Pharma Focus Asia - Issue 15

Issue 15 2011

www.pharmafocusasia.com

The New Education for Future Pharma & Biotech Leaders Similar Biologics A golden bird to tame Emerging Trends in Functional Service Outsourcing

In Association with

Foreword Pharma Industry Breaking new ground New tools and innovative developments in tech-

The cover story, in this issue of Pharma Focus

nology have played a key role in the field of

Asia, by Mayurkumar Kalariya and Mansoor Amiji

medicine. One such technology that is enabling

from School of Pharmacy, Northeastern University,

great amount of efficiencies in pharmaceutical

USA provides insights into how cancer immu-

development is mobile phones. This technology,

notherapy boosts immune response to balance

which has revolutionised sharing of information

shifts from tolerance to rejection. The article also

digitally, has wide applications in the pharma-

talks about the development of different combina-

ceutical industry.

tion therapies for cancer treatment, challenges

Mobile applications offer greater benefits like making R&D process more efficient and costeffective, providing a faster path to trials, assisting investigators in administering trials, etc.

involved in cancer immunotherapy and the future outlook of cancer vaccines.

This issue also covers how robust analytical characterization techniques are employed to

Meanwhile, improved research aided by faster

develop robust approaches for effective charac-

data collection and integration a novel approach

terization of biosimilars, complexities involved in

for prevention and treatment of cancer has been

manufacturing biologics, emerging trends in func-

developed.

tional service outsourcing and many more.

According to the American Cancer Society, in 2011 about 1.6 million new cases of cancer will be diagnosed and approximately 570,000 deaths will occur due to cancer in the United States.

Cancer immunotherapy that includes development of prophylactic and therapeutic vaccines is designed to reduce the burden of disease.

Prasanthi Potluri Editor

22

CoverStory

Contents

Research & Development 28 Layer-by-layer micro and nano drug encapsulation with polyelectrolytes Progress and challenges Yuri Lvov, Professor, Eminent Endowed Chair on Micro and Nanosystems, Institute for Micromanufacturing, Louisiana Tech University, Ruston LA, USA Tatsiana Shutava, Research Professor, Institute for Micromanufacturing, Louisiana Tech University, Ruston LA, USA Kirill Arapov, Doctoral Candidate in Biomedical Engineering, Louisiana Tech University, Ruston LA, USA Vladimir Torchilin, Distinguished Professor of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Director, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, USA Melgardt DeVilliers, Professor, School of Pharmacy, University of Wisconsin, Madison WI, USA

MANUFACTURING 34 Similar Biologics A golden bird to tame Rajneesh Kumar Gaur Krishan K Tripathi Department of Biotechnology, Ministry of Science and Technology, India

Prophylactic and Therapeutic Vaccines A novel approach for treatment of cancer Mayurkumar Kalariya Mansoor Amiji Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, USA

42 Developing Robust Approaches to the Effective Characterisation of Biosimilar Shaligram S Rane, Sr. General Manager, Quality Nilam Diwan, Assistant Manager, Quality Assurance Om Narayan, Principal Scientist, Research and Development Rustom Mody, Executive Vice President, Science & Technology & Corresponding Intas Biopharmaceuticals Ltd, India

Strategy 06 Metabolic Biomarker and Target Discovery in Obesity-Associated Comorbidities Matej Orešič, Research Professor, Systems Biology and Bioinformatics, VTT Technical Research Centre, Finland

09 The New Education for Future Pharma & Biotech Leaders Joachim M Greuel, Adjunct Professor of Finance & Healthcare Management, Academic Director, Master in Biotechnology Management programmeme, IE Business School, Spain

14 Contract Research Organisation An outlook Somesh Sharma, Director, Jubilant Chemsys Limited, India

CLINICAL TRIALS 18 Mobile Phones “Always There Always On” Why not use It to enhance patient compliance, trial effectiveness and reduce trial cost Vikram Marla,CEO, NowPos M-Solutions, India

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INFORMATION TECHNOLOGY 46 Emerging Trends in Functional Service Outsourcing Vijay Moolaveesala, I3 Statprobe, Inc, UK

21 Events 50 Books

28

18

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Veronique Toully Managing Director UCB Pharmaceuticals

Digital innovation and engagement for pharmaceutical companies, physicians and pharmacists

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Rob Dickerson Mal Joseland Global Digital Lead, Sales and Marketing Director Emerging Markets and Warner Chilcott Asia Pacific GlaxoSmithKline

Network with local and international pharmaceutical marketing specialists Listen, learn and interact with peers and key industry thought leaders

Post-conference Workshop: Will Collie Senior Manager, External Affairs Sanofi

Andrew Moore Product Manager, Diabetes Sanofi

Exploring what social media can do to enhance marketing strategy in the pharmaceutical industry Led by Alex Butler, EMEA Marketing Communications Manager, Janssen-Cilag UK

Plus, Pharma Focus Asia readers

receive a further 15% off the registration price, quote voucher code ‘Pharma Focus Asia’ when you register online or call +61 2 9021 8808.

www.terrapinn.com/digitalpharma Judith Brimer Edward Stening Executive Officer Marketing Manager Therapeutic Goods Pfizer Australia Advertising Code Council

Media partners:

Researched and produced by:

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Advisory Board

Editor Prasanthi Potluri Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank A Jaeger Director, New Business Development Solvay Pharmaceuticals, Inc., USA

Art Director M A Hannan Copy Editor Sri Lakshmi Kolla V Rashmi Divakar Rao Jenny Jones Sales Team Khaja Ameeruddin Jeff Kenney Breiti Roger Compliance Team P Bhavani Prasad P Shashikanth Sam Smith Steven Banks CRM Yahiya Sultan P Rajesh

Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy

Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA

Laurence Flint Associate Director, Clinical Research Schering-Plough Research Institute, USA

Neil J Campbell CEO, Mosaigen Inc. and Partner Endeavour Capital Asia Ltd., USA

Subscriptions incharge Vijay Kumar Gaddam IT Team Ifthakhar Mohammed Azeemuddin Mohammed T Krishna Deepak Yadav D Upender Head - Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

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

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

Confederation of Indian Industry

Ochre Media Private Limited, Media Resource Centre #204, 2nd Floor, Navketan Complex, Sarojini Devi Road, Opp. Clock Tower, Secunderabad 500 003, Andhra Pradesh, INDIA Tel: +91 40 4961 4444 Fax:+91 40 4961 4488 Email: asianhhm@ochre-media.com www.pharmafocusasia.com|www.verticaltalk.com|www.ochre-media.com

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

The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Sasikant Mishra Business, Policy and Network Strategist Pharmaceutical Industry, India 4

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Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

www.pharmafocusasia.com

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Strategy

Metabolic Biomarker and Target Discovery in ObesityAssociated Comorbidities Millions of adults are diagnosed as obese each year.

Many of these people are at risk of developing additional diseases, such as diabetes mellitus. The mechanisms by which obesity leads towards its complications are poorly understood. Recent research points to adipose tissue as the key target to treat obesity-related complications.

Matej Orešič, Research Professor, Systems Biology and Bioinformatics, VTT Technical Research Centre, Finland

M

illions of adults are diagnosed as obese each year worldwide. Many of these people suffer from a disorder known as metabolic syndrome, which includes symptoms such as hypertension and elevated blood cholesterol. They are also at risk of developing additional diseases, such as heart disease and diabetes mellitus. Obesity may, in fact, be a major cause of all these problems, but the mechanisms by which obesity leads towards its metabolic co-morbidities are generally poorly understood. Recent research points to adipose tissue as the key target to prevent and treat obesityrelated complications. Obesity is characterized by excess body fat, which is predominantly stored in the adipose tissue.

The specific mechanisms that may lead from obesity towards its metabolic complications such as insulin resistance and diabetes mellitus remain poorly understood. One attractive hypothesis, supported by the growing evidence from clinical as well as experimental model studies, is the “adipose tissue expandability” hypothesis. This hypothesis states that obesity associated metabolic complications are due to the limited capacity of adipose tissue to expand and therefore to store energy. If this limit of expansion is reached, the overflow of lipids leads to their deposition ectopically, leading to potentially toxic effects in peripheral tissues via the excessive accumulation of “lipotoxic” or pro-inflammatory lipid species such as ceramides.

Individual’s capacity of adipose tissue may depend on genetic and environmental factors. While epidemiological studies suggest that there is a near linear relationship between the body weight and risk of diabetes mellitus as measured, for example, by a degree of insulin resistance, such an association may in fact be due to the “averaging effect” across a large population. Individually, adipose tissue expandability hypothesis would suggest that there is a threshold for body weight, as dependent on individual’s adipose tissue 6

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Strategy

Figure 1. Model of physiological regulation of lipid membrane composition in obesity (MUFA, monounsaturated fatty acid; PL, phospholipid; SFA, saturated fatty acid). Reproduced under the terms of the Creative Commons Attribution License from K. Pietiläinen et al., Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans, PLoS Biol. 9(6), e1000623 (2011)

capacity. Reaching the threshold would then be accompanied by a notable decrease of insulin sensitivity. When averaging over a population level, increase of body weight would linearly associate with lower insulin sensitivity. However, in a population-wide analysis the information about the individual’s threshold is being lost.

This has important implication when considering early markers of risk of obesity-associated metabolic complications.

While body weight is a well-established risk factor for diabetes, at an individual level it has very little predictive diagnostic value. Instead, biomarkers should be sensitive to the pathophysiological mechanisms leading to obesity-related complications.

For example, marker sensitive to the status of adipose tissue may be able to detect when a person is close to reaching its capacity to store lipids in the adipose tissue and thus being at a higher risk of developing metabolic complications.

In addition to adipose tissue, liver is another key organ associated with diabetes risk. In fact, according to a recent study by The European Association for the Study of the Liver, based on current trends of incidence the non-alcoholic fatty liver disease (NAFLD) may affect 50 per cent of all US adults by 2030.

NAFLD, which is characterised by the deposits of fat in the liver, mainly in the form of triglycerides, is a major risk factor

leading to chronic liver disease and liver failure. In addition, liver fat is a major determinant of metabolic syndrome. There is currently no non-invasive test available for determining patient’s liver fat which is applicable in healthcare setting. Liver fat is usually determined by histology or estimated by magnetic resonance spectroscopy. The former is highly invasive as it requires the liver biopsy, so it is only applied in the case of chronic liver conditions. The latter may be too expensive for healthcare screening purposes. There is therefore a great clinical need for establishment of molecular markers sensitive to liver fat amount. Such markers could be applied for screening of patients, as well as in clinical trials aiming to treat the obesity-related complications.

Early detection of pathways associated with development of diabetes

There is a need for paradigm shift from searching for early disease biomarkers in the epidemiological setting towards the search for molecular biomarkers of “intermediate phenotypes” which reflect the pathophysiological mechanisms behind the processes leading from obesity towards its complications such as diabetes mellitus.

This will not only establish more powerful marker applicable in personalized healthcare setting, but also provide powerful tools for detecting persons at risk much earlier than currently possible.

In the studies of adipose tissue, significant advances have recently been made by K. Pietiläinen et al. (K. Pietiläinen et al., www.pharmafocusasia.com

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There is a need for paradigm shift from searching for early disease biomarkers in the epidemiological setting towards the search for molecular biomarkers of “intermediate phenotypes”

study, the statistical network analysis was applied to attempt to identify the regulatory mechanisms underpinning the adaptive changes and found the gene encoding the fatty acid elongase Elovl6 might be involved in fatty acid remodeling in obese people. This finding was further validated in vitro. When Elovl6 was silenced in an adipocyte cell line, the cells could no longer maintain the right level of the adaptive lipids observed in obese twins.

In summary, the study described above revealed how lipid membranes of adipocytes remodel to maintain normal membrane function in metabolically compensated individuals, and how this adaptation breaks down in individuals characterized by metabolic complications of obesity (Figure 1). Adipocyte membranes may therefore hold the answers about the early pathophysiological processes leading to diabetes.

Consequently, measurement of adipose tissue membrane lipids or their correlates

A u t h o r BIO

Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans, PLoS Biol. 9(6), e1000623 (2011)). The team used mass spectrometry based lipidomics, a comprehensive strategy to profile molecular lipids, to study the fat tissue biopsies among several sets of monozygotic twins. In each twin pair, one twin was obese but metabolically compensated (i.e., “healthy obese”), while the other twin exhibited a normal weight. Because monozygotic twins share the same DNA and early upbringing, the impact of these factors on adult body mass phenotypes is accounted for, leaving other factors such as adult diet and lifestyle choices as the major variables.

When dietary intake was compared within twin sets, the obese twins were found to have lower amounts of polyunsaturated fatty acids in their diets than did their non-obese counterparts.

Unexpectedly, the obese people had higher amounts of membrane lipids containing polyunsaturated fatty acids in their adipose tissues than did their non-obese twins. This finding is important because cell membranes are primarily composed of lipids, and different lipids can alter a membrane’s physical properties, such as fluidity and thickness. A novel approach was then introduced to model lipidomics data from membrane lipids by comprehensive molecular dynamics simulations. The computer modeling of lipid membranes indicated that the new lipids observed in the cells of the obese twins balanced each other in such a way that overall membrane fluidity was unaffected. The results therefore suggest that lipid-content changes in obese individuals might actually be an adaptation that serves to preserve membrane function as the cells expand.

Additional analyses suggested that this adaptation can only go so far, and breaks down in the morbidly obese.

Furthermore, the elucidation of adaptive mechanism to maintain the membrane function in growing adipocytes also provides a clue about the potential novel targets to prevent or treat obesity related complications. In the same twin

from serum could provide powerful early markers of diabetes risk, applicable in personalized healthcare setting.

The study may also help explain why obese people are at risk of developing inflammatory disorders such as diabetes mellitus: the kinds of lipids that accumulate in the adipocytes of obese people are precursors for compounds that are known to aggravate the immune system.

Furthermore, the study suggests that the lipid network controlling the lipid membrane remodeling is amenable to genetic or therapeutic modulation. If small molecules can modulate this network to control for both membrane functional maintenance as well as for vulnerability to inflammation, new opportunities may arise for the prevention or treatment of obesityrelated metabolic complications.

Conclusions

There is a great clinical need for establishment of early molecular markers sensitive to pathophysiological mechanisms leading to obesity-related co-morbidities such as diabetes mellitus. While epidemiological studies may be of help in search of specific risk factors associated with the disease, more studies are needed focusing on identification of disease-associated intermediate phenotypes and their markers. The latter may hold a better chance of becoming applicable in personalised healthcare setting because they detect presence of a specific pathophysiological process in each individual, which is indicative of disease progression. Furthermore, as discussed in this article, such intermediate phenotypes and their markers may also hold clues about novel therapeutic avenues

Matej Orešič holds a PhD in biophysics from Cornell University. Since 2003 he leads the research in domains of quantitative biology and bioinformatics at VTT Technical Research Centre of Finland (Espoo, Finland), where he is a Research Professor in Systems Biology and Bioinformatics. Prof. Orešič is a director of the newly established Finnish Centre of Excellence in Molecular Systems Immunology and Physiology Research (2012-2017). He is also a co-founder and board member of Zora Biosciences, Oy. (Espoo, Finland) and a board member of the Metabolomics Society. His main research areas are metabolomics applications in biomedical research and integrative bioinformatics.

Strategy

The New Education L for Future Pharma & Biotech Leaders Specialized Master degree studies such as the “Master in Biotechnology Management” or “Master in Healthcare Management” are now available at some top European and US-American business schools. These specialized programs become increasingly popular as they offer the industry-specific training that is so critical in order to excel in the healthcare sector. I feel that the article would appeal to the readers of Pharma Focus Asia as some readers may think already about an advanced university education in healthcare. In fact, some business schools wish to increase their recruiting in Asia to reflect the growing importance of Asia as a major future pharma/biotech market.

Joachim M Greuel, Adjunct Professor of Finance & Healthcare Management, Academic Director, Master in Biotechnology Management programmeme, IE Business School, Spain

eading pharma or biotech executives often hold degrees in science (including medicine) or in business. For scientists who are interested in pursuing careers in management one hurdle is to acquire the knowledge and skills necessary to excel in a business environment, and for executives with a business education it can, at times, be challenging to understand the implications of new developments, e.g. in molecular biology.

Therefore, many regard a dual education, e.g. a Ph.D., MD, or any other science degree combined with an MBA or MBM (Master in Biotechnology Management) as the eminent training to advance a professional career in the pharmaceutical and biotechnology industries. In fact, quite a few CEOs of well-known healthcare organisations share this kind of education: Michael Maves, MD & MBA, former Executive VP and CEO of the American Medical Association (AMA), Risa LavizzoMourey, MD & MBA, President and CEO of the Robert Wood Johnson Foundation in Princeton, USA; Gary L. Gottlieb, MD & MBA, President and CEO of Partners HealthCare, www.pharmafocusasia.com

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Strategy

an integrated health system founded in 1994 by Brigham and Women’s Hospital and Massachusetts General Hospital in Boston; David Zarling, PhD & MBA, CEO of Colby Pharmaceutical Company in Menlo Park, USA; Elisabet de los Pinos, PhD & MBA, Founder and CEO of Aura Biosciences in Cambridge, USA; or Oded S. Lieberman, PhD & MBA, CEO and Chairman of the Board of Neuroderm, a biotech company located in Israel. That list could be continued.

Although the examples focus on the healthcare sector, similar careers are possible in, e.g. financial services or consulting. A typical dual degree graduate may work as investment manager in a venture capital company analysing biotech investment opportunities, or she may, as a consultant, provide advice how to optimise a clinical development programme or how to modify a term sheet of a licensing agreement in order to maximise return.

General vs. Healthcare-Specific Management Education

Although popular, a general MBA programme has one disadvantage: its case studies are on a variety of industries not related to healthcare. A student may find himself analyzing a case on McDonalds hamburgers or Mariott hotels; although without doubt educational, the conclusions cannot always be transferred to healthcare. Take the definition of a customer, for example.

