Pharma Focus Asia - Issue 22 by Ochre Media Pvt. Ltd.

Issue 22 2015

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Antimicrobial Resistance Confronting the threat

What are the 10 Hot Topics in Pharmaceutical Operational Excellence for 2015? Prospects for Personalised Medicines in the Asia-Pacific Region

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Foreword

Tackling Antimicrobial Resistance Bacterial resistance is developing quickly and many critically important drugs risk becoming obsolete, warned the World Health Organization (WHO) in April 2014. Antimicrobial resistance (AMR) has emerged as a major threat for public health worldwide, owing to ineffective use of antibiotics due to increasing patientsâ&#x20AC;&#x2122; demand, lack of quality medicines, dearth of infection prevention & control programmes etc. AMR is affecting the utility of modern medicine, in turn impacting companiesâ&#x20AC;&#x2122; revenues. The problem of AMR is not just limited to a few countries but is prevalent across the globe. In April 2015, WHO published a survey report, which revealed that efforts to contain AMR are underway in several countries, but challenges remain because of the widespread gaps in actions taken. Antibiotics are an invaluable resource for the global populace and they ought to be developed and managed on a sustainable basis. There is an urgent need to fight resistance by developing new business models for sustainable antibiotics. Producing new drugs that create short-term benefits will not suffice. There has to be a method to ensure these drugs sustain and achieve longterm success in prevention and cure of diseases. Companies need to move beyond the predominant business model of recovering their R&D investments through sales revenues. Tackling the challenge of AMR through antibiotic delinkage models is a viable option for companies while addressing the public health needs in an effective manner.

Under the delinkage model, governments encourage and incentivise manufacturing companies to invest in R&D to put new products on the market at the right time, safeguard antibiotics from overuse and premature resistance, and also to make effective antibiotics accessible to people across the globe. An effective delinkage model would result in increased revenues for companies as the focus would be on value delivered rather than volume of drugs sold. In the cover story by Karl Rotthier, President of DSM Sinochem Pharmaceuticals, talks about how producers are using outdated technologies to manufacture their APIs in combination with poorly managed waste streams, which is leading to unnecessary and harmful disposal of antibiotic residues into the environment contributing to AMR. He emphasises on the need to protect reputation and brands through developing sustainable supply chains and implementing stringent measures that enhance production and quality standards. Karl also talks about tackling the challenge of supply chain security in the face of antibiotic resistance.

Prasanthi Potluri Editor

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Contents Cover Story

Sustainable Antibiotics Evolving pharmaceutical supply chain to ensure effectiveness Karl Rotthier, President, DSM Sinochem Pharmaceuticals Belgium

40 STRATEGY 05 The Lasting Advantage Brian D Smith, Managing Director, PragMedic, UK

08 What are the 10 Hot Topics in Pharmaceutical Operational Excellence for 2015? Status Quo Analysis from an Operations Management Perspective

Thomas Friedli, Director, Institute of Technology Management

University of St.Gallen, Switzerland

Christian Maender, Research Associate, University of St.Gallen Switzerland

Nicolas Ponce, Research Associate, University of St.Gallen Switzerland

18 Regulatory Considerations for Forced Degradation Studies to Assess the Stability of Drugs

M V Narendra Kumar Talluri, Asst. Professor, Department of Pharmaceutical Education and Research, India

26 Microfluidic Organs-on-a-Chip The patent landscape

Robert W Esmond, Director, Biotechnology / Chemical Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., USA

Stephanie L Elmer, Associate, Biotechnology / Chemical Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., USA

34 Prospects for Personalised Medicines in the Asia-Pacific Region

Christopher Milne, Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

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Research and Development 46 Enabling the Delivery of Poorly Soluble Drugs via Drug-Polymer Solid Dispersions

Thomas D端rig, Senior R&D Director, Pharmaceutical and Food Specialties, Ashland Specialty Ingredients, USA

Divya Tewari, R&D Director, Global Pharmaceutical R&D and Technical Services North America & Rest of Asia

Yunxia Vivian Bi, Technical Director Solubilization and Contract Services, Ashland Specialty Ingredients, USA

MANUFACTURING 52 Antibody Drug Conjugates in Reducing Disease Burden Immense Promise with Some Challenges

Vivek Sharma, CEO, Pharma Solutions, Piramal Enterprises, India

Brian Smith

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Advisory Board

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

Editorial Team Grace Jones Sasidhar Pilli Art Director M A Hannan

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

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Product Manager Jeff Kenney Senior Product Associates Veronica Wilson Ben Johnson Circulation Team Naveen M Sam Smith

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

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

Subscriptions In-charge Vijay Kumar Gaddam IT Team Sitaram Y Jareena K Ranganayakulu V Head-Operations S V Nageswara Rao

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

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Pharma Focus Asia is published by

In Association with

A member of Confederation of Indian Industry

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The Lasting Advantage A transforming market quickly renders existing assets and capabilities obsolete. In a life sciences market where technology, customers and competitors are evolving, organisational learning is the only lasting advantage. What organisational learning is, what it is not, and how it is achieved emerges from the practice of exemplary companies. Brian D Smith, Managing Director, PragMedic, UK

hy are some firms more competitive than others? This is the central question of my research in the field of strategic management. Decades of research, in both the life sciences and other industries, have converged to suggest there are perhaps three over-arching reasons. The first is the most obvious: what academics call the ‘Resource-Based View of the Firm’ (RBV for short) says that firms’ advantages come from their distinctive assets. These might be tangible, like R&D facilities or cash reserves; or they may be intangible, like intellectual property or brand reputation.

The second reason builds on RBV with the idea that sustained competitive advantage flows from firms’ distinctive capabilities. Capabilities can be anywhere in the value chain from discovery to marketing but, to be distinctive, they must be superior to those of your peers. Taken together, resources and capabilities explain most success stories. Today’s exemplar companies, such as Gilead in pharma or Medtronic in medical technology, are good illustrations of resources in R&D and capabilities in marketing. However, there’s an important problem with these first two explanations of

competitive advantage. Both are built on the premise of strategic alignment, meaning that firms succeed when what they do matches the market environment. Gilead’s success stems largely from aligning to the rise of viral diseases, like HIV and Hepatitis, as important disease categories. Medtronic’s success can be seen as aligning to the rise of electronic stimulation as an emergent technology. In other words, both RBV and the distinctive capability-based school of thought are about aligning to the market. Therein lies the problem. When the market is changing, as it is today (See ‘Six Great www.pharmafocusasia.com

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Shifts’ in issue 21), any market alignment is only temporary and even firms with fabulous resources and outstanding capabilities can fail. The history of our industry is littered with once-great firms which lost alignment as the market changed. To understand success in changing markets, we need the third reason. This is the dynamic capabilities perspective, which explains long term success as the ability to adapt and reconfigure resources and capabilities to changing market conditions. Many things fit under the dynamic capabilities umbrella such as finding and acquiring partners and re-organising command chains. But the seminal dynamic capability is organisational learning. As the influential academics Sparrow and Hodgkinson said, in turbulent times, the organisation’s capacity to learn is a firm’s only sustainable source of competitive advantage. But what is organisational learning and how can life science companies develop this critical capability? What is Organisational Learning?

Organisational learning is the acquisition of new knowledge by the organisation. This seems a statement of the obvious until one defines what it is not. Organisational learning is not the acquisition of data or even of information; it is when your company learns, for the first time, how something is caused, how something works or what something is. For example, how markets really segment, how a market access decision is made or what a compelling value proposition looks like. Nor is organisational learning an individual or even team activity; it is when that new knowledge is embedded into the organisation (so that it is not lost when personnel change) and can be commercially exploited. Finally, organisational learning is not the acquisition of obvious knowledge that every competitor can gain without difficulty; it is the attainment of intelligence that competitors could not easily acquire or copy.So, for example, a firm that acquires lists of Key Opinion Leaders (KOLs) is not really 6

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learning; any competitor can imitate that easily. But a firm that acquires that list along with an understanding of where those opinion leaders fit into the market’s decision making processes is beginning to learn; and the firm that understands what that knowledge implies for the structure and capabilities of its sales team is truly learning. Two Ways to Learn

If organisational learning is not simply data collection and is critically important in changing markets, then an obvious question arises: How can our firm learn faster and better than our strategic rivals? My research and that of many earlier workers suggests that there are really only two ways: buy or make. Life science firms buy knowledge all the time. If I want to buy knowledge about how the respiratory market works, I might buy, partner with or out-license to another firm already strong in that disease area. That is what Almirall did recently when it sold its respiratory business to AstraZeneca. If I want to buy knowledge about antibiotic resistance, I might in-license or acquire a specialist firm. That is what Merck did recently. Buying knowledge is quick, but there are many reasons why it is not always the best option. Firstly, you might not know what knowledge you need to buy. Secondly, the knowledge you need may not be available anywhere. Thirdly, if it is available and it is valuable, you will pay heavily for it. A fourth reason is that bought knowledge is rarely unique; if I pay a consultant or contractor for knowledge, it is unlikely I am their only customer. Finally, it may not be very easy to assimilate and act on the knowledge, such as when clients fail to act on the market research they have bought. For these and other reasons, a firm may decide not to buy its knowledge but to make its own. Making new knowledge is, however, easier said than done and in the rest of this article I will discuss how exemplary learning companies manage the

important, differentiating process of organisational learning. Starting From Somewhere

My research into how life science firms are evolving reveals many examples of organisational learning. How branding influences pricing in emerging markets, how payers use prescribers’ advice and how to create value beyond the product are three examples. But, in all of the examples of excellent organisational learning I have uncovered, there is one common denominator: we start with an opinion. We might, for example, think we know who would be involved if our customer had to reshape their patient pathway to use our product. We might work on the assumption that the decision making process for our new primary care product is the same as for our existing products. We might feel confident that the first adopters of our new diagnostic test will be a certain innovative target segment. Whether the existing “knowledge” is fact-based or an opinion, whether it comes from experience or from research, we rarely address a business situation without some level of existing knowledge about the situation. Knowledge creation is rarely “ab initio” and is almost always about improving the validity and value of our existing knowledge or opinions. It is this insight, originally developed by the great US researchers Agyris and Schon, that allows us to understand how firms create the actionable knowledge that leads to competitive advantage.

Organisational learning is not the acquisition of data or even of information; it is when your company learns, for the first time, how something is caused, how something works or what something is.

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List actions

Revise assumptions

Identify assumptions

Test hypotheses

Develop hypotheses

Figure 1: The Learning Loop

Agyris and Schon realised that firms transformed weak, invalid knowledge into strong, actionable insight through a learning loop. In essence, the loop has five stages, as shown in Figure 1. In my work, I have learned that, although simple in principle, there are important, real-world lessons that we can learn from exemplary companies about implementing the loop. The first step in the learning loop is to list all of the major activities you either have planned or are currently executing. For example, this might include a KOL campaign, a health economics comparative study vs. another brand or a shift to Key Account Management programme. The practical lesson to note is that all significant resource-consuming projects should be identified because each one indicates where you are operating with some existing knowledge or opinion. The next step is to identify the one or two underlying assumptions upon which each activity is predicated. In our examples, these would be that KOLs drive sales, that the customer-perceived comparator is the other brand, or that product choice in big accounts is centrally directed. Typically, these assumptions are

implicit, and exemplary companies work hard to make them explicit. The third step is to develop hypotheses based on these underlying assumptions. In our examples, good hypotheses would be that our sales should be strong in the area where the KOL is favourable to us; new usage in our disease area is the comparator brand; and that key accounts concentrate their purchases onto one brand. Best practice in this important step is to ensure that the hypotheses are testable with unequivocal results. The penultimate step is to test the hypotheses using real data. In our examples, we would look for correlation between local market share and KOL attitude, for usage patterns in new prescriptions, and for share distribution within major accounts. Our most interesting finding here is that many firms may collect the right data to test their hypotheses but their information systems are often set A u t h o r BIO

The Learning Loop

up to support management control and not organisational learning. The final step in the learning loop is to revise your assumptions in light of the tests. Sometimes, prior assumptions are supported, but in our three examples (all taken from real cases) they were not. These cases revealed that KOLs were not very influential, that the customer-perceived comparator was not the competitor brand but a generic, and that many key accounts had such uncoordinated purchasing systems that they should not be treated as key accounts. These cases also revealed that important lessons, even when evidenced by data, were often hard for executives to swallow. This five-step process is of course a simplification. In practice, organisational learning is a skilled craft that relatively few companies have mastered and which is the hallmark of only the greatest. One final practical lesson emerged from this research. Specifically, most of the advanced learning organisations not only applied the learning loop to their current activity but also built it into future plans. So product launches, for example, can be designed to uncover their key assumptions and build on data collection that tests those assumptions. When applied in this way, organisational learning allows firms to identify flaws in their launch plans very early and so take timely corrective action. The core message of this work is simple. Whatever your current capabilities and assets, a rapidly changing market means that organisational learning is an essential component of sustained competitive advantage. It may be time consuming and, in some cases, costly, but, as one of our research respondents said, â&#x20AC;&#x153;If you think learning is expensive, try ignorance.â&#x20AC;?

Brian D Smith is a world-recognised authority on competitive strategy in the pharmaceutical and medical technology sectors. He researches the evolution of the sector at the University of Hertfordshire, UK and SDA Bocconi, Italy. He welcomes comments and questions on brian.smith@pragmedic.com

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strategy

Managing Complexity

OPEX Leadership

OPEX Maturity

CI Culture

Shift from Tool to Culture

Organising OPEX

Benchmarking the Quality Org.

OPEX in Network

Hot Topics Quality Metrics

Knowledge Management

Pharmaceutical Operational Excellence for 2015 Status quo analysis from an operations management perspective

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The following article presents an overview on the 10 hot topics in regards to pharmaceutical manufacturing. This analysis is based on research work of St.Gallen Operational Excellence (OPEX) team from the University of St.Gallen. Perhaps not surprisingly one of the main issues is the increasing integration of OPEX and quality, which requires novel management approaches. This and further topics are described in order to be primed for upcoming changes. Thomas Friedli, Director, Institute of Technology Management University of St.Gallen, Switzerland Christian Maender, Research Associate, University of St.Gallen, Switzerland Nicolas Ponce, Research Associate, University of St.Gallen, Switzerland

he competence centre for Operational Excellence (OPEX) at the Institute of Technology Management at the University of St. Gallen, Switzerland (ITEM-HSG) has focused its research for more than ten years on the challenges faced by pharmaceutical companies in their pursuit of Operational Excellence. Over time the researchers have been able to sustain a database consisting today of 281 data sets from 123 different pharmaceutical companies from all over

the world. With this data, and on the basis of several continuous exchange platforms, we are able to follow the trends in the manufacturing sector in real time. From an operations management perspective, we were able to identify ten topics that are on the agenda of almost every production manager in the pharmaceutical industry. This allows us to make a projection about where pharmaceutical OPEX is headed in the near future. Figure 1 exhibits an overview of the mentioned topics.

1. Quality metrics

The starting point of our “hot topic” list, quality metrics, goes back to the publication of the US Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, and a subsequent public docket in February 2013. In this work the FDA announced their intention to examine the use of selected Quality Metrics to support their riskbased inspection programme. The purpose of the metric is to support the industry to deliver high quality medicines across all sites (US Congress, 2012). The quality metric programme is supported by the big pharma associations (ISPE, 2013; PDA, 2013). The first draft of the FDA’s quality metrics is expected by the end of this year. Depending on the chosen set of metrics the impact on the industry could be supportive for the above mentioned objectives but also the opposite could become true. If the final metrics are not based on mutual trust between the regulators and the industry and has limits concerning comparability and interpretability it could lead to unwanted behaviour. A positive impact so far can be seen in the fact that, based on the discussion, more and more quality and OPEX have become to be integrated in pharmaceutical companies.

