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Volume 7 Issue 2

- 2015

ED

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Allergy Therapies Increasing the Probability of Clinical Development Success Prioritising Health Economics Responsibilities To Impact Payer Pricing and Formulary Decisions The Present and Future Of Non-Vascular Stents LIMS As An EnablingTechnology For The Pharmaceutical Industry

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh orsolya@pharmapubs.com EDITORIAL ASSISTANT Olga Henschke BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: John Sympson john@ipimedia.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Heather Bayran Heather@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in September 2015. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2015 PHARMA PUBLICATIONS Volume 7 issue 2 - Summer - 2015

08 The Future of Commercial Innovation in a Global Multichannel Marketplace In an increasingly global marketplace, the challenge facing life sciences companies to harmonise their operations for maximum efficiency is greater than ever. This growth in commercial opportunities is paralleled by an explosion in communication channels between healthcare organisations and stakeholders. Jan van den Burg, Vice President of Commercial Strategy, is responsible for strategy and product marketing for Veeva Commercial Suite of Applications, focusing on the European market, and he shares his thoughts on the future of commercial innovation. 12 US Healthcare Prepares for ICD-10 Transition This year US healthcare organisations are preparing to move from 13,000 ICD-9 codes to 68,000 ICD-10 codes (and this does not include procedures). It is a monumental task requiring strategies that apply to any organisational change of this size. Within this white paper Jeffrey Goldstein, Clinical Transformation Consultant at Allscripts, shares his thoughts on how US healthcare prepares for ICD-10 transition. 16 Life Sciences in Asia : Is the Tiger an Endangered Species? The story of Western expansion into the life sciences in Asia has been one of rapid change. Nick Stephens, Executive Chairman of RSA, the leading global life sciences executive search and executive interims specialist, explains how the war for talent in Asia has been adapting to the unpredictable landscape. 18 Prioritising Health Economics Responsibilities to Impact Payer Pricing and Formulary Decisions Throughout a product’s lifecycle, health economics and outcomes research (HEOR) teams take on a number of activities to support a company’s broader market access efforts. In addition to supporting brands nearing regulatory approval, HEOR groups must be able to support teams negotiating pricing and reimbursement. Victoria Cavicchi, Research Analyst at Cutting Edge Information, discusses prioritising health economics responsibilities to impact payer pricing and formulary decisions. 24 Changing Healthcare Landscape and its Impact on the Pharmaceutical Industry The pharmaceutical industry is a success story providing employment and ensuring that essential drugs at affordable prices are available to the therapeutic naïve population. At the same time it is one of the most regulated industries globally. Until recently, pharma investments in R&D and innovation resulted in patentprotected, high-margin revenue streams. Within this white paper, Sunil Shewale and Sameer Parekh from Serum Institute focus on the pharmaceutical industry from a different point of view. 28 The Evolution of the Life Sciences Sector and the Role of Biotech Incubators The life science sector is growing in significance to the world economy, and in particular for London and the UK. A biotech incubator with a 15-year history, the London BioScience Innovation Centre is ideally placed to serve the changing needs of biotech companies and to identify future opportunities and developments in the life science sector. Lucy Garnsworthy, Communications Manager at the London BioScience Innovation Centre, deals with the evolution of the life sciences sector and she explains the role of biotech incubators. 32 The Cambridge/London Corridor: Its Strength and Impact on the UK The UK has one of the strongest and most productive life sciences sectors in the world, generating turnover of over £50 billion. There are nearly 5000 companies in the wider health life science

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Contents sector (including non-manufacturing and service companies) in the UK. £4.21 billion was spent on pharmaceutical R&D in the UK in 2012, 25% of the total industrial R&D spend and 34% of total manufacturing industry R&D. Harriet Fear, Chief Executive at One Nucleus, shares her thoughts on the Cambridge/London life science and healthcare corridor. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 36 The Virtual Elaboration of Fragment Ideas: Growing, Merging and Linking Fragments with Realistic Chemistry Dr Robert Scoffin and Dr Martin Slater from Cresset serve readers with a fragment-based drug discovery article. Fragment-based drug discovery seeks to identify relatively simple and low molecular weight molecules which interact with protein targets, then grow or link them into active leads. Molecular design software can be used to create realistic chemistry between and around fragments. 42 ISO IDMP Short Timelines and Limited Information: How Do You Solve the Challenges and Prioritise your Efforts? ISO IDMP has been around since 2012, when the standards were initially published, and since November 2012 the implementing regulation 520/2012 has been in place. Now, four years later, the deadline of July 1st, 2016, is closing in and information on how and what to implement is still scarce due to outstanding implementation guidelines from ISO, and hence no implementation guidelines from EMA. Rune Bergendorff from NNIT looks into the ISO IDMP short timelines and limited information, and then he answers the question, how do you solve the challenges and prioritise your efforts? CLINICAL RESEARCH 48 Allergy Therapies: Increasing the Probability of Clinical Development Success The prevalence of allergic diseases is increasing sharply in both developed and developing countries. These diseases include: asthma; rhinitis; anaphylaxis; drug, food, and insect allergy; eczema; and urticaria (hives) and angioedema. Allergic asthma and rhino-conjunctivitis are the most common. Asthma incidence is rising, affecting some 300 million people worldwide. Allergic rhinitis (AR) affects an estimated 10-30% of the world’s population, with prevalence rates also increasing worldwide. Dr Juan Gispert, Senior Medical Director and Head of Quintiles’ Allergy and Respiratory Center of Excellence, provides an overview of allergy therapies. 56 The Present and Future of Non-Vascular Stents In our fascination for new-age medical devices such as smart pills and wearable health devices, we do not often pause to think about some of the less-fancy, but equally important medical devices. A class of devices in particular – non-vascular stents – receives much less attention than its 500 million dollar market size demands. In this white paper, Debarati Sengupta and Bhargav Rajan, Research Analysts of Frost & Sullivan, review the present and future of nonvascular stents. LOGISTICS 62 Track-and-Trace – A Challenge for IT Although a few years ago the number of impressive reference projects and the price of a track-and-trace solution were the deciding factors when selecting a provider, the focus has shifted significantly towards integration capacity and the capability of providing comprehensive support with a strong local presence. Barbara Schleper at Awikom discusses track-and-trace technology, explaining those challenges also. 66 Obtaining European Regulatory Approval The aim of this article is to provide an overview of the European regulatory environment and to outline some of the main pharmaceutical regulations and requirements for companies to

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Contents

consider when bringing a new medicinal product to the European market. Graham Donaldson, Regulatory Affairs Project Manager for TRAC Services, explains. LABS 72 LIMS as an Enabling Technology for the Pharmaceutical Industry In the pharmaceutical industry, just as in many other industries, the purchase of a laboratory information management system (LIMS) is not a trivial exercise and requires a good deal of involvement from both the customer and the vendor. John Boother, Managing Director at Autoscribe Ltd, has had involvement in around 5000 LIMS projects. He describes LIMS as an enabling technology for the pharmaceutical industry. MANUFACTURING 78 Syringe Siliconisation Trends, Methods, Analysis Procedures Ready-to-fill, i.e. sterile, prefillable glass syringes, are washed, siliconised, sterilised and packaged by the primary packaging manufacturer. They can then be filled by the pharmaceutical companies without any further processing. These days the majority of prefillable syringes are made of glass and the trend looks set to continue. Within this article, Claudia Petersen and Bernd Zeiss from Gerresheimer deliver updates on syringe siliconisation trends, methods, and analysis procedures. 86 Freeze-drying with Collapse is not Necessarily Bad for Stability and can Reduce Cost Lyophilisation is often used to increase the stability and shelf-life of proteins which are physically and/or chemically unstable in aqueous solution. Freeze-drying removes water protein solutions, including water from the protein surface which plays a major role within the protein structure, and this frequently causes damage. In this editorial Sophie Declomesnil, R&D Manager, LYOFAL- Groupe SYNERLAB, focuses on freeze-drying, stability and cost reducing.

