Pharma Focus Asia - Issue 05

Strategy | Research & Development | Clinical Trials | Manufacturing | Information Technology

Issue 5

2007

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Published by

Getting to the Heart of a Tumour Cell

Pharmaceutical Manufacturers

Clinical Trial Integration

Targeting the nucleus

Embracing Lean Six Sigma

Adopting an innovative approach

Where knowledge talks business

In association with

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Contents Cover Story

Generic to Innovative Transition of Indian pharmaceutical companies

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13

Dilip G Shah, CEO, Vision Consulting Group, India

International Strategic Alliances Positioning the Asian biotechnology company

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Stephen M Sammut, Senior Fellow, Wharton Health Care Systems and Entrepreneurship, USA

Research & Development 21

Getting to the Heart of a Tumour Cell Targeting the nucleus

David Andrew Jans, Professor and Head Kylie Michelle Wagstaff, Researcher, Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Australia

The Next Generation of Recombinant Immunotoxins Reducing immunogenicity of the cytotoxic part

Drug discovery from natural products has reclaimed the attention of the pharma industry and is on the verge of a comeback due to new technological inputs that promise better returns on investment.

Stefan Barth, Head, Department of Pharmaceutical Product Development, Fraunhofer IME, Germany

Assessing the Immunogenicity of Protein Therapeutics

Kamlesh Kumar Bhutani, Professor and Head, Department of Natural Products and Dean, National Institute of Pharmaceutical Education Research, India

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From little acorns David Twinberrow, Senior Director, Oncology, EMEA & Asia Pacific, IMS Health, UK

Automated Purification of Natural and Synthetic Compounds

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Athos C Rosselli, Sales & Marketing Manager, Pacific Rim

Reinhard Angelmar, The Salmon and Rameau Fellow, Healthcare Management and Professor, Marketing, INSEAD, France

Liver Cancer Treatment in Asia

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Philippe Stas, Chief Operating Officer, AlgoNomics NV, Belgium

Strategy Challenges for Pharmaceutical Sales Forces Lessons from other sectors

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Jack E Silver, Product Manager, Chromatography Scientific Instruments, Teledyne Isco, Inc., USA

Biomedical Polymers Drug delivery and molecular imaging

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Zheng-Rong Lu, Assistant Professor Furong Ye Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, USA

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OchreDesignLab

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Issue 5

Clinical Trails 46 Clinical Outsourcing in Japan Ready to fulfill its destiny?

Christopher R Albani, Partner Yorozu Tabata, Principal

Editor : Aala Santhosh Reddy

Editorial Team :

Visualiser : N Raju

Clinical Trial Integration Adopting an innovative approach

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Solomon Shacter, Director, Product Manager - Platform Solutions, ClinPhone Plc, USA

Site Management Organisations in Asian Clinical Trails Providing competitive advantage

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Sergei Drapkin, Managing Director, ERGOMED Clinical Research, Russia

Clinical and Non-Clinical Investigations Improving the quality of development candidates

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Colin W Vose, Senior Director, Strategic Drug Development Group, Quintiles Ltd., UK

Manufacturing

Akhil Tandulwadikar Prasanthi Potluri Jagadeesh Napa Bhamoti Basu Omer Ahmed Siddiqui

Art Director : M A Hannan

PRTM, Japan

2007

Copy Editor : Jagadeesh Napa

roject Coordination Team : P

Nathan Jones Suresh Pudivitikal Jubin Mathew Jacob Sam Smith Bhavani Prasad Pasupuleti Rajkiran Boda

Project Associates :

Shadaan Osmani Ifthakhar Mohammed Madhubabu Pasulla Sankar Kodali

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

Where knowledge talks business

Manufacturing Control Systems 65 The “next big thing” for the life sciences industry

Chief Executive Officer : Vijay Chintamaneni Managing Director

: Ashok Nair

Mark Albano, Life Sciences Marketing Manager, Honeywell Process Solution

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Rajeev Joshi, Manager, Development Engineering, Honeywell, USA

70 Advanced Emulsification Technologies

Narrow drop size distributions in the nanometer region Ludger Fischer, Managing Director, AC Serendip Ltd, Germany

Developing a Process Excellence Culture

Email: pharmafocusasia@ochre-media.com www.pharmafocusasia.com | www.imshealth.com | www.ochre-media.com

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Pharmaceutical Manufacturers Embracing Lean Six Sigma

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Dennis Constantinou, Senior Director Life Sciences, Oracle, USA

Information Technology Life Sciences Manufacturing Promise of service oriented architecture Daniel R Matlis, President, Axendia, USA

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Foreword Drug Discovery

Back to Mother Nature “A large fraction of the drugs currently approved are derived from natural products, which have always been a great source for new lead compounds offering new structural diversity.”

Ulrich Betz, Head of Strategic Innovation and Research Portfolio Management, Merck KGaA

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fter more than a decade of showing disinterest, the pharma industry is taking a relook at natural products-based drug discovery. Pharma companies had shifted their focus from natural products to combinatorial chemistry because of lower costs, clarity on intellectual property and, importantly, because it could supply huge synthetic libraries in short periods. On the other hand, natural products were unable to generate enough numbers due to the slow and inefficient identification, isolation and purification technologies which couldn’t keep pace with the High Throughput Screening methodologies. Apart from this, historically, deriving chemical entities from natural products was perceived to be difficult.

This led the pharma companies to focus on combinatorial chemistry to deliver potential compounds to be used as drug leads. While combinatorial chemistry did just that, far too many compounds differed little in their properties, which affected drug discovery adversely.

of unique molecular frameworks, both of which are highly desirable. Nature’s pool offers a much higher, though complex, chemical diversity than combinatorial chemistry.

Advances in separation technologies are now helping pharma companies overcome the practical difficulties in using natural products in drug discovery. For instance, a combination of techniques such as High Pressure Liquid Chromatography with Ultraviolet Spectroscopy, Mass Spectroscopy and Nuclear Magnetic Resonance are increasingly being used in identifying suitable drug leads. Further, only a fraction of the around 300,000 plants identified have been systematically investigated for drug leads.

This provides tremendous scope for identifying more leads from the huge library of nature, which is still unexplored. Also with the availability of advanced tools, the hurdles in using natural products in drug discovery are increasingly being overcome.

Natural products-based drug discovery is gaining prominence once again.

As it happens, pharma companies today are under immense pressure owing to factors such as shrinking product pipelines, patent expiries of blockbusters and shorter drug discovery timelines, to name a few. Adding to these, increasing R&D costs and combinatorial chemistry’s failure to deliver diverse and potent chemical entities have made pharma companies look at other alternatives.

Equipped with sophisticated technologies, the companies are now looking at mother nature for drug discovery. Researchers believe that natural products are the ideal sources for drug discovery as they possess drug-like properties and complement the “drug space” with their rich pool

Today, a number of smaller pharma companies rely on natural products for generating drug leads and many global pharma companies, which had disowned or sold off their natural products divisions, are looking at outsourcing natural products-based drug discovery. While combinatorial chemistry and natural products have not tasted much success on their own, a combination of the two along with the advances in technology and chemical synthesis can show the way ahead for this industry.

Aala Santhosh Reddy Editor

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Challenges for Pharmaceutical Sales Forces Lessons from other sectors

Pharmaceutical sales forces can overcome their challenges by learning how companies from other sectors have dealt with similar challenges.

Reinhard Angelmar, The Salmon and Rameau Fellow, Healthcare Management and Professor, Marketing, INSEAD, France

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ales force, the main communication channel of the pharmaceutical industry, faces many challenges: lower perceived product differentiation, great heterogeneity in the needs of customers and the value of customers to the company, pressure to find more efficient communication channels, restricted physician access, tighter regulatory constraints, the growing power of non-physician customers, and adversarial relationships with payers and other non-physician customers.

Are these challenges unique to the pharmaceutical industry? Companies in other sectors have successfully addressed challenges similar to what the pharmaceutical industry faces today.

Changing the sales force structure to compensate for the loss of product differentiation Many primary care physicians are visited by different representatives from the same company. While this makes it more difficult to obtain a holistic understanding of physician needs and respond to them, it allows a sharp promotional focus on individual products. However, in many primary care categories competing brands are perceived to be only weakly differentiated, and the promotional focus on products has become less effective.

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Xerox was facing analogous issues in the 1980s. Many of their customers received visits from five different Xerox representatives, each promoting a different product line. However, intense competition—especially from Japanese competitors in the copier category—had reduced perceived product differentiation. This led Xerox to abandon its product-based sales force structure in favour of a market segment-based structure.

Customers were assigned to segments on the basis of size (large, mid-sized, small businesses) and other characteristics (two additional segments comprised distributors, and “institutional” customers respectively).

Sales representatives were responsible for the sales of all of Xerox’s products to all customers in their designated segment, within a geographic area. The new sales force structure allowed Xerox’s sales representatives to better understand their customers, tailor the offerings to their needs and, thereby, compensate for the loss of product differentiation. Together with other initiatives, the restructuring of the sales force resulted in a significantly improved market position for Xerox.

Confronted again with a loss of differentiation in the 1990s, Xerox further sharpened its customer focus by sub-segmenting the largest business segment into several industry segments (e.g. financial, manufac-

turing, graphic arts and others), and restructured the sales force by industry segments.

Tailoring the communication channels to differences in customer needs The sales force is a very effective communication channel, allowing face-to-face, interactive communication of a considerable amount of information. But, considering the high cost of a sales representative’s call, do all physicians have a similar need for the extensive information that can be provided in a face-to-face visit?

Similar to the pharmaceutical industry, the traditional stock market investment firms such as Merrill Lynch and Morgan Stanley employed highly-paid professionals who provided customers with sophisticated advice, often based on proprietary research. However, the growing availability of stock market information in a variety of media enabled motivated investors to form their own preferences about where to invest. Targeting these “self-directed” investors, who preferred to manage their investments on their own, Charles Schwab’s low-price “discount brokerage” firm eliminated the high-cost information services and concentrated on making stock market transactions easy.

After having successfully penetrated the “self-directed” investor segment, Charles Schwab defined two other segments— “validators,” who also wanted to manage their own portfolios but required some consultation, and “delegators,” who wanted someone else to manage their portfolio for them—and designed communication

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channels that responded to the different needs of these segments.

Finding the most efficient communication channel for each function A face-to-face sales representative visit operates as a multi-function communication channel, which can carry many types of communications from the firm to physicians and other types of customers (e.g. information about diseases, products, patients, other physicians), and from customers back to the firm (e.g. customer needs, perceptions, preferences and behaviours; competitor activities). But face-to-face visits are expensive, and some of the functions performed by such visits might be carried out with equal or greater effectiveness at lower costs by some other channels.

Traditional thinking in the copier market had it that copiers, especially large ones, could be sold only through face-to-face visits, particularly to key accounts. Like at other copier companies, the doctrine at Rank Xerox, Xerox’s European subsidiary, was that sales representatives should spend as much time as possible on the road seeing customers face-to-face, and minimise the time in the office. But Rank Xerox discovered that salespeople in Colombia and Dubai interacted with customers mainly by telephone, for different reasons: to avoid the risk of being shot while driving in Colombia, and to avoid the sizzling heat in Dubai. Dubai was especially successful. They used the telephone for clients of all sizes and all types of copiers, small to large, visiting customers face-to-face only as required (e.g. to provide a demonstration), and achieved an average revenue-per-salesperson three times that of Europe. When introduced in Europe, the new channel strategy was rapidly adopted throughout the region, boosting Rank Xerox’s market share and revenue-per-salesperson.

Matching customer value and the cost of communication channels Physicians differ in their value to pharmaceutical companies. Indicators of value include actual and potential revenue generation, influence (e.g. opinion leadership) and knowledge (e.g. advisory board members selected for their knowledge of physicians’ needs).

Communication channels differ in their cost, e.g. face-to-face sales representative visits are more expensive than other channels such as the telephone, fax, and e-mail. The greater a customer’s value, the greater can be the cost of the communication channel.

For example, Dell in the U.S. assigned its customers to nine different segments varying in their value to Dell, and provided a channel mix that matched each segment’s value. Customers in the highest-value segment were connected to Dell through all conceivable channels including dedicated account teams comprising field and telephone sales personnel, program managers and technical support, and customer-specific websites with extensive functionality. Individual consumers, on the other extreme, could reach Dell only via telephone and Dell’s website. Segments in between these two extremes were served by a channel mix in which the availability of costly channels such as field salespeople increased with the value of the segment.

Creating new channels to increase customer access Not all physicians receive visits by pharmaceutical sales representatives. Some refuse to see pharmaceutical sales representatives.

Others are not visited by pharmaceutical sales representatives for a variety of reasons: they may not show up on the list of physicians, live in remote areas, or may not prescribe enough to be worth a visit.

Avon, which sold beauty products directly to consumers in one-to-one meetings in the consumer’s home, also was confronted with problems of consumer access. As more and more women entered the workforce, they were not at home during the day and, therefore, not available to meet with Avon representatives. Realising that many representatives sold Avon products as a second job, the company encouraged Avon representatives with other jobs to sell the Avon products at work. By 1998, the at-work-sales accounted for about 28 percent of all Avon sales.

More recently, Avon discovered that the company’s sales model kept it away from

almost 60 percent of its target consumers; 18 percent of the women in Avon’s target group were willing to buy from Avon but not through an Avon representative, and 40 percent had no access to a representative.

In order to increase access to both of these groups, Avon decided to add a web channel to its traditional face-to-face channel. Women who like to be in contact with an Avon representative can now use the personalised websites of Avon representatives while the women who dislike the sales representative channel can buy directly from Avon’s online store.

Creating new channels to overcome regulatory constraints Pharmaceutical promotion is subject to a growing number of constraints, arising from laws, regulations and industry codes such as the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Code of Pharmaceutical Marketing Practices and company-specific promotion codes. This should stimulate companies to search for novel promotion channels that are both compliant and effective.

Like the pharmaceutical industry, the tobacco industry is subject to many constraints on promotional practices.

In fact, the industry has been engaged in a race of adaptation with regulators; every time regulators impose a constraint, the industry invents novel promotional methods, which trigger new regulations, which in turn stimulate new promotional practices, and so on. For example, the ban on TV advertising led to a surge in sports sponsorships (e.g. Formula 1 races), until sports sponsorship was banned. Other novel promotional methods invented by the industry over the years include the promotion of non-tobacco products with the same brand name as tobacco products (e.g. Salem music stores, Camel clothing stores, Peter Stuyvesant Travel outlets, and Benson & Hedges bistros), overt and covert bar and nightclub promotional events (e.g. models and actresses place a pack of the sponsored cigarette brand on the bar and get men to bum a smoke), and product placement in films.

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Targeting new types of customers Pharmaceutical promotion has traditionally targeted primarily physicians. However, the influence of non-physician customers such as pharmacists, patients, and payers is rising in many countries. Pharmaceutical companies need to allocate more promotional efforts towards these new target audiences.

The success of Federal Express in the small package airfreight industry resulted in part from its decision to target non-traditional customers. Prior to the emergence of Federal Express, in most organisations the responsibility for selecting a carrier to handle a specific shipment rested with individuals whose title typically was traffic manager, mailroom supervisor, shipping clerk, or dispatcher. The individuals who originated most of the shipments—executives and their assistants—and who had most to lose from a shipment which arrived late or in poor condition, were rarely involved in shipping decisions for lack of information about the options. Research comparing delivery speeds for Federal Express and its main competitors showed that Federal Express delivered 93 percent of packages the next day compared to 42 percent by the best competitor. Federal Express used this result as the basis for a television and business magazine campaign targeted at executives and their assistants. The campaign sensitised them to the risk of late arrival of shipments, increased awareness of Federal Express and its superior performance, and empowered them to increase their influence over shipping decisions. This resulted in a significant increase in Federal Express’s sales and market share.

Transforming an adversarial into a collaborative relationship With the rise in power of non-physician stakeholders comes the risk of heightened conflict, for the interests of the pharmaceutical industry may not be perceived to be aligned with the interests of pharmacists, payers and others. Each party’s attention may be focused on value appropriation. For example, the price of each individual product may become the main focus of discussions, with pharmaceutical companies always insisting on a high price, and pharmacists and payers always demanding a lower price.

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Relationships between many fast-moving consumer goods companies and large retailers were similarly focused on price negotiations for each individual product. For example, Procter & Gamble (P&G) and Wal-Mart were in an adversarial relationship whereby each of P&G’s salespersons, representing one of P&G’s twelve product divisions, was negotiating independently with one of Wal-Mart’s purchasing agents. P&G’s representatives were wedded to a “load ‘em and leave ‘em” strategy: “If I can swap more of my product for more of your dollars, I will ‘control’ the store” (Lou Pritchett, former Vice President for Sales, P&G). Wal-Mart’s purchasers, naturally, pursued the opposite goal, namely to minimise Wal-Mart’s inventory and the price paid to P&G. Discussions between senior managers at both companies led to the recognition that their adversarial relationship destroyed opportunities for mutually beneficial value creation. This paved the way for a collaborative partnership, in which the two companies saw themselves as members of a common team with the following mission: “The mission of the Wal-Mart/P&G Business team is to achieve the long-term business objectives of both companies by building a total system partnership that leads our respective companies and industries to better serve our mutual customer—the consumer.” P&G assigned 300 full-time staff to its global WalMart team, more than 200 close to WalMart’s headquarters alone. Sharing a great deal of information, the team and Wal-Mart cooperated to develop new profitable products and services, allocate resources to inmarket products and services and optimise the supply chain. The partnership has served both companies well not only in their relationship with one another but also in making each of them a more valuable partner in other relationships. In an annual survey, in which manufacturers rate the performance of retailers and retailers rate manufacturers, both P&G and Wal-Mart have held the number one spot for many years in a row.

Conclusion Pharmaceutical companies are facing many challenges in relation to their primary com-

munication channel, namely the sales force.

But these challenges are not unique to the pharmaceutical industry. Companies in various other sectors have been confronted with analogous challenges, and some have addressed them successfully. The specific solutions at which they arrived may not be transferable to the pharmaceutical industry.

What is transferable, however, is the need to challenge the status quo, the need for creativity, ingenuity and an open mind in the search for solutions, and the need for courage and skill in managing the necessary organisational transition.

Book shelf Pharmaceutical Innovation

Incentives, Competition, and Cost-Benefit Analysis in International Perspective Edited by: Frank A Sloan and Chee-Ruey Hsieh Year of Publication: 2007 Pages: 346 Description:

The pharmaceutical industry worldwide is a rapidly burgeoning industry contributing to growth of gross domestic product and employment. Technological change in this field has been very rapid, with many new products being introduced. For this reason in part, health care budgets throughout the world have increased dramatically, eliciting growing pressures for cost containment. This book explores four important issues in pharmaceutical innovations: (1) the industry structure of pharmaceutical innovation; (2) incentives for correcting market failures in allocating resources for research and development; (3) competition and marketing; and (4) public evaluation of the benefits and costs of innovation. The lessons are applicable to countries all over the world, at all levels of economic development. By discussing existing evidence this book proposes incentive arrangements to accomplish social objectives.

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

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Liver Cancer Treatment in Asia From little acorns

Oncology is currently one of the most exciting but demanding areas for developing successful brand strategies. Companies entering smaller and niche markets in this area should clearly differentiate their products from competition to command and sustain a premium price.

David Twinberrow, Senior Director, Oncology, EMEA & Asia Pacific, IMS Health, UK

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ncreasing competition in the oncology space is heightening the importance of marketing competence and impacting decisions made long before a product enters the market. Assuming proven favourable efficacy and toxicity across a number of potential areas, choosing the right point of entry for a molecule is critical, given that some indications will be shared with competitors sooner rather than later. To command and sustain a premium price, companies must not only consider where they will launch and the sequence of successive launches, but also how their products will be clearly differentiated from potentially competing products.

The more prevalent cancers such as breast, lung, bowel and stomach in major markets of North America and Europe, where patient populations are large and lucrative, clinical trial infrastructure is well-established, and development partnerships can be fostered with relative ease are certainly tempting.

But what about starting in a small, low-visibility pocket—one that nonetheless offers tremendous opportunity—getting established in that niche, and then branching out into other areas from there? Recent developments in the treatment for primary liver cancer may provide some interesting pointers—particularly in the Asian market

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Most commonly prescribed molecules for advanced HCC European Union Gemcitabine 28%

Oxaliplatin 17%

Mitomycin 10% Others (11) 5% Docetaxel 3% Capecitabine 8%

Epirubicin 4%

Vinorelbine 7%

Cisplatin 6% Doxorubicin 6%

Fluorouracil 6%

United States of America Gemcitabine 31%

Bevacizumab 12%

Florouracil 10% Others (8)10% Cisplatin 3%

Oxaliplatin 8%

Carboplatin3%

Doxorubicin 8%

Docetaxel 4% Capecitabine 5%

Irinotecan 6%

Source: IMS Oncology Analyzer (EU); IntrinsiQ (USA)

where morbidity and ethnic characteristics demand evaluation and offer opportunities in the oncology arena—notwithstanding access issues that may require a novel commercial strategy.

Primary liver cancer, or primary Hepatocellular carcinoma (HCC), is the 13th most common cancer and the ninth leading cause of death in the developed markets of North America and Western Europe. However, in the underdeveloped regions, such as East and South-East Asia it is the third most common tumour and the second leading cause of death. Treatment for liver cancer is dependent on several factors including age, type

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and size of the tumor, and whether the cancer has spread beyond the liver. The prognosis for advanced conditions is poor and overall two-year survival for all HCC patients is less than 10 percent.

Drug therapy for HCC is fragmented from country to country, as well as by the lack of a widely supported or well-established treatment pattern. Variations in treatment patterns are apparent in the five major European Union markets (France, Germany, Italy, Spain and the U.K.), the U.S., Japan and China and even within each region. Japan is specifically affected by a significant lag in the launch of newer therapies compared to other

major markets, mainly because the Japanese regulatory authorities still have to evaluate and approve many innovative therapies that are already available elsewhere.

R&D spotlight Despite the modest worldwide incidence— 560,000 cases per year worldwide, well behind the million-plus new cases of breast or lung cancer—and its historically uncharismatic therapeutic portfolio, liver cancer management has recently received a boost with the emergence of a few novel agents, most notably sorafenib (Nexavar®, Bayer/Onyx).

Sorafenib is a multikinase inhibitor, already approved as first line (i.e., the first type of therapy used) in advanced renal cell carcinoma, which decreases both angiogenesis and tumour cell proliferation, blocking tumour growth. In a phase III trial of 600 previously untreated patients with primary HCC randomised to placebo or to sorafenib, patients treated with sorafenib demonstrated a 44 percent improvement in overall survival, and nearly doubled the median time to progression compared to the control group. This finding was more than significant to merit closing the trial early, declaring success for sorafenib, and switching patients initially randomised to placebo over to receiving sorafenib. Welltolerated and easy to administer as a twicedaily pill, sorafenib is the first agent shown to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. Studies are going on in Japan, Taiwan, Europe and the U.S. Sorafenib is also being evaluated in clinical trials by its developers, international study groups, government agencies and / or individual investigators as a single agent or combination treatment in kidney cancer (potentially in the adjuvant setting), metastatic melanoma, breast cancer and Non-small Cell Lung Cancer (NSCLC). The Phase III Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy (ESCAPE) in a NSCLC trial recently completed enrollment of more than 900 patients previously untreated with NSCLC. East Asia - A key challenge New standard for HCC or not, can sorafenib change the profile of liver cancer? To do so,

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Most commonly prescribed molecules for advanced HCC China Oxaliplatin 13%

Pirarubicin 20%

Cisplatin 11%

Fluorouracil 21%

Hydroxycamptothecin 11%

Capecitabine 2%

Mitomycin 11% Epirubicin 8%

Floxuridine 3%

Japan Gemcitabine 16%

Mitomycin 15%

Cisplatin 13%

Epirubicin 25%

Fluorouracil 10%

Mitoxantrone 1% Doxorubicin 1%

Tegafur & Uracil 10% Tegafur/Oteracil/Gimeracil 9%

Source: IMS Oncology Analyzer

it would have to change treatment algorithms in East Asia, a less-familiar market than the U.S., Europe, and Japan but the market featuring the greatest unmet need for HCC. IMS Oncology Analyzer data shows the frequency of primary HCC in Shanghai to be 35 in 100,000 men—compared with only approximately 9 per 100,000 men in the U.S. About three-quarters of all cases of liver cancer worldwide are found in East Asia where up to 50 percent of diagnosed cancers are HCCs. A wealth of opportunity is conceivable in this region. More than half of the Chinese healthcare spending is devoted to drugs (ver-

sus 10 percent in the U.S.), indicating that current obstacles for drug purchasing and distribution are not insurmountable. Westernstyle state-of-the-art medical facilities that would be suited to distributing sorafenib are present in China, albeit in a limited number of wealthy districts. And again, the fragmentation of the East Asian market is an opportunity for sorafenib; with no one drug therapy boasting enough market dominance to ward off opportunistic newcomers.

The challenges to sorafenib’s ability to penetrate this market, however, revolve around issues like market access, awareness and affordability as much as medical merit.

These challenges stem in large part from the current state of China’s healthcare system.

In an effort at reform in the 1980s, China’s healthcare system transitioned from high government control to a largely decentralised system soon characterised by privatisation and increasing drug costs, and by tremendous disparities between urban and rural healthcare—being considerably inferior in the rural communities with large population.