Figure 1: 10 Hot Topics in Pharma from an Operations Management Perspective www.pharmafocusasia.com

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Overall Score Resource Consumption

100% 80% Site 6

60%

Site 7

Site 5

40% Site 4 Site 1

20%

Site 3 Site 2

0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Degree of goal attainment

Figure 2: Benchmarking the Quality Organisation

2. Benchmarking the quality organisation

As OPEX and Quality is more and more integrated the efficiency of the whole quality organisation becomes a focus topic in pharmaceutical companies. The hard separation of the quality organisation had the effect that there hasn’t been a true evaluation of effectivity and efficiency of the quality organisations. Nevertheless, it needs some sophistication to do this in a way that the overall perspective and the quality performance are not sacrificed for costs. It is especially important to measure the right KPIs and to evaluate them in a meaningful way. The team at the University of St. Gallen proposed to constantly consider the entire picture. A separation in resource consumption (efficiency) and goal attainment (quality performance) both being aggregated KPIs consisting of diverse single KPIs could be a way to keep the overall understanding in the centre of the discussion. Figure 2 shows an example of the evaluation of quality organisation. Managers in this company should further investigate the differences between site six and four in this specific production network.

concerning OPEX varies depending on the maturity level a company achieves in relation to Operational Excellence. The formal organisation structure has a strong influence on the efficiency of an organisation. The researchers of the University of St.Gallen are developing a management model for organising OPEX relating to the level of implementation over time. 4. Opex maturity

Three key observations are often made when talking about the pathway to Operational Excellence: 1) Companies have to know their current state of OPEX

3. Organising OPEX

In general there is no ‘best’ structure for Operational Excellence in an organisation that is valid for all situations. The share of corporate to site based resources 10

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Figure 3: Operational Excellence Maturity Model

implementation; 2) They should be interested in the next steps to improve the level of OPEX implementation; 3) They need to know the level their competitors achieved to benchmark themselves against the peer’s OPEX levels. The team of the University of St. Gallen developed an OPEX maturity model that can be backed up with data to give answers to these questions (see figure 3). The core elements of the model are equipment stability, process stability, pull production and continuous improvement. It is important to understand that higher maturity levels can only be sustainably reached if the requirements of the lower levels have been fulfilled. 5. Managing complexity

Increasing complexity is a topic every pharmaceutical company is facing. The researchers of the University of St. Gallen separate the complexity as internal and external. Internal complexity consists of the elements people, processes and products, external complexity addresses the market and the supply side of a plant. Figure 4 gives an overview of the complexity drivers. Sites that are able to translate a high external complexity into a low internal complexity are considered as complexity masters. Furthermore, the idea is to compare the ability of a site

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Figure 4: Overview of Complexity Drivers Relating to the St.Gallen Understanding

to handle complexity with the overall operational performance of the site. If this evaluation shows that a site has achieved the level of mastery and has very high operational performance we name the site a true master. True masters are especially well-structured in their processes, have an above average level of OPEX practices implementation and find ways to optimally adapt their internal processes to their external requirements. 6. Shift from tool to culture

For many years, pharmaceutical companies mostly focused on training of specialists and technical aspects on their pathway to OPEX. This emphasis on methods and tools somewhat distracted from one of the most important success factors for a sustainable implementation: culture. The importance of a continuous improvement culture has been notoriously underestimated in the past. Of course, tools are the prerequisite to achieve a better performance, but sustainability is only achieved with a cultural change. OPEX has to become omnipresent in structures, behaviour and actions. Managing this shift from single tool oriented company programmes to a continuous improvement culture 12

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is an essential step in the pursuit of excellence. To successfully accomplish this transformation, a strong leadership commitment is necessary, but without neglecting other crucial aspects such as the involvement of all different network players, as well as the implementation of a collaborative knowledge management system. 7. OPEX leadership

The fundamental purpose of managers is to help an organisation to become more successful (Pavur, 2012). Leadership is

OPEX is not only about streamlining the processes and waste elimination, but also about the engagement of every single employee and the establishment of a continuous improvement culture.

therefore not an end in itself, but an enabler of success. Leading OPEX is not only about creating a vision and a sense of urgency. It is more about “forming a powerful coalition, communicating a vision, empowering others to act on that vision, planning for and creating shortterm wins, consolidating improvement while producing still more change and institutionalising the new approaches”. To achieve long-term success and impact, it is essential to anchor changes in the corporate culture (Kotter, 1995). “Again, this requires communication, and OPEX has to become visible in structures, activities, incentive systems, etc. To some degree, OPEX has to become a routine operation, even if it will continue to be about change. It is both, fostering change and ensuring stability, what is required from leadership, and these two perspectives on OPEX together define the basic requirements for leaders: establishing structures, planning for improvements, organising activities, establishing routines but also being present where the action is, caring about people, communicating, coaching, supporting and motivating employees” (see figure 5). An effective model for leading OPEX has to include all of this (Friedli/Werani, 2013).

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8. Continuous improvement culture

In comparison to other manufacturing industries, the pharmaceutical sector was initially slow to focus on OPEX practices and adopt a continuous improvement mindset. Various companies launched a limited number of initiatives by the late 1990s, but they were not widespread until the first decade of the 2000s (Seller/Davis, 2013). Today, however, pharmaceutical companies are at the forefront of driving performance by embracing the goals of OPEX and fostering a continuous improvement culture throughout the organisation. Their aim is to improve efficiency by optimising processes and eliminating wasted efforts. Problems are solved fast and efficiently at the level of occurrence in order to ensure that fewer problems occur and output gradually increases (Mejlvang, 2013). To accomplish this type of culture we already mentioned that a strong leadership emphasis is essential. But this is not the only requirement (see figure 6). Further elements of a successful OPEX culture are: Credibility of message, involvement of employees, and employee ownership. The first element is aimed at creating a shared vision amongst all employees, promoting the existence of a continuous pursuit for excellence and communicating the overall goals and performance. The involvement of employees is aimed at fostering teamwork through total involvement and committed personnel, and also about ensuring that decisions are made at the lowest possible level. Finally, employee

Figure 5: Leaders become Teachers

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ownership aims to share the gains with the total workforce and to provide personal and professional satisfaction for the employees (Srinivasan/Kurey, 2014). Hence, a continuous improvement culture requires new ways of working, leading and thinking. Many people believe that first they have to change the culture and this will have an impact on the work. But it is the other way round. Only by making changes in the work will you be able to change the culture. Therefore, culture is more an outcome than an input. 9. OPEX in network

As global competition intensifies, companies face difficult challenges in every aspect of corporate management. In particular, corporate OPEX initiatives must be examined anew when markets and manufacturing operations become global. For example, what are the implications of globalisation in terms of cycle times and production costs? Is it really possible to empower OPEX to all functions and levels across all country organisations within a global corporation? Pharmaceutical companies often do not use the full potential of their globally scattered manufacturing sites. Most often, they use them to benefit only from cheap labour, tariff and trade concessions, and reduced logistics costs. Therefore, they assign a limited range of work, responsibilities, and resources to those sites. Successful companies, however, may use various sites to unlock all the potential by getting access to new customers and suppliers, or accessing

knowledge and skilled workforce. Such companies use their sites as a competitive advantage (Ferdows, 1997). A lack of transparency is another common issue within global manufacturing networks. In various projects the authors discovered that managers often know neither the potential a site has, nor the purpose and reason of their sites, nor the range of competencies the respective sites have. Furthermore, sites were developing but corporate management was not able to describe the current state of the sites, not even to speak of prescribing the path the sites would take in the next years. Assigning well-defined roles to the sites within the network is crucial to overcome these problems and unlock hidden potential in a globalised world (Friedli/Liebetrau/Luetzner, 2013). 10. Knowledge management

Sharing of information and knowledge within a manufacturing network often happens to be a challenge in everyday business. In several industry projects, operation managers reported difficulties concerning, for example, the flow of information related to successful practices within the global network. Existing knowledge was not being exploited to its full potential whereby reaching improvements was costing extra resources. We believe that sharing information and knowledge is essential for good management. Transparency about production volumes, for example, enables load levelling in the network. Increased data quality in general enables managers in making well informed decisions (Friedli/ Liebetrau/Luetzner, 2013). Chew et al. consider information sharing in manufacturing networks as the main coordination mechanism. Accordingly, they find the management of information flow as important as the management of the flow of physical goods between sites (Chew et al., 1990). Therefore, establishing a structure for knowledge management and knowledge exchange is a key lever to increase productivity and ensure improvements using own capabilities and competencies.

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Figure 6: Circle of Key Influencing Factors to Develop an OPEX Culture

Conclusion Thomas Friedli is Head of the Chair of Production Management, where he leads a team of 14 researchers, and is lecturer in Business Administration. His main research focus is on the management of industrial enterprises with an emphasis on Production Management. He is editor and author of several books. Among others, his latest book â&#x20AC;&#x153;Leading Pharmaceutical Operational Excellenceâ&#x20AC;? within the field of Operational Excellence attracted interest from pharmaceutical industry.

A u t h o r BIO

Operational Excellence can be seen as a philosophy that helps to tackle the mentioned challenges. OPEX is not only about streamlining the processes and waste elimination, but also about the engagement of every single employee and the establishment of a continuous improvement culture. With the systemic approach of OPEX the quality and complexity related issues and challenges can be solved. Management commitment and sharing of knowledge are absolutely crucial for the success of every initiative. The proper way of organising OPEX throughout the production network matching the OPEX maturity levels of a company is also a key to success. Having all the mentioned elements aligned under control OPEX can be seen as a competitive priority to ensure the overall competitiveness of a company.

Christian Maender is a Research Associate at the University of St.Gallen (Switzerland). His research at the Institute of Technology Management focuses on the challenges faced by the pharmaceutical industry. The focal point of his industry and research projects is the management of Operational Excellence programs. Christian graduated from the Karlsruhe Institute of Technology (Germany) with a degree in Mechanical Engineering, majoring in Production Techniques. Nicolas Ponce is a Research Associate at the University of St.Gallen (Switzerland). His research at the Institute of Technology Management focuses on the challenges faced by manufacturing companies on the pathway towards Operational Excellence, with an emphasis on the pharmaceutical industry. Nicolas graduated with honors from RWTH Aachen University (Germany) with a degree in Mechanical Engineering, majors in Production Engineering.

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CPhI & PMEC India 2015 Your essential stop for entry into pharma’s most dynamic market a vast contribution to the global generics market. Not content with making vital drugs available and affordable across the developing world, India also supplies the USA with over 40%of its medicines. Additionally, 85 % of drugs Non-Governmental Organisations supply to Africa are also sourced from India.

The Indian economy’s contribution to global healthcare is undoubtedly staggering. Its dramatic growth figures over the past decade exemplify just how this dynamic market is taking the lead in supplying healthcare globally – pharmaceutical exports from India have grown at a CAGR of 21% over the last 10 years. It is with this performance as its backdrop that CPhI & PMEC India return (1-3 December 2015) to Bombay Convention and Exhibition Centre, Mumbai, India. The three-day premier ‘show of strength’ for India’s pharma industry is expected to again attract over 40,000 attendees from across the globe. In 2014 the event witnessed a record participation of 1087 exhibitors from 25 countries and was spread over 55,000m² in eight exhibition halls. It’s a truly gigantic show that is representative of this burgeoning pharma economy both domestically and in terms of exports. The India pharmaceuticals industry already represents around 10% of global volume and is one of the world’s largest producers. The country provides 16

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What is most impressive about this market’s growth is its ability to continually adapt and evolve its offering, moving up the pharmaceutical value chain. McKinsey & Company predict that the India pharmaceuticals market will reach an impressive US$45 billion by 2020. The driving force behind this is an expansion in the number of cGMP facilities and generics exports –India’s pharma exports stood at US$15 billion in 2013-2014. Most interestingly, India no longer supplies just simple formulations, but is actively focused on delivering complex formulations, highly potent compounds and biosimilars. In fact, 90% of formulation approvals for Anti-retrovirals (ARVs), Anti-tubercular and Antimalarials (WHO pre-qualified) have been granted to India. At CPhI & P-MEC India, industry professionals meet first hand with peers from within the biggest and most advanced companies across this diversifying market

Some of the Exhibitors at CPhI& PMEC India 2015

—from formulations, technology, machinery solutions, contract research, and process developments to packaging—with companies servicing all aspects of the global pharmaceutical supply chain. Technical Seminar run across all three days of the event and provides a platform to present unique products and offerings to visitors and prospective customers. With the recent CPhI pharma insights report on the Indian pharma economy pointing clearly towards a period of accelerating growth, 2015 is set to be a key year for the industry to meet its new partners and sustain relationships in India. The report—entitled ‘CPhI India Pharmaceuticals 2015: Industry explorations’— included a combined analysis of Indian companies showing an extremely confident domestic outlook in both the near and medium term. Companies reported that outsourcing and exports are again pushing ahead rapidly, with most firms forecasting double-digit growth, meaning any potential market entrants must act now or get left behind. Commenting on CPhI India’s contribution to the transformation of the regional industry, Chris Kilbee, Group Director Pharma at UBM EMEA, added “CPhI has been a key presence in India for a number of years and the event is an essential cog in internationalising this pharma hub. What’s been most impressive is the ability of companies here to constantly develop themselves through new services and technologies. With the highest number of USFDA approved facilities outside of the US, it is unsurprising that India has seen impressive growth in the number of exports. India’s domestic pharma economy is thriving, at the same time as demand for generics is on the rise, and international companies are looking to drive down manufacturing costs. This is an exciting time for the CPhI community to meet at this world-class pharma event. If you want to be a key contributor in global pharma, you need to have a presence in India, and that means… you have to attend CPhI & P-MEC India 2015.

ACG Worldwide

IMA Industria Macchine Automatiche S.P.A

Agilent Technologies

Indoco Remedies

Alembic Pharmaceuticals Limited

Marchesini Group

Àurobindo Pharma

Merck Millipore

BASF

Mitsubishi Electric India

Bosch Ltd.

Morepen

Cadmach Machinery Co. Pvt Ltd.

MSN Laboratories Limited

Capsugel Healthcare

Parle Elizabeth Tools Pvt. Ltd.

Clearsynth Labs Ltd

Pharmexcil – India pavilion

Elmach Packages (India) Pvt Ltd

PrajHiPurity Systems Limited.

Evonik Degussa India Pvt. Ltd.

Shimadzu

Fette

Thermo Fisher Scientific

Gansons Limited

Tofflon (India) Pvt. Ltd.

Gattefosse India Pvt. Ltd.

UK Trade & Investment

Hikal Ltd

Waters India

UBM India is proud to announce the 3rd annual UBM India Pharma Awards scheduled to be held on 30th November 2015 at The ITC Mumbai. The event is a celebration of the India pharma success story and brings together the luminaries of the industry…In a night of glamour, entertainment, jubilation and of course, the pride of being the crème de la crème of the Indian Pharmaceuticals sector! The UBM India Pharma Awards provide a platform to demonstrate organisational capabilities across Innovations in different categories. This most prestigious of evenings is attended by a diverse mixture of pharma industry executives, policy makers and regulators from within the country, as well as officials from Asia and Europe. As the pharma industry is increasingly looking towards India for higher quality, low cost pharma solutions, the UBM India Pharma Awards is the perfect place for companies to engage with the movers and shakers in India's pharma machinery, technology, ingredients, outsourcing and biopharma industry. To learn more about the awards or to nominate a company, please visit: www.indiapharmaawards.in Advertorial www.pharmafocusasia.com

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Regulatory Considerations for Forced Degradation Studies to Assess the Stability of Drugs Quality, safety and effectiveness are the most important attributes of drugs and pharmaceuticals. The ICH issued the guidelines on pharmaceuticals stability. The present article focuses main regulatory considerations for the stability of drugs including typical acceptance criteria for HPLC based SIMs and WHO pre-formulation stress testing protocols and QbD etc. M V Narendra Kumar Talluri, Asst. Professor, Department of Pharmaceutical Education and Research, India

uality, safety and effectiveness are the most important attributes of drugs and pharmaceuticals. Because of its key role in public health, the pharmaceutical industry has always been a comparatively highly regulated industry. Until the end of 2nd World War, the quality of pharmaceutical products was determined mainly by assaying the content of their active ingredients. Since then, analytical instrumentation has undergone an extraordinary revolution, successively enabling the resolution of increasingly complex samples and the detection of minor amounts of any kind of analyte contained therein. This revolution facilitated the setting of an analytical chemistry-based regulatory framework to govern the development of pharmaceuticals. This paradigm has been continually evolving, especially in those aspects that define their standards of quality. Since the early 1970s, it has become a concern that unstable Drug Products (DPs) may not be able to maintain their quality attributes

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50 employees of which 6 as QA/QC

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after being stored over a period of time, so, in 1975, the United States Pharmacopeia (USP) included a clause regarding the drug-expiration-dating period. The regulatory timeline

• 1975- USP included –Drug expiration period • 1984 - The US Food and Drug Administration (FDA) issued the first stability guideline • 1987- Publication on specific requirements on statistical design and analysis of stability studies for human drugs and biologics with the aim of establishing expiration dates • 1987- FDA - Guidelines on stability data for applications to the Investigational New Drugs (INDs) and New Drug Applications (NDAs) • 1993- The International Conference on Harmonization (ICH) issued the Q1A guideline on stability. In 1993, the International Conference on Harmonization (ICH) issued the guidelines on stability (Table 1). The regulatory bodies of Japan, USA, the European Union, Canada, Australia and other countries have adopted and now have the law in force. In general, pharmaceutical items intended for the global pharmaceutical market are currently tested for stability under normal storage conditions for as long as 36 months, though, typically, regulatory agencies would initially assign only a 24-month conformance period, thereby providing an extra stability reserve. Thus, a satisfactory 3-month accelerated data submission may also permit granting a 24-month tentative expiry date, provided the room temperature data also meet specifications. Hence, Stability-Indicating Methods (SIMs) play a key role in current pharmaceutical regulation. However, despite the official requirement to use SIMs, as emphasised in the British Pharmacopoeia, the USP and several ICH regulatory guidelines, none of these documents provide the definition of a SIM. Moreover, the stability-indicating requirement is absent from several 20

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Subject

Code

Contents

Stability

Q1A (R2)

Stability stability testing of new drug substances and products

Q1A-Q1F

Q1B

Stability testing: Photo stability testing of new drug substances and products

Q1C

Stability testing of new dosage forms

Q1D

Bracketing and matrixing designs for stability testing of new drug substances and products

Q1E

Evaluation for Stability Data in court.