4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

88 Accelerating and Automating Sterility Testing in Microbial Quality Control In 2009 the influenza A (H1N1) pandemic struck the United States and, according to CDC estimates, affected approximate 60.8 million people with 274,304 hospitalisations, and 12,469 deaths. While this strain of the flu virus continues to circulate worldwide, the rapid and significant impact of this pandemic revealed the need to find ways to speed response to future events. One area of opportunity is the sterility test. Anna Mills, Senior Validation Specialist at Rapid Micro Biosystems, deals with accelerating and automating sterility testing in microbial quality control. PACKAGING 98 Inspection Technology - Patient Safety and Product Quality Come First Thorough inspection is a key quality safeguard for pharmaceuticals, and contributes significantly to patient safety. With the advent of new and highly potent drugs, quality requirements have dramatically increased. Joachim Baczewski, President of Bosch Packaging Technology K.K. in Japan and Head of Inspection Technology, reflects upon patient safety and product quality, and he explains the demand for highly potent medicines. 102 Global Traceability: From Factory Floor to Pharmacy An update on progress as the final countdown to compliance begins. Craig Stobie, head of the Life Sciences team at Domino Printing Sciences, looks at the current progress within the EU and beyond, exploring how some of the greatest concerns for manufacturers around serialisation – equipment effectiveness and data collection and interrogation – can be remedied as the deadline for compliance edges closer.

Summer 2015 Volume 7 Issue 2


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Editor's Letter Medical innovation looks rather different now. In the 1990s many big companies made billions from small improvements in care. Then a number of important patents expired and manufacturers began losing intellectual property protection for their medicines. Pharmaceutical companies such as Merck trimmed their research departments. Since then a new crop of drug companies has sprung up. Genomics, the study of man’s genetic code, has brought dramatic advances in the understanding of disease.

include red eyes and a runny nose, asthma attacks, itchiness, eczema and hives. In some people, severe allergies to environmental or dietary allergens, or to medications, can result in a lifethreatening reaction called anaphylaxis. Allergies play a major role in healthcare, especially around this time of the year when people are also facing the symptoms of hay fever.

In the pharmaceutical industry, as in many other industries, the purchase of a LIMS is not a trivial exercise and requires a good deal of involvement from both the customer and the vendor. John Boother, Managing Director at Autoscribe Ltd, has been involved in around 5000 LIMS projects. He describes LIMS as an enabling technology for the pharmaceutical industry.

The prevalence of allergic diseases is increasing sharply in both developed and developing countries. These diseases include asthma; rhinitis; anaphylaxis; drug, food and insect allergies; eczema; and urticaria (hives) and angioedema. Allergic asthma and rhinoconjunctivitis are the most common of these. Asthma already affects some 300 million people worldwide, and its incidence is rising. Allergic rhinitis (AR) affects an estimated 10–30% of the world’s population, with prevalence rates also increasing worldwide. Dr Juan Gispert is Senior Medical Director and Head of Quintiles’ Allergy and Respiratory Center of Excellence; he provides an overview of allergy therapies.

We are happy to welcome Gerresheimer on board again, who inform us about syringe siliconisation trends, methods and analysis procedures, and we also take a look into the world of freeze-drying, with the contribution from the Synerlab Group.

Laboratory information management systems (LIMS) offer a variety of key features that assist in the operations of a modern laboratory. These key features include workflow and data-tracking support, flexible architectures, and smart data exchange interfaces, which fully support its use in regulated environments.

The Pharma Publications team and I wish you a very pleasant summer, and many more successes over the rest of the year.

Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Jagdish Unni Vice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac

In this issue of IPI, we have looked into a series of articles focusing on the latest trends in the drug discovery market. Our team and I have brought you an extensive selection of market analyses on health economic responsibilities, while paying attention to other regulatory issues overseas as well. We are also able to bring you remarkable editorial pieces on healthcare in Asia and the USA. In our Drug Discovery & Development section, we have had the chance to meet with realistic chemistry on fragmentbased drug discovery. Continuing this trend, we take a look into the ISO IDMP timelines, along with NNIT. of

Allergies are hypersensitivity disorders the immune system. Symptoms

The success of the Anglonordic Life Science Conference continues, and we had the chance to attend the most recent event this April. In our Special Features section, we publish a review by Mattias Johansson, Director of the Anglonordic Life Science Conferences, who gives us some feedback about the conference as well as sharing some of the plans for the upcoming event.

Orsolya Balogh Editor

Editorial Advisory Board

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Summer 2015 Volume 7 Issue 2


Regulatory & Marketplace

The Future of Commercial Innovation in a Global Multichannel Marketplace In an increasingly global marketplace, the challenge facing life sciences companies to harmonise their operations for maximum efficiency is greater than ever. This growth in commercial opportunities is paralleled by an explosion in communication channels between healthcare organisations and stakeholders. Veeva Systems recently hosted an industry roundtable at its European Commercial Summit to share perspectives on how life sciences leaders are using data and technology to meet growth objectives and strengthen relationships with a diverse and growing global customer and patient base. Each discussion focused on disruptive innovations shaping life sciences, and how to turn regulatory realities into competitive advantage. Panellists debated how a new drug’s route from laboratories to hospitals is being transformed by rapid developments in technology. Experts agreed that the companies that will gain advantage tomorrow are recruiting smart data collectors today. From improving compliance and reputation through transparency reporting to optimising customer interactions, enterprise-wise data analytics are at the centre of a variety of efforts to unlock new value in the global sales and marketing of new therapies. Business Transformation as the Digital World Takes Over and Emphasis Settles on the End Customer The dialogue centred on the pivotal question of whether life sciences companies need to radically reinvent themselves in order to gain competitive advantage in today’s multichannel global environment. Across all industries, companies will benefit from quickly harnessing the power of emerging communication channels to better engage customers, gain more insight, and identify new efficiency savings. Can today’s life sciences companies use digital advancements such as data analytics and social media to facilitate more effective exchanges with stakeholders and meet the unmet needs of patients? 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For Nestle Nutrition, a leading supplier of natal and antenatal health products, the business challenge is to remain focused on the end customer, while navigating changing regulatory environments and a head-spinning number of new digital and non-digital engagement and communication channels. In response, the company put compliance and transparency at the heart of the company’s commercial and IT strategy for 2015 and beyond as this is part of the company’s DNA, and is migrating to a cloud-based enterprise environment that integrates commercial interactions, data, and content platforms, providing a single snapshot of customer interactions. Dirk Abeel, global performance development manager at Nestlé Nutrition, believes, “In a business like ours, face-to-face interactions between a company representative and healthcare professionals remain the most effective marketing channel. But we know HCPs are time crunched and facing information overload. At the same time, the parameters of our marketing are continually being tweaked and influenced by new regulations. To effectively differentiate ourselves among HCPs, we need a clear idea of when and how our customers prefer to be approached, and to easily access records of every customer interaction, to allow us to better serve them.” Raj Wickramasinghe, life sciences lead for SaaS in Accenture’s CRM business, agreed that life sciences marketers are making a necessary shift from masters of the message to managers of data and analysts of insight. “Brand marketing is getting much more crossfunctional, sometimes reaching back almost into the discovery stages to inform positioning and market-entry strategy. Global brand management is really about insight gathering, strategy setting, and data mining.” Using Analytics to Put the End Customer at the Centre of Commercial Strategy Through the widespread adoption of cloud computing, data mining has already grown exponentially, and over

the last few years the life sciences industry has discovered many new and profitable uses for data analytics. Insight is driving improvements in everything from clinical trial management to marketing plans, and from quality control to regulatory compliance. How will Big Data drive commercial innovation in 2015? There was strong consensus among the panellists that the declining contact with front-line doctors and increased pressure to get new drugs to market quickly put customers and trial data analytics at the heart of commercial strategy for life sciences companies. “The decline in one-on-one brandphysician relationships can teach us something important as an industry,” said Abeel. “Even putting regulatory restrictions to one side, HCPs are not willing to make time to meet with company reps who simply regurgitate messages. Physicians want us to engage them in an intelligent conversation about their patients’ needs. Too many companies still follow the old approach in their HCP communications.” Data analytics, he argues, allows commercial strategists to “change this paradigm, this tendency, by really taking healthcare providers seriously. We can use data to understand what physicians are looking for. What are they expecting from us? What channels do they use to research new therapies? If we can use aggregated customer data to answer these questions, as a company, we can begin the shift from product provider to solutions provider.” According to Jan van den Burg, vice president of commercial systems at Veeva, this shift will require a significant change in marketing managers’ mindset, and in the CRM and data analytics systems that support their cross-functional collaboration and decision-making. A life sciences sales rep with a full view of the customer, for example, can effectively coordinate what information goes to which customer through what channels, when and, importantly, based on a customer-centric engagement strategy. That is not to say that sales determine Summer 2015 Volume 7 Issue 2


Chapter Title

WE’RE SOARING TO NEW HEIGHTS End to End Services for Patient Recruitment and Retention

THE PATIENT RECRUITMENT-RETENTION REVOLUTION “Over MediciGroup’s 24 year history, the last 4 years has witnessed more change than the previous 20 years. The speed of change is unprecedented as more than 85% of patients and families obtain health and clinical trial information online. Medici is proud to be at the forefront of this digital revolution, spearheading more than 30 global online patient communities, and leading in the delivery of successful patient recruitment through digital and social media on a global scale.” Liz Moench, President & CEO MediciGroup® Inc.

