Pharma Focus Asia - Issue 06 by Ochre Media Pvt. Ltd.

Strategy

Expert Talk

Research & Development |

Clinical Trials

Issue 6

Manufacturing

2008

ÂŁ12 â&#x201A;Ź18 $25 Rs.300

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Biosimilars

Web 2.0 in Pharma

Adaptive Trial Design

Special Nanomedicine Vaccines PAT

Foreword

Partnerships A pill for growth

“The whole pharma industry is hungry for deals…there is a shortage of drugs in pipelines” Rob Hockney, Director of Alliance Management, Global Discovery Alliances, AstraZeneca

he pharma industry is treading a new path for sustaining growth—partnerships. Escalating R&D costs, tough regulations and price controls continue to trouble the industry. Further, a severe blockbuster drought, patent expiries and anaemic drug pipelines have only added to the industry’s woes. Innovation did provide hope but even that has become a high-risk and high-cost function for the industry. Similarly, the recent convergence of drugs, devices and diagnostics promises the industry another opportunity for revenues, one that probably will not suffice for long-term growth. On the other hand with strong scientific capabilities, proven expertise in developing novel drugs and an ability to deliver personalised medicine, the biotech industry looks to play a strategic role in defining the future and growth of the pharma industry. Caught in the “Innovation Deficiency Syndrome”, and under serious pressure to compensate declining revenue streams from saturated markets, soon-to-expire / already expired blockbusters, pharma companies are

increasingly partnering with biotechs to help reduce their losses. The complementary strengths of biotechs and pharma companies especially Big Pharma promise to pay rich dividends in the long run. This issue’s cover story “Partnerships: Win-Win Strategy” covers these issues and how the pharma industry can overcome hurdles through partnerships. I am pleased to introduce a new section “Expert Talk” that will feature opinions of leading pharma experts on a wide range of issues. I would also wish to express my gratitude for the tremendous response we have received for the magazine’s paid subscription model. This is a big boost for us and I hope this association continues for many years to come.

Aala Santhosh Reddy Editor

Note: The magazine will be published quarterly starting this issue.

Contents CoverStory

Strategy Pharma and Biotech Is it possible to continue growing?

Joachim M Greuel, Founding and Managing Partner, Bioscience Valuation BSV GmbH, Germany

Expert Talk Partnerships and Innovation The growth factors

R B Smarta, Founder and Managing Director, Interlink Marketing Consultancy Pvt. Ltd. and Member, Drugs and Pharma National Committee, Confederation of Indian Industries, India

Biosimilars What lies ahead?

Cecil Nick, Principal Consultant, PAREXEL Consulting, UK

Research & Development

Drug Research and Development

Bridging the innovation gap Neil J Campbell, CEO, Mosaigen, Inc. and Partner, Endeavour Capital Asia Ltd., USA

Mitochondrial Nanomedicine

US Biotech and Indian Pharma

Is there a win-win partnering strategy?

Tailored and efficient therapeutics Volkmar Weissig, Associate Professor of Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy Glendale, Midwestern University, USA Gerard G M Dâ&#x20AC;&#x2122;Souza, Formulation Development Scientist, Bouve College of Health Sciences, Northeastern University, USA Sarathi V Boddapati, Formulation Development Scientist, Novavax Inc, USA

Vipin K Garg, President and CEO, Tranzyme Pharma, USA

Multi-functional Nanomedicine

Technology convergence in development of targeted therapeutics

Mansoor M Amji, Professor and Associate Department Chairman and Co-Director of Nanomedicine Education and Research Consortium Padmaja Magadala, Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences Northeastern University, USA

Finding the Way in China

Critical issues for partnership and investment Mark J Benedyk, Head, La Jolla Incubator, The Pfizer Incubator, LLC, USA

Drug Discovery A decentralised multi-polar model Panchapagesa Muthuswamy Murali, Managing Director Shriram Raghavan, Head, Compound Assessment Evolva Biotech Private Limited, India

P h a r m a F o c u s A si A

ISSUE - 6 2008

VaccinesSpecial

Information Technology

The Asian Vaccine Industry Opportunities and challenges

Controlling Infectious Diseases 47 Evaluation of vaccines

Simon Revell, Manager of Enterprise 2.0 Technology Development, Information and Knowledge Management, Pfizer Inc., UK

IT Outsourcing Strategies in Drug Discovery

Chip Allee, CEO, CeuticalSoft Inc., USA

Manufacturing Pharmaceutical Manufacturing Embracing process analytical technology

PAT and ROI A holistic approach

Ingrid Maes, Consultant, Innovative Technologies, Competence Centre Phamaceutics, Siemens AG, Belgium

Ready-To-Use Technologies Driving process excellence and product safety

Yoshinobu Horiuchi, Head, Laboratory of Pertussis and Endotoxin Control, Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Japan

Using tumour-associated peptides

Pala Bushanam Janardhan, Business Consultant, Manufacturing & Plant Automation Services, Life Sciences and Healthcare Practice, HCL Technologies Ltd., India

Pele Choi-Sing Chong, Investigator and Director, Vaccine Research & Development Center, National Health Research Institutes, Taiwan

Developing Cancer Vaccines

Web 2.0 in Pharma Enterprise Improving internal communication

Eric Grund, Director, FastTrak Biopharma Services, GE Healthcare, India

Lean Transformation Superficial imitation or a paradigm shift?

Harpreet Singh, Managing Director and Chief Scientific Officer Toni Weinschenk, Head of Discovery

Randy Cook, Director of Education Jacob Raymer, Assistant Director of Education

immatics biotechnologies GmbH, Germany

Brian Atwater, Associate Professor, Business Administration The Shingo Prize — for Operational Excellence Jon M Huntsman School of Business, Utah State University, USA

Clinical Trials Japan’s Step Towards 57 Global Studies

88 Identifying Counterfeit Drugs An unexpected benefit of PAT / QbD

Mark A Goldberg, President, Clinical Research Services and Perceptive Informatics Inc., PAREXEL International Corporation, USA

Adaptive Trial Design Enhancing the quality of clinical trials

Emil W Ciurczak, Chief Technical Officer, Cadrai Technology Group, USA

Mark Chang, Scientific Fellow, Biostatistics and Medical Writing, Millennium Pharmaceuticals Inc, USA

Metabolomics Strategy Identifying tissue-specific drug effects Matej Orešic, Research Professor, Systems Biology and Bioinformatics, VTT Technical Research Centre of Finland, Finland

Anti-Counterfeiting Technologies What makes them effective?

Thomas Völcker, Marketing & Sales Director, Schreiner ProSecure, Germany

Biopharmaceutical Manufacturing in India Drivers, trends and future

Satish D Ravetkar, Senior Director, Serum Institute of India Ltd., India

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Issue 6

2008

Editor : Aala Santhosh Reddy

Editorial Team : Jagadeesh Napa Bhamoti Basu

Editorial Advisors : Sasikanth Misra

Deputy Director, Drugs and Pharma, Confederation of Indian Industries

Akhil Tandulwadikar

Editor, Asian Hospital & Healthcare Management

Art Director : M A Hannan

Visualisers : N Raju Mastan Sharief K Ravi Kanth Ayodhya Pendem

Copy Editor : Jagadeesh Napa Sales Head : Rajeev Kumar Sales Manager : Sunita John

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The B2B Division of Ochre Media

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P h a r m a F o c u s A siA

ISSUE - 6 2008

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Pharma and Biotech

Is it possible to continue growing? While the industry still performs on a high level, growth prospects are not as they had been in the past.

Joachim M Greuel Founding and Managing Partner, Bioscience Valuation BSV GmbH, Germany

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S tr a te g y

ovartis recently released the results for its fourth quarter of 2007. While the company’s turnover increased 6% to US$ 9.9 billion, its net income decreased 42% to US$ 931 million. If the income statement is corrected for extraordinary expenses, Novartis’ operating earnings for the fourth quarter of 2007 were US$ 1.3 billion, about 20% less compared to the earnings of the fourth quarter of 2006. Although the financial performance is still good, many analysts are disappointed with Novartis’ actual financial results. Novartis’ performance is representative for the whole pharmaceutical industry. While the industry still performs on a high level, growth prospects are not as they have been in the past. For the year 2008, analysts expect an overall growth in global sales of about 5% to 6%, in contrast to the double digit growth at the beginning of the decade. The US market, arguably the most important one, may only grow by about 4%. The modest growth will not only affect big pharma but also large biotech firms. Genentech, for example, used to report double digit growth; however, it reported only single digit growth in the last quarter of 2007. One reason for the declining performance of pharma and biotech is the lack of true innovation. Last year the FDA approved only 18 drugs, one of the lowest numbers since 20 years. Despite the fact that the mean pipeline size of larger companies has constantly increased during the last years, attrition rates have increased as well, leading to a shortage of promising drug candidates for approval. At the same time the costs for developing and taking a drug to the market are escalating. Experts believe that the costs to develop a molecule until launch are approaching US$ 1 billion if attrition is factored in. Furthermore, aggressive cost containment efforts in most European countries are compounding the problem of diminishing returns.

Not surprisingly, many industry observers doubt whether pharmaceutical companies can maintain growth rates as seen in the past. Indeed, for many diseases that are ‘easy’ targets in terms of well validated pathophysiological mechanisms, a reasonably high therapy standard has already been achieved. For example, currently available statins control low-density lipoprotein quite well and it may not be worth the effort trying to identify more efficacious drugs specifically targeting, e.g., artherosclerosis. The same may be true for antihypertensives. Calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors are effective therapies commonly prescribed in many countries, and it may not pay to develop new antihypertensives.

Net Present Value How is it calculated

NPVs are calculated by discounting future expected cash flows back to the present day. The NPV is a measure of value: if a project’s NPV is positive, the project creates value, if, however, the NPV is negative, a project may not create value. Net present value analysis

The current pharmaceutical dilemma can be well illustrated by calculating the net present value (“NPV”) of an average drug in discovery or pre-clinical development. “Average” refers to a compound that can be characterised by an average, or benchmark, risk of failure and average cost of development. An ordinary compound today generates about US$ 250 million in peak sales, a low figure compared to the blockbusters that generate on an

average worldwide sales that are clearly above US$ 1 billion. Still, most drugs in development do not have blockbuster potential. If the projected cash flows of those ‘average’ projects are adjusted for potential attrition and discounted to present day values, many will end up with negative NPVs. A negative NPV means that a project may not generate value; thus, the project may be abandoned. Figure 1 shows the result of a NPV analysis for a typical project, using three different discount rates. The discount rate represents the annual return expectation of investors. An 8% to 10% discount rate is often used by large pharmaceutical companies. Smaller biotech companies require higher rates as they are riskier investments; 15% to 18% is typical for small capitalised public biotech firms, and a rate in the order of 25% is usually applied by venture capitalists. Discovery projects show negative NPVs at all discount rates and may appear, therefore, not as good investment opportunities. Pre-clinical projects have a positive NPV only in the hands of big pharmaceutical companies; more aggressive discounting, i.e. applying 18% or 25% discount rates, produces negative NPVs also for pre-clinical projects. The preclinical NPVs at the 18% and 25% rates are more negative than the NPVs of the discovery projects because, for discovery, early attrition prevents higher losses. Fortunately, development projects are often regarded as real options: managers analyse the increase in a project’s value that would occur when reaching the next milestone and the investment needed to reach that milestone. This kind of analysis often demonstrates that it is worth pursuing negative NPV projects. Nevertheless, based on classical finance theory, negative NPV projects are regarded by many as critical investments and building a business case for a pharmaceutical development project is not at all a ‘no brainer’

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S tr a te g y

Value /$ million

NPVs of typical discovery and pre-clinical projects at different discount rates 6.0 4.0 2.0 0.0 -2.0 -4.0 -6.0 -8.0 -10.0 -12.0 -14.0

Discovery

10%

18% Discount Rate

Pre-clinical

25% Figure 1

anymore. Most projects require, at least from a financial point of view, a second thought and more detailed analysis. Potential strategies

One may now ask: What can the pharmaceutical industry do in order to find positive NPV projects that, if successful, would support further growth. Financial analyses indicate three potential strategies: i) selection of indications with a high sales potential, ii) risk reduction and iii) cost reduction. Sales potential

A drug’s sales potential tends to be strong for high prevalence diseases with significant unmet need, such as in oncology. In line with the ageing population cancer prevalence increases steadily; still, despite intense research efforts, our ability to treat advanced malignant tumours is very limited. Projects targeting neoplasms tend to have positive NPVs when the drug considered is, or will be, developed for several distinct cancers. For example, the blockbuster sales of Taxol® or Rituxan® are the result of broad development programs that cover various cancer indications. One may argue that attempting to develop a new cancer therapy is quite risky and, therefore, value may be compromised by a low launch probability. Although this is true, the high

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sales potential usually compensates for the higher than average risk of failure. Another argument against an engagement in oncology, or any other indication with high unmet need, is the competitive nature of the market. The higher the sales potential in a certain indication, the more competitors can be expected. The resulting potentially lower market share may actually compromise a drug’s sales potential. This argument is partly true: if a drug is distinguished by its clearly superior profile, it will capture the lion’s share of the market, irrespective of the number of competitors. Recent licensing agreements show that many pharmaceutical companies offer premium terms for drugs that have a high potential in the oncology market. In contrast, strategies to focus on niche markets are hardly ever rewarded by the stock markets; companies engaged in niches often have poor valuations. Risk reduction

Another potential strategy to increase value is to invest in low risk development candidates. For example, a company may focus on developing ‘branded’ generics. As with all generics, the original drugs’ patents have expired. However, the formulation of a drug may have been suboptimal, thus allowing further improvement. For example, Abraxane® is an albumin enhanced formulation of paclitaxel. Paclitaxel is a very successful chemotherapy without patent protection for the active molecule. As paclitaxel is an approved drug to treat cancer, the reformulation will be less risky and market acceptance likely if clinical benefits can be demonstrated. As Abraxane® enjoys patent protection for its formulation, its sales potential is maintained and not subject to generic competition. Cost reduction

Finally, a company may try to reduce a drug’s development cost in order to increase value. However, NPVs are not

very cost sensitive and cost reduction provides much lower NPV improvements compared to increases in sales potential or the reduction of development risk. Also, excessive attempts to reduce development costs may lead to a poor clinical study design and thus increase the risk of failure. Therefore, cost containment rarely helps to significantly increase a project’s value. High sales and low risk business strategies are not the only means to increase a company’s potential for growth. Much can be done to improve the R&D operations. Companies that implement professional portfolio management systems tend to grow more than companies that lack those systems1. One reason may be that for companies without good portfolio management, gaps in the development pipeline are realised too late, or the mix of projects does not balance the portfolio risk in the optimal way. Another intelligent way to support growth is to routinely check whether a project’s development risk has been minimised. There are numerous ways to design pre-clinical and clinical development, and companies do not always choose a design that maximises a project’s chance of success. Finally, most companies engage in market research much too late. For example, conjoint analyses are usually performed while a drug is in Phase III. However, it is very difficult, if possible at all, to change a drug’s profile that late in development. It would be a much wiser strategy to perform market research early on, when a drug’s target profile can still be modified. The growth of biotech firms is tightly linked to the growth of the pharmaceutical industry. Many biotech companies depend on licensing agreements with Big Pharma. If growth of the pharmaceutical industry slows down, for exam1 Kerstin M. Bode-Greuel and Klaus J. Nickisch: Value-driven Project and Portfolio Management in the Pharmaceutical Industry: Drug discovery versus drug development: commonalities and differences in portfolio management practice, Journal of Commercial Biotechnology, in press.

S tr a te g y

Conjoint Analysis A conjoint analysis is an advanced, computerised market research method that allows the analyst to compare a product’s target profile against other drugs, thus enabling to optimise a drug’s profile before launch or to identify a drug’s optimum price.

In conclusion, further growth is possible if the rate of innovation for ‘high impact’ drugs increases. High impact drugs are compounds addressing significant unmet need in high prevalence markets, thus having A uthor

ple, by governmental cost containment initiatives, pharmaceutical companies will not be able to pay adequately to license promising compounds from biotech firms. As a result, pharmaceutical innovation will decrease and harm the entire industry. The US plays a central role in supporting worldwide growth. We have to acknowledge that we all benefit from a comparably free pharmaceutical market in the US, one that is less restrictive when it comes to drug pricing. When a drug is developed for the world market and the US is compared to Europe, a drug’s NPV may be negative for Europe and positive for the US if development costs are allocated based on the number of diseased patients and cost containment in Europe is factored in. From an economic point of view, drugs are developed for the US (where it is profitable even if development costs are fully loaded to the US) and then sold worldwide.

considerable sales potential. Alternatively, low risk development strategies may be pursued, such as developing ‘branded generics’. Advanced portfolio management systems and risk mitigation strategies may support biotech and pharmaceutical companies to generate maximum value with the resources available. Asian companies are well positioned to play a leading role here, and its increasingly skilled workforce will soon compete head-on with the most advanced Western pharmaceutical companies to develop innovative, high value drugs.

Joachim M Greuel is the founding and managing partner of Bioscience Valuation and of Bioscience Market Research based in USA. He holds a PhD in Physiology and an MBA with a finance focus from the Wharton School of the University of Pennsylvania, USA. Joachim supports pharmaceutical and biotech companies in project and portfolio valuation, the implementation of value-driven project and portfolio management spin-off and company management and in the evaluation of licensing opportunities.

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CoverStory

â&#x20AC;&#x153;Partnerships have seen benefits accruing to both partners in terms of cost, quality and time.â&#x20AC;? Swati Piramal, Director, Strategic Alliances and Communications, Nicholas Piramal on the occasion of their alliance with Eli Lilly in February 2008.

Given the current scenario in the global pharma industry, companies are desperately pursuing different strategies to strengthen their bottom lines. The idea of developing medicines customised to target populations is already getting popular while many countries are under pressure to bring down their healthcare costs. Among the options available to the pharma companies, partnerships and strategic alliances seem to have the potential to open the doors for synergic collaborations to create win-win situations in the long-run. The present day partnerships are being tailored to help companies find the much required blockbusters, economies of scale, cost-effective clinical trials and market creators such as personalised medicine. Strategic partnerships and acquisitions are bringing companies with complementary strengths from different segments and countries together to boost their chances of success. And a very promising model is that of the pharma companies working together with biotech companies. Standing to gain so much by working together, partnerships could be the right path for the industry to overcome its hurdles.ďż˝ w w w . p h a r m a f o c u s a s i a . c o m 13

Drug Research and Development

Bridging the innovation gap

What needs to be done to improve or change the R&D productivity of the pharmaceutical industry? Is biotech consolidation the answer, and if not, what is? Neil J Campbell, CEO, Mosaigen, Inc. and Partner, Endeavour Capital Asia Ltd., USA

Perspectives on the drug industry

The pharmaceutical industry, as we know it today, can be traced back to about 150 years when the source of pharmaceuticals was from nature. Plants and organisms played a vital role in establishing the mainstay of drug pipelines. The strategy was to

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improve upon the natural biological properties and deliver the compounds in a format that modern humans could take and comply with. The advent of small molecule drugs came about because of their availability for discovery, development and their ability to provide for “incremental” development strategies. These incremental strategies of creating synthetic molecules, in what we now call medicinal chemistry, allowed for smaller molecule drugs and less

risky development changes to the parent compound. These new derivatives of a proven drug or family of drugs have become commonplace and have defined the scope of the large pharmaceuticals to this day. According to analysts, small molecules still dominate the overall number of new drug candidates being developed with 135 out of 254 (53.1%) entering the Phase I human clinical trial process in 2007. These figures are based on the records of

The Pharma Innovation Gap Increased R&D spending yielding lesser drug approvals $60

$50

40 Pharma Innovation Gap

$40 $30

$20

$10 $0

New Drug Approvals

Pharma R&D ($Billions)

any think that 2007 may be regarded as the year that Big Pharma went beyond merely embracing biotechnology, but decided that consolidation with its biologics breathren may well be the answer to the many problems currently plagueing them. Over the past couple of decades, Big Pharma has consolidated with other Big and mid-size Pharma companies in a so called Pharma-Pharma consolidation. This Pharma-Pharma consolidation occurred several times and with it brought about ever-larger companies with even-greater drug pipelines. The goal was to acquire pipelines from rival companies to boost revenues and, in some cases, scientific capabilities in key growth disease areas. But this approach eventually would not be sustainable as the primary means for new drug discovery and development. Times have changed.

1992 ‘96

2000 ‘01

Pharma R&D Investment

‘02

‘03

‘04

�� BioPharm R&D Investment

‘05

‘06

‘07

�� New Drug Approvals by US FDA

Sources: Pharmaceutical Research and Manufacturers (PhRMA) Annual Report 2007; Burill & Company Report 2003; PhRMA Annual Member Survey, 2007: US Food & Drug Administration Databases.

Figure 1

S tr a te g y

Investigation of New Drug Applications (INDs) submitted to the US FDA and announced by drug companies from around the world. Although this may sound impressive for pre-clinical candidates entering Phase I, according to the latest statistics from the Tufts University Drug Development Study and the trade association of large pharmaceuticals companies, Pharmaceutical Research and Manufacturers of America (PhRMA), the drug attrition rates are still one in ten of making it to that market: a mere 25 drugs out of 254 entered Phase I in 2007. The Big Pharma spent over US$ 55.2 billion in 2006 (2007 estimates are over US$ 63 billion) on drug R&D a 100% increase over the US$ 26 billion they spent in the year 2000 with a declining number of drug approvals after that according to the PhRMA report released in 2007. This so-called pharma innovation gap is huge and getting larger each year. So why still focus on the small molecule approach? Although not revolutionary, it provides a limited source of continuing drug candidates along with new and extended forms of intellectual property protection. Combining small molecule pipeline strategies with other drug product / formulation strategies will give greater leverage to the research and development efforts of these larger pharmaceutical companies. If it weren’t for a lack of innovation on the part of Big Pharma companies, the Biotechnology industry as we know it today would probably have not existed as an industry, but would have been another chapter in the evolution of Big Pharma. We all know that large organisations struggle with creativity, entrepreneurship and original thinking. But large organisations can thrive on execution of ideas (sales and marketing), and the later-stage development of products (manufacturing). A creative and original thinking movement began out of the seminal

discoveries that were occurring in the late 1970s in the biology and chemistry disciplines. These discoveries quickly grew into a nascent industry that would change the way drugs would be discovered, designed, developed and administered. With the advent of the discovery of DNA and the ability to manipulate it in the 1970s and 1980s, came a new science of genetic engineering that promised to fulfil the shortcomings of the pharma industry. The commercial aspect of the Biotech industry started out slowly in the early 1980s, but has become one of the fastest growing and strategically important industries of the 21st century. Issues facing the pharmaceutical industry

Big Pharma lost US$ 14 billion worth of annual drug sales to patent

Issues facing the Big Pharma companies Declining productivity with small molecule programs Increased costs and longer clinical development timelines Additional regulatory requirements for safety and efficacy during trials and post-approval Spiraling healthcare costs and pressures on drug pricing Expiration of drug patents of blockbuster drugs increasing over next several years Increased generic drugs coming to market replacing many off-patent blockbusters Acquisition of biopharmaceutical companies to bolster science capabilities and drug pipelines Costs to market drugs to consumers are exceeding the costs of drug R&D; this puts companies at risk of not directing enough resources to developing drugs. The current Direct-to-Consumer marketing strategy is creating a larger problem as less drugs are developed and more are coming off patent. Spending should be in R&D, not promotion of existing drugs.

expirations in 2006 and is expected to lose another US$ 12 billion in 2007, according to IMS Health. But biotechs don’t have this problem, at least not yet. They don’t have to compete with “biogenerics” because the USFDA hasn’t created a system for regulating them, which is a requirement for drug companies to get their products onto the market. Europe has proposals, but implementation may prove to be more difficult than originally thought. Another issue that is plaguing Big Pharma is the increasing cost to market drugs to the healthcare consumers. In a January 2008 published study in the Public Library of Science (PLoS), Marc-Andre Gagnon and Joel Lexchin conducted a study that showed that Big Pharma spent almost twice as much on marketing and promoting their drugs than on R&D. The pair analysed data from market research companies IMS and CAM and found that Big Pharma spent US$ 57.5 billion on promotional activities in 2004. By comparison, spending on pharmaceutical R&D in the US was US$ 31.5 billion in the same year, according to a report by the National Science Foundation. So, why biotech?

Biotech drugs or biopharmaceuticals are made out of living biological compounds and provide some attractive alternatives to synthetic small molecules that create traditional pharmaceuticals today. Although there is strong regulatory and political support in Europe for Biosimiliars (biological generics) and strong resistance to date in the US (where there is still predominance with the most drugs being developed in the US) with the FDA, the complexities of redesign, manufacturing and generating economies of scale in production costs could be some obstacles for certain biosimiliars than others. Big Biotechs can provide new scientific capabilities, knowledge in new drug classes and revenue generation

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3000 United States

2500

104% Increase in US

Number of Compounds in Development (Clincal - Pre-registered)

Worldwide Biopharmaceutical Development

2000 1500

Rest of World EU

1000

Japan

500 1997

1999

2001

2002

2005

Sources: Pharma Annual Report 2007 Note: Comparisions were completed in June of each year. Some compounds will be at different phases for different indication: Adis R&D Insight Database, customized run in December 2005

Figure 2

Biopharmaceuticals can be attractive for the following reasons The Biotech industry is research intensive and can provide for better knowledge of disease pathways and drug mechanisms thereby possibly reducing risks with safety and efficacy The biological drug candidates can be specifically engineered to target particular sources in the body in a more directed and personalised approach, hopefully providing better odds of achieving approval with better responding populations The biological drugs can provide for very complex and expansionary strategies for patent protection Strategies for developing generic biotech drugs will be harder to do from both a regulatory and technical standpoint.

potential for the Big Pharmas. This latest trend shows no signs of slowing down in the next couple of years. Although it should be noted that the number of viable candidates will diminish over time and force a movement towards more creative options. Many of these creative options have started with some Big Pharmas taking the proactive approach and implementing some potentially very accretive plans. Could these be just shortterm trends or longer-term models of commercialisation? New models for consideration?

A few companies have started deploying more original strategies out of necessity and 2007 had seen some

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first-mover tactics which could become the trends for the next few years. Are generics really that bad? Generics, if proactively incorporated into a drug portfolio, can provide for additional growth in a broader drug portfolio management strategy. In many pharma companies, life cycle management could be adjusted to incorporate their own generics instead of planning on how to “defend” against them once the patent protection expires. In fact, Novartis has made it a part of its aggressive strategic plan. It has seen generics as part of its product line and market penetration strategy by using M&A to gain new groups. Many of the pharmaceutical companies in the Indian sub-continent are now

realising the importance of having both generic and ethical / prescription drugs in their marketing efforts to improve growth and revenues. Because taking on biopharmaceuticals means learning and hiring a large amount of people with a different set of skills and knowledge can be daunting for single in-licensing or acquisition scenarios, it may be better to take on a complete company with larger capabilities that could be integrated well with a Big Pharma. Some examples from 2007 are the US biotech, MedImmune’s, acquisition for US$ 1.6 billion by AstraZeneca Plc to integrate with its prior acquisition of Cambridge Antibody Technologies (CAT) of the UK to form a very large and capable foundation for the creation of a biotechnology division. AstraZeneca also added the UK firm, Arrow Therapeutics to expand their original science in infectious diseases along with drug candidates for development. Others are taking on more original thinking and entrepreneurship with a long-term view of drug development by setting up incubators with an idea of turning them into scientific centres of excellence. Pfizer announced in late 2007 its intention of setting up a biotech research centre in California, similar in concept to Xerox’s PARC centre that launched dozens of products and developed cutting-edge technologies, by investing huge amounts to setup and finance the existing technologies. Aventis moved quickly to acquire Sanofi and is aggressively pursuing more sizable biotech buyouts in the not too distant future. Most of the Big Pharmas will continue to transform their drug pipelines with consolidations of biopharmaceuticals for several years to come. Big Pharma looks more like big biotech

Some drug makers like Novartis have diversified so much that they have

S tr a te g y

Looking ahead

Just as generics provide for a greater opportunity with expanding drug portfolios and life cycle management challenges, a new and emerging group of product categories and technologies could provide new proprietary market growth to augment and complement the addition of biotech products and technologies. Many companies are expanding their product offerings and are diversifying outside traditional prescription

Accretive Strategies Pharmaceutical Products

Organisational Strategies

New drug formulations/applications

�� M&A of larger Biopharmaceuticals

�� Nutriceuticals

�� Incubate and accelerate directed startups at various stages of development

�� Cosmeceuticals

�� Develop targeted therepies (personalised)

�� Therapeutic Devices �� Biopharmaceuticals �� Small Molecule Generics �� Biogenerics/Biosimiliars

�� Expand geography with therapies �� Grow expansion plans into Asia Table 1

Value Drivers: Alternative growth strategies? Nutraceuticals are fast becoming a strong growth category with the global market valued at the retail level, was approximately US$ 110 billion in 2005 according to the American Chemistry Report. Nutraceuticals are pharmaceutical-grade, cGMP manufactured products that can provide drug-like benefits and stop short of the extensive clinical trials and efficacy claims that approved drugs go through. Cosmeceuticals are pharmaceutical grade and, in some cases, regulatory-approved products for cosmetics, dermatology indications, etc. One of the most recognised cosmeceutical is Botox®, the derma filler for wrinkles sold by Allergan of the US. Botox® is an engineered attenuated version of botulism and is approved by regulatory authorities. Another approach is to combine pharmaceutical compounds with medical devices to create a therapeutic device. These therapeutic devices can deliver, be formulated into a drug and/or be used as a device itself with therapeutic benefits. The drug-eluting cardiovascular stents used in angioplasty to prop open an artery are a good example of therapeutic devices. Many devices are being developed to work in the eye and other organs to provide a more targeted, localised approach to therapeutic intervention.

drug formats. The accretive strategies table shows some of the more accretive new strategies currently being employed by pharmaceutical companies to expand product portfolios and growing more protected revenues. In the end, larger Pharma companies will have to take a broader look at how they serve the overall healthcare marketplace and provide, where needed, focussed solutions to unmet medical and healthcare problems. An expand and contract scenario is most likely with A uthor

effectively become pharma-biotech hybrids. The biotech industry is expanding more rapidly than the pharma industry now. According to the data released by IMS Health in 2007, the sales of US biotech grew 20% to US$ 40.3 billion in 2006, while pharma sales grew by only 8% to US$ 275 billion. Another consideration is the size or economies of scale. The sheer size of Big Pharma, if they could become more creative with these alternative strategies, could bring advantages in several critical areas for biotech companies, especially through complete acquisitions by the Big Pharma. The large size of a Big Pharma company provides an edge in launching and promoting new drugs or additional indications or formulations. A large company can increase the number of bets that it can place on new technologies, novel therapies or additional disease indicators. If a big pharma company manages its clinical programmes well, it can do the clinical trials both in-house as well as outsource to Contract Research Organisations (CROs) to help it complete clinical trials more quickly and broadly. The growth of Asia as both a technology and manufacturing region has become more mature in terms of product manufacturing and clinical trial programmes. Also, growth in original research represents a vast new population of people who would serve a growing pharmaceutical market.

Big Pharma reaching a point of critical mass where they will have to find ways to deconsolidate and yet, control the development and expansion of its estate of drugs and intellectual property. The biotechnology industry has provided and will continue to provide cutting-edge science, innovated technologies and products that Big Pharma will be interested in. Biotech provides some, but not all, of the answers to the growth problems Big Pharma faces in the years to come.

Neil J Campbell is currently Chairman and CEO for Mosaigen™, Inc., a global Life Science development corporation, located in Rockville, Maryland and Partner with Endeavour Capital in Asia. During his career, he has successfully developed and introduced over 200 products in healthcare, life sciences and information technology. He earned his MBA and MA in Management Systems from Webster University in Saint Louis, Missouri and his BS-BA from Norwich University in New England.