A typical customer makes the purchase decision, pays for the product, and consumes the product. In healthcare it is different: the physician chooses the drug, the healthcare insurance pays for the drug, and the patient consumes the drug. It is obvious that marketing and pricing decisions are not following the same rules as for ordinary consumer products. A dedicated business education for future healthcare leaders needs to consider the specific attributes of the healthcare market.

Furthermore, the development of a pharmaceutical drug is extraordinarily risky and expensive. Any pharma 10

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or biotech executive needs, therefore, a good understanding of the pharmaceutical development process and how to analyze and manage development risk. A good grasp of decision sciences, together with some knowledge of benchmark probabilities for the development process and a solid understanding of the principles of portfolio management are mandatory for anyone operating in a biotechnology environment. The way preclinical and clinical development is organised is a key determinant of how likely it is to reach the market. Some experts believe that up to 35% of clini-

There are over one hundred programme worldwide that provide a Master in Healthcare Management (or similar) education. However, only a few allow students to continue working while studying, only a few are outside the USA, and only a few focus on the pharmaceutical and biotechnology industries. cal failures are not the result of a true lack of efficacy, for example, but rather a result of suboptimal clinical research design or conduct. We probably all know examples of drugs that show promising and clinically meaningful efficacy results in Phase II but just miss statistical significance in a Phase III trial by a hair's breadth. Enrolling 5% more patients might have provided the level of significance desired and turn a failed study into a successful one.

Another important area rarely covered extensively in traditional MBA programme is related to intellectual property (IP). The process of filing a patent and the requirements of getting a patent

granted such as, e.g. utility, novelty, and unobviousness need to be understood as well as the concept of 'freedom to operate'. Unique to the healthcare industry are also the regulatory requirements to get a new treatment approved.

Biotechnology companies, more than firms operating in other industry sectors, need licensing deals in order to attract capital. First, any biotech firm will receive direct cash compensation when certain milestones are reached so that internal projects can, at least in part, be funded from income generated from licensing agreements. Second, biotech companies 'validate' their technologies and scientific approaches to treat a disease through agreements with established pharmaceutical developers. Therefore, business development in healthcare is an important subject that is rarely covered by traditional MBA programmemes.

Although finance may appear as a subject that requires little, if any, adaptation to the healthcare sector, this point of view may change when considering the risks imminent in pharmaceutical development. How shall a manager account for that risk? Ordinary discounted cash flow analyses rarely deal with cash flow uncertainty that is as high as in the pharmaceutical industry. Often, investments in drug development are seen as a series of options with multiple sources of uncertainty, or, in other words, as 'compound rainbow options'. As the underlying is a real asset (the drug) rather than stock, the value of a pharmaceutical project can be calculated as a 'real option' with attributes of compound rainbow options. Few MBA programmemes cover these kind of financial instruments.

Finally, entrepreneurship and the ability to write a business plan is particularly relevant for the biotechnology industry. How shall a business plan be structured? How shall the opportunity be described, a financial plan be created, and how to approach investors? These skills can be trained in good entrepreneurship classes, but they rarely focus on

Strategy

the biotechnology industry in the vast majority of MBA programmemes. Thus, if a potential student already knows that she wants to work in the pharmaceuticalbiotechnology industries, she may be better off looking for a specific programmeme that provides the dedicated education needed to excel in the healthcare sector, rather than enrolling in a more general MBA programmeme.

Dedicated Healthcare programmes

There are, in principle, two possibilities to acquire the specific expertise that is unique to the pharma and biotech environment. The first is to search for an MBA programme that offers a healthcare management major. The second possibility is to enroll in a specialized programme offering, for example, a Master in Biotechnology Management (MBM). Among the top business schools, only a few offer this kind of healthcare specialization.

One example for an MBA offering a healthcare management major is the Wharton School of the University of Pennsylvania, located in Philadelphia in the USA. Beyond the MBA core courses Wharton's Healthcare Management Department offers courses in, e.g., Health Services System, Economics of Health, Managed Care, Financial Management of Health Institutions, Health Care Marketing, Comparative Health Care Systems, Management and Economics of Pharmaceutical, Biotech and Medical Device Industries, and Health Care Entrepreneurship.

Wharton's Health Services System course provides an overview of the evolution and structure of current healthcare systems covering payors, healthcare providers, suppliers, patients, and physicians. Among other areas of interest the course examines the impact of cost containment, disease management and the role of epidemiology in assessing population health needs and risks.

The Economics of Health course takes advantage of fundamental economic concepts to evaluate health policies and analyze the healthcare market. Wharton's

In particular, IE's MBM programme is structured as follows

General Management Courses: • Cost Accounting and Management Control • Financial Accounting • Fundamentals of Finance • Competitive Strategy • Organizational Behavior and Human Resource Management • Information Systems Fundamentals

Financial Management of Health Institutions course explains important concepts such as net present value as applied to pharmaceutical companies, decision tree analysis and real options.

The Healthcare Marketing course focuses on aspects that distinguish marketing in the pharma-biotech industries from marketing in non-healthcare industries.

Finally, the Comparative Healthcare Systems course looks at the structure of healthcare systems in different countries, focusing on financing, reimbursement, delivery systems and adoption of new technologies. In summary, Wharton's healthcare management education is an excellent example how a dedicated healthcare education can be integrated in a general MBA curriculum.

A second example is IE Business School's Master in Biotechnology Management (MBM) programmeme.

IE Business School is located in Madrid, Spain, and known for inno-

Specialized Courses: • Biotech Industry Fundamentals • Legal Issues in Global Business • Marketing and Sales for the Biomedical Market • Operations and Quality in the Life Sciences • Economic Environment and the Economics of Healthcare • Intellectual Property in the Life Sciences Industry • Business Development in the Life Sciences • Innovation and R&D Management in the Life Sciences • Finance and Global Life Sciences Business • Strategy Implementation & Uncertainty Management • Global Entrepreneurship in the Life Sciences • CSR & Stakeholder Communications Management

vative concepts in management education. Unlike an MBA with a healthcare focus, IE's MBM is fully dedicated to a pharma-biotech management education. About 30% of the MBM courses are equivalent to IE's MBA programme (introductory courses such as, e.g., Cost Accounting, Financial Accounting, or Competitive Strategy), whereas 70% are focusing on the healthcare industry (such as, e.g., Biotech Industry Fundamentals, Marketing and Sales for the Biomedical Market, or Innovation and R&D Management in the Life Sciences). IE's MBM programmeme has the advantage over some other programmemes that its 'blended', meaning that three short faceto-face periods alternate with intense, highly interactive online periods. Thus, students that are already employed do not need to give up their jobs in order to receive their Masters' degrees, and they can study from anywhere on the world at any time. www.pharmafocusasia.com

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8

-

9

12

15

13

16

22

13

18

20

9

11

12

13

14

15

15

17

18

18

20

Rank in 2009

22

29

13

8

19

10

14

15

11

-

9

12

6

4

16

6

5

3

1

1

3 year average rank

21

22

15

16

17

13

14

13

11

-

9

11

7

6

10

5

5

3

1

1

Duke University: Fuqua

HEC Paris

Dartmouth College: Tuck

Ceibs

Yale School of Management

New York University: Stern

IMD

Indian School of Business

University of Chicago: Booth

Country U.S.A.

France

U.S.A.

China

U.S.A.

U.S.A.

Switzerland

India

U.S.A

India

U.S.A.

Spain

Spain

U.S.A.

China

GSB U.S.A

France / Singapore

U.S.A.

U.S.A.

U.K

Audit year [1] 2008

2008

2008

2011

2008

2008

2009

2011

2007

2011

2009

2009

2009

2009

2011

2010

2009

2008

2008

2010

Salary today (US$) 136,248

123,287

155,732

118,514

151,451

138,398

145,539

132,352

152,370

174,440

158,353

133,338

142,894

167,366

133,334

182,746

147,974

170,817

175,153

146,332

Weighted salary (US$) 136,563

122,828

155,020

126,315

146,959

138,865

145,846

134,406

151,373

174,440

158,387

131,890

149,584

163,407

133,334

183,260

147,883

170,238

171,551

145,776

Salary percentage increase 107

106

113

155

133

119

89

187

109

152

121

138

136

117

142

115

108

116

123

132

Value for money rank 93

36

90

46

79

91

6

39

95

26

88

65

28

97

16

98

4

87

89

57

Career progress rank 68

14

56

43

41

34

5

28

55

1

10

3

4

17

36

9

18

22

33

11

Aims achieved rank 22

4

3

48

6

9

66

15

69

30

0

2

1 40

35

1

14

16

25

49

23

52

20

44

32

11

41

66

26

94

54

8

82

28

31

17

14

51

32

2

Placement success rank

Footnotes: 1. KPMG reported on the results of obtaining evidence and applying specified audit procedures relating to selected survey data provided for the Financial Times 2011 MBA ranking for selected business schools.

Enquiries about the assurance process can be made by contacting Michelle Podhy of KPMG at mpodhy@kpmg. ca. The specified audit procedures were carried out between October and November 2010. The audit date published denotes the survey for which the specified audit precedures were conducted.

Indian Institute of Management, Ahmedabad (IIMA)

MIT Sloan School of Management

Iese Business School

IE Business School

Columbia Business School

Hong Kong UST Business School

Stanford University

Insead

Harvard Business School

University of Pennsylvania: Wharton

London Business School

School name

Table notes: Although the headline ranking figures show the changes in the survey year to year, the pattern of clustering among the schools is also significant. A total of 210 points separate the top school from the school at number 100 in the ranking. The top 10

6

11

8

6

7

9

4

5

4

9

3

3

4

2

1

6

1

Current rank

P h a rm a F o c u s A s i A

Rank in 2010

12

1 19 22 14 19 25 18 33 18 22

2 1 7 3 50 6 29 17 8

82[10] [10]

90[16] [8]

15 10 16 19 13 21 27 18

28 15 11 20 40 13 27 16

98[9] [6]

30

26

35

37

37

36

23

Women board (%) 4. (89) 12. (87) 20. (80)

10

7

17

17

24

10

16

5

13

30

13

28

23

10

39

17

17

48

8

16

39

65

31

65

31

49

98

21

37

0

32

49

54

62

88

38

90

37

37

39

83

40

42

33

35

100

5

44

8

51

80

87

46

93

41

92

34

34

92

International students (%)

5. (95) 13. (92) 21. (82)

International faculty (%) 85

International board (%) 74

5

55

50

72

59

1

35

65

42

51

3

31

49

19

56

8

52

43

2

International mobility rank 6. (100) 14. (93) 22. (62)

41

41

12

50

17

16

81

55

38

0

60

90

82

35

94

25

80

21

66

60

International experience rank 7. (91) 15. (98) 23. (71)

28

13

38

22

35

31

46

77

50

81

25

4

34

57

9

15

5

59

33

11

Languages 0

99

99

100

96

97

100

100

100

96

96

100

00

93

97

100

92

97

92

100

98

Faculty with doctorates (%) 8. (90) 16. (86) 24. (79)

1[26]

0

1

0

0

1

0

0[26]

0

0

1

1

0

1[26]

0

2

0

0

[26]

1[26]

FT doctoral rank

3

33

22

76

33

13

67

81

4

92

19

70

62

10

14

8

10

1

2

7

9. (99) 17. (94) 25. (39)

20

47

n/a

n/a

35

5

n/a

n/a

8

55

11

48

69

7

19

4

17

14

2

23

FT research rank

26. School runs additional courses for MBA students for which additional language skills are required. These figures are included in the calculations for the ranking but are not represented on the table to avoid confusion.

2. (84) 10. (97) 18. (88)

77[6]

89[2]

93[9]

92[5]

90[10]

86[10]

83

28

35

7

35

24

29

35

34

39

33

36

40

28

Women students (%)

3. (96) 11. (85) 19. (73)

12 15

10 89[6]

97[6]

9

89[3]

94[10]

91

69[8]

92

90[6]

84

24

Employed at three months (%) 4

Alumni recommend rank

[3]

Women faculty (%)

91[10]

Strategy

Strategy

products and pipeline management in the biotech and pharma industries is a central part of the course.

All concepts learned during the programme culminate in writing a business plan during the Global Entrepreneurship in the Life Sciences course. Understanding the requirements and expectations of investors and sources of capital is a major objective of the course. Prerequisites to analyze viability of a business proposal such as, e.g., market research, R&D and intellectual property generating strategies, business development avenues, financial forecasting and access to capital markets are covered by the course.

The above examples demonstrate how a dedicated programme can provide the knowledge and skills required to excel in the complex healthcare environment.

Equipped with these skills graduates of IE's MBM programme typically follow four career paths: • they advance within their organizations, e.g., one graduate from a major, multinational Japanese pharmaceutical company was put on a fast-track career development programme immediately after graduation (only two out of 10,000 employees are selected for the company career development programme each year); • they advance in another organisation belonging to the same industry sector, e.g., one graduate moved from an entry-level position to Business Development Director of another healthcare company after finishing his MBM; • they switch industries, e.g., one graduate moved from the lab bench to an analyst position of a leading Spanish

A u t h o r BIO

The courses are complemented by World Awareness Seminars, Leadership Workshops, and Specialised Industry Conferences.

The contents of the individual specialised courses examine important, industry-relevant issues. For example, MBM's course on Strategy Implementation & Uncertainty Management investigates to what extent the concept of uncertainty, including the concept of risk as one of its dimensions, can be analysed and dissected into manageable components. The course looks at the value of portfolios and proposes useful approaches to build and manage them.

The Business Development course discusses the process of identifying opportunities with good potential for strategic fit with the business and structuring the strategically most adequate relationships ranging from limited IP licenses to long term partnerships. This includes the process of negotiating and arriving at agreements structured to make for a successful deal for both parties.

During the Economics Environment & Economics of Healthcare course students get exposed to the concepts of pharmacoeconomics including costeffectiveness, cost-utility, and cost-benefit analyses. These concepts are increasingly relevant for pricing decisions of new treatments.

In the Finance and Global Life Sciences Business course students learn how diverse financial instruments can be used to fund biotech and pharma companies, and understand the role of venture capital in the birth and growth of new biotech ventures. The course also introduces the role of international acquisitions, joint ventures and strategic alliances in the global life sciences industry.

The Innovation and R&D Management in the Life Sciences course focuses on the design and management of R&D processes, assessing and building innovation capabilities and optimizing interfaces between players affecting the R&D process. Development of new

bank, analysing healthcare stocks; • they start their own companies, often based on the business plans they developed during their Entrepreneurship course and with the support of the course's professor, e.g., one US-American student started his own biotech company in Berkeley in the USA and became the company's CEO; another talented, young molecular biologist co-founded a biotech financial advisory firm.

The above examples illustrate that a specialized programmeme provides the right education in order to advance careers. IE's MBM programmeme probably is one of the most internationally diverse programmemes available. As Asian students are, compared to the relative importance of the region, still underrepresented, the IE currently seeks to recruit more Asian students, specifically from India and China.

There are over one hundred programme worldwide that provide a Master in Healthcare Management (or similar) education. However, only a few allow students to continue working while studying, only a few are outside the USA, and only a few focus on the pharmaceutical and biotechnology industries. Given the success of those programme that provide the optimum preparation for future careers in biotech and pharma, or in related sectors, it is likely that more programme will be developed offering a specialised training in healthcare. This will not only benefit students who wish to pursue a career in healthcare, but also the society as a whole as those graduates are ready to master the challenges the industry is likely to face in the near future.

Joachim M Greuel is Adjunct Professor of Finance and Healthcare Management at IE Business School in Madrid, Spain. He is also a partner of financial services firms BioScience Valuation (Germany) and BioCapital Advisors (Spain). He studied biology in Marburg (Germany) and Cambridge (UK) and received his Ph.D. summa cum laude from the Max Planck Institute for Brain Research in Frankfurt (Germany).

Joachim holds an MBA with a finance and healthcare focus from the Wharton School of the University of Pennsylvania (USA).

www.pharmafocusasia.com

13

Strategy

Contract Research organisations An Outlook

Contract research organisation is a place to reckon to address the dwindling research and development budgets of big pharmaceuticals; having skill, capabilities and potential to provide services at excellence. Success of these Organisations relies on their competency, human intellect, experience, leadership and business model.

Somesh Sharma, Director, Jubilant Chemsys Limited, India

F

inancial performance of large innovative pharmaceutical companies in 2010 indicated a gloomy prospect for these well-established leaders in their domain. This trend is expected to grow as many drugs are going off-patent in time to come, and with very few blockbusters drugs entering to market due to strict FDA regulations. For instance, Pfizer, stands to lose huge revenue when its patent on Lipitor, the blockbuster cholesterol drug, expires. This will impact the sales and profit of these companies. Interestingly, these changes are giving opportunities to generic drug companies to boost their profit. For example, Teva, an Israel-based generic manufacturer recorded a 67% growth in 2010 as compared to previous year.

These trends in pharma market pose a great challenge for innovative companies in terms of cost reduction in R&D and bringing new drugs to market. With dwindling R&D budget, patent expiries and increased competition in generic business, contract research organisations have flourished.

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The CRO concept was created to control the cost of in-house R&D and maneuvering the budget of big pharmas to improve their core skills and expand capacities. Seeing these prospects, CROs started offering services at all levels in value chain of drug discovery. They built their capabilities from early to late stage of drug development with emphasis on partnership, collaboration and fee for service models. This also led to the development of specialist companies having niche services, catering to a number of clients and also a ‘one stop shop’ providing all services under one roof to curtail the pre-clinical development budgets.

The selection of these CROs providing various services becomes critical in evaluation before outsourcing.

There are other challenges in term of business models when CROs approach to customers. There is always fear and apprehension in the mind, when CROs showcase their capabilities in drug discovery value chain to clients. Risk of IP and becoming a potential competitor in long run is a threat to their identity.