Accelerating Enrollment

Digital Marketing

Locating Lost Patients


Regulatory & Marketplace the marketing plan. Instead, the informed multichannel sales rep can serve as a “solutions provider” – with the ability to provide physicians with the information they require through the channels they frequent. The result is a sales rep who takes into account physician preferences and builds a useful, personal relationship through a mix of communication channels. Each communication will be more impactful and more likely to be consumed, whether it’s a personal email, an online detail, or a face-to-face interaction. With each positive experience, the physician is more receptive to communications from the rep in the future. Talking to End Patients in the Digital World As social media grows in ubiquity, it is an increasingly important channel for reaching physicians and engaging them about therapies. The official hashtag of the 2014 American Congress of Oncology generated 39,000 tweets over the five-day meeting – an increase of nearly 4,000% compared with the 979 tweets sent at the 2010 congress. Although many life sciences brands have been wary of venturing into social media, as more physicians use Twitter and other platforms to communicate professionally, how is pharma keeping its voice in the conversation about its therapies? Tim White, senior director and head of global customer interaction of Lundbeck, which develops therapies to improve the quality of life of people suffering from brain diseases, sees social media as a game-changer in how life sciences companies build relationships with partners, customers, and patients. “Social media means we are no longer the only source of information about our therapies, and this is a very powerful shift,” said White. “The stories our patients and customers are telling about our brands online are, in many ways, more important than what we're saying about them. They expect us to be present online, and somehow part of the dialogue.” This, he said, has led to a greater demand for companies to be present and responsive online. A customer’s ability to call, click, like, follow, or visit should not be mistaken for an optimised approach to digital customer communication. Many life sciences companies are still hard-pressed to deliver a seamless and consistent customer 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

experience. Although the industry is moving toward integrated technology platforms that effectively support multiple communication channels, incorporating social media is an additional challenge. According to van den Burg, cloudbased content management systems are among the tools the industry is using to manage communications with customers and stakeholders. When integrated with CRM and data platforms, companies can gather an accurate view of what information customers and their patients need from the company. As instant cross-platform mobile messaging apps such as WhatsApp grow in popularity, establishing a compelling and holistic multichannel customer journey will be critical to success. Panellists agree that pharma needs to fully embrace integrated, cloud-based content, data, and CRM to enhance customer and patient communications. Ultimately, whether delivered face-to-face or online, useful real-time information will engage HCPs, build trust among patient groups, and help life sciences companies establish their voice in the multiple, multichannel, global conversations taking place about their therapies. Customer-outcome Focus Causes Patient Engagement and Services to Grow As patient groups form cross-border networks online, many life sciences companies are mirroring these efforts and experimenting with new patient engagement teams. With the growth of speciality pharma and a shift toward outcomes-based reimbursement, leading drug makers are realigning research, sales, and marketing resources to build networks of patients, payers, healthcare professionals, and life sciences stakeholders. The question remains, is patient engagement a new way to create value, or just the latest in a long line of pharma marketing buzzwords? “Patient engagement has always been a priority for Janssen and the industry. The better we understand the patient journey, the better we can serve our primary customer – the physician,” said Michel Baes, vice president of marketing operations, customer orientation, and transformation at Janssen. “Those companies working in heavily researched, rapidly developing therapy areas like oncology are already seeing the need to stop focusing on product information only, and start offering

patients and physicians holistic solutions – from prevention through to aftercare.” As 4G and sensor technology grow, the opportunities to gather accurate, context-based data from large patient groups in real time are also changing how life sciences companies approach patient engagement. Some pharma companies are seeking to bring clinicians, payers, and patients together in therapy-specific social networks, online, and through traditional professional conferences and sponsorships, which they hope will result in greater information exchange and data-mining capabilities. There are two technical challenges life sciences companies face when building successful multi-stakeholder therapy-area networks: providing relevant, compliant content, and managing the impending flood of incoming context-based data from customers and patients. According to van den Burg, forwardthinking life sciences technology leaders are resolving this dual challenge by integrating their CRM and content management systems into a unified cloudbased system that supports a holistic approach to customer engagement and data management. From ensuring all communications are compliant to gathering and analysing customer insight, integrating disparate legacy platforms in the cloud has potential to make big pharma agile and responsive enough to effectively lead global networks of multiple stakeholders around a specific therapy area. Looking Ahead The combination of skyrocketing sources of data and the scalable cloudbased technology to manage it all is transforming how the life sciences industry informs customers and uses patient data to develop life-saving therapies. By combining next-generation technology with well-informed brand marketing teams, companies are finding new ways to more holistically engage physicians, patients, clinicians, and payers and enhance these relationships. Jan van den Burg, Vice President, Commercial Strategy, Europe. Jan, our VP, Commercial Strategy, is responsible for strategy and product marketing for our Veeva Commercial Suite of Applications focusing on the European market Email: jan.vandenburg@veeva.com Summer 2015 Volume 7 Issue 2


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Regulatory & Marketplace

US Healthcare Prepares for ICD-10 Transition This year US healthcare organisations are preparing to move from 13,000 ICD9 codes to 68,000 ICD-10 codes (and this does not include procedures). It is a monumental task requiring strategies that apply to any organisational change of this size. The International Classification of Diseases (ICD) is the standard diagnostic tool for epidemiology, health management and clinical purposes. Clinicians use this code set to monitor the incidence and prevalence of diseases and other health problems, providing a picture of the general health situation of countries and populations1. On October 1, 2015, the United States will join 25 other countries in using ICD-10, the version that has been the standard for coding diseases, findings, medical complaints, causes and conditions of illness and injury since 1995. European countries have been using ICD-10 since the 1980s and have documented no decreases in morbidity or mortality solely related to ICD-10 implementation. When the Centers for Medicare and Medicaid Services (CMS) announced in 2014 that it would delay ICD-10 implementation until October 1 2015, the healthcare industry breathed a collective sigh of relief. However, much of the industry has not used this extra time to further readiness. In a September 2014 letter to HHS Secretary Sylvia Burwell, Jim Daley, the chairman of Workgroup for Electronic Data Interchange (WEDI), stated: “It appears the delay has negatively impacted provider progress, causing two-thirds of provider respondents to slow down efforts or place them on hold … while the delay provides more time for the transition to ICD-10, many organisations are not taking full advantage of this additional time.” Those organisations that are taking full advantage of this additional time to prepare, recognise that ICD-10 is already here. However, with less than a year to go until the transition, half of the physicians who answered a Medical Economics’ 2014 physician survey said they are not ready for ICD-10.2 There are many reasons for this, but on the whole 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

it comes down to cost, productivity and technology hurdles, and lack of certainty in the transition. While many physicians are not ready, the number who are prepared is up significantly from a large-scale survey in 2013 by the Medical Group Management Association, in which fewer than 5% of practices reported having made significant progress towards ICD-10 readiness3. Acknowledging the enormous outlay of resources required to transition to ICD-10, the CMS, through congressional action, has twice pushed back the compliance date, first from October 2013 to 2014, and then to 2015. But physicians, health plans and electronic health record (EHR) vendors should not assume another delay. Stanley Nachimson, principal of Nachimson Advisors and an expert on ICD-10, estimates there is a 75% chance that the ICD-10 transition will actually take place in October 2015. Most EHR vendors have already upgraded their software to reflect the new codes. “The health plans and vendors are moving forward and getting out ahead of the providers,” Nachimson said. “It’s time for the providers to catch up. Doctors need to be somewhat assertive and start taking steps to move forward on ICD-10. I’m not sure I’d want to take a chance of my revenue getting interrupted.” The US healthcare industry will require diligent, comprehensive actions to be fully prepared for the transition. This article will explore the successful strategies in the key areas of ICD-10 readiness, starting with general approach and governance. The Biggest Challenges in ICD-10 Preparation No coding system mandates that you have to use an electronic documentation system. However, with more than 68,000 Clinical Modifications (CM) codes and 76,000 Procedure Coding System (PCS) codes, an EHR greatly simplifies aligning the correct code to the service(s) provided. The

problem

many

organisations

continue to face is that no matter how comprehensive an EHR is, it is only as good as the information entered into it. Coding and Billing must be able to work together to retrieve clinical information and produce a clean and accurate claim. Or, as one CFO said, “For me to keep my job, I need to be able to quickly drop a bill that will be paid and doesn’t leave ‘money on the table’ due to under coding.” There is a wide range of diversity in how hospitals and health systems respond to the task. Perhaps the biggest challenge is that few organisations have truly embraced the concept that ICD-10 affects every part of the organisation. ICD-10 workflows start at registration and continue up to the moment the patient is discharged from the hospital or goes home from the physician’s office. Too often organisations consider ICD-10 as an “IT problem” or a “Medical Records matter,” when in fact the touch points involved in ICD-10 are significantly greater. To put this in perspective, there are consistently three major themes that emerge during assessments: • • •