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US Biotech and Indian Pharma

Is there a win-win partnering strategy? Due to emerging factors such as escalating financial risks, lack of new blockbuster drugs and evolving global capabilities, the time is right for US biotechnology firms and Indian pharmaceutical companies to join forces in the pre-commercial phases of drug research and development. Vipin K Garg President and CEO, Tranzyme Pharma, USA

ecent trends in the global pharmaceutical industry suggest that the time may be right for a new business model to emerge. Especially, a model that draws upon the existing strengths of US biotechnology companies and Indian pharmaceutical

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companies to cost-effectively discover and develop new drugs. This would help simultaneously address the considerable barriers to continued success facing the Big Pharma companies worldwide. These partnerships promise to reduce risks and costs at all stages of the

process from discovery to commercialisation, and maintain or increase margins for all participants. Ultimately, this will ensure that important, innovative and new therapies are made available at affordable prices to patients all over the world. As the current global

S tr a te g y

structure of the industry clearly becomes less and less sustainable, the demand for new solutions will grow. This will create an ideal atmosphere for the type of win-win partnership envisioned here. The opportunity

Today, Big Pharma is in a big squeeze. They are realising diminishing returns from their massive research and development efforts. The costs and risks associated with drug discovery, lead optimisation and pre-clinical and clinical development continue to escalate sharply, while productivity is dwindling. The US$ 100 million Investigational New Drug (IND) threshold has been reached and the US$ 1 billion discovery-to-market threshold looms. At the same time, many of the blockbuster drugs (annual sales >US$ 1 billion) that have driven the industryâ&#x20AC;&#x2122;s remarkable success in recent decades are soon to lose their patent protection. Also, there are very few drugs in the pipeline to replace potentially huge losses in revenue. Recognising these long-term trends, most of the companies in the recent years have been cutting costs associated with their internal R&D activities. This is being done primarily by eliminating non-performing programmes and focussing more tightly on retaining potential drug candidates in specific therapeutic areas. Rapidly escalating development costs have taken a toll as well. They have elevated the risks involved and the losses incurred when drugs fail in the clinical development phase of the process. Many inevitably do. The stakes have never been higher and the huge cost of failures is making it increasingly difficult to build the losses into the price of the compounds that can successfully make it all the way to market approval and commercialisation. The global players have turned more and more towards two practices to address this growing imbalance. To maintain the flow of innovative new products, they are feeding their

pipelines through licensing deals and acquisitions, often with US biotechnology firms which are the hotbeds of drug discovery today. The exponential growth in the number and value of Phase II inlicensing deals is a strong evidence of the trend. To reduce the risks and costs associated with developing promising compounds, they are outsourcing many pre-clinical and clinical development programs on a fee-for-service basis. Indian and Chinese companies are preferred as many of them have built sophisticated developmental infrastructures at substantially reduced costs. Seizing the opportunity

Given these established, well-recognised trends, the next step seems obvious. But so far, not many companies have taken it. In this model, the Indian pharma companies contribute access to their world-class chemistry and manufacturing infrastructures. The US biotechs contribute their advanced research and discovery capabilities. And both partners contribute to the pre-clinical and clinical development activities. This is an area of increasing overlap between the two as Indian companies reverse integrate into clinical development. For example, many Indian pharma

companies now have their own animal facilities, Phase I units and even the capability to conduct proof of concept studies. With many US biotechs needing cost-effective access to such developmental resources, there are substantial opportunities for productive and synergistic collaborations. Risks are shared by the participants and the cost-efficiencies achieved in the process create considerable value. These attributes will make the offerings from such partnerships all the more attractive to the Big Pharma. They would then apply their enormous commercialisation capabilities, particularly their global resources in regulatory affairs, sales and marketing. The ability of these partnerships to offer novel drugs that have already achieved proof-of-concept in human, eliminates much of the tremendous early-stage pipeline risk now faced by the Big Pharma. At this point, the potential value of a drug candidate is clear and all of the major pre-clinical safety and efficacy issues have already been addressed. Many drugs still fail at that stage, of course, but the Big Pharma companies are clearly willing to bear the remaining risk and invest the US$ 200300 million that might be required to get a drug approved.

Indo-US Biopartnering areas of increasing overlap Research and Innovation

Development

Chemistry and Manufacturing

U.S Biotech Competencies and Values

Areas of Increasing Overlap

Indian Partner Competencies and Values

The US biotechs contribute their advanced research and discovery capabilities. And both partners contribute to the pre-clinical and clinical development activities. This is an area of increasing overlap between the two as Indian companies reverse integrate into clinical development. For example, many Indian pharma companies now have their own animal facilities, Phase I units and even the capability to conduct proof-of-concept studies. With many US biotechs needing cost-effective access to such developmental resources, there are substantial opportunities for productive and synergistic collaborations.

Figure 1

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Opportunity for India...? Product Development & Manufacturing

Building World Class Companies

High quality work force at a cost advantage

Chemistry Biology

World class institutions and resources

Strengthening Small & Medium Companies

Large, expanding internal market

Innovation and discovery of novel compounds (NCEs) Expansion into preclinical and clinical development

Over the past several decades, Indian pharmaceutical companies have built an impressive infrastructure of world-class chemistry and manufacturing capabilities. This they have achieved mainly by concentrating on the low-cost production of generic drugs. As the industry has evolved and matured, today there are more than 75 plants in India approved by the US FDA to manufacture drugs for the American market. This is the most in any country outside the US. There is a plentiful trained labour force in pharmaceutical manufacturing and development in India, where labour costs are typically 30-50% of those of US employees. Indian pharmas are driven by the quest to build infrastructure—bricks and mortar and expertise. Figure 2

Bridging the gap

The Indo-US partnership model represents a natural progression for both partners, playing to the strengths of each other while bridging the gap between them creatively and

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productively, as the risks and rewards are shared in equal measures. US biotechnology companies tend to focus their efforts on research and development of portfolios of intellectual property. They are often relatively “virtual” companies, concentrating their investments on intellectual resources and capabilities without building manufacturing facilities, animal facilities, or clinical trial units—they are driven by the quest for innovation in drug discovery. As their candidate compounds evolve, they will typically A uthor

The combination of reduced risk and reduced costs will also encourage the development and marketing of new drugs that are not anticipated to be blockbusters. Biotech companies are discovering many drugs today with smaller potential markets. The creation of a model that makes it financially viable to bring them to market will not only help revitalise the pharmaceutical industry, but will also contribute substantially to public health around the world. The benefits of pharmaceutical care will be extended to more diseases.

seek outside relationships to continue the development process. By avoiding cumbersome infrastructures and by targeting their research and development efforts within very specific therapeutic areas, costs are controlled. This model (along with the inherent value of a given intellectual property portfolio, of course) attracts capital investment. With such a robust industry, however, many Indian pharmas appear to have a strong desire to become global players. Within the context of the generics industry, several Indian companies have bought other generic companies, particularly in Europe. Although such acquisitions expand the companies’ critical mass, it will remain difficult for them to forward-integrate into proprietary drugs, as discovery efforts would essentially start from scratch. It will make more sense for them to enthusiastically pursue partnerships along the lines proposed here, integrating the discoveries generated by the US biotechs into their own development infrastructures and jointly moving them forward to the point where Big Pharma come calling with their cheque books in hand. In this scenario, everyone wins. US biotechs and Indian pharmas maximise their returns based on their core competencies and ensure efficient use of capital and development resources. Big Pharma evolves beyond the nearlydefunct blockbuster model. In the end, patients and consumers win as innovative new drugs become available to treat conditions previously unserved by the pharmaceutical industry. And diminishing drug development costs will help keep overall healthcare costs under control.

Vipin Garg is the President and CEO of Tranzyme Pharma. He has over 20 years of biotechnology industry experience in both technical and management positions. During his career, he has been involved in several financings and liquidity events, including, IPOs, mergers and acquisitions. He received his PhD in Biochemistry in 1982 from the University of Adelaide, Australia, and his MS from New Delhi, India.

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Mark J Benedyk Head, La Jolla Incubator, The Pfizer Incubator, LLC, USA

n the news almost constantly, the Chinese business climate seems to be changing daily. Overall international capital flows to Asia reached US$ 88 billion in 2006, compared to US$ 60 billion in 2005 and they are expected to have remained high in 2007, despite the recent turmoil in the banking and the capital markets. Just as the US is seeing increasing globalisation in its business environment through cash infusions from sovereign funds and tremendous capital investment by overseas companies, China is itself seen by many in the business community as a greenfield opportunity to develop a business for billions of consumers. China represents by far the largest potential pharmaceutical consumer market in Asia, valued at US$ 23 billion in 2006.

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Does the large scale perspective on doing business in China jibe with on-the-street experience of the average company? How does the average company make inroads into China? As is often found in the pharmaceutical industry when dealing with other issues, when it comes to doing business in China, the devil is in the details. A top-down look on issues critical to developing opportunities for partnerships and investment in China in the pharmaceutical industry will be of great help. Scale – There are many Chinas

Although approximately 20% of the global population is in China, to date, only 1.5% of the global pharmaceutical market is represented in the country. China itself is far from

homogeneous in economic terms. Economists often talk about the “Three Chinas” that exist within China as a whole: the economically active South-West coastal region, the growing region slightly inland, and the most inland provinces that abut the Central Asian republics, Mongolia and India. In keeping with the sweeping changes that have taken place in China, those “Three Chinas” overlap with the other “Three Chinas” sometimes mentioned in recent years: privatised zones in the SouthWest coastal regions, the many State Owned Enterprises (SOEs) located slightly inland, and the extremely poor rural areas further inland. Clearly, as one moves inland on a map of China, there is less economic development—for now.

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Finding the Way in China Critical issues for partnership and investment

Multinational pharmaceutical companies are rushing to China with an aim to access the low-cost scientific talent and also claim a stake in Asiaâ&#x20AC;&#x2122;s largest pharmaceutical market. But the Chinese business climate is far from what one normally encounters in the West.

Challenges

The competitive landscape presents a challenge to someone looking for pharmaceutical opportunities in China: There are over 3,000 drug companies in China and over 15,000 distributors as well. On top of this, China lacks the infrastructure necessary to distribute pharmaceuticals outside of large urban centre and the potential for counterfeiting is very high. After a series of highly publicised crimes of corruption and graft at the Chinese State Food and Drug Administration (SFDA) that were disclosed last year, the Chinese government has made drastic changes

to processes and personnel there. It remains to be seen if those regulatory changes will be rigorously enforced such that they bear fruit in the near term for companies focussed on the Chinese pharmaceutical industry in the coming years. Because of these questions about the regulatory environment and concerns about enforcement of intellectual property law, instead of focussing on the immediate potential for sales to the Chinese market, global companies are focussed on setting up research centres in China. Their intention being not only to capitalise on a

low-cost technical workforce, but also, for the strategic reason, to establish a stake in the large and growing market that represents a tremendous revenue base for the pharmaceutical industry. The need for commitment

Setting up alliances for research or manufacturing purposes can be bewildering given the vast landscape of options available to foreign companies in China. With a flood of potential business and investment partners aggressively seeking deals with US companies, a deep understanding of the business culture in China is

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essential for success. Key for any company is having someone committed to be on the site where a company decides to have a footprint. He or she should be bilingual, have a deep network in China among both business and government contacts, and should have clear goals in mind that focus solely on cultivating and managing relationships in China. Those responsibilities alone are more than a typical full-time job.

needing a Chinese presence to facilitate business activities or research the developing Chinese market. However, this type of entity is limited in the extent of what type of business it can conduct. For instance, representative offices cannot legally conduct business transactions such as billing clients in China. This is an excellent arrangement for a company wanting to take a slow, measured approach to establishing a presence in China.

Pick the right structure – Incorporation in China

Joint venture

But how should that footprint look? China is a place where the government owns all intellectual properties of universities and research institutes and a vast amount of other assets that would normally be privatised in the West. Keeping this in mind, a key issue in determining how to incorporate in China involves a consideration of corporate goals in the region. Is the goal a permanent long-term presence in the market, or establish a plant for the lowcost manufacturing for a project with a limited timeline and budget? The majority of press coverage in recent years has highlighted the latter, trumpeting the low cost of manufacturing in China across the board. Lax environmental regulations and poor oversight, however, show this to be a double-edged sword: the ‘lead paint in toys’ crisis and the surfeit of counterfeit pharmaceuticals coming out of China are examples of how the legal and regulatory systems in China are still playing catch up with the tremendous growth in the low-cost manufacturing sector that has occurred in the past few years. With that in mind, the first thing to think about is the type and scope of business planned in China. Generally, there are three ways to proceed. They are:

A joint venture is a type of business where a foreign firm enters into a legal arrangement to create a new entity with joint equity ownership with local Chinese partners. Given the shifting sands of the Chinese legal environment, this can be a risky route for a company to take. A joint venture structured one year, may be arbitrarily considered illegal by the government another year. Keep in mind, if your company is new to China, this path may be fraught with possible risks, given the evolving nature of the Chinese legal environment and a government that is only now just beginning to enforce intellectual property law provisions in a meaningful way. Wholly foreign owned enterprises (WFOEs)

WFOEs are 100% foreign owned companies. For many biotech companies and smaller pharmaceutical companies, this is an increasingly common route taken towards establishing a presence in China. It allows a company to establish a presence in China with minimal capital requirements. In addition, it offers a company significantly more control over decision making than a representative office or a joint venture.

Representative office

Key cultural issues – A western perspective

A subsidiary of a foreign company in China is called a representative office. This arrangement is best for a company

To be successful in doing business in China, it is critical to understand cultural influences which drive

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alliances and partnerships. The concept of Guanxi (connections or relationships) is central to all business alliances in China, from start to finish. For instance, a purely formal business arrangement starting with a phone call and ending with signed contracts would be seen as grossly inadequate by a Chinese partner. The proper cultivation of a relationship with a Chinese partner both socially and from a business perspective influences the success or failure of the partnership and will dictate the tenor of the interaction going forward. Spending time in the town where potential partners reside and leveraging common contacts to network with Chinese companies do play an important role in the success of a business in China. The process of developing the relationship is almost as important as the closing of an executed agreement itself which should be accompanied by a signing ceremony that celebrates the new partnership. But companies need to keep in mind that the final executed agreement is just a starting point for a partnership. There will be constant communication back and forth once an alliance is put into place. Hence, from a management perspective, it is critical to have someone in charge of interfacing with that partner or partners. Given the need for frequent and accessible contact to do business in China, again, it is important to have personnel who are bilingual, bicultural and who can improve the interaction between both parties. It is difficult to imagine how a successful Chinese partnership can be established remotely, without the rich interaction that faceto-face meetings and conversations bring to a business alliance. Driving collaboration

A few simple drivers will help immensely in developing business and investment partnerships in China. First of all, the need for a long-term

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interaction is key. It is self-defeating to focus on a goal of doing business in China without dedicating the time and resources required to doing it right. If a company merely wants to appoint an agent to act on its behalf in China, it shouldn’t expect a huge return on its investment. On the other hand, if there is a strong commitment to developing business in China and that is reflected in a clear dedication of senior management and resources to the job, the rewards can be handsome, indeed. Understand China: Local relationships = Local knowledge

As mentioned at the beginning of this article, there are “many Chinas”. The SFDA regulatory offices in Beijing are half a continent away from the pharmaceutical R&D centre in Pudong, Shanghai, and the cultures and languages in both locations are equally distant from each other. Knowing the local power structure and the local way of doing business is the key to success in China. The freewheeling aspect to all of life in Shanghai is in stark contrast to the straitlaced atmosphere of Beijing, where the seat of government power lies. For all intents and purposes, they might as well be two different countries, deserving of two different offices, one for each city. Understanding the power of the government

The concept of a central government is often very foreign to Westerners. All university intellectual property is the property of the government, and until recently, the military was the largest corporate shareholder in China. The Chinese regulatory authorities oversee a vast landscape of approval applications that boggle the mind. Every aspect of business is government regulated as well, to an extent not always apparent to Western eyes.

If companies do not have a good relationship with government officials in the region where they do business, getting business done gets quite difficult. It is that simple. Forging relationships with potential partners who themselves have good relationships with government representatives and due diligence on potential partners is a must. Everything cuts both ways

As a foreign entity in China (read nonChinese), a foreign company is a ready target for exploitation by unscrupulous businesses that see it as a walking bank account. The companies are also seen as an invaluable asset by the sophisticated Chinese business owners looking for long-term partners. Companies should not jump to conclusions about potential partners until their due diligence is not complete. Similarly, a Chinese businessman or businesswoman acting alone is one of literally tens of millions of small business owners. A Chinese business owner who has a highly visible alliance with a Western partner, though, is something entirely different. Your affiliation has value in itself. If partner is chosen wisely, foreign companies can benefit tremendously through their affiliation. Guanxi is more powerful than a formal contract

In a country where the concept of a uniform rule of law is relatively recent, relationships and face count for everything. In many ways, they are more powerful forces than the contract law that governs business transactions in the West. Companies need to keep this in mind when dealing with local business owners. Each is part of a local network of people that do business together. If the company can help the social standing of its Chinese partner in that network, it will be a valuable ally and help get value in return for the relationship.

Negotiation never ends

Negotiations never end in a fastmoving environment like the Chinese economy, and partnerships may evolve very quickly as the business environment evolves. Chinese partners are not only allied with foreign companies, but with a host of other Chinese companies in a vast network of players about whom foreign companies may know very little or nothing at all. If the relationship is not going in the direction they want, speaking up is the best choice. Companies should remember that the contract is just a starting point for their interaction with Chinese investors or business partners, and that said, a contract is always a two-way agreement. Keeping an open mind, and being open to possibilities for change when doing business in China, benefits everyone. Be open to change, but not too open

Where does this leave the newly arrived foreign businessman or businesswoman, just getting off the plane in China? China is changing, and nothing breeds business opportunity like a crisis of change. Contrary to popular belief in the West, however, the Chinese word for crisis (weiji), is not composed of the characters for “danger” and “opportunity”. To achieve success, a company should do its homework, just as it would anywhere else. Often the chaos and excitement of a rapidly changing environment like China can be alluring to opportunistic companies, but as always the standard business rules apply here. Partnerships are about mutual self-interest, and there is a lot of that in China, at the moment. Companies should be vigilant about due diligence and above all, persistent, as the Chinese business environment is very new as well as fluid. If they run into a roadblock, they should be persistent and adaptable and remember the Chinese proverb, “Where there’s a will, there’s a way.”

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Partnerships and Innovation The growth factors Developing a product pipeline is being considered seriously and will be an essential factor for the growth of the Indian pharma market.

R B Smarta Founder and Managing Director, Interlink Marketing Consultancy Pvt Ltd. and Member, Drugs and Pharma National Committee, Confederation of Indian Industry (CII), India

How important will be strategic alliances and partnerships for the growth of Indian pharmaceutical market? Alliances and partnerships will be very important because of two reasons. 1) The Indian market has already entered into the patent era and 2) Indian companies still have very lean product pipeline as of now. Developing a product pipeline is being considered seriously and will be an essential factor for the growth of the Indian pharma market. Strategic alliances in terms of co-marketing and co-promotion will be an important issue for those who would like to promote their products in Indian markets.

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Similarly, partnerships with Indian companies as well as multinationals which are happening at different levelsâ&#x20AC;&#x201D;at equity level, market level, manufacturing level and R&D levelâ&#x20AC;&#x201D; will be very useful for the growth of the pharma market in India. Is there a need for a centralised drug regulating authority in India? India needs to have a centralised drug regulation authority. It is essential because a lot of products such as combinations or fixed dosage combinations are being sold in India which are permitted by state drug authorities. Whether they

are rational or irrational drug combinations is a separate issue, but if there is a centralised drug regulatory authority, there will not be many deviations in the law itself. This will also help the harmonisation of all the existing regulatory authorities or bodies. There will be an accountability on the part of Government to monitor fixed-dose combinations, single ingredients, rational and irrational drug combinations. All those issues which are important can be taken care of. Similarly, there is the big issue of counterfeit medicines today. And these counterfeit medicines are medicines which are

E x pert T a l k

manufactured on valid or invalid licenses. Obviously all these issues can be curtailed or streamlined by a centralised drug authority. This is a not a practice issue, but a structural issue and the government has been taking steps in this direction. For example, fixed dose combinations and irrational drug combinations have been banned now. Indian pharmaceutical industry is expected to grow at a healthy rate and also attract lot of investment. Do you foresee any hurdles that India could face in the future? Yes, there are hurdles that India could face going forward. First, the quality standards or measurements that international companies look at in terms of investing in countries such as India. The quality of R&D, clinical trials, etc., in India should give confidence to the investors that the processes are stronger, quality is right and is of international standards. Second, the time consumed for setting up industries or investment is also of vital importance. The investors should not be involved or engulfed in red-tapism or time consuming procedures. And third, cost factor. India is still economical and provides the cost advantage for conducting clinical trials but if that is lost then it would become a major hurdle. In addition, there could be hurdles from the regulatory authorities, government policies etc. Beside all these issues, there is a big gap between the potential India has and the actualisation of that potential. For example, there are 35 million diabetic cases in India. As per reports from market researchers, the number of patients treated are just around one million. This means 34 million diabetic patients are not being treated. Given the population of India, there could be more than 35 million diabetic patients as India is likely to be considered as a diabetics capital of the world. If this type of a market mismatch exists, investors might be misled into thinking that their investments may not give expected ROI.

Though big Indian pharma companies are embracing innovation as their growth engine, the global pharma companies do not treat Indian companies as innovative as themselves. Your views on this. Indian companies are very innovative in marketing and sales. The market dynamics in India are different. However, after the product patents replacing the process patents, the Indian pharma industry needs to be innovative as there is intense competition now. Innovation is often considered only in terms of R&D which is new product or productspecific innovation. But, innovation can be classified in two different ways, operational innovation and R&D innovation. The operational innovation includes marketing, sales etc. and India is far ahead in this type of innovation. In the second type, as everybody is aware, investment in R&D is very low in India. This is due to price control, lack of brands (as India is more into generics) and Indian pricing of generics which is around one-tenth of the branded drugs. Hence, by selling generic drugs in India, companies cannot possibly get enough revenues to invest in R&D as other multinational competitors have. If a national company is not able to invest in R&D, how will it be innovative enough to really give more and more new products? In spite of having numerous limitations or constraints such as monetary conditions or investment conditions, the Indian pharma companies are still innovative. Yes, perhaps if we look at innovation as creation of new products, India hasnâ&#x20AC;&#x2122;t got many patents so far. But it is in the anvil. India is just two years old in the patent regime. India might need to have a re-look at it. Another aspect is that most multinationals think that their value chain originates from R&D and then moves to the patients. Now the time has come where the thinking and proposition might change. This value chain will be reversed and hence it may start with the patients and end in customised R&D. It has to start with the disease of the patients, then facilitation and at the end of the chain comes the product. It will be no longer enough that a good product will generate huge revenues. The value chain and the migration which started from R&D for everybody is likely to go wrong if it remains that way. We need to really look at the vision; it should start with the patient, to hospitals with facilities, then diagnostics and finally the product and treatment. All said and done, there still is a big gap today which is a big hurdle.

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E x pert T a l k

How can India address the challenges of infrastructure, lack of regulations and qualified personnel that could hamper the growth of its drug discovery and clinical trials market? The Indian health and education ministry is trying its best to address these challenges. Some more thoughts could be introduced in the forthcoming budget. More important is the issue of the education system for the healthcare and pharma sectors. There is a big gap between qualified personnel for clinical trials and the actual requirement. India is trying to revamp the syllabus of its pharmacy colleges, because there is a huge gap between the skill set, knowledge and attitude needed by the industry and what is currently available. While attitude can change with opportunities, infrastructure needs to be improved in institutions like the pharmacy colleges, etc. to really train and develop human resources for the industry. Overall, it is an issue of investment and it is an issue of education. If these things are taken care of, India will be comfortably placed to garner a bigger share of the clinical trials market worldwide.

A uthor

How are the Indian clinical trial companies faring on the ethics front while carrying out the clinical trials? The Indian companies are faring well on the ethics front. There aren’t many issues regarding ethics in clinical trials because, it is partly being monitored by the Drug Controller General of India (DGCI), in terms of policies on the number of patients, multi-centre or single centre trials among other such

things. Ethics part has been properly handled with the government’s timely interventions at appropriate phases. Reports estimate that India will garner a good share of the clinical trials market in the coming years. Will India be really able to emerge as a stronger player and sustain its advantage? Yes, and it is not because of only cost advantage but the intelligence India has. What needs to be looked at is • necessary procedures which are required like recruitment of patients, • information that needs to be passed onto the patients so that they participate in the clinical trials with their full consent

The Indian companies are faring well on the ethics front. Ethics part has been properly handled with the government’s timely interventions at appropriate phases.

• the necessity for toxicology and other studies which are required before really getting into the clinical trials • aspects like safety, etc. that needed to be studied. If they are studied properly, India can very well get the sustainable advantage as it will have more numbers. Recruiting 300 patients in India is not a difficult task. The speed will improve, patients will come and regulatory bodies will get proper atten-

R B Smarta is the Founder and Managing Director of Interlink Marketing Consultancy Pvt Ltd. Through Interlink he has added value to corporate brands, therapeutic brands, fast moving healthcare brands, in-organic and organic growth of corporates and sales & marketing ROI of corporates. He is also a member of CII Drugs and Pharma National Committee for the Year 2007-08. He is currently working on Business Models, Business Strategy, Emerging Markets and Global Business Opportunities for Pharma, Healthcare Industries.

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tion and also relationships with proper doctors and other clinical trial staff will improve. Hence, India could be a very good outsourcing hub for clinical trials for the entire world. How do you see the Indian pharma industry in the next five years in terms of innovation as well as partnering with the big pharma? In terms of partnerships, there are very good chances—a number of companies are likely to come to India. India has created that hype—now we can use the word hype. Today every country is looking at India and everybody sees India as a very big opportunity. So partnering with India will definitely happen. In terms of innovation, it will be at the codevelopment level where lot of innovations will take place in collaborations like codevelopment, co-assistance, co-marketing, co-selling, copromotion, etc. There is a lot to be done because, still people are worried about taking the responsibility of hiring and training manpower. Everyone would like to get into more innovation partnerships in India and that will happen. Should the Indian pharma companies look at partnering with other Indian companies? Yes. But there is a mindset issue. It is the not issue of economics but the identity which Indian companies try to keep intact. For example, in Indore, we have nearly six or seven companies which are operating in formulations. Each one of them has around 300 to 400 people and is worth not more than Rs. 25 crores. Merged together they will perhaps become a Rs.150 crore company and may not require the 1800 (300 x 6) people. Given the economies of scale that will follow will they be able to come together? The answer is perhaps NO.

Biosimilars

What lies ahead? “Biosimilars will eventually bring down the cost of biological medicines and in doing so will expand the market.”

Cecil Nick Principal Consultant, PAREXEL Consulting, UK

How different are Biosimilars from traditional generics in terms of manufacturing and approval? The differences between traditional generics and biosimilars are really quite fundamental. Biologicals are orders of magnitude more complex both in structure and in terms of impurity profile compared to small molecules. As a consequence of this increased complexity, it is more challenging to convince the regulatory authorities that the “biosimilar” is similar to the innovator product. Therefore, biologicals will not be treated as standard generics. With standard generics, the primary concern of regulators relates to whether the formulated generic will behave similarly to the innovator formulation specifically with respect to the drug release and absorption profile.

Therefore, there is the need for bioequivalence studies to demonstrate that peak and total plasma levels are equivalent, i.e. within 80 - 125% of each other at the 90% confidence level. With biologicals, the situation is far more complex. In fact, there is a spectrum of complexity from simple peptides through to complex products such as live viruses. It follows that some biologicals are in fact so complex that they will not be suitable for development as biosimilars. For now, the biosimilar concept is generally applied to the simpler and highly purified recombinant proteins such as insulin, somatropin, GCSF, epoetin and interferon. But, even with these products, the prevailing view is that they are too complex to enable similarity to be demonstrated using physico-chemi-

cal and biological testing alone. These proteins are comprised of long chains of often over a hundred or many hundreds of amino acids (the natural building blocks of proteins). This amino acid chain is intricately folded and correct folding is essential to ensure the desired biological activity of the protein. The folded structures are held together by weak non-covalent bonds that are easily disrupted and dependant on the environment in which the protein is contained. Additionally, there is potential for the existence of a multitude of degradation products and contaminating impurities arising from the manufacturing process. These impurities can impact the activity of the protein and more importantly contribute to immunogenicity. Therefore, regulatory authorities will require a higher level of assurance that the similar biological medicinal product possesses

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a similar safety and efficacy profile as the originator product. This will require extensive bridging with non-clinical and clinical data to achieve regulatory approval, something which is not required for standard generics. Therefore, biosimilars differ from traditional generics in two fundamental ways. First, they require greater expertise and infrastructure for their production and second, they will only be approved following successful completion of a costly non-clinical and clinical development program. What are your views on the market for biosimilars? Clearly biological medicines are generally expensive and consequently may be somewhat unaffordable to many patients throughout the world. This is not just the case in emerging markets but even in established markets where budget limitations could mean that patients may not always receive the latest treatments. It might appear that the introduction of biosimilars could provide the “magic solution.” In Europe, for instance, the environment for biosimilars is very complex. Biological medicines currently remain expensive to produce and with stringent regulatory requirements for biosimilars in Europe, development costs will most likely remain high. Thus, there may be relatively limited scope for price reductions at least for some products. In this respect, it is interesting to note that one pharmaceutical company announced discontinuation of their epoetin development program, since epoetin was unlikely to be a good return on investment. A number of factors, which vary between regions, influence the market. First and foremost is the affordability of the originator product and the extent of price saving on switching to a biosimilar. In Europe a 25% reduction has had little sway in persuading the prescribers to switch to biosimilars or other cheaper brands. There are many reasons for this, including a number of hurdles

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that need to be surmounted in order to persuade prescribers and patients to change to cheaper brands. If a patient is doing well, for instance, there will be a reluctance to switch to a different medicine, which might lead to or more likely be falsely implicated with adverse effects. Furthermore, the innovator companies have developed a symbiotic relationship with the prescribers, providing them with support that may include research fellow funding, educational support, and associated materials, such as pen delivery devices. This may make it difficult for biosimilar companies to break into the market initially. However, as the cost of medicines increases, health economics is becoming more and more of a driving factor in prescribing decisions and this should swing the market towards greater usage of biosimilars. In parts of the Asia region, affordability of medicines is a challenge. For instance, a driving force behind increasing biopharmaceutical industry activity in India appears to be the need to deliver affordable healthcare to the domestic market. In South-East Asia, for example, regulators are determining how to best deal with biosimilars. This also points towards a potentially sizeable market in this region. The biosimilar market is complex. Unlike standard generics prescribers and purchasers will need to be educated directly, and also indirectly, for instance through journal articles. Innovator companies are making efforts to protect their market, and biosimilar manufacturers will need to do the same. Ultimately, existing perceptions will need to be changed, reinforcing that biosimilars are not of inferior quality and utilise the latest technology to ensure quality. Furthermore, the latest analytical technology is being employed together with confirmatory testing so that biosimilars are as safe and effective as the innovator products. Biosimilars will eventually bring down the cost of biological medicines and in doing so will expand the market.

What are the new developments in the regulatory framework for approving biosimilars in the EU and US regions? In the US there is only one example of a biogeneric approval, for Omnitrope, which was approved after years of prevarication by the FDA. When Omnitrope was finally approved in the US, the FDA advised that this approval should not be seen as a precedent for other follow-on biologicals. Omnitrope was approved under Section 505(b)(2) of the Food Drug and Cosmetic (FD&C) Act, which essentially allows a bibliographic / hybrid type of application. Largely for historical reasons, most biological medicines are regulated not by the FD&C but instead by the Public Health Service Act (PHSA). The PHSA arises from legislation that is over 100 years old and defines a biological medicine as “any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, or blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment or cure of a disease of human beings.” It seems that most recombinant proteins, which were not even conceivable when the legislation was drafted, now fall under this definition. At the time when the PHSA was passed, the analytical tools available today did not exist, so that the only way of ensuring product consistency was by relying on an established and consistent process. Consequently, a similar product from a new manufacturer was perceived as a novel product and there was therefore no need for a mechanism for filing of truncated submissions for biological medicines. Today the manufacture of similar biologicals is possible but there remains no legal basis for their approval in the US until the current legislation is changed. In fact, not all proteins are covered by the PHSA. Included in these exceptions are hormones such as insulin and somatropin which when they were introduced were regulated under the FD&C

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fusion of expertise from regulatory professionals, clinicians, statisticians, pharmacologists, toxicologists, analytical biochemists and others. What kind of threat do manufacturers of biosimilars pose to other pharma companies and vice-versa? Some innovator companies see biosimilars as an opportunity to enter new markets themselves. However, others see their entry as a significant threat and are exerting effort to keep biosimilars out of the market. For example, some innovator companies are engaging in political lobbying to make regulatory requirements as arduous as possible and to block substitution. They are also priming the market against biosimilars through articles and sales and marketing activities. These companies which have been working closely with their customers for years often have strong relationships with the prescribing community. Also, list prices are not necessarily the prices hospitals pay and innovator companies may well meet the challenge of biosimilars with targeted discounting. These activities will present formidable hurdles to the biosimilar companies which will need to approach the sales and marketing of a biosimilar more like a branded medicine and not in the same way as traditional generics. Of course, innovator companies will need to continue to be innovative, since additional innovation is their key protection against biosimilars. New and better patent protected products have and will supplant the older products which are the focus of attention for the biosimilar companies. On the other hand, by making medicines more affordable, A uthor

and therefore do qualify for truncated marketing application procedures, specifically under Section 505(b)(2) of the FD&C Act. It was under this legislation that Omnitope was approved as a biosimilar in the US. There is now the need to clarify the legislation in the US to bring practices in line with current thinking to allow the FDA to regulate biosimilars as it can for generic drugs. Several bills have been prepared but so far none have made it into legislation. As far as the EU is concerned, when Omnitrope was filed the EU found itself in the same position as the US with no appropriate regulatory framework to deal with biosimilars. So, while in the EU Omnitrope was granted a positive opinion by the assessment committee (Committee for Medicinal Products for Human Use, or CHMP), approval was blocked by the European Commission because there was no appropriate legal basis for such an approval. However, unlike the US, European regulators promptly amended the legislation, which conveniently happened to be under revision at the time. In Europe, there is as a result now a very clear legal pathway for the approval of biosimilars. Subsequent to revision of the EU legislation, a raft of guidelines has been produced to provide further direction to companies intending to bring biosimilars to the EU market. Despite this, regulatory data requirements are relatively extensive and the guidelines are not fully transparent. To date only four products have been approved in Europe (two somatropins and two epoetins) and one product has been rejected (an interferon alpha). Therefore, approval cannot be considered as a forgone conclusion. There is the need to give careful consideration to the development program and to go to the European regulators for scientific advice. In fact, getting the biosimilar program right requires considerable skill and the

biosimilar companies will naturally expand the market. Furthermore, healthcare payers, such as national healthcare systems, are becoming more and more influential and biosimilars will be perceived as good value, which is what purchasers are looking at and insist on buying. Overall, there is room for both innovators and biosimilar manufacturers but clearly both are in competition, and only the skillful companies will endure. The innovators will need to innovate and the biosimilar manufacturers will need to keep production and development costs as low as possible. Above all, there is a need to appreciate that marketing a biosimilar involves trail blazing new approaches that are different from those applied to traditional generics. How can the developers of biosimilars maximise their success / revenues from their portfolio? While there is a need to apply the latest technologies to make manufacturing as efficient as possible and thereby keep the cost base as low as possible, there is no reason why biosimilar manufacturers should not be innovative themselves. Customers will pay extra for innovation and thereby provide for increased profits for the biosimilar manufacturers. And innovation does not need to always produce altered proteins (which are not strictly biosimilars), although that is certainly worth considering. With respect to biosimilars innovation could involve novel formulations, presentations, delivery systems and packaging. With biosimilars the world of generics and innovation merge to generate a new breed of medicinal products entirely.