How these CROs present themselves to safe guard their needs and protect the interest of customer, depends on the business acumen of leader. Talent retention, avoiding brain drain from the organisation, upgradation of knowledge and bringing new technology is a healthy confrontation for the success of CROs. For every challenge, there is an opportunity to grow and demonstrate their skills, knowledge, experience and capabilities. In present scenario big pharma is cutting the R&D budget and always keeping M&A strategy open to achieve top line growth. They are under tremendous pressure to bring new products to market at low cost, and maintaining the faith of stakeholders and patient community. The role of CROs becomes critical in aligning their business thought process rather than posing a threat to them, providing services at affordable price and with high quality.

Contract research organisation offers a space for every individual to excel their skills and knowledge as this gives them

Strategy

Various parameters which governed CRO’s choice

1. Trust factor: In order to build any collaboration or business, it is really critical to have admiration for each other. This can put together by mutual understanding of cultural differences between partners and effective communication. Respecting each other requests and demands for commanding the relationship for fruitful outcome.

6. Infrastructure: It should be adequate enough to meet the current demands, and should have the capacity and capabilities for expansion. There should be strong back-up mechanism to handle/ oppose any kind of eventuality that might deter the business process.

2. Service and Price: The mode of service delivery and payment model become crucial in selection process. Whether the service being offered is at appropriate price and have infrastructure to bring the cost in control. How fast is the response time to address any urgent needs? How the reports are being generated and shared with customer. What are the IP protection techniques and security system in place for securing confidential data?

7. Human capital: Aptitude and skill of people in-charge is key for success of any business. Human resource techniques/policies, recruitment process, talent attraction and branding of company is important for retention and magnetism. It is also critical to have employee engagement and development program to address current and future needs of employees to handle any upcoming challenges and responsibilities.

3. Quality: The major risk which generally alerts anybody before outsourcing is ‘quality’. What are the tools, techniques and mechanism in place to supply the quality product? What standards are maintained in terms of GRP/GLP/GMP, how the documentation process is being implemented, what is the internal or external audit process, etc.

8. Culture: The culture of any organisation speaks about the attitude, behaviour, approach and dynamism of the team. Environment in the company should be conducive for learning, innovation and performance of the employee.

4. Stakeholders: Investors acceptance and ethical considerations are important in making the bond stronger. There should not be any conflict of interest between the partners.

9. Supply Chain: For any service industry, it is important to have excellent supply chain department as it constitute backbone for organisation. Vendor management and sourcing of raw materials at reasonable price, helps deliver the service at low cost and quality.

5. Experience and expertise: Knowledge and skills of technical and non-technical team is vital to meet any kind of requirement. Learning new techniques, sharing knowledge and experience among themselves is important for building a successful team. Familiarity and proximity with technology is crucial for differentiation with respect to competitors.

Success in new product development, exposure to new disease targets and excellent track record builds confidence in collaborators

In addition to these factors, it is really important to deploy the environment, health and safety protocols according to national and international standards. Customers really feel good when they are associated with Organisations that too have high standard of safety of employees and environment.

Despite these points, there is always a debate whether somebody should go for small or big CRO. This is a difficult choice as big CRO always present themselves as ‘one stop solution’ and attract the customers for their infrastructure, diversity, varied portfolio and experience in dealing with different clients. On the other hand small

CROs portray themselves as niche providers. They have the ability to understand the ‘exact requirement’ of the client, commitment for the quality and time lines, flexibility in changing the course of service and delivery pattern. Further, small CROs can become an extension of the client’s in-house teams. However, bottom line for both small and large CROs is the quality operation, excellent relationship management and molding capabilities to tackle any business requirement. These things can be handled in various ways: proper resource allocation to improve processes, execution of project plan, delivery metrics and recommendations, review and capture learning.

CROs is quite bright, provided service providers maintain their credibility, keep on improving their knowledge,

A u t h o r BIO

exposure to diverse work environment, working with scientists of outstanding caliber and learning things in fast pace.

It is important place for those who are interested in contributing & partnering to a company to get a product to market as opposed to in-house research programme, where work is more predictable and various facets of research tools are limited. For the success of CROs, the notion of engagement and commitment of people is really significant. Future of

10. Information Technology: IT, which is really a backbone of any business today, drives all the process and systems in maintaining, securing and transferring the information from one end to other.

Compatibility of IT infrastructure and their willingness to expand to new direction drives the business in positive direction and improve the relationship with customers.

productivity and demonstrate their differentiator tactics as customers are becoming more demanding.

Somesh Sharma has over 12 years experience in Medicinal chemistry and Drug discovery. He has formerly worked in Ranbaxy Research laboratory and Piramal Life Sciences. He is currently engaged in managing international outsourcing projects in Medicinal Chemistry domain.

www.pharmafocusasia.com

15

SECUREJECT® – A NEW APPROACH TO PREFILLED SYRINGES Prefilled syringes provide convenient, sterile, fixed dosages and healthcare professionals around the world appreciate and count on these advantages.

But even after 30 years from their first introduction in market, the prefilled syringes find very limited application to pack expensive drugs or drugs required for emergency use.

Most of these pre-fillable syringes are commercialized in nests or matrix of few tens up to hundreds of sterile ready to be filled syringes. Nested pre-fillable syringes still, is most popular, albeit most expensive way of manufacturing prefilled syringes.

The production of nested pre-fillable syringes (made from glass or polymers like COC, COP or PP) require several manufacturing steps. Each additional step increase risk of contamination, and the cost. In addition, nested pre-fillable syringes are made of several components. Each additional component increase risk of contamination and contribute to the cost of final product.

With SYFPAC® SECUREJECT® MACHINE, we propose an alternative approach to manufacture prefilled syringes. SECUREJECT® SYRINGES are made using Advanced Blow Fill Seal process, through

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which, molding of syringe, filling of syringe and insertion of the piston and final closing takes place within the same equipment in just 15 to 18 seconds. To realize SECUREJECT® prefilled syringe, only the basic components - Needles and Pistons are required to be fed to the machine along with medical grade polymer.

SYFPAC® extrudes medical grade polymer at about 200°C, syringes are formed and a needle is embedded during syringe formation. Formulation is filled in the newly formed syringe almost immediately, sterile plunger is introduced at the top of syringe body which gets covered and sealed hermetically with plastic capsule. All the above operations take just 15 to 18 seconds, and are carried out exclusively within SYFPAC® SYRINGE components (plunger and needle) are protected under sterile air shower to ensure aseptic assembly and filling.

- SYFPAC® machine employs philosophy of worldwide renowned Blow-Fill-Seal technology - The core zone where filling, assembly of components and sealing occurs, is protected by grade A air shower. Additionally, machine has automatic internal CIP/SIP procedures to sterilize and clean the circuit where solution and process air can pass.

- Only three components are in direct contact with the filled product, which are: syringe barrel and tip closure made from medical grade inert polymer, sterile elastomeric Plunger and sterile stainless steel NEEDLES. Both sides of syringe are secured with hermetic plastic protections formed during molding process.

In addition, SECUREJCT® prefilled syringes offer other advantages over glass PFS such as: • Polymer syringe is an unbreakable primary packaging container during normal handling and transportation.

• Polymer syringes can have tighter tolerance, and perfectly round on the inner diameter compared to glass syringe. This reduces the necessity of higher interference between plunger and syringe barrel, resulting in reduction of force to move plunger.

• Plastic syringe does not have issues related to traces of tungsten (tungsten can cause catalytic breakdown some biological compounds and proteins or create agglomerate with tungsten residues).

• Plastic barrel does not require siliconization and so, silicon related problems are reduced.

Advanced manufacturing technologies

DIRECTLY from polymer to aseptic in product in 12 seconds by... SYFPAC®

Our Blow Fill and Seal machines are flexible and versatile to carry out aseptic packaging of pharmaceutical liquids including cytotoxic or live virus and or highly active substances in the vials, bottles, or canisters of 0,25 ml up to 13 liters made either from Polypropylene, LDPE or HDPE. Our new patented SYFPAC® - SECUREJECT® is designed to make Prefilled syringes directly from plastic granule.

BREVETTI ANGELA S.R.L. VIA DELL’INDUSTRIA, 99 (PO BOX 175) 36071 ARZIGNANO (VI) ITALY Tel. + 39 0444 474200 - Fax: + 39 0444 474222

brevettiangela.com

Clinical Trials

Mobile Phones “Always There Always On”

Why not use It to enhance patient compliance, trial effectiveness and reduce trial cost With rapid growth of mobile smart phones and discovery of remote diagnostics devices, there are enormous opportunities to use mobile technologies and integrated wireless devices during clinical trials to improve patient’s medication regimen, reduce dropouts, reduce site visits, and improve clinical data - all contributing to reduced clinical trial cost and improved compliance.

Vikram Marla, CEO, NowPos M-Solutions, India

C

linical trials and Medical research is experiencing the fastest transition that it ever experienced. With continuous innovation in technology, drug research initiatives are getting tremendous support in terms of getting more compliant and secure processes in place, making the research more result oriented. With a fact that the cost to develop a drug and bring it to market costs pharmaceutical companies about a billion dollars, which is largely based on the efficacy of the drug towards a particular therapeutic area. Since the efficacy of a drug will ultimately be determined by patients participating in the trial, it is important that patients follow their medica-

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tion intake regimen and are monitored constantly for compliance, non compliance of which only raises the bar for pharmaceutical companies in terms of revenue outflows.

With rapid growth of mobile smart phones and discovery of remote diagnostics devices, there are enormous opportunities to use mobile technologies and integrated wireless devices in different industry verticals. With mobile technology penetrating deeper into the lives of the citizenry and across the socio economic strata, the clinical trials and drug development industry is no exception to it. With patients or subject populations from different levels of society using and familiar with such

technologies, mobile technology can see multifarious use in clinical trials and research studies such as: improve patient’s compliance towards their medication regimen, reduce drop-outs, reduce site visits, and improve clinical data - all contributing to reduced clinical trial cost and improved compliance.

Because cell phones are “Always there and Always on”, there could be numerous opportunities to use them for Life Sciences Research and Healthcare management. It’s now the time for clinical studies to take advantage of these technologies and to benefit from it.

Patient Reported Outcome capture is a key component during any clinical or behavioral trial for the research teams

Clinical Trials

billion phones globally, its usage is growing by leaps and bounds. Most illiterate patients living in remote areas of developing countries have access to mobile phones with the knowledge to maintain and use basic its functions.

PaDiSys – The Patient Diary System

to get clear indications on efficacy of the drug being developed. During clinical trials, medication intake and outcome compliance among patient population is less than 45%. Archaic methods of recording outcomes contributes to high levels of non-compliance, compounded by a patient population that is elderly or have low literacy levels to understand the importance of medication intake schedules and reporting outcome needs.

Drug efficacy is determined with data secured from such low levels of compliance. In a non-clinical medication regimen, the cost of non-adherence to the healthcare system is estimated to be in the excess of about $100 billion in the US alone.

While patient data capture comes in as an important factor to determine the efficacy of an experimental drug, treatment adherence is another major component of the research and study.

There are various reasons for which patients can be non-adherent to their medication intake regimen and other interventional activities as specified in the clinical trial protocol and thus it becomes imperative for clinicians to take additional steps such as reminding, alerting and following up with them.

It is evident from pharmaceutical companies and health care providers, that there are enormous opportunities for improving patient outcome and treatment adherence. Additionally, with 4

PaDiSys is a mobile based patient data capture solution that includes Medication Intake Adherence. We have taken the most common features of mobile phones to develop an application that will help patients stay disciplined in their medication intakes and help provide QOL feedback in patients’ regional language – both in textual and audio prompts.

Investigators and pharmaceutical sponsors can now monitor outcomes and patient health more closely in between site visits.

Mobile phone devices can be integrated with other wireless vital monitors to empower principal investigators make better decisions of patient outcomes. The PaDiSys System allows the clinical staff to track and monitor patients in terms of their adherence to the protocol and also to the assessments (PRO questionnaires).

With standard and custom reports the clinical staff can analyze patient information as required and thus take critical decisions at appropriate times, without wasting time and resources.

Some of the key issues that the Life Sciences and the Pharmaceutical Industry is facing in their research initiatives are non-compliance in patients in their medication intake and filling up of QOL assessments, inconsistent patient related information, Multilingualism – catering to patient population coming from different regions, literacy levels of the patients, geographical distances between the research centres and patients, who in most cases are from rural areas, administration and logistics related to paper based information collection systems etc. Mobile phones can this way bring a revolutionary change in the way operations are managed, helping organizations to reduce overall costs, closely monitoring patients, walk away

www.pharmafocusasia.com

19

Clinical Trials

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The goal is to raise the compliance levels in clinical studies from the current levels to upwards of 95% and reduce patient drop-outs, which put together should help pharmaceutical companies capture better data when determining drug efficacy and hastening their product launch faster in the market.

In cases of chronic treatment, having patients reminded of their medication should reduce re-hospitalizations and recurrence of an illness. Additionally, with better outcomes from patients, doctors can prescribe dosages more effectively or to justify their insurance re-imbursements.

A u t h o r BIO

from a paper based approach that is a major cost factor, bringing multimedia and translation features for patients from rural areas to be as compliant to their trial protocol as patients from urban area are.

In most trials today adverse event reporting is a challenge with patients not able to record the A.E or an SAE or not reporting the same on time, which is of a grave concern to the research fraternity.

With mobility solutions, patients or their caregivers can now alert the clinical staff by the click of a button on their mobile devices. With the ability of systems to maintain an audit trail of all actions performed on the device with time and date stamps, the research teams can zero in on to the exact time and date of the event. With the latest row in the industry and government with regards to the number of people being victims of drug side effects during clinical trials, mobile technology can help sponsor companies to be more proactive in taking decisions based on the alerts from the patient at the time of SAE/AE. A major concern that has always been within the life sciences industry, especially drug development is the aspect of security of technology and the various technology supported tools. From a security standpoint, mobile phones used for patient data capture can come as a handy option for Pharma companies to use it as it can be developed and controlled as per the requirements of the trial protocol, following global security and international standard guidelines.

Other areas where mobile technology can be used are as follows: • Medication reminders to improve medication adherence • Real time information exchange to investigator and monitors • Improved trial compliance due to reminders and monitoring tools • Reduced chance of, patient drop-outs and inaccurate data capture from patients • Use of regular mobile smart phones to capture data

Several other areas in the Life Sciences and Healthcare sectors can benefit from mobile technology, some of which are widely known but less used. We, from the PaDiSys Team, want to go a step further and spread more awareness on such forward looking technologies to the Clinical and public research industries, helping them enhance their results and improving patient monitoring by assisting them with our mobile competencies. It would be our primary motto and consistent effort to keep the clinical trials fraternity educated and execute such advancements and initiatives towards making the patient’s health better.

Vikram Marla has 20+ year experience in pharmaceutical drug development technology solutions and an extensive knowledge of the clinical trial processes.

Mr. Marla developed Clinicopia –a clinical supply management system that is used by many of large global Pharma companies to manage their clinical trials.

For the past 12 months, Mr. Marla is heading a company based in Hyderabad that has developed the most innovative clinical patient data capture and treatment adherence system using mobile phones.

Events

Mar 19 - Mar 22, 2012

5th annual BioPharma Asia Convention 2012 Marina Bay Sands, Singapore http://www.terrapinn.com/exhibition/biopharma-asia Mar 19 - Mar 22, 2012

Biologic Manufacturing World Asia 2012 Dec 6 - Dec 8, 2011

9th BioPharma India Convention 2011

Mumbai, India http://www.terrapinn.com/2011/biopharma-indiaconvention/ Dec 6 - Dec 7, 2011

BioPharma India Convention 2011

Grand Hyatt Mumbai, India http://www.terrapinn.com/biopharmaindia Jan 26 - Jan 27, 2012

15th Annual Workshop in Japan for Clinical Data Management Tower Hall Funabori http://www.diahome.org/DIAHome/Education/ FindEducationalOffering.aspx?

Mar 19 - Mar 22, 2012

Pharma Trials World Asia 2012

Marina Bay Sands, Singapore http://www.terrapinn.com/conference/pharma-trialsworld-asia/ Mar 19 - Mar 22, 2012

Pharma Partnering and Investment World Asia 2012 Marina Bay Sands, Singapore http://www.terrapinn.com/conference/biologicmanufacturing-world-asia Mar 19 - Mar 22, 2012

Pharma Manufacturing World Asia 2012

Mar 19 - Mar 21, 2012

5th Lean Sigma & Kaizen For Pharma R&D Loews Philadelphia Hotel, Philadelphia http://info.exlpharma.com/c132-more-info.html

91 40 4961 4444

Marina Bay Sands, Singapore http://www.terrapinn.com/conference/biologicmanufacturing-world-asia

Marina Bay Sands, Singapore http://www.terrapinn.com/conference/pharmamanufacturing-world-asia/

info@ochre-media.com

www.pharmafocusasia.com

21

CoverStory

Prophylactic and Therapeutic Vaccines A novel approach for treatment of cancer

D

Cancer immunotherapy, including the development of prophylactic and therapeutic vaccines, is considered a novel approach for prevention and treatment of cancer.

Mayurkumar Kalariya Mansoor Amiji Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, USA

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espite progress on several preventive and therapeutic fronts, cancer remains one of the major causes of morbidity and mortality worldwide. According to the 2011 estimates, about 1.6 million new cases of cancer will be diagnosed and approximately 570,000 deaths will occur due to cancer in the United States (Cancer, Facts and Figures 2011, The American Cancer Society). Surgical resection of the primary tumour, conventional cytotoxic and newer antibody-based chemotherapy, and radiation remain the most widely used clinical strategies for cancer treatment. These approaches, however, have several limitations, including inability of surgical resection to affect distal metastatic disease, toxicity to healthy tissues due to non-specific distribution of chemotherapy and development of multi-drug resistance, and lack of effectiveness of radiation therapy in more aggressive tumours.