This level of inequality in access is an important issue and presents a legitimate challenge for sorafenib in East Asia that could potentially place the drug out of range, financially and logistically, for the majority of Chinese HCC patients. Just 29 percent of Chinese have health insurance; only 7 percent or fewer of rural Chinese, specifically, had health insurance (as compared with 49 percent of urban Chinese) when surveyed in a 1999 study. A 2001 survey found that half of the people surveyed said that they had foregone healthcare because of cost considerations.

To counter this, one consideration could be differential pricing. The same drug often has a different price in France than in Germany, for example; could sorafenib be priced low in rural areas in order to maximise uptake, and high in the wealthy urban districts to compensate? Conventional wisdom suggests no; drug purchasers, whether physicians or patients, would be likely to pursue parallel trading, travelling to the bargain-districts to purchase the drug. This “bargain hunter” scenario is already being witnessed in the U.S., for instance, where patients travel to Canada to purchase lower-priced versions of branded drugs. Furthermore, rural areas in China outnumber wealthy areas to the extent that differential pricing would likely be a funding challenge in even the wealthy regions.

An alternative approach would be to work with Chinese manufacturers and distributors to control the delivery costs of sorafenib, enabling a lower price-point without narrowing profit margins. Or, accept a lower pricing model for East Asia than would have been acceptable in the U.S., justifying shortterm loss in sales in order to become established and lay the groundwork for indications beyond liver cancer—conducting clinical trial costs an estimated

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30 percent less in China compared to the United States or Europe. With drug development programmes in the U.S. and Europe costing in the region of US$ 800 million, 30 percent savings could be put towards researching, marketing, and distributing sorafenib for additional disease niches.

Competition in the wings Any strategy would also need to acknowledge that sorafenib would not be alone. Pfizer’s competing oral multikinase inhibitor, sunitinib (Sutent®), is in phase II trials for HCC. The fact that sunitinib’s current trial locations include Taiwan implies that powerhouse Pfizer also plans to target the East Asia market should sunitinib meet its trial endpoints, and be submitted and approved for HCC. Sunitinib and sorafenib each have demonstrated similar efficacy in renal cancer (both drugs’ lead indication) and liver-cancer clinical trials. They, are easy-to-administer oral agents and have the backing of significant financial resources. The best option for securing sorafenib’s leadership in HCC, then, may be through a savvy costeffective approach through as much clinical due diligence as possible. Virtually every market in the world is exploring the value of health economic data when developing reimbursement guidelines and approving drug formularies. Taking the proactive step of supplying East Asia’s drug policymakers with cost-effective mod-

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els of liver cancer treated with sorafenib, compared to wasted treatments, comorbidity and death without it, would give tremendous weight to sorafenib’s place in this market—quickly and without the expense of a major clinical trial or, for that matter, a major advertising or physician education campaign.

Is liver cancer worth pursuing?

Theoretical approaches aside, the bottom line in evaluating the liver cancer market is whether a small indication with no existing standard for pharmaceutical care and a limited survival window can be worth considerably more than the investment in it. In other words, considering the small size of the liver cancer market in the U.S. and Europe and the dynamics of East Asia, should manufacturers go through the work necessary to access the East Asian liver cancer market?

The answer, analytically speaking, is yes. As case studies of other recent launches have shown, size is not necessarily important when judging the financial attractiveness of an indication. Consider Novartis’ Gleevec/ Glivec (imatinib) for Philadelphia chromosome-positive Chronic Myeloid Leukemia (CML). Though the prevalence of CML in the U.S. at the time of Gleevec’s U.S. launch was estimated at only approximately 20,000 people, in its first six months on the market Gleevec generated sales of more than US$ 150 million, and quickly went on to

deliver blockbuster sales (exceeding US$ 2.5 billion in 2006). The caveat here is that unrestricted access and high price premiums are becoming increasingly elusive goals in all indications without clear demonstration of product value and meaningful improvement in survival and quality of life.

Ethnic diversity in the response to different treatments is also an important consideration within the context of return on investment for niche populations. Take as an example AstraZeneca’s Iressa (gefitinib) for NSCLC. Although a troubled post-launch history led to eventual withdrawal of Iressa’s European submission and to regulatory authorities in the U.S. and Canada limiting the use of Iressa to those patients already experiencing benefit from the drug, Iressa is accepted as an effective therapy for pre-treated advanced NSCLC in the Asia Pacific region (which may feature a different molecular profile for lung cancer) and is being evaluated in the first-line advanced setting.

And, long-distance relationships with East Asia have proven successful. Major manufacturers have been selling their products in China since the 1980s and several have built manufacturing plants in that country. In 2002, AstraZeneca set up the first Western-owned clinical research organisation in China. In 2003, Eli Lilly made a deal with a Chinese company to purify, synthesise and analyse compounds supplied by Lilly researchers. In 2004, Roche dedicated a new research and development lab in Shanghai that is focussed on medicinal chemistry.

With these examples to lend credence to drug commercialisation outside the U.S. and Europe, and on the basis of sorafenib’s efficacy and its relevance to the Chinese population, Bayer should have the confidence to make East Asia a very successful market for sorafenib.

If we can measure the future marketing of niche cancer products using the case studies of the recent past—and assuming evidence of demonstrable value—sorafenib’s entry into East Asia may well point towards mighty oak trees growing from the “little acorn” of liver cancer treatment in this region.

Full references are available on www.pharmafocusasia.com/magazine/

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Generic to Innovative

Transition of Indian pharmaceutical companies While generics continue to drive the Indian pharmaceutical industry, it is set for rapid growth in its new avatar as a supplier of finished dosage forms to the world.

However, challenges abound. companies that were charging very high prices for pharmaceutical products. This was more prominent in the case of imported products, where the foreign companies refused to part with their technology even on payment of consideration and the public health concerns for access to medicines. The abolition of product patents thus enabled national companies to “reverse engineer” commonly used drugs. Almost at the same time (1970) the government introduced, for the first time, a formal system of price controls on medicines. The companies having local production witnessed the beginning of a system of price control that turned draconian in the years to come. However, in hind sight, one may say that the system of price control at home made them very competitive in the world today.

The year 1995 is also significant for the composition of its production and subsequent transformation as supplier of APIs to supplier of finished dosage forms to the world.

Dilip G Shah, CEO, Vision Consulting Group, India

N

ot many people recall that India remained a net importer of pharmaceutical products until 1987-88 (Table 1). The 1990s witnessed a marked departure and saw India emerging as a major supplier of generics to the world.

The situation changed rapidly thereafter.

By 1994-95 India’s exports grew ten-fold to US$ 504 million as against imports of US$ 219 million, generating a trade surplus of US$ 285 million.

The foundation for the emerging trend was laid by the years of strangulating controls: the Government policy that forced local manufacture of Active Pharmaceutical Ingredients (APIs) and the cost-based price control system that forced the companies to improve their efficiency. Moreover, the presence of the foreign companies and the government support to the Public Sector Units (PSUs) helped in the development of the pharmaceutical industry. The absence of product patent provided both an opportunity and a challenge for the Indian companies.

The milieu played a key role in the emergence of the pharmaceutical industry in India and thereafter in its transformation from manufacturing generics to developing innovative drugs. The need for being competitive laid the foundation for a very cost-effective industry in the country. The opportunity of earning premiums pushed the companies to concentrate on innovation: innovation in plant design, layout, chemistry, and drug

delivery system. The combination of innovation and competitive edge is very potent and that is what the transformation of the Indian pharmaceutical industry brings to the world today!

1995 – A landmark year The year 1995 is a significant landmark for the pharmaceutical industry in India. That is the year when Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement came into force obliging India to re-introduce product patent. India had abolished product patent in 1971, while retaining process patents for pharmaceuticals, agrochemicals and food products. The abolition of product patents was prompted mainly by the dominance of foreign

Change in focus 2000

2005

5%

30% NCE

30%

65%

NDDS

Chiral

Analogue

Process Development

35%

35%

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“training institutes” for many technocrats who used them for experience before setting up their own units, thus helping diffusion of ownership. The growth of SSIUs is a unique phenomenon and could be traced to the spirit of enterprise, education and enabling environment. Most of the major companies today were at one time SSIUs. The continued presence of foreign companies, their forced investment in local manufacture of APIs and involuntary dilution of equity holdings served the cause of development of a very vibrant and broad-based domestic industry.

They provided ready market for domestic manufacturers of raw materials and APIs and became footboard for technocrats to set-up their own units.

Thus, by 1995, when India signed the TRIPS Agreement, the foundation blocks were already in place. The industry had demonstrated its ability not only for technology absorption but also to develop alternate processes independently and improve upon existing know-how. The time period

for “reverse engineering” a product was reduced from 36-48 months to 12 months.

Formulation development, use of conventional technology, plant design, etc. had all been in place. This is what differentiated Indian pharmaceutical industry from the domestic industry in many developing countries which also did not have product patent regime.

Moving up the value chain of R&D The TRIPS Agreement therefore triggered a strategic shift in the business. The companies, having excelled in synthetic chemistry and process development decided to focus on innovation. The spending on R&D recorded a marked increase in the 10-year period from 1995 to 2005.

The Indian companies not only increased their spending on R&D, but also changed the quality of R&D. Until 1995, almost the entire effort was on “reverse engineering”, but by 2000 the industry showed signs of moving up the value chain.

OchreDesignLab

The key factors contributing to this change are government policies regulating pharmaceutical industry, presence of government owned PSUs, policy of encouragement to Small Scale Industrial Units (SSIUs) and the potential of Indian market to foreign pharmaceutical companies that remained invested in India.

Noteworthy among the government policies were the abolition of product patents, introduction of measures that forced every company in the organised sector, whether national or foreign, to invest in and undertake production of APIs and use specified share of indigenous materials as against imported materials; involuntary dilution of equity holding by the foreign companies; and costbased system of price control that compelled companies to improve efficiencies. The PSUs adopted a policy of “social pricing” which put competitive pressure on the private industry.

In addition, easy access to APIs encouraged new units to enter the industry, raising the level of competition. The PSUs also became

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By 2005, it was very evident that twothird of its effort were on R&D that generated some sort of intellectual property. The evidence of this shift is incidentally also taken note of by the Government of India-appointed Technical Expert Group (TEG) on Patent Law Issues. Its report lists 215 PCT applications for drugs and pharmaceuticals (not 339 as shown) in Annexure IV. Territorial expansion The second major shift triggered by the TRIPS agreement relates to territorial expansion of markets. As the data on Drug Master File (DMF) filing and Abbreviated New Drug Application (ANDA) submissions up to 1995 indicate, Indian companies did not have any significant presence in the USA. The situation in Europe was no different. The Indian companies had focussed on the markets in Africa, Russia and Asia for exports. However, all this changed with the emergence of the product patents that deprived Indian companies of their ability to bring in new products. Their response to the TRIPS Agreement was to invade the largest and most lucrative pharmaceutical markets of the world. It is now reflected in the export data.

As may be seen from the Table 4, the North America and the Western Europe accounted for 40 percent of India’s exports of US$ 3,697 million in 2004-05.

Aggressive M&As The Indian companies, encouraged by initial success in the regulated markets, acquired confidence to move aggressively. They started looking at acquisition opportunities to cut short entry and gestation periods. They began with small acquisitions ranging from US$ 2 million to US$ 10 million and soon found out that they can do it. Having tested the waters, their appetite grew bigger. They looked for larger companies and the budget for acquisition rose from US$ 100 million to US$ 500 million.

The mergers and acquisitions were not confined to a few front runners only. Many mid-size and smaller companies also took the plunge. Thus, territorial expansion received a greater boost and became deep-rooted.

Import-Export of Pharmaceuticals @ Constant $ Exports

Imports

Trade Balance

US$ Mn

US$ Mn

US$ Mn

1980-81

10.3

21.5

(11.2)

1981-82

18.8

23.8

(5.0)

1982-83

14.7

26.9

(12.2)

1983-84

17.8

28.1

(10.3)

1984-85

28.6

41.9

(13.3)

1985-86

31.1

49.8

18.7

1986-87

42.1

50.9

(8.8)

1987-88

50.7

56.8

(6.1)

Year

Table 1

Source: OPPI Pharmaceutical Compendium 2001(Ex. Rate $1 = INR 45)

Production of Pharmaceuticals @ Constant $ API

Formulations

US$ Mn

US$ Mn

Ratio of API: Formulations

1994-95

337.3

1,763.3

1:5.2

1999-00

839.3

3,546.7

1:4.2

2000-01

1,007.3

4,078.7

1:4.0

2001-02

1,208.9

4,690.4

1:3.9

2002-03

1,450.6

5,394.0

1:3.7

2003-04

1,740.9

6,203.1

1:3.7

Year

Source: OPPI Pharmaceutical Compendium 2001/2003 (Ex. Rate $1 = INR 45)

The entry of the Indian pharmaceutical companies in the regulated markets had some unintended and indirect benefits.

The globally innovative and generic companies started taking note of the quality of their products, management capability and competitive strength, opening up new opportunities for strategic alliances. The Indian pharmaceutical companies discovered to their surprise that the very companies they were overawed by were looking to form alliances with them for Contract Research and Manufacturing (CRAM). Most technocrats in the industry had grown in stature by “learning while earning”. The CRAM provided yet another opportunity to do what they were good at. They did not waste

Table 2

R&D Spend of Pharmaceutical Industry @ Constant $ Year

US$ Mn

1995

31.1

2000

71.1

2005

411.6

Source: IPA (Ex. Rate $1 = INR 45)

Table 3

any time to seize the opportunity. Some, sensing the need of alliance partners, took time to carve out better deals. Thus, many major Indian generics companies started working closely with the leading global pharma companies. The proximity and ongoing interactions provided rare learning opportunities in the fields of

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2004-05 Region wise Exports of Pharmaceuticals @ Constant $ Market

2003-04

2004-05

Contribution

Growth

US$ Mn

US$ Mn

%

%

West Europe

759.7

805.8

21.8

6.1

North America

594.3

681.7

18.4

14.7

East Asia

597.0

601.3

16.3

0.7

Africa

405.6

443.6

12.0

9.4

East Europe

309.4

399.9

10.8

29.3

South Asia

244.0

281.1

7.6

15.2

Latin American Countries

241.2

256.0

6.9

6.1

West Asia

169.2

180.2

4.9

6.5

53.2

47.0

1.3

-11.6

3,373.4

3,696.6

100.0

9.6

Other American Countries Total

Source: Chemexil (Ex. Rate $1 = INR 45)

Table 4

Illustrative list of recent acquisitions Year

Acquirer

Target

Country

Deal Size US$ Mn

2005

Matrix Labs

DocPharma

Belgium

263

2005

Torrent

Heumann Pharma

Germany

30

2005

Dr Reddy’s

Roche’s API (Unit)

Mexico

59

2005

Glenmark

Bouwer Barlett

South Africa

ND

2005

Sun Pharma

Able/Valeant

US/Hungary

33

2005

Ranbaxy

Efarmes Sa

Spain

18

2005

Strides Arcolab

Strides Latina

Brazil

16

2006

Ranbaxy

Terapia

Romania

324

2006

Aurobindo

Milphar

UK

ND

2006

Dr Reddy’s

Betapharm

Germany

571

2006

Wockhardt

Pinewood Labs

Ireland

150

2007

Wockhardt

Negma Labs

France

265

2007

Sun Pharma

Taro Pharma

Israel

441

2007

Agnus

Strides Arcolab

-

47

Total

2218

Source: Business World 28/06/04, Media Report

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Table 5

patent challenge and discovery research.

The Ranbaxy-GlaxoSmithKline, Dr. Reddy’s Laboratories-Novartis, Torrent-AstraZeneca and a host of other such alliances in the field of R&D are examples of this nature. They not only provided valuable experience and learning but also built the confidence of the Indian companies to commit more funds to R&D. Journey to innovation The journey from generic to innovation has just begun for the Indian pharmaceutical companies. The spirit of enterprise drives the journey. The willingness and capacity to take risks fuels its growth. The technical education, access to skilled manpower and their exposure to global multinationals are acting as catalysts.

The enabling policy framework provided the building blocks and facilitated the journey. The Indian pharmaceutical industry is still three years away from the first major land mark, the launch of an original research molecule, that will herald its entry into the big league. That is the day when people will refrain from calling the Indian pharmaceutical companies “pirates” and “copycats”.

However, in the meantime, generics will continue to be the driver of growth and territorial expansion. The current momentum and acceptance of safety and quality standards of the Indian pharmaceutical companies will raise its share of the world generic market from about 18 percent in 2006 to over 28 percent by 2010. The major challenges in this path are • India being forced to amend its patent law (either under new accord on Substantive Patent Law Treaty at the World Intellectual Property Organisation or under dispute settlement mechanism of the WTO) to dilute flexibilities.

• the Indian policy makers succumbing to the pressure of providing data protection beyond its obligation under Article 39.3 of the TRIPS Agreement.

The Indian pharmaceutical industry is aware of both these challenges and is working closely with the government to pre-empt them.

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International Strategic Alliances Positioning the Asian biotechnology company Asian biotechnology companies’ lack of experience in pharmaceutical alliances can be quickly overcome by deliberate preparation, careful identification of potential partners and anticipation of the due diligence process of partnering.

Stephen M Sammut Senior Fellow, Wharton Health Care Systems and Entrepreneurship and Venture Partner, Burrill & Company, USA

S

trategic alliances and partnering between biotechnology companies—at all stages of their development—and established pharmaceutical companies have characterised the biotechnology industry since its inception. Many companies in the U.S. and Europe have accumulated the experience in developing relationships, executing transactions and delivering completed projects and products. Those that are successful, follow a plan of analysis and preparation that serves as a model for companies new to the field. Asian biotechnology companies are largely new to the culture of pharmaceutical alliances. The lack of experience can be quickly overcome by deliberate preparation, careful identification of potential partners and anticipation of the due diligence process of partnering.

Partnering: Issues and challenges If there is a common thread in the 30-year history of the biotechnology industry, it is

that strategic alliances between companies for R&D, marketing or both have been a consistent source of funding, diversification and growth. Each year some 400 to 500 partnering transactions occur within the industry. But this is perhaps a mere 10 to 15 percent of all the opportunities promoted by more than 8000 biotechnology companies globally. As the proliferation of biotechnology companies in Asian countries continues, and as their technology develops, the number of prospective deals will increase dramatically. There are thousands of business opportunities in a year for any pharmaceutical company. Are the winners and losers separated solely by technology or commercial factors? There are companies that have projects not quite ready for partnering while many others would be appealing to partners with better positioning and planning. Asian companies have additional challenges that, with the right thinking, can become advantages.

Putting assets into the global context Good managers and their scientific colleagues know what their companies have, but often they do not place that within the broader context of the interests of the markets, the clinical perception of needs, and the universe of activity in their area of work.

The process of establishing the context requires the management team to step back, engage in a little humility, and ask critical questions: • Are we at the stage of development that we think we are?

• To what extent are we free to operate and in which geographies?

• What companies are working in this area (use published reports, patent studies)?

• Where does the project fit into the “global” pipeline?

Forming the context is the critical foundation of determining how a project can be appealing. For Asian companies targeting US

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or European partners, this context requires profound understanding of the regulatory and reimbursements frameworks operating in those geographies. Historically, the US has been accepting high pharmaceutical prices.

Current trends are to the contrary and over the coming decade there will be significant pressure on pricing and reimbursement.

The major companies will be dramatically reassigning their own strategic interests.

Defining and identifying prospective partners Having established a context, the difficult work begins in targeting specific prospective partners. All too many firms make a decisive error in broadcasting their projects too widely with obvious consequences: shifting of the emphasis from quality to quantity; dilution of management time; curious but no serious responses; and failure to identify and target the correct pathway into what would have been the most promising of companies means that the project will fall through the cracks.

What are some of the best practices in identifying, targeting and approaching a prospective partner? To understand best practices, do two things: place yourself in the position of the management and scientific staff at your target, and work backwards. Put another way, look at role playing as a way to get ready and then imagine that you have been successful in forging an alliance with a given company and asking yourself how and why we were successful.

Research and role playing The role playing dimension can be revealing, but not unless some homework has been done and answers to the following are available: the product lines and pipelines of prospective partners; the number and commercial characteristics (such as general financial terms, sharing of responsibility, and exclusivity or non-exclusivity) of the deals that they have announced over, say, the previous two years; the internal structure and composition of their business development teams; their decision making process; their transaction process; where announced, the general economic and commercial structure

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Intellectual Property Due Diligence Package • Identification of all patent filings and dates • Establishment of clear ownership title or documented licensing rights • Identification of relevant publications or uses (clinical trials) • Description of how patent claims cover the product or product candidates • Patent term extensions or adjustments • Record of maintenance fees, liens, security interests or encumbrances • Articulation of the intellectual property strategy and the basis on which decisions were made • Countries selected and why; schedule and deadlines for “National Phase” filings under the Patent Cooperation Treaty (PCT) • Identification of all product candidates • Identify alternative/non-patent avenues to exclusivity • Opinions related to validity, enforceability or scope • Freedom to operate • Identification of any alleged infringement by your company • Receipt of notice letters, cease and desist letters, threats • Third party infringement • Invention disclosure forms • Employee agreements/non-compete agreements • Confidentiality/Non-Disclosure agreements • “Exit interview” system—this is a common practice in the U.S. and Europe. In these interviews, employees are reminded of their agreement with the company as to IP and they will have to sign documents that they are carrying any documents, notebooks, research materials etc. Currently, there is an awareness that scientists and engineers have extraordinary employment mobility (particularly in India) and this causes prospective partners major anxiety with respect to your technology as well as their own that may become part of the work relationship • Any sponsored research agreements or research and collaboration agreements • Trade secrets—not what they are but in general terms what they cover, why you have chosen that strategy, and the steps you have taken to secure trade secrets • Internal IP audit protocol

of the deals that they have done; the general time frame of the process; and history in co-managing projects.

Obtaining historical information is a tall order. Consider where such sources might be and how to get to them. At a biotech company business development professionals attend almost every scientific and in-

dustry conference but this isn’t the effective deployment of human resources. Scientific staff of a company is an extension of the business development team and generally welcome training and networking at conferences outside their peer group. Everyone in the organisation is a source of partnering intelligence. Every prospective partner being

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Regulatory Due Diligence Package • Good Laboratory Practices (GLP) and Good Manufacturing Processes (GMP) as reviewed and certified by drug regulatory national authorities • Sourcing of raw materials, intermediates and capital equipment • Animal use certifications (although not clinical trials per se, this may be a subset of GLPs and an audit will likely be part of the regulatory review process) conformance with all applicable national requirements and/or World Health Organisation standards for clinical trials and human subjects • Exhaustive description and justification for the number of patients in each phase • Thorough and documented review and approvals by human subject review boards (in the US these are know as Institutional Review Boards or “IRBs”) • Documents and procedures for informed consent • Identification of all product candidates and all clinical indications

•

• Classification of these as: New Chemical Entities (NCE) New Drug Formulations (NDF), Pediatric, orphan drugs or vaccines • History of regulatory management to date • Description of clinical trial sites and reasons for selecting them; profile of all clinical investigators and their history in conducting trials • Chart of pre-clinical, clinical and/or marketed products • Status of all regulatory agency reviews and approvals

•

•

• “Orange Book Listings” if in the U.S. • Applicable generic entry/Abbreviated New Drug Applications (ANDA) for generics production in the U.S. or outside the U.S. filings with the US-FDA or similar filings with the regulatory agencies in other countries • Manufacturing facility inspection certificates and approvals • Are there potential “off-label” uses and how these will be monitored and managed

• •

• Approaches available for post-marketing surveillance

studied and profiled will have unique attributes, but the typical commonalities are: • In most instances there is no substitute for data, but this does not mean that preclinical or Phase 1 projects are disqualified from consideration. Of course most pharmaceutical companies would prefer to in-license drugs with a New Drug Application (NDA), but there are far too few of these around. In fact, of the 500 deals announced annually, the majority are pre-phase III and earlier • Projects received on a personal basis or

through a respected referral get better attention than those sent blindly • Internal review at the prospective partner is done on a matrix basis among a mix of scientific, clinical, regulatory, manufacturing, market, legal and transactional staff. The role of the business development professional may range from a coordinating function at one end to a key champion and decision maker on the other • Patents are exclusionary rights and allow the owner or licensee only to restrict

•

other parties from infringing on the claims of their patent. In many instances, particularly in the biotech and pharmaceutical industries, there are aspects of discovery, enabling technologies or production that are the property of other parties, which in turn have the right to exclude others from use of these claims.

Any licensee will determine if they need rights to other patents that are needed.

These reviews are known as “freedom to operate.” Companies will often have their own FTO studies generated by their own counsel. Any freedom to operate an intellectual property study done by a prospective licensor will pale in comparison to the one done by a prospective licensee In most instances, the process is measured in many months to a year or more, unless there is the rare circumstance of an auction of a valuable new technology Several stages of management approval are generally required—deals can fall apart at each step At any given time, your deal is just one of possibly dozens under consideration suggesting that you must monitor where your project falls into the strategic priorities of the prospective partner and whether those priorities are changing or not Confidentiality is a critical concern for both parties The financial consideration on the part of the prospective partner is the tip of the iceberg for them. More important are the internal resources that they will have to invest in managing the relationship and collaborating on the project. In the not too distant past, the distance and time differences between east and west were alone major factors in discouraging interaction. This is clearly no longer the case, but an Asian company that can demonstrate its own capacity and skill in managing collaborations will automatically be at an advantage Partnering activities on both sides are resource intensive, but the stakes are often dramatically asymmetrical and remain focussed on growing the business at the same time

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Learning from working backwards What is “working backwards?” Simply stated, you describe to yourself a (reasonable) dream deal and imagine that the ink on the contract is dry. How did your company get to that point? Almost certainly you realised success by walking through an intensive gauntlet of due diligence. Success is a function of anticipating the range and depth of due diligence and having a full portfolio of information to satisfy the most rigorous of reviews.