Cecil Nick Principal Consultant, PAREXEL Consulting provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. He has been involved in the development and regulatory approval of a number of innovative and biosimilar medicinal products in Europe. He also has extensive experience in the development and EU registration of biotechnology and blood products, devices, new chemical entities, CMC, orphan drugs, health economics, and scientific advice.

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Mitochondrial Nanomedicine Tailored and efficient therapeutics The ongoing merger of nanoscience with mitochondrial medicine gives rise to novel strategies for diagnosis and therapy of mitochondrial disorders. Volkmar Weissig Associate Professor of Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy Glendale, Midwestern University, USA Gerard G M D’Souza Formulation Development Scientist, Northeastern University, Bouve College of Health Sciences, USA and Sarathi V Boddapati Formulation Development Scientist, Novavax Inc, USA

ignificant progress has been made in elucidating the central role of mitochondria in influencing the life and death of a cell. Yet, effective therapies for mitochondrial diseases remain elusive. However, the ongoing merger of nanoscience with mitochondrial medicine gives rise to novel strategies for diagnosis and therapy of mitochondrial disorders. Mitochondria as cell organelles

The mitochondrion as the “power house” of the cell is essential for energy metabolism. And as the “cell’s arsenal” this organelle is crucial to the regulation and execution of programmed cell death (“apoptosis”). Further,

mitochondria are critically involved in modulating the intracellular calcium concentration, which in turn impacts almost the entire cellular biochemistry. The mitochondrial respiratory chain (thought to be contributor to ageing) is the major source for damaging reactive oxygen species and mitochondria play a crucial role in numerous catabolic and anabolic cellular pathways. The number of mitochondria per single cell generally depends on the cell’s energy demand. Metabolically active organs, such as the brain, liver, cardiac and skeletal muscle tissues contain cells with a large number of mitochondria, while cells needing less energy contain only a few dozens of them. Mitochondria form a complex tubular network that constantly changes shape by undergoing fission and fusion as shown by some recent work. Interestingly, this network has also been shown to be tightly intertwined with cytosolic microtubule. These new insights into the mitochondrial morphology have far reaching consequences in the design of future strategies for the delivery of drugs and DNA to and into mitochondria.

Mitochondrial DNA diseases

Mitochondria are unique in comparison to other animal cell organelles. Mitochondria contain their own genome (mtDNA) and associated machinery for the synthesis of mitochondrial proteins, all of which are crucially involved in the process of converting food into metabolic energy. Any mtDNA defect eventually reduces the energy production of this organelle. Clinical symptoms vary with the magnitude of damage and depend on the energy demand of the corresponding tissue. The causal link between mtDNA defects and human diseases was described for the first time in 1988. Since then the number of diseases identified to be caused by defective mtDNA has skyrocketed. To date, 347 distinct mitochondrial disorders have been recognised. The majority of these disorders exhibit either neurodegenerative or neuromuscular pathologies. According to an estimate made by the United Mitochondrial Disease Foundation (UMDF), a child born every 15 minutes either suffers from a mitochondrial disease or will develop one by the age of five. Unfortunately, despite the

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Mitochondria-specific Nanotechnology DQAsomes

Liposomes

Nanoparticles

Quantumdots

Self-assembly of Mitochondriotropic bola amphiphile

Surface-modification of Liposomes with mitochondriotropics

Surface-modification of Nanoparticles with mitochondriotropics

Surface-modification of Quantumdots with mitochondriotropics

Mitochondria-targeted bolasomes (DQAsomes)

Mitochondriatargeted Liposomes

Mitochondria-targeted Nanoparticles

Mitochondria-targeted Quantumdots Figure 1

staggering occurrence of mitochondrial diseases they are generally underdiagnosed or misdiagnosed. They are characterised by a bewildering array of signs and symptoms. For example, one single point mutation in mitochondrial DNA has been reported to lead to over nine different disorders, including diabetes, congestive heart failure, chronic progressive external ophthalmoplegia (CPEO), schizophrenia and kidney malfunction. Mitochondrial medicine is a rapidly growing area in biomedical research giving rise to the development of new sub-disciplines such as Mitochondrial Pharmacology and Mitochondrial Pharmaceutics. And providing the much needed tools for probing, accessing and manipulating mitochondria as well as their sub-organellar components is the ongoing incursion of nanoscience into the realm of mitochondrial research. Mitochondria-specific nanotechnology

Figure 1 displays different types of nanovesicles and particles, generally referred to as nanotechnology, that have been designed to manipulate or probe mitochondrial functions. The majority of these systems employ active targeting mechanisms. Their mitochondria-targeting capability is primarily achieved through association with “mitochondriotropic” residues. Further,

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mitochondrial leader sequence peptides and antibodies also provide for alternative targeting mechanisms. Through intrinsic design or surface modification, these nanosystems exhibit mitochondriotropism and represent the convergence of nanotechnology with the many facets of mitochondrial research. DQAsomes

DQAsomes (i.e. dequalinium-based liposome-like vesicles), proposed in 1998, represent the prototype of nanoscale mitochondria-specific drug delivery systems. The design of these unique mitochondria-targeted drug carriers is based on the intrinsic mitochondriotropism of dequalinium and its derivatives. Prerequisite for creating this system was the distinct self-assembly behaviour of dicationic quinolinium derivatives. These are mitochondriotropic cations resembling “bola”-form electrolytes, i.e. they are symmetrical molecules with two charge centres separated by a hydrophobic chain at a relatively large distance. Such “bola”-form like amphiphiles form upon sonication of aqueous suspensions cationic vesicles (“bolasomes”) termed “DQAsomes” when prepared from dequalinium salts. DQAsomes represent the first vector for selectively delivering DNA to mitochondria within living mammalian cells thereby making mitochondrial gene therapy at least feasible. DQAsomes are also

being explored as mitochondria-targeted carriers for small molecules, for example drugs that are able to trigger apoptosis via interacting with mitochondria. Such approach will eventually make it possible to “talk” cancer cells normally resistant to programmed cell death “into committing suicide”. In vitro and in vivo data from ongoing investigations in the author’s laboratory demonstrate that encapsulating pro-apoptotic drugs into this mitochondria-specific nano drug delivery system increases the sub-cellular (mitochondrial) bioavailability of this drug, which in turn increases the drugs’ therapeutic efficiency. For example, DQAsomal encapsulated paclitaxel triggers apoptosis at paclitaxel concentrations, at which the free drug does not have a significant cytotoxic effect. Human colon cancer cells were incubated with DQAsomal encapsulated drug and for control also with the free drug, with empty DQAsomes and with a mechanical mixture of the free drug and empty DQAsomes. Following the staining of the treated cells with the DNA-binding fluorophore Hoechst 33258, apoptotic nuclei showing the typical apoptotic condensation and fragmentation of chromatin were counted and expressed as a percent of the total number of nuclei. Figure 2 shows that under identical incubation conditions, 10 nM paclitaxel encapsulated in DQAsomes more than doubles the number of apoptotic nuclei in comparison to the control, in which cells were treated with a mixture of empty DQAsomes and 10 nM free paclitaxel. Likewise, a DNA ladder caused by DNA fragmentation typical for apoptosis could be detected upon incubation of colon cancer cells with 10 nM DQAsomal encapsulated paclitaxel, but not upon incubation with the free drug either alone or in mixture with empty DQAsomes. Mitochondriotropic liposomes

Phospholipid vesicles (liposomes) were described for the first time in 1965 by Alex Bangham. Their enormous poten-

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Activity of 10 nM paclitaxel encapsulated in DQAsomes under identical incubation conditions 25

Apoptotic nuclie[%]

20 15 10 5 20 nM DQA

20 nM DQA + 10 nm paclitaxel (mixed)

tial as a colloidal drug and DNA delivery system for biomedical applications was discussed in two prescient papers published in 1976 in the New England Journal of Medicine by Gregory Gregoriadis. DOXILTM, liposomal encapsulated doxorubicin, was approved by the US FDA in November 1995 and represents the first injectable nanomedicine ever developed. Liposome technology has had addressed and solved issues and problems associated with the clinical application of solid nanoparticles such as biodistribution and drug release long before the term “nano” became trendy for pharmaceutical scientists. Utilising established procedures for the surface modification of lipid vesicles, established mitochondriotropic triphenylphosphonium cations have been used to render mitochondria-specific liposomes. Extended confocal fluorescence microscopic studies demonstrate the ability of these mitochondriotropic liposomes to deliver hydrophobic drugs almost exclusively to mitochondria. Studies with drugs known to trigger apoptosis by acting on mitochondrial targets show that delivering these drugs directly to mitochondria by encapsulating them in mitochondria-targeted liposomes significantly increases their therapeutic efficiency. For example, in vitro studies show that ceramide encapsulated in mitochondriotropic liposomes triggers apoptosis at a concentration at

20 nM DQA w/ 10 nm encapsulated paclitaxel

Figure 2

which the free drug does not show any toxicity. Besides the huge potential such liposomes have for the development of novel anti-cancer chemotherapies, they may also form the basis for future mitochondrial gene therapies. Most recent and still unpublished studies in the author’s laboratory strongly suggest the ability of mitochondriotropic liposomes to transfer functional DNA into the mitochondrial matrix. Solid nanoparticles

Salnikov et al. employed calibrated gold nanoparticles (AuNPs) of different sizes to probe the permeability of the mitochondrial outer membrane. The authors using such nanotechnological approaches, were able to assess the physical diameter of the VDAC most likely to be between 3 and 6 nm. The investigators incubated rat permeabilised ventricular cells as well as isolated mitochondria under different conditions with 3 nm and 6 nm AuNP’s, respectively.

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They found that while the outer mitochondrial membrane was impermeable to 6 nm AuNPS in the absence of permeability transition, the smaller 3 nm AuNPs were able to enter mitochondria even in the presence of Cyclosporin A, which is known to prevent mitochondrial permeability transition. Ju-Nam et al. recently introduced a strategy for attaching mitochondriotropic ligands to the surface of AuNPs. With their new approach, the authors have been able to prepare 5-10 nm sized AuNPs with surface-attached triphenylphosphonium residues, the mitochondria-specifity of which is currently being tested in vitro. The future medicine

Merging nanoscience and nanotechnology with mitochondrial medicine will create a large variety of tools and methods for analysing and manipulating mitochondrial functions. Considerable progress should be seen in using mitochondrial nanomedicine for the treatment of common diseases such as cancer, diabetes and neurodegeneration as well as for alleviating symptoms associated with ageing. Increased understanding of malfunctions present in mitochondrial diseases will lead to more efficient diagnosis and eventually to the tailored design of highly efficient mitochondrial therapeutics. Full references are available on www.pharmafocusasia.com/magazine/

Volkmar Weissig received his PhD in Chemistry and his postdoctoral ScD degree in Biochemistry and Biotechnology at the Martin Luther University in Halle (Germany). He is currently an Associate Professor of Pharmacology at Midwestern University College of Pharmacy in Glendale, Arizona. He has published over 60 research papers, reviews and book chapters mostly in the area of nano drug delivery systems. More recently he has turned his scientific focus to Mitochondrial Pharmaceutics. He is also the Associate Editor of the Journal of Liposome Research. Gerard D’Souza received a PhD Degree from Northeastern University, Boston, MA in 2005 and is currently employed as a Formulation Development Scientist. Sarathi V Boddapati received his PhD Degree from Northeastern University, Boston, MA in 2007 and is currently employed as a Formulation Development Scientist with Novavax Inc., USA.

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Multi-functional Nanomedicine Technology convergence in development of targeted therapeutics

The use of multi-functional nanosystems affords convergence of technologies for simultaneous or sequential target-specific delivery of multiple drugs or by combining drugs with different energy modalities. Mansoor M Amji, Professor and Associate Department Chairman, Department of Pharmaceutical Sciences, School of Pharmacy, and Co-Director of Nanomedicine Education and Research Consortium Padmaja Magadala, Department of Pharmaceutical Sciences, School of Pharmacy Bouve College of Health Sciences, Northeastern University, USA

n the context of biomedical imaging and therapeutic applications, nanosystems are defined as particles of less than 1000 nanometers in diameter that can overcome biological barriers and provide efficient delivery and have unique properties. The application of nanotechnology for disease prevention, diagnosis and treatment is receiving significant attention over the last several years. Furthermore, inclusion of image contrast enhancers with drugs can serve an important function as monitors of therapeutic efficacy. Other such combinations are also possible and can have significant clinical benefits, especially in cancer. Overall, multi-functional nanosystems offer an exciting and fruitful area of research with tremendous opportunity for clinical translation. “Nano” is the most widely used keyword today in fields such as telecommunication, electronics, clean energy, transportation, consumer goods and

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in biomedical technologies. Currently, the US government is investing over US$ 1 billion a year in funding for nanotechnology research, while other global investment sums to US$ 4 billion a year. In contrast, private funding for nanotechnology research Nanotechnology, as defined by the U.S. National Nanotechnology Initiative is “the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications”. Nanomedicine, a term coined by the U.S. National Institutes of Health through its Roadmap Initiative, is a branch of nanotechnology that refers to “molecular scale medical intervention for the purpose of prevention, diagnosis and treatment of diseases”.

and development is minimal with a substantial portion being used to fund nano-biotech projects. Nanomedicine is a new interdisciplinary paradigm emerging from the timely convergence of two parallel recent developments. The tremendous advancements in genetic engineering and molecular biology has led to molecular basis of diseases and nanotechnology which offer a powerful means to control molecular interactions. Nanomedicine can significantly affect millions of individuals around the world with acute and chronic diseases including cancer, cardiovascular disease and infectious diseases. According to the 2005 Nanomarket Report, the nanomedicine market is estimated to generate about US$ 1.7 billion in revenues by 2009, and this is expected to increase to US$ 4.8 billion by the year 2012. Based on these encouraging financial forecasts, developments in nanomedicine have the potential to become an essential driving force that can propel the already high-technology

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based pharmaceutical, biotechnology and medical device industries to new heights. Examples of nanotechnology applied in pharmaceutical product development include organic nano-platforms such as polymeric, lipid (e.g. liposomes, nanoemulsions and solid-lipid nanoparticles), self-assembling structures and dendrimers as well as certain inorganic nano-platforms including metal (e.g. gold and silver) and silica-based nanostructures. These nanosystems are designed to provide an optimised formulation for oral or systemic administration, protect the entrapped payload from degradation, allow greater fraction of the dose to be available at the disease site and reduce the rapid clearance of the drug from the body.

Surface modification of these nanosystems can afford passive or active targeted delivery of the payload to the disease site in the body. Doxil® (doxorubicin in long-circulating liposomes) and Abraxane® (paclitaxel in nanoparticulate albumin) are two illustrative examples of nano-therapeutics approved in the US by the Food and Drug Administration. Other nano-platform based drug delivery systems, including micellar and dendrimer-based are undergoing clinical trials in the US and other parts of the world. Although there are several clear advantages in the use of nanosystems for targeted imaging and delivery applications, the number of clinically approved products in the US is fairly limited. There are several major constraints in

clinical translation of nanotechnologybased pharmaceutical products. Due to the inherent complexity of some of the nanosystems, large-scale manufacturing under Good Manufacturing Practices guidelines and appropriate quality control can be major factors limiting development efforts. In addition, the lack of inherent toxicity of the nanocarrier system has to be clearly shown in preclinical and clinical studies. Certain organic and inorganic nanomaterials, such as fullerenes, carbon nanotubes silica nanoparticles, and quantum dots have excellent properties, but their systemic distribution and clearance profiles, tissue and cellular interactions and associated toxicity, especially upon chronic in vivo administration, have not been clearly addressed.

Nanosystems for Cancer Therapy Over the past several years, our group has developed a variety of polymeric nanoparticles for tumour drug delivery all leading to an enhanced in vivo therapeutic efficacy. Some examples of these include the delivery of tamoxifen and paclitaxel in poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles in breast cancer model, the delivery of paclitaxel in PEO-modified PCL and PEO-modified poly(betaaminoester) (PbAE) nanoparticles in ovarian cancer and even the delivery of reporter (GFP and b-galactosidase encoding) and therapeutic genes (i.e. sFlt-1 or VEGF-R1 encoding) in murine and human tumor xenograft models. This versatility of polymer platforms allows for fine tuning of the drug delivery formulation to meet specific advantages. For example, the composition can be tuned to provide precise drug capture or release in response to environmental triggers. Alternatively, the composition can even be optimised to allow for inclusion of multi-functional properties, such as a combination of therapeutics, targeting and / or imaging modalities, all within one nanoparticle platform. Due to overwhelming evidence of multi-drug resistance development with single therapeutic approach, diseases such as cancer and certain infections are treated by using a “cocktail” therapeutic approach. Multi-functional nanosystems have been designed to encapsulate multiple therapeutic agents in a single delivery system for either sequential or simultaneous delivery. For instance, poly(ethylene glycol) (PEO)-modified PbAE / poly (D, L-lactice-co-glycolide) (PbAE / PLGA) blend nanoparticles have been utilised for sequential delivery of paclitaxel and

ceramide in multi-drug resistant (MDR) tumor models. In this system, paclitaxel is encapsulated in pH-sensitive PbAE matrix, while the apoptotic second messenger, ceramide, is encapsulated in the PLGA matrix. When administered to MDR solid tumor or upon cellular internalisation, paclitaxel is rapidly released from PbAE matrix due to drop in pH from 7.4 to less than 6.5, while ceramide is slowly released from the PLGA matrix by diffusion or degradation of the polymer matrix. Additionally, Sengupta, et al. have utilised a “nanocell” concept designed to deliver both anti-angiogenic (i.e. combretastatin A4) and cytotoxic (i.e. doxorubicin) drug in a system made with phospholipid-coated PLGA nanoparticles. The anti-angiogenic agent combretastatin A4 was entrapped in the phospholipids layer, while doxorubicin was conjugated with PLGA for slow release. Relative to all the controls, the nanocell deliver system provided the most enhanced efficacy with less toxicity in Lewis lung carcinoma and B16 melanoma murine tumor models. Acknowledgements Our research effort has received funding from the Alliance in Cancer Nanotechnology of the U.S. National Cancer Institute, National Institutes of Health. We also appreciate the collaborative opportunities with many academic and industrial scientists in the Boston area, and especially with Professor Robert Langer at MIT, Professor Vladimir Torchilin at Northeastern University, Dr Michael Seiden at Massachusetts General Hospital and Dr Takeshi Sano at Beth Israel Deaconess Medical Center.

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Multi-functional nanosystems for targeted delivery of imaging and therapeutic molecules Polymer (and/or PEG Chains) or Lipid Coating

PEG Modification

SPION, Gold Nanoparticle, Quantum Dot

multi-pronged synergistic therapy based on the biological activity of the drug and light-activated photosensitiser. Another promising avenue involves the use of combination chemo and thermal therapies. There is substantial data including animal and clinical studies taking advantage of complimentary interactions between hyperthermia, thermal ablation and intravenously administered liposomes containing doxorubicin. The road ahead

Nanocarrier, e.g., polymeric nanoparticle, liposome, micelle, nanoemulsion Anti-cancer therapeutic (e.g., small molecule, gene, siRNA, protein) Second anti-cancer therapeutic for combination drug therapy, or contrast imaging agent (e.g., SPION, gadolinium, fluorophore) Active targeting ligand

Figure 1

Multi-functional nanosystems

In addition to the first generation nanosystems with very useful properties, such as prolonged circulation in blood, passive or active target specificity and increased cell penetration, opportunity exists to develop multi-functional nanosystems for potentially combining various features for additive or synergistic effects (Figure 1). For instance, the use of nano-materials that respond to physiological stimuli such as pH, temperature, or redox

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status, can also allow for even greater selectivity in delivery to the target tissue, upon cellular internalisation, or even in specific subcellular organelle. Additionally, multi-functional nanosystems can take advantage of a single carrier platform to incorporate multiple therapeutic agents for simultaneous or sequential delivery, combining drugs with energy (e.g. heat, light and sound) for enhanced therapeutic effect and combining drug(s) with imaging agent to monitor the therapeutic efficacy in real time. Nanosystems that can encapsulate multiple therapeutic modalities, such as drugs and photosensitisers, could also provide an interesting

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Additionally, since the biodistribution of nano-encapsulated drug will be quite different from that of the free drug, a comprehensive pre-clinical dose escalating toxicity studies in multiple animal species of the final product as well as certain components is required by the regulatory agency. The associated complexities and higher cost of these studies has profound impact on clinical development. These concerns become even more pronounced with complex nanocarriers having multiple therapeutic payloads, and additional targeting and imaging functionalities.

There is an unprecedented opportunity for nanotechnology in biomedical and pharmaceutical applications. Through parallel advances in understanding molecular basis of diseases and developments in sophisticated nano-engineering strategies, there is significant optimism in development novel nanosystems for prevention, diagnosis, and treatment of diseases. In drug and gene delivery area, multi-functional nanosystems can fill the critical need to overcome adverse effects through target-specific delivery and intracellular localisation, opportunity to combine different therapeutic modalities, overcome multidrug resistance, and overall improve therapeutic outcomes. Through active collaborations between basic and applied scientists and engineers and clinical practitioners, we foresee a great promise for multi-functional nanosystems overcoming many of the challenges in contemporary molecular medicine. Full references are available on www.pharmafocusasia.com/magazine/

Mansoor M Amji, PhD, is Professor and Associate Chairman of the Pharmaceutical Sciences Department and Co-Director of the Nanomedicine Education and Research Consortium at Northeastern University, Boston, USA.

Padmaja Magadala is a doctoral student in the Pharmaceutical Sciences Department at Northeastern University, Boston, USA. She is a recipient of the National Cancer Institute /National Science Foundation-sponsored Interdisciplinary Graduate Education and Research Training Fellowship in Nanomedical Science and Technology.

CaseStudy

Drug Discovery

A decentralised multi-polar model Where the pharmaceutical industry is being unable to successfully translate core models of drug discovery from theory to practice, the two-pronged approach of Evolva Biotech in building a diversified and risk balanced compound pipeline stands as a case in overcoming the hurdles faced by the industry in the R&D paradigm. Panchapagesa Muthuswamy Murali Managing Director Shriram Raghavan Head, Compound Assessment, Evolva Biotech Private Limited, India

he pharmaceutical industry has major, long standing, problems with its R&D productivity. Its core model to discover and develop drugs has not changed in the last 30 years. The problem is that the pharmaceutical industry is actually not very innovative in translating invention and discovery from academics into commercial space. The failure of the pharmaceutical industry to develop a costeffective R&D paradigm is reducing the choice of approved drugs available to society. The only major innovation in this period (the use of recombinant technologies to make proteins in the 1970s) occurred outside the pharma industry and is only now becoming widely adopted by Big Pharma. Because of the lack of productivity, most companies are failing to launch new drugs at their desired rate and in recent years the Big Pharma has not delivered good returns. More companies are adopting “search and develop” strategies instead of intensifying research innovation and are thereby reducing research spending. However, there is still no evidence

Chemistry

Chromosomes From Them

Genome

Interesting Structure

Interesting Functions

Interesting Reactions

>1,000,000,000 Different Yeasts (CEYS) Each with 100-200, New “Chemistry Encoding” Genes

Unexplored Chemical Diversity

Figure 1

that pharma R&D productivity is improving. In some areas, this is leading to innovation from governments, charities and other bodies in how drug development is funded. For startup drug discovery set-ups, this means that public-private partnerships are

becoming increasingly important sources of funds / revenues. The conservatism of the pharmaceutical industry has also meant that it has failed to consider that the discipline of molecular genetics can impact not only large molecules but small molecules

w w w . p h a r m a f o c u s a s i a . c o m 39

CaseStudy

Use Assays to Select Individual CEYS each of the 1,000,000,000 CEYS individually screened

See What Compounds The Best Gene Combinations Make And what genes they use to make them

PRAR receptor driving GFP

14529

10896

Breed

Non-induced CEYS

7254 Induced CEYS

3632

2 3 4 5 6

101

102

103

104

Fluorescence level

as well. Small molecule drugs, account for approximately 90% of the industry revenues. Whilst this figure may come down, it is not likely to radically change in the near future, given the advantages of small molecules. They can penetrate cells, can be made orally available and they are also relatively cheap to manufacture. Instead the industry has remained focussed on synthetic organic chemistry as the mainstay of how compounds are made—an approach with major constraints, including throughputs (a good medicinal chemist can make on an average 10 compounds a month), creativity and chemical diversity (only a fraction of the natural products can be effectively synthesised in a scalable manner). In order to improve both the innovativeness of drugs, and research productivity it became obvious that a new approach was needed. This came about with Evolva’s Genetic Chmistry and decentralised multi-polar business model which overcomes some of the current limitations. Evolva’s decentralised multi-polar model

Evolva Biotech adopts a two-pronged approach to meet the demands of the industry and other stake-holders—in building a diversified and risk balanced compound pipeline. ‘Genetic Chemistry’ is a proprietary technology owned by the Swiss-based multinational drug discovery company.

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Low

High

Fitness vs. Assay

A technological standpoint of the cutting-edge genetic chemistry includes its directed evolution-based WatchMaker platform and networking with clusters of excellence (of public-private partnerships) to generate win-win collaborations. At an underlying level, all of the problems afflicting natural products derive from one issue—natural compounds are the result of natural selection, and natural selection does not optimise compounds to prepare human pharmaceuticals. Evolva’s technology platform attempts to overcome this hurdle and aims to convert yeast cells into ‘miniature’ drug factories. Evolva’s genetic chemistry begins by sourcing genes, that produce therapeutic small molecules from species with prior established activity in a chosen disease area and cloning them into baker’s yeast after stitching them together. The idea is to confer the power of nature’s combinatorial chemistry capabilities onto these yeast cells grown under controlled conditions. They often have structures Evolva is a Swiss-based drug delivery company whose WatchMaker technology relies on assembling genes and pathways in the development of small molecules to drug targets. Evolva established an India operation less than two years ago with the support of India’s CSIR, IICT and various investors including APIDCVCL pathways

HO CH3

O AcO

O CH2OCCH3

O H

N H

0 100

CO2H

Generation

R N 14

CH3

Founder

Number of CEYS Counts

Breed From Best CEYS

O OH

CH3

Figure 2

and properties that are unavailable to even the best synthetic chemists. Yeasts that get “transformed” with the genes to produce combinations of small molecules are termed as “Compound Enhanced” or simply called ‘CEY’. These CEYs can now produce combinations of natural small molecules (Figure 1). If this yeast is transformed again with the genes relevant to a biological target of interest, then the single yeast can produce small molecules against the biological target upon a trigger. Similar to what a medicinal chemist does in a laboratory. The “successful” yeasts are selected through a high-throughput flow cytometry system, at about 10,000 cells per second (Figure 2). This is an example of an innovative technology that allows access to a diverse chemical space (Figure 3). Having the potential to yield New Chemical Entities (NCE) for a chosen target (in the disease area) that are likely to be ‘safe’ (on the simple assumption that the yeast has survived) and with a potential IP. Known molecules / drugs with “poor” drug-like characteristics can also be passed through this system to improve their drug qualities like solubility and safety. This opens new avenues of in-licensing molecules for the system and out-licensing molecules from the system. Discovering a new drug is all about maximising the probability of success and having an effective risk mitigation

R ese a rch & D eve l o pment

Diversity of CEYs a-Amyrin

Ent-Kaurene Retinol

Resveratrol Isoliquiritigenin Naringenin

Capsidiol 1

e nin ala yl-

L-Alanine D-Glutamine

UDP -Glc

NAc

Dehy

Oleat

ro l

Methylsalicylate

6 1

Jasmonate 4

6 Triboa

Arachidonate

ste

Ind

Berberine

ero

lyc

g le-

l-P

Acyl CoA’s

ate

ikim ro-sh

in Tyros

Norcoclaurine

Capsaicin

/ yl se P rne l-P Fa teny n pe

iso

MurNAc peptides

Matairesinol

Epoxy-squalene

Pregnenolone

Aloesone Erythronolide B

Compactin

# = Number of steps away from yeast

and management strategy. Since genetic chemistry depends on ‘biodiversity’, the Indian site can play a decisive role in this region. India has a traditional chemistry strength which translates to having good chemists (analytical) to assist with the novel scaffolds that come out of the platform technology. Evolva’s model has thus been created around talent pooling across various related domains and sites thereby creating a seamless work flow. This again is completely a different approach to the one site approach followed by many companies.

Figure 3

Translating a technology platform into drugs in clinic requires not just financial support but a dedicated and quality team with sufficient domain expertise and many ‘win-win’ partnerships with an objective ‘ecosystem’ around it. “Seed-funding” Venture Capitalists (VC) play an important role in such start-ups. Evolva has been funded by Novartis, Astellas and many others in Europe and it also required funding and collaborative initiatives to establish the roots in India. However in India, traditionally a promoter-driven industrial scene is predominant that

doesn’t have the appetite for high risk ventures like discovering new drugs; also, not many early stage venture capitalists were present in this area. This was the scene until recently. Andhra Pradesh Industrial Development Corporation’s (APIDC) venture arm, Venture East came up with India’s first dedicated biotechnology venture fund corpus which was created with the main focus on early stage companies. One of the key benefits that these early stage VCs confer upon their portfolio companies is the high level of networking and important business

w w w . p h a r m a f o c u s a s i a . c o m 41

CaseStudy

Accessing natural products library

The first approach is accessing natural product libraries through collaborations with various academic institutions within India and abroad subject to contract terms. These libraries with vast chemical diversity space are a valuable resource for screening on high content assays. While those molecules with prior in vitro activity would be subject to secondary confirmatory ex vivo tests, other molecules with unknown activity (in the disease areas of interest to the company) would be subjected

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to primary ex vivo assays. The thirdparty institutions from whom sourcing was done, is kept informed about movement of molecules at every stage through regular communication channels. A few hundred molecules with expected activity profile are progressed to the next stage. Rational drug design

The second approach is rational drug design. In each of the chosen disease areas, a validated drug target with crystal structure availability is chosen for the in silico modelling approaches. Several thousand diverse set of compounds from commercially available natural product libraries and catalogues can be chosen and screened against the targets in silico—by a carefully chosen bioinformatics collaborator. India’s established IT skills and bioinformatics prowess presents a variety of options of collaborating either with academia or industry or both. Top scoring molecules are then purchased and subject to screenings. If they are found to perform the desired activity, they can be passed onto the next stage. Public-private partnerships and in-licensing models

The other two approaches of Evolva include public-private partnerships and conventional in-licensing models. Networking with clusters of excellence—both within and outside India considered a key to future success of drug discovery start-ups. Also bridging industry-academia gap is an important component to increase odds of success—as witnessed by activities in the discovery pipeline. Most of the premier

A uthor

contacts in that region. It was just natural that Evolva and Venture East came together in India. Evolva established operations inside the Indian Institute of Chemical Technology (IICT), a premier Council of Scientific and Industrial Research (CSIR) institution of the Government of India. Through this collaboration, Evolva could access the country’s premier chemistry resources for analoging, scale up and, synthesis while IICT benefits from the biology expertise of Evolva. This association led to further collaborations. Evolva has forged a nation-wide collaboration with National Chemical Laboratory (NCL) Pune, Indian Institute of Chemical Biology (IICB) and other CSIR institutes to harness the wealth of chemistry and biology. Though Evolva’s genetic chemistry promises to deliver innovative small molecules, yet other avenues for sourcing small molecules through a fast tracking concept was also needed to hedge risks. The multi-polar model of Evolva adopts four diverse routes to source and acquire natural small molecules for the discovery pipeline in a cost-effective mode utilising the collaborations. Molecules sourced from each of the approaches would enter various stages of drug discovery cycle directly. Each approach requires a collaborative partner to succeed and primarily designed to avoid “late-stage attrition” or to encourage “early failure” of drug candidates.

institutions of the Government of India have research programmes but, they are not going all the way to drug discovery. In most of the cases the research culminates into a preliminary pre-clinical work. Evolva has successfully managed several collaborations with leading CSIR research institutions of the Government with a very clear road map of progressing on these compounds with appropriate milestones. The costs for development are shared under a mutual agreement and in-licensed wherever possible. In a few cases, where there is more conclusive pre-clinical evidence, Evolva tries to have an outright in-incensing deal early in the discovery stage. Evolva also leverages the India advantage in the development phase where there are various Contract Research Organisations (CROs) in each segment in animal pharmacokinetic and efficacy studies, GMP scale-up operations, GLP compliant animal trials and even all phases of clinical trials that can be conducted by the Contract Research and Manufacturing Services (CRAMS) companies. Indian CRAMS not only offer cost advantages but also the value additions which are again key to maximising chances of success. In short, Evolva has used a very pragmatic, aggressive and international business model to bring out drugs with drug development costs possibly below the sub-billion dollar level. This trend setting decentralised model is rather unique for a small company. Nevertheless, this is likely to be “different” business model which leverages the strength of cost arbitrage and value of human capital from across multiple sites.