Analytical validation

Q2 (R1)

Validation of analytical procedures: text and methodology

Q3A - Q3D Impurities

Q3A (R2)

Impurities in new drug substances

Q3B (R2)

Impurities in new drug products

Q3C (R5)

Impurities: guideline for residual solvents…

Table 1: ICH Guidelines Related to Pharmaceutical Stability and Impurities

well-recognised Pharmacopoeias (the Japanese Pharmacopoeia,15th Edition). From the FDA perspective, a SIM must ‘accurately measure the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities’. Furthermore, available official guidance concerning scope, timing and best practices for degradation studies, required for developing SIMs, is still very general. SIMs are required for stability studies, and stability information is needed for regulatory submissions, such as INDs and NDAs, and to set expiration dates for APIs and Drug Products. SIMs are also required for complying with other regulated events, such as API and DP release, toxicology dosing solutions, excipient-compatibility evaluation, preformulation and packaging studies, and line extension. They are also powerful tools for routine quality control and for investigating out-of-specification and out-of-trend results. Bakshi and Singh distinguished the terms ‘specific stability-indicating method’ (specific SIM) and ‘selective

stability-indicating method’ (selective SIM). A specific SIM is an analytical method suitable for unequivocally measuring the API in the presence of all of its degradation products, as well as excipients and additives, expected to be present in the formulation. However, a selective SIM is a method capable of unambiguously measuring the API and all of its degradation products in the presence of excipients and additives, expected to be present in the formulation. They considered that the development of a SIM likely to meet regulatory requirements is a seven step process that entails: i. Critical study of the drug structure to assess the likely decomposition routes ii. Collection of physicochemical properties information iii. Conducting stress studies iv. Preliminary separation studies on stressed samples v. Final method development and optimisation

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vi. Identification and characterisation of degradation products and preparation of standards and vii. Validation. The ability of a SIM to monitor changes in the chemical properties of the drug over time, according to the regulatory guidance, is that they provide valuable information, including the determination of the degradation pathways of Drug substances and Drug Products, revealing the intrinsic stability of the API in the solid state and in solution and its susceptibility to hydrolytic, oxidative, thermolytic, and photolytic degradation. Moreover, the resulting structural elucidation of the degradation products enables the discernment of compounds in formulations related to the drug substances from those arising from the excipients. Stress tests also fulfil the purpose of providing meaningful amounts of degradation products, which can be isolated and purified for complete characterisation and acquisition of impurity standards before carrying out the method development and validation studies. Alternatively, by resorting to the high sensitivity and excellent separation capability of hyphenated techniques, such as UPLC Stress factors

Condition

A specific StabilityIndicating Method (SIM) is an analytical method suitable for unequivocally measuring the API in the presence of all of its degradation products, as well as excipients and additives, expected to be present in the formulation.

with Mass Spectrometry (MS) detection (UPLC-MS), which also provide structural information, In this case, no purified impurity standards are generated by the approach. Monitoring of degradation reactions is also helpful for better understanding of some important characteristics of the drugs (polarity, stability etc.) and to decode which degradation product is really relevant and which is not. WHO suggested pre-formulation stress testing protocol for the development of FixedDose Combination (FDC) - Finished

APIs concentration1

Time

Acid

0.1 N HCl

2:1 in 0.1 N HCl

1-10 days

Base

0.1 N NaOH

2:1 in 0.1 N NaOH

1-10 days

Heat

60Â°C

1:1 with diluents2

1-10 days

Humidity

â&#x2030;Ľ75% RH

Solid state

1-10 days

Metal ions

0.05 M Fe2+ or Cu2+

1:1 with solution of metal ions

1-10 days

Oxidation

3% H2O2

1:1 in 3% H2O2

1-3 hours

Photolysis

UV-B fluorescent

1:1 with diluents2

1-10 days

Table 2: WHO Pre-Formulation Stress Testing Protocol 1. When testing degradability of APIs in combination, the APIs should be in the same ratio as in the FDC-FPP. 2. The diluent is excipients (approximate ratio as in the formulation).

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Pharmaceutical Product (FPP). (Table 2). In addition, Table 3 depicts typical acceptance criteria for an HPLC-based SIMs. The current WHO guideline is modelled on ICH Q1A(R2). ICH Q1A is now two decades old. Also, there is wide adoption of the ICH CTD format for dossier submission, so ICH requirements that were meant for new drugs/products have been extended to generic drugs/products, including limits of degradation products, as evident in the WHO stability-testing 2009 guideline. So, there is a clear trend towards aligning global, regional and country requirements for stress testing to ICH CTD. While ICH guidelines require stress testing results as a part of registration dossier, US-FDA emphasizes stress testing requirement in IND phases 2 and 3. Similarly, EMA seeks stress testing details in application for permission on investigational medicinal and biological products in clinical trials. USFDA and EMA include stress testing in their guidelines on individual product categories, such as metered doseinhalation aerosols, nasal sprays, liposomal products, biological and protein products, vaccines, coronary drug eluting stents, transdermal patches and botanical drug products. Stress conditions that can cause incremental product degradation over a defined time period are also mentioned. While USFDA insists on stress testing of herbal drugs and products to establish an analytical method capable of detecting degradation products, the same is not a clear requirement under EMA guidelines, where omission is allowed, if justified. Stress testing of radioactive substances is not considered feasible, so simulated testing is recommended in certain cases on the non-radioactive chemical form, and on radiopharmaceutical kits Accordingly, any regulatory agency would appreciate the presence of an elaborate study as a part of the dossier for a new or generic drug or attachment with dossier application of an intensive study, if available in the literature for an existing molecule. It is in the interest of

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Parameter

Limit of related substance/degradation product

Active ingredient

Specificity (peak purity by PDA/MS)

> 0.999

Linearity ( ≥ 5 concentrations)

r > 0.99

r> 0.98

Range %

80-120%

LOQ to 120

Accuracy

98 to 102%

70-130 (@0.1%)

Precision (%RSD)

≤2

Table 3: Typical Acceptance Criteria for HPLC Based SIMs

lines Q3A and Q3B for degradation products/impurities in the new drug substances and products, respectively. The general reporting, identification and qualification thresholds are 0.05

M V Narendra Kumar Talluri is an Asst.Professor & In Charge A u t h o r BIO

the manufacturer to assess that in-house or the literature study has been conducted systematically and would prove so as a right-first-time data package. Moreover, the major emphasis of regulatory agencies in the current times, as projected well through the requirements laid down in ICH quality guidelines Q1–Q11, is that new drug substances and products should be designed and produced to optimal quality, batch after batch, in line with the stringent limits contained in the guidelines. Incidentally, stringent thresholds have been prescribed under ICH guide-

per cent, 0.1 per cent and 0.15 per cent, respectively. Higher limits are allowed for specific degradation products if they prove to have a better safety profile, while the confines are much more stringent for genotoxic degradation impurities. As the same ICH thresholds now even apply to existing and generic pharmacopoeial products, in that respect, all kinds of drug substances and products need to be designed and manufactured so that degradation products/impurities are under control through their total life cycle, starting from manufacture to consumption by the patient. The importance of drug degradation can be gauged from the fact that plenty of recalls ordered from the market by USFDA in recent times, involving huge quantities of drug products, have been due to degradation in them surpassing the approved limits. Quality by Design (QbD) initiative was introduced by the FDA in 2002 and is being promoted within the pharmaceutical industry with the aim of increasing regulatory flexibility and creating an easier path for the manufacturers to introduce process/product improvements. The QbD concept is also being implemented for analytical method development. Application of statistical design of experiments is currently encouraged by the regulatory agencies, sometimes together with the use of chromatographic modelling and optimisation software (DryLab, LC Simulator, Fusion AE and Design Expert). This allows systematic assessment of the critical parameters of the SIM, since method sensitivity, specificity and robustness are properties especially addressed by QbD approach with a few experiments and relatively little laboratory efforts.

LC-MS at NIPER-H. Previous positions held by him include Associate Scientific Manager at Biocon. He received PhD from IICT, Hyd. The Indian Drug Manufacturer’s Association conferred prestigious ‘Young Pharmaceutical Analyst Award 2011’ for his outstanding research contribution in the field of Pharmaceutical Analysis. Science direct declared 4 times one of his article published in journal of pharmaceutical and biomedical analysis was among Top 25 hottest articles.

www.pharmafocusasia.com

Biotechnology A solution or a problem

PrashantNagre CEO, Fermenta Biotech Limited, India Prashant Nagre is the Chief Executive Officer at Fermenta Biotech Limited since September 2010. With over 20 years in the pharmaceuticals industry, he has in-depth experience across spheres encompassing the API business, production, Research and Development. Additionally, Prashant has acquired practical experience in regulatory compliance.

How did Fermenta Biotech evolve to be a leader in the manufacture of Immobilized enzymes and a pioneer in bio-catalysis? Enzymes are biomolecules which serve to accelerate the chemical reactions of living cells (often by several orders of magnitude and sometimes, carry out impossible

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reactions effortlessly!) Without enzymes, most biochemical reactions would be too slow to even carry out life processes, this attribute has made enzymes the right candidate for commercial applications. Immobilized enzymes or â&#x20AC;&#x153;support fixed enzymeâ&#x20AC;? enable the enzyme to be used for variety of applications. Based on the

type of application, the way immobilization needs to be custom designed. This is a challenging science, whose competency has been developed by Fermenta Biotech Limited (FBL) over the past two decades. With a data bank of over 800 types of polymer support, FBL customizes the immobilization technology for each new enzyme it embarks on. So a combination of proprietary enzyme and the immobilization platform enables FBL to take the pole position.

With traditional chemical reactions being replaced with bio enzymatic processes, is the change commercially viable? What are the advantages? FBL pioneered the popularization of first generation enzyme, popularly known as “white enzyme” for the chemical transformation of Penicillin to 6-APA in India. This has changed the way 6-APA, the main building block of vital betalactam antibiotics ever produced in this sub-continent, by replacing the hazardous chemistry. Over the years, use of enzyme for the production of 6-APA has become the “golden’ standard for green manufacturing. By keeping the legacy, FBL has introduced the next generation enzyme for the enzymatic synthesis of Amoxicillin /Ampicillin from 6-APA. The main advantages of these enzymatic processes are high purity product, higher yield, and lower pollution foot print. Needless to mention the economics this enzymatic process offers. This has been the main driver for the global adaptation of enzymatic processes in traditional chemical processes. What did Fermenta Biotech foresee as opportunities and risks associated with Biotechnology industry to capitalize on market? FBL has played a pivotal in popularizing enzymatic synthesis of antibiotics at a broader user base. With the current level of “enzyme empowerment” in beta lactam and cephalosporin antibiotics by many companies, FBL foresees a huge opportunity for the application of enzymes in various aspects of green manufacturing, especially in mass production hubs like India and China. This transformation would not only drive the development of novel enzymes from niche natural resources but also promote directed “evolution” to make enzyme to fit the process. Thanks to the advancement of molecular biology and genetic engineering science. The challenge would be to protect and implement IPR propriety and to regularize the biosafety issues.

What has biotechnology got to offer for developing countries with regard to environmental issues such as air pollution, water contamination etc.? Biotechnology, by taking cues from the nature provides technological solutions for the amelioration of environmental solutions. In all the effluent treatment practices, be it polluted lake water or the treatment of effluent water, the biodegradation is catalyzed by the prevailing natural organism. Understanding the principles of this natural phenomenon combined with intelligent design has led to a lot of biotechnological solutions. For example, for air pollution, the use of biofilters made by specific organisms helps to remove the air pollutant at source. Biofilters, worldwide have proved to be very effective to remove specific air pollutant. This is not possible otherwise by the conventional technologies. Similarly, for highly polluted water bodies, specific highly active bioenzymes combined with aeration technologies offers unique solutions. Developing countries, especially Asia have serious environmental issues but lack infrastructure to implement the conventional technologies. Biotechnology based solutions comes handy as it can work effectively in space and fund constrained conditions. What are some of Fermenta's brilliant solutions in the environmental space that attracted the attention of global industries? FBL offers basically two conceptual solutions in environmental space, one aimed at reducing pollution foot print by transforming the way the chemicals or pharmaceutical products are being manufactured and the other, providing biotechnological and innovative solutions to treat and manage the already polluted landscape. In pharmaceutical applications, FBL enzyme platform offers alternative green manufacturing platforms, which not only reduces the environmental impact but also gives high product purity profile. In environmental treatment area, FBL’s bioenzyme products combined with treatment methodology

offers, cost efficient, eco-friendly solutions in waste water treatment, lake water bioremediation, oil sludge management, solid waste management etc., In addition to biotechnological solutions, FBL is also collaborating to bring in state of the art, ash fly treatment and management technology into India. What are the novel techniques of manufacturing / unique products introduced by Fermenta Biotech Limited? In the pharmaceutical segment, FBL is synonymous with novel, proprietary products. In the recent past, FBL’s enzyme platform NPGA ( Fermase PS 250 and Fermase AMP 170) has helped in the transformative production of antibiotics Amoxicillin and Ampicillin in a more ecofriendly way than ever. This is the reality now and most of these antibiotics is being produced only by enzymatic approach. This change has inspired many such products to follow suit and FBL continues to provide thought leadership in offering integrated enzyme solutions in antibiotic manufacture. In addition, FBL has also introduced a versatile enzyme CALB lipase, which is finding immense use in variety of applications, spanning from pharmaceuticals to cosmetics to fine chemicals. With the continued innovation spirit, FBL is poised to make positive contribution in this green manufacturing initiative. What are some of Biotechnology applications that Fermenta pursues finding use in medicine and pharmaceutical industry? Conventionally FBL products were focused on providing enzyme leadership in beta lactams and cephalosporins, by evolving the enzyme as per the prevailing process challenges. This has helped the pharmaceutical industry to have a better product, better process and better pricing. While this efforts continue to cater the needs of the market, FBL is finding new applications or new integrated process routes to use enzymes at multiple steps, which otherwise would be nearly inefficient by using traditional chemistry. Advertorial www.pharmafocusasia.com

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Microfluidic Organs-on-a-Chip The patent landscape

Organs-on-a-chip are research tools that offer an alternative to the costly and time consuming use of clinical trials used in drug development. This article will discuss patents covering organson-a-chip, in particular those that contain multiple cells or tissue(s), the exceptions to patent infringement for experimental uses, and the prospects for further patenting. Robert W Esmond, Director, Biotechnology/Chemical Group of Sterne, Kessler Goldstein & Fox P.L.L.C., USA Stephanie L Elmer, Associate, Biotechnology/Chemical Group of Sterne, Kessler Goldstein & Fox P.L.L.C., USA

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raditional methods of drug discovery â&#x20AC;&#x201D; in particular, the use of animal testing â&#x20AC;&#x201D; suffer from many limitations including: (a) the length of time and high costs associated with animal trials; (b) the loss of animal lives; and (c) the failure of animal tests to accurately predict human responses. Two-dimensional (2D) cell cultures have shown value in biomedical research; however, they cannot adequately simulate the multiple functions of many cell types or

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accurately predict in vivo tissue functions and drug activities. Limitations with conventional two-dimensional (2D) cell cultures have led to the development of more complex systems such as three-dimensional (3D) cell cultures and organs-on-a-chip. These products are often protected by various forms of intellectual property laws. The great potential of using organs-on-a-chip as research tools in the areas of tissue development, organ physiology, and disease etiology is likely to pose many intellectual property rights challenges.

The simplest organs-on-a-chip are microfluidic devices that contain a single, perfused microfluidic chamber containing a single type of cultured cell that exhibits the functions of a single tissue type. More complex devices contain two or more channels or chambers that are connected by porous membranes which are lined on opposite sides by different types of cells in an attempt to mimic interfaces between different tissue types. These devices can incorporate physical forces such as cellular interactions, liquid flow, and liquid residence parameters, allowing analysis of organ-specific responses. The manufacture and use of organson-a-chip may infringe intellectual property rights as described in the table below. The limitations on enforcing the rights are also set forth. Products of commerce may be protected by any one of these IP rights. Organs-on-a-chip can be used for multiple research purposes, including drug discovery and development, and may find protection under a number of areas of intellectual property. For example, the software and code used to manufacture organs-on-chips may be protected by copyright. But it is unlikely that organs-on-a-chip will have a means for expression, ornamental features, or source of origin that can also find protection. The best way to protect innovation related to organs-on-a-chip is with utility patents. In order to determine what patents might dominate the making, using, and selling of organs-on-chips, we carried out a patent landscape search. The landscape search did not attempt to cover all patents filed on potentially large number of manufacturing techniques and uses related to organs-on-a-chip. The most important patents issued are described below. Pending applications are not included as their issuance as patents is speculative. The first successful design of a microfluidic device containing two or more channels was termed a "body-on-a-chip" in an article in Newsweek. This device is described in the following patent:

US 7288405 "Devices and Methods for Pharmacokinetic-Based Cell Culture System" (Exp. Date: October 29, 2022). What is claimed is: 1. A pharmacokinetic based microscale culture device, comprising: a first microscale chamber containing a first type of cell, wherein the first microscale chamber is dimensioned to maintain the first type of cell under conditions that give rise to at least one pharmacokinetic parameter value comparable to a value for the same at least one pharmacokinetic parameter obtained with respect to the same type of cell in vivo, wherein the at least one pharmacokinetic parameter value is selected from the group consisting of a measurement of liquid residence time, and liquid to cell ratio, wherein the first chamber comprises a first inlet and a first outlet for flow of culture medium; a second microscale chamber containing a second type of cell, wherein the second microscale chamber is dimensioned to maintain the second type of cell under conditions that give rise to at least one pharmacokinetic parameter value comparable to a value for the same at least one pharmacokinetic parameter obtained with respect to the same type of cell in vivo, wherein the second chamber comprises a second inlet and a second outlet for flow of culture medium; and a microfluidic channel interconnecting the first and second microscale chambers wherein the microfluidic channel is dimensioned to transport a culture medium, and wherein the microscale culture device is dimensioned to maintain at least one desired value for shear stress under a condition of flow of the culture medium. The patent is assigned to the Cornell Research Foundation, Inc. It was filed in the United States, Australia, Canada, China, European Patent Office, and Japan. This patent appears to cover a microscale culture device comprising a first microscale chamber containing a first type of cell and a second microscale chamber containing a second type of cell. According to the patent specification, the specific chambers provide www.pharmafocusasia.com

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The manufacture and use of organs-on-a-chip may infringe intellectual property rights as described in the table below. The limitations on enforcing the rights are also set forth. IP Right

Nature of Right

Limitations

Protects means of expression of an idea. Useful to protect software, code, CAD drawings, sculptures, and 3D models. Easy and cost-effective to obtain. Statutory damages are available in many countries.

Protection does not extend to the utilitarian features of a product. Difficult and expensive to enforce in court.

Design patent

Protects novel ornamental features of a product, i.e., the way an article “looks.” Easy and inexpensive to obtain.

Protection does not extend to the utilitarian features of a product. Difficult and expensive to enforce in court.

Trade Dress

Protects the visual appearance of a product that indicates the source of origin. No filings required.

Protection does not extend to the utilitarian features of a product. Difficult and expensive to enforce in court.

Trademark

Protects indication of source of origin and protects consumers from being confused by the origins of a product. Easy and inexpensive to obtain.