Your first experience with due diligence will be as informative to you as it is to your prospective partner. Detailed profiling of the team and demonstration as to how and why they fit each task can be the first step in this direction. In the Asian setting, companies (and venture investors) often find it difficult to do the indepth analysis of management backgrounds. This is not to suggest that there is inherent mistrust, but in the U.S. and Europe, it often seems like everyone knows everyone else in the industry. Hence, it becomes imperative for you to be prepared with extensive professional references. Clear statement of your business model with an informative executive summary as to why you are seeking a partner need to be developed. This model should also cover the other aspects like co-marketing, reserve rights in specific countries, manufacturing, etc.

Organise the material in a meticulous logical framework and cross-check the evidence of your own assertions.

Conduct internal due diligence relating to specific and achievable scientific and clinical milestones with detailed corresponding budgets for each phase. Be prepared to make a solid case as to why the milestones are appropriate as well as demonstrate why these coincide with value infection points. Develop a strategy for regulatory and intellectual property rights that would look at regulatory issues and patent issues from your would-be partner’s point-of-view. Finally, sketch out the respective roles that your team and your partnering team will perform.

By far, the major concerns of a prospective pharmaceutical partner are managing intellectual property rights and regulatory issues.

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Intellectual property due diligence Intellectual property remains the cornerstone of the pharmaceutical and biotechnology industries. In the U.S., Europe and Japan, there is vast, accumulated experience going back three decades on IP issues in partnering. Many Asian companies are relatively new to the landscape of IP issues and will have to prove their ability in managing and using IP. A list of items for the preparation of the same is given in ‘Intellectual Property Due Diligence Package’.

Regulatory issues The second most influencing factor in the pharma and biotech industries is the regulatory issues. Regulatory issues determine the feasibility of the project and hence it is highly imperative for you to carry a due diligence on the same. Regulatory issues in this regard include disclosure of the use of a clinical research organisation and its role in your clinical development, which is a mustbe-stated fact. Prospective partners will spend considerable time conducting separate due diligence on the CRO, even if it is an internationally known company. Your regulatory due diligence should include all the items mentioned in ‘Regulatory Due Diligence Package’.

Other business models and commercial issues Generally, there are varying levels of concern about your business models and commercial plans. Prospective partners will have their own ideas which may differ considerably from your own. Nevertheless, you should have a well-documented explanation and justification for your position. These issues also form the basis for the economic negotiations in the licensing discussions and the amount and pace at which funds will flow from the partner to your company.

The foremost issue is to position your company in the value chain from discovery to distribution and the role you play in this position in terms of development and manufacturing. Second issue can be costs and pricing. This includes forecasted cost of goods across geographies and target markets; breakdown of cost of labour versus cost of

materials; and pricing forecasts by country markets targeted and the research that supports the estimates. Third issue is the distribution network in your country—how they work and their pricing. Fourth issue can be Intellectual property rights, risks of counterfeiting and drug re-importation. Fifth, clinical context issues; and issues in detailing to physicians; target patient population; and the costs involved therein. Finally, competitors’ response to your entry, their pricing and growth strategies should also be taken care of.

The most critical issues It is axiomatic that most young biotech companies are in a constant sell-mode or in some instances a survival mode. Any prospective partner knows that, but it is less of a factor in negotiations than it might seem to be. A good negotiation team on the side of the smaller company can compensate for the disadvantage. There is, however, a more insidious dynamic. Do not stop asking yourself the most critical issues of all: • Does your asset fit well into their portfolio?

• Do they share your commitment and vision?

• Do they have complementary skill sets?

• Do they have a competing project?

• Can you work with the group that will be doing the work? In fact, do you know who the team will be?

• What do they bring? Can the total value of the asset be increased through partnership?

• How will the distance and cultural differences be bridged?

Once you have thought through all of the above issues and made a candid assessment of the universe of potential partners, you will be ready for the more difficult aspects of doing a transaction, but the homework will produce the highest possibilities for success and the strongest terms in the deal itself. One final caveat, however, is that deals should not be measured on the short-run economics alone.

The real test of success is the probability of reaching the market with a product that offers people real health benefits. The revenues and profits will follow, and your reputation as a desirable partner will soar.

R e s e a rc h & d e v e l opm e n t

Getting to the Heart of a Tumour Cell Targeting the nucleus

In combination with other agents, tumour cell-specific nuclear targeting approaches have great potential in developing truly tumour cell-specific therapeutic treatments.

David Andrew Jans Professor and Head Kylie Michelle Wagstaff Researcher Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Australia

D

espite billions of dollars spent on research every year, cancer remains one of the leading causes of death worldwide. Understanding of the molecular mechanisms underpinning many cancers has progressed rapidly, but our ability to treat the disease remains limited. Most cancer

therapeutics rely upon the ability of the agent to eradicate tumour cells successfully from the patient, but this almost always results in the unnecessary and unwanted death of “normal� bystander cells. Moreover, due to the nature of many of these drugs, the highly proliferating normal cells of

the body tend to be the most affected, including those of the bone marrow and the immune system, resulting in an immunocompromised patient who is then highly susceptible to life-threatening pathogens.

Thus, it is clear that efficient and above all specific anti-cancer agents are urgently required.

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DNA or Drug delivery to the nucleus of tumour cells using an optimal MRT Figure Legends:

Modular Recombinant Transporter (MRT)

1. Cellular targeting is mediated by a tumour-cell specific cellular targeting (CT) moiety, directed at tumour-cell specific targets such as the Her-2 receptor on breast cancer cells.

2. Binding of the CT to its target receptor triggers internalisation of the MRT via endocytosis.

3. The MRT is released into the cytoplasm through the action of an endosomal escape (EE) moiety such as one from the Diptheria toxin or from Adenovirus type 2.

4. Transport of the MRT through the cytoplasm towards the nucleus is mediated by an MTAS moiety such as the p53 MTAS, which interacts with the motor protein Dynein and facilitates movement along microtubules. Elevated expression of Dynein components in breast cancer cells may facilitate this transport further.

5. At the nucleus, the tumour-cell specific nuclear targeting sequence (tNTS) such as that found in Apoptin mediates interaction with Imps and transport into the nucleus, where DNA (5a) or Drug (5b) release from the DNA or Drug Binding moiety (DBD) occurs. In normal cells (not shown), Apoptin is transported out of the nucleus by CRM1; this is prevented in tumour cells by phosphorylation mediated inactivation of the export sequence.

6. Toxic effects of the DNA or Drug are mediated either directly or through secondary processes such as photoactivation (in photodynamic therapy) or expression of an encoded cytotoxic protein (in gene delivery).

Figure 1

Efficient tumour cell treatment using MRTs MRTs containing several tumour cell-specific targeting elements can be taken up by tumour cells and accumulate the encapsulated drug in the nucleus where DNA damage will occur, resulting in cell death. Normal cells remain unaffected as they do not possess the targets required for the MRT moieties to operate. This results in selective killing of tumour cells without detrimental effects to nearby healthy cells and a better prognosis for the patient.

Figure 2

Delivering drugs to the nucleus: Lessons from viruses An effective means to mediate efficient tumour-cell death will be to deliver drugs specifically to tumour cells, and subsequently to direct them to hypersensitive subcellular compartments within these cells. This will avoid harmful side effects on normal healthy

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cells without compromising on tumour cell cytotoxicity. In order to achieve this, one needs to overcome a series of natural barriers, which prevent the entry of foreign material into all cells and more importantly into the nucleus within these cells. Viruses have evolved mechanisms to overcome such barriers, many being able to deliver their

genomes into the nucleus of host cells.

However, safety considerations such as pathogenicity and stimulation of an immune response hamper their use in clinical settings.

To overcome these issues, Modular Recombinant Transporters (MRTs) are being developed that mimic viruses by retaining all of the necessary cellular and subcellular

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targeting functions of viruses, but without the safety concerns.

The first step in drug delivery is cell entry, which involves binding to and passage through the cellular membrane. To achieve this, many viruses utilise recognition of specific receptors expressed on the surface of target cells. Depending on the virus or vector in question, it may be internalised into an endosome subsequent to receptor binding as is the case for non-enveloped DNA viruses such as Adenovirus. Endosomal entrapment will ultimately result in degradation of the enclosed ligand when the endosome fuses with a lysosome.

To overcome this, many viral proteins function as endosomal escape moieties by undergoing conformational changes in response to a drop in pH, and thus facilitating membrane disruption and release of the virus into the cytoplasm. The virus must subsequently traverse the cytoplasm through the crowded network of the cytoskeleton, avoid degradation, and translocate into the nucleus in order to be expressed and replicated, or in some cases, integrated into the host cell genome, as is the case for retroviruses. Nuclear transport is known to be the most rate-limiting step in this process.

The nucleus is the heart or control centre of the eukaryotic cell, being the site of storage and replication of the cell’s genetic material, and of processes such as transcription and ribosome assembly that are central to synthesising the cellular complement of proteins that carry out all of its functions. The nucleus is separated from the rest of the cell cytoplasm by a double membrane known as the Nuclear Envelope (NE), punctated by Nuclear Pore Complexes (NPCs), through which all transport between the nucleus and cytoplasm occurs. Small molecules are able to pass through the NPC via passive diffusion, but molecules > ~45 kDa require specific targeting signals to gain either access to or egress from the nucleus. The signals for transport in the import direction, known as Nuclear Localisation Signals (NLSs), are recognised by members of the importin (Imp) superfamily of nuclear transport receptors. NLSs

tend to be similar in nature, usually consisting of one (monopartite) or two (bipartite) short stretches of basic amino acids, typified by the NLS of the Simian Virus 40 Large Tumour Antigen (T-ag: PKKKRKV132) or that of the Xenopus protein nucleoplasmin (KRPAATKKAGQAKKKK170) respectively. Conventional nuclear transport involves recognition of the NLS by the Imp α subunit of the Imp heterodimer, followed by docking at and translocation through the NPC mediated by the Imp β subunit. Once inside the nucleus, binding of the monomeric guanine nucleotide binding protein Ran, in its GTP bound form, to Imp β actively displaces Imp α and effects release of the cargo into the nucleoplasm. Imp β itself and its numerous homologues can also mediate nuclear transport of various cargoes in an analogous fashion to Imp α/β, but without the need for Imp α. Nuclear export is an analogous process to nuclear import, requiring Nuclear Export Signals (NESs), which are recognised by Imp β homologues known as exportins, of which exportin-1 (CRM-1) is the best known example.

Effective drug delivery agents need to combine elements of each of the above functions. In tumour-cell specific delivery, they additionally need to possess selectivity for cancer cells. For example, ligands for cell-surface receptors that are specific to or upregulated on tumour cells could be included as Cell Targeting (CT) moieties in an MRT system. When combined with an Endosomal Escape (EE) moiety and an effective NLS, an efficient drug or gene delivery agent can be produced. Examples of such MRTs have already begun to emerge, some of which are capable of delivering reporter genes or drugs specifically to tumour cells in culture, as well as targeting expression of a luciferase reporter plasmid to the liver of mice following an intravenous injection.

NLSs as a key to efficient nuclear delivery It is becoming increasingly clear that nuclear transport of DNA is the key determinant of effective gene delivery, and that increasing nuclear delivery by incorporating an efficient

NLS results in significantly higher levels of overall gene expression in most cases. For example, we have recently developed an efficient non-viral gene delivery method based upon engineered histones, where optimised nuclear targeting of the constructs through inclusion of an optimised T-ag NLS resulted in a significant increase in transgene expression. Similarly, inclusion of the T-ag NLS to an MRT containing β-galactosidase as a carrier, poly-lysine as a DNA compacting agent and the foot-and-mouth disease virus RGD sequence as a CT moiety resulted in a 30-fold increase in transfection efficiency of CaCo2 cells when compared to the MRT lacking the T-ag NLS. In the case of drug delivery, the nucleus is also often the most sensitive site for drug induced damage, such as in the case of photosensitising agents used in Photodynamic Therapy (PDT). PDT relies upon the specific activation of photosensitisors such as protoporphoryn IX or chlorin e6 using long wave length light, releasing singlet oxygen species, the cytotoxic effects of which do not usually exceed 40nm from the site of activation.

Since the nucleus is a hypersensitive site for active oxygen species-induced damage, coupling of the optimised T-ag NLS to chlorin e6 containing complexes, either cross-linked to a carrier or encoded as part of a fusion protein can result in a reduction of the EC50 by a factor of 2000-fold, highlighting the importance of specific nuclear delivery of these chemical agents. In terms of cancer therapy, delivery of these active agents specifically to the nucleus of tumour, but not normal cells, is the key to their being “magic bullets” in terms of effective and safe anti-tumour therapeutics.

Tumour cell-specific nuclear targeting Several proteins have been demonstrated to kill tumour cells selectively, including the Tumour Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) and the adenovirus type 2 Early region 4 open reading frame 4 (E4orf4). TRAIL specifically kills malignant cells, but spares normal tissues, by binding to death receptors expressed

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exclusively in the cancer cell membranes and triggering apoptosis through a mitochondria-independent signalling pathway.

Nuclear localisation appears to be important for the efficiency of killing, but is not essential for E4orf4 induction of p53-independent apoptosis. Chicken Anaemia Virus Viral Protein 3 (CAV VP3, also known as Apoptin) is intriguing, because it is believed to induce tumour cell-selective cell killing, specifically dependent on its ability to localise specifically in tumour, but not normal cells.

Apoptin is a 121-amino acid protein, which can induce apoptosis in chicken thymocytes and several human tumour but not normal cells, through what appears to be a p53-independent, Bcl-2 resistant pathway. However, the use of non-isogenic cell lines in several studies, combined with reports demonstrating apoptosis in non-transformed primary human fibroblasts suggest that Apoptin-induced apoptosis may not be specific to tumour cells. Nonetheless, Apoptin’s preferential localisation in the nucleus of tumour/transformed cells makes it an intriguing possibility as a targeting moiety for cancer therapy applications.

Apoptin contains a basic bipartite NLS in its C-terminus (residues 80-121), which is necessary and sufficient for nuclear accumulation. Interestingly, when the N-terminus of Apoptin is removed, Apoptin (a.a. 74-121) binds to Imp β with 3-fold higher affinity, implying that Apoptin’s nuclear accumulation may be regulated by intramolecular masking of the NLS through the N-terminus.

Apoptin also posses es a CRM-1 recognised NES (a.a. 97-105) located between the two basic clusters of the bipartite NLS, which appears to be the basis for tumour-cell enhanced nuclear localisation of Apoptin.

Most importantly, the NES is regulated by phosphorylation at residue T108 in tumour cells, but not normal cells, whereby phosphorylation of this residue in tumour cells inhibits NES-mediated nuclear export of Apoptin, resulting in increased nuclear accumulation. Thus, residues 74-121

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encompassing both the NLS(s) and the phosphorylation regulated NES represent a tumour cell-specific Nuclear Targeting Signal (tNTS), responsible for Apoptin’s enhanced nuclear localisation in tumour cells. Clearly the tNTS is an exciting prospect in a therapeutic context to deliver drugs or DNA specifically to the nucleus of tumour cells, thereby increasing the safety and efficacy of anti-tumour therapies.

A new class of MRTs: tNTS at the forefront?

The fact that it confers preferential accumulation in the nucleus of tumour as opposed to normal cells makes the Apoptin tNTS a very attractive possibility for use in a modular therapeutic system. However, Apoptin can accumulate in the nucleus of normal cells, but to a lesser extent than their transformed counterparts. Thus, it seems clear that a multifaceted approach will be required to achieve specific killing of tumour cells without damage to normal cells. Utilisation of several moieties, each having tumour-cell enhanced properties in a novel MRT system should result in an overall tumour-cell specific therapeutic drug delivery system. MRTs may be engineered to include ligands (CT moieties) that are recognised by cell surface receptors that are either enriched or specific to tumour cells. For example, receptor tyrosine kinases are frequently over expressed during cancer development and are often specific to tumour types; e.g. over expression of Her-2 is associated with breast cancers.

Receptor tyrosine kinases can be targeted using single chain ligands, either in the form of anti-body fragments or as short high-affinity peptides; if these are utilised as a CT moiety within an MRT system, these should represent the first line of tumour cell specificity in a combinatorial tumour cell-killing approach. Combining tumour cell-specific receptors and CT moieties with endosomal escape (EE) and tNTS moieties would represent a tumourselective targeting MRT with considerable potential.

Additional modules that may act to enhance the intracellular trafficking of the MRT are also desirable. Of interest in this regard are Microtubule Association Sequences (MTASs). MTASs mediate interaction with microtubules directly or with components of the motor proteins dynein or kinesin, which mediate transport along microtubules towards the nucleus or cell periphery respectively. Several known viral and cancer-related proteins, such as p53, Rb and Rabies virus P-protein contain MTAS sequences that exploit dyneinmediated movement towards the nucleus along microtubules, resulting in increased and faster nuclear accumulation of NLS containing proteins. Incorporation of an MTAS moiety should help an MRT navigate efficiently through the crowded cytosol towards the nucleus, thus enhancing the nuclear delivery of the gene or drug of interest. In addition, it has been shown that oestrogen treatment of MCF-7 human breast cancer cells elevates dynein light chain expression, raising the possibility that upregulation of dynein light chains in tumour cells may further contribute to tumour-cell specificity of MRTs containing MTAS moieties. Figure 1 is a schematic representation of an MRT incorporating an ideal combination of targeting signals based on current knowledge. Figure 2 demonstrates the use of such MRTs to kill tumour cells effectively without damaging nearby healthy bystander cells. This results in less damage to the patient and a much better outcome after treatment.

Much remains to be done, but it would seem that achieving the ultimate goal of safe, effective and above all cell-type specific new therapies for the treatment of some of the world’s most life-threatening cancers is fast becoming a real possibility. Importantly, this seems likely to drive the pharmaceutical industry much more in the direction of efficient targeting of existing drugs to particular cell types and away from drug discovery per se.

Full references are available on www.pharmafocusasia.com/magazine/

CoverStory

Drug discovery from natural products has reclaimed the attention of the pharma industry and is on the verge of a comeback due to new technological inputs that promise better returns on investment.

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CoverStory

N

atural products, particularly, microbial and plant products in their native form have been associated with mankind since ancient times.

These have played a vital role in the discovery of New Chemical Entities (NCEs) in the golden period (1981-2002) of drug discovery. Drugs derived from natural sources also served as drug leads suitable for optimisation by synthetic means.

It was estimated that approximately 48 percent of employed new chemical entities between 1981 and 2002 were actually natural products or analogues or derivatives.

Despite this, the higher terrestrial plants that served mankind for millennia as traditional medicines were cast aside for years by pharmaceutical industry owing to highcost, high-risk and time-consuming affairs.

Another reason which has stranded the research of industrial natural products was the incompatibility of the extracts with the available screening methodologies.

The old laborious processes involved in the extraction and isolation were not capable of generating the numbers which were required to keep pace with the High

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Throughput Screening (HTS) requirements.

Further, advancement in the knowledge of molecular mechanisms, cellular biology and genomics not only increased the number of molecular targets but also demanded shorter drug discovery timelines. The advent of newer combinatorial techniques of synthesis and computational methods, with the incongruity of natural products to keep pace with the ever growing competition for novel classes of drugs at a faster rate, has prompted pharmaceutical industries to look towards synthetic chemical libraries. Though pharmaceutical industry appreciates the role of nature as the chief architect of natural products’ libraries and respect the science therein, they fear carrying out research in the area. It is unfortunate that discovery for the industry means custom synthesis of “me-too” kind of molecules instead of novel and therapeutically superior molecules from nature. However, the rethinking on fresh strategies popularly known as “natural product redux” is on the verge of gaining prominence due to disappointing results of combinatorial chemistry and high throughput screening in delivering potent chemical entities.

Combinatorial chemistry generates larger libraries but the compounds therein are relatively simple planar molecules contrary to the natural products’ pool that gives a much higher hit-rate in high throughput screening with high chemical diversity. Further, improvements in isolation, purification and characterisation procedures have fastened the output of natural product research, thereby reviving the interest of the pharmaceutical industry.

The modern natural product research is undergoing a revolution due to recent advancements in combinatorial biosynthesis, microbial genomics and screening processes.

The resourcing of properly authenticated higher terrestrial plants has become easier due to monographs generated by Indian Council for Medical Research (ICMR) and the Department of Ayurveda Yoga Unani Siddha Homeopathy (AYUSH). Moreover, access to hyphenated techniques like Liquid Chromatography-Mass Spectrometry, Liquid Chromatography-Nuclear Magnetic Resonance have raised the hope of drastically reducing the time and cost involved in natural product research by using derep-

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lication processes that are combination of techniques to avoid the already reported compounds.

The unique molecular diversity of natural compounds can be leveraged in the design of combinatorial libraries to improve their inherent biological activity or druglike properties. This can be performed by semi-synthetic modification of the parent molecule or by fully synthetic methods after crucial structural elements required for biological activity are defined from the libraries and refined by computer-assisted drug designing methods. In comparison to the past, more specific targets, efficient in vitro as well as in vivo models are available and can be utilised. Current strategies in natural product research involve a multifaceted approach combining botanical, phytochemicals, biological and molecular techniques.

In a paradigm shift from discovery of single bioactive molecules, multi-constituent mainstay of bioactive extracts can be emphasised for synergistic and antagonistic studies at cellular and molecular levels. Of the 250,000 species of higher terrestrial plants in existence, only 5 to 15 percent are estimated to have been chemically and pharmacologically investigated in systematic fashion. India has a repository of 45,000 different plant species, out of which around 15,000 are medicinal plants.

1.5 million practitioners of the Indian system of medicine use around 10 percent of the medicinal plants for preventive, primitive and curative applications.

Today, the perceivable threat of extinction of biodiversity due to global warming and other environmental reasons is also very high. Thus, there is an urgent need to identify the indigenous natural resources to study them in detail for use in drug discovery.

Moreover, sustainable supply of medicinal plants is essential for practising traditional medicine as well as natural product drug discovery. About 70 percent of the supply of herbal raw material for the Ayurveda, Siddha, Unani and homoeopathic medicines comes from the wild. There is enormous scope for India, with its rich biodiversity, to contribute to this trade. To enhance this, it is important

Kamlesh Kumar Bhutani Professor and Head, Department of Natural Products and Dean, National Institute of Pharmaceutical Education Research, India

An integrative approach by combining the various discovery tools and the new discipline of integrative biology will provide the key for success in natural product drug discovery and development.

that the cultivation programmes of the medicinal plants be carried out using controlled and scientific methods so that these will ensure plant material of desired quality and also help manage the resources effectively.

However, the growing demand for medicinal plants is also threatening their existence.

For meeting the future needs, cultivation of medicinal plants has to be encouraged.

The pharmaceutical industry has to come forward in utilising the knowledge available in traditional medicines like Ayurveda.

Traditional medicines may provide cure for different types of diseases and disorders but need scientific validation. In order to focus the research on traditional medicines to serve national interests, the first priority is to assess the therapeutic quality of herbal medicines objectively since the dividing line between the modern therapies and traditional therapies remains imprecise.

The assessment of quality can be made easier if distinction is drawn between rational and empirical medication taking into account marked psychodynamic effects associated not only with the active substances, but also with their typical indications. It is satisfying to note that companies such as Ranbaxy, Lupin and Nicholas Piramal India Ltd. (NPIL) have started their efforts for using the traditional knowledge in the development of their formulations as well as in drug discovery programmes. The formulations that will be manufactured in these companies use Good Manufacturing Practices and Best Quality Practices to ensure standardised, safe and effective herbs as well as finished phytomedicines that can be made popular like the Chinese medicines all over the world. Ranbaxy has setup its new herbal centre for the development of herbal medicine at Gurgaon, while the NPIL’s research centre is located at Mumbai and Lupin’s at Pune.

The therapeutic areas of inflammation, metabolic diseases and obesity may receive more attention for the development of natural products. Inflammation process is considered to be the root cause of almost all the diseases including cancer at the

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CoverStory molecular level. Lifestyle diseases like obesity and metabolic disorders are silent killers which have gone unnoticed so far.

A huge amount of information is already available in traditional medicine about their cures. Many plants and their secondary metabolites have already been researched for these areas and the pharmaceutical industry should take steps in utilising this valuable information.

Natural Products

Drug Discovery and Therapeutic Medicine Description:

Edited by: Lixin Zhang and Arnold L Demain Year of Publication: 2005 Pages: 400

A fresh examination of the past successes of natural products as medicines and their new future from both conventional and new technologies. High-performance liquid chromatography profiling, combinatorial synthesis, genomics, proteomics, DNA shuffling, bioinformatics, and genetic manipulation all now make it possible to rapidly evaluate the activities of extracts as well as purified components derived from microbes, plants, and marine organisms. The authors apply these methods to new natural product drug discoveries, to microbial diversity, to specific groups of products (Chinese herbal drugs, antitumor drugs from microbes and plants, terpenoids, and arsenic compounds), and to specific sources (the sea, rainforest and endophytes). These new opportunities show how research and development trends in the pharmaceutical industry can advance to include both synthetic compounds and natural products, and how this paradigm shift can be more productive and efficacious.

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

OchreDesignLab

The road ahead An integrative approach by combining the various discovery tools and the new discipline of integrative biology will provide the key for success in natural product drug discovery and development. Natural products can be predicted to remain an essential component in the search and development for new, safe and economical medicaments.

Pharmaceutical industry must awaken to change its mindset and reorient its resources towards the natural product-based drug discovery programs.