P M Murali is PhD in Microbiology from Madurai University having over 20 years of experience in Pharmaceutical/FMCG R&D. He has remained the Founder and Director of the Dalmia Centre for Research and Development for 16 years. Prior to that he has worked as an Indo-US Researcher at the Battelle-Kettering Research Centre, Ohio. Shriram Raghavan is the Head of Compound Development at the Evolva Biotech. He specializes in Bio-informatics. Prior to this he worked for ReaMatrix in Bangalore. A post graduate from Himachal Pradesh University in India, Shriram has overseas experience as well.

R ese a rch & D eve l o pment

VaccinesSpecial

The Asian Vaccine Industry Opportunities and challenges

Pele Choi-Sing Chong, Investigator and Director, Vaccine Research & Development Center, National Health Research Institutes, Taiwan

Controlling Infectious Diseases Evaluation of vaccines

Yoshinobu Horiuchi, Head, Laboratory of Pertussis and Endotoxin Control, Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Japan

Developing Cancer Vaccines Using tumour-associated peptides

Harpreet Singh, Managing Director and Chief Scientific Officer Toni Weinschenk, Head of Discovery, immatics biotechnologies GmbH, Germany

w w w . p h a r m a f o c u s a s i a . c o m 43

The Asian Vaccine Industry Opportunities and challenges

A roadmap for Asian vaccine research and development programmes can lead to a strong regional vaccine industry, self-sufficient healthcare policy and the possibility of economic growth through the manufacturing of valuable biological products.

Pele Choi-Sing Chong, Investigator and Director, Vaccine Research & Development Center, National Health Research Institutes, Taiwan

sian governments are looking to Biotechnology to accelerate their food supplies and healthcare improvement, and some are even thinking about the economic growth through manufacturing valuable biological products. Companies and government agencies in Asia have been closing the gaps in regulatory compliance in manufacturing biologics in the last few years. However, countries such as China, Korea and India still lag behind in vaccine R&D and production techniques due to a lack of financial support and technology transfers from foreign companies. Emerging infectious diseases (pandemic avian influenza and global shortage of flu vaccines supply) have raised new challenges. They have changed the landscape of the vaccine industry. The processes involved in research to product launch normally take 7 to 13 years to go through multi-stage R&D and still have a low success rate. Today, novel technologies are being used and investigated for new vaccine developments. Background

As Nelson Mandela once wrote, â&#x20AC;&#x153;life or death for a young child too often depends on whether he is born in a country where

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the vaccines are available or notâ&#x20AC;?, this may be regarded as a political description of the current global healthcare problems. Vaccine manufacturing capability has been used as an index to profile whether a country is developed or not. Despite having the economic wealth, Asian governments now recognise that they do not have access to sufficient vaccine supplies, leaving their populations at high risk. The Taiwanese government is self-financing a vaccine manufacturing programme and is looking for international collaborations to have sufficient vaccine supplies in the future.

As more shots were given to infants, multivalent combination vaccines were invented and have now become the trend. In addition, most global vaccine companies are now embarking on vaccine R&D to position themselves as the target and portfolio-specific manufacturers as shown in Figure 1. Global vaccine markets and current manufacturing technology

The current global vaccine market is growing rapidly, having seen doubledigit growth for the last 10 years and was worth US$ 10 billion in 2007. Over 95 percent of the current global vaccine supply is controlled by five international vaccine manufacturers: Sanofi Pasteur, GlaxoSmithKline,

Combine Vaccines for the 21st century Infant Vaccines

Adolescent Vaccines

Adult Vaccines

Targetted Combination Vaccines

RSV A and B PIV 1, 2, 3 Pneumococci Rotavirus Otitis Media Meningo A, B, C Tuberculosis

CWV Epstein Barr Gonococci Hepatitis C Propionibact.acne Papilloma Virus HIV Herpes simplex Cytomegalovirus C. trachomatis.

Improved Influenza Penumococci Toxigenic E. Coli H. pylori Nosocomial infections C. Pneumoniae

Bacteria Parasites Cholera Malaria Shigella Schistosomi ETEC Leishmania S. paratyphi

Issues: cost, compatibility, formulation

Viruses Dengue 1, 2, 3, 4 JEV Enterovirus 71 Tick-borne encephalitis. Hantan Virus Figure 1

R ese a rch & D eve l o pment

Merck, Wyeth and Novartis. These companies will continue to dominate vaccine markets since they not only buy up small vaccine R&D companies but are also expanding their manufacturing capacity by building more facilities globally. In the last 25 years, vaccine branches within big pharmaceutical companies were either closed or sold to other vaccine manufacturers. Specific industrial challenges, such as complexity of the vaccine development and clinical trials; sustained R&D investment from annual revenue; balancing high-risk projects in product portfolio; production cost and yields of immunogens (cost driver); large investments in upgrading and building new manufacturing facilities and potential liability issues (IP, Regulatory and Safety issues) had prevented small and middle-size vaccine companies to compete with big international pharmaceutical companies. Instead, they were vulnerable as targets for acquisitions. In addition, manufacturing technologies require specialists and the entry fee for vaccine manufacturing is also extremely high. For example, building a cGMP vaccine plant for 20 million doses of flu vaccine could cost between US$ 60 to 100

million. The long-term investment and high risk of poor return keep most venture capitalists at bay. Anti-vaccination movement in the past also did not help the vaccine industry to grow. All of the above issues describe well why the vaccine industry did not develop in Asia. Although the vaccine industry has many issues and hurdles mentioned above, the desire for disease control and eradication, the long-term healthcare cost savings, the prevention of economic loss due to emerging pandemic diseases and the national security reasons against bioterrorism have changed the governments’ vaccine supply policies. The increasing middle class population in Asia demands better living quality. Also, the success of anti-cancer immunotherapeutic drugs (monoclonal antibodies), the potential application of vaccine against allergy and autoimmune diseases and the constant market values have totally revitalised the landscape of vaccine industry. However, the issues of intellectual property and the availability of low-cost vaccines are the last hurdles in fulfilling Mandela’s dream. Professor R Klausner recently proposed new approaches to solve the global healthcare problems. They are:

• Two-tier pricing policy is necessary to help global shortage of biomedical supply • Private enterprises must link to public interests with governments assisting in price adjustment • Funding from philanthropy are not designed for biomedical research, but should be seen as seed money for third-world medical purchases As mentioned above, vaccines in the past have been viewed as commodities with low rewards, but Hepatitis B vaccine and anti-cancer immunotherapeutics have changed the whole vaccine market analysis. The initial market price for Hepatitis B vaccine was US$ 200 for three doses. There are 10 new vaccines licensed in the past few years and the vaccine market has grown from less than US$ 600 million in 1985 to US$ 10 billion in 2007. As new vaccines come up through technologies, what are the new proven manufacturing technologies for vaccine and immunotherapeutics industry? Most old vaccines are attenuated and could be non-pathogenic strains of bacteria (BCG and S. typhi) or viruses (polio, influenza, mump, measles, and rubella). New vaccines like varicella and rotavirus which were introduced in

w w w . p h a r m a f o c u s a s i a . c o m 45

the market have brought about higher profits for companies like Merck. The capsules of the bacteria have been used alone (Meningococcal A, C, Y, W or 23 serotypes of pneumococcal) or conjugated to a carrier protein (Hib, PCV-23 and tetravalent of meningococcal) as vaccines against meningitis and pneumococcal infections. The conjugated vaccines were introduced recently and are very expensive (US$ 300 for three doses). Currently, there are several subunit vaccines (Acellular pertussis, diphtheria and tetanus toxoid, hepatitis B and HPV). A peptide-based vaccine is currently licensed as an animal vaccine for Foot-Mouth Diseases Virus (FMDV) in China. Although live microbial either lives virus or bacteria have been investigated as vectors for vaccine development, so far none of them is successful. There are many reasons why these novel technologies have not been successful in vaccine development. Risk of oncogenicity and poor immunogenicity in humans are the most important factors that need a lot of research. Edible vaccines have been proposed to be the next wave of human vaccines for the developing countries. However, beside the poor immunogenicity of edible vaccines in humans, the regulatory issues will most likely prevent any edible vaccines from being licensed and used in humans since the stability of edible vaccines will not be longer than two months, and the conditions for growth of plants can hardly be validated. In the bioprocesses for manufacturing biologics, the processes for producing inactivated bacterial vaccines have not been changed. However, the manufacturing processes for attenuated or inactivated viral vaccines have significantly improved since the introduction of polio vaccines. The cell-culture has now moved from the egg-based to the roller–bottles technology and now to 6000-litre bioreactors with serumfree media that is preferable due to

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New Novel Technologies for Vaccine Development Protective Antigen Discovery - Bioinformatic analysis/ Reversed Genetic Immunisation - Receptor-Binding Domains Discovery Novel CTL Epitopes Discovery and Vaccines - Biochemical Micro-analysis (Affinity Chromatography/LC/MS/MS) - Discovery of CTL Epitopes Using MHC-Binding Motifs Predictive Algorithms - Epitope Discovery using Genomic Sequences - CTL epitopes based Vaccines Plasmid-based Chimeric Reassortant live Vaccines Virus-Like Particles (VLP) In vitro, Antigen and Adjuvant Screening HLA-tetramers or dimers Development Transgenic mouse models Prime/Boost mixed modality of Immunisations Microencapsulation for controlled-release Figure 2

Prion potential contamination. New technologies like “Wave” developed by Wave Biotechnology (US) or “BelloCell” by CESCO Bioengineering Co (Taiwan) provide easy start-up and scale-up disposable cell culture technology. The other method to increase cell growth is by using micro-carrier beads that give cells more growing areas. Increasing cell growth by tenfold is still possible. To improve virus yield, several technologies have been recently developed. The most promising one is to transfect more viral receptor genes into the host cell, so that the virus infection increases with lower MOI. The other method is to remove the genes inhibiting viral replication within the host cell by gene-lockout. Reverse-Genetic (RG) technology has also been applied to improve virus yield by inserting specific protease cleavage site or temperature-sensitive growth mutants. Serum-free media has given cell culture technology a big boost, but the downstream purification processes are still critical for the whole production cost. Zonal centrifugation with sucrose gradient is the best way to purify virus from the culture media. The additional diafiltration and concentration steps are always helpful. All these improvements in virus

production have allowed the traditional influenza vaccine production method to overcome the potential shortage of eggs during the pandemic influenza outbreak by switching to cell-culturebased vaccine production. Novel technology for vaccine & immunotherapeutics development

Now most big pharmaceutical companies have set out criteria for their R&D projects. The projects are now evaluated in three areas: the statement of interest, project prioritisation ranking and return of investment analysis. The Statement of Interest will show the market needs, global or regional. The product information such as the disease and epidemiology is known; scientific rationale is fully supported by animal model, easy phase III end-point evaluation, cost-effective with optimal profile; favourable in the SWOT analysis; market opportunity and consistent with company portfolio and foresee no potential hurdles. The project ranking for the feasibility and success is high. For the scientific criteria of a vaccine candidate, safety, efficacy and cost effectiveness are the most important factors. The vaccine candidate should have safety profile and easy compliance to cGMP. Significant advancements in molecular biology, immunology, protein engineering, upstream and downstream bioprocesses engineering and microbiology have brought new tools and concepts to vaccinology and immunotherapeutics development. The most important novel and new emerging technologies for vaccine development are summarised in Figure 2. The first step for vaccine development is identifying the protective antigens. Bioinformatics and reverse vaccinology (DNA immunisation) have increased the potential to identify protective antigens and active pharmaceutical ingredients (API) from genomic sequences of a bacterium or virus. Receptor-binding domain

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Vaccines R&D in Asia

Traditional vaccines and Japanese R&D are not considered here Country

Company

China China

China National Biotech Group (CNBG) Contai

China

Biotech

China

ChengDa Biotech

Taiwan

UBIAsia

Taiwan

Academia Sinica

Singapore

Singvax

Singapore

Dr. Tsai of NSU

R&D Status Live-attenuated vaccines Licensed in (SA14-14-2 strain in BHK cell) China HBV immunotherapeutic vaccine, recombinant Exploratory rotavirus vaccine, liposome adjuvant Rabie vaccine (Vero Cell), chromatographic Licensed in purified seasonal flu vaccine China Microcarrier JE vaccine Phase 2 (Beijing strain) Peptides based vaccine for Alzeimer, HIV, Pre-clinical allergy and prostrate cancer DNA Vaccine against HIV and H5N1, Pre-clinical CD1 synthetic adjuvant Mucosal JE vaccine and EV71 enterovirus Pre-clinical vaccine Dust-mice based allergy DNA vaccine Exploratory

Korea

IVI

H5N1 flue vaccine

Exploratory

India

Indian Immunological Limited (IIL) Biological E

Hib conjugate, acellular pertussis, cell-based JE vaccine JE vaccine (SA14-14-2 in Vero)

Exploratory

India

Disease Targets

Source: 2007 World Vaccine Congress Asia, Singapore

discovery using protein engineering also helps identify authentic receptor and functional domains of either the viral or bacterial surface proteins. In turn this result will validate the protective antigens. By isolating critical and functional cytotoxic T lymphocytes (CTL) using advanced chromatography and mass spectroscopy technology or computing predictive algorithms, the protective antigens can be identified. Now by using fresh human blood the in vitro B-cell immune response screening method can be performed to evaluate the potency of the protective antigens. However, purifying the protective antigens from a natural source or production by recombinant technology is still the best way to validate the potency of the vaccine candidates in animal models (transgenic mouse with human HLA genes or non-human primates). Not all antigens are immunogenic by themselves. Some of them require adjuvant or special formulations. Again by using fresh human blood, in vitro screening of the potency of the adju-

Phase 3 Table 1

vant candidates can be performed by analysing the cytokine profiles of T-cell immune responses. Since all vaccine candidates can not be evaluated in the Phase I and II clinical trials, transgenic mouse and tetramer technology are used as surrogate markers. Sometimes the adjuvant may not give the right immune responses such as mucosal or specific effectors. Vaccine vectors or carriers are created for these types of immunisation route and schedules. More and more literature has been documented to demonstrate prime/boost mixed modality of immunisation schedules which give the best immune responses in animal model and human clinical trials. A few years ago, during Phase 1 clinical trials conducted and sponsored by WHO, a single dose of microencapsulated and controlled release tetanus toxoid showed long-term immune responses compared to those obtained from multiple injections of current tetanus toxoid vaccine. Therefore, microencapsulated and controlled release vaccine technology will certainly change the landscape of vaccinology.

The other technology that currently has significantly changed the influenza vaccine R&D and annual tri-valent flu vaccine production is the reverse genetics. Using plasmids and reassortant method, the right vaccine strain can be selected and designed for production. In fact, the nonpathogenic avian flu vaccine strains are created by 8 plasmids reassortant technology by WHO reference laboratories. Bioprocesses validations and regulatory issues

The production of vaccines and immunotherapeutics are highly regulated and need to comply with cGMP guidelines. Biosafety is highly emphasized in manufacturing vaccines since there are huge potential health hazards involved in the bioprocesses. Therefore, the facilities are normally designed to protect the workers as well as prevent product contamination. The man-flow and material-flow are clearly outlined in each room. With the new guidelines from the Pharmaceutical Inspection Cooperation Scheme (PIC/S), everything involved with or contacted with the products need full validation. Starting from the manufacturing facility design qualification (DQ) to facility installation qualification (IQ), operation qualification (OQ) and performance qualification (PQ) are also required as the part of facility validation. In addition to the facility, Quality Assurance is particularly important and the biologics manufacturing must strictly follow carefully established and validated methods of preparation and procedures (SOP). Therefore, cGMP quality management training and biosafety are very important. The consistency of manufacturing vaccine products is very important. The production processes validation is getting complex and needs a master plan and validation schedule. Some of the new bioprocesses technologies look promising at the R&D level, but are never used in production due to the regulatory and validation issues.

w w w . p h a r m a f o c u s a s i a . c o m 47

biotechnology companies and academics do not have sufficient budget for Phase I Japan has been very successful and trials, government vaccine centres should currently leads the Asian vaccine collaborate with them, playing the tranindustry. On the other hand without sition roles by using the pilot plants for immediate government funding and cGMP-grade clinical materials producsupport, other Asian countries may tion, providing cGMP quality managenot be able to compete globally in ment training and initiating Phase I and the near future. Vaccine industries in II clinical trials with Investigational New China, India and elsewhere in Asia are Drug (IND) dossier submissions. In this catching up by implementing cGMP way, the government vaccine centres quality management, manufacturing take the risk for conducting the Phase I and supplying traditional vaccines to and II human clinical trials. If the their local markets. They do not have vaccines successfully go through the enough funding proof of product in and technologies human trials, private to truly compete Asian vaccine globally in novel manufacturers can As an incentive to local vaccine research invest to license vaccine industry, governments the vaccines from and development. The vaccine R&D can provide long-term vaccine the government in Asia is still in its vaccine centres, purchasing contract policies. infancy. As shown build manufacturin Table 1, two ing plants, take unique features of the proven vaccine vaccine R&D in candidates to Asia are identified. Two vaccines needed market by conducting Phase III clinical regionally, enterovirus 71 (EV71) and trials and develop global marketing stratJapan encephalitis virus (JEV) seem egies. As an incentive to local vaccine to be the priority targets for vaccine industry, governments can provide longdevelopment. High risk vaccine R&D term vaccine purchasing contract polisuch as vaccines against HIV, dengue, cies. In this way, all parties (academics, allergy and meningococcal group B, is small biotechnology company, governalso being embarked on. ment vaccine center and vaccine manuTo develop a successful vaccine facturers) will be the winners, sharing the business in Asia, all parties (Academic, profits and securing the national vaccine Government funded vaccine R&D supply chains. centres with cGMP pilot plants and Certainly if Asian countries can private industries) need to work together build strong vaccine industry, then the with risk/profit sharing in mind. national healthcare industry will be Academic and government funded self-sufficient, and the country would vaccine centres play the upstream roles: be able to think about economic antigens discovery and proof of concept growth through manufacturing valuable in animal model. Since most small biological products.

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Opportunity and challenges for Asian countries

Pele Choi-Sing Chong earned his PhD from University of Alberta, Canada in 1983 and spent the next 15 years in human vaccine research and development at Aventis Pasteur. In 2003, he joined National Health Research Institutes (NHRI) to set up Vaccine Center for Research and Development. Over the course of his career, he has also authored over 80 original research articles and holds over 40 patent grants.

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BOOK Shelf

Statistical Issues in Drug Development (Statistics in Practice) 2nd Edition

Author: Stephen Senn Year of Publication: 2008 Pages: 524 Published by: Wiley-Interscience ISBN-10: 0470018771 Description: Statistical Issues in Drug Development presents an essential and thought provoking guide to the statistical issues and controversies involved in drug development. This second edition has been updated to include: • Comprehensive coverage of the design and interpretation of clinical trials. • Expanded sections on missing data, equivalence, meta-analysis and dose finding. • An examination of both Bayesian and frequentist methods. • A new chapter on pharmacogenomics and expanded coverage of pharmaco epidemiology and pharmaco economics. • Coverage of the ICH guidelines, in particular ICH E9, Statistical Principles for Clinical Trials. The accessible and wide-ranging coverage make it essential reading for both statisticians and non-statisticians working in the pharmaceutical industry, regulatory bodies and medical research institutes. For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Controlling Infectious Diseases Evaluation of vaccines

Although vaccine evaluation differs in various aspects from that for therapeutic drugs, many procedures specific for therapeutic drugs have been applied to vaccine evaluation.

I Yoshinobu Horiuchi Head, Laboratory of Pertussis and Endotoxin Control, Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Japan

n the recent years, many vaccine developments have focussed on therapeutic vaccines. However, prophylactic vaccines for infectious diseases continue to be of major importance. The infectious diseases can impact the public health and the socioeconomy. People are not aware of the threat of traditional diseases such as whooping cough (pertussis) or diphtheria because of the high vaccination coverage.

Japan experienced a recurrence of whooping cough when acceptance of Diphtheria (D) Tetanus (T) Pertussis (P) combined vaccine (DTP) lowered after temporary suspension of the vaccination due to two post-vaccination mortality cases in mid-1970s. Pertussis incidence and related mortality increased from around 300 and 0 to over 13,000 and 40, respectively, by 1979.

w w w . p h a r m a f o c u s a s i a . c o m 49

Efficient control of population immunity and disease No one can be aware when and how endemics begin. Once an endemic is suspected, health officials are asked to take urgent action to prevent it. If the endemic is limited to a certain generation, information on age bracket immune state would help urgent investigation. Information on immune state, such as proportions of those having protective immunity and those being susceptible, of each generation would be useful for controlling population immune state and infection. D, T and P antibody levels of Japanese population of 0 to over 60 years of age are surveyed every 5 years, in which data on approximately 75 subjects each for every 5-year age group are collected nationwide and analysed. Probit-transformed inverse cumulative rate of antibody positivity for several cut-off antibody levels should be a straight linear for normally distributed antibody titers as seen in Figure 1-a for diphtheria and Figure 1-b for tetanus. The straight lines fitted to the

probit-transformed positive rates for each of the 5-year age groups could be used for estimating mean antibody titer and proportions of below protective level for each age group as shown in Table 1 for diphtheria and Table 2 for tetanus. Such information is essential for immunisation-related urgent action at the time of an endemic. This could easily be obtained by a small scaled surveillance using the normal distribution model. All DTaPs from these manufacturers comply with uniform regulations on lower limit for potency and upper limit for antigen content and are, therefore rather homogeneous. Distribution of antibody titers of the population so far immunised with such homogeneous vaccine lots seemed to be log-normal, which is essential to survey according to the normal distribution model. In case of age-limited endemic, an urgent identification of those necessary to be immunised would become feasible based on such information. aD antibody

Anti diphtheria 7.0

Age group

Averavge (IU)

100

0-4

0.4382

5.5

640.9

5-9

0.2489

3.3

55.4

10 - 14

0.1928

6.5

79.8

15 - 19

0.1740

3.7

24.5

20 - 24

0.3418

1.8

61.1

25 - 29

0.0476

17.9

9.0

30 - 34

0.0974

11.0

29.9

35 - 39

0.1081

11.3

46.9

40 - 44

0.0890

16.6

94.5

45 - 49

0.0064

58.8

2.8

50 - 54

0.0084

53.1

9.7

55 - 59 > 60

0.0189

39.1

23.4

0.0198

35.1

4.8

6.0 5.5 5.0

4.5 4.0

Probability density of antibody titer

Probit transformed inverse-cumulative positive rate

6.5

120

3.5 20

3.0 2.5 0.01

0.1

aD(U/ml)

Rate (%) > 0.01 IU

Figure 1a

Table 1

aT antibody

Anti tetanus

7.0

120

Age group

Mean (IU)

100

0-4

0.4618

2.3

170.7

5-9

0.6343

0.7

122.1

10 - 14

0.5811

1.0

127.7

15 - 19

0.5476

0.3

49.3

20 - 24

0.7159

0.2

72.8

25 - 29

0.2284

8.5

263.3

30 - 34

0.2265

8.2

230.9

35 - 39

0.0086

51.9

173.8

40 - 44

0.0018

73.9

6.6

45 - 49

0.0011

76.9

10.6

50 - 54

0.0014

73.5

20.0

55 - 59 > 60

0.0005

86.1

2.2

< 0.0001

86.1

139.7

6.5 80

6.0 5.5

5.0 40

4.5 4.0

3.5 3.0

0 0.01

0.1

aT(U/mL)

Figure 1b

50 P h a r m a F o c u s A si A

Probability density of antibody titer

7.5 Probit transformed inverse-cumulative positive rate

Max. IU/ 100,000

* Limit level for protection

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Rate (%) Max. titer < 0.01 IU* in 100,000

Table 2

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How the whooping cough re-emerged

How do vaccinations protect us against diseases? A vaccine like Live Oral Polio works in the same way as natural immunity would work once a patient is infected. Many vaccines are given parenterally (intra-muscularly or subcutaneously) to induce mainly humoral IgG and, in some cases, cellular immune responses. Infection in many cases begins with the bacteria or viruses attaching themselves to the mucosal surface of the respiratory tract, digestive tract or genitalium to multiply to further transfer or secrete virulence factors into the blood stream to affect target organs. Mechanisms of pathogenicity and protection of vaccination would differ for different pathogens. The causative agent of whooping cough is Bordetella pertussis, which produces various virulence factors or toxins, but the etiology of the disease and protection mechanism of vaccination have not been fully understood. Pertussis vaccine is also given parenterally and is reported to induce humoral IgG and cellular immune responses. But the vaccine thus administered is generally not adequate for induction of secretory IgA which is crucial for the local immunity to prevent attachment of the bacteria onto the surface of the respiratory

tract. Therefore, the current vaccination might not be preventing pertussis infection but would be protecting vaccinees by the cellular and humoral immunities from symptomatic disease. This means that the bacteria may not have been eliminated but likely to be multiplying, instead, on the surface of the respiratory tract of the vaccinated individuals and may be circulating in the population infecting those who are not vaccinated or with waned immunity. Therefore, it is important to keep the population sufficiently immunised for controlling the disease. Efficacy evaluation

Vaccines should be definitely efficacious so that vaccinees could be protected. After implementing an effective vaccine, the number of incidents should decrease to the level at which a meaningful clinical efficacy trial is not feasible. This means evaluating efficacy based only on clinical study and developing a new product and modifying production process of existing products would become impossible. It is essential, therefore, to develop a reliable laboratory model for efficacy evaluation. Such model should be able to evaluate the vaccine quality to induce functional protective immunity. A model for evaluating immunogenicity of vaccine antigens to induce

Rate of clinical febrile response to endotoxin in practical vaccine lots 3.4

r=0.749 (p=0.0021) Y=0.509X+2.629

3.2 3.0 2.8 2.6 1

EU/ml

Endotoxin content of DTaP lots distributed log-normally. When endotoxin content increased, number of the susceptible and probability of showing febrile reaction increase. However, rates of febrile response even to the lots with equivalent endotoxin content significantly varied. This was because vaccinees of each lot were not randomly selected and probability of injecting to those sensitive to the level of endotoxin varied among the groups. Therefore, investigating lots showed a higher rate of adverse events (febrile response) would give no useful information. It is necessary, instead, to analyze the correlation of AEFI probability and a toxicity parameter as shown here. Figure 2

Severe adverse events after DTP immunisation Year

Vaccine Encephalopathy Death Shock

to Death

1952-59

1955-72

3 6

1966-74 DPT

Total

Approximately two morality cases and three encephalopathy (per Ca. 5 million doses) a year by wP during 1952 and 1974. Table 3

Severe adverse events after DTaP immunisation 1995 DTaP

1996 DTaP

1997 DTaP

1998 DTaP

1999 DTaP

2000 DTaP

Sum DTaP

Total

196

270

167

198

225

1113

25,760

Local

124

108

525

54,612

Convulsion

924,873

Japan

Allergic reaction Anaphylaxy

Neuropathy Encephalopathy

Immunized

2,867,107

1,592,837

28,671,071

1 1

Death

(1) 1*

4,793,117

4,880,134

1 4,800,174

Severe adverse events significantly decreased for aP comparing to wP # Viral; * Sleep positioning

4,800,894

Frequency (1 in)

4,645,598

4,751,154

28,671,071 Table 4

w w w . p h a r m a f o c u s a s i a . c o m 51

Theoretical bases for vaccine adverse events Suceptible population

120

Vaccinees with AEFI Normal Vaccinees

100

Toxicity of lots

Vaccine lots

Improved vaccine lots

Frequency

-7

-6

-5

-4

-3 -2 Toxicity

Population distribution of sensitivity toToxicity

-1

Usually, a vaccine lot can not cover whole target population. AEFI may take place only when injected to extremely sensitive individuals. However, even a lot with stronger toxicity, so far as not given to such sensitive individuals, no AEFI would occur. When toxicity level became low enough to have no susceptible individuals, no AEFI takes place. Figure 3

antibodies that can bind to antigen would not always be adequate without ensuring protective function of the induced immunity based on a reliable laboratory protection model. Some of the well known models are the potency test for pertussis vaccine in mice and that for tetanus vaccine in guinea pigs. Evaluation of vaccine safety Severe adverse events

Some general confusion might exist in interpreting the results of clinical safety trials. It is easy to find the expression â&#x20AC;&#x153;vaccine with proven safety in a clinical trialâ&#x20AC;? in formal documents or guidelines. But the important question is, can vaccine safety be really proven in a clinical trial? A clinical trial can only ensure applicability of a vaccine.

The important question is, can vaccine The current safety evaluation of vaccines is similar to that of safety be really proven in a clinical trial? therapeutic drugs being based on clinical evaluation in which a couple of lots are evaluated in subjects enrolled in a way to eliminate Results of a clinical trial can not be used bias as far as possible. While therapeutic for denying causal relationship between drugs target a limited number of patients, adverse events and vaccination because, vaccines target the whole healthy popualthough not randomly selected, routine lation and should be definitely safe. vaccination is for a much bigger number Once a vaccine loses its public reliance of subjects compared to that of a clinion safety, people may avoid the vaccine cal trial and would be more likely to which could lead them to more severe involve those who are highly sensitive to sufferings from the infection. vaccine toxicity than in a clinical trial.

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To discuss about the adverse events in a vaccination, we need to take the lotto-lot variation and sensitivity variation of individuals to vaccine toxicities into consideration. It is generally not feasible to examine peopleâ&#x20AC;&#x2122;s sensitivity to toxicity of vaccines due to ethical reasons. However, there could be an exceptional case that creates no ethical problem. In the late 1970s to early 1980s when developing or newly implementing acellular pertussis vaccines (aP), various clinical studies were done in Japan. And among them, there were many reports on febrile response to aP lots. Data on the rate of febrile response of over 37.5 degrees celsius of more than 100 infants each to aP lots in such reports were summarised. The probit-transformed response rate and endotoxin (A cell wall component of gram negative bacteria can induce fever to the recipient) content of stud y lots are shown in Figure 2. There was a clear correlation between endotoxin content and probit of febrile response rate, but febrile response rate varied for the lots containing a homogeneous level of endotoxin. This variation in the response rate would reflect the variation in the rate of sensitive individuals in the vaccination groups for the lots. This fact may suggest as in Figure 3 that sensitivity of individuals to vaccine toxicity would distribute, in most cases, in a log-normal manner and that toxicity of vaccine lots would also vary. Therefore, lower the level of toxicity, fewer the sensitive individuals. There may be some individuals who are sensitive to the lot when its toxicity was the highest level among lots. Even a lot with a higher level of toxicity would cause no adverse reactions so far as it is administered only to those who are not sensitive to higher levels of toxicity. But a lot with lower toxicity, if administered to a highly sensitive individual, may cause an adverse reaction. However, if toxicity was lowered to the level of having no sensitive

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Tissue injuring effects of practical vaccine lots A(DTaP)

J(DTaP)

Mouse Footpad SC 2.5mL/kg (day 5)

Local reactivity

Rabbit back skin id 0.05mL/kg (3 weeks)

Mouse im SC 2.5mL/kg (4 weeks)

Figure 4

Causal relationship of adverse events and vaccine

WHO has been encouraging to investigate adverse events following immunisation (AEFI) cases as quickly as possible when reported to collect relevant information for analysis. It is generally considered to have a need case definition criteria for AEFI but there

is no clear guidance yet. Severe AEFI is quite rare and the number of cases could be further reduced by reducing toxic activities of vaccine lots as shown in the previous section (Figure3). For a meaningful approach to AEFI analysis, it is necessary to have quantitative toxicity parameters to evaluate vaccine over individual lots as shown for endotoxin. Furthermore, as seen for febrile response and endotoxin, vaccine lots with similar endotoxin content varied in febrile response rate to show that occurrence of adverse events depends not only on the vaccine quality but also on the probability to administer to sensitive individuals. Therefore, a meaningful approach to AEFI analysis would be to identify such toxicity parameter by correlation

A uthor

individual, no adverse event would occur. Annually, two cases of mortality and three encephalitis cases on an average used to be reported among more than 5 million doses of whole cell pertussis vaccine (wP) in Japan before 1974 (Table 3). On the contrary, almost no such severe adverse events have been reported for aP (Table 4) whose measurable toxicities were reduced, at least, to 1 in 10 of the level of average wP, although the relevant toxicity or toxicities are not known. The relevant toxicity might be some unknown biological activity that was detoxified in parallel to the measurable toxicities and may behave differently to a future modification of production process.

analysis on probability of AEFI and the parameters as seen in the example of endotoxin and febrile response in Figure 3. Local reaction to vaccine, if severe and frequent, may affect public reliance on safety. It is evaluated by the surface observation in a clinical study. This procedure is not appropriate for detecting injection site injury, if any, by a vaccine dose given deep in the muscle. Such clinical evaluation would not be sufficient to prove that a vaccine is safe enough to cause no severe tissue damage at injection site. It is necessary to evaluate the safety at least in a histopathological examination. To facilitate meaningful interpretation of results, two different products such as a newly developed product and an exisiting one of the similar vaccine can be compared at least in more than three laboratory models, for example, by injecting subcutaneously to mouse footpad, intra-dermally to rabbit back and intramuscularly to mouse thigh. If a significant difference in tissue injuring effect was consistently detected between the products in comparison irrespective of the model, the products did differ in their tissue injuring effect (Figure 4). Can we then be sure that only response of human tissue would not reflect such difference? As discussed here, public reliance on safety of vaccine is essential to maintaining high vaccine acceptance. All the blame of those related in not making necessary efforts can not be shifted to official guidelines for the sake of public health.