Protection is limited to the mark and does not extend to the utilitarian features of the product. Difficult and expensive to enforce in court.

Trade Secret

Protects against misappropriation of secret information about a product maintained as a secret. Such information may include design plans, software and code used to make the product. No filings required but steps must be taken to ensure secrecy of the information.

Competitors can reverse engineer the product and method of manufacture. Unless trade secret misappropriated, there is no protection once the information is no longer “secret.” Difficult and expensive to enforce in court.

Utility Patent

Grants limited right (generally 20 years) to exclude others from making, using and selling claimed a product or process.

Expensive and time consuming to obtain. Difficult and expensive to enforce.

cellular interactions, liquid flow, and liquid residence parameters for cells, tissues, and organs in vivo. The patent specification makes clear that it covers not only cells and tissue, but also organs are contemplated: ‘the device replicates a re-circulating multi-organ system by segregating living cells into discrete, 28

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interconnected ‘organ’ compartments (see e.g., FIG 15).’ Additional patent applications were filed, one resulting in a patent and one currently pending, which claim priority to this application. US 7725267 ‘Synthetic Microfluidic Microvascular Network’ (Exp. Date: July 5, 2028)

Assignee: CFD Research Corporation. It was filed in the United States only. What is claimed is: 1. A microfluidic microvascular chip comprising: one or more fluid inlets, one or more fluid outlets, and a plurality of non-linear flow channels forming a synthetic microvascular network allowing fluid flow between one or more fluid inlets and one or more fluid outlets wherein said non-linear flow channels forming said synthetic microvascular network possess a geometric characteristic selected from the group consisting of a variable crosssectional shape, a variable cross-sectional area, a turn, a bend, a bifurcation, a junction, a convolution, an anastomosis, and combinations thereof. This patent appears to cover a microfluidic microvascular chip comprising one or more fluid inlets and outlets and a plurality of non-linear flow channels. The patent is limited to a synthetic microvascular network. Additionally, seven patent applications were filed, six resulting in patents and one currently pending, which claim priority to this application. The following patent in this family contains claims that are not limited to a microvascular network: US 8355876 ‘Microfluidic Assay for Selection and Optimisation of Drug Delivery Vehicles to Tumors’ (Exp. Date: February 3, 2027). What is claimed is: 1. An optically transparent microfluidic chip comprising: a) a network of nonlinear, interconnected flow channels in fluid communication with a network inlet and a network outlet, said flow channels having luminal cross-sectional dimensions of between 10 and 500 µm, the network of non-linear, interconnected flow channels having a geometric characteristic selected from the group consisting of a variable cross-sectional shape, a variable cross-sectional area, a turn, a bend, a bifurcation, a junction, a convolution, an anastomosis, and combinations thereof; and b) a tissue space in fluid communication with a tissue space inlet and a tissue space outlet, said tissue space having crosssectional luminal dimensions of between

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100 µm and 1 cm wherein: the tissue space is separated from a lumen of at least one flow channel by a porous wall containing pores or gaps having crosssections of between 0.2 and 5 microns and is in liquid communication with said flow channel through said porous wall and the tissue space contain cultured cells. This patent appears to cover a microfluidic chip comprising a network of interconnected flow channels in fluid communication with a network inlet and a network outlet and a tissue space in fluid communication with a tissue space inlet and a tissue space outlet. According to the patent specification, while the invention is directed primarily towards tumour drug delivery, the invention may also be used for drug delivery to other tissues. US 7763456 ‘3D Micro-scale Engineered Tissue Model Systems’ (Exp. Date: March 29, 2028) Assignee: University of Washington. It was filed in the United States, European Patent Office, and Japan. What is claimed is: 1. A polymeric chip, comprising, at least one porous scaffold, wherein the porous scaffold is formed from the polymeric chip and is localized within a portion of the polymeric chip, wherein the porous scaffold includes a first surface and a second surface, and wherein the first surface is opposite from the second surface; a first microfluidic inlet channel, wherein the first microfluidic inlet channel is in fluid connectivity with the first surface of the porous scaffold; and a second microfluidic outlet channel, wherein the second microfluidic outlet channel is in fluid connectivity with the second surface of the porous scaffold. This patent appears to cover a polymeric chip comprising at least one porous scaffold, a first microfluidic inlet channel, and a second microfluidic outlet channel. According to the patent specification, the porous scaffolds can contain a plurality of living cells. Thus, this patent appears to cover all polymeric chips comprising a porous scaffold, cells, a microfluidic inlet, and a microfluidic

outlet in the United States through its expiration date in 2028. US 8266791 ‘Method of Fabricating Microfluidic Structures for Biomedical Applications’ (Exp. Date: September 8, 2030) Assignees: The Charles Stark Draper Laboratory and Brigham and Women's Hospital, Inc. It was filed in the United States and European Patent Office. What is claimed is: 1. A method for fabricating a microfluidic structure, comprising: (a) providing a patterned wafer comprising at least one exposed electrically conductive region and at least one exposed electrically insulating region; (b) electroplating an inverse channel portion with substantially semicircular cross section onto the wafer, thereby forming a first master mold; (c) employing the first master mold so as to emboss a channel portion in a first polymer sheet; (d) aligning and bonding the first polymer sheet with a second polymer sheet having a corresponding channel portion such as to define a first channel with substantially circular cross section between the polymer sheets. This patent appears to cover a method of preparing a microfluidic structure by aligning and bonding polymer sheets together. According to the patent specification, an advantage to the described method is the ‘ability to produce vascular networks having vessels with substantially cylindrical geometries, and to construct smooth transitions at vessel bifurcations and vessel diameter changes in a manner similar to healthy physiologic structures.’ US 8343740 ‘Micro-Organ Device’ (Exp. Date: October 31, 2031) Assignee: United States of America as Represented by the National Aeronautics and Space Administration. It was filed in the United States only. What is claimed is: 1. A method for fabricating a microorgan device comprising: providing a microscale support comprising at least one microfluidic channel and at least one micro-chamber for housing a microorgan; bonding the microscale support to a substrate by covering the contact

As shown in the table below, the most frequent patent filers were located in the US Company / Institution CFD Research Corporation (USA) The Charles Stark Draper Laboratory, Inc. (USA) The Children's Medical Center Corporation (USA) President and Fellows of Harvard College (USA) Massachusetts Institute of Technology (USA) TissUse GmbH (Germany) Vanderbilt University (USA) Cornell Research Foundation, Inc. (USA) Nortis, Inc. (USA) Fraunhofer-Gesellschaft (Germany) University of Washington (USA) National Aeronautics and Space Administration (USA) Corning Incorporated (USA)

surfaces of each with titanium tetra (isopropoxide); and printing a microorgan on the microscale support using a cell suspension in a syringe controlled by a computer-aided tissue engineering system, wherein the cell suspension comprises cells suspended in a solution containing a material that functions as a three-dimensional scaffold, and wherein the printing is performed with the computer-aided tissue engineering system according to a particular pattern. This patent appears to cover a method of preparing a micro-organ microfluidic device in which the micro-organ is printed on a microscale support using cell suspension in a syringe controlled by a computer-aided tissue engineering system. According to the specification, the invention may be produced by ‘direct bioprinting of specific cells, human or animal, to form micro-organs in micro-chambers www.pharmafocusasia.com

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of microchips.’ It is noted that the claim requires that the microscale support is bonded to a substrate using titanium tetra (isopropoxide) — therefore, it may be possible to avoid infringement of this claim by using another binding agent. A second patent in this family is: US 8580546 ‘Micro-Organ Device’ (Exp. Date March 28, 2028). What is claimed is: 1. A micro-organ device, comprising: at least one micro-chamber for housing a micro-organ; and at least one microfluidic channel connected to the micro-chamber, wherein the micro-organ comprises cells arranged in a configuration that includes microscale spacing between portions of the cells to facilitate diffusion exchange between the cells and a medium supplied from the at least one microfluidic channel, wherein the micro-organ device is prepared by process comprising: providing a microscale support comprising the at least one microfluidic channel and the at least one micro-chamber for housing a micro-organ; bonding the microscale support to a substrate by covering the contact surfaces of each with titanium tetra (isopropoxide); and printing the micro-organ on the microscale support using a cell suspension in a syringe controlled by a computer-aided tissue engineering system, wherein the cell suspension comprises the cells suspended in a solution containing a material that functions as a three-dimensional scaffold, and wherein the printing is performed with the computer-aided tissue engineering system according to a particular pattern. This patent appears to cover a microorgan device comprising a micro-chamber, a microfluidic chamber, and a microscale support in which a micro-organ is printed onto a microscale support using cell suspension in a syringe controlled by a computer-aided tissue engineering system. It is noted that the claim requires that the microscale support is bonded to a substrate using titanium tetra (isopropoxide) — therefore, it may be possible to avoid infringement of this claim by using another binding agent. 30

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Organs-on-a-chip can be used for multiple research purposes, including drug discovery and development, and may find protection under a number of areas of intellectual property.

US 8481303 ‘Microfluidic Device for Cell Culture’ (Exp. Date: July 10, 2031) Assignee: Corning Incorporated. This patent was also filed in China, European Patent Office, and Japan. What is claimed is: 1. A cell culture apparatus comprising: a cell retention chamber having a first structured surface, wherein the structured surface includes a major surface from which a plurality of projections extend into the chamber, wherein the plurality of projections are arranged to suspend cells cultured in the chamber above the major surface; and a first perfusion channel (i) configured to carry a cell culture medium and (ii) forming a plurality of openings in communication with the cell retention chamber, the openings configured to prevent cells from the retention chamber from entering the perfusion channel. This patent appears to cover a cell culture apparatus comprising a cell retention chamber having a first structured surface and a first perfusion channel — a channel through which a cell culture medium may flow — with openings to prevent cells from the retention chamber from entering the perfusion channel. According to the patent specification, the microfluidic devices of the invention may mimic the architecture, perfusion, and flow of tissue in vivo, allowing for cultured cells to adopt in vivo-like morphology and functionality. Thus, this patent appears to cover

microfluidic devices comprising a plurality of cells suspended above a surface in the United States through its expiration date in 2031. US 8647861 ‘Organ Mimic Device with Microchannels and Methods of Use and Manufacturing Thereof’ (Exp. Date: July 16, 2029) Assignee: Children's Medical Center Corporation. This patent was filed in United States, Australia, Canada, China, European Patent Office, Japan, and Korea. What is claimed is: 1. An organomimetic device comprising: a body having a central microchannel therein; and an at least partially porous membrane positioned within the central microchannel and along a plane, the membrane configured to separate the central microchannel to form a first central microchannel and a second central microchannel, wherein a first fluid is applied through the first central microchannel and a second fluid is applied through the second central microchannel, the membrane coated with at least one attachment molecule that supports adhesion of a plurality of living cells wherein the porous membrane is at least partially flexible, the device further comprising: a first operating channel separated the first and second central microchannels by a first microchannel wall, wherein the membrane is fixed to the first chamber microchannel wall; and wherein applying a pressure to the first operating channel causes the membrane to flex in a first desired direction to expand or contract along the plane within the first and second central microchannels. This patent appears to cover a microfluidic device comprising a central microchannel and a partially porous membrane positioned to separate the central microchannel into a first and second microchannel in which the porous membrane supports living cells adhered to it. A very important feature of the claimed organomimetic device is that is provides for expanding or contracting the living cells along a plane thereby providing mechanical forcing regimens similar to those found in vivo. Such mechanical

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environments. The specification discloses that the microfluidic device is used for conducting pharmacokinetic and/or pharmacodynamics analysis of the effect of an agent (e.g., drug, chemical composition, toxin) on cultured cells. There is room for additional patentable innovations

While it may seem that it is too late to start filing patent applications on organson-a-chip research tools, there remains room for further patentable improvements. As stated in an article by Michael Schuler at Cornell University, ‘an in vitro system will probably never be able to capture the complexity of the human body in its entirety.’ Innovation is needed to develop new techniques for patterning cells in a three-dimensional manner, for developing new materials to mimic organs in the human body, and for developing new methods to simulate the environment in the body. For example, researchers at the Wyss Institute at Harvard University have built human lung-on-a-chip and human gut-on-a-chip devices and are currently working to build ten different human organs-on-a-chip and link them together on an automated system to mimic the physiology of the whole body. Existing patent filings may require a license to commercialisation of Organs-on-a-chip research tools

While many patents are being granted worldwide claiming organs-on-

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forcing regimens reportedly improve tissue- and organ-specific functions of cells.1 Thus, this patent appears to cover microfluidic devices with multiple channels containing flexing living cells in the United States through its expiration in 2029. Additional patent applications were filed, three of which are currently pending, which claim priority to this application. US 8748180 ‘Microfluidic Device for Pharmacokinetic-Pharmacodynamic Study of Drugs and Uses’ (Exp. date: July 29, 2030) Assignee: Cornell Research Foundation, Inc. This application was only filed in the United States. What is claimed is: 1. A microfluidic device for culturing cells and/or tissue comprising: a base layer; a cell culture chamber layer comprising one or more cell culture chambers; a fluidic channel layer comprising a plurality of fluid channels; a bottom frame; a gasket; and a top frame, wherein: the cell culture chamber layer is positioned between the fluidic channel layer and the base layer so that the one or more cell culture chambers are fluidically connected to one or more fluid channels of the plurality, the fluid channels have defined geometries that produce one or more desired flow rates through the fluid channels that simulate one or more physiological environments or conditions of interest, the bottom frame has an inlet hole and an outlet hole, the base layer has an inlet hole and an outlet hole, and the cell culture chamber layer has an inlet hole and an outlet hole, and wherein the inlet holes of the bottom frame, the base layer and the cell culture chamber layer and the outlet holes of the bottom frame, the base layer and the cell culture chamber layer align with one another, thereby allowing circulation of fluid through the cell culture chamber layer and the fluidic channel layer. This patent appears to cover a microfluidic device contain one or more cell culture chamber layers and a fluidic channel layer in which the fluid channels simulate one or more physiological

a-chip, some countries have an exception to patent infringement under what is called the experimental use exception. Under this exception, if one just tests a patented invention without commercial purposes, there is no infringement of the patent. However, if one makes and sells a patented organs-on-a-chip as a research tool, they may be held liable for patent infringement. The United States has a very narrow experimental use exception to patent infringement which focuses on whether the use is solely for amusement, to satisfy idle curiosity, or for strictly philosophical inquiry. In a 2002 decision, a court held that Duke University's use of a patented invention for research purposes was not exempt from infringement because the use involved objectives that were commercial in nature. The United States does have an exception to patent infringement so long as the patented invention is used solely for the purpose of generating data for submission to the U.S. FDA. However, this exception does not extend to the use of a patented research tool to test a drug and submission of the resulting data to the FDA. In conclusion, the use of organson-a-chip to model organ responses to drugs has a very bright future. And, the patenting activity will continue. References are available at www.pharmafocusasia.com

Robert W Esmond is a Director in the Biotechnology/Chemical Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., Washington, DC, USA. His intellectual property law experience has principally been in the biotechnology and chemical areas. His legal experience includes counseling clients in various intellectual property matters such as patentability investigations, validity and infringement analyses, freedom to operate and FDA/ANDA practice. Stephanie L Elmer is an Associate in the Biotechnology/Chemical

Group of Sterne, Kessler, Goldstein & Fox P.L.L.C., Washington, DC, USA. Her intellectually property law experience has been concentrated in the biochemical and chemical arts. Her legal experience includes preparation and prosecution of US and foreign patent applications and providing support in various intellectual property areas such as validity and infringement analyses and patentability opinions.

www.pharmafocusasia.com

So you’ve received a warning letter... what do you do now?

Let our experience and track record work for you! It’s important to get a clear understanding of the message that the regulatory authority (FDA) is trying to send to your company. It’s not just about the words, it’s more about what the observations listed are trying to convey. More often than not, the observations are illustrative of wider compliance concerns, so you need to look past just answering/addressing observational deficiencies. This is a trap that many fall into and it’s often a big mistake! It’s important that you look at this in terms of total quality management of the manufacturing operations and assess what the relative risks of the individual operations are for product quality and product safety. Patient safety is of paramount importance to regulatory agencies, so process and product quality will be high on their list of agency responsibilities when inspecting manufacturing and testing facilities. In addressing these severe regulatory compliance situations, it’s important to clearly understand the intent of the regulatory agency and to focus the scope of any remediation 32

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response to rectify those deficiencies to produce a sustainable compliance condition. Having a plan and appropriate methodology are required to do this effectively and efficiently together with an experienced team to manage and execute the process.

Experience and track record! In Smart Consulting Group you have an experienced team with a proven track record that can help you navigate the regulatory compliance process.

How do we structure things?

 Access to a diverse quality and technical team that has complimentary skill sets.  A team that has an outstanding reputation with the FDA.  Programs that are tightly project managed to assure the best use of resources and life-cycle management.  Internal quality assessment capability to assure the needs of the client are being met.  Robust Quality System driven approaches that encompass quality by design and risk management across every facet and phase to deliver sustainability.  A ruthless appetite for assuring Lean Compliance so that resources are appropriately used when needed.  Flexible approaches that cater to evolving needs.  A receptive responsive partner to customer needs and requests.

One of the first things we do is to assess all the areas involved to see whether they meet the appropriate standards. We do this by developing a gap analysis profile for the situation and supplement this with a SWOT analysis to fully understand the scope of what’s involved. This will act as a Current State profile for the remediation situation. We will then set up a core team to develop key quality attributes and apply these against the gaps for individual Quality System deficiencies. By ranking these as critical, major, and minor we can develop the working project timeline for the remediation activities and extend appropriate resources to execute each task. Each task will be identified by the resource who would in turn complete it. This new Work Plan will provide a snapshot of what the future remediated state will look like; it is important to challenge that prior to the commencement of the plan. Using a SIPOC analysis is often a helpful tool for this process. Once completed, the Work Plan will itemize each task/issue by quality system element with a timeline for completion and the resources needed to close out and neutralize the situation. Upon completion, each task will have a closeout checklist which Quality Assurance can refer to during follow-up system maintenance audits.