Governance Education Documentation

While these areas are not unique to ICD10 readiness, each one has a number of critical elements that need to be in place to be ready for October this year. Strong Governance: Leading a Successful Change For a project as vast and complex as ICD-10, a successful organisation needs a strong governance structure assigned specifically to this endeavour. Leadership needs to define the operational structure required for ICD-10 readiness. It’s essential to have an ICD-10 executive sponsor and an ICD-10 “czar” responsible for maintaining the project on a steady and consistent path. Once leadership designates these roles, they need to communicate them throughout the organisation.

Summer 2015 Volume 7 Issue 2


next step in industrial research If your industrial research reaches limits, the Austrian Centre of Industrial Biotechnology (acib) comes into play. Indeed we can’t solve every scientific riddle, but with 30+ years of experience in many disciplines of industrial biotechnology we can point to many successful industrial projects. Additionally we can fall back on a broad international network/partnership of specialists to solve scientific challenges for industry. acib adopts the tools and methods of nature for i) new production processes & products with improved ecological efficiency, ii) new production processes with higher economic efficiency, iii) products with higher quality and purity, iv) functional innovative products for everyday use and v) sophisticated computational methods for the health care, pharmaceutical or chemical industry... acib – science ist our success.

acib GmbH Austrian Centre of Industrial Biotechnology Petersgasse 14, 8010 Graz, Austria t: +43 316 873 9301 f: +43 316 873 9302 m: office@acib.at w: www.acib.at


Regulatory & Marketplace The next step is to establish an operational committee with representation from the key areas affected by ICD10 (for example, HIM, Coding, Billing, Finance, IT, Education, Nursing, Medical staff). This committee’s charter defines its roles and responsibilities. It should also provide specific guidelines, such as weekly meetings, a defined agenda and a mechanism for apprising the C-suite of both current state and meeting upcoming milestones. Leadership should empower this committee to recommend changes to the project’s overall structure and advise course corrections. Communicating ICD-10 as a Top Priority With the governance structure now in place, effective communication provides the underpinning for a project of this size and importance. From the beginning, leadership must show its involvement and dedication to a successful transition to ICD-10 by informing everyone that this is top organisational priority. The organisation can use various channels, such as meetings, newsletters, and even an ICD-10 blog that speaks to the project’s goals, objectives, milestones and successes. Assigning Sufficient Resources Many organisations soon come to realise that a project such as ICD-10 readiness relies heavily on having sufficient resources available. For ICD-10, this means people, money and perhaps the most important element – time. Staff will require training, and this means identifying trainers not only for those who provide care, but for billers and coders. It means budgeting the money both for these resources and for upgrades and modifications to your existing IT systems so that ICD-10 can successfully operate within your environment. But beyond this, leadership must realise that a project as important as ICD-10 will require time – time for education and training, time to ensure that the work proceeds as anticipated, and time for those overseeing this work to make certain it is being done effectively and efficiently. Summary ICD-10 is the largest mandate in US healthcare history. Full ICD10 implementation will require diligent, comprehensive actions. The three pillars to ICD-10 success are the same with any enormous organisational change: governance, 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

education

and

documentation.

Many organisations have called for additional delays before full implementation while other organisations across the US have already made significant strides to prepare for the change. But is another delay of ICD-10 the solution? Many believe not, because any further delays can hinder forward momentum. Organisations that fell behind before the delay haven't taken the extra time to get up to speed, and therefore additional time to prepare isn't likely to motivate them any more than the first delay did. Organisations delaying ICD-10 preparations are risking a huge financial hit. The US Department of Health and Human Services (HHS) estimated that the cost of transitioning from ICD9 diagnosis and medical procedure codes to ICD-10 codes would be $1.64 billion.4 Healthcare organisations that were prepared for a 2013 conversion deadline have already incurred most of the costs for training and system changes, and they must continue to spend more on training during the delay to ensure skills gained don’t disappear through disuse. A second ICD-10 article in the Autumn edition will address the key issues surrounding education and documentation. It may appear to be a daunting task, but with the right approach, it can benefit the patient, the physician and the organisation. References 1. The World Health Organization. International Classification of Diseases (ICD) (Internet) http:// www.who.int/classifications/icd/ en/ [Accessed 13/04/2015] 2. Rachael Zimlich, 2015. ICD-10 in 2015: What physicians need to know about testing, costs and preparedness. (Internet) http:// medicaleconomics.modernmedicine. com/medical-economics/news/ icd-10-2015-what-physiciansneed-know-about-testing-costs-andpreparedness?page=full [Accessed 13/04/2015] 3. Medical Group Management Association. 2013. New MGMA ICD-10 research suggests industry coordination lagging. (Internet) http://www.mgma.com/practiceresources/articles/washingtonconnection/2014/februar y/

new-mgma-icd-10-researchsuggests-industr y-coordinationlagging [Accessed 13/04/2015] 4. Jeff Tenant, 2015. Why physicians should support, not oppose, ICD-10. (Internet) http://www. healthcarefinancenews.com/blog/ why-physicians-should-supportnot-oppose-icd-10 [Accessed 13/04/2015]

Jeffrey Goldstein is a Clinical Transformation Consultant at Allscripts and an internationallyrecognised consultant with over two decades of experience in senior administrative and clinical management for hospitals, ambulatory care centres and longterm care facilities as well as extensive consulting experience in both the provider and payer segments of the industry, with a focus on the medical management payer practice. He provides analytic and operational consulting expertise related to medical management, optimising the quality of healthcare, improving clinical efficiencies and integrating interdisciplinary evidencebased medicine programmes into an organisation. Jeff has been an active voice in the healthcare community on the importance of quality and efficiency. He has spoken on this subject before numerous professional meetings including the American College of Healthcare Executives (ACHE), the New York Association of Homes and Services for the Aging (NYAHSA) and the Gartner Group’s national conference on new technologies in healthcare. He has authored several white papers to guide the consumer in making educated, appropriate choices when selecting both a hospital and a physician. During his career, Jeff had worked with private and not-for-profit healthcare organisations in the US, the UK, Canada and Hong Kong. He has advised facilities ranging from rural community hospitals to academic medical centres to help them identify opportunities to improve care and then to guide them through the process of implementing the interdisciplinary changes needed to achieve their goals. Summer 2015 Volume 7 Issue 2


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Regulatory & Marketplace

Life Sciences in Asia: Is the Tiger an Endangered Species? The story of Western expansion into the life sciences in Asia has been one of rapid change. Nick Stephens, Executive Chairman of RSA, the leading global life sciences executive search and executive interims specialist, explains how the war for talent in Asia has been adapting to the unpredictable landscape. Asia is proving a volatile but vital market for the life sciences industry. The initial flare of optimism in “the Chinese opportunity” has recently been dampened by less-than-stellar growth figures, declining profit figures, high R&D costs and, of course, the corruption charges faced by GSK and other multinationals. Following their record $490m fine in 2014 for paying out bribes to promote their products, GSK – and other Western pharmaceuticals – will understandably be considering their operations in the region carefully. This certainly wasn't part of the plan when the much-heralded eastern expansion was being touted in recent years. For some, there is a feeling that investment and activities in China were overplayed. But the diverse nature of the sector means that global companies still stand to gain in the coming years. The strategy for life sciences in Asia is largely unchanged because the markets are still growing, and the burgeoning middle class in the region can afford either to buy their own drugs, to pay the taxes to fund socialised healthcare systems, or both. What has changed is how the industry is approaching Asia. They are being smarter about where companies operate, and more diverse about where they invest their money and how they apply it. All of this has an impact on the talent they need to succeed. Home is Where the Heart Is If the continued presence of Western pharmaceuticals in Asia seems assured, how will they approach recruitment in the wake of recent 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