Yoshinobu Horiuchi graduated from Kyushu University in 1971. After experiencing vaccine production in Chiba he assisted JICA to establish a vaccine laboratory in Jakarta in 1988. He later moved to the National Institute of Health (current NIID) of Japan in 1991 to work on vaccinology, biological statistics and endotoxin control.

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Developing Cancer Vaccines

Using tumour-associated peptides Effective next-generation cancer vaccines have to include relevant and well characterised antigens known to be presented by real tumour tissue. Harpreet Singh, Managing Director and Chief Scientific Officer Toni Weinschenk, Head of Discovery immatics biotechnologies GmbH, Germany

he goal of therapeutic cancer vaccines is to activate specialised cells of the immune system like cytotoxic T-cells to specifically destruct the cancer cells leaving the healthy tissues untouched. To facilitate this, the knowledge of tumour-specific antigens is required and such antigens have to be used in the right context for T-cell activation, a process referred to as vaccination. Such vaccine-induced immune responses should be effective, long-lasting and specifically directed against tumour cells. However, today’s reality of cancer vaccines is still far from this point. On the contrary, the development of cancer vaccines has faced an especially difficult history so far. Like antibody-based therapies, cancer vaccines were greeted with enormous but premature enthusiasm when they showed initial impressive anti-cancer efficacy in mouse models However, when transferred into the human setting and with observation of the first clinical failures, enthusiasm turned to skepticism which remained for almost two decades. Interestingly, therapeutic cancer vaccines have now started experiencing a renaissance. This is largely based on • an increasing understanding of the activation of immune cells and the requirement of immunomodulators

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• an increasing knowledge about mechanisms that allow tumours to evade or inhibit the immune cells • increasing possibilities to monitor vaccine-induced immune responses in vaccinated patients participating in clinical trials and utilising such information for the enhancement of the clinical design, and • the first successful randomised clinical trials in cancer patients that may leadto the first FDA registration of a therapeutic cancer vaccine within the next few years. It seems that today’s perception of such immunotherapeutics is rather driven by knowledge and data than mere enthusiasm and premature expectations. Still, understanding of the immune system is not complete and for most tumour entities only few tumourspecific or tumour-associated antigens are known. Even more importantly, the relevance of the known tumour antigens is mostly unclear. Another justified point of criticism still applying to the majority of clinical trials is that the assumed relevant biological endpoints in clinical trials (vaccineinduced immune responses) firstly are not always evaluated and secondly rarely correlate with relevant clinical endpoints

(objective clinical responses, prolongation of progression-free survival or overall survival). Tumour-associated peptides

Treating cancer patients with active immunotherapy activates T-cells of the immune system specifically against the tumour cells. Tumour cells differ from healthy cells by the over-expression of tumour-associated proteins, also known as Tumour-associated Antigens (TAAs). HLA (Human Leukocyte Antigen) receptors on the cell surface display fragments (i.e. peptides) from cellular proteins to the outside, thus enabling T-cells to differentiate between healthy and tumour cells. Peptides arise from immature translation products and ageing proteins. Inside living cells, peptides are bound to HLA receptors and shuttled to the cell surface. These peptides that are presented by the tumour cells are called Tumour-associated Peptides (TUMAPs). There are two classes of TUMAPs. HLA Class I TUMAPs are short peptides (8 to 10 amino acids) that activate Cytotoxic T Cells (CTLs). Activated CTLs can directly kill tumour cells by secreting cytolytic substances, or by driving tumour cells into apoptosis. HLA Class II TUMAPs are slightly longer peptides

w w w . p h a r m a f o c u s a s i a . c o m 55

Advantages of TUMAPs TUMAPs offer many advantages along several important dimensions, as they are Safe: Various TUMAPs (mainly in the field of melanoma vaccination) have been administered in thousands of patients and were tolerated very well. Scalable: Peptide synthesis is a robust and semi-automatic chemistry in completely cell-free system without the requirement of any recombinant expression. Manufacturing up to the kilogram range is feasible at low costs compared to manufacturing of proteins. Stable: Peptides as well as peptide mixtures can be lyophilised and have been shown to be stable when stored at -20°C or 4°C for years. They can be shipped at room temperature conditions. Pure: Similar to small molecules synthetic peptides can be manufactured at very high purities excluding any tolerising cellular antigens and normal proteins found in all cellular and autologous approaches, thus avoiding the inclusion of autoantigens. Processed: In contrast to protein-based vaccines TUMAPs can be bound directly by antigen processing cells, such as dendritic cells in the skin, which subsequently can activate naïve T-cells. No further antigen processing by the Antigen Presenting Cell (APC) is required.

(approximately 15 to 25 amino acids) that activate T helper cells. Activated T helper cells provide help to CTLs by locally increasing the concentration of certain cytokines. T helper cells can also have direct anti-angiogenic effects on the tumour, suppressing the growth of new blood vessels. The platform described in this article allows discovery and development of both Class I and Class II TUMAPs. XPRESIDENT – Identification, selection and validation of relevant TUMAPs from cancer tissues

XPRESIDENT, a technology platform originally created in the laboratories of the pioneering immunologist Hans-Georg Rammensee and colleagues at the University of Tuebingen (Germany), and continuously enhanced at the spin-off immatics biotechnologies. XPRESIDENT is the first platform that allows:

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Specific: The activation of T-cells by TUMAPs is a highly specific process. Additionally, TUMAPs, in sharp contrast to monoclonal antibodes (mAbs), give access to tumour antigens irrespective of the intra or extra-cellular location of the target allowing a more careful selection among a much larger pool of antigens. mAbs can only recognise target antigens expressed either as soluble factors (e.g. Vascular Endothelial Growth Factor VEGF) or as surface-standing molecules (e.g. VEGF receptor). Evaluable: TUMAPs are not only used for vaccination but are also of use in the direct read-out of immunological responses to specific antigens, an important parameter in early-stage clinical development. Combinable: Pharmaceutical development and GMP manufacturing of mixtures of 10 or more peptides is feasible allowing to create defined multi-target vaccines. Matching regulatory requirements: TUMAPs match expectations of regulatory authorities, i.e. clean technology, exactly defined compounds, clear characterisation of all compounds and impurities.

1. the identification of large numbers of naturally presented novel HLA-binding peptides directly from primary tumour tissues 2. selection of tumour-associated peptides by differential gene expression and peptide presentation analysis and 3. validation of selected candidates by measurement of in vitro T-cell responses. This approach combines methods from genomics, proteomics/peptidomics, bioinformatics and T-cell immunology. Using this technology, offthe-shelf cancer vaccines consisting of multiple tumour-associated peptides can be developed. Samples from surgically removed malignant and normal tissue from patients and blood from patients or healthy donors are analysed in a stepwise approach (Figure 1): 1. HLA-bound peptides from the malignant material are isolated and identified (i.e. sequenced) with high sensitivity using latest technologies

for on-line chromatographic separation and high-end mass spectrometry on the nano scale. 2. Genome-wide mRNA expression analysis by microarrays is used to identify genes over-expressed in the malignant tissue compared with a range of normal organs and tissues. 3. Identified peptides are compared to gene expression data. Peptidesencoded by selectively expressed or over-expressed genes as detected in step 2 are considered suitable candidate TUMAPs for a multi-peptide vaccine. 4. Literature-knowledge is used for additional evidence supporting the relevance of the identified peptides as TUMAPs. 5. The relevance of overexpression at the mRNA level is confirmed by redetection of selected TUMAPs from step 3 on tumour tissue (as well as normal tissue for one selected TUMAP) and optionally by quantification of the TUMAPs themselves.

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IMA901 â&#x20AC;&#x201C; The first product generated with XPRESIDENT

Stepwise approach of analysis of malignant and normal tissues Nomal Tissue Samples

Tumor Sample

Overexpressed genes Literature research

TUMAPs

Vaccine candidate TUMAPs

PBMCs

Immunoassays

HLA ligands Mass spectrometry

Microarray gene expression analysis

RNA

Blood Sample

TUMAPspecific T Cells

6 Figure 1

6. Peripheral T-cells of patients or healthy individuals are tested for reactivity against the tumour-associated HLA ligands using several standardised immunoassays (in vitro T-cell assays). The first major advantage of this approach is that resulting TUMAPs are confirmed to be naturally processed and naturally presented in real tumours reflecting the actual in vivo situation in cancer patients. This has several advantages over other technologies relying on cell lines or computer algorithms used for prediction of putative TUMAPs. Cell lines are known to be very distinct from primary tumour material because they display different gene expression patterns and antigen profiles compared to primary tumours. For instance, this is the case when tumour-associated antigens have relevant functions for interaction with the extra-cellular matrix. Also, cell lines may use different antigen processing rules (e.g. different proteasomal species). Furthermore, cell lines reflect only one type of tumour cell out of a larger population of cancer cells. When looking at primary cancer tissue, it is also possible to look at different cell types within tumour samples, such as tumour-supporting stroma cells and endothelial cells of tumour vascularisation.

The second major advantage of this platform is the identification of a relatively large number of novel tumour antigens. This allows developing peptide-based vaccines based on multiple TUMAPs (typically 10 or more TUMAPs and each TUMAP known to be presented by at least 50% of analysed tumour tissues) in one single product even for tumour entities where only few antigens have been known so far. The advantages of using multiple peptides are: No tumour-associated antigen is present in every tumour. With every additional antigen used there is an increased chance that the vaccine will reach its target or even several relevant targets simultaneously. Priming of only one kind of cytotoxic T-cell(CTL) with one TUMAP is usually insufficient to eliminate all tumour cells. Tumours are very mutagenic and are thus able to respond rapidly to CTL attacks by changing their pattern of expressed proteins, allowing them to escape from the recognition by CTLs. Several activated T-cells can act synergistically by simultaneously attacking a corresponding number of independently encoded tumour antigens reducing the chances of a tumour cell to evade the immune response by down-regulating single targets.

The HLA peptidome of 32 primary renal cell carcinoma samples routinely resected from patients was systematically investigated using the XPRESIDENT technology. 9 HLA-A*02- and 1 HLA-DR- restricted TUMAPs, derived from nine different tumour antigens were selected. All selected TUMAPs were confirmed to be immunogenic in vitro, although immunogenicity varied between single TUMAPs. This mixture was pharmaceutically developed to a stable lyophilised formulation that is rapidly dissolved in physiological buffer and ready for intradermal administration in a single shot. The product was designated IMA901. In the first-in-man trial, one additional well described viral peptide derived from Hepatitis B virus was included into IMA901 as a marker. First proof-of-principle in the clinical setting

Twenty-eight HLA-A*02-positive stage III/IV RCC patients were enrolled in a single arm, multi-centre study and received eight intradermal vaccinations each consisting of IMA901 (including the HBV-derived viral marker peptide) and GM-CSF as immunomodulator. T-cell responses were measured systematically in peripheral blood using IFNgamma ELISPOT and HLA multimer analysis and CD4+ Foxp3+ regulatory T-cell (Tregs) levels. IMA901 rapidly induced T-cell responses in 75% of evaluable patients (N=27). T-cell responses were detectable already within the first 14 days after the first vaccination, peaked subsequently and were sustainable until follow-up in the majority of patients. The overall tumour assessment in patients with measurable disease (N=23) revealed that eight patients (35%) demonstrated a clinical benefit (one partial response and seven stable diseases). Most importantly, patients eliciting multiple TUMAP responsesâ&#x20AC;&#x201D;observed in 30% of patients â&#x20AC;&#x201D;showed a higher clinical benefit rate.

w w w . p h a r m a f o c u s a s i a . c o m 57

Outlook

Although conclusions from this pilot trial should be treated with caution due to the small study size and short duration of clinical observation, results seem remarkable due to the fact that most

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immunotherapy trials have failed to demonstrate correlations between immune responses and clinical benefit. It can be speculated that this may be due to two important characteristics of IMA901: the use of multiple peptide antigens as well as the use of naturally presented peptides. Multi-centre randomised clinical trials are currently conducted in Europe with the goal to demonstrate the clinical benefit of IMA901 in a larger study population treated and observed for a longer duration.

A uthors

This correlation was found to be statistically significant (p=0.018).Furthermore, another correlation was observed: patients with lower levels of so-called regulatory T-cells at study onset showed a higher proportion of immune responses to multiple TUMAPs (p=0.016). Such CD4+ Foxp3+ regulatory T-cells (Tregs) have been recently described as key mediators of peripheral immune tolerance and may be important inhibitory cells against immunotherapeutics in vivo. Importantly, both correlations were only observed for T-cell responses to TUMAPs. However, no correlation of HBV marker peptide responses to either Tregs or clinical benefit was observed.

Additionally, the XPRESIDENT platform is not limited to renal cell carcinoma but has also been successfully applied to other tumour entities. Further, multi-peptide product candidates will soon be introduced into clinical development. It remains to be seen whether this novel class of naturally presented antigens will be able to make a difference to cancer immunotherapy. The first results have provided some hopeâ&#x20AC;&#x201D;a hope driven by data and new knowledge.

Harpreet Singh received his PhD in Immunology at the University of Tuebingen (Germany), working in the group of Professor Hans-Georg Rammensee. He is the co-founder of immatics biotechnologies, a Tuebingen-based company. As Chief Scientific Officer of the company, he is responsible for the development of novel peptide-based cancer vaccines from drug discovery to clinical development. Toni Weinschenk received his PhD in Immunology at the University of Tuebingen (Germany). He has developed the technology platform XPRESIDENT, which combines methods from peptidomics, genomics and immunology in order to find novel and naturally presented cancer antigens. The platform is commercialised by immatics biotechnologies, where Toni Weinschenk, also a co-founder of the company, is heading the drug discovery group.

C l inic a l T ri a l s

Japan’s Step Towards Global Studies A new guideline on trial data provides opportunities for Japanese biopharmaceutical companies and global contract research organisations to work together to speed up drug development in Japan Mark A Goldberg, President, Clinical Research Services and Perceptive Informatics Inc., PAREXEL International Corporation, USA

n September 28, 2007, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) released a new guideline for the biopharmaceutical industry entitled “Basic Concept for International Joint Clinical Trials.” The PMDA issued the guideline in response to growing concern about the “drug-lag” challenge facing Japan. As of now new biopharmaceutical products typically enter the Japanese market more than four years after their approval in the US or the European Union. The guideline addresses this problem by expanding the criteria for

accepting clinical data from non-Japanese patients. It also encourages Japanese biopharmaceutical companies to participate in joint international clinical trials. The goal is to have the latest therapies available to Japanese patients at the same time as patients in North America and Europe. This should contribute to overall healthcare improvements in Japan. The new guideline offers significant opportunities for Japanese biopharmaceutical companies to speed up their drug development programmes. It also provides a way to expand the market

potential of their products by conducting joint clinical trials in the Asia-Pacific region and other parts of the world. The opportunities are equally important for CROs with the right combination of experience and resources to provide global clinical services for the Japanese biopharmaceutical industry. The challenge for all of those involved is to find the best way to take advantage of this new regulatory flexibility and increase the scope of clinical trials for the Japanese biopharmaceutical industry globally. However, those involved have to understand the differences and

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limitations that continue to characterise the drug approval process in Japan. Working together is the mantra to overcome these challenges and generate clinical data from outside Japan that meets the new guideline. Doing this will allow the Japanese biopharmaceutical companies and global service providers to shorten development times, speed up regulatory approvals, and bring innovative therapies to Japanese patients more quickly. Understanding the new guideline

The PMDA’s new guideline makes it clear that Japanese health authorities are concerned with the worsening druglag situation in the country. The PMDA is aware that Japan’s drug development regulations need to be more flexible to allow the inclusion of data from global trials involving non-Japanese patients. At the same time, the guideline states that companies conducting international trials across different geographic regions and populations must account for ethnic differences when gathering and submitting study data for drugs intended for sale in Japan. In addition, any clinical development plan must specifically assess the efficacy and safety of an investigational drug in Japanese subjects. The guideline strongly recommends early clinical pharmacology and single-dose studies involving healthy volunteers and patients from Japan to obtain pharmacodynamic (PD), pharmacokinetic (PK) and safety data. There is some indication in the guideline that the inclusion of other Asia-Pacific populations in a joint international trial could help address the question of ethnic differences for drug safety and efficacy in Japanese patients, if the equivalency of those other populations to Japanese patients can be scientifically demonstrated. This flexibility offers the possibility that the growing inclusion of other Asian countries could provide valuable data to support new drug applications in Japan. However, the guideline emphasises that the long-term

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Key Capabilities to Look for in a Partner Offices and experienced personnel in Japan, major Asia-Pacific countries and other global markets Well-established local capabilities and expert resources in Japan Experience working with regulatory authorities in Japan, the Asia-Pacific region and throughout the world History of conducting successful clinical trials in Japan and throughout Asia ICH / GCP compliant services in all markets Wide range of therapeutic area expertise Access to qualified investigators and patient populations in multiple regions around the world Strong expertise and capabilities across all phases of clinical development,

goal of the PMDA is the greater participation of Japanese biopharmaceutical companies in international trials covering multiple regions and populations, with development schedules that coincide with those in the US and Europe. The guideline lists several other important conditions that international joint trials would be required to meet if their data is to be considered for inclusion in a Japanese regulatory filing, including: • All nations and institutions participating must conduct trials under Good Clinical Practices (GCP) regulations as defined by the International Conference on Harmonisation (ICH) • All participants must accept onsite GCP inspections by Japan’s regulatory authorities • The study design, protocols, and analytical methods must be acceptable to the PMDA. Additionally, standards of medical practice should be similar to Japan. Most importantly, the guideline states that the PMDA will evaluate proposals for joint trials and the inclusion of foreign data on a case-by-case basis. This approach allows for additional flexibility in the case of an orphan drug

including clinical pharmacology and early-stage trials Familiarity with the myriad regulatory and operational differences for conducting clinical trials in various Asian countries and other regions, such as: - Medical practices and clinical procedures - Regulatory requirements and review timelines - Ethics committee / IRB guidelines - Investigator and patient recruitment practices - Language and translation issues - Importation of drug supplies and exportation of blood / tissue samples - Data security and communications issues

where an insufficient number of Japanese patients may be available for a trial, or for oncology drugs and other therapies that address unmet medical needs in the Japanese population. In all cases, the PMDA guideline strongly recommends direct consultation with the Agency in the early stages of every clinical trial to discuss the study design and the criteria for including data from non-Japanese patients. The guideline also notes that these criteria may change over time as the Agency’s experience grows with international trials and the use of foreign patient data. Finding the right partner

How do Japanese biopharmaceutical companies take advantage of this new opportunity to speed up their development efforts? The best approach is to partner with a global CRO with international clinical trial experience, as well as specific experience in the Asia-Pacific region. The right partner would provide access to a wide range of resources and expertise that will help Japanese biopharmaceutical companies quickly and effectively expand their clinical trial programmes into other areas to reduce drug development times.

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Addressing key challenges

Although the PMDA’s new guideline on joint international clinical trials offers opportunities for faster clinical development, a number of significant challenges remain in the effort to reduce the druglag problem in Japan. Part of the delay results from global biopharmaceutical companies waiting until they have “proof of concept” from Phase II trials in the US or Europe before undertaking a trial strategy for Japan. If early phase studies are not conducted in Japan in parallel with early phase studies in other markets, an inherent delay is created. While the new guideline does not address this problem directly, the Agency’s increased flexibility and desire to support joint global trials should encourage global biopharmaceutical companies to include Japanese or Asia-Pacific studies earlier in the development process so their products can be introduced sooner in Japan. Another factor in the “drug-lag” is the relatively slow review and approval process in Japan, which takes around 2.5 years longer than in the US. Part of that delay results from a shortage of review-

ers. In 2005, Japan had just 197 reviewers for drug applications, compared with 693 in the UK, 942 in France, and 2,200 in the US. In June 2007, the PMDA announced that it was increasing the number of reviewers by 236 over the next three years to help speed up regulatory reviews. A third challenge is the requirement by the PMDA that later-stage trials must continue to enroll mostly Japanese patients. This requirement is particularly difficult due to the shortage of Japanese patients willing to participate in clinical trials. The availability of a strong national healthcare system reduces one of the incentives for patients in Japan to enroll in trials. By comparison, patients in some countries do not have such ready access to high quality health care and might be motivated to participate because of the improved general care that might be received. Finally, reimbursement practices favour payments to institutions rather than individual physicians, which can create a barrier to physician recruitment. Therefore, there are multiple contributors to the Japanese “drug lag” and further change will likely be required. Looking into the future

While the amount of non-Japanese data accepted by the PMDA will be limited at first, it is possible, although not guaranteed, that the new guideline could eventually result in the acceptance of more data (perhaps up to 30-50 percent) from non-Japanese patients. This type of increase may occur within a few years as the Japanese regulatory authorities gain experience with—and confidence in—trial data from other populations. The PMDA is most likely to be A uthor

Japanese biopharmaceutical companies can work with a CRO partner to help accelerate the introduction of novel therapies. Additionally, they can leverage partner capabilities to conduct Asia-Pacific or global studies to support expanded indications for products already on the market in Japan, or to introduce their existing products to other markets. The key to all of these partnership opportunities is access to global capabilities combined with in-depth local knowledge and experience. With the many differences and challenges of drug development and approval in Japan and the emphasis by the PMDA on caseby-case consultations about clinical plans and data acceptability—a partner with strong resources in Japan and the Asia-Pacific region offers the greatest chance of success in taking advantage of the new guideline.

flexible with development programmes that address unmet medical needs. Increased flexibility in the regulations should also encourage multinational biopharmaceutical companies to undertake clinical pharmacology and dosage testing in Japan and Asia earlier in the global development process. This will help to establish equivalency data that would support the inclusion of additional Asia-Pacific study patients. These changes should lead to wider inclusion of Asia-Pacific countries in global clinical development plans. More important than the growth of Asia-Pacific studies, however, are the long-term PMDA goals: increasing Japanese biopharmaceutical company participation in global clinical trials and encouraging global companies to include plans for the Japanese market earlier in the drug development process. There is some evidence that these changes are already underway. In 2007, for example, the number of Japanese investigators signing on to conduct FDA-regulated trials rose to 154, from just 24 the year before. If the PMDA’s goals are realised, the Japanese public will have access to innovative therapies more quickly than in the past, and the biopharmaceutical industry will some day be able to introduce its novel therapies in Japan at the same time as in other major world markets. Achieving this vision of the future will require both perseverance and industry partnerships that leverage the right combination of experience, resources, and local knowledge to overcome the challenges and take advantage of the new opportunities available in the Japanese biopharmaceutical marketplace.

Mark A Goldberg, MD, is President of Clinical Research Services and Perceptive Informatics, Inc., a wholly owned technology subsidiary of PAREXEL International, a leading global service provider to the biopharmaceutical industry. Goldberg joined PAREXEL in 1997 and established the Company’s Medical Imaging Group. In 2000, he was involved in founding Perceptive Informatics to deliver advanced technology solutions that improve development and commercialisation processes for the biopharmaceutical industry.

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Adaptive Trial Design

Enhancing the quality of clinical trials Adaptive / flexible trial design has begun to catch-up with the clinical trial services providers due to its umpteen benefits that go a long way in delivering better drugs in a much shorter time. This article looks at different types of adaptive designs available, their characteristics, infrastructure, and the associated legal aspects. Mark Chang, Scientific Fellow, Biostatics and Medical Writing, Millennium Pharmaceuticals Inc, USA

nvestment in pharmaceutical research and development has more than doubled in the past decade; however, the increase in spending for biomedical research does not reflect an increased success rate of pharmaceutical development. Reasons for this include: (1) a diminished margin for improvement escalates the level of difficulty in proving drug benefits; (2) easy targets are the focus as chronic diseases are more difficult to study; and (3) genomics and other new science have not yet reached their full potential. We cannot apply last century’s techniques to today’s problems and expect a great success. The idea of adaptive trial design was initiated in late 1970s. However, they became such attractive only in 2004 when FDA issued the “Critical Path” document (FDA, 2004). Indeed, adaptive clinical trial designs open a whole new territory for drug development. Benefits of adaptive trial design include: (a) improve efficiency of the trial design; (b) improve drug efficacy; (c) improve effectiveness of the trial; d) reduce the time of drug development and (e) reduce all the associated costs.

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What is adaptive design?

An adaptive design is a clinical trial design that allows the users to adapt or modify a trial during its progress based on interim results without affecting the validity and integrity of the trial. These adaptations can be based on internal or external information to the trial.

Interim Analysis All adaptive designs include interim analyses. An interim analysis is a statistical analysis conducted during on-going trial based on trial data. The purpose of interim analysis is to determine whether the trial should stop early or continue to further collect data or make modifications.

There are many different adaptive designs, each fits particular situations. The commonly used adaptive designs include group sequential design, samplesize re-estimation design, drop-loser design, response-adaptive randomisation, adaptive dose-finding / dose-escalation, and biomarker-adaptive designs. We are going to briefly describe the different adaptive designs and their applications.

Group Sequential Design

A Group Sequential Design (GSD) is an adaptive design that allows for premature termination of a trial due to a strong efficacy or futility evidence at interim analyses. GSD was originally developed to obtain clinical benefits under economic constraints. If a trial experiences a positive result at an early stage, GSD ensures an early stop of the trial leading to an earlier launch of the new drug. If a negative result is indicated, early stopping avoids wasting resources. Sequential methods typically lead to savings in sample-size, time and cost when compared with the classical design with a fixed sample-size. Also, limited resources can be judiciously put to use across different trials through interim analyses. GSD is probably one of the most commonly used adaptive designs in clinical trials. Sample-Size Re-estimation Design

A Sample-Size Re-estimation (SSR) design refers to an adaptive design that allows for sample-size adjustment or re-estimation based on the review of interim analysis results. The sample-size requirement for a trial is sensitive to the treatment effect and its variability. An inaccurate estimation of the effect size and its variability could lead to an underpowered or overpowered design, neither of which is desirable. If a trial is underpowered, it will not be able to

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Drop-Loser Design Interim Analysis

PLA

Ä Ä Ä Ä Ä

Drop inferior arms & early stop trial or adjust sample size

Frequentist & Bayesian results P-values &

Ä Ä Ä

Randomised Play-the-Winner:

Response

Probability

Response

Active

Randomise Patients with five initial arms

Response Adaptive Randomisation

Dose

Learning Phase

detect a clinically meaningful difference, and consequently could prevent a potentially effective drug from being delivered to patients. On the other hand, if a trial is overpowered, it could lead to unnecessary exposure of many patients to a potentially harmful compound when the drug, in fact, is not effective. In practice, it is often difficult to estimate the effect size and variability because of many uncertainties during protocol development. Thus, it is desirable to have the flexibility to re-estimate the sample-size in the middle of the trial. Drop-Loser Design

A Drop-Loser Design (DLD) is an adaptive design consisting of multiple stages. At each stage, interim analyses are performed and the losers (i.e., inferior treatment groups) are dropped (Figure 1). Ultimately, the best arm(s) are retained. If there is a control group, it is usually retained for the purpose of comparison. This type of design can be used in phase I-II or phase-II/III combined trials. A phase-II clinical trial is often a dose-response study, where the goal is to assess whether there is treatment effect. If there is treatment effect, the goal becomes finding the appropriate dose level (or treatment groups) for the phase-III trials, which are the pivotal trials for confirming efficacy. This type of traditional design is not efficient with

Ä Ä Ä

Treatment effect

Confirmatory Phase

Wei’s Urn Model (1978)

One ball of each color in the urn initially. Randomly select a colored ball from the urn to determine patient’s treatment assignment. When a response is seen in a treatment arm, a ball of the corresponding color is added to the urn. Therefore more patients will be randomised into efficacious arms.

Figure 1

Figure 2

respect to time and resources because the phase-II efficacy data are not pooled with data from phase-III trials. Therefore, it is desirable to combine phases II and III so that the data can be used efficiently, and the time required for drug development can be reduced.

randomisation is commonly used to ensure a balance with respect to patient characteristics among treatment groups. However, in a Response-Adaptive Randomisation Design (RARD), the allocation probability is based on the response of the previous patients. RARD was initially proposed because of ethical considerations (i.e., to have a larger probability to allocate patients to a superior treatment group). The Randomised Play-the-Winner (RPW) is a well-known RARD (Figure 2). Early applications of RPW are found in two-group trials. However, RARD is probably more useful in multiple-arm dose-find trials.

Response-Adaptive Randomisation Design

An adaptive randomisation design is a design that allows modification of randomisation schedules during the conduct of the trial. In clinical trials, Advantages of

Adaptive Trial Design Compared to a classical design with a fixed sample size and other static design features, an adaptive design with dynamic or modifiable features will increase the probability of success; reduce the cost and the time to market; deliver the right drug to the right patient. An adaptive design may allow for stopping a trial earlier if the risk to subjects outweighs the benefit, or when there is early evidence of efficacy for a safe drug. An adaptive design may allow for randomising more patients to the superior treatment arms and reducing exposure to inefficacious, but potentially toxic, doses. An adaptive design can also be used to identify better target populations through early biomarker responses.

Adaptive Dose-Escalation Design

Dose-escalation is often considered in early phases of clinical development for identifying the Maximum Tolerated Dose (MTD), which is often considered the optimal dose for later phases of clinical development. An adaptive dose-finding (or dose-escalation) design is a design at which the dose level used to treat the next-entered patient is dependent on the toxicity of the previous patients. There are some traditional dose-escalation rules are adaptive, but the adaptation algorithms are somewhat ad hoc. More advanced dose-escalation rules have been developed using modelling approaches such as the continual

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reassessment method and other accelerated escalation algorithms (Chevret, 2006, Chang, 2007). These algorithms can reduce the sample-size and overall toxicity in a trial and improve the accuracy and precision of the MTD predictions. Biomarker-Adaptive Design

Biomarker-Adaptive Design refers to a design that allows for adaptations using information obtained from biomarkers. In clinical trial set-up, a biomarker is defined as an indicator of biologic or pharmacologic response to a therapeutic intervention. Biomarkers can be used to select the most appropriate target population, or even for personalised treatment using adaptive design. It is often the case that a pharmaceutical company has to decide whether to target a very selective population for whom the test drug likely works well or to target a broader population for whom the test drug is less likely to work well. However, the size of the selective population may be too small to justify the overall benefit to the patient population. In this case, a biomarkeradaptive design may be used, where the biomarker response at interim analysis can be used to determine which target populations should be focussed on. Characteristics of adaptive designs

Despite differences among adaptive designs, there are common characteristics. Adaptive design is a sequential data-driven approach. It is a dynamic process that allows for real-time learning. It is flexible and allows for modifications to the trial, which make the design cost-efficient and robust against the failure. Adaptive design is a systematic way to design different phases of trials, thus streamlining and optimising the drug development process. In contrast, the traditional approach is composed of weakly connected phasewise processes. Adaptive design is a decision-oriented, sequential learning process that requires up-front planning

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Streamlined

Characteristics of Adaptive Designs

Dynamic

Sequential learning

Flexible

Adaptive Design

Optimised

Cost-efficient

Data-driven

Robust

Systematic

Real-time

Decision-oriented

Validity

Integrity

Bayesian

Simulation Figure 3

and a great deal of collaboration among the different parties involved in the drug development process. To this end, Bayesian methodology and computer simulation play important roles. Finally, the flexibility of adaptive design does not compromise with the validity and integrity of the trial or the development process (Figure 3). Adaptive designs require the ability to rapidly integrate knowledge and experiences from different disciplines into the decision-making process and hence require a shift to a more collaborative working environment among disciplines. Clinical trial simulation and IT infrastructure

Clinical Trial Simulation (CTS) is a process that mimics clinical trials using computer programs. CTS is particularly important in adaptive designs for several reasons: (1) the statistical theory of adaptive design is complicated with limited mathematic solutions available under certain assumptions, whereas CTS can be used to model very complicated situations with minimum assumptions; (2) CTS can be used to study the validity and robustness of an adaptive design in different hypothetical clinical settings, or with protocol deviations; (3) CTS can be used to monitor trials, project outcomes,

anticipate problems, and suggest remedies before it is too late; (4) CTS has minimal cost associated with it and can be done in a short time. Meanwhile, the design software and simulation tools for adaptive trials are highly desirable. EAST from Cytel Inc., well-known for its group design capability for years, has recently implemented a model to allow sample-size reestimation. Cytel also provides services for clinical trial design. ExpDesign Studio from CTriSoft, emerged just about 6 years ago, can provide a broad adaptive design with a fraction of the cost. ExpDesign Studio has implemented over hundred methods for classical designs. The ExpDesign is quickly increasing its popularity in designing clinical trials can be seen in international medical journals. However, CTriSoft only provides free online technical support for its clients, but is not a clinical trial service provider. An adaptive design often requires real-time or near real-time data collection and analysis. In this regard, data standardisations, such as CDISC and Electronic Data Capture (EDC), are very helpful in data cleaning and reconciliation. Note that, not all adaptive designs require perfectly clean data at interim analysis, but the cleaner the data are, the more efficient the design is.