Why is a consultant helpful in this process?

When your own company's credibility with the FDA has been damaged due to a Warning Letter or other serious compliance situation, it is difficult to effectively negotiate reasonable solutions and terms for delivering those solutions. That is when you need the help of a third party consultant that you can lean on that will help advocate reasonable points on your behalf. With the appropriate skill sets, resources and credibility, it is often easier for a third party to advocate the solution. The client company can leverage that situation to its best advantage with the regulatory agency.

What makes Smart Consulting Group a suitable resource to help you with this process?

Specifically, what does Smart Consulting Group bring?

What happens when the project ends? Analyzing the situation and deploying a solution to fix a Warning Letter is only part of the real answer. The best approach is to provide ongoing monitoring capability to assure that the situation remains on track once a remediation program has been instituted. Smart Consulting Group provides a periodic assessment check to support and supplement the new ongoing QA oversight that any Smart Consulting Group program puts in place as part of the Warning Letter remediation Work Plan. In brief, we serve as a safety net through an ongoing pre-agreed plan to assure that standards and commitments are being maintained and continuously improved.

SMART CONSULTING GROUP 20 East Market Street, West Chester, PA 19382 office@smartconsultinggroup.com www.smartconsultinggroup.com Call us at 610-344-9218 Toll Free at 1-844-593-LEAN Advertorial www.pharmafocusasia.com

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Prospects for Personalised Medicines in the Asia-Pacific Region Personalised Medicine (PM), also called precision medicine, targets the therapeutic component of the treatment regime based on the diagnostic test characteristics, typically including genetic profiling, of the individual patient rather than population-based norms. The personalised medicine approach is changing the way medicine is practiced, especially for cancer (late-breaking sales figures indicate half of oncology drug sales last year were targeted medicines), and other therapeutic areas, such as infectious disease, will follow suit but more slowly. Nonetheless, use of personalised medicines is indeed growing, and globalizing. How fast this will happen in the emerging markets (EMS) of the Asia-Pacific region depends on a number of factors presented in the article. Christopher Milne, Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

ersonalised Medicine (PM) is the wave of the future, but will the waves be bathing the shores of Asia-Pacific with the same market force as they do on either side of the Atlantic? Personalised medicine, also called precision medicine, encompasses treatment approaches that target the medicines used based on the characteristics of the individual patient rather than

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population-based norms. Those individual characteristics, in turn, are based on diagnostic tests, which would typically assess the genetic profile of the patient to determine the appropriateness of available treatments. In the most targeted approach, companion diagnostics are actually co-developed with the drug and the labelling reflects that the drugdiagnostic combination comprises the

recommended or required regime. In another approach, complementary diagnostic tests can be used more broadly to assist the Healthcare Practitioner (HCP) in identifying the right medicine, monitor treatment status, determine likelihood of side effects etc. The advent of the age of personalised medicines heralds some very positive changes in the way medicine is practiced, but it is in its infancy, as the

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first personalised medicine, Herceptin, hit the market at the end of the 1990s and the availability of such medicines has only recently become more of a reality than a novelty. Use of Personalised medicines is indeed growing, as IMS reports that 46% of global oncology sales were targeted therapies in 2014. PMs, both old and new, are not only transforming the landscape of the major markets of Western Europe, Japan and the US, but are making inroads into global markets as well. How fast will PMs grow and how fast will they spread to the Asia-Pacific markets depends, on a number of factors. The Asia-Pacific (APAC) market – size, strength and access

Although some consider the APAC market to be overestimated in terms of likely sales by as much as US$50 billion—especially in view of the recent downgrade of GDP predictions for the region by the World Bank and the IMF—others feel that the current slowdown in the blooming of the EMs in the region are the lingering effects in the global aftermath of the US recession. Indeed if the biopharmaceutical market sales for 2009 to 2014 come in as expected for Southeast Asia (including China and India) at about US$150 billion, it will represent a 16 per cent CAGR and the share of the global biopharma market will have jumped from 9 per cent to 16 per cent in just a five-year period. Certainly, the demographics and GDP performance of India and China are positive indicators of the size and strength of those markets. Over 50 per cent of the world’s population which is above 65 in age lives in Asia-Pacific but their contribution to the age pyramid varies with China, South Korea and Thailand at just over 7 per cent, but Japan at 23 per cent (nevertheless, even at its current rate of ageing, by 2020 China will account for 46 per cent of the elderly worldwide). GDP growth is even more dramatic, 10 per cent of Chinese households possess 40 per cent of the wealth and for India 50 per cent

Use of personalised medicines is indeed growing, but it is still a small share of the total market, even in the major, or so-called, mature markets of Europe, Japan, and the US.

of the wealth (see Figure 2). Together then, India and China, would have a wealthy adult population equal to that of the United States or Europe. With an ageing population, cancer absorbs a much greater proportion of the health dollar, and with increased spending power, wealthy Asians will be looking for the best treatment that money can buy. Meanwhile, consultant surveys point to a number of market access problems in the emerging markets. For example, lack of reimbursement and public funding, lack of healthcare infrastructure, lack of affordability, price pressure, all scored 3.8 or higher (scale: most relevant = 5 vs. least relevant = 1), while regulatory and market access restrictions and reference pricing were considered major or moderate threats by half to 2/3 respondents in another expert survey. In India, for example, 78 per cent of total expenditure on healthcare is out-ofpocket (OOP). Also in India, patented drugs are available at 27 per cent of the prices in China, Mexico and South Africa and account for only 0.9 per cent of the Indian drug market by dollar totals. In China, McKinsey reports that hospital costs outweigh revenue, which they have buffered by over-prescribing drugs, but the government is seeking to reform the payment system and cost structures to decrease this reliance. Distribution is another challenge to access: the number and complexity of ‘middlemen’ (e.g., China –currently

9,000 distributors being deconstructed under five year plan), or challenging geography (e.g., islands of Indonesia). One option for tackling with this challenge is to deal with regional buying consortia (e.g., such as ones that exist among the small island counties of the Caribbean). Another option is…city not country market. The UN climate change panel predicts that the growth rate of the world's urban areas will equal two Manhattans a day until 2030. China has 50 cities with over a million people. Or go even smaller—focus marketing efforts on a few specialty centres within cities or countries. This may be a viable strategy for dealing with China’s immensity and complexity, where hospitals are the dominant distribution channel(s), but according to Decision Resources, only 6 per cent are considered to be tier 3 at which hi-priced biologics are most likely to be administered as of 2010. Therapeutic area factors

Study of economic analyses of genetic tests in personalised medicines indicates that the most common therapeutic areas among the cost utility analyses were cancer at 39 per cent and infectious diseases at 15 per cent. In terms of market entry points for personalised medicines, these are the most likely therapeutic areas. Cancer drugs can be viewed as part of the problem, or part of the solution, by third party payers. Worldwide sales of branded prescription cancer drugs by the top 40 pharmaceutical companies globally amounted to US$61.6 billion in 2012, but that is only 5.6 per cent of the total cost of cancer to society, as estimated by IARC in the WHO World Cancer Report 2014. Although globally, tumour profiling was worth US$13.3 billion in 2012, with a CAGR of 18.5 per cent that will grow the market to US$35 billion by 2018, providing market entry for Molecular Diagnostics (MDx) in general, its use in infectious diseases is what really drives the market for linking molecular testing to precision treatment. Personalised medicines for infectious diseases may www.pharmafocusasia.com

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play the role of a loss leader in precision medicine. Health Care Systems (HCS) in the APAC increasingly realise that they can no longer treat infections indiscriminately with antibiotics at hand. In other words, they will have to ‘identify to prioritise.’ Gastro-intestinal infections, for example, have high heterogeneity of results, and variation in pathogens tested; respiratory bugs, death rates for pneumococcus in children <5 vary sharply by source. As with RSV and Hib; often no pathogen is identified in a substantial fraction of cases. In more forward-looking regions, such as China, many hospitals employ MDx test for HBV, STDs, HPV, TB and HIV as these are reimbursable and many are profitable with EBIT profit margins of 50 per cent. Drugs and labs are the most important profit centres for the hospital-based healthcare system. China’s MDx market is expanding due to PCR testing for infectious diseases, but the Multinational Corporation’s (MNC) piece of the pie is mostly selling instruments; however, Qiagen was the exception with purchase of local companies to get a share of the domestic HPV market and PCR kits. Oncology provides opportunity for MNCs to enter the molecular reagent market since local competition is low. FISH-based breast and bladder

testing and HPV molecular screening for cervical cancer are the main entry points; there are 300 million women of screening age for HPV. Oncology testing based on next generation sequencing, CTC, Lab-on-a-Chip etc. represent the next major market opportunity in MDx space. Can MNCs and domestic producers co-exist in the APAC?

How do patients in the emerging markets feel about MNC brands in general? In the Credit Suisse 4th annual survey of emerging market(s) (EM) consumers, 60 per cent said they were not willing to pay any premium for international brands; about 30 per cent would consider a 0-10 per cent premium; and, about 10 per cent would consider a >10 per cent premium. On a more specific country level, another survey found that where trust in local brands was high, as in Indonesia, there was less willingnessto-pay (WTP) for foreign MNC brands, compared to countries where trust (in local brands) was lower, as in China, WTP was higher. The biggest mistakes by big pharma in the EMs are insufficient tailoring of approaches to local needs; lack of patience, and a long-term strategy. However, some MNCs such as Sanofi have been judged, even by their peers,

Demographics tell the story of the future! Median age & percentage of Pop.>60: 2000 vs. 2050 (Source: UN Population Database)

2000

2050

2000

2050

INDIA

22.6 yrs

38.4 yrs

6.7%

19.6%

CHINA

29.6 yrs

45.2 yrs

10%

31%

GDP per Capita (PPP), 2000-2013 (Source: IMF, World Economic Outlook 2008)

2000

2010

2013

INDIA

1452

2317

3218

4118

CHINA

2372

4064

7206

9709

Figure1

2005

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to be models of success in the EMs. How did Sanofi do it? By having a big presence. In China, for example, Sanofi has 11 regional offices, 7,000 employees (4,000 in sales), six manufacturing sites, and a regional R&D platform. In fact, using local partners, licensing, acquisitions, expansion of known brand to build loyalty, and local presence are often prerequisites for any MNC to be successful in the EMs, especially China, India, South Korea, and Taiwan. Working with local MDs is advisable for learning about regional clinical practices, especially in case of cancer types less prevalent in the US (e.g., GI stromal tumours), and dosing levels (e.g., genetic differences with 30 per cent of Asians having P4502C19 gene variation that limits the ability to metabolite up to 15 per cent of all clinically useful drugs, compared to 6 per cent of Caucasians with this variation). Other tactics used in China as market entry points are local acquisitions, or working with local partners as Roche which is working on basic biomarker research in China-specific cancers like nasopharyngeal cancer. Another tactic is to provide equitable access to critical drugs through tier pricing, especially in next wave EMs, e.g., Indonesia and the Philippines; where there are instances of big pharma lowering prices dramatically, e.g. Sanofi for Taxotere by as much as half. Other lessons learned provide a checklist of do’s and don’ts:

• Don’t ‘assume the gloom’ of a compulsory license is unavoidable in the face of a public health emergency. China is not a big fan of compulsory licenses so far; for example, they even denied one against Roche’s Tamiflu in the SARS crisis (contrary to the threats made by the US against Cipro’s manufacturer in the anthrax scare) • Don’t assume that just because a country follows the NICE model, as do 25 per cent of countries comprising the world market, that there’s no room left to negotiate. Instead look at NICE’s recent approach to orphans as paving the way

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for specialty focus/high-priced personalised medicines, with its new Highly Specialised Technologies (HST) process, for high-cost orphan drugs (e.g., Soliris for a HUS) which require information on the drug’s R&D costs. Some believe it is meant to coerce patient access schemes (aka risk-sharing, or pay-for-performance deals), as it did for 43 per cent of the 44 drugs recommended by NHS since 2012, half negotiated after initial evaluation was negative? • Don’t assume that cost-effectiveness will always triumph over cost considerations. Vaccine market access and Pap tests used routinely in ‘rich’ countries make cervical cancer deaths rare, but 275,000 die in poor countries every year. Advanced medicines that keep people out of hospitals may not be that valued when hospital charges comprise a smaller relative portion of the total healthcare spend • Do think about how the argument can be made in a particular market for Region 1: Mini-mites

technology-skipping i.e. chemotherapy becoming obsolete except as salvage therapy or when targeted therapy not available; chemotherapy drug shortages, continued disincentives to remedy i.e. thin margins and reluctance to open up NDAs to upgrade GMP; doctors say new hep C drugs make useless ‘older generation of products’ with serious side effects • Do take into account the increasing impacts of medical tourism. According to ‘Patients Without Borders’, about 8m patients are medical tourists, a US$25-40 billion growth business actively promoted among 87 countries; reasons for travel – cost, better treatment, long waiting lists , privacy, etc. About the same number of patients travelled to the US (600,000800,000 foreign patients to places like Johns Hopkins, Cleveland Clinic, the Mayo Clinic) as traveled from the US seeking healthcare abroad in 2013, some 750,000-900,000, according to CDC.

Recent performance of PMs in the major markets

In terms of what’s currently trending in the PM market, cancer drugs dominate. Six out of the top 10 best-selling cancer drugs worldwide in 2013 were PMs: Rituxan (US$8 billion, NHL, CLL); Herceptin (US$6.56 billion, breast, esophagus and stomach cancers); Gleevec (US$4.7 billion, leukemia, GI cancer); Alimta (US$2.7 billion, lung cancer); Erbitux (US$1.9 billion, colon, head & neck cancers); and, Revlimid (US$1 billion, multiple myeloma, mantle cell lymphoma). Owing to the obvious success, examining the experience of these market leading drugs is instructive for the prospects of the field as a whole. Biosimilars are changing the life cycle prospects for personalised medicines. For example, Rituxan has been a target for biosimilar competition but would-be competitors have found it a tough go technically, and South Korea’s Celltrion, for example, abandoned its attempts

Region 2: Up-and-comers

GDP per capita (USD)

Population

GDP per capita (USD)

Brunei

407,000

36,700

Thailand

67,764,000

3,900

Singapore

4,987,600

35,500

Malaysia

28,318,000

7,525

Hong Kong

7,055,071

30,000

Myanmar

50,496,000

500

Brunei: Hub for Halal pharmaceutical exports and guidelines for pharmaceuticals. Entire Halal market worth US$1-2 trillion, herbal/ traditional medicines comprise 25 per cent; Singapore’s Gleneagles Hospital has subsidiary in Brunei providing advanced cancer therapies. Singapore: Low corporate taxes, strong IPR, >30 leading biomedical companies using it as beachhead in Asia-Pacific; strong scientific foundation with 7 research institutes and 5 research consortia, i.e., Translational Medicine hub; Gleneagles Hospital is one of world’s top 10 medical tourism destinations for cardiology, transplants, and oncology. Hong Kong: Free market economy highly dependent on international trade, value of the goods and services trade, including sizable share of re-exports, is four times GDP (i.e., just under two-thirds of Hong Kong’s annual drug imports are re-exported); medical tourism site for mainland China.

Population

Thailand: Free-enterprise economy, generally pro-investment, but compulsory licensing, weak IPR, counterfeiting; semi-reimbursed HCS; public health prevention (e.g., cervical cancer vaccines for girls under 15); use of herbal meds; 1.2 million medical tourists / yr.; Bumrungrad International seeing foreign patients for 20 years with over 900 physicians across 55 specialties and sees around 1,000 international patients every day Malaysia: Seeking international sponsors; MOH established six Entry Point Projects: health tourism, insurance services, clinical trials, generics manufacturing, diagnostics services, and the creation of health metropolises; ethnic diversity for patient recruitment (50 per cent Malay, 25 per cent Chinese, 10 per cent Indian, 15 per cent other); medical tourism of 670,000 / yr (English fluency and cost savings comparable to India); semi-reimbursed HCS. Myanmar (Burma): Solid economic growth, political reforms, but basic infrastructure problems & political tensions; market features antiinfectives, urban consumers, Indian generics and traditional medicines.

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strategy

late-stage. Herceptin, the pioneer of PMs, has had a good 15-year run, and remains Roche’s third best-selling drug, attesting to the potential for remaining profitable in a highly competitive field due to first-mover momentum, brand loyalty, scientific complexity, as well as high thresholds for regulatory approval and reimbursement. Nonetheless, in the APAC market, competition is knocking on the door. Mylan and Indian partner Biocon have launched their own versions in India, and South Korea’s Celltrion has a biosimilar that competes in Korea, while Hospira has an aggressive biosimilar programme under way, no doubt looking to compete globally. Fighting off competition as the patent cliff looms is another Herceptin experience in the APAC. In China, Herceptin sold at a 75 per cent discounted rate due to a cost-sharing deal between Jiangsu provincial government and Roche (who donated 8 vials of Herceptin if they bought 6) to avoid competition from copycats, a Region 3: Next wave

Population

deal believed partly responsible for a four-fold increase of Herceptin patients who say they would rather pay a year’s income than suffer nausea/vomiting from chemotherapy. Roche was also pursuing an insurance approach with re-insurer Swiss Re, by offering private insurance for cancer, which garnered 20 million customers by the end of 2013, a 66 per cent increase over what was expected. In India, a vial of Herceptin costs more than 15 times the average per capita monthly income, but Roche sold it off-brand in partnership with a domestic firm in 2012 at one-quarter the price, and discounted it down to a biosimilar price of about US$600, but patient groups want the government to make available at US$100 per vial. Wrangling in court over IP rights is another feature of the PM market in the APAC. Gleevec was the subject of a years-long court battle by Novartis to gain Indian patent protection for the drug, which they finally lost at the India GDP per capita (USD)

Population

GDP per capita (USD)

Philippines

91,983,000

1,700

Taiwan

23,318,000

16,400

Indonesia

237,556,363

2,200

Japan

127,470,000

39,700

Vietnam

88,069,000

1,100

South Korea

50,062,000

20,000

Philippines: Remittances of 5m from overseas Filipinos & business process outsourcing; bribery as ‘cost of doing business’; reliance on imported medicines; OOP market but doubling to US$8.29 billion by 2019; drivers are expansion of healthcare services and modernisation, but increasing emphasis on generics. Indonesia: Vast polyglot nation, reliance on domestic consumption; young population and corruption drag on government funding; established manufacturing base, relatively high prices for drugs paid for mostly OOP with few controls, regulatory system favours local manufacturers; MDs expect incentives, increasing interest in cost-containment and health promotion; demand for traditional medicines, especially ‘fitofar,’ has 1,000 plants already used for medicines; domestic generics is 75 per cent of market; MNCs entry via stepped coverage / CER; 4th pharma mkt. in ASEAN. Vietnam: Key economic drivers of young, growing labour force and switch from agricultural to manufacturing/services economy; growth rate will be 0.6 per cent this decade compared to 2.8 per cent in 2000-10; shortage of hospital beds; rising drug consumption and government investment but small pharmaceutical market (US$1.82 billion), projected increase 70 per cent.