scandals? In a word – defensively. One theme across the multinational pharmaceutical companies in Asia is a withdrawal of power back to headquarters, which are taking more active roles in management and oversight. Home-grown talent is increasingly being favoured for the senior roles, with regional leaders even more frequently being assigned from Western headquarters. Regional headquarters are finding that they have less freedom to appoint local people into these 'signature' positions. The exception to this trend is for those leaders who have already established strong, credible, and trustworthy experience in “blue chip” companies in the region. Companies are increasingly keen to hear from these individuals. Meanwhile, we are told by “agency” friends that the demand for local junior staff remains strong. Turnover remains high, reflecting both the ambition and drive of the people, and what is often perceived to be a lack of loyalty to and from the companies concerned. In the recent past, senior executives often felt they needed the “Asia badge” on their CV in order to progress to VP levels and above. As the Asia market matures and becomes a leader in healthcare innovation, the “badge” is increasingly becoming a career goal in itself. The Science of Compliance With the Sunshine Act due to come into effect next year, transparency is more important than ever for the industry. The Act, which compels pharmaceuticals to track data on payments and gifts made to physicians and teaching hospitals and to make it publicly available, means that compliance is top of the agenda for life sciences businesses. Life sciences multinationals are therefore increasingly recruiting for compliance roles in or for Asia, whether that's in clinical quality, manufacturing quality, regulatory, or finance staff. This has a knock-on effect for on-boarding and training too.

Diversity is Opportunity The growth of government-backed socialised healthcare systems is helping to fuel the growth of the sector across several countries in Asia. In China, South Korea and Singapore there exists a blend of healthcare systems. In Indonesia, Vietnam and the Philippines, governments are striving to develop new, universal healthcare systems. As the economies grow and healthcare becomes more established, so too will the market opportunity. The relative youth of the Asian market presents unique opportunities for Western pharmaceuticals. Companies are able to extend ageing brands, giving them a new lease of life. Products that are no longer profitable in the West can make a profit in Asia as the brand implies quality and commands a premium over “local” products. The markets for some related (but nonlife-saving) categories, like cosmetic procedures, health & beauty and nutrition, are growing very fast across Asia. These are interesting changes in the market and are themselves driving an increase in demand for talent from consumer marketing in Asia and beyond. It remains to be seen which company, which sector, and which countries will benefit most as “Western” businesses continue to adapt to the Asian market. But one thing is for sure; the potential rewards remain huge.

Nick Stephens is Executive Chairman of RSA. He has been a Director of the RSA group since 1986 and joined the business full-time in 1995. Nick’s role is to lead the development of the RSA business, drive the creation of new ventures across the world and support the development of new value added services. Email: nick.stephens@thersagroup.com Summer 2015 Volume 7 Issue 2


Regulatory & Marketplace Pharmaceuticals in Asia: Where to Watch All the Asian pharmaceutical markets will change over time. But where are the opportunities for talent today? Nick Stephens, Executive Chairman of RSA, the leading global life sciences executive search and executive interims specialist, explains. Japan “The Japanese market is evolving rapidly. Originally a very insular, inward-looking market, it is now lifting its head to the global market and its regulators are working hard to enable pharma to develop drugs in the region/for the region. Japan also leads the way in some cutting edge areas for example, stem cell research. As a result, we're seeing a big upsurge in related roles in the region.” South Korea “South Korea is exploding. It's likely that there will be some big IPOs there soon, with a consequent upsurge in demand for talent. The market is often seen as safer than China and data gathered there is seen positively by the SFDA. There is a burgeoning demand for talent across the industry.” Singapore “Singapore is usually seen as the safe base for businesses in Asia. This perception is correct and increasingly true. Its economy is benefiting from new investment by companies who find the environment conducive because of the substantial government investment in basic science, translational science and bio-manufacturing; as well as in developing an environment where business can operate to US/EU standards with ease. Multinational pharmaceuticals are flooding to Singapore, especially at the “consumer end” of things such as nutrition, consumer healthcare, OTC medicines and health and beauty. Demand for expertise in these areas is rocketing. China “With 1.4 billion people, China remains a priority, you simply can’t ignore! Although the industry is licking its wounds, it’s too committed to pull out completely. If you have access to “safe pairs of hands” you have a competitive advantage. “Across the whole region, countries and businesses are able to use the comparatively “blank sheet” to experiment with moving from an IP focussed healthcare model to a “patient outcome” model. The winners will transform global healthcare and drive value for shareholders and patients alike. Watch this space!” www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace Prioritising Health Economics Responsibilities to Impact Payer Pricing and Formulary Decisions Throughout a product’s lifecycle, health economics and outcomes research (HEOR) teams take on a number of activities to support a company’s broader market access efforts. In addition to supporting brands nearing regulatory approval, HEOR groups must be able to support teams negotiating pricing and reimbursement. To best advocate for evolving brand goals, health economics efforts also shift focus as products move through the lifecycle. HEOR groups must anticipate payer needs pre-launch and then shift to support marketplace and product changes as the brand matures. To best showcase a product’s value, companies may leverage multiple internal functions — ranging from medical personnel to managed care liaisons (MCLs) — to support health economics strategy. For example, Company A* begins preparing a brand’s health economics strategy early in development — a minimum of 18 months before product launch — as part of a launch readiness process. During this process, managed care support and medical groups work together to prepare brand materials for payers. All materials go through an internal review process to ensure that they can be distributed compliantly to payers prior to these organisations asking their own questions. These groups also consider the kinds of questions to anticipate from payers so that they can prepare answers and determine which accounts are priorities. However, the work does not end with launch readiness. An executive at Company A noted that HEOR information development and distribution are ongoing. The group assesses account-level payer needs, and the HEOR team equips Company A’s MCLs with the appropriate information. As products move through development and field liaisons prepare to meet with payers, HEOR teams must consider the best ways to support their products. Innovative teams look beyond traditional models to demonstrate brand value. A Company C director explained, “As products move to launch, our HEOR 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

team really shifts toward looking at ways to collect real-world evidence and the real-world benefit of the product — whether it’s observational or noninterventional studies, post-approval or claims database analysis — to get a sense of how the product is actually performing.” This outlook is increasingly important as brands are priced closer to their value threshold. Companies must be able to demonstrate brand impact in both efficacy and cost-effectiveness to maintain profits. Embrace Multiple Strategies to Disseminate Key HEOR Data to Payers While piecing together meaningful health economics information is the first part of the battle, delivering it to stakeholders in the healthcare community can be a real challenge. HEOR teams often look to a combination of publications and payer presentations to support brands — presenting both a broad look at a brand’s health economics and outcomes performance and a tailored view for individual stakeholders. Field forces including health outcomes liaisons (HOLs), medical science liaisons (MSLs) and MCLs then reach out to payers and other HEOR stakeholders to deliver this information. Company E uses publications to spread its health economics data throughout the scientific community. This company’s published data combine high-quality research, on-label clinical outcomes and strict adherence to industry publication guidelines. However, outside of publishing articles, Company E often has difficulty distributing this information and is resigned to hoping that the right stakeholders — pricing and contracting committees and managed markets groups — see it. “Our company has a system in place to approve materials for our sales force’s promotions, but they threw their hands up when dealing with our health economics materials,” explained a Company E executive. “All health economics analysis is off-label. Nobody has a comparative or costeffectiveness claim on the label — and that scares people.”