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According to US FDA, Critical Path initiative is “a serious attempt to bring attention and focus to the need for targeted scientific efforts to modernise the techniques and methods used to evaluate the safety, efficacy, and quality of medical products as they move from product selection and design to mass manufacture”. In the past five years, FDA has received different adaptive design protocols. The design adaptations FDA reviewers have encountered are: SSR, drop-losers, change of the primary endpoint, change of statistical tests, and change of the study objective such as from superiority to non-inferiority or vice versa, and selection of a subgroup based upon externally available studies. Two primary motivations for adaptive trials are well recognised by FDA statisticians, i.e. to allow some type of mid-study changes that are prospectively planned to maximise the chance of success of the trial while properly

preserving the Type-I error rate because some planning parameters are imprecisely known and to enrich trials with subgroups of patients having genomic profiles likely to respond or less likely to experience toxicity (Hung, et al., 2006). “Adaptive designs should be encouraged for Phases I and II trials for better exploration of drug effects, whether beneficial or harmful, so that, such information can be more optimally used in latter stages of drug development. Controlling false positive conclusions in exploratory phases is also important so that, the confirmatory trials in latter stages achieve their goals. The guidance from such trials properly controlling

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Regulatory aspects

false positives may be more informative to help better design confirmatory trials.” (Hung, et al., 2006). So far, the FDA has not released a formal guidance on adaptive designs and adaptive design protocol review is case-by-case. To sum up...

Adaptive design methods represent a revolution in pharmaceutical research and development. With a lot of benefits through adaptive design, better science can be developed for testing new drugs, and in turn, better science for prescribing them. Full references are available on www.pharmafocusasia.com/magazine/

Dr Mark Chang is a Scientific Fellow at Millennium Pharmaceuticals with extensive experience in PreIND, IND, NDA submissions. He is the Vice President of the International Society for Biopharmaceutical Statistics, an executive member of ASA Biopharmaceutical Section, and a member of Expert Panel for the NCE in Canada and also Co-chair of Biotechnology Industry Organization Adaptive Design Working Group.

BOOK Shelf

Leading Pharmaceutical Innovation: Trends and Drivers for Growth in the Pharmaceutical Industry Authors: Oliver Gassmann, Gerrit Reepmeyer, Maximilian von Zedtwitz Year of Publication: 2008 Pages: 186 Published by: Springer

ISBN: 3540407170

Description : Pharmaceutical giants have doubled their investments in drug development in the past decade only to see new drug approvals remain constant. This book investigates and highlights a set of proactive strategies aimed at generating sustainable competitive advantage 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 cooperation and internationalization, such as open innovation in the early phases of R&D. Our findings are illustrated by cases from Europe, the US, and Asia.

Adaptive Design Methods in Clinical Trials Authors: Shein-Chung Chow, Mark Chang Year of Publication: 2007 Pages: 277

Published by: Chapman & Hall/CRC ISBN: 1584887761

Description : One of the first books on the topic, Adaptive Design Methods in Clinical Trials presents the principles and methodologies in adaptive design and analysis that pertain to adaptations made to trial or statistical procedures that are based on accrued data of ongoing clinical trials. The book also offers a well-balanced summary of current regulatory perspectives and recently developed statistical methods in this area. After an introduction to basic concepts and statistical considerations of adaptive design methods, the book questions the impact on target patient populations as the result of protocol amendments and discusses the generalization of statistical inference. The authors also present various adaptive design methods, including where hypotheses are modified during the conduct of clinical trials, for dose selection, and commonly used adaptive group sequential design methods in clinical trials. The book concludes with computer simulations and various case studies of clinical trials. For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Metabolomics Strategy Identifying tissue-specific drug effects

The maturation of metabolomics technologies is expected to have profound effect on pharmaceutical R&D. Over the past few years, technologies have matured to the stage where comprehensive and quantitative investigation of global metabolome has been made possible. Matej Orešic, Research Professor, Systems Biology and Bioinformatics, VTT Technical Research Centre of Finland, Finland

linicians commonly rely on a tiny fraction of the information contained in the metabolome, measuring e.g. glucose and cholesterol to monitor diabetes and cardiovascular health, respectively. New analytical platforms for metabolomics and tools for informatics that afford extended and sensitive measurement of the metabolome are therefore expected to become an essential tool in pharmaceutical and clinical research. Pharmacometabolomics – Towards personalised drug treatment

There is a clear need for personalisation of drug treatment, i.e. drug and dose selection according to individual patient characteristics in order to improve efficacy and reduce the risk of adverse reactions. In order to achieve this goal, one would need to first understand and predict how different individuals respond to specific drug-dose combination. Since metabolome is affected both by genetic and environmental factors, including variation in the diet, gut microbial composition, age, disease status and drug administration history, it provides a very sensitive quantitative measure of inter and intraindividual variation due to multitude of factors affecting the drug response.

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What is metabolomics? Metabolomics is a discipline dedicated to the global study of small molecules (i.e., metabolites) in the context of cellular, tissue, and organismal physiology. Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate and amplified response of biological systems to genetic or environmental changes.

Drug treatment may induce potentially harmful yet asymptomatic events in specific tissues. One of the promising new applications of metabolomics is therefore detection of markers of specific pathophysiological mechanisms and related biological pathways. Such markers may help identifying patients at risk of adverse effects and for individual’s dose recommendations. In a first application of this kind, effects of high dose simvastatin and atorvastatin on genome wide expression profiles of muscle tissue as well as on global plasma lipid composition were studied. The study revealed that statins at high doses may induce significant changes in the expression of multiple genes controlling metabolic and inflammatory pathways in muscle. It has led to elucidation of relevant biological pathways as well as to identification of plasma metabolic biomarker candidates related to potentially toxic statin-induced changes in muscle. Such muscle sensitive markers are not only useful for identifying patients at risk of developing adverse muscle effects, but may also help as surrogate safety biomarkers used for development of new lipid lowering drugs. The concept of tissue-specific functional biomarker as measured by biofluid metabolomics and the methodology to obtain it, as applied in author’s high dose statin studies, can

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Role of metabolomics in translational pharmaceutical research

As metabolites are common among different species, they have more chances of representing cross-species biomarkers. Utilisation of such metabolomic phenotype links between species will have a profound effect on development of future therapies. In a recent study, the author compared the lipidomic profiles of Zucker Diabetic Fatty rats (ZDF) and the hypertriglyceridemic patients. The lipid molecular species level changes

Benefits of metabolic signatures Prognostic, diagnostic, and surrogate markers for a disease state are easily known Diseases can be sub-classified Provide biomarkers for drug response phenotypes (pharmacometabolomics) Information about mechanisms of disease and therapeutic intervention are easily revealed relative to controls (lean wild type rats in preclinical study; and 2 healthy siblings of each diagnosed patient) in clinical study) were generally remarkably similar between the diabetic animal model and the human subjects. Such a panel of cross-species markers can be for example correlated with tissue-specific changes following drug interventions in nonclinical studies. The measurements of these markers in clinical drug trials offer new sensitive monitoring tools for evaluating drug safety and efficacy. The use of metabolomics in translational pharmaceutical research may be particularly useful for diseases where animal models are difficult to validate,

A uthor

be extended to other areas of pharmaceutical R&D, e.g. liver toxicity or drug efficacy studies. The metabolomic biomarkers may thus also offer a window to investigate the drug response and mechanism of action in the physiological setting. With a panel of tissue-specific markers for specific pathways of importance, one could thus track the responses of specific pathways following therapeutic intervention in different tissues using biofluid metabolic profiles in clinical setting. The key challenge to achieve such a goal will be to obtain sufficient number of representative samples, both from clinical and nonclinical studies, in order to develop reliable and validated biomarkers. However, return on such investment is potentially huge, as such approach would empower us with ability to detect subtle pathophysiological changes in responses to drug interventions much earlier than is currently possible. This would be particularly important in early clinical stages of pharmaceutical pipeline, where key decisions need to be made on clinical safety and efficacy of the drug based on studies in small populations. Tissue-specific metabolic biomarkers could thus provide important evidence on biological response to the drug, which may be extrapolated to larger populations for later clinical stages of pharmaceutical pipeline.

such as in psychiatric disorders or cancer. Application of metabolomics in such setting will require starting the drug discovery and development process top down, with the clinical studies. Clinical studies, focusing on a specific disease, should be conducted to obtain samples representative of different stages of disease progression in a representative population. Metabolomics could then be applied as a quantitative phenotyping tool, so that biomarkers can be obtained for different (sub)types and stages of the disease. Such biomarkers obtained in clinical setting are a starting point for validation of nonclinical models as well as characterisation of drug responses in such models. Access to the old and ongoing clinical studies which do not necessarily include the therapeutic intervention, as well as establishment of the biobanks, will therefore play an important role in future applications of metabolomics in pharmaceutical R&D. Conclusion

Although metabolomics is one of the latest additions to the omics nomenclature, the applications of metabolite detection in clinical setting has a long tradition. The metabolites as â&#x20AC;&#x153;physiological end-pointsâ&#x20AC;? are true systemic markers of responses to environmental, genetic or therapeutic interventions. The coming years are likely to see increasing incorporation of metabolomics platforms in nonclinical as well as clinical studies in pharmaceutical R&D.

Professor Matej OreĹĄic holds a PhD in Biophysics from Cornell University. Since 2003, he is leading the research in domains of quantitative biology and bioinformatics at VTT Technical Research Centre of Finland with the main research areas being metabolomics applications in pharmacology, biomedical research and integrative bioinformatics. He is also a founder and chairman of the board of Zora Biosciences Ltd., a company dedicated to metabolomics applications in pharmaceutical R&D. Prior to joining VTT, he was the head of computational biology and statistics at Waltham / Massachusettsbased BG Medicine, Inc., and bioinformatician at LION Bioscience Research in Cambridge, USA.

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I n f o rm a ti o n T echn o l o g y

Web 2.0

in Pharma Enterprise Improving internal communication

The adoption of simple and easy-to-use Web 2.0-inspired technologies and approaches inside the enterprise provides companies with opportunities to improve their collaboration, communication and knowledge sharing.

Simon Revell, Manager of Enterprise 2.0 Technology Development, Information and Knowledge Management, Pfizer Inc, UK

uring 2007, use of ‘Web 2.0’ ‘social media’ sites on the World Wide Web finally started to break out of the exclusive domain of the young and the technically-focussed. Rise of Social Web

Increasing number of people are looking for information in Wikipedia, the free wiki-powered online encyclopaedia. Some, if not all, are even contributing to it in the form of new articles and edits. The social networking site for business users, LinkedIn, exploded into many people’s consciousness for the first time, as professionals started issuing invites to connect to their work colleagues and contacts. Some users are experiencing their first taste of consuming content via RSS using Google Reader or the Bloglines site, and social bookmarking and tagging have become more mainstream through the growth of bookmarking websites like del.icio.us. More individual blogs are being added to the ever-expanding web ‘blogsphere’, and users have found it quick

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and easy to set up online communities to support their societies or clubs through Yahoo Groups, Facebook, etc. Those with a desire to express their creative side have found outlets in Flickr for photo-sharing, and YouTube for videos, while PowerPoint has become fashionable again with the introduction of SlideShare, a site for sharing PowerPoint presentations. There are obvious benefits in using these Web 2.0 sites. Users are rewarded with enriched collaboration and communication capabilities. Web 2.0 software designed around the user has resulted in sites and tools that are easy to access, and incredibly simple to pick up and use. This ease of authoring has facilitated the availability of content for a ‘long tail’1 of interests, and with the support of RSS, individuals find that they have the ability to subscribe to and consume information specific to their own personal needs. Also highly visible are ‘opensource’ collaborations. Efforts made by individuals connected through a shared objective and through the 1 “The Long Tail” by Chris Anderson, Wired, Oct. 2004.

Web 2.0 Hot Spots If you’ve not heard of all of the Web 2.0 sites covered in the introduction why not visit and try them out. Here are links to the most popular sites:

http://wikipedia.org Free online encyclopaedia available in eight different languages

http://www.linkedin.com Manage your professional relationships

http://www.bloglines.com Online RSS Reader

http://del.icio.us/ Tag and share your bookmarks

http://www.flickr.com/ Share your photos

http://www.youtube.com/ share videos

http://www.slideshare.net/ Share PowerPoint presentations

use of Web 2.0 software are able to contribute based on their personal passions and skills, regardless of where they live and what time-zone they inhabit. Web 2.0 into the enterprise

For those experiencing Web 2.0 and working within a big global corporation a similar thought probably came

I n f o rm a ti o n T echn o l o g y

to mind, “Why can’t I have IT like this inside my place of work?” In industries such as Pharma, the need for knowledge management and collaboration tools is being recognised of late. Also, there is an increasing focus on facilitating ‘Open Innovation’2 through the utilisation of the full breadth of talent available within the organisation and through partnerships and collaborations with other companies. Hence, with all such developments gaining prominence in this industry, there is obvious potential in the idea of applying Web 2.0-like software and approaches. Enterprise 2.0

Enterprise 2.0 is a fast emerging and new area of IT dedicated to delivering on that idea. Enterprise 2.0 is quite literally, “the application of Web 2.0 within the enterprise”. The specifics of Enterprise 2.0 are still evolving, and in most cases it is never quite as simple as implementing or using existing Web 2.0 software, mainly due to perceived security constraints or the need to integrate software with existing enterprise technology standards or platforms. The good news is that purpose-built software now exists for all of the major categories most commonly associated with Enterprise 2.0. Wikis

Wiki software has been around for almost ten years, and while there is now a wide choice of wiki products available, the fundamental purpose of the software has remained the same, namely the ability for communities of users to quickly and easily create, edit and link web pages. The most famous application of wiki software on the World Wide Web is Wikipedia, and many organisations make the mistake of assuming that the use of wiki software inside the enterprise has to take a similar form. However 2 A term first used by Henry Chesbrough. See http://en.wikipedia.org/wiki/Open_innovation for more details. http://www.chicagocrime.org/

there are many different potential uses organisations can make of wikis. For instance traditional company intranets can easily be hosted on a wiki, and at much less cost and effort than traditional approaches and platforms (both from the perspective of end-users and IT). Purpose-built information or knowledge management systems can be replaced by a single wiki instance, reducing the organisational IT support and maintenance overheads. Content stored within wikis is much more accessible and easier to navigate than if stored within multiple individual documents. Wikis negate duplication of content, since subject text can be stored once and then easily linked to from within other pages in the wiki. Wiki functionality offers opportunities in the area of true collaborative authoring. Even if the end product has to be published in a Document Management System, there is no reason why it can’t be developed first within a wiki. Here authors can work in

Uses of different internal blogs • Project team blogs: Posting status and update communication to the project blog enables face-to-face time to be used for value-added activities and supports globally distributed teams • Leadership blogs: Excellent for communicating message, direction or developing understanding of strategy, and generally reaching-out, connecting, and receiving feedback • Functional group blogs: A means of connecting and sharing within a functional area • Subject matter expert / ‘idea leader’ blogs: A platform for inspiring and educating across the organisation, even when the individual doesn’t necessarily have the advantage of natural visibility via a management or leadership position • Special interest group blogs: For connecting those with an interest in a particular subject area, regardless of where they sit in the organisation

parallel, in real-time, and the need for time-consuming iterative review loops can be slashed in favour of ‘live documents’. This ensures duplication of content development and feedback is eradicated as the most up-to-date version of the text is always on display for everybody to see. Blogs

Blogs are certainly the most discussed component of the Enterprise 2.0 toolset for those yet to take the plunge. This is probably due to the notoriety and popularity that blogging has sometimes attracted on the World Wide Web. However, in a consistent theme within Enterprise 2.0, the internal version of blogging takes a much different form to its web-based predecessor. Internal blogs can be put to many different uses as described in Box 2. Wherever there is a need for some form of communication or discussion, a blog is a good candidate for a solution. In common with all of the tools discussed here, a successful blog will often lead to lesser email traffic— certainly something to strive for in our era of unmanageable inboxes. By surfacing information and discussion via a team or community blog, the inbox can start to be reclaimed for action-oriented correspondence. Really Simple Syndication (RSS)

RSS, the most low-key of the Enterprise 2.0 tools, actually has the potential to be the most significant. If successful, RSS stands to become part of the average PC user’s ‘core productivity toolset’, sitting alongside packages such as email and office suite software. RSS offers a very basic premise. Users no longer have to visit web or intranet based sites of interest to see what new changes or posts have taken place. Instead the new content is delivered to the user, or at least a summary enabling them to decide whether to click through to the site itself to see the full body of the text.

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may evolve over time, and hence one might struggle to re-plot the path to the resource in question. Application of tags that are meaningful to the users provide them with multiple routes back to finding the link in the future. The social aspect results from other people storing bookmarks and tags in the same application. As the number of users and bookmarks stored increases, the potential for the individual to find value in what others have stored increases. For instance, through the discovery of links to resources of interest that have been stored by other users using tags that are identical to, or related to, tags the user has added themselves. The online community acts as a valuable filter with the passage of time. Combining metadata generated within an enterprise social bookmarking application with the results of an enterprise search indicates the value of a link. The very act of somebody storing a bookmark suggests there is usefulness in that link, and the addition of tags and a brief description provides context that would not otherwise be available in an enterprise search.

Social bookmarking

Mashups

Social bookmarking is a good entrypoint for new Enterprise 2.0 users. It provides a very simple function that can be seen to provide almost instant pay-back to the users and also gently introduces them to the benefits of social software, in this instance the sharing of bookmarks online with others. On the web, the most famous instance of this category of software is del.icio.us. It allows the user to create an online space for the storage of their web or intranet bookmarks. Rather than forcing the users to organise their bookmarks in a rigid hierarchical folder structure, del.icio.us allows them to apply any number of freeform tags to describe the nature of the link. A limitation of folder structures is that the categorisation of a resource

Mashups are an emerging category within the Web 2.0 world. The mashup name was stolen from the music scene, where it describes the art of mixing two pieces of music together to produce a new track. To date almost all examples of Mashups on the web have revolved around Google Maps, for instance the Chicago Crime Database Mashup, which takes a Google map of Chicago and ‘mashes’ it with available crime statistics by area, thus enabling the casual

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The user views the updates in an RSS reader. RSS readers now come in many different shapes and sizes, including Outlook email client plug-ins, standalone desktop clients, or via an Internet browser. Because all content is displayed in a standard format, regardless of where it was originated, it is possible to quickly scan a large number of posts from a variety of sites and focus only on those which are of most interest. Because content is pre-arranged into specific ‘channels’, the individuals have control over (a) what they chose to subscribe to and (b) what priority they place in terms of the frequency with which they will review it. RSS has emerged as a pre-requisite for successful take-up of whatever Enterprise 2.0 tools are deployed. But even if one decides not to implement any of the other Enterprise 2.0 tools, RSS can still provide huge benefit to the organisation since many legacy intranet sites and web-based applications can easily be adapted to provide RSS subscription feeds, and most Web-based sites now support RSS.

browser to see where the crim hotspots in Chicago are physically located. Inside the enterprise, this is perhaps one area where the corporate sector is slightly ahead, at least in the variety of uses of mashups we can identify. While purpose-built software designed to facilitate it is slowly starting to emerge, we are fortunate in already having existing access to powerful data-querying software that can be turned to this pursuit if so desired. Applying Enterprise 2.0

There can be no doubt there are plenty of compelling reasons for organisations to consider the introduction of Enterprise 2.0 software into their environment. Indeed they may need to consider it in relation to the talent emerging onto the marketplace for the first time, who will expect nothing less. Companies risk appearing as out-of-date and out-of-touch if they are not seen to be embracing it. Use of these tools within organisations will evolve over time, as will the software itself. There is no ‘one size fits all’ approach. The strength of Enterprise 2.0 is that users have the flexibility in the way they choose to apply the technology, meaning improvement in their productivity. If successful, the net effect of implementing Enterprise 2.0 within the organisation will be an environment where workers are less constrained by organisational or geographical barriers, have easier access to information and knowledge that can help them carry out their roles more effectively, and the organisation is able to better optimise the skills, passions and experience of the workforce.

Simon Revell is Manager of Enterprise 2.0 Technology Development at Pfizer, the global pharmaceutical company. In this role he focusses on exploring and managing the implementation of Web 2.0 inspired technologies and approaches for internal use within the company.

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IT Outsourcing Strategies in Drug Discovery Outsourcing pharma or biotech research IT can be very difficult to implement but with a well-planned strategy the benefits can easily outweigh the risks. Chip Allee, CEO, CeuticalSoft Inc., USA

here are many potential benefits that can be derived from IT outsourcing. Apart from cost savings, access to resources is also a driving force behind the outsourcing phenomena. With the right outsourcing partner enabling a flexible allocation of resources, IT projects can be scaled rapidly and affordably. Success or failure of outsourcing often has less to do with the provider and more to do with the customer. This is because discovery R&D organisations are rarely equipped to manage IT and have great difficulty specifying and implementing their goals. If any organisation has a poor track record of defining, managing and deploying IT projects either with internal capabilities or outside vendors, then outsourcing will probably create more problems than it will solve. Delivery models for outsourcing

There are several possible delivery models that can be applied to IT outsourcing. On-site contractors, offshore contractors, hybrid sourcing and cyber sourcing are the broad categories. On-site contractors can be provided from overseas on a short term visa or they can be arranged for a longer term through an offshore company that has an onshore presence. In many countries, a company with operations in the local country can arrange internal transfers under visas that can last several years.

Another effective option is to place an offshore contractor on site for a knowledge transfer period of one or two months and then send them back to the offshore site to continue working for the customer. This builds a working relationship, nails down technical issues and facilitates the transition to executing projects remotely. Hybrid sourcing involves working with a company that combines onshore resources with offshore resources. This is the â&#x20AC;&#x153;best of both worldsâ&#x20AC;? scenario since subject matter expertise, technical support, requirements gathering, field service and administrative functions can be handled onshore while highcost labour-intensive work like software programming can be executed overseas. Companies that do not have sophisticated project management capabilities will benefit greatly from the hybrid model. Cyber sourcing is rapidly making headway in the outsourcing arena under the banner of Software as a Service (SaaS). SaaS essentially involves web delivered software applications that are entirely hosted by the provider and currently has many viable entries in the business intelligence area soon to be followed in more specialised areas such as pharmaceutical R&D. Cyber sourcing is an option that is usually not mentioned in the outsourcing conversation but it is

rapidly becoming an attractive solution to remove the hassles of developing and maintaining in-house software. Some of the advantages of SaaS include banking level security, low cost of entry since there are no large up-front costs, rapid implementation that in some cases can entail nothing more than logging in and simplified software evaluation for purchasing decisions. Benefits of IT outsourcing

It is prudent to evaluate outsourcing in terms of expected benefits and with realistic objectives in mind. The most obvious potential benefit is cost savings. A realistic expectation in this regard is probably about a 50% or lower cost reduction. This is because a competent provider will have all the ingredients for success including highly qualified personnel, project management, modern facilities and quality communications capabilities. It is possible to find independent programmers who will charge very low rates and they can be very effective for small, well-defined projects. But this type of engagement will not scale and can be very difficult to manage. Another, arguably the most important reason, is access to resources. It is often very difficult and very expensive to find qualified personnel locally and outsourcing becomes the only viable option. A large project can be scaled and resourced in India very fast and for reasonable costs if the provider has the right systems in place including a comprehensive HR capability.

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Another key benefit of outsourcing IT comes when key scientific personnel are relieved of time consuming IT duties and redirected to basic R&D. Some types of projects that lend themselves to outsourcing include legacy migration, new system design / build, database consolidation and maintenance, code migration and maintenance, commercial software development and web portal development. Indian outsourcing companies can be roughly split into three categories: major players, mid size and small life science specialty firms. The major players are companies with revenues of US$ 1 billion or more, mid size are companies with revenues below US$ 500 million and the small firms are companies that have a particular expertise in some area of life science IT. Table 1 gives a brief list of some companies that fall into these categories and whether or not they have a life science practice or offer life science software products. Engagement models

Most offshoring business relationships consist of one or more of the following engagement models: 1. Project-Specific Engagement: This involves conveying a specific project to the provider with an expected completion period. It can be based on a fixed price, milestone payments or time and materials. A project based engagement is likely to be more expensive than other models since they are difficult for the provider to resource especially for smaller projects. The project model is more likely to succeed if the provider has an onshore presence. 2. Full Time Equivalent (FTE) Engagement: This is the practice of committing to long-term contracts for a specific number of dedicated people working exclusively for the customer. This has a number of advantages not the least of which is cost optimisation. Since the provider can safely hire personnel without concern

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Outsourcing Companies Major Players Life Science Practice/Products

Company Tata Consultancy Service

Yes/No

Infosys

Yes/No

Wipro

Yes/No

HCL Technologies

Yes/No

Satyam

Yes/No

Patni

Yes/No Mid Size Players

Company

Life Science Practice/Products

Syntel

Yes/No

Fusion Software Technologies

No/Yes

Sonata Software

No/Yes

Hexaware

No/Yes

Zensar (remote oracle dba service)

No/Yes

Small Life Science Speciality Players Company

Products

Phoenix & York

Yes

Brainwave

Yes

Jubilant

Yes

Strand Genomics

Yes

Molecular Connections

Yes

Deciphar

Yes Table 1

for project duration they can operate at lower margins and share the risk reduction benefits with the customer. FTEs can be thoroughly trained on customer processes and can establish good working relationships with customer personnel. The customer can also have a hand in selecting FTEs that fit their needs. All these factors make the FTE model very effective for long term ongoing work which is why it has been used extensively for organic synthesis. 3. Build, Operate, Transfer (BOT) Engagement: This model consists of hiring an outsourcing firm to help establish a permanent facility in an offshore location. The provider can start and manage the entire operation for an appropriate time period and then hand over the keys to the customer when the time is right. BOTs represent a substantial commitment on the part of the customer

and should not be attempted without signif cant experience with other forms of outsourcing. One caution is that key roles may disappear when the provider pulls out due to overlap with their permanent staff who may have been filling those roles. 4. Offshore Dedicated Centre (ODC): This is the latest trend in outsourcing jargon and is essentially a BOT without the T. In other words, the provider establishes a dedicated team and facility but is expected to permanently manage the operation. ODC eliminates the risk of being hung out to dry but provides the continuity that may be lacking in an FTE approach since FTEs are often stopped and started on as needed basis. The reality is that most offshoring engagements will not fit neatly into any particular mould. The essential ingredient for any model is the presence of key roles on both the customer and provider side such as project managers, engineers, support and particularly subject matter expertise. Ideally, there should be a solid triad of available subject matter experts that include someone on the customer side, someone on the provider side but located onshore and someone from the provider side located offshore. This is of particular importance to highly technical enterprises such as pharmaceutical R&D. Productivity measures

The following discussion is critical to IT offshoring but can be equally applied to any version of IT implementation, including exclusively in-house operations. It can be encapsulated with the statement that IT tends to be predominantly framed in terms of technology and rarely in terms of productivity. Without this fundamental shift in thinking about how to measure achievement it can be very difficult to implement any IT objective and particularly difficult to transfer objectives to a third party. Some measures of productivity that can be applied are as follows:

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6. Process automation: The careful analysis of actual laboratory processes can result in the elimination of manual intervention steps, sneaker nets (carrying data around on disks or paper) and Cliffware (dedicated instrumentation software that drops data off a cliff in terms of downstream integration). In order to stay focussed on productivity, technology discussions that obsess over things like the latest technology, eye-popping graphics, Web delivery, fastest servers, grand unifying database backbones and feature myopia need to be avoided. Obstacles to successful IT implementation

IT implementation is also a generic topic but the obstacles are amplified when pursuing an outsourcing strategy. One of the common obstacles is poorly defined requirements. This is a direct result of the stake holders not having the time or expertise to determine and convey requirements. Also, front line practitioners are often left out of the loop which guarantees that the assumed processes will have many undiscovered variations. Additional obstacles to successful IT implementation include high level mandates without end-user buy in, poor architecture, and the deployment of systems that do not scale. Other areas of concern are designing applications for poorly defined processes and assays, especially processes or assays that do not exist yet or systems that have not been stabilised and are therefore subject to frequent changes (moving targets). The most common hindrance to successful IT implementation is the lack of support. This can take the form of no qualified support, no embedded support (no one in the lab with advanced application A uthor

1. Discovery IT efficiency: This is a programme of continuous improvement to reduce bench scientist information processing time. This means that there is an intentional objective to focus on reducing time consuming repetitive IT related tasks. Scientists often find themselves drowning in these tasks but they seldom get attention because they are not related to large scale enterprise systems that IT groups tend to be enamoured with. 2. Application utilisation: This is the continuous monitoring of software application usage. Some utilisation road blocks include: show stoppers (hard coded application requirements that do not fit established processes and make the software unusable), unregulated laboratory process changes, manual intervention steps, home grown patches, stagnation (applications are not maintained or upgraded), lack of proper file conversion capabilities and lack of effective database integration. By monitoring application utilisation many opportunities may present themselves such as the elimination of unwanted applications or major usage improvements through additional training and customisation. 3. Data quality: Reviewing database and other data storage resources for inconsistencies, false positives and false negatives and the effectiveness of data validation procedures can lead to many productivity enhancements. 4. Compliance monitoring: This is the practice of monitoring actual usage of sanctioned IT systems versus gorilla work-arounds that lab personnel frequently engage in primarily involving Microsoft Excel workbooks. 5. Data availability: Data published in corporate black hole databases often requires an act of God to recover in a desired format and complicated reporting tools and the lack of enduser self sufficiency means everything has to be channelled through an IT fortress on a glacial schedule.

knowledge), no DBA support (particularly in smaller companies), dying of thirst next to the well (in-house IT not available), IT support preoccupied with grandiose self serving schemes and inadequate provider support (including no onshore presence). Counter measures

Some effective counter measures to IT meltdown include: 1. Develop embedded super-users: These are laboratory software end-users that have advanced knowledge and understanding of particular applications and can serve as ambassadors to their colleagues. They can be critical to successful implementation and often represent the difference between success and failure. 2. Engage front line practitioners (FLPs): Front line practitioners are the people actually executing a particular process. FLPs should always be consulted when defining processes and gathering requirements. 3. Implement pilot programmes. Any software project should be tested in a pilot setting prior to large scale rollout. 4. Choose outsourcing providers with domain expertise. 5. Focus on productivity and not on technology. Discovery R&D operations can often be chaotic because of intense financial pressures, immature processes and lack of engineering support. Effective IT implementation needs to adapt to this reality and cater to scientific rather than technological goals. An effective Discovery IT strategy does not operate in a vacuum and is guided by periodic productivity measures. This feedback loop is the gatekeeper for taking on new ground.

Chip Allee is the CEO of CeuticalSoft, a company dedicated to the design and development of expert data analysis applications for the pharmaceutical industry. He has twenty years of experience with scientific programming and an extensive background in drug discovery research. He is also the Chairman of Phoenix & York Business Solutions a company based in Chennai India.

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Pharmaceutical Manufacturing Embracing process analytical technology

The idea behind Process Analytical Technology has been a proven technology in oil refineries, petrochemical, food & beverage and semiconductor industries. Pharmaceutical and Biotech companies can ensure improved quality, reduced scrap and enhanced productivity by learning from the experiences of these industries.