Book shelf

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The Next Generation of Recombinant Immunotoxins Reducing immunogenicity of the cytotoxic part

Immunotoxins comprise cell-specific targeting components coupled to cytotoxic agents.

Although clinical data are encouraging, the problem of immunogenicity remains unsolved.

To allow repeated administration, human immunotoxins with greatly reduced immunogenicity need to be developed.

Stefan Barth, Head, Department of Pharmaceutical Product Development, Fraunhofer IME, Germany

T

oday’s cancer drugs have considerable side effects caused by off-target activity. Various therapeutic concepts have been developed to improve drug specificity through the use of ligands that bind uniquely to cancer cells. Immunotoxins comprise a cell-specific targeting component coupled to a plant or bacterial toxin, and many such molecules have been evaluated for the treatment of malignancies.

Although clinical data are encouraging, the problem of immunogenicity remains unsolved. To allow repeated administration, human immunotoxins with greatly reduced immunogenicity need to be developed. A series of novel constructs encoding different human enzymes to induce targeted apoptosis have been generated with an overall objective to develop tailor-made immunotoxins not only in terms of the targeting component, but also carrying appropriate cytotoxic agents specifically to destroy tumour cells.

The high relapse rates in malignant diseases predominantly reflect the survival of residual tumour cells after standard therapy.

Additionally, today’s cancer drugs have the disadvantage of inducing side effects due to their off-target activity. Various therapeutic concepts have been developed to increase

specificity and reduce non-specific toxicity.

Tumour cells display unique surface markers, making it possible to develop rational strategies for targeting tumours without harming the surrounding normal cells.

Thus, the selective elimination of minimal residual disease using adjuvant immunotherapeutic agents, which specifically bind to the diseased cells or tissues, could dramatically improve the prognosis in cancer patients.

Immunotoxins are protein-based therapeutics consisting of a component that binds to disease-specific cell-surface target molecules and another that confers cytotoxicity. The two components are either joined covalently by chemical conjugation or expressed as a fusion protein generated by recombinant DNA technology. The binding moiety is usually a monoclonal antibody, a derivative thereof or a cytokine, ultimately of mammalian origin. In contrast, the cytotoxic moiety is a catalytically active protein-based toxin or enzyme and may originate from any source, including plants and bacteria as well as mammals. After selective binding to diseased cells, immunotoxins are internalised and released into the cytosol.

The cytotoxic component then induces cell death through its catalytic activity.

The first generation of immunotoxins were prepared by conjugating native, glycosylated plant toxins to tumour-specific antibodies. This resulted in some non-specific toxicity due to the affinity of the native B chain for common oligosaccharide groups, as well as binding between the glycosyl groups of the toxin and non-parenchymal mannose receptors on liver cells and cells of the reticulo-endothelial system. In the second generation of immunotoxins, tumourspecific antibodies were therefore conjugated to the deglycosylated, catalytically-active A chain, resulting in increased activity and better tolerance both in animal models and phase I/II trials in cancer patients. In patients, the major non-specific and dose-limiting toxicity associated with immunotoxins is Vascular Leak Syndrome (VLS), characterised by fluid leakage from capillaries, a fall in serum albumin, fluid retention, edema and weight gain. Vitetta and colleagues identified a (x)D(y) motif present in both the ricin A chain and human interleukin-2 that caused non-specific binding to integrin receptors on vascular endothelial cells. However, endothelial cell damage caused by high immunotoxin concentrations can usually be managed by adequate hydration of patients. Major challenges for the continued development of chemically-linked immunotoxins include better purification strategies for these heterogeneous compounds, reducing the production costs, and removing the

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non-specific integrin-binding motif to reduce toxicity towards endothelial cells.

The current third generation of immunotoxins consist of mutant versions of bacterial toxins such as Pseudomonas aeruginosa exotoxin A (ETA) and diphtheria toxin (with the internal integrin-binding motifs deleted) genetically fused to targeting components that recognise disease-specific ligands. The ETA deletion mutant retains the original domain II (responsible for translocation) and catalytic domain III. After binding to its cell-surface receptor, the immunotoxin is internalised and guided to the trans-Golgi network and Endoplasmic Reticulum (ER) by its C-terminal ER retention signal. In these compartments, the immunotoxin is bound to the protease furin, located on the inner membrane, through its furin consensus site in domain II. After cleavage by furin, only the C-terminal portion of the toxin (including the catalytic domain) is actively translocated into the cytosol, where its catalytic activity causes the arrest of protein biosynthesis and cell death.

The first immunotoxin approved by the Federal Drug Administration (FDA) was a fusion of the catalytic/translocation domains of diphtheria toxin with interleukin-2. This was known as DAB389IL2, Denileukin diftitox and Ontak. In a phase III trial of 71 cutaneous T-cell lymphoma patients, a 30 percent response rate was achieved, including 10 percent complete remission.

Impressive data was subsequently published on the recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22). This dose escalation study involved the treatment of 16 Cladribine-resistant patients suffering from hairy cell leukemia. Eleven patients went into complete remission; two showed partial remissions and the remaining three had lower doses of the immunotoxin or had pre-existing antibodies against Pseudomonas aeruginosa. Recently, 46 patients with LeYpositive metastatic carcinomas were treated with the recombinant anti-LeY immunotoxin BR96 scFv-PE40. Stabilisation of the disease was documented in 31 percent of the patients. The major problem in comparison to the BL22 study was the immunogenicity of the bacterial toxin.

Theoretically, all non-human structures can provoke these kinds of immune responses. Thus, in patients with functional immune systems, the immunogenicity of recombinant immunotoxins continues to be a major challenge and repeated administration is inappropriate. Possible solutions include the deletion of T-cell or B-cell epitopes, modification with polyethylene glycol or treating patients with immunosuppressive agents. The most obvious modification would be the complete humanisation of the recombinant immunotoxins following the identification and integration of human enzymes that induce apoptosis when internalised. The first new constructs of these fourth-generation immunotoxins are now in development.

Since human RNases are present in extracellular fluids, plasma and tissues, they are considered to be less immunogenic when used for the generation of immunotoxins.

Angiogenin, a 14-kDa protein with 64 percent sequence identity to RNase A, was first isolated from tumour cell-conditioned medium, where it was discovered because of its ability to induce angiogenesis. Subsequently it was demonstrated that angiogenin can develop cytotoxic potential with its t-RNA-specific RNase activity. Corresponding chemically-conjugated immunotoxins also showed cell-specific toxicity. Mammalian ribonucleases linked to a recognition moiety that binds a specific cell surface marker have been described and protected.

Granzyme B is an immune defense protein that, following the activation of cytotoxic T-cells or natural killer cells, is secreted from their cytotoxic granules. Following the perforin-dependent translocation of Granzyme B into the cytoplasm of the target cells, a proteolytic cascade is initiated which culminates in the target cell undergoing apoptosis.

The initial examples were fusions of Granzyme B with vascular endothelial growth factor and with an antibody fragment targeting gp240 on melanoma cells showing specific in vitro toxicity against antigen-positive tumour cell lines. Complexes of human proteases including Granzyme B and a binding activity for cellular surface structures have been described and protected in Europe and the US as well as in the rest of the world.

Another tumour-specific property that can be exploited therapeutically is the epigenetic modification that often accompanies the activation of oncogenes and inactivation of tumour suppressor genes, as often seen in apoptosis-associated pathways. It has previously been shown that tumour development can be suppressed by re-establishing the expression of single tumour suppressors such as retinoblastoma protein and p53. In each case, however, the expression construct was delivered on a plasmid or viral vector, making the approach unsuitable for specific tumour targeting in vivo. Drugs that inhibit aberrant kinase activity have been developed to treat proliferative and inflammatory diseases, and some are currently in clinical use, including small molecule inhibitors such as Gleevec (imatinib), Iressa (gefitinib) and Tarceva (erlotinib), and monoclonal antibodies such as Avastin (bevacizumab) and Erbitux (cetuximab). Until now, there have been no reports of therapeutic agents based on the restoration of a missing kinase activity. A novel combined approach has been developed involving the selective delivery of a putative tumour suppressor protein to CD30-positive Hodgkin’s lymphoma cells by genetically fusing a constitutively active version of death-associated protein kinase 2 (DAPK2) to a CD30 receptor-specific binding ligand. Constitutive reconstitution of DAPK2 activity by this immunokinase resulted in efficient induction of cell death in these tumour cell lines. Complexes of constitutively active human kinases and extra-cellular surface structures internalised after binding have been described and protected.

Having shown the specific cytotoxicity of these human immunotoxins, ongoing studies aim to develop human enzymes as novel immunotherapeutic agents for the future. The ultimate objective is the application of tailor-made immunotoxins not only in terms of the targeting component, but also the cytotoxic agents which will be chosen specifically to destroy tumour cells.

Full references are available on www.pharmafocusasia.com/magazine/

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Assessing the Immunogenicity of Protein Therapeutics Immunogenicity poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters drug characteristics including pharmacokinetics and bioavailability. Immunogenicity assessment strategies combine pre-clinical predictive methods with clinical stage measurement of anti-drug antibodies.

Philippe Stas, Chief Operating Officer, AlgoNomics NV, Belgium

Top view of the HLA Class II DRB1*0101 binding groove, with ι and β chains in respectively blue and green and the bound peptide in orange (PDB-code 1KLU).

Figure 1

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ost therapeutic proteins in clinical trials and on the market are to a variable extent immunogenic. Formation of anti-drug antibodies poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters drug characteristics including pharmacokinetics and bioavailability.

The immunogenicity risk assessment is dependent on the nature of the protein therapeutic, and should be analysed on a case-to-case basis.

Immunogenicity The immune system has evolved to protect hosts against potentially harmful antigens.

Immunogenicity is the immune response a host mounts against an antigen, such as a protein therapeutic. Typically, immunogenicity is characterised by measuring the production of Anti-Drug Antibodies (ADA) against the protein therapeutic.

The fast growing number of therapeutic proteins and related immunogenicity data shows that most of them induce ADA. These ADA can have an impact on drug-characteristics including the pharmacokinetics, bioavailability and drug clearance rate.

While in many cases the ADA are non-neutralising antibodies, there are documented cases where the immunogenicity gives rise to Neutralising Antibodies (NAb). These NAbs have a direct effect on the drugs’ effector-function. Upon development of a protein therapeutic, the likelihood of observing immunogenicity has to be estimated. Moreover, the severity of an observed immunogenicity should also be evaluated. The severity of this response has to be evaluated on a case-to-case basis, as the immune response ranges from a transient appearance of ADA with no clinical effect

R e s e a rc h & d e v e l opm e n t

to severe life-threatening conditions. Both industry and regulatory instances are currently developing immunogenicity risk assessment strategies for protein therapeutics.

Characterising immunogenicity The measurement and characterisation of antibodies formed against a therapeutic protein by a host is not without technical challenges.

A stratified approach (Figure 2) includes several assays to be optimised and validated for each individual drug, in order to 1. screen for circulating antibodies against the protein therapeutic 2. to confirm the positive read-outs with a competitive immunoassay, thereby differentiating false positive read-outs from the actual positive serum samples 3. characterise the type of response and 4. screen for NAbs Interpretation of immunogenicity percentages’ data for protein therapeutics should be done with care. The measured immunogenicity is to a certain extent dependent on the assays used, and moreover, many of the studies comprise only a small number of patients, sometimes submitted to different treatment schemes based on their individual medical history and disease state.

An example of the variability of observed immunogenicity is Alemtuzumab, a humanised anti-CD52 antibody. The observed ADA response in the treatment of rheumatoid arthritis varied between 0 to 75 percent throughout six clinical studies published between 1995 and 2005. The combined data resulted in an immunogenicity of 45 percent for 120 patients. On the other hand, in the treatment of patients with B-cell Chronic Lymphocytic Leukemia (B-CLL) only 1.9 percent ADA response was measured for a group of 167 subjects, suggesting a possible influence of the disease state on immunogenicity.

Similarly, Rituximab, a chimeric antibody directed against CD20, does not elicit ADA when used to treat patients suffering from B-CLL. This again may be explained by the antibody causing B-cell depletion, the presence of a B-cell lymphoma and the concomitant use of immunosuppressive drugs, three factors that hamper the over-

all production of antibodies. Rituximab administered to patients with auto-immune disease like systemic lupus erythomatosus or primary Sjogren’s syndrome showed 65 and 27 percent immunogenicity respectively.

Pre-clinical immunogenicity assessment For the time being, there are no in vitro methods available to measure the antibody responses raised against protein therapeutics.

Therefore, one has to rely on other approaches to estimate the expected immunogenicity of a protein therapeutic. One possibility is to estimate the protein therapeutics’ T-cell epitope content by computer based methods, or by in vitro measuring the level of T-cell activation upon administration of the protein therapeutic to donors or patient material.

on the presence of peptides that can bind to the HLA Class-II receptors, one could minimise the immunogenicity of a protein therapeutic by selecting protein therapeutics with as little T-cell epitopes as possible.

However, the HLA Class-II system contains many polymorphisms, in order to be able to respond to a broad range of “pathogens”, translating into several HLA receptor allotypes on the cell surface, each with different peptide-specificity.

The diversity is generated: (i) by the presence of several HLA class-II genes, and (ii) by a very high degree of polymorphism of most of these genes (Table 1) Therefore, assessment of the immunogenicity of a therapeutic protein should take into account the prevalence of the different variants within the patient population that is being targeted.

Th-epitopes

In silico approaches

Being only a part of the host’s immune system, the mechanism to generate antibodies against the protein therapeutic or any other antigen involves at least three cell types: i) B-cells producing antibodies directed against the antigen ii) T-helper cells supporting this function by the production of cytokines, and iii) Antigen Presenting Cells (APC) stimulating the T-helper cells. Typical APCs include dendritic cells, macrophages and B-cells The APCs take up protein through endocytosis, cleave the protein into peptides in the endosomes, where the peptides can be loaded on membrane-bound Major Histocompatibility Complex (MHC)—in humans these are called Human Leukocyte Antigen (HLA)—class II receptors (Figure 1).

The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.

As peptides bind on HLA in an outstretched fashion (Figure 1), this greatly limits the number of possible binding modes of any peptide to the receptors, as well as the number of interactions between its side-chains.

HLA polymorphism

As the cascade-process is critically dependent

Assay strategy for the assessment of the immune response (IIR 2007) Serum sample

Negative

Screening Immunoassay Positive

Negative True negative

Confirmatory assay Positive

Neutralization Assay

Characterization

Reporting Figure 2

w w w . p h a r m a f o c u s a s i a . c o m 35

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affinity. Rankpep, Propred, Tepitope, and Syphpeiti are Caucasian Oriental Afro-American HLA Class II examples of such DRB1*0101 14 5 4 statistical methDRB1*0301 17 8 12 ods. More elaborate DRB1*0701 24 13 14 models based solely DRB1*0803 1 13 ~0 on inference have been constructed as DRB1*0901 3 23 5 well, using neural DRB1*1101 9 13 14 networks and classiDRB1*1102 1 1 10 fication trees.

DRB1*1202 1 20 ~0 Structure-based DRB1*1301 10 3 13 methods are more recent. These directly DRB1*1302 7 3 14 model the molecular DRB1*1404 ~0 13 ~0 interactions between DRB1*1501 17 19 4 a peptide and reDRB1*1503 1 ~0 18 ceptor, using forceTable 1 fields. This has the advantage that there Comparison of predicted (Y-axis) versus experimental results (X-axis) of is less possibility of Epibase, Propred and Rankpep for six highly prevalent DRB1 molecules overfitting the model towards experimental data, which is a serious problem in statistical methods. Structure-based approaches such as Epibase can predict peptide affinities for any HLA allotype, provided that a good Figure 3 model of its structure can be created.

This allows building models that predict For most allotypes this is feasible given carethe affinity of a peptide for a particular ful homology modelling.

HLA allotype.

The accuracy of predictive methods has The previous generation tools to predict evolved strongly over the past 15 years. In binding peptides to HLA merely focussed on Figure 3, the high accuracy of structure-based sequence comparison in observed bindmethodologies is illustrated by comparing ing peptides. The earliest such models three methods, Rankpep, Propred and Epiwere statistical. Based on a number of exbase, on six of the major HLAII receptors. perimentally known epitopes, the binding peptides can be aligned to look for In vitro approaches amino-acid preferences throughout the While in silico methods assist the R&D sequence positions. Given the final alignprocess in selecting the lowest immunoment, a statistical profile or matrix is then genic lead-candidates, they can be useful constructed for the binding groove posiin some applications to measure the actual tions and any new peptide can be aligned T-cell activation level on donor or patient to that. The alignment score of the peptide material. Indeed, when comparing different against the matrix is then a measure of its formulations of a drug, or when comparing Population frequencies of some highly prevalent HLA Class II DRB1 molecules in different ethnicities.

a biosimilar product with the reference product, the T-cell activation and proliferation assays can document the comparability and immunogenicity risk.

A number of assays have been developed to characterise the T-cell responsiveness. Typically Peripheral Blood Mononuclear Cells (PBMC) from patients or naĂŻve community donors are harvested and primed with the protein therapeutic. After a number of days of culture, the cells are restimulated with autologous PBMC and the protein or derived peptides. The T-cell stimulation can then be determined by a suitable proliferation assay.

Routinely, Enzyme-linked Immunospot analysis is used to measure the number of cytokine secreting T-cells. By using Fluorescence Activated Cell Sorting (FACS) based systems, the read-outs can characterise the specific T-cell subsets that are being stimulated, thereby refining the interpretation of the type of response triggered. Typically, population wide responses have to be assessed, and therefore the in vitro assays are performed on 50 or more donors.

Conclusions In silico T-cell epitope characterisation can reliably guide experimental analysis, thereby significantly reducing cost as well as enriching data interpretation of the in vitro T-cell activation data at the HLA allotype level. A combined approach is essential to address important yet poorly understood issues in immunogenicity, such as the immunodominance of T-cell epitopes.

The combined technology allows to estimate the expected immunogenicity of a protein therapeutic. Since the actual measurement of ADA is only possible during clinical trials, the pre-clinical T-cell read-outs allow optimisation of the lead selection of the formulation process and support a comparability analysis. As the animal models for immunogenicity testing are low to non-predictive for the immunogenicity observed in humans, the T-cell work forms an alternative assessment method prior to the first dose in humans.

Full references are available on www.pharmafocusasia.com/magazine/

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CaseStudy

R e s e a rc h & d e v e l opm e n t

Automated Purification of Natural and Synthetic Compounds The purification of naturally derived and synthesised compounds via automated flash chromatography allows unattended separation while reducing errors and repurifications.

Athos C Rosselli, Sales & Marketing Manager, Pacific Rim Jack E Silver, Product Manager, Chromatography, Scientific Instruments, Teledyne Isco, Inc., USA

P

urification of compounds is often the rate-limiting step during the discovery of novel compounds. In a typical discovery sequence, chemistry can account for as much as 20 percent of the total task-time. Automated flash chromatography systems allow unattended separation of both synthesized compounds and those isolated from natural sources, freeing chemists to perform other tasks and help advance the project more quickly. Automated systems also help reduce errors and repurifications and are able to separate difficult samples more easily than manual methods.

Natural products Natural Products are an important base for anti-cancer drugs. A review of new chemical entities from 1981 through 2001 indicates that 74 percent of anti-cancer drugs were natural products, based on natural products, or were natural product mimics.

Automated flash systems are particularly well suited for work on natural products. The wide variety of readily available media, coupled with the resolving power of true linear gradients and the

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ability to easily switch from normal phase to reverse phase conditions greatly simplifies the process of separating complex mixtures.

Automatic fraction-collection coupled with UV-Visible peak detection eliminates the need for constant monitoring thereby improving productivity.

Polymethoxyflavones and hydroxylated polymethoxyflavones isolated HL-60 inhibitors Polymethoxyflavones (PMFs) have been isolated predominately from Citrus species. These are interesting due to a wide spectrum of biological activities. In vitro and in vivo studies suggest that PMFs exhibit protective effects against cancer.

Five polymethoxyflavones and two hydroxylated polymethoxyflavones were isolated from cold-pressed sweet orange peel extract.

The initial separation was performed on a Teledyne Isco flash system using a 120g pre-packed Silica gel column with a hexane-ethyl acetate gradient. 10g of orange peel extract was dissolved in 2ml dichloromethane and 2ml hexanes.

R e s e a rc h & d e v e l opm e n t

2

1 OMe

OMe O

MeO

OMe

MeO

OMe

OMe MeO

O

MeO OMe

OMe

O

OMe

OMe

OMe

MeO

OH

OH

O

OCH3

H

O

H H

O

O

10

OH

OCH3

O

11 O O

12 O

2

O

3

3

2

3

9 HOOC

9 CH2 NH(CH2)4CH2OH CH3 O

OH

Cytotoxic constituents from Butea superba Butea superba is a legume with the common name “red Kwao Krua” in Thailand. This species has shown anti-proliferation effects on the growth of MCF-7 and HeLa cells.

The dried tubers of Butea superba were extracted with methanol and the methanolic extract was re-extracted with hexane followed by CH3Cl. The chloroform extract was separated by flash chromatography with 100% CH3Cl with 1% step

Fractions were collected by monitoring their absorbance at 254 nm. The fractions were evaluated by LC-ESI-MS. Preparative High Pressure Liquid Chromatography was used to further purify the fractions.

The natural PMFs (1–5) had only moderate anti-cancer activity, however the modified 5-hydroxy-6,7,8,3’,4’-pentamethoxyflavone (6) and 5-hydroxy-3,6,7,8,3’,4’-examethoxyflavone (7) strongly induced apoptosis and showed strong inhibition of HL-60 cell lines.

6

O

OMe

2

OMe

9

O

OMe

CH3 O

O

8 OMe

MeO

O

OMe

MeO OMe

O

O

O

OMe MeO

O

O

OMe

OMe

6

OMe

7

OH

O

MeO

MeO

OMe

MeO

MeO

5 OMe

OMe

OMe

O

4

MeO

OMe OMe

O

MeO

3

6

N

9 HO CH3 O

6

N

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

R e s e a rc h & d e v e l opm e n t

13

14

15

16

17

18

gradients of methanol. The compounds were identified by spectral comparison with reported values in the literature without further purification. Cytotoxicity was determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Compounds (8) and (9) showed moderate cytotoxic activity on KB cell lines.

Compound libraries Synthesized compound libraries provide another area where automated flash chromatography systems improve laboratory efficiency. Chemists can synthesize compounds while the flash chromatography system purifies the results of earlier reactions. Labs that use automated flash chromatography to create compound libraries for screening report a 37 percent increase in the number of purifications that they perform, leading to increased lead diversity.

Phenanthrene based tylophorine derivatives Lee et al have used flash chromatography to purify reaction mixtures in their work on synthesizing phenanthrene based tylophorine derivatives (PBTs). The authors suggest that novel synthetic PBT analogs may exhibit some desirable properties including possibly increased cytotoxicity and fewer side effects than presently known molecules.

An automated flash system was used to purify the products of reactions involving reductions, hydrolysis, and peptide bond condensations. The peptide bond condensation product was purified with on silica gel with an ethyl acetate / hexane gradient. The other reaction products were purified with methanol / methylene chloride gradients on silica gel.

Of the 33 novel PBTs synthesized by the authors, three (10–12) exhibited strong cytotoxic properties. Two of the three (10, 12) compounds showed IC50 values comparable to etoposide.

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Full references are available on www.pharmafocusasia.com/magazine/

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compact than the run from silica gel. Further optimisation of the gradient could be employed to sharpen the harmaline peak. The use of amine functionalised silica in this example illustrates the ability to separate even difficult samples.

Separation of harmine and harmaline on a silica gel column with a methylene chloride/methanol gradient solvent system

harmine harmine 1.00

100 90

Purine and pyrimidine cyclopentyl C-nucleosides 60 0.50 50 In this work, the authors describe the synthesis of harmine harmine 40 1.00 100 various carboxylic and C-nucleoside analogs of inter30 0.25 90 20 est because of their reported anti-tumour and anti-viharmaline harmaline 10 80 0.75 70 ral properties, as well as their chemical stability. Some 0.00 0 60 carboxylic and C-nucleosides have been isolated from 0.50 50 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 natural sources, but no naturally occurring carboxylic 40 30 C-nucleosides have been thus far reported.

0.25 20 harmaline harmaline For their purification needs, the authors relied on 10 100 0 0.00 column chromatography, vacuum flash chromatogra0.45 90 phy and automated flash chromatography.

0.40 0.0 8040.0 Separation and15.0harmaline amine column with 5.0 of harmine 10.0 20.0 on an25.0 30.0 35.0 hexane/ Of particular interest was their use of amine func0.35 70 ethyl acetate gradient solvent system 0.30 60 tionalised silica gel and prepacked columns (RediSep® 0.25 50 Amine, Teledyne Isco) in the purification of (15) and 0.20 40 100 (16). It is doubtful that these separations would have 0.15 30 0.45 90 harmine 0.10 20 proceeded easily with only bare silica, as was illustrated 0.40 80 harmaline 0.05 10 0.35 70 in the example of Banisteria caapi, above.