This director is aware of distribution tactics at other companies; these include leaving HEOR-related flyers and other materials behind in doctors’ offices and other venues, as well as distributing scientific posters or giving conference presentations. But the director and other Company E executives are very concerned about remaining compliant while disseminating their findings. “The FDA doesn’t want to see health economics as a backdoor for off-label promotions, but at the same time decision-makers need to know this information,” said the Company E director. “It’s a hard balance and we’re still trying to find it.” At Company A, the managed care support group plays a large role in disseminating HEOR information. During a brand’s launch readiness programme, internal stakeholders compile a number of different materials focusing on key HEOR data. Right now, these materials are evolving to look at real-world data in addition to budget impact studies and cost-effectiveness data. The company’s medical and health economics-focused groups feel that real-world data — how the treatments are performing in real patients and how they are impacting healthcare savings — are the most useful and most persuasive information for their customers. To maximise their resources, Company A’s field force prioritises customers — by labelling them as either Tier 1, Tier 2 or Tier 3 — and tailors health economics presentations accordingly. These priorities are based on how a product’s therapeutic area has been met in the past by that account. The managed care support director at Company A explained, “If a company has a pretty open application, there’s a different level of information we might present. If the therapeutic area has been tightly managed, we might be more aggressive. The last consideration is based on [pure size] — a very large entity with a lot of coverage will be assessed early on. Last would also be referred to as malignancy: If you have someone regardless of size, if they have influence in a particular area, Summer 2015 Volume 7 Issue 2


Chapter Title

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


Regulatory & Marketplace then you may want to highlight them early on for what you do.” Coordinate Payer and Stakeholder Visits with Commercial Representatives Company E, which does not maintain HOLs, looks to MSLs to disseminate health economics information. These field agents often accompany sales representatives and managed markets account managers to meet with stakeholders. Because health economics data are typically considered off-label, commercial reps will leave during these presentations to maintain compliance. Like Company E, top 10 biotech Company A’s internal HEOR stakeholders also collaborate with commercial reps to distribute information to payers and other external targets. Often, the MCLs — a key force in payers’ health economics education — have schedules and visits that overlap with managed markets account managers’ efforts. In these cases, the two representatives may be present at the same meeting. However, as noted before, the commercial representative must leave before the MCL can present health economics and outcomes data. If the MCL is sharing information approved for a proactive setting, the managed

20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

markets account manager may be present. However, if the stakeholder has questions that are beyond the label — beyond what has been approved for these proactive discussions — the MCL will address those concerns at the end of the meeting, after the account manager has left the room. Tailor HEOR Presentations to Specific Payer Expectations Company B’s EU-based team splits HEOR responsibilities between an inoffice group and a field force. The health outcomes team in the office is responsible for generating data and compiling them into presentations and health economics models. Often these data originate in regulatory documents — either the National Institute for Health and Care Excellence (NICE) or Scottish Medicines Consortium (SMC) submissions. While these documents may be 200 or more pages of brand data, the EU-based HEOR team condenses this information to around 20 PowerPoint slides. “There’s an element of simplification and summarisation when presenting our key HEOR data to our customers,” explained a Company B executive. Company B’s team also tailors information so that it is region-specific as

the field HEOR team visits payers. “We take national data that’s associated with regulatory submissions and refine it,” said one interviewed health outcomes consultant. “Our data is focused and relevant to the key customer we’re speaking to on a face-to-face basis.” The field team is responsible for delivering this information to stakeholders, as well as informing the in-office team of HEOR needs in the scientific community — letting them know which data would be most helpful in supporting clear conversations with customers. This tailored approach aids the HEOR team and the company’s field force as they work through the multiple levels of market access. For example, in the UK, there are tiers at the national, regional, local and sublocal levels. Because each tier has its own evaluations, a medicine recommended at the national level — by NICE, for example — may not make it through a formulary committee at the regional level. Each tier must recommend the brand for patients to get access to the medicine. Tailoring HEOR data to specific expectations helps to ensure that brands are proactively prescribed post-approval.

Summer 2015 Volume 7 Issue 2


Regulatory & Marketplace Stay Vigilant to Respond to Newly Released Comparative Effectiveness Research Comparative effectiveness research plays a key role as companies carve out brand positions in the commercial space. Proving a product’s superior efficacy or safety can be an engaging argument as health economics groups prepare value propositions for payers. However, teams must also be vigilant in reviewing competitor publications — making sure that they are not the competitor in question. Company E’s brand was recently used in a competitor’s comparative effectiveness study. The competitor’s product is a much cheaper medical device — costing $50 per device versus Company E’s $200 device. “Our competitor has no efficacy, but they’re saying that they perform just as well as our product. That’s very attractive to someone working under budget constraints,” said an interviewed Company E director. In response, the health economics team pulled together a study to demonstrate

the brand’s value. This study is a direct contradiction to the findings shown in their competitor’s retrospective study. “Responding to these situations is a high priority,” explained the director. “We have to look for ways to do highquality comparative effectiveness work to either negate or discredit those claims.” Prioritise HEOR Team Activities Based on Team Scope: Central Global Groups Focus on Preparing Information for Government and Private Payers Health economics and outcomes research teams must take on a wide range of responsibilities to support brands throughout their lifecycle. However, not all HEOR activities command the same percentage of a team’s time and focus. Surveyed HEOR teams were asked to consider their regular responsibilities and the allocation of their time. They then ranked specific HEOR activities as one of four categories: •

Core activities: Responsibilities that consume more than 20% of a team’s time

• •

Supplemental activities: Responsibilities that consume between 5% and 20% of a team’s time Minor activities: Responsibilities that consume between 0% and 5% of a team’s time Not performed: Responsibilities that are covered by other internal teams or are not regularly performed by HEOR teams

Data show HEOR team priorities across multiple group types and geographies. Data also examine the range of time allocated to surveyed teams’ major activities. Figures 1.1 and 1.2 examine key HEOR activities performed by central global groups. These groups are headquarterlevel teams that provide HEOR information and support to country-level teams worldwide. At small companies, these central global groups may also have contact with external stakeholders; for larger firms, these groups will primarily support country-level HEOR

Product News Sartoclear Dynamics®: Sartorius Stedim Biotech launches a new single-use harvesting technology for high cell density cultures up to 2,000 L • • •

Single-use clarification system eliminates centrifuges High cell density harvesting performed in a single step Process robustness and predictability ensured

Goettingen, Germany, April 14, 2015 - Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, has introduced Sartoclear Dynamics®, a clarification system featuring new single-use technology for harvesting mammalian cell cultures with high cell densities.

Continuous improvements in growth media and cell lines have elevated biomass concentrations in bioprocesses. Therefore, these increasingly higher concentrations place growing challenges on the purification process. As body feed filtration has proved to be the best solution to solve similar challenges in related industries, Sartorius Stedim Biotech has now developed this robust technology for biotech applications.

Nowadays, 2,000 L is a standard size for single-use bioreactors, but a centrifuge is still required for removing cells from such volumes. This technology now enables a fully singleuse process, which brings enormous flexibility to our customers’ facilities. It also eliminates considerable capital investments, which is attractive for newcomers from emerging biotech markets.”

Specially designed for cGMP processing, Sartoclear Dynamics® consists of prefilled singleuse bags containing ultrapure diatomaceous earth (DE) in a choice of 0.5 kg to 10 kg. With a new quick-connect adapter for dust-free powder transfer, DE can be directly mixed into the cell culture fluid. This porous filter aid prevents blockage of the Sartoclear Dynamics® filters. As the system maintains a constant ratio of biomass and filter aid, users will benefit from continuous maximum filter performance. Consistent results, ease of use, tremendous speed and linear scalability are the key characteristics of the Sartoclear Dynamics® technology. Used in combination with precipitation, this technology transforms harvesting from a two-stage process into a single-stage operation, saving valuable footprint – and time.

Contact: Sartorius Stedim Biotech Goettingen, Germany Phone: +49.(0)551.3080 info@sartorius-stedim.com www.sartorius-stedim.com

Stefan Schlack, the Senior Vice President of Marketing at SSB, comments: “With Sartoclear Dynamics®, we are closing one of the biggest gaps in the single-use product offering. www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace Conclusion Despite a wide range of activities, HEOR groups must be able to prioritise responsibilities to best reach their target audiences. Though some activities require more attention and time than others, each one is necessary in developing thorough health economics support for emerging and existing brands across multiple payers and HEOR stakeholders. Stakeholders may have different expectations depending on their region of operation, government versus private oversight and their own resources and priorities. As companies prepare brands for launch, pricing and reimbursement discussions and beyond, health economics strategies must account for distributing best-fit data to address individual payer needs. *The data for this article come from primary survey data collected by research analysts at Cutting Edge Information. Study participants included vice presidents, directors of global and regional HEOR departments, market access managers, and other related personnel from more than 30 companies of all sizes and geographic locations. Company, product and participant names are blinded to ensure that the identities and privacy of all participants are protected. Blinding allows survey respondents to comfortably provide accurate data for all Cutting Edge Information studies.

teams. Among surveyed groups, five identified major HEOR activities are developing information for government and private payers, conducting internal health economics analyses, valuating products for marketing messages, and managing vendors (Figure 1.2): •

The highest percentage of surveyed teams (33%) consider developing information for government payers a core activity. Teams spend an average 16% of time on this activity, ranging between 5% and 42%. Developing information for private payers — which averages 12% of global teams’ time — follows a similar trend; surveyed groups allocate up to 40% of their time on this task. The remaining major activities claim between an average 9% and 11% of teams’ time.