Cancer immunotherapy, including the development of prophylactic and therapeutic vaccines, is considered a novel approach for prevention and treatment of cancer. Immunotherapy involves a wide range of options that can ultimately stimulate the body’s immune system to target and eradicate neoplastic cells. The exquisite specificity of the immune system can be utilised to precisely target the cancer cells without affecting normal cells. This hope has motivated researchers over the last several years to develop tumour-specific,

Research & Development

prophylactic and therapeutic vaccines, by injecting patients with tumour cells and tumour extracts. Although earlier efforts have met with great disappointments, the rapid increase in knowledge of the immune system and its regulation has led to a resurgence of interest in cancer vaccines and has resulted in several approved products.

The ideal goal of cancer vaccine is to elicit potent anti-tumour immune responses without any contributing sideeffects. The major aim is to stimulate both innate and adaptive immunity that can recognise and subsequently eliminate the tumours mass. Cancer immunotherapy continues to be a field of intense research, especially the induction of active immunity. The existence of tumour-specific antigens (TSAs) that can be the targets for an immune response is well established [3]. Advances in cancer genomics anticipate an even greater array of potential TSA targets. To date, a variety of immunization modalities have been employed, including whole tumour cells, tumour lysates, specific tumour antigens, tumour peptides, heat shock proteins, DNA vaccines, exosomes, and dendritic cells (DCs)-based vaccines. As a result, several tumour vaccines showing encouraging results are in the clinics.

In June 2006 the United States Food and Drug Administration (FDA) approved viral oncoprotein-based immunotherapy, known as Gardasil® (or Silgard

by Merck). Gardasil® is indicated for the prevention of certain types of human papilloma virus (HPV) infection that is responsible for most HPV-induced anal, vulvar, vaginal, and penile cancers.

Gardasil® does not treat existing infection and, therefore, it is used primarily as prophylactic vaccination before adolescence and potential sexual activity.

In April, 2010, the FDA approved a DCs-based adaptive immunotherapy, commercially known as Provenge® (or Sipuleucel-T by Denderon Corp.) for the treatment of advanced prostate cancer in men. Provenge® is the first FDA-approved cancer immunotherapy that is targeted towards tumour antigens

that exist in the host; therefore, it is used as therapeutic cancer vaccine. Approval of these cancer vaccines has provided the evidence of increased attention to antitumour immunotherapy development and, hopefully will lead to additional future successes.

Anti-tumour Immunity

It is well established that the immune system has capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes converting them vulnerable to immune cells. Yet, it is self-evident that a growing tumour has managed to evade the host defense mechanisms. The exact ways in which the immune system interacts with tumourtumour cells and how cancers are able to escape immunological eradication have only recently started to be fully explained. It is crucial to understand relationship between the tumour and the anti-tumour immune response and how that can be altered to develop successful immunotherapy for patients with cancer.

Although anti-cancer immunity involves both the innate and adaptive immune systems, it is generally recognized that CD8+ cytotoxic T lymphocytes (CTL) are the most potent anti-tumour effector cells. The T-cell immune response

can be broken down into the following steps. All of the steps need to be satisfied for effective anti-tumour immunity: (1) tumour antigen(s) must be present, and (2) they must be seen as dangerous by the immune system; (3) antigens must be acquired and presented by antigen presenting cells (APC) in the draining lymph node; (4) specific T-cells must then recognize and respond to tumour antigen by proliferation, enter into systemic circulation and reach to the tumour site as CTL; (5) where they need to overcome the local immunosuppressive environment before killing tumour cells. In addition, the memory cells may need to be generated to produce a long-lasting response. It is clear that a growing tumour has managed to escape this process. Failure of the anti-tumour immune response can occur at one or more of these steps. Targeting rate limiting steps with therapies designed to boost the immune response can improve antitumour immunity.

Tumour Antigens

Tumours typically express two types of antigen: neoantigens and self-antigens.

Neo-antigens (tumour-specific antigens) are derived from mutated self-proteins that are not expressed in normal tissues.

Malignant cells express numerous

Figure 1. Induction phase of anti-tumour CD8 cytotoxic T-cells [8]. Reprinted with permission from Nature Publishing Group © 2010.

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neo-antigens as a result of genomic instability. Most of these mutations do not have functional significance for the tumour cell, but may still provide potential antigenic targets for immune cells.

In addition, tumours can also express normal self proteins, but in abnormal quantities or locations (tumour-associated antigens). During T-cell development, T-cell precursors with a strongly selfreactive T-cell receptor are deleted in the thymus, resulting in a T-cell repertoire with a high affinity for foreign antigens and a weak affinity for self antigens. Thus, tumour neoantigens being foreign induce strong immune response whereas tumour associated antigens are considered self and therefore induce weak immune response. CTL responses can be generated to weaker antigens, but require higher antigen concentrations and prolonged duration of exposure.

Role of Antigen Presenting Cells

Although T-cell receptors bind with variable affinity to self- and non-self antigens, they are not competent to discriminate dangerous from harmless antigen by themselves. The antigen presenting cells (APCs), especially DCs, satisfy this crucial role by acquiring antigens and responding to associated danger signals.

Subsequently, they present the antigens to naïve T-cells in the context of major histocompatibility molecules (MHC) with the appropriate information about the level of danger present as shown in Figure 1. The ‘professional’ APCs present the processed antigen bound to MHC class I molecules to naïve CD8+ T-cells and provide the additional co-stimulation needed to activate CTLs. In addition, helper (CD4+) T-cells recognises the antigen presented on MHC class II and allows DCs to release co-stimulatory signal to promote CTL activation. Thus, helper T-cells offer a ‘second opinion’ to the DCs so that antigens recognized as dangerous are promoted as immunogenic. The fate of the T-cells whether it becomes primed or inactivated as a result of encounter with DCs critically dependent on the state of DCs maturation. Immature DCs 24

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are inefficient at cross-presenting antigen and do not express the co-stimulatory molecules required for T-cells activation.

DCs maturation is initiated by ‘danger signals’ from antigen and by inflammatory cytokines such as IFN-γ [7]. DCs maturation results in increased antigen uptake, up regulation of MHC expression, and expression of co-stimulators CD80 (B7-1) and CD86 (B7-2). During maturation, DCs migrate from tissues to draining lymph nodes where they activate naïve T-cells.

Activation of Anti-tumour Cytotoxic T Lymphocytes

Activation of anti-tumour CD8+ T-cells or cytotoxic T-lymphocytes (CTLs) by mature DCs in the draining lymph node requires several signals: T-cell receptor binding to antigen coupled to MHC class 1, ligation of CD28 on the T-cells with CD80 or CD86 on the DCs and release of inflammatory cytokines such as IL-12 and type 1 INFs. In addition, an effective anti-tumour immunity also requires that CTLs proliferate, survive in the circulation, and enter into the tumour site to execute their effector function as shown in Figure 2. Combining tumour antigen-specific CD4+ T-cells with CD8+ T-cells in adoptive transfer treatment in mice increased the accumulation of tumour-specific CTLs in tumour and lymphoid tissues compared to CD8+ T-cells transfer alone. Thus, it indicated that CD4+ T-cells plays a critical role in anti-tumour CTLs activation process [10].

Persistent CD4+ help and IL-2 secretion are required to maintain CD8+ T-cells function and numbers. In addition, direct cell–cell contact from CD4+ T-cells also protects the effector CD8+ T-cells from activation induced cell death. Moreover, CD4+ T-cell help during CD8+ T-cells priming induces memory CTLs that under go clonal expansion upon re-stimulation with tumour antigen.

Challenges in Cancer Immunotherapy

Tumours are already engaging with the immune system in the patients with cancer. The goal of immunotherapy is to boost the immune response such that the balance shifts from tolerance to rejection. An immunotherapy may fail due to limiting factors at any point in the induction or effector phase. There may be inadequate quantity of tumour antigen present, or vaccination targeting shared, self-antigens may produce only weak T-cells responses that are insufficient to cause tumour regression. In addition, there may be inadequate danger signals to generate strong responses to tumour antigens. The recent clinical trial involving human papilloma virus vaccine showed that anti-tumour immunity mediated through a robust effector T-cells response is essential for successful immunotherapy. In this study the measured T-cells responses strongly correlated with regression of tumour lesions. However, in other clinical trials evaluating tumour vaccines against larger, invasive malignancies the

Phases of Anti-tumour Immunity Induction Phase: Immature dendritic cells (DCs) acquire tumour antigen migrate to the draining lymph node. Antigen is processed by the DCs and presented to CD4+ T-cells on MHC class II molecules and cross-presented to CD8+ T-cells on MHC class I molecules.

DCs activation is promoted by danger signals, IFN- and ligation of CD40 by helper T cells.

On activation DCs express co-stimulatory molecules and cytokines, leading to activation of tumour antigen-specific T-cells.

Effector Phase: Cytotoxic CD8+ T-cells (CTLs) exit the circulation and enter in to tumour site. CD4+ T-cells facilitate tumour infiltration and may promote secondary expansion of CTLs. Following recognition of the cognate antigen presented on the tumour cells surface, CTLs execute the effector cell function that results in tumour cell killing. Local immunosuppressive mechanisms may inhibit the anti-tumour response, including suppression by regulatory T-cells and inhibitory cytokines.

Research & Development

effective generation of tumour antigenspecific CTLs in peripheral blood has not predicted clinical efficacy. This difference may reflect the weaker activity of T-cells generated by cancer vaccines targeting shared self-tumour antigens compared to those directed against viral neoantigens. It may also reflect the presence of a number of barriers to effective immunotherapy in established invasive tumours compared to premalignant lesions. The anti-tumour T-cells response may fail downstream of the induction phase because of: (1) CTLs may remain in the periphery or in the draining lymph node without actually infiltrating the tumour site, (2) CTLs may disseminate to the tumour but are unable to mediate anti-tumour activity, (3) Activated T-cells may fail to continue expansion and maintain effector function, (4) Activated T-cells may be switched off by immune suppressors secreted by tumours, (5) Immune suppressive action of Regulatory T-cells on activated T-cells, (6) tumours may alter their microenvironment to escape immune surveillance.

Combination Therapy for Cancer Treatment

Although multimodality therapy demonstrated a potential to cure early stage cancers, a key challenge for cancer therapy is to improve outcomes in the patients with advanced disease. Recently, the cancer chemotherapy is considered to synergise with immunotherapy although it often destroys the immune cells.

Chemotherapy can have the immune stimulatory effects at number of points during immune response. For example, causing lymphopenia it depletes regulatory T-cells as well as tolerised T-cells to tumour antigens. Homeostatic proliferation to restore immune cell numbers occurs following the cyclical chemotherapy. This phenomenon offers a window to skew the regenerating T-cells response back towards active anti-tumour activity. In addition, chemotherapy induced apoptotic tumour cell death increases the quantity of antigen released and augments antigen cross-presentation by mature DCs to stimulate immune

Figure 2 Effector phase of anti-tumour CD8 cytotoxic T cells [8]. Reprinted with permission from Nature Publishing Group Š 2010.

response. Chemotherapy can also sensitise tumour cells that cannot be directly lysed by treatment, to subsequent killing by immune cells. This effect is mediated through up regulation of death receptors such as Fas (CD95) or TRAIL receptors (DR5). Both pre-clinical and clinical studies showed that strategy to combine immunotherapy with chemotherapy reported promising results, however large randomized controlled trials are required to establish the effectiveness.

Radiotherapy can also stimulate an immune response, as evidenced by the phenomenon known as the abscopal effect, where in non-irradiated distal metastases shrink following local primary radiation. Radiotherapy has increased MHC 1 peptide presentation of tumours expressed neo-antigens that were recognized by CTLs. This strategy enhanced the effectiveness of a subsequent adoptive transfer immunotherapy. Immunotherapy in the context of surgery is also interesting, with intriguing paradoxical results following complete or partial de-bulking in a mouse model. The de-bulking surgery can reduce tumour burden and tumour-associated immune-suppression to a level in which chemoimmunotherapy

can be curative. However, continued antigen presence is needed for memory to be established therefore only partial removal generated long-term anti-tumour memory [19]. This implies that patients currently considered unresectable may benefit from de-bulking surgery as part of a multimodality treatment strategy.

In addition, where complete resection is achievable patients may benefit from a continued antigenic stimulus such as a vaccine during adjuvant treatment.

Role of Adjuvant and Vaccine Delivery Systems

Newer generation of vaccines, particularly those based on recombinant proteins and DNA, will have a greater safety profile, but will be less immunogenic that attenuated organisms. An immneadjuvant is an agent that can stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect of its own.

Immuno-stimulatory adjuvants are predominantly derived from pathogens and often represent pathogenassociated molecular patterns, such as lipopolysaccharides and CpG nucleic acid motifs. Adjuvants activate and engage www.pharmafocusasia.com

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The ideal goal of cancer vaccine is to elicit potent anti-tumour immune responses without any contributing side effects and the major aim is to stimulate both innate and adaptive immunity that can recognise and subsequently eliminate the tumours mass.

potent adjuvants in microparticles may allow the development of prophylactic and therapeutic vaccines against cancers that are currently poorly controlled. In addition, microparticle formulations may also allow vaccines to be delivered mucosally.

Future Outlook for Cancer Vaccines

Tumour cell death can be immunogenic and that can be harnessed to improve cancer treatment outcomes. It may be possible to defeat the issues related to tumour antigen specificity by tailoring immunotherapies to individuals based on tumour gene expression profiles and human leukocyte antigen typing.

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components of the innate immune system to enhance T and B cell responses.

Traditionally adjuvants have been used to increase the magnitude of an adaptive immune response to a vaccine. However, recently adjuvants have been employed to guide the immune system to produce the most effective forms of immunity for each specific pathogen; for example T helper 1 (Th1) cell versus T helper 2 (Th2) cell, CD8+ versus CD4+ T cells, and specific antibody isotypes. Adjuvants are used in cancer immunotherapy to: (1) increase the immune response to a weak tumour-antigen; (2) facilitate the use of smaller doses of antigen; and (3) permit immunization with fewer doses of vaccine. Very few vaccine adjuvants have been licensed for use in human. Alum (aluminum salts) has been widely used for more than 70 years and until recently represented the only approved adjuvant in the United States. MF59 and AS03 (squalane oil in water emulsions) are licensed for adjuvanted influenza vaccines in Europe. AS04, a combination adjuvant composed of monophosphoryl lipid A (MPL) adsorbed to alum is approved for hepatitis B virus (HBV) and HPV vaccines in Europe and has been recently licensed in the USA. Vaccine delivery systems are generally nano- and micro-particulate systems, such as liposomes, oil-in-water emulsions, and polymeric micro-particles that can encapsulate the antigen payloads and deliver these to the target site and possibly APC’s – either systemically or upon mucosal administration. Increasingly, more complex formulations are being developed in which delivery systems are exploited both for the delivery of antigens and also for the delivery of co-administered immunostimulatory adjuvants.

The rationale for this approach is to ensure that both antigen and adjuvant are delivered into the same population of APCs. In addition, delivery systems can focus the effect of the adjuvants onto the key cells of the immune system and limit their systemic distribution, to minimize the potential to induce any adverse effects. The formulation and delivery of

However, this approach is likely to be both costly and time consuming. A more readily adaptable strategy may be to manipulate the way tumour cells are killed and are sensed by immune cells such that tumour antigens are able to provoke tumour-specific cytotoxic T-cell responses. One can envision a situation in which chemotherapeutic agents are selected to kill tumour cells in a way that is immunogenic, or sensitize tumour cells to immune-mediated cell death. Further strategies may involve deletion of tumour induced immune-suppression to promote the anti-tumour immune response. This might involve tumour vaccines, local inflammatory stimuli or regulatory T-cell depletion. In patients with high tumour burdens, de-bulking surgery may be helpful to reduce the tumour load to a level in which cancer immunotherapy is more effective. Immunotherapies have the potential to become effective treatments for patients with cancer. It seems likely that immunotherapy will be the most efficacious as part of multimodality treatment that may involve chemotherapy, surgery or radiotherapy. Elucidation of the precise mechanisms by which tumour cell death and cancer therapies interact with the host immune response will offer additional knowledge to develop more effective treatments for malignant diseases in the future.

References will be available on www. pharmafocusasia.com/magazine

Mansoor Amiji is a Distinguished Professor and Chairman of the Pharmaceutical Sciences Department in the School of Pharmacy, Bouve College of Health Sciences and Co-Director of the Nanomedicine Education and Research Consortium (NERC) at Northeastern University in Boston, MA. He received his undergraduate degree in pharmacy from Northeastern University in 1988 and his PhD in pharmaceutics from Purdue University in 1992. His areas of specialization and interest include polymeric biomaterials, advanced drug delivery systems, and nanomedical technologies.

Mayurkumar Kalariya is a doctoral candidate in the Department of Pharmaceutical Sciences at Northeastern University, Boston, MA and working as a Formulation Scientist at Alkermes Inc., Waltham, MA. He has received Dr. T.M.A. Pai Gold Medal and 36th Indian Pharmaceutical Congress Awards for academic excellence during the undergraduate program.

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Layer-by-Layer Micro and Nano Drug Encapsulation with Eolyelectrolytes Progress and challenges

Layer-by-layer encapsulation gives a very stable fine dispersion, so fine that a dollar coin is visible when looked at through the clear dispersion.

Yuri Lvov, Professor, Eminent Endowed Chair on Micro and Nanosystems, Institute for Micromanufacturing, Louisiana Tech University, Ruston LA, USA

Tatsiana Shutava, Research Professor, Institute for Micromanufacturing, Louisiana Tech University, Ruston LA, USA Kirill Arapov, Doctoral Candidate in Biomedical Engineering, Louisiana Tech University, Ruston LA, USA Vladimir Torchilin, Distinguished Professor of Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Director, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, USA Melgardt DeVilliers, Professor, School of Pharmacy, University of Wisconsin, Madison WI, USA

S

ince layer-by-layer (LbL) polyelectrolyte assembly was introduced in the 1990s by G. Decher, Y. Lvov, H. MĂśhwald and M. Rubner it has found application in various fields that study and apply nanotechnology. LbL nanoassembly is based on the sequential adsorption of positively and negatively charged polymers on a surface to form a nano-thick film of coating. The process is illustrated in Figure 1.