Region 4: Tried-and-true

Supreme Court level. Subsequently, Indian drugmaker Sun Pharma continued the struggle in US courts, seeking to launch a copycat version (a suit Novartis has since settled, keeping Sun's generic off the market until February 2016). Despite these efforts and close to US$3 billion in sales in 2013, Gleevec is now facing generic versions in Japan, China, and India. Alimta’s sponsor is also fending off patent challenges, but on its method patents (adding B vitamins to the regime) in the UK and Germany, a problem that is likely to follow suit in the APAC markets. In the meantime, Erbitux has sought an alternative to the usual strategy of extending patent life by expanding indications, by instead narrowing theirs. In 2009, the FDA allowed the sponsor to narrow Erbitux’s indication for advanced colon cancer, changing the label to recommend the drug for treatment of EGFR-expressing tumours only in patients without a mutation in the KRAS gene.

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Taiwan: Exports generate about 70 per cent of Taiwan's GDP growth, exposing economy to upturns and downturns in world demand; local pharma sell products to the local market mostly; government (NHI) is only buyer in fully reimbursed system but pricing conditions are flexible, foreign drug companies get 75 per cent of total payments but provide 30 percent of the drugs; generic prices relatively high; growth depends on mainland and medical tourism. Japan: Japan might be one of the world’s best markets right now for foreign drug companies, experiencing what PhRMA calls ‘emerging market’ growth rates, with sales rises in 2011 for the top 8 MNCs in Japan ranging from 12 per cent to 31per cent; in 2012, whereas FDA and EMA had approved 17 and 13 drugs with biomarker labelling required, Japan had 12; Japan is the 2nd largest pharma market (or close third to China). South Korea: Ramping up medical tourism, targeting 300,000 medical tourists by 2015; 250 life science companies; biotech & stem cell hub; spends 22.5 per cent of health budget on drugs (compared to 17 per cent across OECD), wants to cut price of~9k reimbursed drugs; government runs rigid reimbursed system, but uptake is fast; number of cancer sufferers in the country almost doubled to over 218,000 patients between 2001 and 2011.

strategy

Kaleidoscope of regional considerations

The APAC region sub-markets have certain commonalities suitable for a discussion of their overall prospects as PM boom or bust areas. The mighty mites of Singapore, Brunei, and Hong Kong are comparatively small in volume but rich in medical tourism, well-heeled patients, as well as cognisance and WTP

Region 5: Big Kahunas

Population

GDP per capita (USD)

China

1.36 Billion

3583

India

1.25 Billion

1165

China: MNCs taking advantage of opening of market to targeted drugs with Roche approval of KRAS mutation test, especially for cancer with China having 3.5mm newly diagnosed cancers per year; but Personalised Healthcare (PHC) still in infancy, with some provinces like Shanghai not covering any targeted drugs, while Guangzhou covers several; awareness of PHC is low both among public and HCPs except for those in big cities (Wang Fanqqing, Scrip, 19 Dec 2014). India: Datamonitor predicts that India’s cancer market, now valued at US$271 million will grow 16% annually to US$559 million in 2014 driven by increased demand for latest tumor-fighting therapy (India gets 250,000 patients with cancer treatment among top 5 reasons); drugs largely paid for OOP; Indian government panel is looking at 20 drugs as targets for an initial pulse of 3 compulsory licenses (including drugs for cancer, HIV, diabetes, and arthritis); May 2013 new proposition for price controls of 348 drugs (30 per cent of local pharma sales); India has 100 FDA-approved manufacturing sites (2nd only to US), produces over 20 per cent of worldwide generics; contract manufacturing worth estimated US$916 million in 2010.

for the best in personalised healthcare. The up-and-comers consisting of Thailand, Malaysia, and Myanmar are certainly a mixed bag of prospects with rising populations on the one hand but political tensions on the other. Malaysia and Thailand are forward-looking in terms of healthcare and medical tourism, but Myanmar is the laggard in the group in that regard. The next wave countries of Philippines, Indonesia, and Vietnam encompass 400 million people, and are considered rising economic powers, but currently have low per capita incomes. Philippines patients of a certain SES status are aware of and will avail themselves of the latest advances in medical technology, while Indonesia typically points to its regional neighbours for those seeking the next level of cancer care, and Vietnam is currently struggling with its transitional economy to be able to provide more than the basic health care. The mature markets of Japan, Taiwan, and South Korea are exactly similar to the mature markets in Europe and North America, following the trends in the PMs. The Big Kahunas, China and India, of the emerging markets with 2.5 billion people and upper class patient numbers equal to those in either Europe or the US while pharma market growth numbers are usually 2-3 times that of the mature markets making them attractive prospects for the future, but each will require considerable commitment and creativity to achieve sustainable PM markets and retain enough market control to justify the resources invested. Conclusion

PM markets are evolving markets, so sticking to basics is important (i.e. customer education), but so is adaptability and experimentation. The way into the PM market space in a particular country or region may be different than the way up to market sustainability. Setting up shop in resourceintensive emerging regions or countries should be viewed as part of diversification strategy, not moving away from mature markets, or passing over smaller but less heralded next wave markets. Value determination is local, but certain principles are universal. Social media and other communication technologies will be as much a force for generating worldwide markets for new technologies as was shipping by air in the early era of globalisation; one creates demand, the other supply! References are available at www.pharmafocusasia.com

A u t h o r BIO

On another front, Revlimid ran afoul of cost-effectiveness scrutiny by NICE in the UK, which last year turned down the drug for patients with myelodys plastic syndromes on the grounds that results didn't justify the cost for patients with the bone marrow disorder, and got more of the same treatment from NICE regarding use of the drug for patients whose multiple myeloma relapsed after treatment with Velcade. This bodes ill for its prospects in the APAC market, since some follow NICE’s lead. Meanwhile, Velcade’s encounter with NICE is going in the opposite direction. Just a few months ago, NICE approved it as a first-line treatment for multiple myeloma in a reversal of its earlier decision forcing the sponsor to negotiate a money-back guarantee in a patient access scheme for patients who did not respond to the drug when the sponsor was negotiating its initial approval as a treatment in progressive cases. In another stroke of good fortune, it was discovered that the drug could be used not only effectively, but more safely by the subcutaneous route, a method for which it received further approval by the FDA. Nonetheless, like many of the frontier wave of PMs, Velcade’s patent expires within the next two years almost everywhere, including the APAC.

Christopher Milne has been with the Center since 1998, where his research concentration involves both personalised medicine and the emerging markets, as well as market access and regulatory initiatives in general. He holds an MPH from Johns Hopkins in Public Health as well as degrees in veterinary medicine and law.

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CoverStory

strategy

Sustainable Antibiotics Evolving pharmaceutical supply chain to ensure effectiveness Principles of product stewardship have to be applied to make sure that from production through to use and disposal, along the entire supply and value chain, antibiotics are not just delivering positive direct benefits to patients but deliver positive benefits to society overall. Karl Rotthier, President, DSM Sinochem Pharmaceuticals, Belgium

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ackling the challenge of supply chain security in the face of antibiotic resistance.

Antibiotic resistance

Antimicrobial Resistance (AMR), also called antibiotic resistance is a reality. AMR renders antibiotics ineffective, meaning they can no longer fight bacterial infections and ultimately become useless.

strategy

Every year, AMR is responsible for nearly 50,000 deaths in the US and EU alone. In India, annually nearly 60,000 babies die from sepsis caused by bacteria resistant to antibiotics. In 2012, there were about 450,000 new cases of Multidrug-Resistant Tuberculosis (MDR-TB) worldwide –just one disease that had been long considered easily treatable with modern medicines. Actual numbers are likely to be higher but only patchy data exists for many parts of the world. It is estimated that at the current pace and if no effective steps are taken, the annual death toll related to AMR will top 10 million people by 2050. The direct economic burden of AMR runs in the tens of billions of Dollars each year, not considering indirect costs such as productivity losses. Classified as one of the top threats to humanity by the World Health Organisation (WHO), antibiotic resistance is well known and is on the political agenda. In 2014, UK Prime Minister David Cameron held an inquiry into the issue; the Dutch government held a conference on antibiotic resistance in June 2014, inviting ministers and senior government officials from more than 20 countries to the debate, while in the United States, President Obama produced a report on combating AMR. While AMR is part of the political debate, currently, the major focus of public efforts aims at the right prescription and use of antibiotics by doctors, pharmacists and patients. This is important! But there is another important element that must be addressed in the context of AMR: the manufacturing of antibiotic Active Pharmaceutical Ingredients (API) itself, as well as the management of waste and waste water which is an inevitable part, throughout the entire supply chain.

A sustainable and reliable supply chain is in the self-interest of responsible pharmaceutical producers that have spent years in building a valuable and respected brand.

• As recent as December 2014, an investigative report by CCTV, China’s state television, featured a segment on antibiotics found in the municipal water supply of Chinese cities. The report uncovered that antibiotics producers have been illegally discharging waste water containing high concentrations of antibiotics, making it unsafe to drink. Such reports are concerning and it seems that the pharma industry is adding to the growing problem of AMR, while it should be a part of the solution and participate in the public debate. The industry’s role

Irresponsible behaviour

We work in an industry that, at its core, is not just socially beneficial but fundamental and essential to mankind. Antibiotics save millions of lives every year and enable a range of essential medical procedures to be conducted safely. However, irresponsible behaviour of producers using outdated technologies to manufacture the APIs in combination with poorly managed waste streams, is leading to unnecessary and harmful disposal of antibiotic residues into the environment, contributing to AMR. Thousands of tons of antibiotics are produced every year, both by compliant as well as non-compliant manufacturers. There are outstanding examples of compliant producers, but there are also numerous examples of factories that use insufficient waste management and treatment systems, and even dumping untreated waste water and antibiotics into the environment. • Already in 2009, Joakim Larsson of the University of Göteborg and his team found rivers near Hyderabad - one of India’s pharmaceutical centres - to have concentrations of certain antibiotics higher than that in the blood of a patient undergoing treatment

While we will also need to develop new antibiotics in the future, we cannot solely focus on this approach as a solution. New drugs take time for development, testing and approval before they are available to patients and bacteria keep on evolving. As industry players, we have a responsibility as well. The industry should first and foremost address and improve its product stewardship including its environmental performance throughout the entire production and supply chain. We cannot allow the illegal discharge of waste containing active antibiotics and other non-compliant practices, which contribute to AMR. Today most API for antibiotics are manufactured in China and India. While, there are outstanding examples of compliant manufacturers in both India and China, unfortunately, there are also production plants which have serious compliance and quality problems with some potentially fatal consequences. In recent years we have seen a rising number of product recalls and even import bans initiated often by the US Food and Drug Administration www.pharmafocusasia.com

CoverStory

(FDA) or the European Directorate for the Quality of Medicines and Health Care (EDQM). The Chinese Ministry of Environmental Protection and China’s provincial Environmental Protection Bureaus (EPB) oversee compliance and operate a website where warning letters and violations are posted online and publicly, similar websites are operated by the FDA and the EDQM. In a worst case scenario, this can endanger security of supply, if plants get shut down by authorities. Tackling the issue: a sustainable supply chain

Ultimately, we need to make antibiotics sustainable. But what would an approach to ‘sustainable antibiotics’ mean? It means we need to apply the principles of product stewardship to make sure that from production through to use and disposal, along the entire supply and value chain, antibiotics are not just delivering positive direct benefits to patients but deliver positive benefits to society overall i.e. the negative impacts in production and use are minimised and antibiotics remain effective over time. This is not just the industry’s 42

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responsibility—policy makers, customers and other industries are also involved. However, we must not hide behind thinking ‘it’s not just our problem” and instead we should engage and make a significant contribution to address these challenges. We can take action, as individual companies and as an industry, building foundation for a strong and respected industry, by immediately focusing on: • The highest production standards Ensuring our production standards are of the highest level in terms of minimum pollution and waste throughout the supply chain. This has a direct link to AMR causes and also brings benefits to the communities in which we operate. We cannot allow the discharge of waste water containing active antibiotics. Contaminated waste water and other non-compliant practices contribute to AMR. We all must address such irresponsible behaviour and take action. For example, adopting the highest industry standards for ourselves and insisting that suppliers adhere to the same high standards, ensuring compliance with regula-

tory frameworks in the manufacturing country and also the end target market. Initiatives such as Together for Sustainability audit suppliers on their sustainability performance, extending sustainability monitoring through the entire supply chain and can help to build a reliable and robust supply chain • The highest quality standards Making sure our quality is as good as it can possibly be and is highly regarded across the community and valued by customers. We need to hold ourselves to these high standards and must ensure the same with our suppliers • Security of supply and regulatory harmonisation These are lifesaving medicines and essential products for society. We need to have a safe, reliable and consistent supply chain. We also believe the industry should seek to adopt a combination of industry self-regulation and the right regulation from authorities on a globally harmonised level to ensure minimum environmental impact. It is key that this is accompanied by

strategy

effective regulatory enforcement to ensure compliance â&#x20AC;˘ Industry engagement and leadership We need to apply product stewardship principles and leadership with policy makers and stakeholders. As the industry that produces antibiotics we need to be directly involved in the public debate around our products. To do so we need to develop good relationships with stakeholders in the NGO and policy communities, as companies are committed to high levels of sustainability performance. This requires leadership.

The industry should first and foremost address and improve its product stewardship including its environmental performance throughout the entire production and supply chain.

The need for harmonised regulation

Antibiotics should only be available on prescription from a qualified physician, who can give important advice on correct use and if necessary disposal. This approach will deliver shortterm benefits such as reducing waste, saving energy, building respect in the community and influence with policy makers while building the foundation for long-term value by developing the capacity to navigate what is likely to be a challenging future business environment. The benefits for responsible producers

A sustainable and reliable supply chain is in the self-interest of responsible pharmaceutical producers that have spent years in building a valuable and

A u t h o r BIO

Regulatory authorities in originating countries and in end markets must work together to ensure the highest industry standards and compliance. Regulators must also pay increased attention to environmental compliance and take enforcement actions if necessary. In the United States and the European Union, strict regulatory regimens govern pharmaceutical production and environmental protection, enforced by respected organisations, including the FDA, the EDQM and local environmental authorities. In the United States, the production plant and the final product must be FDA approved. Enforcement of these regulations is carried out through inspections by regulatory authorities and by intermediate and Active Pharmaceutical Ingredient (API) customers themselves. The quality department plays a significant role in auditing suppliers. With thousands of manufacturers, regulators such as the EDQM and the FDA have to follow a risk-based and very selective policy to audit companies. Ultimately, regulation must attack the challenge from several sides to be successful. Better market regulation and ensuring that no antibiotics are sold overthe-counter would help reduce misuse.

respected brand. The fallout from issues such as forced factory closures, product recalls or environmental pollution, whether from own factories or with supplier facilities can greatly impact brand and reputation in the end market. Having a sustainable supply chain also means that reputation and brands are better protected. As part of this industry and as a responsible and sustainable producer DSM Sinochem Pharmaceuticals is implementing supplier sustainability audits and guidelines. We do this via the Together for Sustainability initiative of our shareholder DSM. Together for Sustainability is an initiative to audit suppliers based on a shared set of sustainability criteria. We also are implementing sustainability criteria as a requirement for all future suppliers. In addition, all our plants operate dedicated state-of-the-art waste water treatment plants and we continuously monitor our production and waste streams for possible improvements and compliance. We use a proprietary enzymatic technology to manufacture antibiotics and statins in our plants, which allowed us to significantly reduce impact on the environment (up to 64 per cent lower carbon footprint depending on product). We believe that Sustainable Antibiotics and as such a sustainable supply chain, is our only option, economically, medically and ethically. References are available at www.pharmafocusasia.com

Karl Rotthier holds a Master of Laws from the University of Antwerp (Belgium) and the University of Southampton (UK), and an MBA from Vlerick Business School (Belgium). Since 1 July, 2014 Karl is President of DSM Sinochem Pharmaceuticals. Karl is married with two children.

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20th Anniversary of CHINA-PHARM

The leading sourcing platform of the PHARMACEUTICAL Industry in Asia produced by MNCs in China; Find leading excipient suppliers • Benefit from lower participation fees or a free chance to attend ISPE etc. conferences at which you will be able to obtain the latest technology of the pharmaceutical industry • Learn about and experience the newest Chinese developments of the pharmaceutical industry.

Highlights of CHINA-PHARM 2015 Joining hands with other three trade fairs CHINA-PHARM will be held in Shanghai New International Expo Centre during November 17-20, 2015. CHINA-PHARM was launched in 1996, and co-organised by China Center for Food and Drug International Exchange and Messe Düsseldorf (Shanghai) Co., Ltd.. It will hail its 20th anniversary in 2015. After 20-year accumulation and development, CHINA-PHARM has become the top trade show in Pharmaceutical, Cosmetics and Food industry in Asia.