Though only five major activities are identified, an equal percentage (17%) 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

report prioritising eight different activities as well as the 33% which prioritise developing information for government payers (Figure 1.1). These additional core activities include aiding trial design, meeting with payers, supporting pricing decisions and preparing content for regulatory submissions. While teams note a number of core activities, larger percentages report each activity as either supplemental or minor activities. With the exception of working with government payers and organising or presenting data, some percentages of groups report not performing activities. There is significant overlap in certain activities — such as managing vendors and marketing valuations — that some companies consider core while others do not perform at all. Two-thirds of teams (67%) do not train sales reps, MSLs or account managers.

Reference Presson, J., Cavicchi, V. & Richardson, D. (2015). Building World-Class HEOR Teams: Creating Convincing Value Propositions for Payers (87–93). Research Triangle Park, NC: Cutting Edge Information.

Victoria Cavicchi joined the Cutting Edge Information team in early 2012. Her work includes pharmaceutical consulting and research studies focused on key opinion leader fair market value, sales force management, Big Data, health economics and outcomes research and managed markets account managers. Victoria has a Master of Arts degree in English from Virginia Tech. Email: victoria_cavicchi@ cuttingedgeInfo.com Summer 2015 Volume 7 Issue 2


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Regulatory & Marketplace

Changing Healthcare Landscape and its Impact on the Pharmaceutical Industry Introduction The pharmaceutical industry is a success story, providing employment and ensuring that essential drugs at affordable prices are available to the therapeutic-naïve population. At the same time it is one of the most regulated industries across the globe. Until recently, pharma investments in R&D and innovation resulted in patent-protected, high-margin revenue streams. Doctors prescribed drugs. Patients accepted the doctor’s prescription. And payers footed the bill. The business was lucrative. Lean practices were not needed in the pharma industry. This has increased the value of the global pharmaceutical market. Figure 1 indicates the expected growth worth nearly $ 1.6 trillion by 2020. The growth markets include, in descending order of size, China, Brazil, Russia, India, Mexico, Turkey, Poland, Venezuela, Argentina, Indonesia, South Africa, Thailand, Romania, Egypt, Ukraine, Pakistan and Vietnam. The EU big 5 is France, Germany, Italy, Spain and the United Kingdom.

advantage to maximize its value in terms of R & D efforts, quality products, cheaper medicines and public trust instead of volume. This editorial highlighted the changing healthcare landscape and its impact on the pharmaceutical industry. Maturing Emerging Markets Today, China and India together contain the 40% of the planet’s population and stand on the threshold of global superpower status. There is an increase in the number of middle-class consumers. More than half of the people in China, South Korea, Brazil, India, Russia, Turkey, Mexico and Indonesia are middle-class consumers. These markets are playing a major role in driving the growth of the global pharmaceuticals market. While the market for pharmaceutical products will grow on average by 4.5% annually through 2016, growth in emerging markets will increase by almost 12%.1 Governments are also stepping up for growth across the region. For example, the Indian government has started offering incentives to domestic and multinational drug makers to encourage new drug discovery.2 Simultaneously, companies are eager to capture a portion of the region’s comparative advantages in talent, costs, patient pools and disease demographics from a biopharmaceutical development perspective. Technology Development Competitive and technological

development in the pharmaceutical industry from powerful new drug chemistries to innovative R&D partnerships and marketing plans are reshaping the business strategies of many pharmaceutical and biotechnology companies. Technological growth not only rapidly changed the way we live and work, but it also enabled great leaps in productivity, interactivity, connectivity and transparency. It utilizes the data analytics to identify the best-targeted and most cost-effective therapy, and uses social media to engage with customers. For example, the makers of Clarityn created an app which provides users with detailed information about local pollen count, and where to find nearby medication to help ease seasonal allergy symptoms.3 Various trends in technology impacting the industry are highlighted in Table 1. Changing Government Policies While the goal of the pharma industry is to enhance care and safety remains constant, the methods, resources, and government policies that are designed to reach this goal are continuously being updated. These changing policies may have a positive or negative impact on pharma industry. For example, in 2010 Portugal introduced mandatory price cuts which reduced the prices of generic medicines by 30 per cent, and branded drug prices by six per cent.4 Similarly,

Figure 1: Expected growth of pharma industry Source: Business Monitor International

However, over the last decades the exclusive domain of the pharmaceutical sector has entered an era where they have become confronted by a variety of complex issues affecting their operational efficiency and profitability. Today the pharma industry is scrambling to deal with big challenges and changes that include market uncertainty, responding to price pressure, rising competition, regulatory changes, the patent cliff, power shift from doctors to payers and patients, and patients’ empowerment, etc. Thus every big and small pharmaceutical firm is seeking every 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2015 Volume 7 Issue 2


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Regulatory & Marketplace the Ireland government in 2011 reduced wholesale mark-up on most drug items from ten per cent to eight per cent, which resulted in additional savings of more than €34 million.5 The firm and rigid regulatory framework is needed for stability of the pharmaceutical sector. Consumer Behaviours Many pharmaceutical companies use demographic data and health condition to determine the types of patients best suited for their products. Such data may not always provide an exact picture of consumer behaviour and attitudes. Consumers want their medication experience to be personalized and meaningful. If their expectations are met, they’re more likely to follow the proper course of treatment for longer. Other elements, like strength of social networks, stress and habits, extentof self-reliance and community reliance, willingness to share experiences with others and trust in others, also play an important role in analysing consumer behaviour. In the west, consumers will seek more products and services that are environmentally friendly and are produced according to fair trade practices. Consumers in emerging economies look for affordability, utility and durability to stand up to harsh conditions.Customers in all markets want real value for their money. While analysing the consumer, pharmaceutical companies need to look into their behaviour and motivations and should learn how to create loyal customers. The Patent Cliff Expiry of patent drugs on one side and growing competition of low-cost generics on the other side causes a loss

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of billions in revenues to pharmaceutical companies. For example, in November 2011, four major drugs, viz. Lipitor, Caduet, Combivir and Solodyn, lost patent protection. Combined, these four drugs accounted for more than $7 billion in lost sales.6 Discovery and development of a promising agent will address unmet medical needs and are profitable. Structural reorganization and downsizing will help inpreserving future profitability. Mergers and acquisitions will also change the face of the pharma industry. Some pharmaceutical companies are already entering into agreements with generic manufacturers, licensing them the right to sale “authorized generics” identical to branded drugs that have gone, or will go, off patent. Others have established their own generic manufacturing companies or subsidiaries. In short, the financial future of the industry depends on how they manage the transition of many of their brand drugs to the generic market, and their own efforts to adapt to the changing global business climate. Patients are Empowered Traditionally, pharmaceutical companies have had very little direct contact with patients with regard to treatment. However, as patients are more knowledgeable and empowered, they gain influence, so pharmaceutical companies are changing the nature of their engagement with patients. Today’s patients know more about their diseases, choices for medication and methods of treatment, and are more assertive about defending their interests in a healthcare landscape. In a survey of 1300 patients, most of the patients found medical information online, with 73% of patients

feeling that this gave them greater control over their illness, and 85% of patients taking that information to their doctor.7 Knowledgeable patients can provide benefits to pharmaceutical companies. By using patients as a channel of communication, they can reach out to a different audience effectively. Power Shift An increasing generic market has given a number of choices to patients and payers for the purchase of medicines. With the variety of generic versions of branded drugs, the price benchmark has been reduced and people are insisting on value for money. In the past, the doctor was the final decision-maker in providing healthcare facilities. But nowadays, the power has shifted from doctors to patients and payers. This power shift helps to stabilize the cost of drugs. Thus, the pharmaceutical companies must design a simple, reliable service or solution around the patient. Some companies often express their desire to be patientcentric organisations. Whether inspired by patients or driven by science, the heart of everything is focused on the patient’s needs. Our efforts have to be relevant and meaningful, and we have to be ready to do something that really helps patients. Conclusion In a growing and changing economic environment, pharmaceutical companies are faced with new challenges and opportunities. Some challenges are easy to tackle, and others have consequences for the pharma industry; however, effective dealing will help the industry to grow faster and earn more profit (Table 2). In today’s technological world,

Summer 2015 Volume 7 Issue 2


Regulatory & Marketplace the “Patent Cliff”. U.S. Pharm. 2012;37(6)(Generic suppl):12-20. 7. Andy Robertson.Patients Advocating Pharma – It’s as Simple as Arming them with the Right Information. 27th Feb. 2014. Available at: http:// social.eyeforpharma.com/content/ patients-advocating-pharmaE2%80%93-it%E2%80%99ssimple-arming-them-rightinformation(Accessed on 11th Feb 2015)

manufacturers should consider new kinds of healthcare as opportunities for development. It has become vital for industry professionals to increase their preparedness and be ready to develop tactical plans of action. Companies that can offer high-quality products at reasonable prices require efficient administration, marketing and sales models. Companies should conduct their medical affairs and R&D activities locally, develop a strong local sales organisation and collaborate with regional companies in order to gain effective access to patients willing to pay higher prices. In general, pharmaceutical companies need efficient production and sales initiatives to drive their sales and earnings. Similarly, other stakeholders, including consumers, doctors and regulatory authorities, need to be proactive so that patients can enjoy consistently safer and more effective healthcare systems. Disclaimer The article has been written in the authors’ personal capacities. All opinions expressed herewith are those of the authors and do not reflect the views of their organisation.