During LbL assembly oppositely charged polymers are electrostatically bound to one another producing insoluble nano-thick multilayers. The thickness of this multilayered film is controlled by the number of 2-3 nm polyelectrolyte bilayers that are deposited. Therefore, by simply alternating the adsorption of polycations and polyanions, thin organised films with a thickness ranging from of 5-500 nm that are precise to within 28

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a

b Figure 1 – Schematic illustration showing how LbL assembly is achieved by alternating the adsorption of oppositely charged polyelectrolytes on (a) a flat substrate (film) and (b) a microcore (shell).

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a few nanometers, can be formed. In addition the composition of the film can be controlled and varied because a vast array of polyelectrolytes (synthetic or natural, such as polysaccharides and proteins) and even charged nanoparticles will form LbL coatings and shells. The only requirement is that the positive and negative components are alternated. This means that this relatively simple nanoscale coating process has evolved into a robust platform for the modification of material surfaces or the encapsulation of various substrates (Figure 2). So much so that since the 1994 more than ten thousand papers has been published describing various aspects and applications of the LbL method.

Experimentally various techniques are used to produce LbL films and coatings. The simplest of these is to either

dip a solid object into aqueous solutions containing either polycations or polyanions or alternatively to spray the polyelectrolyte solutions onto the surface of the material to be coated. Using these methods polyelectrolyte multilayers can be formed on larger solid substrates and on very tiny colloidal particles.

Colloidal coating was first reported by J. Kirkland, G. Sukhorukov, F. Caruso and H. Mรถhwald. They showed that a 5-50 nm thick polyelectrolyte shell can be formed on colloidal cores such as drug micro and nano particles. When coating drug particles typically a colloidal suspension of the drug is formed in a polycation solution, and after a few minutes, non-reacted polyelectrolyte is removed by centrifugation or filtration.

This process is then repeated using now positively charged coated drug particles

suspended in a polyanion solution.

Similarly assembly is repeated until the required number of bilayers is formed around the drug core particles.

When coating drug particles a few things should be kept in mind. First, it is important to avoid drug dissolution during the coating process. This is done by adjusting the pH or to do the coating in a saturated drug solution. Secondly, although the first publications on LbL assembly used synthetic polyelectrolytes; recently most researchers interested in drug delivery use natural biodegradable compounds, such as anionic alginic acid, hyaluronic acid, chondroitin sulfate, heparin, dextran sulfate, carboxymethyl cellulose, polyglutamic acid, albumin, glucose oxidase, DNA, and cationic chitosan, dextran amine, polylysine, collagens, protamine sulfate and gelatin

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A. Third, once the coating process is establish for a specific drug the formulator usually pick polycation / polyanion combinations that allow control over drug release from hours and even days.

However, for some drugs longer release rates requires thick 6-12 bilayer shells which could be time and labor intensive.

To date the release and stability properties of the following drugs have been changed

by LbL encapsulation: ibuprofen, furosemide, nifedipine, naproxen, biotin, vitamin K3, insulin, dexamethasone, tamoxifen, paclitaxel, camptothecin, and curcumin.

Earlier this year the first report of changing the functional properties of a drug excipient, microcrystalline cellulose, using LbL encapsulation also appeared.

However, the most exciting application of LbL nanocoating is the encapsulation of 60-200 nm diameter nanoparticles of poorly water soluble drugs. It is exciting because the thin LbL-coating provides a strong electrical surface charge (zetapotential of ca -40 mV) for the production of stable nanocolloids while maintaining most of the increased solubility provided by the nanosized drug particles. Drug loading is also high, 50-80 wt %, and due to their small size these LbL coated drug nanocapsules can be formulated into injectable colloids and suspensions (Figure 2c). A specific application of this general technique will be discussed later.

A second less, attractive for pharmaceutics method used for the LbL encapsulation involves the formation of LbL microcapsules on sacrificed cores with diameters of 2-5 Âľm. The cores are then dissolved to produce empty capsules with pH sensitive shells. Water soluble drugs and proteins are then loaded into these shells through pH depended opening of pores in the capsule walls. A major drawback of this method is that drug loading is only 1-5 wt %. Notwithstanding low loading these microcapsules have been proposed for non-injectable drug delivery such as nasal delivery of LbL coated insulin. Numerous authors also claim that because of the very flexible and thin shells, such microcapsules can squeeze

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a

b

c

Figure 2 - SEM cross-sectional image of a 230 nm thick LbL multilayer deposited on a silicon surface composed of 24 bilayers of glucose oxidase alternated with polylysine (a), fluorescent confocal image of 4-Âľm diameter LbL microcapsules (red) loaded with polyphenols in acrylamide gel (green) (b), and TEM image of 100 x 170 nm LbL paclitaxel nanocapsules.

though the leaky capillary membranes around tumors and therefore might be used to prepare intravenous injections of anticancer and other drugs with targeted delivery to tumors (Figure 2b).

Whichever of the methods described above is used to produce LbL coated nano and micro drug particles or capsules, it faces a number of challenges: 1. Most LbL drug encapsulation is done in an aqueous environment and at low concentrations of the capsules. For clinical testing more concentrated drug nanocapsule dispersions in higher ionic strength buffers are needed. This could lead to more pronounced aggregation.

2. The capsules need to be rendered biocompatible. For example surface PEGylation is considered a necessary step to increase the blood circulation LbL produced capsules.

3. To increase therapeutic activity targeting of LbL nanocapsules to specific diseased cites should be considered. Since LbL coating involves surface modification targeting by including specific monoclonal antibodies or other site specific binders on the surface of the nanocapsules should be possible.

Let us review some recent studies reporting the application of LbL coating to drug nano-formulation with an excellent chance of moving beyond clinical trials. But before looking at LbL applications, it is important to note that nano particulate drugs formulations that to date have reached the market most apply traditional manufacturing processes that have been modernied. The first group

of these processes include high-pressure homogenisation, ultra-sonication and pearl/ball milling. All produce concentrated submicron particle dispersions by mechanical disintegration of insoluble drug particles. A second approach is based on various precipitation methods. Here the formation of nanoparticlesis initiated by mixing a poorly soluble drug solution in an organic solvent, such as acetone, tetrahydrofuran, DMSO or ethanol, with a water-based stabiliser. A drawback of both these approaches is the difficulty of removing or exchanging the milling or precipitation media, usually containing up to 5-10 wt % of surfactants, without negatively affecting the stability of the dispersion. Instability can cause aggregation, crystal form changes and particle growth. This is why, despite several drug nanocrystal formulations, such as Triglige , Rapamune , Emend , Tricore , Megas ES , have been approved by the FDA for medical usage, only few are commonly used in medical practice.

Of these the most popular are the intramuscular injection of paliperidonepalmitate (Invega ) and intravenous injection of paclitaxel (Abraxane ).

Recent studies have shown that LbL coating can potentially eliminate the instabilities associated with many drug nanoparticle dispersions because in contrast to untangled surfactant stabilizers, LbL polyelectrolyte shells do not detach easily from the surface and retain integrity upon dilution in another media. This shell can therefore be designed to improve the stability of drug

Research & Development

nanoparticles in suspension. The inner layers minimize the surface free energy, thereby preventing crystal form changes and nanoparticles coalescence, whilst the outermost layers due to their high hydrophilicity and strong surface charge enhance colloidal stability. Intermediate layers in the shells that tie the multilayer together can be designed to serve as a dissolution barrier thereby allowing modifying and controlling the release of the drug from the nanoparticles.

For example, to avoid drug nanocrystal aggregation and high loss of materials associated with centrifugation or filtration used in classical LbL techniques, we have elaborated a non-washing LbL procedure based on monitoring the particles electrical surface zeta-potential. In this process polyelectrolytes were added step-wise in small aliquots until nanoparticles’ surface charge was reversed to an opposite values (Figure 3). Neither LbL shell integrity nor thickness was compromised, but less polyelectrolyte were used in the procedure avoiding multiple centrifugations. This will prove to be very important for scaling up when, for example, expensive PEG-modified polyelectrolytes are used in pharmaceutical applications. In addition, we have also performed LbL encapsulation of drug nanoparticles under permanent ultrasonication. This further helps to keep the nanoparticles well dispersed even when their surface charge in the preparation process is low.

Figure 3. x-potential of two types of 170 nm paclitaxel nanoparticles coated with poly-L-lysine and heparin using the wash free LbL method. Solid line - cores prepared by powder sonication in the presence of PLL followed by LbL assembly. Dashed line –cores produced by adding alcohol paclitaxel solution to aqueous sodium docusate and Polysorbate 80 followed by LbL assembly using PLL-block-PEG. During the coating process we also found that even better colloidal stability was obtained when at least one PEGylated polyelectrolyte was used in

Figure 3

each bilayer, rather than coating only the outside of the capsule with the PEGylated polyelectrolyte. For example, alternate deposition of linear block-copolymers of poly-L-lysine and PEG and heparin on 170 nm paclitaxel cores allowed for the formation of stable aqueous 5 mg/mL drug colloids (Figure 4). After a three PEGylated polyelectrolyte bilayer shell was formed, the coated nano-crystals were separated from the supernatant by centrifugation. In this nanoformaltion paclitaxel concentration was 5 mg/mL which is almost two thousand times higher than its intrinsic water solubility of 0.3 Âľg/mL. In this LbL coating process PEGylated polyelectrolyte was used because commonly used excipients such as low-molecular weight PEG and PVP do not remain within the LbL shell.

Figure 4 Left: an aqueous colloid of 5 mg/mL paclitaxel nanoparticles coated with PEGylated LbL shell, and, right: opaque paclitaxel dispersion stabilised only with surfactant. LbL encapsulation gives a very stable fine dispersion, so fine that a dollar coin is visible when looked at through the clear dispersion.

Although this new coating process has increased the applicability of LbL coating to the design of nano drug formulations an important practical question still remain. How to combine nano-sized drug dispersing processes with LbL shell assembly to produce injectable particles that are be less than 200 nm in diameter? An intriguing aspect under investigation by us is the possibility to form

LbL shells on nanosized cores drug-mill where the milling medium contains a sufficient excess of uncharged pharmaceutical excipients (e.g. sucrose, glycerol, non-ionic surfactants, polysorbates, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)). The excipients, combined with ionic surfactants, are often added to increase the efficiency of the milling process and the functionality of nanosized injectable drug dispersions. Similar to the LbL process these charged amphiphiles (sodium lauryl sulfate, sodium docusate) or polymeric (carboxymethyl cellulose, chitosan) surfactants attach to the nanoparticle-during grinding and thus serves as anchors for the rest of the shell formed

by LbL coating. This allows the possibility to combine in the shell components with different functionality; for example, to enrich the capsule outermost layers both with PEGylated compounds and albumin as described above during the size reduction process, e.g. milling or precipitation.

Figure 4

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Conclusion

In this paper, in addition to an introduction to LbL coating as applied to drug formulations, we highlighted a recent important breakthrough in LbL coating that allows for the formulation of 100-200 nm nanoparticles consisting of a core of poorly soluble anticancer drug and PEG-modified polyelectrolyte shells.

These nanocapsules are much smaller than traditional LbL produced microcapsules. With this discovery we changed the usual strategy of LbL-encapsulation from making microcapsules with many layers in the shell walls for encasing highly-soluble materials to the use of very thin polycation / polyanion coatings on poorly soluble drug nanocores. We have 32

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shown that this technique for making very stable aqueous nanocolloids works well for poorly soluble drugs, such as paclitaxel, and for dyes, and even insoluble inorganic salts. This approach uses different PEGylated polyelectrolytes that not only provide good physical stability to the nanocolloids at much higher concentrations, but also improves the in vivo performance (for example, better than currently available formulations of the drug paclitaxel). Recently, two of us (MD and YL) edited a special issue

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While the fundamentals of LbL shell buildup on nanocores generally follow the same rules as for larger microparticles, there are size-related limitations as the size of the cores decrease: A limited space for polyelectrolyte adsorption on one nanoparticle, and 2) influence of solution ionic strength on of polyelectrolyte tails protruding into the dispersion medium.

To avoid bridging of neighbor particles and formation of grape-like structures, polyelectrolytes of less than 50 kDa molecular mass are preferable. Another complication is when transitioning from in vitro to in vivo, the colloidal stability behavior change as the particle size of the drug decreases. Many perspective drug nano-formulations end at the stage of in vitro stability testing in buffers and are never tested in vivo in animals or humans because of immediate aggregation after application. However, by combining the above described techniques, we prepared nanocolloids of several anticancer drugs coated with LbL shells of PEGylated polyelectrolytes that are stable in PBS and in serum nanoparticles. Preliminary in vivo experiments show that such shell architecture can be used in intravenously injectable formulations. In addition to PEGylation improving the in vitro and in vivo dispersion stability of LbL nanocapsules, it also prolonged their blood circulation.

of Advanced Drug Delivery Reviews, 2011, v.63, August issue, pp. 701-980 on LbL nanoshells were the reader can find additional information on the topic.

Acknowledgement

This work was supported by Award R01CA134951 from the US National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institute of Health.

Yuri M Lvov is a Professor of Chemistry and T.Pipes Endowed Chair on Micro and Nanosystems at the Institute for Micromanufacturing, Louisiana Tech University. Lvov was among pioneers of the polyelectrolyte layer-by-layer assembly which became an important method in bio/nanotechnology. His research on LbL assembly has been cited more than 9,700 times. In 2008, he received the Best of Small Tech US National Innovator Award in recognition of his achievements in the field of nanotechnology.

Tatsiana G Shutava is a Research Associate Professor at the Institute for Micromanufacturing Louisiana Tech University and a Senior Researcher at the Institute for Chemistry of New Materials, National Academy of Sciences of Belarus. She has over 500 citations of her works on polyphenol LbL encapsulation and smart protective microcapsules.

Kirill A Arapov is a PhD student in Biomedical Engineering Program at Louisiana Tech University. During his university years in Russia, he won The National Chemistry Contest in 2006. He is the author and co-author of 10 articles on the synthesis of nanomaterials and their applications.

He was awarded by 1-st place prize in The International Scientific Conference of Young Scientists Lomonosov – 2008, Moscow.

Vladimir P Torchilin is a Distinguished Professor and Director, Center for Pharmaceutical Biotechnology and Nanomedicine. His research focused on biomedical polymers, polymeric drugs, immobilized medicinal enzymes, drug delivery and targeting, pharmaceutical nanocarriers for diagnostic and therapeutic agents, and experimental cancer immunology. V. Torchilin received the 2005 Research Achievements in Pharmaceutics and Drug Delivery Award from the AAPS and 2007 Research Achievement Award from the World Pharmaceutical Congress. He is the Editor-in-Chief of Drug Delivery and Current Drug Discovery Technologies and serves on the editorial boards of many leading journals in the field. In 2005-2006 he served as a President of the Controlled Release Society, from which he has also received a Founders Award in 2010.

Melgardt M De Villiers is an Associate Professor at the University of Wisconsin School of Pharmacy. His current research is focused on determining the pharmaceutical science involved in developing an understanding of the pharmaceutics, engineering, and materials sciences principles underlying enhanced drug delivery technologies.

Several of his publications have been related to layer-by-layer nanocoating and to solid-state properties of drugs and excipients.

Dr. De Villiers is the associate editor of AAPS PharmSciTech and the recipient of the Outstanding Professor in the College of Health Sciences at the University of Louisiana at Monroe.

Manufacturing

Similar Biologics

A golden bird to tame Biologics are inherently different from chemicals drugs in terms of their source, structural complexity, fragility of the active substance, manufacturing, quality control and stability. Since chemical drugs have well-defined structure, their quality can be easily optimised and maintained, while the large and complex bio-molecules are difficult to manufacture everytime in a similar fashion and therefore, highly susceptible to heterogeneity.

Rajneesh Kumar Krishan K Tripathi Department of Biotechnology, Ministry of Science and Technology, India

I

n the past three decades, biotechnology-led medicines have revolutionised the treatment of several life threatening and rare diseases. The substances produced by living cells and used in the treatment, diagnosis or prevention of diseases are referred to as biologic drugs or biologics or biopharmaceuticals or recombinant therapeutics. Since the approval of first biopharmaceutical, recombinant insulin in 1982, the range and market of biopharmaceuticals has grown significantly. More than 250 biological products approved in various countries and 500 new products are in pipeline.

Biopharmaceuticals are now important therapeutic option for a variety of chronic and non-chronic diseases including the rare diseases.

Biologics are inherently different from chemicals drugs in terms of their source, structural complexity, fragility of the active substance, manufacturing, quality control and stability. Since chemical drugs have well-defined structure, their quality can be easily optimised and maintained, while the large and complex bio-molecules are difficult to manufacture everytime in a similar fashion and therefore, highly susceptible to heterogeneity. As a result,

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avoiding the batch to batch variation during their manufacturing is a highly challenging task. Besides, these manufacturing variations more often lead to immunogenic reactions and compromise the patient’s safety.

The patents of the first generation of biotechnology products have either expired or will expire shortly, thereby opening the market for introducing the follow on substitutes of the original biologics, these follow-on substitutes are popularly known as ‘biosimilars’. There are a number of terms used to describe these substitutes such as biosimilars, biologics, biogenerics, biopharmaceuticals, follow-on-proteins etc. These terms are confusing and do not include vaccines and blood products produced through recombinant route.

Recently, Review Committee on Genetic Manipulation (RCGM), Department of Biotechnology has adopted a substitute term “Similar Biologics”, which is defined as recombinant biologics similar to the original innovator product based on the comparability studies.

In 2009, recombinant proteins accounted for more than 65 per cent of the total global biopharmaceutical sales.