0.00 0 0.30 60 (1’S,2’S,3’R)-4-Amino-7-(2’,3’-dihydroxy-4’0.0 5.0 10.0 15.0 20.0 25.0 30.0 0.25 50 hydroxymethyl-4’-cyclopenten1’-yl)-5H-pyrrolo 0.20 40 [3,2-d]pyramidine (9-deazaneplanocin) (15) was pre0.15 30 harmine pared by stirring a methanolic HCl solution of (17) for 0.10 20 harmaline 0.05 10 2 hours. This was followed by evaporation under re0.00 0 duced pressure and co-evaporation with MeOH. The 0.0 5.0 10.0 15.0 20.0 25.0 30.0 residue was dissolved in MeOH, neutralised with NaHCO3 filtered and concentrated to dryness. This sample was purified with column chromatography using amine Specialised media functionalised silica gel. This compound was subsequently found to Readily available pre-packed columns containing functionalised and show moderate anti HIV-1 activity. other specialty media provide the chemist with a straightforward way (1’S,2’S,3’R)-9-(2’,3’-Dihdroxy-4’-hyrdoxymethyl-4’to purify compounds that would not readily separate on normal silicyclopenten-1’-yl)-deazaguanosine (16) was synthesised by stirring a ca gel. Both examples below use amine functionalised silica although methanolic HCl solution of (18) for two hours, followed by filtration other column chemistries such as C18 are available. and concentration as was performed for Compound 1. This residue was purified via automated flash chromatography using a Teledyne Alkaloids of Banisteria caapi Isco RediSep® Amine column. This compound (EC50 2.5 uM) The plant Banisteria caapi is the source of the alkaloid harmine, was found to exhibit moderate activity without cytotoxicity against known for its hallucinogenic properties. Harmaline (13) was purified Punta Toro virus. from Florisil using a chloroform-methanol gradient. The dried vine was refluxed in methanol. The extract was dried and extracted into Conclusion chloroform with 5% ammonium hydroxide. Harmaline required Automated flash chromatography helps researchers purify com100% methanol to elute from Florisil. We found that harmine pounds faster than with open columns. The flash chromatography (14) would elute readily from silica gel using methylene chloride, system uses a detector that enables the scientist to easily combine but harmaline would only elute slowly with a broad peak even with similar fractions. The computer controlled gradient allows repro100% methanol. We then used a RediSep® Amine functionalised ducible separations and facilitates scale-up. The use of pre-packed column using a gradient from 50 to 100% ethyl acetate in hexane. columns saves additional time, improves reproducibility of results Although the harmaline still produces a broad peak, it is much more and allows the chemist to easily change media.

80

0.75

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

Percent B

Absorbance

Percent B

Absorbance

Percent B

Absorbance

Percent B

Absorbance

70

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Biomedical Polymers

Drug delivery and molecular imaging During the last two decades, significant advances have been made in the development of biocompatible polymers as the platform for drug delivery and molecular imaging.

Zheng-Rong Lu, Assistant Professor Furong Ye Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, USA

D

uring the last two decades, significant advances have been made in the development of biocompatible polymers as the platform for drug delivery and molecular imaging. The idea of using synthetic and natural biocompatible polymers as a platform to improve pharmacokinetics and delivery efficacy of small molecular therapeutic drugs is not new. Biomedical polymers have been widely used as carriers for drugs for example, polymer-drug conjugates, polymeric micelles, polymer protein conjugates and polyplexes have been designed for the delivery of chemotherapeutics, proteins and gene therapeutics. The conjugation of drugs to polymers can increase solubility and stability of the drugs while reducing their systemic toxicity. The coupling of drugs to water soluble biomedical polymers has the principal effect of limiting cellular uptake by pinocytosis, and therefore altering drug pharmacokinetics at the whole organism and cellular level. The polymer drug conjugates can passively accumulate within solid tumour tissues due to the hyperpermeability of tumour blood vessels and poor lymphatic drainage of tumour tissues, a phenomenon termed as “Enhanced Permeability and Retention (EPR) effect�.

Also, polymers can be designed to be multifunctional and can be modified by using targeting-moieties to enhance drug targeting to specific tumour sites.

With the incorporation of imaging agents into biomedical polymers, polymeric drug delivery can also be applied in the design of novel contrast agents or probes for molecular imaging. Unlike traditional diagnostic imaging, molecular imaging has a potential to help imaging various targets or pathways. Imaging modalities that have been applied in human subjects for in vivo evaluation include Ultrasound, Optical Imaging, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). The incorporation of imaging agents into biocompatible polymers alters their pharmacokinetics, prolongs the retention of the agents in the tissue of interest, improves their specificity, and has a potential to help improve the accuracy of clinical diagnosis. Applications for different imaging modalities include MRI, SPECT, PET, Ultrasound and Optical Imaging.

In fact, the applications of biomedical polymers for drug delivery and molecular imaging are not mutually exclusive. The concept of drug delivery can be combined with molecular imaging to design more effective and specific imaging agents; after labelling the polymeric drug delivery systems with appropriate imaging probes, non-invasive visualisation of the delivery system reveals the complicated mechanisms of in vivo drug

delivery and its correlation to pharmacodynamics. The combination of drug delivery and molecular imaging on the same polymer platform will result in more effective imageguided therapies. The earlier a disease can be diagnosed and a therapeutic drug can be delivered, the better the chance that the disease can be cured quickly. This is the rationale for the combination of polymer platform in drug delivery and molecular imaging.

The study of biomedical polymers in drug delivery and molecular imaging is becoming more and more comprehensive.

Already, numerous studies have been undertaken on the application of biomedical polymers in optical imaging and MRI, including development of bioactivatable polymeric fluorescence probes, novel biodegradable macromolecular MRI contrast agents, non-invasive visualisation of in vivo drug delivery of polymeric conjugates with contrast-enhanced MRI, bifunctional polymeric conjugates for image-guided interventional procedures and so on. Molecular imaging with macromolecular imaging probes is effective to non-invasively and accurately assess therapeutic efficacy of new therapeutics in both pre-clinical and clinical drug development.

For example, MRI is an imaging modality that measures the difference in the longitudinal or transverse relaxation rates (1/T1 or 1/T2) of water protons in different tissues. Unlike other imaging modalities, MRI provides very high spatial resolution and is very adept at morphological imaging and functional imaging. High-resolution 3D MR imaging becomes particularly relevant when examining heterogeneous structures such as cancer tissues. Clinically approved

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

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Events MRI contrast agents are mostly low molecular weight Gd(III) chelates, including GdDOTA, Gd-DTPA and their derivatives.

These agents are tissue non-specific and have a transient blood retention time, which lead to short imaging time windows and low signal intensity in the images. Therefore, macromolecular contrast agents have been developed to improve the pharmacokinetic profile of the contrast agents by covalently conjugating them to biomedical polymers including polyamino acids, polysaccharides and proteins. On the other hand, slow excretion of polymers brings in potential toxicity issues because Gd(III) ions are highly toxic and long-term tissue retention of macromolecular MRI contrast agents may result in release of toxic Gd(III) ions due to metabolism. To alleviate the safety concerns related to macromolecular Gd(III) contrast agents, novel designs like polydisulfide Gd(III) complexes and polymer Gd(III) chelate conjugates with disulfide spacers have been introduced. Tissue specific targeted MRI contrast agents could also be developed by incorporating a targeting moiety into the polymer backbone.

With MRI, treatment efficacy can be evaluated over extended periods of time, inter-individual variability is reduced, and therefore statistical significance may be obtained with much smaller groups. Hence, non-invasive visualisation of polymer-drug conjugates’ delivery on in vivo has been applied after labelling the conjugates with imaging probes. Although the MR signal intensity is not linearly correlated to the Gd(III) concentration in the tissues, it provides qualitative or semi-quantitative information about the structural effect of polymeric conjugates on in vivo drug delivery. MR images revealed a size-dependent, dynamic and heterogeneous distribution of the conjugates in organs and tumour tissues and the number of animals used in the study is greatly reduced. Currently, traditional biopsy-based pharmacokinetics studies are still needed for validating the imaging approaches. The two readouts from biopsy and MRI are complementary. Combining sensitive molecular imaging approaches such as PET or optical imaging with MR imaging

allows the accurate and assimilated study of the pharmacokinetics / pharmacodynamics of a polymeric drug delivery system.

Polymers have also been used for image guidance and treatment assessment during interventional procedures. Both imaging agents and anti-cancer drugs can be loaded onto the same polymer platform to prepare bifunctional agents for image-guided therapy.

The combination of contrast enhanced MRI with photodynamic therapy would provide accurate localisation of interstitial lesions, guiding specific light irradiation to the tumour tissue in photodynamic therapy. This has been demonstrated by using a bifunctional polymer conjugate containing an MRI contrast agent Gd-(DO3A) and a photosensitizer mesochlorin e6 (Mce6), poly-(L-glutamic acid)-(Gd-DO3A)-(Mce6) conjugate.

Biomedical polymers are able to favourably modify the pharmacokinetics of therapeutics and imaging probes and improve their efficacy in therapy or disease characterisation. Biomedical polymers based nanomedicine has a significant advantage over that based inorganic nanomaterials in terms of versatility and safety. Application of biomedical polymers in drug delivery, molecular imaging and nanomedicine will generate new and more efficacious therapeutics and imaging probes to improve human health, which will also create tremendous opportunities to pharmaceutical and biotechnology industry. Currently, several polymer drug conjugates and polymeric imaging agents are in clinical trials in the U.S. and Europe, and one is already being used in Japan.

In summary, the application of biomedical polymers benefits from their large sizes and unique pharmacokinetic properties. It has the potential to have an important impact on the way in which drugs are delivered. The impact will be the establishment of powerful diagnostic and therapeutic tools for pharmaceutical industry in the development of effective drug delivery systems and imaging probes, and non-invasive approaches for pre-clinical and clinical drug development.

Full references are available on www.pharmafocusasia.com/magazine/

November 2007 November 25-27, 2007 CPhI India Mumbai 2007, Mumbai, India Organisers : CMPi Email

: cphi@cmpi.biz

http://www.cphi-india.com

December 2007 December 14-16, 2007 Pharma Future Expo’ 07, Singapore Organisers : PS World Events Email

: info@pharmafutureexpo.com

http://www.pharmafutureexpo.com December 21, 2007 Pharmaceutical EXPO 2007, Varanasi, India Organisers : Federation of Indian Chambers of Commerce and Industry Email

: kavitasharma@ficci.com

http://www.ficci-b2b.com

January 2008 January 19-20, 2008 1st Pharm Tech IAPST International Conference, Kolkata, West Bengal Organisers : Indian Association of Pharmaceutical Scientists and Technologists Email

: support@iapst.com

http://www.iapst.com January 28-29, 2008 Bio-Asia 2008, Tokyo, Japan Organisers : Biotechnology Industry Organization Email

: bioasia@bio.org

http://bioasia.bio.org January 29-30, 2008 Operational Excellence in Clinical Research 2008, Singapore, Asia Organisers : IQPC Email

: erwin.tan@iqpc.com.sg

http://www.iqpc.com

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c l i n ic a l tri a l s

Clinical Outsourcing in Japan Ready to fulfill its destiny?

With the increasing popularity of global and regional trials in Japan, most global pharma companies are looking to develop as many compounds in Japan as possible. Yet, with limits to ‘headcount increases’, companies face limited options to achieve their business goals.

Christopher R Albani, Partner Yorozu Tabata, Principal PRTM, Japan

J

apan remains the second largest national market for pharmaceuticals at 11% of the global market—as defined

by IMS. And yet, there remain varying opinions about the status of Japan’s pharmaceutical industry. Japan’s unique regulatory requirements are often cited as a particular cause of frustration by multinationals. However, the Japanese government has taken a very keen interest in improving its regulatory review performance as well as that of the clinical trial infrastructure—much of which promises to improve the situation in Japan in the near future. In particular, the “drug lag”—the delay of introducing

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new drug products—continues to plague patients here.

Now, global companies are trying to get as many products as possible into the Japanese market as quickly as possible to minimise this drug lag. And while they are doing this, the impact of shrinking global margins is often to freeze headcount in places like Japan. Therefore, CROs operating in the Japanese market have enjoyed a surge.

However, the CRO market in Japan, after starting from virtually nothing in the early 90s and growing since then, unfortunately is still immature in both capability and capacity. The increasing workload which global

companies must deal with—in combination with the immaturity of the Japanese outsourcing market—leaves two diametrically opposed options for the pharmaceutical companies. The first option is to significantly improve internal productivity in order to enable the increased workload with the same staffing levels. The other option is to establish truly non-procurement-driven partnerships with CROs. These pose viable, yet challenging, alternatives.

Increasing pipelines For those unfamiliar with the Japanese pharmaceutical market, it must be surprising

c l i n ic a l tri a l s

Total level of outsourcing as a percentage of total clinical development spending 0%

Global (outside Japan)

20%

40%

Outsourced USD 6.4 bn

60%

80%

100%

Not outsourced USD 20.1bn Not outsourced USD 4.2bn

Japan Outsourced USD 0.54 bn

Outsourced

Not Outsourced Figure 1

Q: How often does demand exceed your capacity? # of CROs 0

2

4

6

8

10

12

Demand exceeds capacity most of the time Demand sometimes exceeds capacity while it matches in other times

(91% of respondents)

Demand matches the capacity most of the time Capacity sometimes exceeds demand while it matches in other times Capacity exceeds demand most of the time.

Figure 2

to learn that a mere 22 percent of the drugs launched across the world between 2002 and 2006 are available to Japanese patients and that up to 40 percent of the world’s top ninety-nine compounds in the market today are not available in Japan. While this seems dire, corrections are being made to close this gap; often called the “drug lag.” This means that there is a large number of proven products to be developed and approved in Japan.

Meanwhile, increasing competition, blockbuster patent expirations and new technologies are driving an increasing number of compounds into development.

So, it is clear there are lot of compounds which could be developed in Japan. And companies are trying to do just that with a likely result of diminishing the magnitude of the “drug lag” significantly. Yet, it is the same global competition which is driving pipeline growth that is limiting headcount growth as well. While the era of the blockbusters allowed big pharmaceutical companies to significantly increase the headcount,

today’s pressures demand restraint. So companies are trying to develop a large number of compounds in Japan, without increasing headcount. In addition, the regulatory requirements in Japan demand that clinical data be collected on Japanese subjects in order to accomplish registration, thus creating significant pressure on both corporate managers and functional managers involved in late-stage drug development. From a global company’s perspective, the first reaction is to look to outsourcing to save the day.

An immature market Unfortunately, the market for outsourcing services in late-stage clinical development (later than Phase IIa) is not yet mature. To understand why this is the case, we need to go back in time about a decade. While several of the major CROs were founded in 1 Source: Goldman Sachs, PhRMA, EEPIA and PRTM’s analysis as well as JCROA Annual Report 2005 figures, PRTM estimates that Japan’s total R&D expense accounts for 60% of the total clinical development expense.

the early 90s, it took Japan’s late adoption of International Committee on Harmonization (ICH) E6 guidelines on Good Clinical Practices (GCP) in 1997 to kick-off the growth cycle which continues to this day.

So the industry is relatively young in Japan.

But, from a business perspective, market maturity is not driven by age. If we look at the total level of outsourcing as a percentage of total clinical development spending, for Japan, we see that it is about half that spent outside Japan (Figure 1). Unfortunately, very little research has been done on this market.

As a result, in late 2006 and early 2007, PRTM undertook an in-depth survey of this market in Japan. More than 50 pharmaceutical companies, CROs, medical device companies and other related companies participated. The survey investigated the various activities in clinical development and sought to understand the maturity of this important market.

The maturity of a market can be judged through many measures. In this survey , PRTM examined maturity as represented by multiple willing and able suppliers in combination with willing and ready buyers. In looking at the relative maturity levels of the specific service areas in clinical research, we estimate that a few services, such as randomisation and patient registration, services are truly mature in Japan. The most commonly outsourced services on a global scale such as monitoring, biostatistics and data management are still in a growth phase. This means that demand regularly outpaces supply as can be seen in Figure 2. In fact, many CROs are currently quoting a nine-month or more waiting period for monitoring resources. Other key outsourcing areas, such as protocol development, common technical document (CTD) development and filing preparation are in the early stages of development as services in Japan.

2 PRTM is a global management consultancy focused on helping companies execute truly innovative strategies.

3 For this survey, PRTM has characterised each service segment of the clinical outsourcing market by (1) revenue— status of revenue growth, (2) product (quality)—status of service variety and customer’s satisfaction level on quality, (3) place (availability)—status of service availability against customer demand (4) price—status of pricing and customer’s satisfaction level on price.

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(Q) Do you have a documented, standard process for managing CROs?

Ratio of the pharmaceutical companies that have a written procedure of CRO performance management

No/40%

Yes/33% Yes/60% No/67%

Figure 3

Meanwhile, the practices of managing interactions between CROs and pharmaceutical companies are also immature. Global pharmaceutical companies’ management process elements including selection, contracting, performance management and evaluation were originally developed in headquarters and transferred to Japanese subsidiaries assuming that outsourcing market is as mature as elsewhere.

Not surprisingly, survey results also reveal that managing CROs performance is critical for pharmaceutical companies to receive reasonable level of services (Figure 3).

The survey reveals that large pharmaceutical companies are just beginning to bring more formal procurement-like systems into Japan to improve how they interact with outsourcing vendors. Unfortunately, this also means that some are tending to treat clinical outsourcing as a traditional procurement transaction, focussed on short-term cost alone.

Unfortunately, for such procurement transactions to work effectively, a mature marketplace is needed. Meanwhile, many of the smaller firms are yet to “professionalise” their outsourcing practices.

As a result, pharmaceutical companies, as a whole, report receiving unsatisfactory services at unsatisfactory price.

The alternatives PRTM believes that sourcing in an immature market, in particular requires top management’s involvement to evaluate the two

apparent strategic options in order to fulfill their development needs: 1. On one hand a pharma company can focus its energy on significantly improving its internal efficiency. This can take on several flavours such as improving the usage of global facilities/functions like data management or dramatically improving the efficiency of functions on the ground in Japan. Even though many companies have gone through operational improvement phases such as six-sigma, PRTM’s practical experiences with various pharmaceutical companies in Japan reveal that there is much to improve and by careful calculation, some companies have become aware that the fully-loaded costs of an outsourced staff member can be more than that of an in-house resource. Part of this is driven by factors such as oversight to assure quality of services provided. One leading global company, for example, typically reserves one manager for 8 internal staff but is forced to use one manager for 4 outsourced staff in the case of Japan. And this approach depends upon a company’s ability to attract and retain strong, talented staff. Overall, this approach could be termed “best and brightest.”

2. On the other hand, a company may take on this pressing need by forming a true non-procurement-based partnership with an outsourcing service provider. This could be in the form of a joint venture, stock purchase, or spin-off (also known as a “carve-out”). It is important to note

that the approach cannot be simply focussed on cost containment. The reason for this is simple: many CRO companies will be better off from selling resources on the “spot” market, rather than selling “futures” to interested pharmaceutical companies. This means that a real winwin situation is needed. It also means that companies need to share risks and benefits of clinical development. Other industries have taken strong steps in this direction.

For example, in the automotive industry, many companies outsource the full development, assembly and test of large modules of a car such as the interiors and brake systems. In these cases, the partner is contracted for a long period of time to develop and make these key automotive components.

With each of these alternatives, it is true that there are cases of success and failure.

Much of that can be attributed to the effective execution of a strategy. Yet, it is up to the management of each firm to find its way between these two extremes. The characteristics of management and its staff will dictate which approach or combination thereof makes the most sense.

Conclusion Faced with mounting pressures to do more with less people, development managers at pharmaceutical companies operating in Japan face some tough choices ahead. We’ve seen that many organisations are inefficient and could use a strong dose of option (1) above to improve efficiency. Meanwhile, stories abound regarding companies who have tried and failed at option (2). We argue that the proof in these cases is in the execution of the strategy at these companies. So far, results are yet to be seen in any consistent manner in the industry. And, while there are many management styles, there are equally as many choices along the spectrum outlined above. In the end, then each company must choose its own course. Some will opt for organisational excellence and some will move completely in the other direction. Neither option is right nor wrong. But, it is important to be wary of execution and trying to fit Japan into a box defined by other markets.

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Clinical Trial Integration Adopting an innovative approach

A clinical trial interchange platform can solve complex data integration challenges and also provide enterprise reporting, searching and aggregation capabilities.

Solomon Shacter, Director, Product Management - Platform Solutions, ClinPhone Plc, USA

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he number of solutions available to automate the clinical trials process is increasing at a fast pace with each solution providing a variety of targeted benefits to suit different requirements. Often the same data point is imported into and processed by these different solutions, affecting specific aspects of the clinical trials process in a similar way. Yet, these solutions are most commonly used separately which inevitably lead to timeconsuming, costly and unnecessary duplication of documentary data and long-lasting procedures of collaborating information between systems.

Current technology Data automation, integration and presentation are required to successfully conduct a clinical trial and it is not uncommon that all these parameters impact one another. Only a platform solution can deliver benefits and features, such as Single SignOn (SSO), beyond simply transferring data between disparate systems to support a clinical trial.

Traditionally, biopharmaceutical companies have employed various information technology solutions in order to accelerate the clinical trial process, manage data and minimise costs. The most widely used solu A “platform solution” is a trial interchange system that orchestrates data exchange between systems. Applets built on the platform actually perform the work.

tions are Clinical Data Management Systems (CDMS), Clinical Trial Management Systems (CTMS), Electronic Data Capture (EDC), Drug Supply Management Systems (DSMS) and Interactive Voice Response Systems (IVRS). Although these systems offer many logistical and commercial benefits, they would be more effective and efficient if they can share information with each other.

The early software solutions tried to tackle this issue through software automation but they didn’t have a standard way to share clinical data. To solve the problem, companies started writing their own custom code to bridge one application with another.

To provide an industry standard for describing the clinical data the Clinical Data Interchange Standards Consortium (CDISC) was set up. Unfortunately, the CDISC standard describes a small sub-set of all trial information.

Sponsors and site managers must devote hours every day to keep the different systems synchronised. Typical activities include • programming or converting data structures from one system to another • transferring data between physical locations • verifying the transfer and checking data after the transfer • defining the clinical trial protocol within the different systems in terms of data structures and edit checks

For years, drug and medical device developers have dropped information gathered

by Case Report Forms (CRFs) into data ‘silos’, i.e., databases designed for only one trial. The main focus being on completing a specific trial as quickly as possible to accelerate the Food and Drug Administration’s (FDA) submission and approval process, the usefulness of raw data in the future has been given less importance. Some vendors of health software attempted to address the integration issues by developing health information solutions which used standardised messages to exchange information within a hospital or region. While basic communication problems have been addressed, these solutions have not achieved complete interoperability and integration of information.

As clinical trial applications became more dynamic and interconnected, vendors started providing standard “hooks” or Application Program Interfaces (APIs) to connect their applications to others. A series of standards evolved to help IT organisations share data across applications and organisations.

“Middleware” vendors created software to help define data, connect applications and transfer data more quickly in order to increase productivity, efficiency and customer satisfaction.

Data integration example In a typical study, a subject may be screened as patient “4321-AAC” in an Electronic Data Capture (EDC) system, randomised as “014321” in the IVR system and tracked as subject ID “4321” in an eDiary hand-held system. In addition to the same patient being referred to with three different identifiers, the IVR and eDiary solutions share data

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Point-to-Point Integration Randomisation & Trial Supplies Management

Enterprise eClinical Data Management Platform (EDC & CDMS

“014321”

eDairy

“4321-AAC”

File Share

“4321”

Wireless Access Point Figure 1

using different methods; a file-based system and a sophisticated wireless access point respectively.

Point-to-point (P2P) integration method Collectively termed P2P, this solution aims to

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share data between two systems by modifying the underlying application code and data on each system for the sole purpose of sending and receiving data, usually through a set of files. Using P2P results in increased trial costs and timelines, more data synchronisation errors, lower flexibility and incomplete

decision-support ability. P2P can create more challenges than it solves because: • it obliges tight integration of the two systems, meaning that any updates incorporated in one of them will affect the operation of the other as well as the custom connection • the custom connections can be built, tested, maintained and supported only by technical specialists • it forces external vendors and partners to adapt their systems to the proprietary needs of the P2P connection when data is to be shared outside the Clinical Research Organisation (CRO) or pharmaceutical company.

Using the clinical trial data integration example from above, a P2P approach can be illustrated and summarised as in Figure 1.

In the case that the three systems have been purchased from different vendors, changes to all of them may not be possible.

Further, custom code is needed to manage security between each point. Finally, P2P estabilishes a synchronous workflow that relies on all systems being available to send

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Trial System

Workflow

Change Required

Translation Required

EDC

Export the patient screening details

Create a custom patient IVR export file

Export patient as “4321-AAC”

IVR

Import the patient screening details from EDC then randomise the patient data

Create a custom EDC import file mechanism and create a custom EDC export file

Export patient “4321AAC” as “014321”

EDC

Import the patient randomisation details from IVR

Create a custom patient IVR file import mechanism

Link “4321-AAC” to “014321”

EDC

Export patient data to eDiary

Create a custom data link to eDiary system

Export patient as “4321-AAC”

eDiary

Import and store patient data from EDC

Create a custom data link to EDC system

Link “4321-AAC” to “4321” Table 1

and receive data through a local file sharing system and the Internet, as well as requiring the EDC system to track the different identifiers representing the patient in each system. This solution is limited, costly to maintain, difficult to support, inflexible and does little to represent the overall clinical trial processes or shared data at decision support level. The High-tech industry has

responded by providing solutions designed to solve the shortcomings of manual data entry and P2P approaches. One such solution is Web Services.

Web services The least mature set of technologies available for integrating clinical data, Web Services, enable data sharing between

web-based applications irrespective of the underlying platforms or programming languages used.

Web services use Extensible Markup Language (XML), an open standard that was originally designed to facilitate easy exchange of information over the Web. Multiple XML standards have proliferated, but they present serious downfalls impeding easy integration. Many industry-specific definitions are not incorporated into XML. The standard also lacks security, verification and confirmation functionalities necessary for inter-enterprise communication. XML also can’t achieve integration alone.

