Pvt. Ltd. Profile Solutions Radpharm Scientific Scilla Biotechnologies (P) Limited SPR Pharma Stamfag

45 33 28 36 IFC 25 IBC 2,3 26 30 34 46 32

Outsourcing Arihant Engineers Bang & Olufsen Medicom Recon Consulting (P) Ltd. Syngene

23 21 23 OBC

Packaging Anil Printers Ltd. Bharat Box Factory Ltd.

54 50

49 25 35

Company

Page No.

Brevetti Angela Srl Delta T Dr. Lauterbach & Partner GmbH EFD Inc High Class Art Intl Hi-Glo Holo Images Pvt Ltd. IMA Headquarters MachinePlatform Pack Cheon Machinery Co., Ltd. Profile Solutions Saeplast hf Sigpack Systems AG

58 55 60 61 57 52 54 53 07 26 61 59

Quality Assurance & Control High Class Art Intl Saeplast hf

57 61

Research & Development Chemische Werke Hommel GmbH & Co. KG Health Protection Agency High Class Art Intl Syngene Vertis Biotechnologie AG

Strategy Pack Cheon Machinery Co., Ltd.

07

Trade Fairs & Exhibitions CPhI India Messe Düsseldorf China Ltd.

45 04

45 28 57 OBC 18

Suppliers Guide Company

Page No.

A Choksey Chemical Industries Anil Printers Ltd. www.anilprintersltd.com Arihant Engineers www.arihant.net Ascent Solly Chem Pvt Ltd. Bang & Olufsen Medicom www.medicom.bang-olufsen.com Bharat Box Factory Ltd. www.bbfgroup.com Brevetti Angela Srl www.brevettiangela.com Celogen Pharma www.celogenpharma.com Chemische Werke Hommel GmbH & Co. KG www.hommel-pharma.com CPhI India www.cphi-india.com Delta T www.deltaT.de www.pharma-logistic.com Dr. Lauterbach & Partner GmbH www.dr-lauterbach.de EFD Inc. www.efd-inc.com

Company

Page No.

Company

Page No.

49 54

Gujarat Liqui Pharmacaps Pvt. Ltd. www.glplindia.com

33

Pack Cheon Machinery Co., Ltd. www.packon.com

07

Health Protection Agency www.hpa.org.uk

28

Prachi Pharmaceuticals Pvt. Ltd. www.prachipharma.com

2,3

23

High Class Art Intl www.highclassintl.com

57

Profile Solutions www.profauto.com.au

26

Hi-Glo Holo Images Pvt Ltd. www.higloholo.com

52

30

50

IMA Headquarters www.ima.it

54

Radpharm Scientific www.radpharm.com.au

23

58

Kanha Biogenetic Laboratories

36

Recon Consulting (P) Ltd. www.recon-consulting.com

IFC

Saeplast hf www.saeplast.com

61

35

Kores (India) Limited www.korescd.com Lomapharm www.lomapharm.de

25

Scilla Biotechnologies (P) Limited www.scillabiotech.com

34

MachinePlatform www.machineplatform.com

53

Sigpack Systems AG www.sigpacksystems.com

59

SPR Pharma www.sprpharma.com

46

25 21

45 45 55

M. B. Sugars & Pharmaceuticals Ltd. IBC www.mb-pharma-sugar.com Messe Düsseldorf China Ltd. www.mdc.com.cn

04

Stamfag www.stamfag.ch

32

60

Notox www.notox.nl

42

Syngene www.biocon.com

OBC

61

Novasep SAS www.novasep.com

38

Vertis Biotechnologie AG www.vertis-biotech.com

18

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.

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2. IBC: Inside Back Cover

3. OBC: Outside Back cover

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