Pala Bushanam Janardhan, Business Consultant, Manufacturing & Plant Automation Services, Life Sciences and Healthcare Practice, HCL Technologies Ltd., India

utside Life Sciences one would not hear much about Process Analytical Technology (PAT), a system for designing, analysing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes. The idea behind PAT is not new. It is more than a 50 year old concept and a proven technology in several other industries. Advanced Process Control (APC), which is comparable with PAT, has been used for a long time in Oil refineries, Petrochemical, Semiconductor and the Food & Beverage industries. Usage of APC enabled the determination and control of product performance to specification in near-real time. APC is composed of different kinds of process control tools. Statistical Process Control (SPC) is one of them, others being model predictive control, Run2Run & fault detection and classification. The PAT tools comprise of continuous improvement and knowledge management tools, multivariate tools, process analysers and process control tools. Advanced process control

In oil refineries and petrochemical industries quality problems need to

be corrected before they contaminate large volume of products. In a typical vegetable oil refinery as much as 25 tonnes of edible oil can flow through the plant every hour. Considering the volumes handled, frequent information about the oil in the production process is important. Any abnormality in the production flow would result in a lot of re-work and ultimately, lost time and profit. Traditional analytical methods are time consuming exercises. Hence critical information is not available at the right time for decision making. Usage of APC systems enables availability of a continuous stream of results ensuring better control of production.

Benefits of APC Usage of a comprehensive suite of APC software in Oil refineries, Petrochemical, Semiconductor and Food & Beverage industries has: • Ensured quality improvement benefits to a wide range of processes • Ensured high utilisation of plant equipments and hence high Overall Equipment Effectiveness (OEE) • Delivered real-time control • Optimised manufacturing operations and ensured performance improvements

Semiconductor industry in a bid to enhance productivity and reduce cost looked for technology and solutions in process control. They adopted SPC & APC for: • Better understanding of the processes and their interdependencies • Reduction in wastage • Shortening lead times to detect process faults and to trace them back to the root cause. SPC is a method for monitoring, controlling and improving a process through statistical analysis. In this technique the process output is monitored to detect an out-of-control process. Semiconductor industry using SPC attempted to assign a cause to an external disorder. The process was considered out of control if output variance could be attributed to a cause. The disadvantage of using SPC alone is that the controlling process is offline, as the process performance evaluations mainly focus on past performance, using all available historical data to see how a process has been operating and suggest improvements. Apart from the time-lag the cost of rework or wastage is also another disadvantage in using SPC. Composed of different kinds of process control tools APC is often used for solving multivariable control problems. An APC application will calculate moves that are sent to regulatory controllers.

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Some of the key business benefits of APC Industry

Application

Key Business benefits

Petrochemicals

On-line blending

• Increased operator safety through automation • Tighter compliance • Reduced cycle time

Semiconductor

In-line Process & Equipment Monitoring

• Standardised process • Minimised tool downtime

Food & Beverage Process Automation & Control

• Improved yields, throughput and product quality Table 1

APC utilises a model of the plant to adjust operating conditions of the process so as to minimise raw material usage and maximise profits. The output of APC therefore sets the targets for the local closed loop controllers, taking into consideration the operational limits of the plant and effectively bridging the gap between the plant’s true business objectives and its actual operations. By adopting APC the semiconductor industry used measurements of important process variables to incorporate a feedback loop into the control strategy. With APC, a mathematical model of the process is used to control the closed loop online and correct the process based on the measurements. APC accomplished this by transferring variability in the output variable to an input control variable. As the process is monitored continuously in APC, it generates useful information about every wafer and helps to identify systematic drifts and offset of the tool and helps in correcting them. Also this control loop in APC can adapt to changing process conditions and control the closed loop in optimal way. Another approach taken by semiconductor manufacturers was in adopting in situ measurements where in-theprocess measurements are taken before the material goes out of the processing tool. But due to the high cost of the integrated tools, this technique did not gain credence. Instead semiconductor manufacturers adopted a combination SPC and APC in coming up with a solution called Run To Run (R2R) control system where in the process results are fed back to the process tool as well as

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fed forward to the next process tool to correct the variability in the process. This is being adopted by almost all leading semiconductor manufacturing companies. Semiconductor manufacturers like Intel, AMD, Infineon have benefited by implementing APC solutions. These solutions are ensuring better control of the process and thereby enhancing the productivity. Conservative technology adoption plagues pharmaceutical industry

Pharmaceutical processes are complex with potential product variability due to variation in operating conditions and raw materials. Process steps, ingredients, the condition of the equipment and changes in the manufacturing environment itself can lead to variations in product quality. The pharmaceutical industry makes good use of technology in product development, but does not do the same in its manufacturing facilities. The pharma industry has lagged in using information technology to automate the manufac-

Challenges in Pharmaceutical Industry Pharmaceutical companies still suffer from excessive rework and scrap, high work-inprocess, low capacity utilisation, prolonged cycle times and Laboratory bottlenecks According to the figures released by AMR in its research report the industry average for both rework and discarded product is about 50%, on-hold product inventories are at the 40 to 60 day level; The plant utilisation is in the range of 40 to 50%. The average cycle times in the industry are in the 30 to 90 day range. Laboratory bottlenecks can add as much as 75% to the cycle time and even more when an investigation prevents routinely scheduled activities.

turing processes, specifically in its batch record systems and for maintaining process quality control. Learning for the pharmaceutical industry

Considering the benefits that have accrued to Oil refineries, Petrochemicals, Food & Beverage and Semiconductor industries by adoption of process control technologies, Pharmaceutical industry, should shed the conservative approach and incorporate the learnings from the above said industries to address the challenges that plague the industry. PAT solutions are provided for research and development, scale-up and manufacturing of drug substances. Some of the areas being: • Raw material identification • On-line monitoring of manufacturing processes • On-line analysis The key modules of any PAT solution are: • Data acquisition • Data storage • Data mining, visualisation and multivariate analysis • Control Data acquisition

The various process parameters are acquired by using multiple analysers, like Infrared (IR), Ultraviolet-Visible Spectrophotometry (UV-VIS), Raman, High Performance Liquid Chromatography (HPLC) and Mass Spectroscopy. Of all the analytical technologies utilised in PAT applications, spectroscopy is the largest in terms of dollars (Figure 1), with Near Infrared (NIR) by far the most common technique. Electrochemistry, while smaller in dollar terms, is more commonly applied due to the lower cost and relative simplicity of this technique. Other analytical techniques that are now seeing significant application include particle size analysis, HPLC, mass spectrometry, and the small but fast growing technique of thermal effusivity. The market of software for instrument

M a nu f a cturin g

Worldwide Usage of PAT Instrumentation and Software Spectroscopy 38%

Mass Spectrometry Other 4% 6%

Particle Size 6% HPLC 6%

Reduction in cycle time

PAT quality assurance approach involves processing to a quality-based endpoint and eliminates wasted cycle time associated with processing using a fixed timebased end-point. Reduction in costs

PAT enabled unit operations reduce the dependence on laboratory testing and associated lead times, thus reducing the overhead costs associated with product quality.

Software 12%

Electrochemistry 28%

Data storage

The management of PAT data is complex and the flow of information is enormous. Hence a unique data manager that would store all the data in a single distributed database and handle huge flows of data coming from the analysers, the Process Control Systems and Supervisory Control and Data Acquisition systems is required. Data mining, visualisation and multivariate analysis

A normal PAT suite includes modules that provide operator workplace, central method configuration, multivariate analysis batch configuration and asset management for analytical and process equipment.

Control

Controlling processes requires a thorough process understanding to be realised within regulated environments. PAT solutions aid in process understanding and control. Benefits of PAT

PAT improves asset uptime and availability for pharmaceutical unit operations by up to 40 %. Costs are reduced by up to 30 % while product quality is maintained. Improved process understanding

The process of pharmaceutical manufacturing is complex and not well understood. However, PAT-enabled processes provide access to information in real-time. The information when mined enables to find the critical quality parameters through multivariate analysis. Once the critical quality parameters are determined, it is then easier to establish accurate control schemes for the relevant process parameters thereby a more robust process can be established in a shorter timeframe A uthor

control, process modelling, and data collection and analysis lags significantly behind the instrument technologies in terms of development, and is primarily the realm of software consultants who develop highly customised solutions for individual manufacturers. According to the market analysis and perspective report of Strategic Directions International, Inc the combined worldwide PAT instrument and software market was worth nearly US$ 150 million in 2005, but should see annual growth of about 15% through 2010.

Figure 1

Improvement in Overall Equipment Effectiveness

Improved OEE is ensured through reduction in batch down-time achieved through better control and early fault detection measures The way forward

PAT provides an opportunity to move from the current “testing to document quality” model to a “continuous quality assurance” model that can improve a company’s ability to ensure that quality is by design PAT will revolutionise the way pharmaceuticals are made in future. The need of the hour for the Pharmaceutical and Biotech companies is to adopt best practices from other industries to ensure improved quality, reduced scrap and enhanced productivity. The author acknowledges the inputs from Alison Smith, Roddy Martin of AMR Research, Thomas Buijs of ABB Automation Technology, www.confectionerynews. com, Stratus Technologies and Strategic Directions International Inc. Full references are available on www.pharmafocusasia.com/magazine/

Pala Bushanam Janardhan is a Business Consultant (Manufacturing & Plant Automation Services) in the Life Sciences and Healthcare Practice at HCL Technologies Ltd., since April 2006. Prior to joining HCL, he has served the Pharmaceutical industry in various capacities—handled process technology development, technology transfers etc.—for more than 18 years.

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PAT and ROI A holistic approach

Despite the advantages PAT offers to the pharmaceutical industry, many companies remain hesitant about its implementation due to high investment costs. Ingrid Maes, Consultant, Innovative Technologies, Competence Centre Phamaceutics, Siemens AG, Belgium

y offering companies a chance to understand and control their processes, both at the R&D and manufacturing stages, PAT enables continuous quality verification and, with it, a chance to deliver consistent quality, lower costs, speed up product development and release, improve market responsiveness and reduce supply chain bottlenecks. Companies will also be rewarded by a lighter regulatory touch if they can gain PAT-led control of the product design space. Nonetheless, many companies face difficulties in implementing PAT projects. An important building block is to develop a clear ROI analysis. Such an analysis delivers a number of benefitsâ&#x20AC;&#x201D; the objectives and implications of PAT should become clearer for the company; it should provide a clear framework for investment and for evaluating outcomes; and the case for PAT could be articulated to top management and other key personnel within the company.

The ROI context of pharmaceutical PAT projects

Returns

Stakeholders, Regulators, Patients

Pharma Company

R&D / Manufacturing Processes

PAT/QbD System

Starting Point â&#x20AC;&#x201C; The full ROI context

A vital starting point is for companies to consider the full context of PAT. Only by doing so can companies judge the true worth of PAT. This requires a consideration of the wider environment in which PAT will be

Investment Figure 1

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implemented (Figure 1), not just looking at quality and process control but going far beyond this to consider regulatory relationships, the needs of healthcare organisations and, ultimately, the links with patients. An important part of the US Food and Drug Administration’s vision for PAT, for example, is that the adoption of the technology by the pharmaceutical industry will help close the gap between drug product development and the patient. In the future, it is hoped that PAT will be part of a feedback loop that can enable companies to take account of how a specific drug is performing in specific patient contexts and adjust formulations and manufacturing accordingly. In addition to these future visions, the development of PAT and decisions about the best roll-out of the technology needs to be taken in the context of a company’s current and projected drug portfolio, reflecting the different manufacturing needs of products that are in the pipeline. In other words, decisions on PAT cannot be taken away from the context of the three key major elements—the company’s future business and product strategy, its

organisational setting and external environment. However, in my experience, this consideration of wider external or internal context often does not take place when it comes to PAT projects in pharmaceutical companies. Companies frequently view PAT in exactly the opposite way, deciding to buy a couple of tools to replace existing lab measurement methods and see where that leads them. This consideration of context outlined in Figure 1, in turn, leads to some of the parameters for the ROI analysis both on the cost and the benefits side. For example, investment in PAT should be expected to deliver tangible performance improvements in R&D and manufacturing processes, such as reduced waste, faster throughput times and, ultimately, the potential for real-time product release. At the same time, there will be wider company implications, such as retraining or redeployment whose costs will need to be fully factored in. Rooting ROI in strategic ambition

The design and extent of the ROI analysis will be largely determined by

the extent of strategic ambition behind the PAT implementation. There is a big difference between a company that is seeking to develop PAT in a greenfield setting, aiming for full realtime product release, and a company that is seeking to improve an existing aspect of manufacturing, perhaps on a single unit operation such as drying. In many situations, companies can start with a small application of PAT on one part of the production process, for example on a single unit operation such as drying, before moving on to a more global view. A typical start point, for example, might be the establishment of an end-point detection for a dryer or granulator. Indeed, in our experience, the most common applications of PAT relate to online monitoring of blending, drying and granulation steps. In all instances, the goal should be some clearly identifiable performance improvement. However, as discussed, many companies do not even start by identifying such clear change but instead fall into the trap of seeing PAT merely as an alternative to existing activities, for example investing in an in-line process analyser as a replacement

Key ROI Questions Companies need to identify the situations where PAT investment is most likely to be cost-effective and be clear about the purpose and scope of the project as well as how it helps the company to achieve its longer term manufacturing vision and strategy. The following series of questions can help in such identification: Strategic gain – How does the PAT project fit with the company’s wider product and manufacturing strategy? Also, what are the project’s specific R&D or manufacturing benefits, such as operational savings, faster time to market, increased machine availability, less waste etc? Required investment – How much investment, including capital expense, planning and deployment, training, and ongoing management and support, will the project require? Financial return – What are the expected financial returns of the project, including ROI, savings and what is the payback period?

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Operational efficiency – How will the PAT project contribute to overall enterprise efficiency? Is the enterprise and knowledge architecture in place to capture these gains? Risks – What are the potential risks associated with the project? How likely are they and what contingencies need to be in place? What would be the impact on the financial return and strategic gains? Competitive and reputational impact – What competitive advantage can be gained? What are the reputational implications of investing or not investing in PAT? How does the proposed investment compare with competitor’s PAT plans? Accountability and ownership – Who is accountable for the project’s success? Is the project owned by top management? Is there sufficient leadership to deliver the change in working methods and culture that will be needed for the project to be successful?

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The importance of integration

For any pharmaceutical company seeking to use PAT to achieve real-time product release or, indeed, to move towards the FDA’s vision of closing the gap between drug development and the patient, the state and extent of existing infrastructure will be critical. Realtime product releases requires a PAT system that is linked to an electronic batch record and other support infrastructure. Integration of equipment is essential, otherwise the product may be ready but the next machine in the process may not be. Companies that already have such infrastructure in place will be able to achieve much faster ROI payback times. Similarly, an important condition for being able to link clinical batch manufacturing and quality data to clinical outcomes, is the possibility to store data in the same format with the appropriate meta data / context data, so that different data sources can be combined and evaluated. Systems and data formats have to be aligned and be able to be merged. This puts the emphasis on common IT systems throughout the whole R&D process as well as on data mining tools to be able to discover relationships. The long-term benefit is that companies will be able to quickly gain insight and knowledge in therapeutic efficacies and mechanisms and how they are impacted by the manufacturing process. In fact, this is nothing new, as such principles have for long been applied in other industries, where customer satisfaction and product performance appreciation by customers is fedback into process development and improvement cycles.

One inhibiting factor in the development of pharmaceutical PAT has been the absence of software that enables the full integration of PAT tools and all information flows during processing and online comparison of process data with previous or historical data. This is now being addressed with the development of software that enables the collection of data and the full integration of all information flows during processing and online prediction calculations as well as comparison of the actual batch trajectory with the “golden batch” trajectory. Companies now have the important

The design and extent of the ROI analysis will be largely determined by the extent of strategic ambition behind the PAT implementation.

ability to have a common user-friendly interface for all PAT tools (process analysers, multivariate statistical tools, LIMS, MES, process control, historian etc.) and the ability to fully integrate PAT into the manufacturing and development architecture. The importance of leadership

As discussed above, any ROI analysis should take full account of the risks surrounding a PAT project. In doing so, companies should take care not to underestimate the less tangible, ‘internal risk’ that can occur if personnel fail to capitalise fully on the potential of PAT.

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for offline analysis in the laboratory. Such a narrow view of PAT is unlikely to prove cost-effective and, indeed, may fail to deliver sufficient ROI to be justified in isolation.

This can arise for a number of reasons such as inadequate attention to training, existing cultures that promote ‘silo working’ or other organisational inertia factors. PAT does require a greater focus on multi-disciplinary skills and teamwork than some pharmaceutical R&D and manufacturing units are used to. Different departments, such as regulatory affairs, quality control, process engineering and the manufacturing teams, need to work together on PAT. The potential of ‘cultural drag anchors’ to slow the progress of PAT is a very real project risk and can be minimised significantly by having clarity on the key ROI questions as outlined in the above box and the consequent leadership and backing of top management. Way forward

PAT projects are being developed by pharmaceutical companies in a wide range of circumstances, ranging from the development of greenfield future development and manufacturing facilities, to the fixing of specific snags in current manufacturing processes, such as end-point detection for a dryer or granulator. In all cases, the development of a clear ROI analysis will be important to the success of such projects. The best ROI framework needs to answer key questions that link the project to the company’s wider strategy and environment. Those companies that succeed in bringing together a holistic view of the short and long-term are more likely to make PAT implementation decisions that deliver a more effective ROI.

Ingrid Maes is responsible for innovative technologies, including Process Analytical Technology within the Siemens Headquarter Competence Centre Pharma, located in Antwerp (Belgium). She has worked for 15 years in Process Analytics and Multivariate Data Analysis as marketing & sales manager, and for developing new application fields for Process Analytics and control, in many industrial branches. She is an Executive Committee member of ASTM E55 (Pharmaceutical Manufacturing) and the ISPE PAT Interest groups (SIG).

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Ready-To-Use Technologies Driving process excellence and product safety

Biopharmaceutical manufacturing processes like cell culture, harvesting and downstream purification are rapidly gaining importance as process robustness and assurance of product safety in these processes are being considered seriously. This article looks into the lean concepts and ready-to-use technologies that are gaining prominence in the manufacturing of biopharmaceuticals.

Eric Grund, Director, FastTrak Biopharma Services, GE Healthcare, India

iopharmaceuticals have enjoyed good success since the introduction of the first genetically engineered insulin by Eli Lilly in 1982, and we have seen hormones, vaccines, interferons, and the recent triumphs of humanised monoclonal antibodies (Mabs) adding to a long list of commercialisations. As traditional pharmaceutical companies continue their struggle to discover and bring new chemical entities to market, battling with side effects and long development

times, those pursuing biopharmaceuticals have found high success rates for difficult healthcare problems whilst meeting a different set of challenges including risks of viral contamination, impurities and potential immune reactions. Roadblocks in biosimilars production

Today, the number of “biosimilars” in the biopharmaceutical pipelines has been increasing, especially when

considering the industry from a global perspective. In Europe, growth hormone and erythropoietin have been approved in this category, whereas in the US the regulatory approach to “follow-on biologicals” has not been finalised. Although biopharmaceuticals are attractive for many reasons, cutting corners in their development and production is not advisable. The processes of genetic manipulation of host cells, cell culture, harvesting and downstream purification (DSP) are not trivial, and assurance of product safety must be taken seriously. Manufacturers of biosimilars should not be looking to use different and

DSP scenarios to produce 1 ton and 10 ton of Mab / year. Output from six bioreactors is handled by one DSP train

1-ton/gr scenario

Mab Cell Culture

10-ton/gr scenario

(6 x 2.000 L, 5 g/L)

10 kg/batch 126 batches 80 yield

Cell Removal Capture

(1 x 120 cm f, 30 cm height)

- 313 L bed volume - 40 g/L capacity - one cycle

Virus Inactivation Polishing 1

(1 x 80 cm f, 25 cm height)

Polishing 2

UF/DF Formulation

Cell Removal Capture

(1 x 160 cm f, 40 cm height)

- 780 L bed volume - 40 g/L capacity - three cycle

Virus Inactivation - 125 L bed volume - 100 g/L capacity - one cycle

Virus Removal (1 x 60 cm f, 23 cm height)

75 kg/batch 168 batches 80 yield

Mab Cell Culture

(6 x 15.000 L, 5 g/L)

Polishing 1

(1 x 160 cm f, 42 cm height)

- 850 L bed volume - 100 g/L capacity - one cycle

Virus Removal - 62 L bed volume - 200 g/L capacity - one cycle

Polishing 2

(1 x 140 cm f, 30 cm height)

- 425 L bed volume - 200 g/L capacity - one cycle

UF/DF Formulation Figure 1

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cheaper manufacturing methods and less analytical rigour than the original developers of protein drugs. Process robustness and safety requirements for biosimilars will always remain the same as for the original proteins. In fact, biosimilar manufacturers will be under greater scrutiny to demonstrate comparability and they may find it easier to use similar processes they have used in manufacturing the originals. We saw how a related area, plasma proteins, was hit by virus contamination in the 1980s, and it is clear that complex biological processes and large, difficult-to-characterise biological molecules are not amenable to the short-cuts available to the producer of small-molecule chemicals. However, technologies are advancing and it is time to take stock of the issues and the direction for improvements. Overcoming the downstream purification bottleneck

In Mab production, there is frequent talk of a bottleneck in DSP. This is largely due to the considerable investments that have been made in mammalian cell culture capacity for highly successful products used for rheumatoid arthritis and cancer treatment. Coinciding with the establishment of numerous “sixpacks” of bioreactors exceeding 10,000 litres in volume, upstream technologies have improved to the extent that Mab titres frequently exceed 1 g/L. This is a hundred-fold increase over the last 15 years and obviously places significant stress on the capacity of DSP processes that were designed to handle the initial output levels envisaged when the plants were conceived. However, using modern chromatography media in platform processes, it is certainly possible to purify Mabs at levels of around 100 kg per bioreactor batch and 10,000 kg per year. Typically, six bioreactors are used to feed one DSP train, the high titre of the bioreactor being balanced by the short processing time of DSP.

A process improvement methodology like Lean can be used to find ways to create better flow in a process, take out stops, and reduce non-productive activities such as change-over time between production campaigns, cleaning procedures, or preparation of equipment and process buffers. In Lean terminology these activities are referred to as “muda” (Japanese for “waste”). While “muda” can be removed easily, some waste is necessary for the technology in use and also useful for flexibility and robustness. Although the output of Mab from each bioreactor has reached impressive levels, it can only be harvested after 10 days (usually it takes even longer to achieve the very high titres frequently reported at conferences), whereas a DSP process can turnaround in two days. By applying Lean, this can be squeezed into 24 hours and with the latest DSP platform approaches, involving only two highly-developed chromatography steps, it should be possible to reduce this even further. The big question is what capacity will be required in the future. The real need is agility, especially for start-up companies and companies entering into the biopharmaceutical

arena. There will be few blockbusters that need 10,000 Kg/year as described above. It will be difficult to predict the quantities that will be required for a particular product. Many products in the pipeline are for the same indication or are strict biosimilars aimed at exactly the same patient group. Furthermore, there are developments aimed at increasing the potency or half-life of biopharmaceuticals. Talk of personalised medicine continues with the logical consequence that drugs will be targeted at smaller patient sub-groups, leading to so-called minibusters. In the race to market, speed is needed to produce small quantities for clinical trials long before investing in large-scale capacity. All of these factors are pushing the required scale of operation down rather than up and increasing the need for flexibility and speed. Let us consider what is meant by speed. Apart from the classic desire to be first on the market, there are some new angles. One is illustrated in the area of vaccines, where efforts to be prepared for influenza epidemics require shorter timelines than those available with traditional approaches.

By applying LEAN principles, even a three-chromatographic-step DSP process can be run in one full day day h Total occupation time Centrifugation MabSelect SuRe

1 2

20 22

day h

C-101

Ideal scenario: All waste removed!

#3 #4 #5 #6 CIP & storage, off-line

Capto Q Virus filtration Diafiltration Sterile filtration

DS-101

Cycling #1 #2

Virus inactivation Capto S

V-101 C-102 C-103 DE-105 DE-101 DE-106 Figure 2

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Ready-to-use technologies

A reasonable target is to be able to deliver vaccines within three months from strain identification instead of the current six to nine months with egg-based technology. A promising approach is to use virus-like particles (VLPs). Novavax, a US-based company led by Rahul Singhvi, is developing such an approach based on production methods in insect cells combined with GE Healthcare’s ReadyToProcess™ production lines. Using a genetically engineered baculovirus vector and insect cell culture in bioreactors, influenza, vaccine can be produced based on VLPs much more rapidly than in traditional egg-based methods. Today’s pressures are pushing the vaccine industry towards greater speed and flexibility, which is enabled by cell culture in disposable bags, rapidly changeable fluid lines, ready-to-use

disposable filter cartridges, and the latest innovation, ready-to-process pre-packed production columns for chromatography. By combining these technologies, Novavax believes that it can cut project times in half and start-up costs down to a third (based on calculations at the 100 million dose level). In addition, operator exposure to potential pathogens is limited. There has been much talk in the last few years regarding the use of the terms like disposable, single-use and ready-touse interchangeably, when in fact each refers to systems and products with quite different qualities. Ready-to-use technologies bring “plug and play” options to biopharmaceutical manufacturing; many of these are indeed also single use and disposable, but others can be re-used a number of times before disposal. The key, however, with ready-to-use platforms is not disposability, but speed and flexibility.

In the Mab area, standardisation and flexibility will be required. The winners will be able to run large number of projects in parallel, dropping those that fail and switching to the successful ones. Again, the ready-to-use revolution, the move away from stainless steel towards plastic, is key to success. Again, the issue is not disposability per se, rather it is the speed at which a production change can be made, as well as the ability to work in a closed environment and reduce risks related to manual operations. Cross-contamination ceases to be a major headache. Cleaning steps are removed in line with Lean principles, and many validation problems are reduced. For Mabs, all unit operations from the bioreactor to the pure product can be substituted by ready-to-use plastic components, including bioreactors, normal flow filter assemblies, cross-flow filter assemblies, mixers, fluid handling and two or three chromatography steps.

For Mab production platforms, ready-to-process technology solutions are available for all unit operations from the bioreactor to final product

Figure 3

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Day 1

rtPCR

Day 3

Cloned

Day 7

Bacmids

rtPCR cloning HA, NA and M1 genes Day 21

rBaculovirus

Master and Working Seed stocks Day 30

Master stock

Day 40

Working stock

Day 45

Seed stock

Wave Bioreactors 500L working Day 47

cGMP Manufacturing

HA/NA/M1 VLPs Secreted Day 52

Purification

Bulk VLPs Day 60

Formulation/Filling Figure 4

A quick calculation reveals that a 500 litre operating volume plastic bag bioreactor and a Mab titre of 5 g/L would produce 2.5 kg Mab product per batch. Thus a “six-pack” of such bioreactors would potentially be capable of producing 400 kg per year, well into the range of product need for most Mabs currently on the market. Such a setup would potentially allow extreme flexibility, use little space, need low upfront investment, and offer quick commissioning and short installation time compared with classic stainless steel production bioreactors. Cleaning and sterilization steps (typical “muda”) in the upstream process would be removed along with their validation, adding more available production time for the facility. Looking at the DSP of Mabs, with pre-packed, pre-tested and pre-sanitized columns, resin slurry preparation

and column packing is not necessary and the corresponding “muda” or waste in the process is removed upfront. Since the devices are stable to typical CIP regimes, it is left on to the user to decide whether or not multiple-use is the preferred and more economical option. The novel pre-packed columns are available in sizes which allow up to about 600 g of Mab to be captured per cycle. In practice this means that the 2.5 Kg of Mab from the bioreactor mentioned above could be captured in a five-cycle operation, followed by smaller columns used in one cycle for final polishing by ion exchange. Savings on the setup side are considerable, in time, in water for injection (needed for the cleaning solutions) and in hardware costs. Since none of these ReadyToProcess solutions require start-up cleaning, the burden of validation studies is also considerably reduced. And finally, it might be argued that a ReadyToProcess solution requires a smaller staff of highly skilled operators than does a conventional bioreactor and DSP chain. This is not to say that the large, dedicated stainless steel plants will not have a place in the future of biopharmaceutical production. They always have an economic advantage in well-established large-scale production centres where there is limited need for change-over and flexibility. There are size limitations on disposable and ready-to-use solutions. Any true blockbuster of the future will still demand hard-piped facilities due to the scale limitations caused by lack

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106 pfu influenza virus CDC/WHO

of mechanical stability of disposable plastics. A successful biopharmaceutical company will use both approaches, to be agile in the race to market and cost-efficient when the race is won. The outlook

At present, the biopharmaceutical industry is undergoing a rapid change. We have not had a major set back, and Mabs in particular hold great promise, as do new approaches to vaccines and certain oligonucleotide-based therapies. With the increasing globalisation of the industry, the new entrants from Asian countries will be able to bypass the old-fashioned inflexible facility setups and leap onto the fast and flexible approaches now available. Now Asian players can also address diseases prevalent in the region and develop innovative new biopharmaceuticals and vaccines. Although, there are shortages of experienced personnel in the region, this is changing now. Also, there are many uncertainties that producers face before establishing a product in the market. Agility is the key quality that will differentiate the winners. The use of disposables and ready-touse systems is an important change that needs to be embraced by engineers who traditionally love their stainless steel. This is not because of disposability, but because of the speed and flexibility that they offer, allowing the time saved to be more usefully spent on innovation and re-inventing the industry. Full references are available on www.pharmafocusasia.com/magazine/

Dr Eric Grund has worked in the field of bio-molecule purification for about 30 years. Currently based in Bangalore, India, he heads GE Healthcare’s FastTrak business, supporting bioprocess applications world-wide. Grund has wide international experience having worked for several years in Sweden, Canada, Japan and Germany. During the last ten years his focus has been on large-scale industrial purification of monoclonal antibodies, vaccines, plasma proteins and recombinant proteins.

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Lean Transformation

Superficial imitation or a paradigm shift? True innovation is not achieved by superficial imitation or the isolated or random use of lean tools & techniques and systems (“know how”), but instead requires the “know why”—i.e., an understanding of underlying principles.

Randy Cook, Director of Education Brian Atwater, Associate Professor, Business Administration Jacob Raymer, Assistant Director of Education The Shingo Prize – for Operational Excellence, Jon M Huntsman School of Business, Utah State University, USA

or 20 years The Shingo Prize has educated, assessed and recognised operational excellence in outstanding companies. What makes these organisations stand out and challenge their paradigm? What tools and techniques are they using—what is their silver bullet? Shigeo Shingo, a managementconsultant and a practicing engineer, grasped that true innovation and transformation is not achieved by superficial imitation or the isolated or random use of tools & techniques and systems (‘know how’), but instead requires the ‘know why’— i.e. an understanding of underlying principles. The Shingo Prize Approach is based on the lean management concepts taught by Shigeo Shingo. Shingo recognised vital management philosophies and shared them through his many books. His teachings describe three levels of business improvement, which we refer to as levels of transformation: Principles, Systems, and Tools & Techniques (Figure 1).

As organisations begin a lean transformation, it is usually at the Tools & Techniques level in specific areas of the organisation. Many organisations start with 5S, Visual Management, and Kaizen events. These tools improve what is currently being done, but lack a structured approach and sometimes create a disconnect to the ultimate purpose if not evolved to the next level. Ideally, the lean journey then proceeds to the Systems level, creating a more integrated and sustained improvement model. Eventually all employees throughout all business processes develop a deeper understanding of principles (the ‘know why’), empowering the organisation to develop and deploy specific methodologies and practices unique to the organisation.

Figure 1

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The Shingo Prize model (Figure 2) is composed of four dimensions: Enablers; Process-Focussed Improvement; Enterprise Thinking; and Business Results, to which all lean transformation must lead. Within these dimensions, organisations are also adapting and moving through the levels of transformation. Lastly, the dimensions overlay five business processes—Product / Service Development, Customer Relations, Operations, Supply and Management—categories defined to cover all activities that take place within an organisation, regardless of industry. When evaluating an organisation,we recognise real transformation is not a sequential, well-cadenced progression throughout a company. The dimensions are not meant as separate and successive achievements of progression. The Shingo levels of transformation can vary within a dimension or business process; further still, some aspects of a business process might be developed to an Enabler dimension while others operate at a more advanced Process-Focused Improvement dimension. Similarly, business processes will move through dimensions at varying rates (e.g. in manufacturing companies it’s not unusual to see operations leading the lean charge, well ahead of other non-production functions). While attempts are made to place specific practices and concepts

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Figure 2

within the dimensions, some overlap is obvious in their use and applicability throughout dimensions (e.g. scientific thinking). While progress for companies working through this transformation varies, the ultimate goal is clear: integration of lean philosophy across the enterprise and its value streams to create a complete, systemic view, leading to consistent achievement of business results. Consequently, a Shingo Prize recipient is expected to have applied lean Principles—the highest level—in most aspects of all its business processes: Product / Service Development, Customer Relations, Operations, Supply, and Management. Lean transformation cannot be accomplished through top-down directives or piecemeal implementation of tools. It requires a widespread

commitment throughout the organisation to operate using lean Principles. Management must also demonstrate a high level of respect for the individual, which is encompassed in the Enabler dimension. Respect for the individual drives education and development of people, creating the impetus for empowered associates to improve the processes that they “own.” Respect for the individual naturally evolves into respect for the community. Individuals—customers, suppliers, employees, members of the community—are energised when this type of respect is demonstrated. It is important to note that respect is only a slogan unless leadership takes seriously its responsibilities in protecting both the environment and the health and safety of all the organisation’s stakeholders.