Using the previous clinical trial data integration example, a web service approach can be illustrated and described as as in Figure 2. Just like with P2P, when the three systems have been purchased from different vendors, changes to all of them may not be possible. However, proprietary custom coding is not necessary since

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Web Services Integration Randomisation & Trial Supplies Management

Enterprise eClinical Data Management Platform (EDC & CDMS

“014321”

eDairy

“4321-AAC”

“4321”

Wireless Access Point

File Share Internet Web Services

Figure 2

Trial System

Workflow

Change Required

Translation Required

EDC

Export the patient screening details

Create a web service method to retrieve patient screening data in XML and export it as an IVR file

Export patient as “4321-AAC”

IVR

Import the patient screening details from EDC then randomise the patient data

Create a custom EDC import file mechanism and create a custom EDC export file

Export patient “4321AAC” as “014321”

EDC

Import the patient randomisation details from IVR

Create a web service method to retrieve an IVR file and convert it to XML

Link “4321-AAC” to “014321”

EDC

Export patient data to eDiary

eDiary uses existing web service method

Export patient as “4321-AAC”

eDdairy

Import and store patient data from EDC

Create a custom data link to EDC system

Link “4321-AAC” to “4321” Table 2

web services enforce security and data standards. Web services generate benefits only when all systems are capable of sending and receiving data. Moreover, they require the EDC system to track the different identifiers representing the same patient in each system. A Clinical Trial Interchange Platform (CTIP) solution succeeds where P2P and Web Services fail because it lowers integration costs, time and data errors between internal and external clinical trial systems by serving as a trial interchange to automate processes, share data seamlessly and provide a single decision-support portal for all study resources and activities.

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It enables all of the solutions used during the trial process to respond to actionable alerts, orchestrate events and report status and results in real-time.

Clinical trial interchange platform CTIP facilitates unattended asynchronous communication between two or more trial systems. There are instances, however, where synchronous communication is required. As a result, a platform capable of handling both types of communication is needed.

With CTIP, communication between systems is achieved without any system

modifications. It therefore allows the different business units to keep operating through the clinical trial life cycle.

CTIP breaks down operational silos with Single Sign-On integration and delivers a holistic solution with a single view of all trial related systems and application dependencies along with server configuration and security information.

CROs or pharmaceutical companies can access, search and organise all study related data and resources in one central location that catalogue the identifiers used in each connected component.

A consistent mechanism helps users to navigate within the central repository and find the required information. Without a platform to route messages and perform automation, compliance enforcement is, at best, labour-intensive, but often, nearly impossible across trial systems. The interchange platform completely automates the task of setting and enforcing regulatory and best practice standards and delivers executive-level, at-a-glance visibility into a system generated audit trail for regulatory compliance. From the previous clinical trial integration example, a CTIP solution can be illustrated and summarised as in Figure 3.

Cross-trial integration With regards to clinical trial integration, the most important question to answer is whether it is more effective to build integration capabilities into different systems or build a flexible single platform solution. Building a CTIP product would not only make single trial integration easier to implement but also make cross-trial integration a reality. Collecting and combining raw data from different trials can result in billions of cost savings as well as additional revenue. However, formatting data across systems that do not feature integration capabilities can be an extremely labour-intensive task.

Implementing cross-trial integration systems Unfortunately, relatively few systems offer the ability to deliver real-time data

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Clinical Trial Interchange Platform Randomisation & Trial Supplies Management

Enterprise eClinical Data Management Platform (EDC & CDMS

“IVR randomised patient 014371”

eDairy

“New patient 4321-AAC screened”

“Screened patient 4321 added from FDC”

Clinical Trial Interchange Platform Master Resource Catalog: “4321-AAC” from EDC system “014321” from IVR system “4321 from eDairy system Figure 3

Trial System

Workflow

Change Required

Translation Required

EDC

A patient is screened

None

None

CTIP

Listen for new EDC patient screened event and Alert the IVR system to randomise and store the data

Message based service created to Listen for and trigger events in the trial systems

Tag the EDC patient in the CTIP catalog as “4321AAC”

IVR

Randomise the patient data

None

None

CTIP

Listen for new IVR patient randomised event, Alert the EDC and eDiary systems to store the data

Create trial interchange Audit Trail to record the workflow

Tag the IVR patient in the CTIP catalog as “014321”

EDC

Store the patient details under “4321-AAC”

None

None

eDiary

Store the patient details under “4321”

None

None

CTIP

Listen for new eDiary patient

eDiary message system created

Tag the eDiary patient in the CTIP catalog as “4321” Table 3

exchange across multiple platforms and databases, let alone completely different trials. Some solutions can integrate with other proprietary systems, but they do not necessarily work with inhouse or other third-party solutions. Implementing a CTIP system designed for multiple trial integration and re-use prevents the need for trial-by-trial development of data schemas, table joins etc. all

of which are time-consuming activities and expensive to continually re-invent and validate. However, building a CTIP solution can be difficult.

Other industries already employ flexible, standards-based data models, which the pharmaceutical industry can use as templates to discover whether they are applicable for clinical trial applications.

These models can be easily achieved as

almost every trial involves the same links between notions such as protocol, patient, treatment group and visit. With traditional P2P single-trial integration systems, every time something changes it impacts on the effectiveness of the integration by potentially upsetting and delaying a lot of the work which has already been completed. When a platform integration approach is implemented, the version of the system being used and its integration capabilities are not interrelated. Data can be imported and exported regardless of their original location. This means that data is collected into a central repository enabling study staff to review all the information at a glance.

Regulations Until now, no industry regulations have been enforced to mandate integration of clinical trial systems. Whilst just a recommended approach, CDISC standards have become the preferred choice of many sponsors and vendors. Using a CTIP to gather and manage clinical trial information can help achieve FDA approval. With CTIP, every event occurring throughout the entire trial is automatically captured and stored, eliminating the time-consuming and labour-intensive process of coding each event separately for the FDA audit.

Conclusion Most biopharmaceutical companies are currently examining the potential benefits of integrating clinical trial data from different electronic solutions and some even making integration capabilities a pre-requisite of vendor selection. Companies need to adopt innovative integration systems, which will provide them not only with the ability to integrate data but also the capacity to automate processes and report status in real-time across different systems and trials.

A CTIP approach forms the next stage in clinical trial integration providing important benefits such as cost savings, reduced time-to-market and improved R&D impact. Implementation of such a system can ultimately make products more competitive.

Full references are available on www.pharmafocusasia.com/magazine/

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Site Management Organisations in Asian Clinical Trials Providing competitive advantage

In a changing market for clinical trials where fast recruitment of large patient numbers is of the essence, Site Management Organisations (SMOs) operating as independent CRO divisions offer some significant advantages in the Asian market.

Sergei Drapkin, Managing Director, ERGOMED Clinical Research, Russia

S

ite Management Organisations (SMOs) frequently act as both partners and competitors in the conduct of clinical trials for Contract Research Organisations (CROs) and claim to show advantages over them to pharmaceutical companies. Most effective is the integration of study site management in the classical CRO clinical services as it eases the communication between organisation and all parties involved in a trial.

During the last two decades, Asia has become home to the world’s fastest emerging economies and the most challenging market in the world. It is crucial for CROs in important emerging markets, such as Asia Pacific and Eastern Europe, to determine the current market landscape regarding the use of each service; understand customers’ needs and wants; understand perceptions regarding the CRO’s service capabilities versus other service providers (for example management consulting firms); and obtain reactions to each service concept, including likes and dislikes.

Sponsors are increasingly trying to find the most cost-effective strategic solution on which activities to outsource and which type of CRO (full-service, niche-service, regional) to contract with. Consistent service delivery is key strategic objective to

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enable CROs to deliver superior service in developing countries.

Pharmaceutical companies are increasingly outsourcing to the CROs’ wider spectrum of tasks in emerging markets. Apart from traditional contract clinical services (e.g. monitoring, data management etc) the following offerings are in big demand outside of established pharmaceutical markets: early-stage drug development, medical consulting, laboratory selection, pharmacovigilance, staffing, management of opinion Reasons cited by SMOs as to why they can reduce study timelines.

Improved pre-study planning and feasibility Partnerships with experienced investigators Optimal patient recruitment On-going communication Site-specific support and guidance Proactive ethics committee management Higher patient retention.

leaders’ network, collaboration with external partners, supporting of sales initiatives, educational Internet sessions etc.

The pharmaceutical industry in emerging markets of the Asia Pacific region and Eastern Europe has developed rapidly over the past 10 years. Clinical trials used to be conducted by out-patient departments and specialists within large municipal and university hospitals and were fitted around day-to-day clinical responsibilities. Challenges from different local regulatory systems and cultures are becoming a crucial issue which is increasing the costs of clinical trials. Knowledge of local requirements is vital to avoiding delays.

Independent market research conducted to help in designing and implementing the appropriate recruitment and retention strategy, awareness campaign, appreciation of local ethical, cultural and regulatory requirements, patient referral mapping and site logistics has also shown that international regulatory demands have grown. Consequently, the time needed to conduct high-quality trials has increased, resulting in some investigators becoming less willing or able to concentrate on clinical trials.

At the same time, the pharmaceutical industry has come under increasing pressure to reduce drug development cycle times and to achieve cost efficiencies throughout the process. With clinical trials contributing a significant proportion of drug development time and patient recruitment being a

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key factor in trial delays, a new way of identifying and managing clinical-trial investigators has been needed. To address this need, site management organisations have evolved as organisations dedicated to conducting clinical trials using specialist physicians and nurses.

Getting the right services into the right markets is the obvious mainstream of modern clinical research industry.

SMOs that work as independent CRO divisions are most suitable for the Asian market. They usually work when district physicians or hospital doctors act as investigators. Study visits are controlled largely by the patient’s own doctor, supported by research / practice nurses.

Such SMOs would have a regional coordination structure and be responsible for site training and support. Patients are recruited through database searches and during visits to their physicians, making the model suitable for recruiting a large pool of subjects.

The potential benefits of an SMO are well known: rapid and reliable patient recruitment, improved data quality and consistency, reduced study timelines primarily due to quicker study start-up, more accurate doctor contact information, reduced site management time, improved relationships with investigators.

The following pictures show the advantages of conducting clinical trials with site management support in 12 CEE sites in comparison to approximately 50 Western European sites. The CEE sites brought pretty late in the study and with site management support brought to rapid recruitment of Cancer cachexia patients. Additionally the second picture shows that quality of the trial has not been compromised with such a fast recruitment, but in fact the patients’ eligibility was higher in CEE sites.

The reason for it is certainly better patients’ selection as well as higher retention of these terminally ill patients in the study.

Unfortunately, many sponsors are still unwilling to pay more or even reschedule the timing of their study budget in order to reap the potential benefits of working with an SMO.

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and attainment of aggressive milestone timelines. Their success is dependent on first hand knowledge of patient popula100 tions and well defined relationships with 80 broad investigator networks. Where they 60 are able to deliver, they obviously add value, and importantly for a sponsor this 40 value is added to a different line of the cash flow analysis to that of a CRO. 20 CROs and pharma companies often 0 struggle to ensure the quality or accuSites EU Without SMO Sites CEE With SMO racy of protocol feasibility because they work infrequently with their investigator Successful Recruitment Path sites and have limited knowledge of the local clinical and logistical arrangements.

Recruitment in Ca. Cachexia Similarly, they are rarely able to access No. of patients hospital data to verify the recruitment claims of potential investigators. Because 500 SMOs work closely with sites that they 400 manage and support, they should have 300 an intimate knowledge of the strengths 200 and weaknesses of the clinical trial proc100 ess within each site and be well placed to make thorough assessments of their 3 6 9 12 15 Months suitability for a particular study. While Study Start (50 sites EU, without SMO) feasibility assessment is a key tool for CEE Start (12 sites, incl. SMO) accurate project placement, these exercises can also offer sponsors the opportunity to develop relationships with An SMO derives income primarily opinion-leading specialists in key markets. from clinical trial fees, usually related to Because an SMO works regularly with completion of a specific patient visit. In the same group of investigators, there this way, the balance between income and should be clear benefits in terms of both costs can be delicate with too few studies data quality and consistency. SMOs have or slow recruitment causing a dip in intheir own standard operating procedures come. For this reason, SMOs must focus on and may put their investigators through a highly efficient patient recruitment systems common, generic training programme as in order to obtain new studies and on qualwell as providing study-specific training. ity systems to deliver the best possible data.

Effectively, the SMO provides an umbrella Both these deliverables are expensive, but over its network of investigators reducing they can distinguish an SMO from an orthe administrative or management support dinary clinic-based investigator. To benefit, that a sponsor would otherwise need to sponsors need to realise that they have to provide individually to each site. increase their study budgets so as to work SMO capability in the Asian market successfully with SMOs—sponsors cannot is limited to a few small companies. Site demand rapid recruitment and high quality Management Organisations operating as without paying for it. independent CRO divisions offer some In a decade where there has been no sigsignificant advantages in the Asian market. nificant decrease in time-to-market, but an Expanding geographic coverage with a view increase in the average number of patientsto contributing more investigators and per-license application, SMOs offer sponsors more patients to an international study is a lifeline for enhanced patient recruitment. the way of doing this.

They can pledge improved recruitment rates Ca Cachexia Evaluability

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Clinical and Non-Clinical Investigations

Improving the quality of development candidates Improving the quality of the exploratory development candidates selected to go into confirmatory clinical development should further reduce the risk of late-stage failures.

Colin W Vose, Senior Director, Strategic Drug Development Group, Quintiles Ltd., United Kingdom

T

he pharmaceutical industry continues to face challenges in improving its R&D cost-effectiveness. Despite the steady increase in the R&D expenditure in the U.S. pharma industry over the past 10 years, from US$ 17.5 billion to US$ 55.3 billion, the number of new products launched has decreased from 53 in 1996 to 22 in 2006 (Price Waterhouse Coopers, Pharma 2020, 2006).

There is not a single solution to the problem, but improving the quality of the exploratory development candidates selected to go into confirmatory clinical development should further reduce the risk of late-stage failures.

cell death and differentiation. The three layers of kinase activity modify the expression of a series of downstream products. This cascade can affect the innate immune response and offers potential routes to modulate inflammatory diseases such as Rheumatoid Arthritis.

However, modulating such pathways may mean the clinical side-effect profile and safety of drugs acting on such new targets cannot be predicted accurately by non-clinical studies. An improved understanding of the relationships between the target, physiological effects, pharmacology and toxicology is needed, increasing the focus on the search for and evaluation of biomarkers.

Target complexity and selection of outcome measures Many new drug discovery targets have been influenced by information from sequencing of the human genome. However, they may complicate the understanding of the physiological outcomes of modulating biological activity via these new targets. An example of the complexity is shown for the Mitogen Activated Protein (MAP) kinase cascade (Figure 1).

The MAP kinases are involved in coordinating the activation of gene transcription, protein synthesis, cell-cycle activities,

Biomarkers, surrogate and clinical endpoints These parameters were defined by the Biomarkers Definitions Working Group in 2001 as follows: • A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes and/or pharmacologic responses to a therapeutic intervention • A surrogate endpoint is a biomarker that is intended to substitute for a clinical endpoint e.g. HbA1c

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• A clinical endpoint is a characteristic or variable that reflects how a patient feels, functions or survives In some therapeutic indications there are no easily measurable clinical endpoints available and biomarkers may be used to support Go/No go decision. Therefore, novel biomarkers are needed that can: • serve as indicators of potential toxicity or efficacy to support early Go/No go decisions either in lead candidate selection or in early clinical studies • support patient inclusion/exclusion in clinical trials and support the submission for regulatory approval • provide a diagnostic to identify the patients most likely to benefit from treatment with the drug (individualised medicine) Various biomarkers have been used in the evaluation of drug activity and safety, and no single biomarker can provide all the desired information. Some have been available and used for a long time e.g. clinical blood biochemistry and haematology parameters such as liver enzymes creatinine and Hb. However, the application of new biomarkers must inevitably be empirical, as selection, measurement and evaluation of their relevance proceeds parallely.

The effects of drugs on in vitro, ex-vivo and in vivo lipopolysaccharide stimulated release of IL-1β, TNFα, IL-6 have been used to assess potential anti-inflammatory activity, and provide early mechanistic proof of concept for some kinase inhibitors. In some cases, such techniques can also provide an

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Biomarkers answers or questions?

There is no simple answer as many of the disStress, environment, growth factors, inflammatory cytokines ease-modifying targets involve multiple procMAPKKK esses and interactions in the target species. The MAPKK value of the information provided will depend MAPK on the understanding of the relationship between Substrates, protein kinases, cytosolic proteins, transcription factors the biomarker(s) and the wanted or unwanted efCellular responses fects. This is more difficult with newer biomarkers Figure 1 where such relationships are being evaluated in indication of the potential to disrupt normal parallel with their non-clinical and clinical immune responses. applications.

Drug induced changes in gene-expresThus, the p38 MAP kinase inhibitors’ sion in vitro or in vivo can provide early concentration-effect relationships can be indications of mechanistic proof of concept studied in vitro in human blood using the and/or toxicity. Huang et al. investigated the addition of LPS to stimulate the release of expression of 684 genes in rat liver followa pro-inflammatory cytokine e.g. IL-1β, ILing acute oral hepatotoxic doses of acetami6 and/or TNFα in samples containing difnophen, methapyrilene, furan, methotrexferent concentrations of the inhibitor. The ate and phenytoin. Principle Component experimental conditions e.g. whole blood, Analysis (PCA) of the expression patterns diluted whole blood, measuring effects on was able to distinguish the different hepaspecific cells and the cytokine stimulant totoxic changes caused by these compounds concentration e.g. LPS in vitro, ex-vivo or in and also estimate the type and severity of the vivo can influence the intensity of response toxicity. in controlled and treated samples and hence As with toxicogenomics, investigation the results and their interpretation. of the expression patterns of tissue proDepending on the biomarker being teins can indicate the potential toxicity of measured and the target indication, the relanew drugs. Petricoin et al. successfully used tionship between the drug concentration-reproteomic analysis of low molecular weight sponse curves may well be different in blood proteins (<15,000) by high-resolution, from healthy volunteers and patients. This time-of-flight mass spectrometry to search may influence the selection of the populafor serum biomarkers of cardiotoxicity tion for the initial clinical investigation i.e., in rat. healthy volunteers or patients.

Depletion of glutathione in vitro or Therefore, careful consideration of in vivo is an indicator of the production the experimental conditions used in vitro, of reactive species e.g. drug metabolites, ex-vivo and in vivo and target population is products of auto-oxidation and may be important in biomarker application. used as an early indicator of an increased risk of toxicity in early non-clinical Microdose studies in Go/No go decision-making evaluation.

Such biomarkers can help identify Microdose studies in man are being used wanted and unwanted effects early in drug more frequently to support Go/No go candidate selection. decisions. This approach uses a dose not Summary of the MAP kinase cascade (Based on C. Ropert, Curr. Enzyme Inhib., 1, 75-84, 2005)

expected to produce any pharmacological response, with a maximum dose of 100μg, to define aspects of the clinical Pharmacokinetics (PK) of novel drug candidates early in development.

These studies require more limited nonclinical safety evaluation and a number of analytical techniques have been used: • Highly specific, high-sensitivity (LLOQ ~ 10-15 g/ml) LC-MS/MS or GC-MS methods for drug and/or metabolite(s) • Accelerator mass spectrometry (AMS; LLOQ ~ 10-18 to 10-21g/ml) with a carbon-14 labelled drug microdose (≤ 100μg; nCi) • Positron Emission Tomography (PET; LLOQ ~ 10-15g/ml) with a carbon-11 labelled drug microdose (≤ 100μg; nCi) AMS and PET detect and quantify drug-related material in biofluids (plasma, urine) and/or tissues measuring total radioactivity, unless combined with chromatography. Combining them with a specific LCMS/MS method for the drug can increase the value of the PK data. The method(s) used should be influenced by the question(s) to be answered, in order to obtain the required information as efficiently and costeffectively as possible.

PET studies have been used to investigate blood-brain barrier penetration to support the selection of Central Nervous System (CNS) drugs and AMS has been used to select drug candidates with appropriate PK characteristics e.g. absorption, clearance and half-life in microdose studies.

The extent to which microdose PK predicts those at pharmacological doses was investigated by Lappin et al. in an AMS study.

The PK obtained in a microdose study were in good agreement with those at pharmacological doses for diazepam, midazolam and ZK253. The clearance, but not volume of distribution of warfarin, showed reasonable agreement. Microdose data could not be obtained for erythromycin, possibly because of degradation in stomach acid.

Microdose studies are finding increasing application in support of early candidate selection. However, they will not always be successful in predicting PK, and do not allow any PK/PD investigations.

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Biofluid metabonomic analysis Experience with H-NMR biofluid analtoxicities occur in less than five percent Biofluid analysis has been used extensively ysis suggests that it should be used more exof treated subjects, appear unrelated to the to evaluate non-clinical and clinical safety. tensively and consistently in support of early pharmacology of the drug, lack a clear dose Exposure of a biological system (cells in non-clinical and clinical evaluation. response and show inconsistent patterns of culture, animals or man) to a toxin changes appearance with time. the expression of various genes, biosynthesis Reducing risks of hepatotoxicity They are difficult to detect in non-cliniin man of various proteins and ultimately results in cal or in Phase III clinical studies, because a changes to endogenous metabolic pathways.

Liver toxicity is seen as the most serilow incidence (e.g. 1/1000) would require a The effects are dependent on the nature ous drug-induced adverse event in clinical study with some 18,000 subjects. The posof the toxic challenge, but occur at sible mechanisms that could lead different times after the toxic insult, to idiosyncratic hepatotoxicity and Aliphatic regions of 400 MHz H-NMR spectra of 0-8h rat urine: with the metabolic changes tending to potential indicators of the risk of Control (A) and after 25 (B), 50 (C) or 100 (D) mg/kg after appear later than gene expression and such effects have been discussed. injection of ρAP protein biosynthesis changes.

Nephrotoxicity studied by NMR Direct biofluid H-NMR, LCSome indicators of potential idiosyncratic hepatotoxicity MS and LC-MS/MS have been used D 100mg/kg in metabonomic screening. H-NMR Several characteristics appear to be has been shown to be a valuable associated with the potential for acetate indicator of toxicity based on patidiosyncratic reactions, including C tern recognition of time-dependent structural similarities to other hepavaline lactate changes in endogenous metabolite totoxins, glutathione depletion, 50mg/kg alanine concentrations e.g. creatinine, lacglutathione conjugate formation tate, glucose, α-ketoglutarate in plasand covalent binding of drug/meB glucose ma and/or urine. This metabonomic tabolites to cellular macromolecules approach has been defined as “the e.g. at levels ≥50pM. In addition, paracetamol sulphate 25mg/kg study of multi-variate, time-resolved hepatic bioaccumulation, potential metabolic changes in biofluids to for drug-drug interaction, evidence patho-physiological insult or genetic of liver toxicity, liver hypertrophy creatinine A citrate modifications in cells, organs and the and/or P-450 induction with no betaine ketoglutarate Control whole animal.” safety margin in non-clinical toxichippurate succinate The biofluid Nuclear Magnetic ity, were also considered as indicaResonance spectroscopy (NMR) tors of this potential. Drugs exhibtechnique has shown that specific iting several of these characteristics 4.0 3.0 2.0 1.0 PPM changes occur in endogenous meseem to be at more risk of productabolite profiles dependent on the ing idiosyncratic hepatotoxicity.

Figure 2 organ affected e.g. kidney, liver, testis and the site of toxicity in the target organ application of drugs and in the USA some Improving in vitro non-clinical test systems - Hepatotoxicity e.g. proximal or distal renal tubule toxicity in 40 percent (patients >50 years) and 10 perthe kidney. Single and repeated dose toxicity cent (all age groups) of liver disease is attribDrug metabolism e.g. CYP-450 oxidation, and its reversibility can be studied with the uted to drugs. glutathione or glucuronic acid conjugation added benefit that the nature of the metaHepatotoxicity has stopped the developmay result in hepatotoxicity via reactive mebolic change does not have to be known in ment or marketing of several drugs including tabolites. These may cause immune-mediadvance. troglitazone, bromfenac, tienilic acid and teated toxicity by covalent binding of a reactive A collaborative project using some 80 mofloxacin and resulted in restricted use or metabolite with an endogenous protein e.g. known toxic compounds has confirmed and withdrawal in some countries of zileuton, practolol. Oxidative stress, glutathione depleextended previous experience on identifying trovafloxacin, tolcapone and felbamate. tion, damage to cellular proteins/membranes, biomarkers of liver and kidney toxicity in rats Non-clinical safety testing detects 50 and/or lipid peroxidation are also routes to and mice. Biofluid H-NMR clearly identipercent of observed human liver toxicities. hepatotoxicity. fied control, low and high dose animals and, Although there is a good correlation across Whether such effects result in hepabetween-laboratory differences were much species allowing detection of intrinsic hepatotoxicity may depend on the extent to smaller than those between animals and totoxins, detection of idiosyncratic hepawhich they occur in association with a posdoses. totoxins has proved more difficult. Such sibly unrelated predisposing inflammatory

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This system was validated by comparing in vitro predictions with the observed hepatotoxicity for 679 marketed drugs. The system correctly predicted 585 of 587 non-hepatotoxic drugs, 15 of 21 severely hepatotoxic and 51 of 71 variably hepatotoxic drugs. The system scored false negatives for six severe, non-CYP450 dependent, hepatotoxins, and failed to detect 20 hepatotoxic drugs acting via cholestatic mechanisms.