Growth in this class is expected to be low

in most of the developed markets as a result of biosimilar entry and increasing cost containment measures. The market share of emerging markets (Brazil, Russia, India, China, Mexico, Turkey and South Korea) is likely to increase from less than 5 per cent in 2009 to more than 8 per cent by 2015. The similar biologics have the potential to provide affordable biotech medicines, however, the issues and challenges associated with them needs establishing the appropriate regulatory pathways to ensure quality, safety and efficacy. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was the first to recommend the guidelines for biosimilars but it is the European Union (EU), who implemented them first in 2006. EU was followed by several other countries like Australia, Canada, Malaysia, Japan and organisation like World Health Organization (WHO).

International status

European Medicines Agency i.e. EMA was first to develop a regulatory pathway for biosimilars, which they designated as ‘Similar Medicinal Biological Products

Manufacturing

(SMBP)’. Article 10(4) of the EU’s Code for Human Medicines Directive (2001/83/ EC) was amended in 2004 (by Directive 2004/27/EC) to authorise the abbreviated approval of biologic products that claim to be similar to an original innovator product. However, the legislation leaves a wide margin of discretion to the Committee for Medicinal Products for Human Use (CHMP; EMA) to develop product class-specific guidelines that determine the extent of nonclinical and clinical testing required to establish the safety and efficacy of a SMBP. EMA first released overarching guidelines on quality issues of SMBPs containing biotechnology derived proteins as active substance followed by separate guidelines focused on non-clinical and clinical issues. In addition to these general guidelines they also drafted customized guidelines for different biotechnology based products such as Insulin, Erythropoietin (EPO), Granulocyte Colony Stimulating Factor (GCSF), Interferons and Growth Hormone.

In the USA, biologics are authorised for marketing through two regulatory pathways i.e. Biological License Application (BLA) procedure under Public Health Service Act (PHS, 1944) for regulation of biological produced by biotechnological methods (e.g., MAbs and therapeutic proteins) and abbreviated New Drug Application (NDA) procedure under Food Drug & Cosmetic Act (FD&C, 1938), which covers conventional pharmaceutical and certain natural proteins (e.g. insulins and growth hormone). The ANDA procedure allows approving only a limited range of biosimilars. In March 2010, US Federal Government amended Section 351 of the Public Health Services Act to create abbreviated biologic approval pathway for a “highly similar” biologic product.

A biosimilar must possess no clinically meaningful differences in the safety, purity and potency from the original innovator product and the product may be interchangeable if the product is biosimilar and show no clinically significant difference to the reference product.

Very soon, more biotech based drugs are going to be out-of-patent and the related guidelines will decide the strategy of investment, molecule selection and marketing plans.

The new act also includes a 12 year data exclusivity period for all original products (with a six-month extension for products supported by paediatric studies). The act also provides one year data exclusivity to a first biosimilar approved for marketing to boost the availability of biosimilars. Though there is a mechanism now, the FDA is still not ready to give final shape to its biosimilar guidelines as a result of highly debatable data exclusivity and patent issues. Currently, both EMA and FDA guidelines are under revision.

WHO has developed a framework of general principles as monograph and part of its “Biological Standardization Process” and prepared a “Guidelines on evaluation of similar biotherapeutic products (SBPs)”. Biosimilar is designated here as “Similar Biotherapeutic Product (SBPs) and defined as a “biotherapeutic product claimed to be similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product (RBP), which must have been licensed by national regulatory authorities on the basis of a full registration dossier”. However, WHO emphasises that its framework is generalised and will only apply to well-established biologics. Its guidelines emphasise the high standard of safety and require at least one clinical study for approval. In addition to pre- marketing safety study, the applicant has to submit a well devised plan for post-marketing clinical safety and surveillance.

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a joint initiative

involving both regulators and researchbased industry representatives of the European Union, Japan and the USA in scientific and technical discussions of the testing procedures required to assess and ensure the quality, safety and efficacy of medicines. The goal of ICH is to promote international harmonisation by bringing together representatives from the three ICH regions (EU, Japan and USA) to discuss and establish common guidelines. In July, 1997, ICH recommended the harmonized tripartite guidelines, for the preclinical safety evaluation of biotechnology-derived pharmaceuticals. The active substance include proteins and peptides, their derivatives and products of which they are components; they could be derived from cell cultures or produced using recombinant DNA technology including production by transgenic plants and animals. The guidelines may also be applicable including recombinant DNA protein vaccines, chemically synthesized peptides, plasma derived products, endogenous proteins extracted from human tissue and oligonucleotide drugs. The primary goals of preclinical safety evaluation are: 1) to identify an initial safe dose and subsequent dose escalation schemes in humans; 2) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; and 3) to identify safety parameters for clinical monitoring. In these guidelines, the biosimilars have not assigned any separate name and the list of products covered is too wide though they are considering them on case-by-case basis and don’t consider them as ‘same’.

Indian scenario

In India, Review Committee on Genetic Manipulation (RCGM), Department of Biotechnology is responsible for preclinical, export and import approval of biotechnology based recombinant drugs, while Central Drugs Standard Control Organization (CDSCO) and the Drugs Controller General of India (DCGI) is responsible for approvals of clinical trials, new drug applications, www.pharmafocusasia.com

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Table窶的: Recombinant biological products (total 38) marketed in India Molecules

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Therapeutic applications

Human insulin

Diabetes

Erythropoietin

Treatment of anemia

Hepatitis B vaccine (recombinant surface antigen based)

Immunization against Hepatitis B

Human growth hormone

Deficiency of growth hormone in children

Interleukin 2

Renal cell carcinoma

Granulocyte Colony Stimulating Factor

Chemotherapy induced neutropenia

Granulocyte Macrophage Colony Stimulating Factor

Chemotherapy induced neutropenia

Interferon 2Alpha

Chronic myeloid leukemia

Interferon 2Beta

Chronic myeloid leukemia, Hepatitis B and Hepatitis C

Interferons Gamma

Chronic granulomatous disease and Severe malignant osteopetrosis

Streptokinase

Acute myocardial infarction

Tissue Plasminogen Activator

Acute myocardial infarction

Blood factor VIII

Haemophilia type A

Follicle stimulating hormone

Reproductive disorders

Teriparatide (Forteo)

Osteoporosis

Drerecogin (Xigris) alpha

Severe sepsis

Platelet Derived Growth Factor (PDGF)

Bone marrow induction and osteoblasts proliferation

Epidermal Growth factor (EGF)

Mitogenesis and organ morphogenesis

Eptacogalpha (r-F VIIa) r-coagulation factor

Haemorrhages, congenital or acquired hemophilia

Bevacizumab

Treatment of various cancers, including colorectal, lung and kidney cancer,

Trastuzumab

Treatment of breast cancer

Rituximab

Treatment of many lymphomas, leukemias, transplant rejection and some autoimmune disorders.

Darbopoetin alpha

Treatment of anaemia

Human Serum Albumin

Treatment of liver disease with ascites.

Insulin Glargin

Treatment of Type I Diabetes Mellitus

Insulin Lispro

Treatment of Diabetes Mellitus

Insulin Aspart

Treatment of Diabetes Mellitus

Met-h-GCSF

Chemotherapy induced neutropenia

Peg-r-metHu-GCSF

Chemotherapy induced neutropenia

h-Interferon alpha 2b

Treatment of Chronic Hepatitis B

Peg-Interferon alpha-2b

Treatment of Chronic Hepatitis B

h-INF beta-1a

Treatment of multiple sclerosis (MS)

Peg-h-GCSF

Chemotherapy induced neutropenia

h-PDGF-BB-beta-TCP

Bone marrow induction and osteoblasts proliferation

r-h-Chorionic Gonadotropin Hormone

Role in Pregnancy

Hemophilic factor IX

Treatment of hemophilia

Cetuximab

Treatment of metastatic colorectal cancer and head and neck cancer.

Luteinising Hormone

Treatment of Reproductive disorders

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Manufacturing

marketing and the import of drugs in association with Directorate General of Foreign Trade (DGFT). The state drug control authorities are responsible for licensing a drug maker’s research and manufacturing facilities, while Institutional Biosafety Committees (IBSC) oversees the containment facilities.

As of now, no separate pathway for approval of recombinant drugs under the category of “similar biologics” exists in India. Over 40 biologics are marketed in India, out of which around 25 are similar biologics. Another 25 similar biologics are in the final stages of development.

In India, whichever similar biologics is available, they are approved as ‘new drug’ under Drugs and Cosmetic Act, 1940.

Table-I represent the r-DNA technology based biopharmaceuticals already having marketing authorization. Table II & III includes the r-DNA technology based biopharmaceuticals for pre-clinical studies or recommended for clinical studies to DCGI by Department of Biotechnology in a financial year 2010-2011. Under the current relaxed regulatory environment, Phase I & II clinical trials are typically not required for similar biologics approval in India unless it is found necessary in special cases. Phase III trials with a minimum of 100 patients are mandatory for establishing bioequivalence.

Currently, there are two serious concerns about the Indian regulatory system related to similar biologics. First, number of drug regulatory authorities involved in approval procedure, which makes the overall process time consuming and unnecessary lengthy. Second is the lack of clearly defined guidelines for similar biologics approval. The Indian government acknowledged the need for tighter regulatory standards. The major regulatory initiatives have been taken to make the approval process streamline through establishing a single window mechanism. Department of Biotechnology (DBT) has drafted a bill for the development of Biotechnology Regulatory Authority of India (BRAI), which will be tabled in the monsoon season (2011) of Parliament for discussion and hope-

fully will be cleared for developing the BRAI as an independent authority. BRAI will be an “autonomous and professionally led body to provide a single window mechanism for the biosafety clearance of genetically modified products and processes.” In other words, BRAI will replace many of the other bureaucracies. BRAI will also include a training center for its biotech regulators, to build and maintain their professional competence.

DBT is also in the process of preparation of separate guidelines for preclinical evaluation of similar biologics. DBT holds series of public meetings especially with Indian biotech industries to find out the issues related to the manufacturing and marketing of similar biologics. RCGM is a group of experts having both academic and on-field experience is entrusted for the formulation of similar biologics draft guidelines. RCGM is performing the judicious analysis of all the factors that affects the quality, safety and efficacy of a similar biologics product. It is pertinent to discuss some of these issues briefly.

A similar biologic is generally compared with an original innovator product to establish the safety and efficacy of the product. There are two major concerns related to the selection of a reference product. First, in the absence of availability of original innovator product in India, whether a similar biologics, already authorised for marketing in India, can be used as a reference product?

Second, whether some of supporting data of a reference product may be used as a part of subsequent similar biologics clearance and approval? In general, the

European Medicines Agency i.e. EMA was first to develop a regulatory pathway for biosimilars, which they designated as ‘Similar Medicinal Biological Products (SMBP)’.

EMA Guidelines (2004) indicate that the chosen reference product must be authorised in the country on the basis of a complete dossier. Utilising the reference product data for similar biologic approval makes the process less time consuming and expensive but it is not acceptable on grounds of manufacturing heterogeneity often observed in biopharmaceuticals.

Also any differences observed between a similar biologics and a reference product will have to be justified by appropriate studies on a case-by-case basis.

In general, the biophramceuticals are large, complex and heterogeneous molecules with more variable molecular weights in comparison to chemically originated small-molecules. The inherent complexity of these molecules makes their manufacturing susceptible to variation. Therefore, it is essential to maintain rigorous quality control at each step of manufacturing i.e. from fermentation to packaging. Changes may occur in the expression systems used for production, culture conditions (e.g. temperature and nutrients), purification and processing, formulation, storage and packaging. Small changes in, or differences occurred during manufacturing processes may have a significant impact on the quality, purity, biological characteristics and clinical efficacy of the final product e.g. “Valtropin”, a similar biologic growth hormone is different from its reference product “Humatrope”, probably because different cell lines are used in the production of these two drugs: yeast for Valtropin and Escherichia coli for Humatrope. Another example is the occurrence of pure red blood cell aplasia as a result of production of neutralising antibodies against a particular form of Epoetin-alpha.

Structural differences between proteins may arise for a number of reasons, including oligomerization, modification of the protein primary sequence, glycosylation patterns or the conformational state. The analytical homogeneity is extremely crucial between a similar biologic and reference product to maintain the quality of a product. There are numerous examples where presence of process and product related www.pharmafocusasia.com

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Table-II: List of r-DNA biotech medicines approved for pre-clinical studies during 2010-11.

Products

Institute/Industry

Pegylated Erythropoietin (PEG-EPO) Recombinant anti-CD 20 mAb Recombinant human Follicle Stimulating Hormone (rhFSH) Pegylated recombinant human Interferon Alfa 2b (PEG-IFN)

Intas Biopharmaceuticals Ltd., Ahmedabad

Darbepoetin alfa Recombinant humanized mAb against VEGF-A Recombinant mAb against HER2 receptor Recombinant human Pegylated Granulocyte Colony Stimulating Factor (rhPEG-G-CSF)

Reliance Life Sciences Pvt. Ltd., Mumbai

Recombinant human Parathyroid Hormone [rhPTH(1-34)] Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF) Recombinant human Interleukin-11 (rhIL-11)

Lupin Limited, Pune

Recombinant anti-CD 20 chimeric mAb Recombinant mAb against HER2 receptor

Biomab Pharmaceuticals (India) Pvt. Ltd., Mumbai

Recombinant human Pegylated Granulocyte Colony Stimulating Factor (rhPEG-G-CSF)

Bioviz Technologies Pvt. Ltd., Hyderabad

Darbopoetin alfa

Hetero Drugs Ltd., Hyderabad

Recombinant Interferon -1b (rhINF- -1b)

Zenotech Laboratories Ltd., Hyderabad

Rituximab-Recombinant anti-CD 20 monoclonal antibodies

Cadila Healthcare Ltd., Ahmedabad

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF) Recombinant human Insulin Analog (B28Lys, B29Pro)

Biogenomics Ltd., Thane

Recombinant human Exendin-4 (VB 63) Recombinant Enfuvirtide internally coated

Virchow Biotech Pvt. Ltd., Hyderabad

Live attenuated Rabies Vaccine

Intervet India Pvt. Ltd., Pune

Recombinant human Insulin

Bigtec Pvt. Ltd., Bangalore

Recombinant Anti-Staphylococcal Protein P128

Gangagen Biotechnologies Pvt. Ltd., Bangalore

Table-III: List of r-DNA biotech medicines recommended

by RCGM to DCGI for appropriate phase of clinical trials during 2010-11.

Products

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Institute/Industry

Polysialylated Erythropoietin

Serum Institute of India Ltd., Pune

Recombinant monoclonal antibody targeting Vascular Endothelial Growth Factor “VEGF”

Biocon Ltd., Bangalore

Recombinant human Granulocyte Colony Stimulating Factor (rhGCSF)

Lupin Ltd., Pune

Recombinant human Follicle Stimulating Hormone (rhFSH) Pegylated recombinant human Interferon Alfa 2b (rhPEG-IFN-α-2b)

Intas Biopharmaceuticals Ltd., Ahmedabad

Recombinant Anthrax Vaccine

Panacea Biotec Limited, New Delhi

Recombinant anti-CD 20 Chimeric mAb Recombinant human Growth Hormone (rhGH) Palivizumab-Recombinant monoclonal antibody Abciximab-Recombinant chimeric monoclonal antibody (IgG1k)

Reliance Life Sciences, Mumbai

Modified Streptokinase

Symmetrix Biotech Pvt. Ltd., Mumbai

Recombinant Epsilon Toxoid

Indian Immunologicals Ltd., Hyderabad

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF)

Scigen Biopharma Pvt. Ltd. (SBPL), Pune

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF)

Cadila Pharmaceuticals Ltd., Ahmedabad

Recombinant Anti-Rho(D) Immunoglobulin

Bharat Serums and Vaccine Ltd., Mumbai

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impurities resulted in substantial variation in a similar biologic. For example, almost 60 per cent of patients treated with recombinant human Growth Hormone (rhGH) powder manufactured by API Covance (Somatropin Sandoz powder) developed anti-GH antibodies and all patients developed antibodies against E.coli proteins, while only about 2% and 0% of patients develop anti-GH and anti-HCP antibodies respectively when treated with a innovator/reference product ‘Genotropin’ (Pfizer), [4]. The additional purification steps are included in order to ensure the tolerability and efficacy of the product.

Another hurdle in quality assurance is the inherent limitations of the biological assays. Therefore, the biological assays should be performed simultaneously and parallelly on a similar biologic and reference product under the same laboratory conditions to mitigate or reduce the assay errors. The most important among all the biological assays is the toxicity studies including toxicokinetic measurements such as determination of antibody titres, cross-reactivity and their neutralising capacity. A biological product may be toxic due to its degradation during storage in the distribution chain before reaching to the end consumer. Therefore, the comparability studies may also include the comparative data for accelerated and long term stability to make sure the quality and safety of a product during storage.

The analytical comparison of a similar biologic with a reference product does not guarantee about the behaviour of a product in human biological system.

Therefore, it is undoubtedly essential that the applicant must submit elaborate in-vitro and in-vivo pharmacological and toxicological studies data as a part of application dossier. Safety pharmacology, reproduction toxicity, mutagenicity and carcinogenicity studies may not be required unless specifically desired in a particular case.

Generally, the biological products obtained from one system are immunogenic when introduced in another biological system. Mostly similar biologics

are recombinant proteins and antibodies, their introduction might trigger a severe immunogenic reaction especially when the patient is already exposed to a molecule. Immunogenicity should be evaluated using appropriate studies and methods to characterize type, concentration and titre of antibodies. When neutralizing antibodies are detected, the impact on Pharmacokinetic (PK) and Pharmacodynamic (PD) parameters and overall efficacy and safety should be analysed well. This is particularly true for proteins with post-translational modifications such as glycosylation where small differences in glycosylation pattern can result in significant differences in immunogenicity profile.