Continuous Process Improvement does not—cannot—occur by sticking with traditional management and engineering approaches. The lean concepts necessary for transformation have become increasingly common in the language of many businesses and industries. To keep them from being misunderstood and poorly applied, lean concepts must migrate from a narrow Tool-level application to a deeper, ingrained Principles level understanding…the silver bullet. It becomes obvious that this paradigm shift from Tools & Techniques to Principle focus is not merely for automotive manufactures. We now look to educate and recognise companies in all industries—public and private sectors, profit and non-profit— throughout the world. The pharmaceutical industry has recognised the need for such transformation to compete in an ever increasing global economy. The Shingo Prize has recognised companies such as Baxter, Boston Scientific, Medtronic, Cordis, DJ Orthopedics, and several others—that have embarked on this continuous journey. Summary

Lean is becoming the preeminent means by which organisations in every industry strive to improve, because it is based on timeless principles which help all members of organisations to see improvement opportunities more clearly. A wide array of implementation models are used in varying rates of success. At one end of the spectrum, organisations approach lean transformation in the systematic manner outlined within the Shingo Prize Model; while at the other end, many more firms are haphazardly trying individual tools or techniques, failing to understand what Shingo, Toyota’s leaders, and other lean thought leaders really taught.

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Examples of Lean Concepts: Levels of Transformation Lean Concepts

Tools Level

Systems Level

Principles Level

Kaizen

• Kaizen events planned by management for selected parts of the process; not tied to strategic direction.

• Systematic and ongoing identification and elimination of all forms of waste, variation, and overburden tied to value-stream mapping and company strategies; that are still managementand engineering-driven.

• Spontaneous continuous improvement via project, event, or a just-do-it approach; sponsored by management, engineering, work team, or worker. • Kaizen activity is part of everyday work.

5S, Workplace Visuality, and Visual Management

• 5S is an event-based activity that happens irregularly. It focuses on junk removal and keeping things clean. • Questions must be asked to distinguish normal from abnormal. • Visual Displays / Production Control Boards are either nonexistent or superficially functional.

• Visual displays and Production Control Boards capture a substantial level of operational detail and feedback. • Operational employees demonstrate an understanding and use a visual vocabulary as well as the principles of workplace visuality. • Visuality is being deployed systematically, as a requirement of all improvement activity. It is understood that if a solution is not anchored in visuality, it is not yet complete. • Measures are collected and made visual on area and company-wide bulletin boards, drive scientific thinking, and change in response to real time data. • Functionality is captured through visual devices and systems.

• It is easy to distinguish, at-a-glance, between normal and abnormal conditions and outcomes. • Creating a visual workplace is owned as a vision, process, and an outcome by executive leadership. • Visuality is a constant, dynamic and required component of the company’s improvement, lean conversion and Total Productive Maintenance processes. • The level of current visuality demonstrates a work environment that is self-ordering, self-explaining, self-regulating and selfimproving—where what is supposed to happen, does happen, on time, every time, day or night—because of visual devices. (definition provided by Quality Methods International)

Transition from large lots towards one-piece / continuous flow

• Kanban implemented in limited production and supply processes, with attention to disciplined use. • Reduced production lot sizes through quick changeover (SMED).

• Continued reduction of kanban quantities as process instability issues are resolved.

• Where feasible, kanban quantities reduced to 1 or zero pieces—the continuous-flow ideal. • Process improvement actions initiated when kanban reductions stall.

Level loading

• Leveling of product volume and mix in large time buckets applied to a few sub-processes in the value stream.

• Leveling of product volume and mix in smaller time buckets applied to complete value streams, including suppliers.

• Integration from customer to supplier to level product volume and mix, in smallest possible time buckets.

Product-family / customerfamily (value-stream) focus

• A few value-stream maps with limited usage to impact change or improvement. • Key production resources and support functions reorganised and re-laid out by value streams.

• Multiple value-stream maps, reaching to key suppliers, which determine the appropriate kaizen improvements and set priorities. • Systematically finding stress points and their root causes. • High degree of internal resources reorganised by value streams (few “silos” remaining).

• Thinking supports economies of flow rather than economies of scale. • Management recognises benefits of flow (e.g., reduced inventory, space, and cost). • Organisation-wide commitment to shorter lead times. • Value-stream management integrated into the daily work of leaders. • Value stream focus extending to customers and suppliers.

TPM (considered relative to equipment, but also extends to IT applications and systems in accounting, HR, quality, etc.)

• System assures regular preventive maintenance on all systems, predominantly by maintenance team. • Goal of minimal MTTF (mean time to failure), MTTR (mean time to recover)—limited interruptions.

• System assures productive maintenance on all systems; cooperation of operators and maintenance. • Goal of zero unscheduled downtime —100% availability. • Operators assuming first responsibility for equipment, with backup and oversight by plant maintenance experts.

• Includes designing systems for reliability and maintainability. • Predictive maintenance programmes where needed. • Goal of OEE (comprehensive of performance, quality, and availability). • Operators acquiring technician-like knowledge and responsibility for their equipment.

Cells

• A few cells and cross-trained cell teams in use—in assembly, fabrication, and/or support services.

• Feeder cells/cell teams integrated— physically, or through kanban—with user cells. • Cross-trained cell members rotating frequently to maintain skills.

• Cellular integration, beginning to ending operation, where feasible. • Understanding of the power of teams, proximity, employee involvement and empowerment, TPM, etc.

PDCA / DMAIC

• Major project focused usage of the scientific thinking process and associated problem-solving tools. • Tool Thinking—“What is the solution?”

• Systematic use of the scientific thinking process throughout the organisation. • Root cause and corrective action processes. • Closed-loop continuous improvement methodology, where a solution is the target. • System Thinking—“What is the root problem?”

• Thinking of countermeasures instead of solutions (need to revisit always present and understood). • Reflection becomes the primary learning activity in the process rather than problem resolution. • Scientific thinking permeates the culture and provides a common language and approach to organisational learning and continuous improvement. • Principle Thinking—“What is the need?” Table 1

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Brian Atwater is an Associate Professor of operations management at Utah State University. He earned his PhD in operations management at the University of Georgia. He currently teaches graduate courses in continuous improvement techniques and system dynamics. His current interests center around the teaching of systemic thinking and the integration of those concepts with other problem solving approaches such as creative problem solving, lean thinking, Six Sigma and TOC. Randy Cook is an executive in residence at Utah State University, with a joint appointment between the Shingo Prize and the Department of Business Administration. Randy teaches operations management courses based upon lean principles and also supports the Shingo Prize by conducting site examinations, developing teaching materials, and strengthening relations with faculty and students in the College of Business. He also consults and trains for companies in the areas of lean systems, quality and continuous improvement. Jacob Raymer is the Assistant Director of the Lean Education Initiative for the Shingo Prize. He oversees the course and content development for the on-line training. He is involved with the development and training of the Shingo Prize examiners and their understanding of the Shingo Prize Criteria and Guidelines and was part of the development team that refined the Shingo Prize Model. He currently dedicates time to the United States Air Force Europe in training lean facilitators throughout England, Germany, and Italy.

OchreDesignLab

So while The Shingo Prize Model enables identification of Shingo Prize recipients, its broader goal is to serve as a roadmap for organisations around the world to make the transition more confidently, regardless of their current situation, to a better future state based on trusted lean philosophies. In doing so, organisations gradually migrate through The Shingo Prize Model, expanding their lean focus to all their business processes and through all the Shingo levels of transformation. They implement countermeasures to their corporate challenges, then to the challenges of their supply chains and industries, and, finally, to the challenges of the societies and environments in which they live. No obstacle—affordable healthcare, efficient transportation, emerging global environmental concerns—will be beyond the reach of lean thinkers, provided those seeking to overcome obstacles truly “know why.”

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Identifying Counterfeit Drugs

An unexpected benefit of PAT / QbD

The spectroscopic signature of a product, developed for PAT, may also be used in the field to determine whether a product is real or counterfeit. Emil W Ciurczak, Chief Technical Officer, Cadrai Technology Group, USA

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ounterfeit drugs cost the pharmaceutical industry billions of dollars in lost revenues every year. In addition to the economic impact, these counterfeit products endanger the health of patients. The problem is that there is no one type of deception. Counterfeiting may be as simple as an older “real” product relabelled and rebottled all the way to harmful materials being substituted for the actual product. Internet sales or prescription products allow counterfeiters to distribute spurious materials easily throughout the world. These may be attempts to mimic the actual product, using true active and similar excipients all the way through ground wallboard painted to look like the actual drug. When a shipment of drug materials is intercepted or a legitimate supplier has questions about his stock, there is an inevitable time lag between sampling the stock and finding whether or not there is a problem. Until recently, there were no rapid means of assessing the validity of a sample in the field. Some agents were using portable NIR or Raman instruments to identify pure materials in bags, but little was done with finished products. The role of QbD / PAT

Since 2002, the US FDA has encouraged pharmaceutical manufacturers to control their processes in real time. The finalised Guidance has introduced the term Process Analysis Technologies (PAT) to the lexicon. In short, the FDA was encouraging manufacturers to go beyond the “three production lots then freeze the parameters” approach in use at that time. What was suggested (not required) was that measurements are taken in real time and adjustments be made to conditions to ensure continuous quality. This was later expanded to Quality by Design (QbD), where all raw materials, process intermediates, and finished products were designed and

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If the process signature is this “telling,” it would seem to also be a “quick and dirty” way in which to determine legitimacy of an unknown dosage form.

Using atomic masses to identify the source of drug materials Using atomic masses to identify the source of drug materials Four APIs: Mixed Sources

One API: Six Sources -24

-25

Quinine HCl, 2 Mfrs., 2 Lots each Tropicamide, 1 Mfr., 1 Lots (n=5)

-100

-150 -200 -250

-26

Tryptophan, 5 Mfr., 5 Lots

-50

Hydrocortisone, 1 Mfr., 5 Lots 5

Using the Process Signature

Naproxen

δ13C (%o vs VPDB)

δD (%o vs VSMOW)

Italy, Mfr C -28 Ireland, Mfr E India, Mfr A -29 -30 -31

-32 -33 -5

δ 0 (%o vs VSMOW)

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USA, Mfr F 0

δ 0 (%o vs VSMOW)

produced in what was called a “design space.” That is, conditions of production were such that variations in raw materials, temperature, etc. were accounted for and modified to produce a “good” product. Good was defined as passing the release tests (i.e., dissolution, content, uniformity, hardness, etc.). Since these tests could not practically be run in “real time,” another measure of goodness was needed. Since numerous non-traditional tests were being applied to the process, new “signals” were being generated. Techniques such as acoustics, thermal effusivity, ion mobility, LIBS, TeraHertz, as well as Near-Infrared and Raman spectroscopy were generating information, not formerly available, at an incredible rate. The outputs of these techniques were correlated with traditional parameters and became known as the “process signature.” That is, if the

India, Mfr B

-27

Figure 1

process signature “looked good” (using multivariate math algorithms), then the product was quite likely well within release parameters. The idea of design space, that is where all the process parameters combine to give a “good” product, could be now realised. Formerly, a Design of Experiment (DoE) would give the effect of, say, hardness on the final product. This required a large number of experiments (often an entire batch for each) where the results were studied by Chemometrics/Statistics. Since the product was also spectrally measured throughout these experiments, the design space could be related to the process signature. This allows for real-time input to production parameters, based on the correlation of the process signature to each parameter, determined in the DoE. A hand-held portable Raman instrument being used on bulk powder in plastic

A hand held “free-space” NIR instrument

Figure 2

Figure 3

As mentioned above, most traditional analysis techniques are either large or time-consuming, they are not suitable to be taken on a field mission by the FDA or US Drug Enforcement Agency, European Medicines Agency, or Interpol, etc. There were previously no alternatives to the slow, arduous chemical and physical laboratory tests for counterfeit drugs or for that matter, tests for pure illegal substances. Now several things have happened simultaneously. The PAT guidance has encouraged manufacturers to measure in places along their process stream where no measurements (certainly not in real time) have been performed before. Previously exotic tests such as isotope ratios (Figure 1) are now considered common. Because of the recognition of potential savings and productivity gains, companies have invested heavily in PAT. This immediately began to attract smaller companies that formerly did not make instruments for the Pharma industry. Of course, traditional instrument companies also got into the act and began modifying their current models for process analysis. The result has been a flood of hardware and software that allows for rapid and complex analyses. The hardware consists of a number of hand-held or portable NIR (Figure 2) and Raman devices (Figure 3 and 4) Using a hand-held Raman instrument on blister packs of product

Figure 4

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As these tools are made available to all agencies, they could just as easily be used to inspect gasoline, meat, fabrics, etc. by the agencies responsible for the safety of consumers. As the applications grow, the number of units designed for those uses will grow. Summing up

It is easy to see that the very tools that are allowing pharmaceutical companies to control the quality of their products can now be used to scan for imitation products. The subtleties of excipients ratios, tablet press “signature”, drug substance, and coating specifics all combine to give a “pass / fail” test for counterfeit materials. Thus, it is easy to see what a delightful “surprise” and unexpected benefit of QbD this will be. Adding tools to the marketplace for counterfeiting will only speed up the use of these tools in production. The growth of applications means two things: 1) faster development of newer models and 2) more sales per model. Both these forces will enhance the tools made and allow a larger profit for the instrument companies, allowing more R&D, thus, better tools. So, what started out to be a movement to make a better product, QbD has given us a tool for law enforcement, too. This is the unexpected benefit of PAT / QbD. Full references are available on www.pharmafocusasia.com/magazine/

Emil W Cuirczak is a consultant in the field of Pharma NIR (lab and process), holds patents for NIR-based devices and software, and consults for various Pharma companies, instrument manufacturers, and the FDA. He was a member of the PAT sub-committee (Validation) to the FDA Advisory Board and is a member of the PAT Advisory Committee to the USP. He is past chair of the NY and B-W sections of SAS, is a founder of CNIRS, and 2002 chair for IDRC (Chambersburg Conference). He has taught since 1979 at Stevens Tech, College of St. Elizabeth, Hood College, and Mount St. Mary’s College; he teaches short courses (in NIR and PAT) for the ACS, the CfPA (US and Europe), the SPIE, ASSA, and other organisations.

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plus the capacity to store complex Chemometric algorithms for “goodness” or authenticity checks. A number of companies are making libraries of “true” drug products, using their instruments. It is not inconceivable that pharmaceutical companies will contribute samples of either drugs to regulatory agencies or actual electronic spectra in Raman or Near-infrared format for use in prevention of counterfeiting. While better inspections may not stop the entire gamut of counterfeiting of pharma products, quicker removal of false products from the pipeline will become a lot easier. This will eventually lead to inspecting more sites on field with more samples checked at each site. Instrument companies from other industries will surely follow this development in the pharmaceutical industry. Because, the instrument companies making the smaller, hand-held instruments often come to the pharmaceutical industry, indeed, the instrument world itself, from industries such as telecommunications. One consequence is that they do not have a warehouse full of larger, benchtop or encased process instruments that need to be sold before development work may be started on smaller wireless models. This rapid response is what allows “designer models” to be built for the sole purpose of field work. With no “preconceived notions” of what makes a good spectrometer, these new companies are free to design what makes sense to the investigative industries.

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Anti-Counterfeiting Technologies What makes them effective?

Only a cross-functional and integrated approach can be successful in defeating counterfeiting and fraud, as well as the diversion of pharmaceutical products. Thomas Völcker, Marketing & Sales Director, Schreiner ProSecure, Germany

he fight against counterfeiting, tampering and diversion of pharmaceuticals is a global and complex challenge. No doubt, the traditional definition of drug safety has acquired the additional dimension of drug security—or more precisely, security of the supply chain and custody of the chain. But consumers, accustomed to their governments protecting them from “unsafe” drugs, for example, by requiring pharmaceutical

manufacturers to perform exhaustive lab research as well as largescale and costly clinical trials prior to approving a new drug, now also need to be sensitised to the fact that “only an authentic drug can be considered a safe drug.” Only a cross-functional and integrated approach can be successful in defeating counterfeiting and fraud as well as the diversion of pharmaceutical products. The use of security tech-

nologies in packaging does not prevent counterfeiting. Instead, it primarily supports product authentication, provides an indication of a drug’s purity and allows the supply chain to be tracked. This enables pharmaceutical companies to raise the hurdle for criminals and to protect their most valuable assets: customer health, confidence and satisfaction. Security packaging needs to be effective, reliable, economic and flexible

Only if target groups (experts who dispense and/or administer drugs or customs inspectors) are able to easily authenticate the original product, can the use of authenticity features produce the desired effects. The protection level of security features is contingent upon their limited availability, the combination of different security

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Forensic Taggants and DNA Markers Forensic taggants describe covert, in other words invisible, security features that can be authenticated only by advanced reading systems or laboratory analysis. Nanoparticles may be embedded in packaging substrates or prints. These taggants generally consist of inert materials, very thin aluminium particles or rare particles with a size of 20 – 40 micrometre or even smaller. The taggants carry customer-specific colour codes, engravings or maybe mixed in a special way so that they can be uniquely identified. DNA markers are usually printed in a defined area. Based on the key-and-lock system a second testing liquid is used to prove the authenticity of the product. When the customised DNA pen applies the identifying liquid substance on the printed area either a colour change or luminescent reaction proves the authenticity.

attributes and easy education of the target group responsible for authenticating the product. Obviously, the organisational and financial resources required for the integration of a security system play a key role. Security technology should have a reasonable relationship to the costs of the product as well as to the costs of packaging and distribution. The ideal security technology can be easily integrated into Standard Operating Procedures (SOPs)

without any additional effort. A flexible system allows an individual adaptation and upgrade of the level of security in accordance with the threat posed by counterfeiters. The layered approach

Experts opine that anti-counterfeiting security solutions must be based on the “best practices” of a “layered approach”. At the first level of security are relatively simple, overt features involving the use of holographic technology and colour-shifting effects that are primarily intended to enable product authentication by non-experts such as healthcare professionals, pharmacists and consumers. At the next level, i.e. in the area of covert security features, there is a wealth of highly sophisticated technology available, including nano-sized taggants or chemical markers, and even DNA-based solutions. For the dedicated target group of manufacturer specialists, forensic security features such as spectral fingerprints and molecular recognition markers may allow authentication by laboratory analysis. These features can be combined with each other as well as with simpler, overt features. The intelligent combination of such technologies can result in highly secure solutions. Key to their effectiveness is a careful analysis of the pharmaceutical manufacturer’s security requirements by an experienced security

technology expert who then develops an integrated, tailor-made solution that best meets the needs of the client. While protecting the packaging with authentication devices the security for the patient can only be provided if the packaging indicates the integrity and purity of the product. In order to prevent form exchange or modification of the content, tamper-evident packaging seals may incorporate anticopying devices such as transparent holograms, colour–shift or individual void effects in order to enhance product security. Integration requires inside knowledge and security awareness

Technology providers have developed a wide variety of sophisticated features, but to ensure their viability, it is of high importance to consult with packaging system integrators who have extensive experience in evaluating security technologies as well as in the area of GMP-driven integration of such technologies into packaging. Choosing the right security features is not a question of technical sophistication. In addition, ease of integration into existing pharmaceutical SOPS, implementation of specifications and validation of packaging processes are essential requirements. Understanding the threats of diversion and trafficking of products, it becomes clear that the implementation of security technologies demands reliable management and monitoring processes and practices—from data handling, sourcing, manufacturing, warehousing and all the way to transportation. Additionally, the implementation of a strategy needs to be supported by appropriate training and / or marketing tools to inform the target group performing the authentication of the product. Protection and tracking along the distribution chains

The complex, world-spanning supply chains and the increasing number of cross-border internet sales of

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The EFPIA serialisation concept aims to establish a common standard for product coding in Europe (rather than having 27 different national code systems) and to increase traceability across the supply chain. The EFPIA code will use a Data Matrix based on the EAN.UCC (GS1) standard using an international syntax. The code is very robust in reading and can be applied with rather little extra costs by variable printing technologies. The use of a Data matrix will be mandatory in France by 1st January 2011. The system proposed by EFPIA is intended to be an end-to-end product verification process at the point-of-dispensing. A Pharmaceutical Interchange Logistics Link Database will allow security checks (e.g. for customs) and also allow reimbursement data for governmental tax surveillance programs. The data segregation will be handled by a central database system, generated by the manufacturer, linking back to the respective company database. The system requires that the pharmaceutical manufacturer installs adequate printing systems within their packaging lines whereas the pharmacies need to be equipped with 2D barcode readers. As a next step a pilot trial will be conducted in one European country in cooperation with key stakeholders by end of 2008. The small scale experiment should take place on a regional level with approximately 200 pharmacies with 1 million packs. It will not provide any reimbursement feature at this stage but should test the technical implications before a full European roll-out program is installed.

pharmaceutical products that facilitate the introduction of fakes, or product packaging that is easy to copy or tamper with, require more and more sophisticated tools to monitor the distribution chains. In addition to the physical antitampering security of product packaging, the traceability of drugs is a vital element in securing the pharmaceutical supply chain. The US Food and Drug Administration (FDA) currently requires a bar code identifier of the manufacturer and product on “the lowest level of packaging” for prescription drugs. In 2004 the FDA released a Counterfeit Drug Task Force Report and suggested

a multi-layered approach to secure products and packaging by using appropriate technology and the serialisation of products to monitor the movement of drugs through the supply chain. While the FDA issues a pedigree statement documenting each sale or transaction of the product, in reality the US Federal law states that only wholesalers, who are not officially examined, need to pass a pedigree. The use of Data Matrix was recommended by The European Federation of Pharmaceutical Industries and Associations (EFPIA) to establish a single European symbology for medications as an anti-counterfeiting measure and also for identification purposes. GIRP – the Association of Pharmaceutical Full-Line Wholesalers has also recommended the use of a Data Matrix code. At the Global Forum of the International Medical Products AntiCounterfeiting Taskforce (IMPACT) of the WHO in February in Singapore the participants from international regulatory authorities and manufacturers recommended a global standardisation and serialisation syntax including country code, issuing authorities, manufacturer’s product code and a unique serial number. Today, some manufacturers already use encrypted serial codes to allow authentication of their medical products anywhere in the world via the Internet. For this application each product carries a unique and highly complex security code. The consumer or dispensing person enters the printed code on the brand owner’s website or calls a hotline. If a true code is entered, the system confirms the authenticity, while a false code—suggesting the presence of a fake product—will prompt a warning A uthor

Europe pushes hard the use of Data Matrix for product serialisation

message on the screen. The system logs each product query and rejects multiple entries of the same code at pre-defined levels. Should unauthorised multiple queries be made, this would clearly indicate trafficking of fake pharmaceuticals. The bird’s eye view

Securing the pharmaceutical supply chain and products is a challenging task. As varied as the threat itself are the means available to provide protection—for the consumer as well as the manufacturer. The key to a successful security strategy is a careful risk analysis, followed by the cross-functional development and implementation of an integrated anticounterfeiting strategy. The implementation of an efficient technological anti-counterfeiting strategy requires the following three principles: 1. The use of tamper-evidence packaging all products in order to guarantee the integrity of the packaging content. 2. An individual choice of overt, covert and forensic authentication features, such as colour-shifting inks, holograms, taggants should secure for high risk products. 3. The introduction of a harmonised and standardised serialisation coding system will allow a comprehensive surveillance of the pharmaceutical distribution chain. The implementation of authentication technologies by specialised and security certified system integrators and packaging specialists leverage the best techniques and technologies currently available to deter, detect and avoid the criminal practices that jeopardise human lives and erode legitimate earnings.

Thomas Völcker obtained his MBA from the University of Muenster in 1993. Since July 2001, he has been driving innovations in product, processes and innovations as a director sales & marketing in the ProSecure business unit of the Schreiner Group in Germany. He is responsible for directing global marketing and sales activities for label-based solutions for brand and document protection.

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Biopharmaceutical Manufacturing in India Drivers, trends and future

The biopharmaceutical industry since the launch of its first drug in 1982, has come a long way. With a global market size of around US$ 33 billion, it entails huge growth potential for the Indian biopharma industry. Satish D Ravetkar, Senior Director, Serum Institute of India Ltd., India

he recent announcement of this year’s winners of Nobel Prize in Medicine gives due recognition to the importance of research using stem cells and recombinant DNA technology. This not only highlights importance of these techniques in advanced scientific understanding but also proves importance of biopharmaceuticals in betterment of health of mankind. Biopharmaceuticals generally refers to recombinant therapeutic proteins; monoclonal antibodies (MAbs) used for therapeutic or in vivo diagnostic purpose or nucleic acid based products. After the launch of the first biopharmaceutical in 1982 the industry has grown to astonishing figure of more than US$ 33 billion At present almost 165 biopharmaceuticals are being marketed by various companies across the world By year 2010 biopharmaceuticals market is expected to reach US$ 70 billion. Out of every four drugs introduced in the US or EU, one is biopharmaceutical. All these impressive figures undoubtedly have become drivers for biopharmaceutical

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developments in India. The first biopharmaceutical to be launched in the country was Insulin by Novo-Nordisk back in 1991. Following this Hyderabad based Shanta Biotechnics launched Shanvae B an indigenously developed Hepatitis B Vaccine in the country in 1997. This triggered the entry of Indian Biotech companies into biopharma market. Simultaneously lot of other companies

At present over 240 recombinant therapeutic products have been approved globally for commercial use of which India’s share is 25%.

like Serum Institute of India, Bicon, Bharat Biotech, Cadila, Biological E, Intas, Dr. Reddy’s, etc. have developed various biopharma products and are in the race of controlling maximum market share. As applies for any other segment, the healthy competition in health industry acted as big driver for biopharma industry to develop

at a rapid pace. The confidence levels developed by these companies in their own strengths motivated them to cross national borders and innovate products for international market. Indian biopharma industry

Recent surveys published on biopharma market conclude that compared to the world market of more than US$ 33 billion, Indian market size is about US$ 125 million offering huge growth potential. Average growth rate of market is also high at 25% or more per annum. These figures are encouraging a lot of companies to focus on biopharma market. At present over 240 recombinant therapeutic products have been approved globally for commercial use of which India’s share is 25%. Apart from huge market potential recent government policies have been encouraging for biopharma industry. The recently published National Biotechnology Development Strategy seeks to address a number of challenges relating to the biotech sector in terms of R&D, creation of investment capital, technology transfer, absorption and diffusion and IPR regulatory issues. This strategy will enable the biopharma industry exploit current

M a nu f a cturin g

Upstream and downstream processing

Biopharma industry is getting into trend of “Science-based Manufacturing”. The application of innovative emerging technologies has become imperative to produce high standard biopharmaceuticals. Production processes and testing procedures are rapidly evolving. One of the salient trends of biopharma has been smaller batch sizes with high value products. As the number of batches of each biopharma product manufactured in a year is comparatively less, it has resulted in building multi-product manufacturing facilities. This puts more demand on stringent changeover procedures maintaining ease of set-up and flexibility. Validation of these facilities is also a major challenge for the concerned. This is particularly true for cleaning validation. These factors have set in new trend of use of disposable units starting from bioreactors to down-stream processing. When it comes to upstream processing, certain visible changes are removal of Serum or Bovine Serum Albumin or other animal derived components from the media. The major thrust area is to increase longevity of cells than yield or mass of cells thereby getting more yields of biopharmaceutical products. The fermentation processes are also

being innovated and Fed batch or continuous perfusion are preferred to Batch culture. Continuous perfusion is a preferred method as yields are highest and consequently puts less demand on volumes to be processed. In Down Stream Processing (DSP), more than yield many other selection criteria like product stability, purity of final products, scalability, adsorption kinetics of protein to gel etc. play a major role. In the media selection for DSP, trends are to move from high dilution to high purity, concentrate and stabilise the product early and use of media with bigger pore size which give higher flow rates. Preference is given to resins with higher binding capacities of greater than 250 gm of protein per litre and flow velocities exceeding 1000 cm/hr which improve turnaround time in DSP by decreasing washing, cleaning, re-equilibrium times. Monoclonal antibodies

The future of biopharma is certainly very bright. In terms of technology and products it is expected that monoclonal antibodies will be the class of biopharmaceuticals which will assume more importance in future. Recombinant gene technology and stem cell techniques are being exploited to realise full potential of monoclonal antibodies. The first attempt to reduce human patient immune response to murine antibodies has created a range of ‘chimeric antibodies’ which contain mouse protein sequences as well as human protein sequences. With already one or two monoclonal antibodies appearing on Indian biopharma scenario, many more will be in offing. A uthor

available golden opportunities in manufacturing and exporting or contract manufacturing or contract research by collaborating with companies worldwide. Amongst various factors favourable to the industry one is the availability of talent in biotech sector of the country at a comparatively lesser cost than what is prevalent worldwide. Strengthening of the Indian Patents Act has also attracted many MNCs to set up their R&D hubs in the country. This in turn is pushing up standards in terms latest GMP and Quality Systems to worldwide standards.

Biosimilars

Another area which offers excellent prospects for Indian biopharmaceuticals is the development of what EU refers to as ‘Biosimilars’ and the US as ‘Followon-Biologicals’. They are defined as off patent biopharmaceutical products developed and filed for registration by non-originator company. Biosimilars will need more of bioequivalence study besides pharmaceutical data. Pre-clinical and clinical trials have to be performed on case–by–case basis to support regulatory approval and reduce time to market. Biopharmaceuticals are complex and much bigger molecules demanding high purity levels and immunogenicity which will make development of biosimilars challenging for Indian biopharma sector which is now matured and ready for globalisation. The outlook

The world is also looking at India and China for manufacturing and clinical trials. India has also opportunity to downturn dramatically the increasing drug development cost. Thus Contract Manufacturing Organisations, Contract Research Organisations and Clinical Research Organisations have developed and will lead the way in future for Indian biopharmaceuticals. Even though the road to this is full of challenges and risks, biopharmaceuticals offer real revenue streams. With political back-up, and venture capitalists realising capabilities of Indian biopharmaceutical companies and their resources in terms of talent and new generation entrepreneurs, India is poised for bright future in biopharma sector. Opportunity needs to be translated into fast action to make it a knockout success.

Dr Satish D Ravetkar is a Senior Director with Serum Institute of India. A member of various national and international organisations, he has contributed to many research publications across globe. He has been awarded with various awards and honors like The Marquis WHO’s WHO Award, USA and International Biological, Cambridge, UK. He also chairs the Innovation Panel of CII Pune Chapter.

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PharmaEvents

Products & Services Company

Page No.

Strategy BioMedical Asia 2008

Research & Development BioMedical Asia 2008

Guava Technologies

IFC

LyondellBasell

OBC

Clinical Trials Guava Technologies

IFC

Manufacturing

April 2008 April 14-17, 2008 BioMedical Asia 2008 Venue

: Singapore

Organiser

: TerraPinn Pte Ltd

Web Link

: http://www.biomedicalasia.com

April 24-26, 2008 Bangalore Bio 2008, BIEC Venue

: Bangalore

Organiser

: Vision Group on Biotechnology

Web Link

: http://www.bangalorebio.in

May 2008

Ace Chemicals

BioMedical Asia 2008

LyondellBasell

OBC

May 04-06, 2008 Impact China IV: Pharmaceutical R&D Global Summit

Stamfag

IBC

Venue

: The Great Wall Sheraton Hotel, Beijing

Vaya Jayanthi Drugs Pvt. Ltd.

Organiser

: ALM Conferences

Web Link

: http://www.almevents.com

Suppliers Guide Company

May 15-16, 2008 Pharmamarketing 2008

Page No.

Venue

: Manila, Philipines

Organisers

: Marcus Evans

Web Link

: http://www.marcusevans.com

Ace Chemicals www.acechemicalsindia.com

May 20-22, 2008 API China 2008

BioMedical Asia 2008 www.biomedicalasia.com

Venue

: Dalian, China

Organisers

: Reed Sinopharm Exhibition

Guava Technologies www.guavatechnologies.com

IFC

Web Link

: http://en.apichina.com.cn

LyondellBasell www.lyondellbasell.com

OBC

Stamfag www.stamfag.ch

IBC

Vaya Jayanthi Drugs Pvt. Ltd. www.vayajayanthidrugs.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. IFC: Inside Front Cover IBC: Inside Back Cover OBC: Outside Back cover

Cutting-edge content from those who matter in the pharma industry.

June 2008 June 02-03, 2008 Interphex Asia 2008 Venue

: Suntec, Singapore

Organisers

: Reed exhibitions

Web Link

: http://www.interphexasia.com

June 02-05, 2008 World Vaccine Congress Asia 2008 Venue

: Singapore

Organisers

: Terrapinn

Web Link

: http://www.terrapinn.com

July 2008 July 22-23, 2008 2008 BioBusiness Asia Conference Venue

: Taipei, Taiwan

Organisers

: Industrial Technology Research Institute

Web Link

: http://www.biobusiness-asia.com

July 24-27, 2008 BioTaiwan 2008 Conferences & Exhibition

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Venue

: Taipei, Taiwan

Organisers

: Chan-Chao International Co., Ltd.

Web Link

: http://www.bioclub.com.tw

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