This system was subsequently used to screen novel compounds. Those with a cytotoxic IC50 â&#x2030;¤ 50ÎźM in any cell line were considered to have an increased hepatotoxic risk and were either stopped or subjected to further investigation. The relationship between IC50 and over-expressed CYP-450 indicated the importance of metabolism in the toxic pathway.

Selected drugs tested in this system also showed changed expression of 40 genes and two proteins that distinguished an idiosyncratic hepatotoxic drug (troglitazone) from negative control and six non-hepatotoxic drugs.

Alden et al. used some 20 genes associated with inducible metabolism and inducible toxicity to screen for hepatotoxicity in vitro.

This system correctly identified many classical hepatotoxic drugs, two known idiosyncratic hepatotoxins (zileuton and troglitazone) and negative and positive control drugs when tested at 1 and 5ÎźM. Such hepatotoxic screens should be used as part of an integrated approach taking account of structure-activity data, cytotoxicity and/or enzyme induction in primary hepatocytes, metabolic pathways, and in vivo safety data.

There is no simple way to select better development candidates. However, these are some of the techniques available to screen compounds for wanted and unwanted effects, as part of an integrated strategy to improve decision-making and help improve the success of pharma R&D. Full references are available on www.pharmafocusasia.com/magazine/

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reaction and this added complexity may contribute to the low incidence of such idiosyncratic responses.

Various in vitro test systems including primary hepatocytes, immortalised cell lines, liver slices and non-clinical toxicology studies are used to assess hepatotoxic risk.

Dambach et al. used four separate primary human hepatocyte-derived immortalised cell lines. These cell lines had low intrinsic P-450 and glucuronidation capacity, but were genetically modified to express some 70, 30, 95 and 20-fold higher levels of CYP450 3A4, 2C9, 2C19 and 2D6 respectively.

The intention was to enhance the ability of such a system to produce and detect toxic i.e. reactive metabolites, while having qualitatively similar metabolite profiles to those of normal primary human hepatocytes.

These cell lines were used to measure concentration-dependent cytotoxicity in a multi-tiered screen of acute direct or metabolism-dependent hepatotoxicity.

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Manufacturing Control Systems The “next big thing” for the life sciences industry

Manufacturing Control Systems are likely to emerge as the new standard manufacturing solution by the end of the decade.

Mark Albano Life Sciences Marketing Manager, Honeywell Process Solutions Rajeev Joshi Manager, Development Engineering, Honeywell USA

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nspired by the goals of optimising performance and providing paperless recordkeeping, Process Control Systems (PCS) and Manufacturing Execution Systems (MES) have improved manufacturing operations for many pharmaceutical and biotech companies worldwide. Fuelled by the adoption of industry standards and advances in technology, these two systems are providing plants with a high return on investment.

Traditionally, these systems were viewed as separate entities within plants. The MES is widely regarded as an IT system because of its commercial software, servers and applications, and the PCS as an engineering function for its control and alarm monitoring capabilities.

Systems that operate independently of one another, however, are not enough to answer the evolving demands of the life sciences industry. To improve operational performance, plants require a seamless, synchronised system architecture that provides benefits such as common electronic batch records, as well as common exception reporting for automation and production management with resource traceability.

Merging PCS and MES to create a Manufacturing Control System (MCS) is an effective way to achieve these requirements,

while generating a streamlined, more consistent operation. It also provides more efficient control of unit operations. For these reasons, MCS is likely to emerge in facilities as the new standard manufacturing solution by the end of the decade.

Separate systems unite PCS as a single solution is designed to improve the productivity and profitability of industrial facilities. Batch management software, a product integrated into most PCS, provides a robust solution for designing, modelling and automating batch processes.

Using this solution, manufacturers have improved response time for production orders, as well as efficiency in meeting growing production demands.

MES, meanwhile, has proven effective in managing all steps of the production lifecycle; from specifying the materials to shipping the product. For example, POMSnet MES improves manufacturing performance by controlling and tracking all aspects of production, securing predictable quality and providing a complete history for regulatory compliance. Within the pharmaceutical and biotech industries, MES makes it easier for producers to meet regulatory compliance by managing and recording MES system from Honeywell Process Solutions

activities associated with personnel, manufacturing resources and the process itself.

Additionally, the MES solution is a direct means to reduce human error during data entry. Users can reduce paperwork, improve overall resource management, and produce fully compliant, paperless production records.

From planning and scheduling to production execution, MES is able to assist production personnel in managing execution decisions. As a result, cycle times are improved, the cost of compliance is reduced and a greater responsiveness is achieved. MES applications have matured around integrated material management and paperless plant-floor operations, which provide significant production efficiencies and cost savings. Still, personnel often must manually manage vast amounts of information. Users are required to refine production data so that operations and quality decisions can be made in a timely manner.

An MCS combines the strengths of the MES for material management, manual work instruction, control and electronic batch records with the abilities of PCS technology to manage automated recipes and control unit procedures. By integrating these core strengths, MCS provides a single environment for manufacturing operations and process automation.

Close integration of the MES and PCS allows life science manufacturers to move beyond simply replicating paper tickets, “paper-on-glass” functionality and leverage all the capabilities the two systems have to offer. These capabilities include material reporting, asset

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management, laboratory data logging, produ c t i o n d i s p a t c h i n g , El e c t ro n i c Batch Record (EBR) management and electronic work instruction execution and workflows.

between different systems and personnel are seamless; operators see a unified interface, instructions and displays.

Improved tracking and workflows In plants with disparate MES and PCS systems, the plant operator must pull up a ticket or paper-on-glass in the MES environment to check the status of materials and verify he is adding the prescribed material. He must also acknowledge the material addition is complete and instruct the PCS to complete the execution.

With an MCS, this process is improved by allowing the PCS to interface directly with the MES, which in turn, interfaces with Manufacturing Resource Planning (MRP) as required for inventory updates. During execution of a particular phase, the system reports on the material quality, the quantity that should be added to the batch and other significant details. It then performs system data verification including tracking when the material is introduced into the batch.

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How it works An MCS provides a platform for managing everything from process orders to lab results to updated inventory and lab requests. Within the unified solution, the MES interfaces with corporate-level systems such as electronic document management and enterprise resource planning applications.

The system delivers orders from the corporate-level systems down to the plant floor, and then automatically dispatches orders based on required recipes, equipment status and availability. Next, the system executes the orders within an integrated system architecture. This eliminates the traditional requirement for operators to check equipment status manually, assign equipment, load recipes and initiate batch execution, which results in fewer errors.

At most plants without an MCS, operators are assigned to manage production resources and report their status. The operator must confirm the status of specified equipment in a paper log or database before a batch can be started.

The MCS solution, however, automates this process since the programmed phase in the PCS controls specific equipment. The phase is designed to automatically request equipment and assets from the MES based on their requirement status. A transaction executed within the MES handles PCS requests for information and the MES automatically allocates resources and performs arbitration should conflicts occur. This allows the automation process to continue without interruption.

Demonstrated through MES/PCS transactions, the benefits of the unified MCS approach are evident. Unit procedural control and phase execution with an MCS is more efficient than in a traditional environment with separate system domains. Transactions

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When tracking material consumption, the PCS can send a transaction notifying the MES that it is time to automatically or manually consume a particular additive or ingredient. As the automated steps are processed, a procedure becomes available on the operatorâ&#x20AC;&#x2122;s screen with prompts for completing the task.

An MCS automatically presents instructions and workflows on the screen whenever they are needed, no matter the source. Operators are no longer required to coordinate with the MES activities, while staying ahead of PCS execution. This strategy revolutionises the handling of electronic instructions and workflows, eliminates paper procedures and enables a new level of plant production efficiency.

Previous paper-based systems required endless hours of collecting and reviewing paper records, reconciling discrepancies and approving for release. Subsequent designs of disconnected MES and PCS architectures reduced the product release process to a couple

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of weeks. With the MCS design, it reduces this process to a few hours.

The end result The common goal between manufacturing facilities is improved operational performance. Manufacturers seek shorter product cycle times, faster product changeover, fewer errors and better maintenance scheduling.

To achieve these results, a seamless MCS architecture that provides common electronic batch records and production reporting for automation and production management with reliable traceability for materials, equipment and personnel should be installed.

By using an MCS system, pharmaceutical companies ultimately see more consistent operations between plant-level and corporate-level systems. Facility operators realise that in addition to the benefits of improved operational performance, reducing errors and ensuring compliance are critical to getting life-saving drugs to those who need them the most.

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Advanced Emulsification Technologies Narrow drop size distributions in the nanometer region

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ypical devices for emulsification in industrial practice are, for instance, simple agitating, rotor-stator homogenizing or high pressure homogenizing. Following is an overview on two state-of-the art emulsification technologies, combined with hands-on experience from pharmaceutical and cosmetic applications.

Among others, the examples will comprise a novel rotor-stator system which allows the independent control of shear forces and pumping power. This approach enables the pharmaceutical manufacturer to go beyond the “speed limit” typically imposed by cavitation effects in conventional rotorstator systems plus several additional advantages. The distinction between so called low-shear and high-shear characteristics no longer exists.

High-shear homogenizing In practice high-shear homogenization with rotor-stator systems means powder wetting and dispersion to achieve finely dispersed emulsions with smaller droplet sizes and thus a higher stability and better bioavailability. Also the penetration into the skin is improved with decreasing droplet diameters of the dispersed phase.

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In standard rotor-stator homogenizers the parameters of pumping and shear energy introduction are coupled, i.e., with increasing tip speed of the rotor, the shear rate and pumping capacity both increase accordingly.

The new High-Shear Homogenizer (HSH) separates the pumping capacity from the shear energy introduction in two different stages (Figure 1).

The separation of pumping capacity and shear energy introduction, by installing a pump stage in front of the rotor-stator stage has several advantages compared to standard rotor-stator homogenizers. By pumping the product towards the rotor-stator stage, cavitation is prevented by creating a back pressure on the suction side of the rotor-stator and thus enabling tip-speeds far beyond the standard 30m/s up to 60m/s [Figure 2].

Figure 3 shows the pressure development in front of the rotor-stator stage depending on the speed of the rotor and pump.

Figure 4 shows some dispersion results of a model emulsion which was homogenized with the HSH at different shear rates. It can be seen how the droplets of the dispersed phase of the raw emulsion with droplet diameters of about 20µm were reduced in size to about 0.6µm at 50m/s.

Rotor-stator homogenizer development.

Concept of the HSH: Separation of pumping and shear energy introduction.

Figure 1

P&ID of a mixing vessel with a high shear homogenizer (HSH)

Figure 2

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High shear homogenizing and low pressure homogenizing open new pathways for fine emulsions with narrow drop size distributions. Their flexibility allows the introduction of exactly desired and validated shear forces.

Ludger Fischer, Managing Director, AC Serendip Ltd., Germany

Only 50m/s allows a monomodal droplet size distribution which results in a longer shelf life. On the other hand it is possible to pump shear-sensitive products without noteworthy introduction of shear energy by bypassing the rotor-stator stage. This can be important for the discharge of shear-sensitive gels or for the recirculation of the product via an external heat exchanger for faster cooling or heating.

The induction of powders or liquids by means of the vessel vacuum is done between the pumping stage and the rotor-stator stage for immediate powder dispersion. The pump feeds the rotor-stator with a steady liquid flow, while the vacuum at the induction valve pulls in the powder or liquid. The controlled flow conditions prevent a break through of the powder in the opposite direction through the pumping impeller. This makes sure that all the powder is well dispersed and wetted and no powder lumps float on the liquid surface of the vessel or in the worst case on the inner surface of the vessel lid or in the vacuum pump.

However, the most important advantage of the HSH is its flexibility. By being able to choose independently the flow rate and shear rate it is possible to work in every

operating condition. This enables the simulation of every standard rotor-stator homogenizer that is available in the market today (Figure 5). The ability to copy the homogenization step of other homogenizers makes it possible to produce products with the HSH that have been made or piloted before on other systems without revalidating the homogenization step.

Figure 6 shows a 50 litre HSH pilot unit that is available for testing. Figure 7 shows details of the HSH. Another advantage of the HSH is the easy access to the pump-stage and rotor-stator stage. Just by removing a few tri-clamps the rotor-stator or pumping impeller can be accessed; e.g. for inspection purposes. Removing another tri-clamp allows access to the mechanical sealing level.

Low pressure homogenizing Another innovative approach is the â&#x20AC;&#x153;low pressure homogenizationâ&#x20AC;?. High pressure homogenization systems have been around for over 100 years. In these systems shear forces, elongation, turbulence and cavitation realise the break-up of the droplets through a sudden pressure drop of several hundred bars. A typical set up of a high-pressure homogenizer consists of a premix container for

Pressure development in front of the rotor-stator stage as a function of pump and rotor speed.

Figure 3

HSH trial results: Droplet size distribution as a function of homogenizing shear rate

Figure 4

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Characteristic of rotor-stator homogenizers as a function of flow rate and shear energy introduction. Full flexibility of the HSH 50 litres pilot unit with HSH high shear homogenizer.

Figure 5

the raw emulsion, a high-pressure pump, usually a piston pump, a pressure measurement device and a dispersing unit.

Typically high pressure dispersing units are based on valve systems, sometimes also on nozzle devices. Both technologies have their pros and cons: while the valve systems are versatile due to their adjustability, they generally are not as efficient as nozzle systems.

The “low pressure homogenization” technology (LPH) combines the advantages of a valve system and a nozzle system yielding extremely fine emulsions at very low pressures and gentle process conditions. Lower homogenization pressure means less stress on the active ingredients that are formulated in the dispersed phase of the raw emulsion. Also the heat development is much smaller, as every 100 bar of homogenizing pressure results in an increase of the temperature of the emulsion by about 3°C. In Figure 8 results of a homogenization trial with the LPH are depicted. The “raw emulsion” had been manufactured by the HSH, with a mean droplet size of 600nm. It can be seen that the droplet diameters of the emulsion could be further reduced to about 300nm in a single pass. In many trials it could be proven that the LPH technology is able to disperse smaller droplet sizes with lower pressure than any other system.

LPH technology opens the door to high-quality nano and micro emulsions with their superior properties such as penetration of the natural barrier of the skin, a higher solubility and drug load.

Also the shelf life is extended, as with decreasing droplet diameter the stability of the emulsion increases. Other aspects are the sensory properties of the emulsion that change with decreasing droplet size.

These properties can vary from a different optical aspect such as shining or transparency of the emulsion to different touch and feel of the emulsion during the application on the skin. Figure 9 shows a picture of an LPH-500 low pressure homogenizer with a production capacity of 500L/h. The low pressure homogenizer technology also has the advantage of an easy and safe scale-up. Both systems extend the former limits of those systems with respect to achievable droplet diameters as well as flexibility.

Figure 6

Pressure development in front of the rotor-stator stage as a function of pump and rotor speed.

Figure 8

LPH-500 Low Pressure Homogenizer.

Figure 9

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Developing a Process Excellence Culture

In an increasingly competitive marketplace, the current organisational models for supply chains will no longer be effective. A process excellence culture will enable an organisation’s resiliency and provide a competitive advantage to it in the future.

Bruce Sawyer, Senior Director, Operations Excellence GPSG, Johnson & Johnson, USA

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key question for business leaders focussed on improving their results: What is process excellence and why is developing a process excellence (PE) culture important to them and their organisation? This question is critical irrespective of whether the organisation is a service provider or a product manufacturer. Process excellence is engaging the entire workforce in the relentless, ruthless pursuit and elimination of process variation and its sources.

It involves driving a culture where all levels

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of the organisation are committed to continually improving the total value stream.

Developing a PE culture is critical in an organisation’s effort to dramatically improve its current business performance.

First, organisations must realise that whether their current level of performance is “World Class” or “Worst in Class”, there is always room for improvement. When an organisation stops learning and improving, the competition will surpass it and gain an advantage. When organisations fail to be

competitive, they become irrelevant and their right to exist is at stake.

Examining the business case for developing a PE culture, reveals many documented benefits which can be categorised broadly as improved productivity, top and bottom line growth and the organisation’s evolution from function-centered thinking to process-centered action.

Focussing on experiences in developing a PE culture in a pharmaceutical manufacturing environment are the specific examples of process excellence deployments at various manufacturing sites of Johnson & Johnson in the Americas and Europe.

By systematically deploying process excellence, the company’s sites were able to achieve significant improvement in key areas. An example of these results at Johnson & Johnson is provided in the table below.

Johnson & Johnson’s pharmaceutical manufacturing network encompasses multiple countries, unique national cultures, different languages, and various technologies. Establishing a PE culture is dependent on several key factors such as Leadership, Improvement Methodologies, Culture and Performance Measures.

Leadership Leadership is the single most critical element in driving improvement. The leadership must create a vision of the future and engage the people of an organisation in understanding their role in driving the organisation towards its future. The vision should be a simple but powerful statement, preferably one sentence or phrase that serves as a focusing mechanism for all levels of the organisation. The vision and mission must be broadly communicated utilising a variety of mediums.

In addition to verbally articulating the vision, leaders must model the

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behaviours they dsire in their associates.

Highly visible, authentic leadership is essential. They must â&#x20AC;&#x153;walk the talkâ&#x20AC;?. Less than authentic leadership results in zero credibility and the associates will not take the change management efforts seriously.

Leaders need to clearly articulate that process excellence is important to the businessâ&#x20AC;&#x201D;it is the way things should be done.

An expectation of continuous improvement must be set. Leading by example is the key.

A minimum of 50 percent of the leadership team should be trained and/or certified belts. This increases credibility throughout the organisation and underscores the level of change management that will be required to drive improvement initiatives. Adults learn best by doing and PE culture is a learned behaviour.

Leaders are also accountable for putting in place the organisational infrastructure necessary to create and support a PE culture.

Leadership must create the environment for success. A PE leader must be appointed

to provide the organisation both direction and process management expertise. Failure on the part of leadership to create the infrastructure for success will hamper efforts towards improvement. An organisation will not be able to achieve or sustain improvement outcomes in case its leaders are not engaged, adequate infrastructure is not provided, and there is minimal commitment to the effort. An expectation of achieving different outcomes while utilising the same old approaches and doing the same things is extremely unrealistic. In order to achieve organisational improvement, the organisation should change its approach and utilise different tactics.

Another key role of the leadership team is to identify, prioritise and sponsor improvement efforts. Creating forums can help systematically track and review improvement projects and activities on a 3-4 week cycle.

This relentless review process will create the environment of process execution and accountability.

Improvement methodologies The appropriate deployment and use of improvement methodologies is an important component of creating a PE culture.

Lean thinking, Six Sigma and Design Excellence concepts appropriately deployed are key drivers of improved performance.

Organisations must invest in developing core competencies in these methodologies.

Developing a core group of people who are certified green belts, black belts and master black belts can become internal consulting resources to site and functional leadership teams. Certified belts can help provide various teams with just-in-time training to approach and resolve their business issues.

Each organisation starting down the path of continuous improvement should perform Value Stream Mapping (VSM) of each of their critical work streams and/or processes. VSMs enable leadership teams, process owners and trained belts to visualise the improvement opportunities associated with reducing Non-Value Added (NVA)

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Supply Chain Metrics Metric

Pre-deployment

Post-deployment

Order Fill Rate

83.00%

98.30%

Inventory

179 days

95 days

Plan Attainment

62.00%

88.00%

Plan Attainment

95.00%

98.80%

Overall Equipment Efficiency

24.00%

63.00%

Overall Equipment Efficiency

54.00%

65.00%

Raw Material Lab Cycle Time

28.70%

80.30%

Raw Material Lab Cycle Time

87.20%

95.20% Table 1

Associates Engagement Index

Associ at es Engagement I ndex 80

Sit e Cr it ical Mass

75 70 65 60 55 50 45 Jun

Jul

Aug

Sep

Oct

Nov

Dec

Jan

Feb

Mar

Apr

May

Mont h

Figure 1

work, mistake-proofing, waste reduction, process-variation reduction, etc. The leadership team, under the direction of the PE leader, should prioritise the improvement opportunities, assign resources to the various improvement tasks and review progress on a regular basis.

One of the most important activities in manufacturing sites is to identify their constrained work centres. Once the constrained work centre has been identified, a ‘rhythm wheel’ can be easily established. Rhythm is a product sequence that encompasses production frequency, optimised changeovers, and preventive maintenance and calibration

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schedules. By deploying rhythm wheels in constrained work centres, some Johnson & Johnson manufacturing sites were able to quickly achieve more than 25 percent increase in sustainable throughput.

5S—sort, set in order, shine, standardise, and sustain—is a simple methodology Johnson & Johnson has consistently used to engage its workforce in introducing Lean deployment efforts. 5S helps to create an orderly workplace, optimise material flows, improve the safety profile and compliance profile but most importantly, empowers people at Johnson & Johnson to take an active role in creating the environment in which they work.

Culture An engaged workforce is critical to driving a PE culture. Site-wide Kaizen teams were deployed at Johnson & Johnson to serve as a forum to both engage and empower all of its associates. PE resources were assigned to each team to provide basic training in improvement methodologies. Armed with common terminologies, tools and the vision modelled by the leadership team, the associates were able drive tangible improvements in their work areas. These early wins proved to be contagious in the organisation and the Kaizen concept grew organically. Employee morale increased and improved scores on the Credo index. The associates closest to the processes came forward with their ideas and achieved significant cycle-time and cost improvements. An engaged workforce will convert their discretionary efforts into increased productivity.

But how much time does it take to create a PE culture? The answer is, “It depends”. Based on Johnson & Johnson’s experience, ideally an 18–36 month time frame is required to create a PE culture. As mentioned earlier, PE culture is a learned behaviour. Beginning slowly and by training 5–10 percent of the workforce in tools that are appropriate for their work centre is more effective in creating a PE culture.

Appropriate tools are methodologies that teams can learn and apply immediately.

The target training workforce comprise not just exempts and professionals, but the total workforce. Johnson & Johnson achieved great success with people in clerical, maintenance, craft, operator and technician roles. Appropriately focussed and executed training is a key step in creating the critical mass required to achieve the necessary culture shift.

Once the initial 5–10 percent of the workforce is trained and engaged in continuous improvement activities, they must be recognised and rewarded for their successful efforts. Recognition and reward are critical to building upon the successes and achieving “quick wins”. Achieving critical mass will take 3-4 cycles of continuous improvement activities.

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washers became 73 percent of the population. Why? The yam washers had achieved critical mass by deploying the “each one can teach one” process. Just like sweet potato washing, PE is a learned behaviour and achieving a culture shift is dependent upon building sufficient critical mass to translate ideas and concepts into action.

The PE deployment plan requires tactics to influence and convert critical leaders at every level in the organisation, from the manufacturing floor to functional leadership team. Engagement of seventy percent of the workforce results in transformational change versus simply incremental improvement. The PE adoption rate for one of Johnson & Johnson’s manufacturing sites is demonstrated in the Table 1.

Performance measures Metrics are the quantitative expression of business goals such as service levels, cost, cycle time attainment, compliance, safety performance yield improvements and

other relevant measures of organisation performance. These metrics must be systematically collected, analysed and utilised by the organisation to drive the continuous improvement effort. The organisation’s performance on these critical measures must be constantly communicated to all associates. As an organisation develops and evolves, metrics need to be developed at each individual work centre level. Causal measures such as overall equipment efficiency, changeover cycle time, plan attainment, product yield and others must be collected, analysed and linked to the higher-level metrics so that everyone has a clear line of site between their day-to-day work centre activities and the site business metrics. It helps to communicate the metrics to the relevant people in the organisation.

It is important to measure performance in order to know the improvement. To improve, an organisation must develop the discipline to identify opportunities using data, prioritise

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What percent of the workforce is required to achieve critical mass? To illustrate the challenge, we can utilise a story very loosely based on research conducted in the 1950s on monkeys inhabiting Koshimo Island. There are numerous versions of this story, most taking significant license with the data, but here is a version that is used to articulate the challenge in creating a PE culture. It demonstrates that when enough individuals in the organisation adopt a new behaviour, breakthrough results can be realised.

On the island of Koshimo in the 1950s, scientists conducted research on the behaviours of group of macaque monkeys. The scientists observed that a very limited sub-group of the monkey population began to wash off the sand of the sweet potatoes before they ate them. By 1958, the sweet potato washing practice grew to 57 percent of the population. Over the next four years the practice spread and by 1962, sweet potato

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The relative PE maturity of an organisation can also be diagnosed in a similar fashion.

Transformation involves changing from a traditional business model where each department works separately, to a process-focussed model where everyone works toward the same goal. Transformation may require modifying the organisational structure or co-location of cross functional teams to assure focus on those core processes that enable flawless business execution. This creates an environment where the organisation is focussed on problem and process improvement.

Leadership, Improvement Methodologies, Culture and Performance Metrics are the critical components in achieving a PE culture. Once an organisation optimises its core processes, it can begin to extend its PE culture to its suppliers and customers.

This extended process focus will enable the creation of a value chain that extends from supplier to customer. A PE culture plays a huge part in creating this benchmark level of performance.

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

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these opportunities based on their impact to the business, resource the opportunities appropriately and review team progress on a regular basis. It is critical for leaders to communicate business performance at routine intervals.

As business performance improves, the metrics of the organisation must also change.

The metrics utilised as baseline performance must be evaluated and modified as appropriate. Metrics and the performance thresholds should be revisited on a 9–12 month cycle to ensure that the organisation remains current against any changes in the internal or external business environment. The performance should not be evaluated against obsolete metrics, this measurement system may be out of step with a world that constantly changes and moves on.