Conventional generics of chemical origin are considered to be therapeutically equivalent to a reference product if it has pharmaceutical equivalence (i.e. identical active substance) and bioequivalence (i.e. comparable pharmacokinetics). The inherent complexity of biopharmaceuticals makes it difficult to avoid heterogeneity among different batches and from different manufacturers. The challenging task is to decide whether abbreviated clinical trial should be made mandatory or data requirement should be restricted and desired only on case by case basis. Clinical trial for a similar biologic is estimated to cost US$ 26.5-$53mn. After including the cost of approval through the regulatory process and the cost of marketing and detailing, the estimated cost would be US$ 50mn and US$ 300mn with a manufacturing plant. This is certainly a huge investment for any single copy-cat drug. The estimated cost will definitely reduce the profit margin. Therefore, the major question is can clinical trials be skipped by taking the comparability studies as standard in cases which are known to be safer. The argument in favor of restricting the clinical trials is that if a similar biologic is substantially similar to a reference product during comparability studies and then most probably it will behave in the same fashion in human system as the reference product. Argument in favor of making the clinical trials mandatory is that

even animal (pre-clinical) studies do not guarantee the absolute safety and efficacy of any biological product in a human system. So, RCGM need to weigh the pros and cons of all possibilities related to clinical trials and then appropriately implement the best possibility in case of similar biologics.

Once a product is authoried for marketing, it is desirable to access and monitor its effect in terms of safety and toxicity in human population. In case, the Indian regulatory authorities restricting the clinical trials during approval of similar biologics, the post-marketing surveillance will be extremely important e.g. In Korea, three biosimilars of Epoetin-alfa i.e. ‘Eporon’ (Dong-A Pharmaceutical Company Ltd), ‘Espogen’ (LG Life Sciences), ‘Epokine’ (CJ Corporation) have been shown to differ in the activity, concentration, isoforms, structural stability from the reference product ‘Epogen’ (Amgen, USA) [5]. Like EMA, the Indian regulatory authority may ask companies to submit self-executable pharmacovigilance plan as a part of approval process or collect the similar biologics field samples randomly and then testing them in governmental laboratories. The second option is more practical especially in the absence of a very well established pharamcovigilance system in India. Recently, Central Drugs Standard Control Organization (CDSCO) has taken an initiative to establish a Pharamcovigilance Progarmme of India (PvPI), which is expected to be fully operational by 2015. PvPI will definitely open the door for the regulatory authorities to keep stringent on-field vigil for ensuring the safety and efficacy of drugs in general.

Conclusion

The huge Indian market and the margin associated with similar biologics is highly lucrative for many big players in the biotech sector. Many of them are very curious about the regulatory pathway not only in India but also in other markets like USA. Very soon, more biotech based drugs are going to be out-of-patent and the related guidelines will decide the www.pharmafocusasia.com

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References 1. Global Biopharmaceutical Market Report (2010-2015) by IMARC available at http:// www.imarcgroup.com/global-biopharmaceutical-market-report-2010-2015/ (Last accessed on 16-08-2011) 2. Peterkova, V. et al. (2007). A Randomized,

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Double-Blind Study to Assess the Efficacy and Safety of Valtropin, a Biosimilar Growth Hormone, in Children with Growth Hormone Deficiency. Horm. Res. 68(6), 288-293 3.Casadevall N, Rossert J. (2005). Importance of biologic follow-ons: experience with EPO. Best Pract. Res. Clin. Haematol. 18, 381-387 4. Declerck et al. (2010). BiosimilarsControversies as illustrated by rhGH. Curr.

A u t h o r BIO

strategy of investment, molecule selection and marketing plans. While framing the guidelines for similar biologics, Indian regulatory authorities will try to keep a balance between making available the high quality similar biologics at a cheaper price to Indian consumers and cost advantage to biotech industries so that they remain interested in manufacturing them. DBT has advocated to keep biotech medicines out of price control (DPCO) to facilitate growth of this industry for the benefit of society and has the aim that let market forces decide the price through competitive process.

Med. Res. & Opin. 26, 1219-1229 5. Deechongkit et al. (2006). Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex. J. Pharm. Sci. 95, 1931-1943 Note: The views expressed are personal to the authors and have no relation with their official position in Department of Biotechnology.

Krishan Kumar Tripathi is Doctorate in Microbiology from Panjab University, Chandigarh. He worked in the pharmaceuticals and biological industries and has got extensive exposure to production and quality control techniques of life saving bacterial and viral vaccines. His noteworthy work includes the reduction in immunisation-schedule of neural rabies vaccine, saving livestock and mam-hours to visit clinics, having indirect benefits to economy. Since last 21 years, he has been working in the Department of Biotechnology, Govt. of India Rajneesh Kumar Gaur completed his doctorate in Structural biology from RWTH, Germany and having almost 8 years of experience in active science research. He is currently engaged in planning, co-ordination and International cooperation in Department of Biotechnology, Ministry of Science and Technology, New Delhi, India. He is interested in S&T policy matters.

Micronization of Active Pharmaceutical Ingredients

Development of the particle size distribution obtained during a grinding test in a laboratory bead mill

Results of the scale-up from a laboratory agitator bead mill to a production-size mill

A medium-size laboratory mill DeltaVITA® 600 with CIP and SIP.

The comminution or desagglomeration of active pharmaceutical ingredients (API) is called micronization and brings about several advantages. The increase of the particle surface caused by the comminution results in a considerably better dissolution rate and bioavailability of the agents and therefore the APIs act faster. Due to the increased bioavailability a lower amount of APIs is required which in turn leads to a more cost-efficient product with less risks and side effects for the patient.

The NETZSCH Grinding & Dispersing Business Unit offers equipment for all process engineering tasks in the fields mixing, dispersing, deaeration, wet- and dry grinding and classifying.

Based on comprehensive experience with the production of GMP-compliant pharmaceutical products, all sizes of NETZSCH DELTAVITA® machines ranging from small laboratory- to production-size machines excel by the following specific features: • All product wetted parts are designed and manufactured according to the latest GMP standards • Material-, production- and calibration certificates are supplied together with the machine • Optional cleaning in place (CIP) and sterilization in place (SIP) • All indirectly product-wetted surfaces are made of stainless steel • Optional data recording and formulation management • Operator management with password protection for different levels of security • Laboratory mills can be used with variable grinding chamber sizes • Various materials like ZrO2, stainless steel 316 or nylon grinding chamber designs are available

• Splash-proof machine stand • Comprehensive testing and qualification documentation, FAT, IQ, OQ, process validation • Production of GMP compliant machines in the US • Trainings and seminars Besides the machine design there are other essential conditions for the successful comminution or dispersion of solids. These are the right formulation of the product suspension as well as the selection of the best grinding media and the optimal operating parameters of the mill.

The development of the formulation and the optimization of the operating parameters can be conducted in laboratory mills. In particular when it comes to the selection of the operating parameters of the mill NETZSCH can revert to a pool of experience of more than six decades. Picture 2 shows the development of the particles size distribution of APIs during a grinding test on a laboratory bead mill. The customer aimed at a close particle size distribution with X99,3 < 400nm.

Moreover, the parameters had to be optimized to ensure that the product suspension would not exceed a defined maximal temperature during the comminution process.

Once the operating parameters have been optimized the results can be transferred to productionsize mills. An essential parameter for the scale-up is the specific energy input, which states the energy input with reference to the product quantity produced. Picture 3 shows the results of the scale-up from a laboratory agitator bead mill to a production-size mill. It clearly shows that the results of the laboratory test can be exactly transferred to the production-size plant.

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Developing Robust Approaches to the Effective Characterisation of Biosimilars Biosimilars can be proved to be analogous to a Reference Medicinal Product (RMP) by employing a set of robust analytical characterisation techniques which basically provides a ‘finger print’ like identification of Critical Quality Attributes (CQAs) and matching them with RMP. Shaligram S Rane, Sr. General Manager, Quality Nilam Diwan, Assistant Manager, Quality Assurance Om Narayan, Principal Scientist, Research and Development Rustom Mody, Executive Vice President, Science & Technology & Corresponding Intas Biopharmaceuticals Ltd. India

B

iosimilars, also known as follow-on biologics or similar biological medicinal product (henceforth referred to as biosimilars) are products that are similar to, but not the same as, an innovator’s drug. Since they are expected to cost less than an innovator’s drug, they bring affordable alternatives for treatment, for patients who previously could not afford them. Unlike generic drugs, biosimilars are generally regarded 42

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as therapeutically interchangeable.

From a historic perspective many biopharmaceutical companies make manufacturing related (process, raw material, equipment, process parameter etc.) changes throughout the product’s lifecycle. In case of biosimilars, it is well accepted that even small changes can potentially affect quality, safety and efficacy of the drug substance and the drug product.

Strategies of product development vary from company to company and from product to product. The approaches towards development and the extent of development vary, depending on the complexicity of the molecule. During development, understanding of product and process knowledge increases. This understanding is essential for determining all potential risk factors that impact product quality (CQAs) and control of these

Manufacturing

factors during the manufacture of drug substance and drug product becomes critical. In case of biosimilars, these risk factors are not only to be determined but also the process needs to be controlled in a way so as to match the product to RMP more closely.

The US Food and Drug Administration (FDA) offered a peek into its thinking on biosimilar drugs recently, by saying that because of their complexity, a “one size fits all” approach will not work. Biosimilar product should be developed, manufactured and controlled according to product specific pharmacopoeial monographs, country specific regulatory guidelines, ICH guidelines, WHO guidelines etc.

An appropriate biosimilarity and characterisation plan is required to demonstrate that the biologic and RMP have similar profiles in terms of quality, safety and efficacy. The quality issues relevant for demonstration of comparability for similar biological medicinal products containing recombinant DNA-derived proteins are also addressed in the EMA’s “Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues” Products which require high run rates, high success rates and minimal cost of goods (COGs) should have “fullblown” process characteriation efforts.

Products with lower run and success rate requirements still require successful validation, but examining interactions and combinations of parameters at the edge of their prescribed range may add little value. Quality Attributes can be laid out in order of their Criticality to Product’s safety and Efficacy.

Manufacturing process of Biosimilars

During development state-of-the-art concepts must be considered (e.g. characterisation of cell bank, viral safety, robust purification, identification of excipients, formulation, degradation study, etc.).

Process related and product related impurities also must be considered and it is important to demonstrate the consist-

ency and robustness of the process in controlling these impurities.

As described in ICH-Q5E, comparability exercise should be considered when a change is introduced into the manufacturing process (either for active substance or drug product) during development or post approval. For the purposes of clarity, any comparability exercise for process changes introduced during development should be clearly identified and addressed separately from the comparability exercise done during product development vis-a-vis the reference medicinal product. The latter is mandatory for biosimilars.

Pros and Cons of Biosimilar Development Pathway for US Market

With an abbreviated biosimilar development pathway finally being formulated by US-FDA companies must decide whether to adopt the 351(k) route or forego it in favor of the traditional biologics license

application (BLA) pathway. Companies will need to compare the advantage of getting to the market a few years faster and with much less development risk with the 351(k) route against potential negatives such as no market exclusivity, indication for use same as in the pivotal clinical phase-3 study, and extensive postmarket surveillance.

Given the intense competition in the rapidly evolving US market for biosimilars, the question often raised is - whether it is better to develop improved versions of the approved protein therapeutics (so-called “Biobetters”) taking the Novel Drug Application (NDA) route [Figure 2(A)] to get 12 years of market exclusivity against risking the “Abbreviated Biosimilar” developmental route [Figure 2(B)] with only 180 days exclusivity (for the first biosimilar) or no exclusivity?

Another risk factor to consider is even after completion of critical early-stage studies for a biosimilar (i.e. CMC, nonclinical, clinical phase-1 / human

characterisation study matrix for biosimilars

Shape / higher-order structure - Circular Dichroism - X-Ray Structure - NMR - Epitope Detection - Specific Binding

Assay - OD, HPLC, AAA, Biacore, ELISA, IFMA, Brandford, Lowry, Bioassay

Activity - Bioassay in vivo and in vitro - Specific binding assay

Purity - RP-HPLC - SE-HPLC - Peptide mapping - SDS-PAGE - Field Flow Fractionation - Elisa (HCP) - Immunobiot - DNA assay - LAL test - Virus test

Structure / Aequence - N-and C-terminus - Amino Acid Analysis - Peptide Mapping and Sequencing - Monosaccharide Analysis - Oilgosaccharide Mapping - Mass Spectrometry - Disulphide linkage Identity - N-Terminal Sequence - Peptide Mapping - Specific Bioassay - IEF

Size - SE-HPLC (also identity and assay) - SDS PAGE / Bioanalyser - AUC - AF4 - LLS

Carbohydrate Analysis - ESI-MS (whole molecule) - MALDI-TOF (released carboh.)

- Separation of labelled released carbohydrates (2-AA, 2-AB)

Surface Charge - IEF - CZE - IEX-HPLC - iCE280 - Chromatofocusing

Figure 1

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Manufacturing

Regulatory Pathways of Drug Development

(A) For ‘Novel’ or ‘Bio-better’ drugs: Novel Drug Application Genomics, proteonomics, proof of concept, animal metabolic studies

Animal toxicity efficacy & safety studies, PK, PD Formulation development. stability, product characterization

R&D

cGMP producation, stability, characterization, PK, PD in healthy humans, partly method validation

Phase I Clinical

Pre-clinical

Safety, PK, effectivess, scale up, stability, dose titration

Full cGMP, QA/QC. stability, release testing, Validation of full scale process including all method validation

Phase III Clinical

Post-market Surveillance

Phase III Clinical

Post-market Surveillance

(B) For Biosimilars: Abbreviated Pathway R&D RMP characterization, CQA identification, Product Development on Biosimilarity basis

Phase I Clinical

Pre-clinical Process Optimization using QbD, Product Characterization, CMC data, Animal Toxicity Efficacy & Safety studies, PK, PD, Formulation & Stability, Studies, Comparability Studies

cGMP production, Stability, identification of Critical Process Parameters to control CQAs, Identifying Risk factors that can affect CQA, PK, PD, Validation of Test Methods, Comparative safety studies

Safety, Comparative effectiveness, stability, establishment of biosimilarity, process, characterization, scale-up to commercial scale GMP, QA/QC, process validation

Immunogenicity, long-term pharmacovigillance

Figure 2

safety, PK/PD) there is no guarantee that the product will be considered a true biosimilar (interchangeable with the innovator’s product).

Complexicity of Biopharmaceutical product

The development of a biosimilar product involves a stepwise approach of optimising the production process, characterisation of the product (physicochemical as well as biological) followed by preclinical and/or clinical studies. It may be noted that demonstration of similarity for a biosimilar product to the innovator product is a pre-requisite for the reduction of requirements for pre-clinical and clinical studies before gaining final marketing approval through an abbreviated regulatory process in most countries / regions. Identification of any significant differences in quality, safety and efficacy studies would mean the need for a more extensive pre-clinical and clinical evaluation and the product will not qualify as a biosimilar. Characterization study 44

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matrix are shown below in Figure-1 Biosimilar product needs to be studied in comparison with an approved product, referred to as the reference medicinal product (RMP), to establish similarity to the approved drug. The RMP provides the basis for dose selection and route of administration and is utilized in the comparability studies to support the application for regulatory approval. Comprehensive information on the RMP is therefore the basis for establishing safety, quality and effectiveness of biosimilars and to reduce requirement of pre-clinical and clinical data.

An approved biosimilar drug cannot be considered as RMP, as the reference product should be the one that has been licensed on the basis of full quality, safety and efficacy data obtained from Complete Drug Development Pathway as shown in figure-2. Same RMP should be used throughout the development of a similar biologics i.e. manufacturing process, comparability exercise, pre-clinical and clinical evaluation.

RMP evaluation is critical in early stage of product development as it helps in setting the product specifications.

Pharmacopoeia Product Monograph may or may not be available at the early stage of product development and hence RMP evaluation is key for successful biosimilar development. RMP evaluation has got an enormous power to refine your process so that you set the process parameters limits to achieve the desired biosimilar quality. Biosimilar developer must procure different lots of RMP at various stages of product development as innovators also conduct improvement of their process and there is a likelihood that the biosimilar under development may looks inferior at later stage of development, if the innovator improves the purity profile.

At times, the innovator makes significant changes in the characteristics of the approved product on the market (RMP), making it mandatory for the biosimilar developer to make changes in the process to restore comparability.

Extensive structural, physicochemical, and biological methods should be applied to detect even “slight differences” in all relevant quality attributes affecting safety and efficacy. Analytical methods used should be appropriately qualified and validated with relevant information like use of standards and reference materials.

Although the ability to fully characterise biosimilars have improved dramatically with improvements in analytical tools and techniques, there are no definitive technologies yet developed to predict immunogenicity of a biosimilar product, let alone determine changes in its immunogenic potential after making changes in the manufacturing process.

Challenges Versus Rewards The field of biosimilars presents some significant challenges – safety, regulatory, legal and economic – which are still being discussed and debated in different forums. Most notable is the fact that, unlike the rather simple and straightforward process of introducing a generic equivalent of an original chemical (small molecule) drug, the process of introduc-

Manufacturing

SUB NOW SCRIB ! E

Shaligram Rane was qualified M.SC. in organic chemistry and M.Ed. with 19 years of experience in quality control and quality assurance department and 2 years in academic.

Nilam Diwan is post graduate in Biochemistry from North Maharashtra university and having 9 years professional experience in biotech industry.

A u t h o r BIO

ing a biosimilar to an original biologic drug is far more complex and requires a battery of test (orthogonal methods) to characterizing the molecule as shown in figure-1. Consequently, generic drugs are sometimes referred to as “carbon copies” where as biosimilars are considered as ‘non-identical’ to the approved innovator drug.

Biotechnology and pharmaceutical companies have been watching the FDA’s decision process closely, as the market for biosimilars promises to be large. The global biosimilars market is expected to hit $19.4 billion by 2014, with a compound annual growth rate of 89.1 per cent from 2009 to 2014.

Asia was the dominant market in 2008 because it commercialised products early, but the US is expected to dominate in 2014, spurred by the US market opening to the biosimilar products, according to a research analyst.

Om Narayan has over fifteen years of experience in developing and manufacturing recombinant products, especially Biosimilars for Biopharma industry. He is developing and manufacturing of Biosimilar products for regulated markets.