Key reasons for visiting CHINA-PHARM 2015

• Meet the top international and Chinese manufacturers of the pharmaceutical machinery and pharmaceutical packaging machinery industry- around 80% of them will demonstrate their machinery on site • Find leading Chinese brand machinery and costeffective international machinery that has been 44

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CHINA-PHARM 2015 will join hands with other three trade fairs to form Shanghai World of Packaging (swop). With four trade fairs, swop will display latest developments in the value chain of the packaging industry as well as related processing industries. It will serve as a one-stop platform for effective procurement and business matchmaking for China and Asia as a whole. The four trade fairs of swop are CHINA-PHARM, PacPro Asia, FoodPex and BulkPex.

National Pavilions will exhibit on an unprecedented scale

Leading industry associations from many countries have shown strong support for swop by organizing country pavilions to display leading technologies. In particular, VDMA - German Engineering Association has gathered its three councils (plastic, printing & packaging) to form the German pavilion. Other national and regional pavilions include Japan, USA, Taiwan, Turkey, Korea and etc.

Global and Chinese exhibitors will be spotlighting the very best at CHINAPHARM Global brands: Rieckermann, Siemens, Marchesini, optima, GE, Jindal, PALL and Millipore etc; Renowned Chinese enterprises: Double-crane, Tianxiang & Chentai, Xiaolun, Shandong SHINVA, Hunan Chinasun, Shanghai Macroprocess, Shanghai Morimatsu, CEFOC, PHAREOUP, WATERTOWN, Tofflon, Chuangbo, Findnovo, Zhongxing Lilian(CAM, groninger, Brevetti, CURTI) and etc.

Four concurrent high-level forums offering a unique opportunity to know about regulations and laws, technology on pharmaceutical industry ISPE-CCFDIE China Conference (Autumn edition in China)

The conference is jointly organized by Center for Food and Drug Inspection of CFDA, China Center for Food and Drug International Exchange (CCFDIE), International Society for pharmaceutical Engineering (ISPE), with the top conference scale in China. It consists of seminar on GMP regulation and policies, technical sub-forums on Aseptic Technique, OSD Technology, Production and Manufacturing Facilities, Quality and Certification and Process and New Technology. There were 45 speakers and 651 participants in last edition.

Pre-Register Right Now! Experience the Benefits!

China Conference on Supervision and Technical Innovation on Pharmaceutical Packaging Materials and Excipients

Pre-Show:

The forum is organized by Special Committee for Supervision and Research of Pharmaceutical Packing Materials and Excipients of the China Society for Drug Regulation, providing a communication platform on the China's and international regulations, technologies and standards on pharmaceutical excipients and packaging materials.

China International Cosmetics Convention The forum is organised by China Center for Food and Drug International Exchange (CCFDIE). It focuses on the GMP technical research on China's cosmetics industry and sub streams are Ingredients Safety, Herbal Cosmetics Review, Cosmetics Safety Testing and Packaging Innovation etc.

China International Food Convention

CHINA-PHARM 2015 will be grand opening at Shanghai New International Expo Centre from November 17 to 20. Please visit www.china-pharm.net to register NOW! • Get e-newsletter to know updated news about the industry and exhibition • Get e-ticket in advance to get quick admission onsite

Onsite: • Get free show catalogue • Get the chance to attend concurrent events preferentially

Post Show: • Get further information about products you are interested • Get CHINA-PHARM 2015 post show report • Get CHINA-PHARM e-newsletter For more information, please visit www.china-pharm.net. Advertorial www.pharmafocusasia.com

Research & Development

Enabling the Delivery of Poorly Soluble Drugs via Drug-Polymer Solid Dispersions Amorphous Solid Dispersions (ASDs) are a preferred technology for improving solubility and bioavailability of poorly soluble drugs. Spray-drying and hot-melt extrusion are the most common ASD production methods, and polymer-drug interactions play a role in each. There are several factors to consider when selecting polymers and processing methods because each method offers advantages and disadvantages. Thomas Dürig, Senior R&D Director, Pharmaceutical and Food Specialties Ashland Specialty Ingredients, USA Divya Tewari, R&D Director, Global Pharmaceutical R&D and Technical Services North America & Rest of Asia Yunxia Vivian Bi, Technical Director Solubilization and Contract Services Ashland Specialty Ingredients, USA

oorly soluble new drugs entering the market are estimated to range from 40 to 70 per cent of the total. This trend of increased poorly soluble drugs on the market is a result of the quest for drugs with increased potency and increased ability to interact with protein receptors. The advent of modern drug discovery techniques such as quantitative structure-activity relationships, combinatorial and high-throughput chemistry has contributed to this quest. The Lipinski Rule of 5 and variants thereof, acknowledge that potential drug molecules tend to be more lipophilic with logP values up to 5 and sometimes higher. Water solubility-enhancing formulation strategies have therefore become a significant need and enabler in drug development. 46

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There are a number of strategies in use to enhance solubility, dissolution rate, and bioavailability of poorly soluble drugs. These include particle size reduction or micronisation, amorphous solid dispersion, cocrystallisation, lipid-based formulation, drug complexation with cyclodextrins, or crystal modification such as salt formation and metastable polymorphism (Figure 1). From: Williams et al., Pharmacol Rev, 65:315–499, January 2013 Among these, Amorphous Solid Dispersion (ASD) is seen as a preferred technology because it offers improved solubility with limited or no impact on permeability. ASD is the distribution of an active pharmaceutical ingredient (API) in molecular or amorphous form

surrounded by inert carriers. The solubility of the amorphous form of the drug is higher than that of the crystalline drug. This enhancement of apparent solubility improves oral bioavailability by achieving a supersaturated concentration and maintaining this for an extended period of time in the intestinal milieu. This is commonly described as the “spring and parachute” effect (Figure 1). Although there are a number of ways to achieve an amorphous solid dispersion, spray-drying and Hot-Melt Extrusion (HME) are by far the most common. These are complementary processes with advantages and limitations. Both can be run as continuous processes. HME is preferred for its simplicity and cost effectiveness, but is not suitable for heator shear-sensitive APIs or for APIs with extremely high melting temperatures. HME also has comparatively low mixing efficiency. Spray drying is preferred for higher drug loads and heat- or shearsensitive APIs, but is not suitable for APIs with low solubility in organic solvents. Spray drying is more expensive and carries the added burden of requiring solvent handling, with associated environmental impacts (Table 1). Typical polymeric solid dispersion carriers can be classified as non-ionic polymers, such as copovidone, povidone, hypromellose, and hydroxypropylcellulose; and ionic polymers such as hypromellose acetate succinate (HMPCAS), hypromellose phthalate, cellulose acetate phthalate, and polymeth-

Research & Development

Figure 1: Common Strategies to Address Low Drug Solubility

acrylate. Currently copovidone, povidone, hypromellose and hypromellose acetate succinate are most commonly used in marketed ASDs. Solid dispersion polymers interact with the drug molecules via hydrogen bonding as well as through hydrophobic interaction. However, the polymers should also dissolve relatively quickly in intestinal fluid. As a result of its amphiphilic characteristics and diversity of substituent groups (succinoyl, acetyl, methoxyl and hydroxypropyl), HPMCAS interacts favourably with diverse drug molecules and is regarded as the most versatile solid dispersion polymer (see Figure 3). Case study: Using HPMCAS to stabilise and enhance the solubility of a rapidly crystallising and low solubility drug

Spray-dried dispersions of ezetimibe and HPMCAS were developed to illustrate the versatility of HPMCAS. HPMCAS is commercially available in various grades of acetyl and succinoyl substitution levels (see Figure 3)that allow optimisation for

differing drug properties and increase the likelihood of finding a suitable polymerdrug combination.

The relevant properties of ezetimibe are shown in Table 2.

Ezetimibe

Spray-dried dispersions were made by dissolving ezetimibe and HPMCAS in 2:1 (w/w dichloromethanol:methanolat

Ezetimibe is poorly water soluble, lipophilic, and a strong crystal former. Technology Hot-mely extrusion

Spray drying

Advantages Cost efficient Continuous process Reduce downstream formulation steps by direct shaping

Limitations Not suitable for heat/ Shear sensitive APIs or APIs with extremely high melting temperatures Comparatively lower mixing efficiency

Multi-purpose Linearity ( â&#x2030;Ľ 5 concentrations)

High mixing efficiency Continuous process Lower process temperatures More polymer choices

Not suitable for APIs with low solubility in organic solvents Cost Solvent handling and environmental impact

Table 1: Two Major Solid Dispersion Manufacturing Technologies www.pharmafocusasia.com

Research & Development

at 37°C under a constant stirring speed of 300 rpm. A 2.0 mg model drug equivalent of each spray-dried powder sample was added to each vial and drug concentration was measured by in situ fiber optic probes at various time points. Case study results

Figure 2: Spring and Parachute Mechanism for Solid Dispersion Solubility Enhancement

30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0

Differential Scanning Calorimetry (DSC)

DSC was performed under a nitrogen purge with a TA Instruments DSC2000 calorimeter (New Castle, DE) on 5 mg samples. Each sample was heated at a rate of 20°C/minute from −20°C to 190°C and then cooled at the same rate back to −20°C. After cooling, samples were held isothermal for 5 minutes and then heated again at the same rate to 195°C. Dissolution

Dissolution experiments were performed using a Pion µDISS Profiler* dissolution apparatus. Spray-dried samples were added to 20 ml of Fasted-state Simulated Intestinal Fluid (FaSSIF) maintained

HPMCAS Specifications

Hydroxypropyl Content 4-28% Methyoxyl Content 12-28% Acetyl Content 2-16% Succinoyl Content 4-28%

Hydrophilicity

Succinoyl Content (wt%)

a concentration of 5 per cent solids. A 60 per cent drug load was chosen to accentuate performance differences among the HPMCAS grades. Spray drying was performed on a GEA SD Micro spray dryer (Columbia, MD). The feed material was atomised using a 0.5 mm two-fluid Schlick nozzle targeting an inlet temperature of 85°C, a process gas flow of 25 kg/hr, an atomising gas pressure of 0.5 bar, and an atomising gas flow rate of 1.5 kg/hr. The liquid feed rate was adjusted to maintain an outlet gas temperature of 55°C. After spray drying, the spray-dried dispersions were vacuum dried for 48 hours at 40°C under −25 in. Hg reduced pressure.

Property

Ezetimibe value

L Grade M Grade

H Grade Hydrophobicity

As the DSC thermogram demonstrates, after 65 hours the L grade sample showed a clear endothermic peak, which results from the melting of crystalline ezetimibe; the M grade sample showed phase separation; and the H grade sample remained as a single-phase amorphous dispersion (Figure 4).The presence of phase separation in the M grade formulation indicates that at some future point this formulation would experience recrystallisation. The different grades have different acetyl substitutions and hydrophobic interactions play a role in the stability of different formulations. The stabilisation effect is greatest for the H grade, followed by the M and L grades. Stronger hydrophobic interaction between ezetimibe and the acetyl-rich H grade contributes to the improved stabilisation. Further differentiating behaviour can be seen in the dissolution profiles (Figure 5).The L grade showed a drastic increase in solubility followed by a sharp drop to below the solubility of the crystalline API. This indicates that there was very little interaction between the API and the polymer in the saturated solution state. The dissolution results for the M and H grades were comparable

Tm(0C)

163

Tg(0C)

Log P

4.5

pK a1

9 (weak acid)

Solubility

8.46 mg/l

Acetyl Content (wt%)

Figure 3: AquaSolve™ HPMCAS Substitution 48

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Table 2: Selected Properties of Ezetimibe

Research & Development

A u t h o r BIO

Figure 4: DSC Curves for Spray-Dried Dispersions Made with Ezetimibe and Varying Grades of HPMCAS

Thomas DĂźrig leads global research and development and technical services for Pharmaceutical and Nutrition Specialties. Tom is a registered pharmacist, with more than 20 years of experience in the industry. He received a Ph.D. in Pharmaceutical Sciences from Temple University, Philadelphia. He has worked in a variety of settings, including R&D, GMP manufacturing at major multi-national corporations and in academia.

With AquaSolveâ&#x201E;˘ L HPMCAS With AquaSolve M HPMCAS With AquaSolve H HPMCAS Ezetimibe API

Figure 5: Dissolution Curves for Spray-Dried Dispersions Made with Ezetimibe and Varying Grades of HPMCAS

to each other, with both a significant increase in solubility and a degree of sustained supersaturation, resulting in similar Area-Under-the-Curve (AUC) values for the two grades. Again, the stronger hydrophobic interactions between ezetimibe and acetyl-rich M and H grades contributed to improved precipitation inhibition effects. For ezetimibe the intermolecular interactions are most favourable with the H grade of HPMCAS followed by the M and L grades. The precipitation inhibition effect of HPMCAS is determined by two major factors: intermolecular interactions between the API and polymer, and the dissolution rate of the polymer. In this case, the H and M grades had similar dissolution rates,

Divya Tewari leads global pharmaceutical research and development group as well as North America and Rest of Asia technical service groups within Ashland Specialty Ingredients. Prior to joining Ashland in 2004, she worked at various generic pharmaceutical companies. She has extensive experience in developing oral solid dosage forms.

both of which much greater than that of the L grade. Conclusions

Solid dispersion technology is an effective approach to enhancing the bioavailability of poorly water-soluble compounds. This paper shows how the hydrophobic interactions promoted by the varying acetyl substitutions play an important role in increasing and sustaining the solubility of ezetimibe. The trend of increasing numbers of poorly soluble drug candidates is likely to continue for the foreseeable future, and solid dispersions will continue to be an important part of bringing them to market. References are available at www.pharmafocusasia.com

Yunxia Vivian Bi leads the global solubilisation technology platform as well as pharmaceutical contract research services at ASI. Prior to joining Ashland in 2010, she held various positions in Pfizer Global R&D, Vertex Pharmaceuticals and AstraZeneca Pharmaceuticals. Her research interests are oral and parenteral drug delivery systems. Dr. Bi has authored and co-authored more than 50 research papers, abstracts and patents. She also serves as a reviewer for research journals.

www.pharmafocusasia.com

PharmaLytica 2015 South India’s preferred pharma business platform is now in Hyderabad

The Indian analytical instrument market including consumables and spares is estimated to be around $1 billion, with an annual growth rate of over 10 percent. It is estimated that this growth rate will continue for the coming years. Hyderabad accounts for nearly a fifth of India's exports of drugs, which stood at Rs 90,000 crore in 2013-14. One of the key reasons Hyderabad is at the forefront in pharma drug production nationally as well as internationally is the co-existing environment for the pharma and bulk drug industries. This is where one third of India’s bulk drugs are produced. This 50

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region is set to see a fillip in the sector as the state and central governments are formulating policies to invigorate the sector. Backed by our business expertise of growing businesses in India’s Pharma sector, Pharmalytica is poised to create the ideal platform for you to grow your business in the rich and conducive pharmaceutical capital of India. PharmaLytica 2015 will be held on 2nd and 3rd September at the HITEX Exhibition Center in Hyderabad, India. The 2nd edition of this international trade fair and conference will help the

Pharmaceutical community pick up the latest industry trends, innovations, and business with Analytical and Outsourcing services. The co-located PharmaLytica conference brings you an entire range of topics in analytical, outsourcing, laboratory, and scientific & biotechnology sector. According to Shri. Raghurama Bhandari, The Drugs Controller for the State of Karnataka, “Indian Pharma Products are exported to more than 200 countries around the globe including regulatory markets of USA, Europe and Australia. Even Pharma manufacturers in Karnataka are exporting Drugs to more than 180 countries across the globe. It is attracting investment from major Pharma companies. This being a preferred location PharmaLytica is offering a great platform to the entire pharma markets.” Serving as an industry platform, PharmaLytica connects the pharmaceutical expertise from India and international markets with the analytical, outsourcing

solution providers, including clinical trials, contract research, custom manufacturing, biotech, IT and analytical services from across India and select global markets. The last edition of PharmaLytica saw a participation of over 100 exhibitors including industry leaders like Aditya Birla Group of Science & Technology, Thermax, Newtronic Lifecare Equipment, Borosil Glass Works, Thermolab Scientific Equipments, Millipore India Pvt, KNF Pumps + Systems (India), Peak Scientific Instrument (India), Clearsynth Labs Ltd, Integrated Cleanroom Technologies and Eureka Forbes Ltd amongst others. For more details please contact: Jayesh Kanaskar, T: +91 22 61727173, M: +91 98195 86780 or E: jayesh.kanaskar@ubm.com

CPhI’s biggest international brand for pharma contract services, ICSE is now collaborating with PharmaLytica, India’s most comprehensive analytical and contract services event. Pharma outsourcing accelerates on an increasing curve and becomes more strategic in nature. ICSE connects the global pharma community with companies providing pharma contract services in clinical trials, contract research, contract manufacturing, bio-services, IT, analytical services, contract packing, logistics and others. ICSE collocated with PharmaLytica enhances the profile of your organisation. Being a part of the ICSE zone is being in a powerhouse of global pharma outsourcing. The zone gives you the platform to grow your business by networking with companies looking for strategic outsourcing partners ticking all the boxes in regards to quality, reliability and affordability. Advertorial www.pharmafocusasia.com

Manufacturing

Antibody Drug Conjugates in Reducing Disease Burden Immense Promise with Some Challenges

Antibody Drug Conjugates provide a high level of promise, and hence there will be a conscious effort to expand the application(s) of this technology to disease indications beyond oncology provide a high level of promise, and hence there will be a conscious effort to expand the application(s) of this technology to disease indications beyond oncology. Vivek Sharma, CEO, Pharma Solutions, Piramal Enterprises, India