The organisation’s culture, in order to be transformed, must begin with the leadership’s vision. That vision must be clear and simple to be understood by all associates. There are various diagnostic tools available to assess the organisation’s readiness for change.

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Pharmaceutical Manufacturers Embracing Lean Six Sigma

Pharmaceutical manufacturers are looking to Lean Manufacturing and Six Sigma principles to help them boost operational efficiency and improve quality, while facilitating compliance.

John E Danese, Product Strategy Director Dennis Constantinou, Senior Director Life Sciences, Oracle, USA

T

oday, pharmaceutical manufacturers are focussed, as never before, on reducing operational costs while ensuring compliance. Cost pressures are increasingly acute as many pharmaceutical manufacturers see a dwindling product pipeline, as well as greater competition from generics. To ensure that their bottom lines remain solid, pharmaceutical manufacturers are looking to increase the efficiency of their operational and manufacturing processes— optimising resources, improving efficiency, reducing waste and controlling inventory.

The regulatory climate is, at last, conducive to focussing on such changes, as the U.S. FDA as well as other regulatory bodies now support approaches that seek to reduce risk by building quality into the manufacturing process from the start, as opposed to relying on end-process testing. In this climate, pharma manufacturers are looking to Lean Manufacturing and Six Sigma principles— proven in other industries—to help them boost operational efficiency and improve quality, while facilitating compliance.

Moving beyond the status quo Despite the pharmaceutical industry’s focus on quality, it has failed to keep up with other industries in terms of manufacturing efficiency and productivity, largely because of the cost and burden involved in revalidating any process changed in the spirit of improvement. Once manufacturers confirm

or validate their processes as compliant, they traditionally have been very reticent to change them. The simple fact is that pharmaceutical manufacturers, which historically have enjoyed consistently robust profit margins, have had little economic incentive to introduce change.

The industry’s focus on maintaining the status quo in its manufacturing environment has produced inefficiency and waste.

It is estimated that the potential world-wide cost savings from efficiency improvement could be as high as US$ 90 billion. While Research and Development (R&D) is generally considered a major cost centre for the pharmaceutical industry, manufacturing quietly accounts for more than twice the expense of R&D—representing, on average, 36 percent of a pharmaceutical manufacturer’s costs. The true cost of manufacturing becomes even more apparent when one considers the amount attributed to nonvalue-added activities and waste which is 80 percent and 50 percent, respectively.

Quality has also suffered under the status quo. It is interesting to consider that the number of drug recalls has risen sharply in recent years—three-quarters of which are attributed to manufacturing defects.

The reject percentage in the pharmaceutical industry ranges from 5 percent to 10 percent (<2 Sigma), compared to 0.0001 (6 Sigma) in the semiconductor industry. This reject-percentage costs the industry between

US$ 4.5 billion and US$ 9 billion per year based on US$ 90 billion/year spent on manufacturing.

Several important factors have converged in recent years to jumpstart substantial change in how pharmaceutical manufacturers approach and manage their manufacturing operations. First, many manufacturers face a declining development pipeline as well as shrinking profit margins as they face increased competition from generic drug manufacturers. As such, they see a growing need to abandon the status quo to focus on improving productivity, efficiency and quality. At the same time, the U.S. FDA and other regulatory bodies are acknowledging that the industry has fallen behind other sectors in terms of efficiency and quality, and have begun to endorse a “quality by design model” that contrasts with the industry’s historical “quality by test” results approach. As part of this shift, the U.S. FDA launched its Process Analytical Technology (PAT) initiative, a risk-based guidance model that seeks to direct pharmaceutical manufacturers toward consistent and predictable quality (higher sigmas). The PAT approach is to build in quality improvements on the factory floor through a deep understanding of how variable process attributes affect product quality at a fundamental level.

The road to Lean Six Sigma As pharmaceutical manufacturers seek to transform manufacturing operations and enhance quality, many are turning to two highly regarded management approaches— Lean Manufacturing and Six Sigma—that have proven effective in other industries, such as electronics and auto manufacturing.

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systems around material and information flow analysis (e.g., optimise layout), create tactical implementation plans, and develop standardised work charts and instructions.

When transitioning to a Lean Six Sigma environment, pharmaceutical companies must also assess their management systems at several different levels and direct changes that support Lean concepts. Transition teams must consider what management tools, including IT systems and communication tools, the company requires. The organisation must also consider how it will define or measure success, by setting Key Performance Indicators (KPIs) at different levels of production.

It is also essential to create a highly visible problem resolution system to drive and institutionalise change. Finally, organisations must implement and scale these capabilities so that they span the entire value chain—which is often dizzyingly complex and can extend beyond traditional organisational boundaries. The final arena for change—transforming mindsets and behaviours—is often

the most challenging for many organisations. Individuals often fear, and in turn, resist change. This truism is especially applicable in the pharmaceutical manufacturing industry, which has, until recently, thrived despite its focus on maintaining the status quo.

In transitioning to a Lean Six Sigma environment, it is critical that the management team defines and communicates a consistent mission, vision and value system throughout organisation—always maintaining the customer focus. The transformation team should focus on achieving top-down buy-in by aligning resources to help build and transfer momentum across the organisation. Training cannot be overlooked. Transformation team must develop a comprehensive strategy that provides training opportunities at multiple points in the transformation as a means of achieving stronger organisational buy-in and competence from both management and the ranks.

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Lean Manufacturing focusses on eliminating manufacturing waste, with the objective of making manufacturers more responsive to customer demand and market changes. Six Sigma is a business process methodology that focuses on minimising variation—in product and process—to reduce product defects.

Using the methodology, one standard deviation from the mean is one sigma; therefore, manufacturers operating at ±6 sigma are operating at 99.9997 percent compliance.

When pharmaceutical manufacturers implement Lean and Six Sigma concepts they have a powerful methodology to help them improve quality, compliance, productivity, costs and speed—ultimately enabling them to bring better products to market, faster and more cost effectively. To achieve transformation to a Lean Six Sigma environment, organisations must focus on change at three levels—operating systems, management systems, and mindsets / behaviours. (Figure 1) At the operating system level, manufacturers must understand demand levels, design lean production

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A Successful Lean Transformation Requires Fundamental Changes Throughout the Organisation Understand demand levels Design a lean production system around material and information flow analysis (e.g., optimise layout) Create tactical implementation plans Standardise work charts and instructions

Current performance

Operating system management system

Support communication Enable performance management (e.g., KPIs available at different levels of the plant) Create a highly visible problem resolution system Build capabilities across the organisational structure

Mind sets and behaviours

Future performance

Define consistent mission, vision and values throughout the organisation Create top-team alignment and transfer momentum Improve training Achieve senior management buy-in Maintain customer focus

Figure 1

The IT factor IT factors heavily in the transition to a Lean Six Sigma enterprise and the subsequent journey of continuous improvement. Because of the complexity of the pharmaceutical manufacturing environment, organisations require flexible and interoperable IT systems that provide information, not just data, across the enterprise. In a Lean Six Sigma environment, information flows must complement and keep pace with physical flows to deliver the information needed (Figure 2).

The ability to mine data and interpret it efficiently, quickly and seamlessly is also very important. Using the data and turning it into information quickly enables pharmaceutical manufacturers to outperform their competition. Having the right data readily available when it’s needed also makes it easier to respond to FDA inquiries.

IT supports several tenets essential to the implementation of a Lean Six Sigma environment, including: Ensuring the integrity of data

Organisations require good data to make wise decisions. Most pharmaceutical manufacturers have IT environments with solutions from multiple IT vendors. These

systems are often siloed, precluding the exchange of information. In addition, manufacturers often have multiple instances of applications across their various production facilities. For example, it is not unusual for pharmaceutical manufacturers to have separate data files for products and customers in different IT systems at different sites. This approach also precludes a comprehensive view of the enterprise, which is essential to a quality-by-design focus.

To obtain the end-to-end visibility needed in a Lean Six Sigma environment, pharma manufacturers must have an integration strategy for linking heterogeneous systems, creating a single source of trusted information that provides a complete picture of the operations.

A Lean Sigma Six environment requires complete confidence in the integrity of an enterprise’s supply chain, manufacturing and distribution-related data. As such, a single source of information is essential. It eliminates duplication and outdated information, driving informed decision-making and lower administrative costs. This approach also provides a streamlined audit trail in the event that a regulatory agency raises a product safety issue. For example, if a bad lot of drug compound is released into

the market, a pharmaceutical manufacturer can quickly establish where the lot was manufactured, which equipment was used, the source of the ingredients, and the locations to which the compound was distributed. A single version of truth, which is helpful in all industries, is especially critical in regulated industries because it eliminates the need to synchronise multiple sources of redundant data and manage a host of different technologies—which increase risk and complexity.

Building quality into the manufacturing process

Process and workflow automation—which allow organisations to build quality into the process—may be IT’s single greatest contribution to enabling a Lean Six Sigma environment. Integrated IT infrastructures allow pharmaceutical manufacturers to rely less on manual checks, which present greater risk and variability, and more on automated checks that are built-in, enforced going forward, and can easily be audited by the FDA and other regulatory agencies. For instance, automation enables manufacturers to enforce electronic signature checkpoints during the processing of a production batch order and automatically notify key personnel of nonconformances, so that reviews and action can be undertaken quickly.

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Information flows must keep up with and complement physical flow IT and Data Management System

Identify Strategic Drivers

Assess the Current State (VS AM)

Deploy Policies and Standradise work

Identify and Establish Projects

Rapid Improvement Projects

Design and Implement Solutions

Achieve and Hold Gains

Replicate Results, Drive Culture Change

Six Sigma Projects

Figure 2

The capture and processing of in-line data is critical to a Lean Six Sigma environment—as well as PAT—because manufacturers must understand all sources of product variability. This understanding cannot be achieved without collecting data from every part of the supply chain and manufacturing process. For example, a manufacturer’s probe sensor might sample the particle size of a batch of product during a granulation process. To make adjustments that would improve product quality or consistency, the manufacturer must determine how the particle size compares to previous batches and standards—a process that depends on the capture and analysis of in-line and benchmarked data—and understand how various possible process adjustments will impact all critical technical attributes of the material.

An integrated IT infrastructure is essential to enabling manufacturers to capture the secure, analysable and actionable data needed to transform their operations.

Electronic record keeping plays an important role in helping pharmaceutical manufacturers build quality into the process. Paper records are cumbersome and expensive to circulate for review and approval when there are multiple staff members or departments involved in the process.

This challenge is compounded in a global

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enterprise. Faster and cheaper product development, manufacturing and quality assurance turnaround is possible with electronic routing of signature requests anywhere, virtually and instantly. Electronic records also improve accuracy. There are limited means to prevent users from entering invalid data on paper forms beyond rigorous and timeconsuming manual checking. Sophisticated electronic record systems, however, are adept at reducing data errors by providing users with lists of appropriate values from which to choose, and by validating data formats prior to accepting or saving the data into files or tables.

Enabling rapid analysis and modelling to respond to change

Pharmaceutical manufacturers possess massive quantities of data on processes as far ranging as purchasing of office supplies and analysis of data from gas chromatographs.

Many, however, cannot analyse or interpret paper-based or siloed information to identify important trends and drive improved manufacturing practices.

A single source of truth, coupled with advanced analytics, enables pharmaceutical manufacturers to run real-time analysis that yield the kind of business intelligence that reduces risk, helps to improve operating

efficiency and agility, and streamlines compliance. For example, a manufacturer can use advanced analytics to conduct quality analysis, risk assessments, yield analysis, on-time production tracking, scrap reason analysis, cost comparisons by job, and comparisons of manufacturing plans and efficiencies between sites, to name just a few of the endless possibilities.

Instituting and controlling businesses processes and standard operating procedures

Removing variability in processes and materials is fundamental to a Lean Six Sigma environment. IT systems provide the information necessary to establish an environment that supports risk-based decisions. IT serves as a lens through which processes can be observed, monitored and measured. Only then, can manufacturers enable greater control over variability.

Process automation further enhances operational efficiencies. On the materials management front, an integrated IT infrastructure drives automation that enables manufacturers to enforce business rules that require materials to go through certain quality tests before they reach a customer, as opposed to relying on a paper document to confirm a test has been completed. Automating controls also reduces ongoing

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Enabling a real-time demand-driven sales and operations planning process

A demand-driven model, which supports Lean Six Sigma principles, allows pharma manufacturers to postpone inventory build-up and reduce inventory carrying costs and the risk of a product expiring before sale. The transition from a maketo-stock approach to a demand-driven environment, however, has not been an easy

one for many manufacturers.

Most companies today have a fragmented process for Sales and Operations Planning (S&OP). Each department tends to have its own process with critical company data stored on spreadsheets. Departmental plans are not aligned, and there is misalignment between how departments are measured and overall company objectives. For example, sales management is often measured on meeting a sales quota that may be achieved by selling products that the supply chain is unable to produce. This tends to lead to a very time-consuming and manual process of trying to come to agreement on “the forecast.” This painful exercise typically yields an inaccurate forecast.

The forecast is then “tossed over the wall” to the supply chain to figure out how to expedite processes to meet the demand with no thought given to the profitability of the decisions. Further complicating the process is the fact that the “approved” plans, which may exist on spreadsheets, are often

filed away, and have little relation to the actual plans being executed.

New IT solutions can help manufacturers address their complex S&OP needs by enabling them to bring all business areas together for the purpose of aligning supply with demand and delivering an operational plan designed to achieve a defined corporate business strategy. Some systems, for example, allow a direct linkage between sales orders and production batches, allowing users to create a batch reservation for a sales order. When the batch is completed, the reservation for the order line is converted into an inventory allocation and can then be confirmed and shipped. Alternatively, if there are no existing batches planned or in process for the required product, a user can initiate a request to create a batch specifically for that order. Automated workflow notifications keep the order entry personnel apprised of any changes to the production schedule that may impact their order.

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complexity, redundancy, the potential for operator error and, ultimately, waste.

Leading IT vendors, such as Oracle, are removing the complexity from process integration by leveraging Business Process Execution Language (BPEL), which allows manufacturers to build a process once and then apply it throughout the environment.

BPEL is emerging as the standard for assembling a set of discrete services into an endto-end process flow, radically reducing the cost and complexity of process integration initiatives.

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Pharmaceutical manufacturers often have multiple manufacturing plants, warehouses, distribution centres, and transportation lanes and modes. Determining the best manufacturing, distribution and logistics choice becomes an exercise in selecting from among thousands of combinations.

Dynamic inputs to the network design process—such as fuel prices, currency exchange rates, real labour rates and seasonal demand—further complicate the process.

Advanced Strategic Network Optimisation (SNO) solutions can help manufacturers optimise choices and combinations. SNO solutions perform two distinct functions, simulating and optimising different supply chain configurations and creating dynamic sourcing rules to be used by downstream planning processes. These solutions, which combine a flexible supply chain modelling environment with highly tuned solver algorithms and visualisation capabilities, allow users to define, simulate and evaluate complex manufacturing, distribution and

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transportation supply chain problems— before making costly mistakes.

Ensuring compliance and security

It is very difficult to determine corrective and preventative actions without a sound understanding of variability sources and estimates. The information required for a corrective and preventative action includes appropriate details of the event, the time and date of the nonconformance, the phase of the batch in which the nonconformance occurred, details of the incident or observation, level of criticality, and required follow up, as well as the signatures of various operator(s) and / or supervisors. This process, which is essential to both quality improvement and regulatory compliance, is costly and time consuming when completed manually.

It also presents many opportunities for data omission or the recording of incorrect data. Corrective and Preventive Action (CAPA) solutions manage issues to closure

through an automated workflow, and provide appropriate documentation required for regulatory compliance.

Pharmaceutical manufacturers are on the cusp of realising the benefits that Lean Six Sigma practices can deliver to their organisations and the industry as a whole.

To successfully transform their organisations, however, pharmaceutical manufacturers require greater visibility into their end-to-end operations—an objective that cannot readily be achieved through paper-based processes or disparate IT systems. To this end, pharmaceutical manufacturers increasingly look to integrated IT infrastructures to help them execute Lean Six Sigma paradigms and, ultimately, achieve new levels of operational efficiency, quality and corporate performance.

Full references are available on www.pharmafocusasia.com/magazine/

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I n f orm a t a tio n T e c h n o l o g y

Life Sciences Manufacturing Promise of service oriented architecture

Service oriented architecture promises to revolutionise the way companies share information internally, as well as with partners, customers and regulators.

Daniel R Matlis, President, Axendia, USA

F

or more than three decades, life sciences manufacturers have been implementing shop floor data acquisition systems to automate their manufacturing processes and systems with the goal of increasing quality and lowering costs.

As part of automation projects such as Computer Integrated Manufacturing (CIM), Supervisory Control and Data Acquisition (SCADA) and Statistical Process Control (SPC), life sciences companies began to rollout computer workstations on the shop floor.

The data storage capabilities afforded by personal workstations on the floor often lead to an unforeseen side effect; the creation of “Data Islands”.

“Data Islands” are created when manufacturing equipment is connected to a computer and begins collecting historical information and process data. Although computers have made it to the shop floor, the bridges required to connect them—including networks and integration technology—will take some time to catch up. Until recently, data islands were connected by “island-hoppers” (Figure 1).

The process involves getting data into a system by walking it over to the next data island in the process and manually entering it.

Ever since the earliest SCADA system implementation, pharmaceutical manufacturers have attempted to make this production information, processes and resources more transparent with varying levels of success. Further, companies have always looked for better ways to integrate operational data

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to allow stakeholders to make timely and informed decisions. The phrase often used is getting to the “Single Version of the Truth”.

Can you handle the truth?

There is an iconic scene in the movie “A Few Good Men”. Lt. Daniel Kaffee (played by Tom Cruise) questions Col. Nathan R. Jessep (played by Jack Nicholson).

Jessep : You want answers?

Kaffee : I think I’m entitled to them.

Jessep : You want answers?

Kaffee : I want the truth!

Jessep : You can’t handle the truth!

The fact is that in some cases life sciences companies may not be ready to handle the truth. This is not due to an unwillingness to get to the truth, but because in some cases facts can turn an accepted practice on its head.

The enlightenment of truth requires organisations to surrender to the process of discovery and analysis. Tools such as Multivariate Analysis and Manufacturing Intelligence allow manufacturers to sift through the terabytes of historical data accumulated over the last thirty plus years to transform it into information, knowledge, wisdom and ultimately truth.

Only after life sciences firms have assessed the facts regarding the current and desired states of their manufacturing processes, can they embark on the next step of the journey, selecting the best technology to enable the change.

Want to buy a “Bridge” Today, software manufacturers are moving away from proprietary systems and interfaces and are working together to develop open standards and interoperability schemas. Known as Service-Oriented Architecture (SOA), this functional design provides a bridge that allows for the connection of data islands in an efficient and effective manner.

In traditional system architectures, software systems are stacked to meet a particular department’s need. By contrast, SOA is composed of clearly defined business functions or services, which are loosely coupled and highly interoperable. The interaction of these services is independent of their operational platform and programming language. The interface standards hide vendor proprietary and technology-specific implementation (such as Java and .NET) allowing for smooth and reusable services.

Functionally, SOA transforms standalone systems and their data islands into “services” that can be accessed with a common connector or bridge, regardless of the location or technical makeup of the system. The functionality and capabilities of these connectors ranges from simple data passing to complete orchestration of multiple services and escalation capabilities based on the rule anthologies required to meet a particular business activity.

SOA implementation is a process, not a project For SOA implementations to be effective in allowing the business to reach new heights, functions must be well defined, self-contained and must be aware of the context and state of other services. Today, web services use SOAs to achieve the loosely coupled yet robust connections (Figure 2).

I n f orm a t a tio n T e c h n o l o g y

The use of SOA has led to development of standards such as Business Process Execution Language (BPEL), which takes the service concept one step farther by providing a method of defining and supporting workflow and business processes.

The journey to successful SOA implementations begins with specific and clearly defined business requirements and process maps. Business needs—not technology—must drive this process.

The journey requires IT departments to undergo a significant shift from their mantra to “align IT with the business” to the reality that IT must “support the needs of the business”.

To enable the implementation of SOA, software companies have developed open standards and are moving their products away from proprietary interfaces that resulted in difficult-tosupport applications. While the pharmaceutical companies have tolerated proprietary systems in the past, to meet the industry’s changing needs, leading software providers must be able to interface with—and acquire data from—other systems in real time. They must also have the ability to share and analyse raw data and transform it into actionable business information. As pharmaceutical companies become more global the need for integrated environments compels the next generation IT solutions to be designed and built to be part of a SOA.

tive sources of data across the organisation to minimise compliance risks by controlling and providing visibility into relevant processes.

The SOA in automation and manufacturing applications requires the development of an integration and intelligence infrastructure that eliminates the traditional application stack model, where point solutions are piled on each other to increase functionality, and transforms it into a collaborative interoperable one based on industry standards. The use of SOA increases situational awareness in today’s ever shifting global and outsourced operations. The implementation of SOA allows license holders to communicate with contract manufacturers, raw materials suppliers and supply chain and

ERP

Analyze ERP

Display Report

SAM

SOA Web Services

Services

ECM

Systems

CRM

Control Forecast Schedule Model Optimize

Blending

Molding

Assembly

Packaging

Sterilisation

MES

Figure 1

Another key step in the process is to evaluate the current IT portfolio. This step seeks to identify and eliminate applications developed as stop-gap measures to address a business need that was not provided by commercial off-the-shelf software. Historically, “pop-up” applications have been critical to running the business and releasing quality products to the market. How many organisations still rely on spreadsheets and home grown Access databases to perform final product release?

One key drawback to “pop-up” applications is the increase in IT support and operational costs due to their adhoc and uncoordinated nature.

Bridging to the future Today, IT organisations play an intricate role in technology decisions at all levels within a pharmaceutical company. This is evident by the consolidation of historically separate R&D, Finance and Automation IT groups into a single Corporate IT organisation spanning all disciplines. This has lead to a more efficient use of IT resources. To take full advantage of this “organisational integration architecture”, companies must implement SOA infrastructure to eliminate redundant systems and data. Finally, to facilitate regulatory requirements compliance, pharmaceutical manufacturers define and identify authorita-

Secure Figure 2

logistics managers instantaneously and cost effectively by building bridges between systems of record. This eliminates the need to build custom interfaces with every system and, thereby minimising system compliance and validation costs.

Although SOA promises to revolutionise the way companies share information internally, as well as with partners, customers and regulators, technology can only enable change not drive it. For change to be effective and accepted, it must be rooted on the drive to provide better products that enhance patient health, on sound business practices, and in compliance with applicable regulatory requirements.

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Strategy CphI India Mumbai 2007 Health Protection Agency IMS Health PRTM Samex Overseas

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Research & Development Basic Pharma Life Science Pvt. Ltd. NOTOX BV Palam Pharma Pvt. Ltd. Prachi Pharmaceuticals Pvt. Ltd. PRTM Teledyne Isco Vertis Biotechnologie AG

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Clinical Trials ClinPhone Impact Labs Pvt. Ltd. NOTOX BV PRTM SPR Pharma Ltd.

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Company

Page No.

Manufacturing Ace Chemicals Ambica Pharma Machines Pvt. Ltd. Basic Pharma Life Science Pvt. Ltd. Bharat Box Factory Brevetti Angela CphI India Mumbai 2007 Create Industries Haldies Chemicals Pvt. Ltd. Health Protection Agency Impact Labs Pvt. Ltd. Kaisha Manufacturers Pvt. Ltd. Padm Industries Palam Pharma Pvt. Ltd. Parag Exports Prachi Pharmaceuticals Pvt. Ltd. Samex Overseas Shriji Polymers India P. Limited SMB International GmbH Speciality Meditech Pvt. Ltd. SPR Pharma Ltd. Stamfag Teledyne Isco

83 75 68 85 IFC 04 68 80 84 64 67 78 28 72 32 14 66 69 77 50 IBC 41

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Suppliers Guide Company

Page No.

Company

Ace Chemicals www.acechemicalsindia.com

83

Health Protection Agency www.hpa.org.uk

Ambica Pharma Machines Pvt. Ltd. www.ambica.co.in

75

Basic Pharma Life Science Pvt. Ltd. www.basicpharma.diytrade.com

Page No.

Company

Page No.

84

PRTM www.prtm.com

48

Impact Labs Pvt. Ltd.

64 OBC

Samex Overseas www.samexoverseas.com

14

68

IMS Health www.imshealth.com

67

Shriji Polymers India P. Limited www.packingpeople.com

66

Bharat Box Factory www.bbfgroup.com

85

Kaisha Manufacturers Private Ltd. www.kaishamanufacturers.com

62

SMB International GmbH www.smb-gmbh.de

69

Brevetti Angela www.brevettiangela.com

IFC

NOTOX BV www.notox.nl

78

Speciality Meditech Pvt. Ltd. 77 www.indiamart.com/speciality-meditech

ClinPhone www.clinphone.com

52

Padm Industries www.vaibhavindustries.co.in

28

SPR Pharma Ltd. www.sprpharma.com

50

Cphi India Mumbai 2007 www.cphi-india.com

04

Palam Pharma Pvt. Ltd. www.palampharma.tradeindia.com

IBC

72

Create Industries www.createpharma.com

68

Parag Exports www.paragexports.com

Stamfag www.stamfag.ch

32

Teledyne Isco www.isco.com

41

Haldies Chemicals Pvt. Ltd. www.halides-pltd.com

80

Prachi Pharmaceuticals Pvt. Ltd. www.prachipharma.com www.activepharmaingredients.com

Vertis Biotechnologie AG www.vertis-biotech.com

36

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3. OBC: Outside Back cover

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