Rustom Mody is associated with Intas for the past 8 years where he has been directly involved in technical, techno-commercial and business progression of five rDNA products from clone to commercialization and is currently involved with the development of 10 other biosimilars.

Serious reading for decision makers in Pharma Industry In-depth articles on innovations and discoveries. Information and insights on the future of the industry. Discussions and debates between names who matter.

Relevant and original content, to help decide your future course of action.

Yes, please start my subscription to Pharma Focus Asia for the term indicated below Print* : e-Book :

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45

INFORMATION TECHNOLOGY

Emerging Trends in Functional Service Outsourcing The IT outsourcing industry has laid down a solid foundation in terms of establishing and providing service and pricing model that can be ramped up to provide value added and highly skilled outsourcing services.

Like the IT outsourcing industry in India, the clinical research industry was also established and expanded by home grown organisations. This sector has grown from a BOT (Build Operate and Transfer) model to a BPO and now to the Full Service outsourcing model.

Vijay Moolaveesala, I3 Statprobe, Inc, UK

F

unctional service has been ranked high among the buzz words of the clinical research industry. Both sponsor organisations and service providers are equally excited about the opportunities this model offers and the potentially winwin situation it provides to them. Sponsor organisations typically send individual

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protocol-related service RFPs (request for proposals) to CROs and follow-up with contract negotiations. Sponsors have realised the benefits of reduced oversight and contract management a complete functional service outsourcing model offers saving valuable time and resources.

Depending on the contract terms and

conditions, there can be a decrease in time and effort to manage the out-ofscope work load discussions. Sponsors are concerned about the management of out of scope work load as this also entails working with finance and extra approvals. This also may help service providers because the structure of the contractual

INFORMATION TECHNOLOGY

Role-based vs. Deliverable-based

The majority of functional services outsourcing contracts are role-based, especially when APEC (Asia Pacific Economic Cooperation) region resources are involved. In the role-based sourcing model, sponsors request a fixed number of resources and pay for the time spent by these resources on their projects. This approach has similarities to T&M ( time and material ) contract but is different in that is provides dedicated resources to sponsors on their projects for the long term. Sponsors can use these resources the way that best suits their needs. This kind of resource management involves some oversight and these oversight members need to make sure that there is sufficient work available to keep the contracted resources busy. Service providers require visibility and commitments on the amount of work they can expect on a regular basis to keep their resources adequately tasked and staffed.

The more innovative and challenging model that benefits sponsors is deliverable-based functional service outsourcing.

This contract can provide much more flexibility for sponsors because they can estimate the amount of expenses they can anticipate based on their book of work for that year or next. This allows them to better plan their financial priorities. In this model, the cost for each deliverable or task will be set. This approach helps to manage and estimate their overall spend. A CROâ&#x20AC;&#x2122;s resources can still be 100% dedicated to a sponsor, but the number needed can be managed by the Service Provider.

Landscape of clinical service providers changing:

Mergers and acquisitions activity in the pharmaceutical industry has inspired CROs and starting 2010, many small-

to medium-sized and niche players have merged to form medium to large-sized CROs. This benefits not just these CROs but also the industry overall.

Pharmaceutical organisations are increasingly looking to have large and long-term functional service outsourcing and are excited to see the consolidation of talent into bigger pools because they can access more stable and cost-effective service.

It is evident from press releases generated by pharma as well as CROs that they are targeting the APEC region as their future destination for conducting clinical trials as well as for other clinical services.

This will be a boon for Indiaâ&#x20AC;&#x2122;s clinical service industry. Unless local players step up their game, global CROs will emerge as winners due to their renewed size and increasing presence in the Indian market.

A u t h o r BIO

terms allow for flexibility and responsiveness to address out-of-scope work.

Organisations can implement work scope contract that deals with ranges for the units of work instead of fixed units.

Global CROs have operational abilities as well as expandable service offerings that may make them more appealing to big pharma.

The functional service model is here to stay. However, the structure is as yet undefined as market forces will continue to define shape it. The APEC region has potential to make this model successful for both Pharma well as for service industry as they have qualified resource pool as well as cost effectiveness on their side. The dedicated work model and long term nature of FSP contracts help in providing stable and cost effective services from India. It is critical for clinical services organisations in India to provide quality, value added, and cost effective service models to emerge as winner in this ever changing service domain.

Vijay Moolaveesala works for PharmaNet/i3, a division of InVentiv Health in India, as Director of Strategic Alliance. Vijay is heading the India operations of one of the biggest client services vertical of PharmaNet/i3. Until recently, he lead the Global Statistical Programming group based out of Columbus, Ohio, USA. Vijay has been working for PharmaNet/i3 for 10 years and before that he also served Pharma and CRO organizations.

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BioAsia 2012 – A Global Confluence of the Who’s Who of LifeSciences Industry

B

iotechnology today has evolved from a science to impacting human life in more ways than one. Paradigm shifts, dynamic changes and interplay between West and East in terms of capital innovation to bring about the much needed sync between biotech research and biobusiness have opened innumerable possibilities. BioAsia 2012’s vision is to further the cause of LifeScience by enabling a global confluence of key industry stakeholders and thought leaders by creating synergies between biotech & biopharma companies, venture capitalists, policy makers, CROs, research institutions, scientific organizations and academia.

BioAsia 2012 - Vibrant theme of “Optimizing Opportunities”

From February 9th to 11th, 2012, BioAsia 2012 will unfold its ninth chapter on a vibrant international platform with the vibrant theme of “Optimizing Opportunities”. BioAsia 2012 has identified 4 key focus areas - viz. Vaccines, Contract Research, Investments and Intellectual Property Rights (IPR) that will drive synergies amongst key stakeholders and participants. BioAsia 2012 intends to focus on all four key areas in the context of changing trends, continuous challenges, potential for growth and future development. The forum will witness industry key stakeholders and thought leaders exchange meaningful dialogue, knowledge sharing and provide networking and biobusiness opportunities besides providing participants an exclusive opportunity to exhibit, launch and showcase their unique strengths, products and services.

The event will focus on the Health, Pharmaceutical and Agribiotech sectors covering areas viz. Challenges faced by Pharmaceutical Industry moving towards Biotechnology sector and the reason to do so; Future of Biotech Industry in India; Global Biotech companies Vs. Asian biotech companies: Are we there?; Experience/ Challenges/ Changes faced

by International companies in Indian Biotech market; Biotech Products in India; and Indian Competitive 48

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Edge in Biotech sector. Other areas that will be focused includes Small Molecule Therapeutics, Generics to Innovative Drugs, Bioinvestment, Bio-Infrastructure, Bio-Incubators, Vaccines, Regenerative Medicine, Oncology, Medical Devices, Diagnostics, Biotech Crops, Issues & Challenges in the Asian Seed Industry, Biofuels , Climate Change, etc.

The driving force – Genome Valley

It has the largest concentration of multitenanted labspace infrastructure in an organized cluster, and has emerged as the preferred destination for major Indian and global life science companies. It is

India's first organized cluster for life science research & development activities, with more than 100 companies located in its eco-friendly environment.

Genome Valley is a perfect blend of knowledge parks, special economic zones (SEZs), multi-tenanted labspace buildings, incubation facilities, office spaces and outstanding support facilities. It has a healthy mix of companies in the realm of Agri Biotech, CROs, Bio Pharma, Vaccine Manufacturing, Regulatory & Testing which makes it one of the most vibrant clusters today in India. The cluster has over 100 life science companies, including some of the world’s fastest growing MNCs. The

cluster features excellent support infrastructure for research & development activities. With a successful response since its inception, Genome Valley is rapidly expanding with an approximate 200, 000 SF of labspace being added every year.

Genome Valley is popularly known as the 'Vaccine Hub of India', with facilities of leading vaccine producers like Biological E, Bharat Biotech and Globion Bio within the cluster and with companies like Shantha Biotech (recently acquired by Sanofi), Indian Immunological Ltd.,etc. present in the city. In order to synergize the advantage of Genome Valley, Government of Andhra Pradesh has proposed the development of a medical devices hub, MedTech Valley, within the proximity of the cluster.

Genome valley consists of the Alexandria Knowledge Park, IKP Knowledge Park, Alexandria Innovation Centre, Alexandria Centre for Technology, APIIC Biotech Park phase III, various Special economic zones, etc.

BioAsia â&#x20AC;&#x201C; The Global Bio Business Forum

BioAsia over the years has emerged as a Global Brand and has been offering the most sought platform for convergence of the business leaders, policy makers, investors, etc. The eighth edition of

the event was held in February 2011, which witnessed a participation of over 2500 delegates from 38 countries from across the globe. The event also realized 400 onsite B2B meetings and featured about 360 companies.

BioAsia has been extremely successful in bringing together the whoâ&#x20AC;&#x2122;s who of biotech and biopharma across the globe.

Participant profile of event reflects the attendance of key decision makers of the industry. The unique strength of BioAsia has been the strong network of FABA directly reaching out to 20 Asian countries and 15 Non-Asian Countries.

The event has evolved as a must attend events in our partners calendars. Major areas of strength of BioAsia over other similar events includes workshops, biopark sessions(Genome Valley visit), Biobazaar(International Buyer Seller Meet), CEO Conclave, Award ceremony, high profile speakers from the top Lifescience, massive media coverages, strong participation from all major Asian and non-Asian countries, support from organizations based out of Italy, Spain, USA, Germany, UK, etc. Not only this, BioAsia facilitated several new projects in the year 2011, including Lonza Knowledge Centre(Switzerland), Lepakshi Knowledge Hub, Sri Bio Integrated Discovery Centre, and Tran-Scell Biologics, a unit of Pacific Hospital for stem cell banking and research in Hyderabad. Renaissance

and Biogenesis Project on Cancer Hospital and Research Centre were also announced at BioAsia 2011.

These projects are expected to bring in investment of INR 2500 crores in Hyderabad.

Another highlight component of BioAsia is the Genome Valley Excellence Award. The award has gained high recognitions and has been considered as one of the most prestigious awards. The recipient history includes Dr. Martin Mackay (Global R&D President, Pfizer), Prof.

Martin J. Evans (Nobel Laureate, Cardiff University, UK), Prof. Marc Van Montagu (Institute of Plant Biotechnology in Developing Countries, Belgium), Prof.

G. Padmanaban (Fr. Director, Indian Institute of Science, Bangalore), Prof.

M. S. Swaminathan (Chairman, MSSRF, Chennai), etc. In order to recognize the young scientists below the age of 35 years who have done extraordinary research in any area of life sciences and who have created a product of applied value or enervated a product of utility for the welfare of human society, was first introduced in the year 2007, which was named after the Late Honorable Chief Minister, Dr.Y.S. R. Rajasekhar Reddy as Dr. YSR BioAsia Innovation Award after his accidental death and in order to promote investigative spirit in young school children, BioAsia Young Minds Award was instituted in the year 2009 for schoolchildren of class 10th, 11th and 12th standards. www.pharmafocusasia.com

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Books

Outsourcing Biopharma R&d to India: A Practical Guide Authors: Probir Roy Chowdhury No of Pages: 116 Year of Publishing: 2011 Description: This book seeks to explore various nuances of the outsourcing sector with respect to biopharma in India.

Key Features This book constitutes the first ever comprehensive insight on the Indian biopharma sector. The author provides a perspective based on practical hands-on legal experience.

The book is aimed towards professionals and practitioners within the biopharmaceutical industry.

Contents Biopharma outsourcing in India: its evolution India's core competitive advantage in R&D in the biopharma sector: the impetus for outsourcing Different modes of outsourcing biopharma R&D to India.

The Indian regulatory environment: a historical perspective Implications of the changing regulatory environment in India. Creating contracts for outsourcing in the biopharma industry Environmental, health and safety guidelines and biopharma outsourcing: an Indian perspective Certifications. The need for due diligence of service providers

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Leading Pharmaceutical Innovation: Trends and Drivers for Growth in the Pharmaceutical Industry Authors: Oliver Gassmann, Gerrit Reepmeyer and Maximilian von Zedtwitz No of Pages: 202 Year of Publishing: 2010 Description: Pharmaceutical giants have been doubling their investments in drug development, only to see new drug approvals to remain constant for the past decade. This book investigates and highlights a set of proactive strategies, aimed at generating sustainable competitive advantage for its protagonists based on value-generating business practices. We focus on three sources of pharmaceutical innovation: new management methods in the drug development pipeline, new technologies as enablers for cutting-edge R&D, and new forms of internationalisation, such as outside-in innovation in the early phases of R&D.

Collaborative Computational Technologies for Biomedical Research Authors: Sean Ekins, Maggie A. Z. Hupcey, Antony J. Williams and Alpheus Bingham No of Pages: 576 Year of Publishing: 2011 Description: Featuring contributions from the leading experts in a range of industries, Collaborative Computational Technologies for Biomedical Research provides information that will help organizations make critical decisions about managing partnerships, including: • Serving as a user manual for collaborations • Tackling real problems from both human collaborative and data and informatics perspectives • Providing case histories of biomedical collaborations and technology-specific chapters that balance technological depth with accessibility for the non-specialist reader A must-read for anyone working in the pharmaceuticals industry or academia, this book marks a major step towards widespread collaboration facilitated by computational technologies.

Clinical Research in Asia: Opportunities and Challenges for the Contract Research Organisation Industry Authors: Umakanta Sahoo No of Pages: 250 Year of Publishing: 2011 Description: Asia is rapidly emerging as the new hub of clinical research - due to the enormous Over the last decade, an increased number of clinical trials globally are being carried out by Contract Research Organisations (CROs) in Asian countries, such as Japan, China, India, Taiwan, Singapore, South Korea, Thailand, Malaysia, Philippines and Vietnam.

Good Clinical Research Practice (GCP) has rapidly developed across the region in order to harmonise the global standards to meet the increased demands of clinical research trials and lingering concerns about ethics in the Asian region for clinical research trials. Recent changes in US and European regulation and regulatory practices also play a role in the global emphasis on GCP and a renewed basis for ethics. The book is divided into 10 main chapters covering the top countries in Asia in the sector.

Key Statistical Concepts in Clinical Trials for Pharma Authors: J. Rick Turner No of Pages: 70 Year of Publishing: 2011 Description: This Brief discusses key statistical concepts that facilitate the inferential analysis of data collected from a group of individuals participating in a pharmaceutical clinical trial, the estimation of their clinical significance in the general population of individuals likely to be prescribed the drug if approved, and the related decisionmaking that occurs at both the public health level (by regulatory agencies when deciding whether or not to approve a new drug for marketing) and the individual patient level (by physicians and their patients when deciding whether or not the patient should be prescribed a drug that is on the market). These concepts include drug safety and efficacy, statistical significance, clinical significance, and benefit-risk balance.

Contract Research and Development Organizations: Their Role in Global Product Development Authors: Shayne C Gad and Charles B Spainhour No of Pages: 224 Year of Publishing: 2011 Description: Contract Research and Development Organizations: Their Role in Global Product Development has been crafted by authors to provide a how to guide for all aspects of working with CROs in selecting, working with and ensuring the best possible desirable outcome of having the R&D function, or substantial parts of it, outsourced. It uses as the exemplary case nonclinical safety assessment, biocompatibility and efficacy testing which are to be performed to select the best possible candidate compound, device or formulation and then moving the resulting regulated therapeutic medical product into and through the development process and to marketing approval. But also covered are the contract synthesis of drug substances and corresponding manufacture of biologics and manufacture of products, formulation development, clinical evaluation, regulatory and document preparation support, and use of consultants.

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Products&Services SuppliersGuide

Company........................................... Page no.

STRATEGY BioAsia..............................................................IBC Brevetti Angela....................................................17 Frost & Sullivan...................................................05 Emirates.......................................................... OBC Terrapinn (Australia) Pty Ltd...............................03 UBM India Pvt Ltd............................................. IFC MANUFACTURING Brevetti Angela....................................................17 Chitra Precious Mechtech Pvt.Ltd......................33 NETZSCH Werbe- und Service- GmbH..............40 Nichrome India Pvt Ltd.......................................21

Company...........................................Page no.

BioAsia............................................................. IBC www.bioasia.in/2012 Brevetti Angela................................................... 17 www.brevettiangela.com Chitra Precious Mechtech Pvt.Ltd..................... 33 www.chitramechtech.com www.preciousgroupind.com Frost & Sullivan.................................................. 05 www.frost.com NETZSCH Werbe- und Service- GmbH............. 40 www.netzsch.com Nichrome India Pvt Ltd...................................... 21 www.nichrome.com Emirates..........................................................OBC www.skycargo.com Terrapinn (Australia) Pty Ltd.............................. 03 www.terrapinn.com/digitalpharma UBM India Pvt Ltd.............................................IFC www.cphi-india.com

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

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

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The Global BioBusiness Forum For Registrations visit: www.bioasia.in/2012

The global confluence of Who's Who of the Lifesciences Industry

Optimize your Opportunities BIOASIA 2012 February 9-11, 2012 Hyderabad, India

With a noticeable difference, BioAsia 2012 will not only provide an opportunity to connect with the key stakeholders across categories, but will also provide a platform to outline a roadmap for growth through the planned consultation programs & policy discussions during the event.

BioAsia 2012 will focus on the four key areas of the host country’s strengths.

Vaccines Contract Research Intellectual Property Rights (IPRs)

Investments

As an Asia's preeminent Lifescience Event, BioAsia 2012 will expand your opportunities to partner with the global players and bring you face- to- face with the global thought leaders and peers from the biotech industry worldwide.

Organizers

Knowledge Partner

Here’s how you benefit: Network with key stakeholders of the industry An opportunity to tap potential businesses International brand exposure at a global forum Showcase your strengths and competencies Hear high-profile speakers Participate in intensive, interactive sessions, workshops & exhibitions

Supporting Organizations

Associates Bio Partnering:

Communication

#0408,RED OOR

Marketing

Mind’s solutions

Media

Event