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he global market for oncology drugs has seen a steady growth in recent years with cancer being the leading area of healthcare spending. Market estimates show that in 2013, the global spending on oncology drugs reached US$91 billion (including supportive care), growing at a CAGR of 5.4 per cent in the period from 2008-2013. This trend is expected to continue in to

Manufacturing

2017 where oncology is expected to drive the global spend on medicines. Analysis of global pharmaceutical pipeline indicates that close to 30 per cent of the overall pipeline is focused towards the development of anti-cancer drugs. Targeted therapies dominate the oncology development pipeline with

recent approvals of immunotherapies such as MabThera / Rituxan, Avastin, and Herceptin marking a trend towards increased use of targeted therapies. The ‘selectively acting’ therapies have increased their share of global oncology sales to 46 per cent from 11 per cent over the period 2003-2013. This has consequently lead to a decline in the share of spend towards cytotoxic and hormonal therapies. Antibody Drug Conjugates (ADCs) provide additional arsenal to the pharmaceutical industry in its bid to develop targeted therapies for cancers. An ADC consists of amonoclonal antibody, a biodegradable linker and cytotoxic drug. The antibody binds to the target cancer cell. The whole ADC is then internalised within the cancer cell, the linker is degraded, and the active drug released. Due to the targeted mechanism of action, the side effects of potent drug are lower. The cytotoxic drugs used in ADCs are high-potent APIs such as Calicheamycin, Maytansinoids and Auristatins. While there are other cytotoxic agents that can potentially be used, auristatins and maytansinoids are the most widely used cytotoxic drug ‘payloads’ in ADCs. History of ADCs

The concept of ADC is not new and can be traced back over a century when the German physician and scientist Paul

Ehrlich proposed the concept of selectively delivering a cytotoxic drug to a tumor via a targeting agent. Ehrlich even coined the term ‘magic bullet’ to describe his vision. Nearly 50 years later, Ehrlich’s concept of targeted therapy was first exemplified when methotrexate (MTX) was linked to an antibody for targeting leukemia cell. The earlier versions of ADCs used murine polyclonal antibodies which were more immunogenic. However, advances in antibody engineering over time have enabled the production of humanised monoclonal antibodies that has significantly circumvented the issue of immunogenicity. The lessons learnt in the development of technology and clinical evaluation of ADCs ultimately led to the first US FDA approval of ADC, Mylotarg (gemtuzumab ozogamicin), in the year 2000. Benefits of ADCs

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumour-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. ADCs use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus reducing exposure of normal tissue to cytotoxic drugs and improving the therapeutic index of chemotherapeutic agents.

www.pharmafocusasia.com

Manufacturing

Spending by Therapeutic Area (2017) *Oncology does not include supportive care

O nc

As Pa th in m O a/ th C er O PD C N S D H ru yp gs Im er te m ns un io os n tim u H la IV nt An s tiv ira D er ls m at ol An ogy tib io tic C s ho le s A Im te ro m ntil un Ep os il up ect ic pr s An ess an tip ts sy ch An ot ic tiu s lc A er An nt a id tiv nt ep s ira re ls ss ex an cl ts us in g H IV AD H In D te rf er on s

ol og y* D ia be te An s tiTN Fs

$ Bn

Source: ‘Innovation in Cancer Care and Implications for Health Systems’, IMS Institute for Healthcare Informatics, Nov’14

trials conducted in the US for ADCs. However, out of this, 79 clinical trials were initiated in the last five years itself from 2009 to 2014, representing a 618 per cent increase over the period 20042009 during which only 11 trials were conducted. A total of 70 clinical trials involving ADCs are currently active in the US with 50 per cent of these trials being in Phase I.

Current Status and Market

Currently, there are two US FDA approved ADCs available - Adcetris (brentuximab vedotin) and Kadcyla (ado-trastuzumab emtansine). As per analyst estimates, the sales of Adcetris and Kadcyla are expected to reach US$1.3 billion and US$1.5 billion by 2020 respectively. The overall ADC market is currently estimated to be US$600 million and is expected to grow at a CAGR of 48.1 per cent in the period 2013 –2018 to reach US$2.8 billion. The pharmaceutical industry has noticed the benefits that ADCs offer, and that has led to an increase in the number of clinical trials being conducted for ADCs. In the past decade, 20042014, there were a total of 94 clinical

The concept of ADC is not new and can be traced back over a century when the German physician and scientist Paul Ehrlich proposed the concept of selectively delivering a cytotoxic drug to a tumor via a targeting agent. Ehrlich even coined the term ‘magic bullet’ to describe his vision.

The Promise of ADCs

Adcetris was granted approval for treatment of patients with Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL). It is commercially available for these indications in more than 40 countries with further market expansion planned.

Oncology - Largest Area of Focus in the Pipeline Total 3500 3000 2500 2000 1500 1000 500 0

3088

1019

(33%)

1082

357

(33%) Pre-Clinical

Phase I

1438

374

(26%) Phase II

449

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103

(22.9%)

Phase III

Source: ‘Innovation in Cancer Care and Implications for Health Systems’, IMS Institute for Healthcare Informatics, Nov’14 54

Oncology

177

(9%)

Pre-Reg /..

Manufacturing

Figure 1

2003

2013

10%

Adcetris is the first new FDA-approved treatment for HL since 1977 and the first one to be specifically indicated to treat ALCL. Clinical trial results show highly impressive response rates observed with Adcetris in patients with HL and ALCL (73 per cent and 86 per cent respectively). Similarly, significant clinical benefit was observed with Kadcyla which is approved as a single agent indicated for the treatment of patients with HER2positive (HER2+), metastatic breast cancer. Approval of Kadcyla was based on the phase III EMILIA trial which compared Kadcyla to lapatinib and capecitabine therapy. The trial showed a strong benefit in overall survival against the current best therapy showing an improvement in overall survival of nearly six months. With the success of Kadcyla against solid tumours comes the real promise of ADCs in tackling the most aggressive and resistant tumours with the worst clinical outcomes. Current targets include cancers with high unmet need for treatment such as triple negative breast cancer, gastric tumours, small cell lung cancer, melanoma and pancreatic cancer. The technology behind ADCs is continuing to develop and mature

15% 11%

24%

48% 46%

26%

Supportive Care

Cytotoxics

Targeted

20%

Hormonal

Source: ‘Innovation in Cancer Care and Implications for Health Systems’, IMS Institute for Healthcare Informatics, Nov’14

at a rapid rate. ADC programs are increasingly progressing from the lab to the clinic with more ADC projects entering the clinic each year. An increasing amount of later phase clinical data on ADC is becoming available and the knowledge and confidence in the technology is growing. Excellent clinical data combined with a low overall failure rate is driving the ADC revolution. Roche/Genentech is one of the most active companies in the ADC market. Banking on the success of Kadcyla and a strong pipeline of ADCs, the company plans to invest more than US$200 million for setting up ADC manufacturing plant in Basel,

Switzerland.3There is now a huge interest in ADCs with other industry majors such as Sanofi, Bayer, GSK, Amgen, BMS, Abbvie, Eli Lily, Astellas, Takeda / Millennium and Novartis also running ADC programs. Challenges

The technology used in ADCs is relatively undeveloped and despite such wide involvement, the ADC technology space is dominated by a handful of players. This means there are a limited number of payloads available. The maytansine platform from Immunogen and the auristatin platform from Seattle Genetics both have the same mechanism of action which may not be suitable for all cancers. Groups are investigating other payloads, but to date few have managed to make a significant impact. In clinical trials, ADC associated toxicities have also been observed due to early release of the payload. These sideeffects point to the importance of linker chemistry in ensuring therapeutic safety

Figure 2 www.pharmafocusasia.com

Manufacturing

Global ADC Market Size ($Mn, 2013-2018) 3500 3000 2500 2000 1500 1000 500 0

2821.4 1905.1 868.6

586.5

396 2013

2014

1286.4

2015

2016

2017

2018

Source: ‘Antibody Drug Conjugates: Technologies and Global Markets’ BCC Research, Feb’2014

of ADCs. There is an effort from the industry towards improving antibody technology, site specific conjugation and linking chemistries to tackle the common toxicities observed across drug platforms. It is likely that the next generation of ADCs will show fewer side effects than the current generation of late phase and approved projects. The manufacturing of ADCs poses several challenges due to nature of the molecules. Some of these are identified as: ADC Pipeline

26%

50%

• Antibody binding activity after conjugation • Biological activity of cytotoxic drug after conjugation • Production of components requiring both cell culture and synthetic chemistry capabilities • Cytotoxic nature of the drug requires high containment facilities • Conjugation of antibody to druglinker requires cGMP containment room/suites As a result, majority of ADC manufacturing (70 per cent to 80 per cent) is outsourced to contract manufacturers. However, only few players provide the complete suite of services for ADC manufacturing. Further, there are several small biotechnology companies which are entering into the ADC market. The resulting growing pipeline has underlined the need for integrated service providers with the capability to handle highpotent drugs and provide complete suite of ADC manufacturing services.3

Piramal is one of the global leaders in providing customer-centric ADC manufacturing solutions. With worldclass facilities in UK and US and backed by highly experienced team, it offers integrated services from development through clinical and commercial ADC GMP batch manufacturing and ADC fill/finish. The focus on quality and on time delivery has led to several recognitions, including recent ones such as the ‘World ADC Award’ in 2014 for conjugation services, and the ‘2015, CMO Leadership Award’ for quality, reliability and regulatory excellence. Summary:

ADCs provide a high level of promise, and hence there will be a conscious effort to expand the application(s) of this technology to disease indications beyond oncology. The lower overall failure rate for ADCs shows promise from a patient perspective, and the hope is that the next generation of this technology will lead to further improvements. In the near future, one can expect CMOs involved in the ADC space to expand, potentially consolidate, and focus on providing end-to-end solutions from development through fill/finish. References:

1) “Antibody–drug conjugates: Current Status and Future Directions”, Heidi L. Perez et.al., Elsevier, December 2013 2) Thomson Reuters Cortellis, Sales Forecasts 3) “ADC Contract Manufacturing Market, 2014 –2024”, Roots Analysis

Phase 1

50%

Phase 1|Phase 2

16%

Phase 2

26%

Phase 3

Phase 4

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A u t h o r BIO

16% Vivek Sharma heads the Critical Care at Piramal Enterprises Ltd. Prior to this, he was Managing Director with THL Partners, a Boston based private equity firm where he was responsible for working with THL’s Portfolio companies to identify value creation opportunities and partner with the leadership of these companies for execution of growth/ restructuring and cost optimization initiatives. Vivek has over 20 years of Global Management experience and is a Chartered Accountant from India, a qualified CPA and also a Masters in International Business from Thunderbird.

Contract Manufacturing of Pharmaceutical Powders Laboratoria Smeets

For the veterinary segment we have recently started a new production plant. The plant is already producing at 50 per cent of its capacity. Further growth is foreseen.

ii. Technology for API solubility and bioavailability

The business of Laboratoria Smeets grew 20 per cent last year. The strategy to focus on powders is clearly paying off for Labosmeets. Three strategic directions have guided us in our development.

i. The sachet business Powders in sachets are the preferred galencic form for rather bulky drugs or food supplements. The powders are usually water soluble. A drink is often more comfortable than swallowing a few thick tablets. This sachet material includes an aluminium layer, which protects the content from oxygen, moisture or external odours. Recently Labosmeets got a BIO certificate which enables it to blend and package bio products. This is a great move for the trend to use powerful and healthy plant powders, which can be used in shakes or other food preparations. We see a growing trend to add more dietary fibers to our diets. Here we see a booming volume of such fibers offered in sachets. Another success story is our involvement in the talcum business. We saw interesting growth in our talcum dispenser business. Our veterinary business is also growing well. A lot is exported to Africa, where quality medicine is more and more appreciated.

Labosmeets has developed, in collaboration with Ghent University, an extrusion technique to produce water-soluble granules containing poorly water soluble drugs of Class II or Class IV of the Bio Classification System (BCS). The main advantage of our technology is that we can make straight soft granules in a low temperature process, which can be used as such or can be used to make tablets. The low temperature protects successfully the API. A new product is being launched for the European market this July. A broad spectrum antibiotic for veterinary usage.

iii. R&D in food supplements for our (potential) customers

Labosmeets has put a lot of effort in developing relevant innovations for health care in general with the help of food supplements. Breakthrough development includes the restoration of bacterial flora of patients with diseases ranging from rheumatoid arthritis to Crohnâ&#x20AC;&#x2122;s disease. We have also developed a product to treat successfully osteoarthritis. The working mechanism is different from what is known. We essentially respect nature and the biochemical pathways. Even a fun product to fight hangover in a new innovative way has been developed. Want to share our success ?

www.labosmeets.com Jefverplaetse@labosmeets.be Mobile :+32488282422 Advertorial www.pharmafocusasia.com

Bachem Pioneering Partner for Peptides

What are peptides? Peptides are organic compounds made up of natural amino acids in living organisms. Originally isolated from biological sources, they are synthesised chemically today. The biological properties of peptides depend on the number of amino acids involved and their position in the amino acid chain. The 20 natural amino acids are enough to form the basis for an unimaginably large number of peptides, each with their own distinctive physical, chemical and biological properties. Peptides are mainly used as highly active and highly specific drug substances. Oncology and diabetes/ 58

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obesity are prominent examples of therapeutic areas in which peptides generate billions of dollars in revenues.

Cyclic peptides â&#x20AC;&#x201C; learning from nature Naturally occurring peptides like the hormones insulin and glucagon are highly active even in small amounts. These hormones are released systematically in the body, take effect rapidly and are broken down by the organism within minutes in many cases. Many biochemical processes are controlled by sophisticated feedback loops of this kind with the aid of peptides. In contrast, the active pharmaceutical

ingredients used for therapeutic purposes, primarily in the management of chronic disease, generally have longer durations of action, enabling extension of the dosing intervals to days or weeks. One strategy used with great success in nature to extend the lifespan and hence the activity of peptides in the organism is cyclisation. In this process, an additional chemical bond - for instance between the two ends of a linear peptide or the side chains of two amino acids - results in the formation of molecules with a ring structure. Also known as macrocycles, such compounds are more resistant to enzymatic breakdown than their open—chain counterparts and bind to their biological target with an even higher degree of affinity and selectivity. Some macrocycles produced from fungi and bacterias—examples being cephalosporins and erythromycin—are wellestablished and essential antibiotics. The use of orally available cyclosporine A since the 1970s to suppress natural immunity has revolutionised organ transplantation medicine. Researchers learning from nature are increasing their efforts to use peptides with a ring structure to reach bonding sites that existing drugs have been unable to target. Unlike conventional small organic compounds, macrocycles are ideal due to their size for modulating Protein-Protein Interactions (PPIs) involving extensive binding surfaces. Inhibition of PPIs is being investigated in a number of clinical trials, including trials to develop cancer treatments, and the first such medicines have already been granted marketing authorisation. New scientific insights are helping us to understand why some macrocycles are absorbed better than others into the bloodstream after oral use or are better able to penetrate cell membranes. This knowledge enables the design of new macromolecules with tailored properties. With the advances in chemical peptide synthesis accomplished in recent years, Bachem is now able to develop efficient manufacturing processes for complex cyclic peptides. In providing these agents, Bachem is making a significant contribution to the further clinical research and exploitation of this promising drug class.

Glycosylated peptides – improving pharmacokinetic properties

The glycosylation technology allows the synthesis of peptides and proteins with pre-attached sugars,

Interferon ß-1a is a glycosylated 166 amino acid protein and an approved drug substance to treat multiple sclerosis.

selected from a proprietary library of over 50 specific glycans. It has been shown to markedly improve drug properties such as half-life, binding affinity and selectivity. Furthermore, compared to recombinant products, the chemically synthesised proteins are more homogeneous. Glycosylation of peptide drugs can be a powerful way to enable optimisation of lead candidates. Selective, site-specific glycosylation leads to a homogeneous product with potential for more defined bioactivity compared to heterogeneous products. Bachem AG and GlyTech, Inc. were 2013 CPhI innovation prize finalist for the groundbreaking work on Interferon Beta-1a. The technology has been used in multiple other projects, such as to manufacture glycosylated somatostatin analogues and glycosylated GLP-1. In all cases, drug improvements were achieved.

For further information please contact: Global Marketing Bachem Group, marcom@bachem.com Advertorial www.pharmafocusasia.com

STRATEGY China Pharm................................................ IBC, 44 & 45 CPHI & PMEC.................................................. 3, 16 & 17 Messe Düsseldorf Asia Pte Ltd.................................... 21 PharmaLytica................................................. 13, 50 & 51 Smart Consulting Group...................................... 32 & 33

SuppliersGuide

Products&Services

Company........................................................ Page No.

MANUFACTURING Bachem..........................................................11, 58 & 59 Bosch........................................................................OBC Laboratoria Smeets.............................................. 19 & 57 World Courier..............................................................IFC INFORMATION TECHNOLOGY Smart Consulting Group...................................... 32 & 33

Company........................................................ Page No. Bachem..........................................................11, 58 & 59 www.bachem.com Bosch........................................................................OBC www.boschpackaging.com China Pharma.............................................. IBC, 44 & 45 www.mds.cn CPHI & PMEC.................................................. 3, 16 & 17 www.cphi.com/pmec/home Laboratoria Smeets.............................................. 19 & 57 www.labosmeets.be Messe Düsseldorf Asia Pte Ltd.................................... 21 www.medicalfair-thailand.com PharmaLytica................................................. 13, 50 & 51 www.ubmindia.in/pharmalytica/home Smart Consulting Group...................................... 32 & 33 www.smartconsultinggrp.com World Courier..............................................................IFC www.worldcourier.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it, or fill it online at www.pharmafocusasia.com by clicking "Request Client Info" link.1.IFC: Inside Front Cover 2.IBC: Inside Back Cove 3.OBC: Outside Back Cover

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