2.

3.

4.

5.

Conflict of interest None References 1. Roland www.ipimedia.com

Berger.

Global

6.

pharmaceutical industry is in a strategic crisis – Business models must be adjusted. January 6, 2013. Available at: http://www. r o l a n d b e r g e r. c o m / e x p e r t i s e / industries/pharmaceuticals/ Pharmaceutical_industr y_in_a_ strategic_crisis.html (Accessed on 14th Jan 2015) http://economictimes.india times.com/news/economy/ finance/Centre-may-inject-2bn/yr-into -drug-research/ articleshow/4210074.cms (Accessed on 10th Dec 2014) Six Tech Trends That Will Shape the Pharmaceutical Industry in 2013. Contributed by Acenture. Dec 10, 2012. Portugal Pharmaceuticals and Healthcare Report Q1 2011, Research and Markets, November 2010. Available at: http:// www.researchandmarkets.com/ research/a948d5/portugal_ pharmaceu. (Accessed on 9th July 2014) Health (Pricing and Supply of Medical Goods) Bill 2012: Second Stage, House of Oireachtas, 19 July 2012. Available at: http://debates.oireachtas.ie/ seanad/2012/07/19/00009.asp (Accessed on 9th July 2014) Jack DeRuiter, Pamela L. Holston. Drug Patent Expirations and

Sunil D. Shewale, M. Pharm, PGDCTM, MBA is an assistant project manager at the Serum Institute of India Ltd. (SIIL), where he has more than seven years of experience in clinical research and quality assurance of pharmaceuticals. He is a professional in product handling, documentation, trial monitor¬ing, data management, medical writing, and overall project management. He has coauthored several original re¬search publications for vaccine trials at SIIL. He has also published number of review articles. He can be reached at Email: ms.shewale85@gmail.com Dr Sameer S. Parekh, BHMS, MBA, CCRP is a clinical trial manager for the Serum Institute of India Ltd., who combines knowledge and experience from diverse fields such as research and clinical development, public health, and pharmaceutical management. He has over eleven years of experience in the biopharmaceutical industry, with increasing responsibility in national and international research and clinical development efforts. With a primary focus on infectious diseases, pediatrics and oncology, his specialties include multifunctional team leadership, development of study design, drug safety and medical writing. He contributed to the conception and design, drafting and final approval of this article. He can be reached at Email: parekhsameer@gmail. com INTERNATIONAL PHARMACEUTICAL INDUSTRY 27


Regulatory & Marketplace

The Evolution of the Life Sciences Sector and the Role of Biotech Incubators The life science sector is growing in significance to the world economy, and in particular for London and the UK. A biotech incubator with a 15-year history, the London BioScience Innovation Centre is ideally placed to serve the changing needs of biotech companies and to identify future opportunities and developments in the life science sector.

the LDA. 2009 saw demand increase still further and the RVC refurbished space in another of its buildings to allow an LBIC client to take on a single floor to itself. Since then, further space in the second building has also been acquired to meet demand, and LBIC’s total lettable space is currently in excess of 26,000ft2, with occupancy rapidly approaching 100%.

The Development of LBIC, London’s First Bio-incubator The London BioScience Innovation Centre (LBIC) was established in 2000 to meet the increasing need for laboratory and office space to house new start-up companies and university spin-outs in London. LBIC was the first life science business incubator in London itself: previously, the options for companies in South-East England were limited to either setting up their own facility (an expensive and complex process) or moving to facilities in Oxford, Cambridge or elsewhere in the UK, away from the financial hub of the City of London and further removed from international transport links.

There are now also two other incubators for biotech in London, both linked to academic institutions: Queen Mary BioEnterprises Innovation Centre (39,000ft2) and Imperial College London’s 24,000ft2 Imperial Incubator. The latter is in the process of building an additional facility in west London, such is the current demand for space in London.

LBIC was created as a subsidiary of the Royal Veterinary College (RVC), itself the UK’s first and largest veterinary school and part of the University of London. The RVC was recently ranked the top university for Veterinary Science in Europe and is the third highest-rated in the world according to the QS World University Rankings 20151. In common with many university-owned incubators, LBIC’s link with the RVC provides valuable opportunities for academic-industrial research collaboration and access to services such as shared equipment and contract research. LBIC was housed in an existing RVC building, refurbished using a £1.4 million grant from the London Development Agency (LDA), with Phase I opening its doors in May 2001. Phase II quickly followed in April 2002, utilising more RVC space to house clients. After successfully filling this space, it was clear that demand existed for more than the existing 12,600 ft2 of space. Thus Phase III was added in 2005, a purpose-built extension of the existing facility increasing LBIC’s lettable space by over 6500 ft2. The refurbishment and new build as a whole had a budget of £8.2 million, of which approximately £4.1 million came from 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What is the Appeal of a Biotech Business Incubator? Housing a biotech company in a specialist incubator provides an extremely attractive alternative to setting up a dedicated facility or converting space in a serviced building. A dedicated facility could require taking out a long lease on the premises, compared with a break clause as short as one month in an incubator. The cost of turning an empty shell into a containment level 2 laboratory is in the region of £3000 per ft2 (based on recent projects by LBIC and the RVC) for the basic fit-out of benching plus mechanical and electrical installation. A 1000ft2 laboratory would therefore cost around £300,000, not including any laboratory gas installation, which would probably cost at least £2000. Additional equipment that an incubator might provide such as air handling, microbiological safety cabinets and access to autoclave equipment would bring the figure to around £350,000 just to create a laboratory. There would also be the need to set up supply and maintenance contracts to cover operations including telephones, data connections, laboratory gases, hazardous waste disposal and specialist equipment. An incubator like LBIC will usually handle most of these contracts and recharge the client company as necessary, enabling clients to benefit from bulk discounts as well as removing the hassle of associated administration. LBIC also employs a sterilisation technician

to provide autoclave services for client companies. When a company is just beginning its research and development, a dedicated facility could prove to be a disastrous drain on resources. Meanwhile, founding scientists or even CEOs may inadvertently find themselves in the role of facilities supervisor, taking time away from their actual job of conducting research or securing funding. Setting up in a business incubator allows a company to move in quickly and carry out their work with minimal disruption. Business incubators are not just about physical space. Even for more established companies, an incubator base provides a wide range of benefits. Life science incubators play a significant role in providing access to funding, research collaborations (often with the institution that owns the incubator) and industry contacts, not to mention other clients who may be able to provide advice and encouragement. LBIC has also set up a business support network to allow clients access to complimentary or discounted assistance from expert service providers on diverse matters such as finance, tax credits, IT management or online marketing. A business incubator may have a ‘graduation’ policy, aiming for client companies to establish themselves within a set period (three years, for example) before moving on. Some companies grow large and successful enough to take the step into their own facility. An alternative path is acquisition by a much larger company, which would usually lead to the eventual vacation of the incubator space. However, sometimes a company prefers to stay in the incubator, or it remains structured in a way that moving on would require too much additional investment or subsequent application of resources. In these cases it depends on the incubator’s policy as to whether the company remains there. LBIC does not enforce a graduation policy at present but has occasionally benefitted by taking on new clients after another incubator enforced their own policy. LBIC

introduced

a

virtual

client

Summer 2015 Volume 7 Issue 2


Regulatory & Marketplace service to meet the needs of companies who wished to benefit from the link with a London incubator without taking on physical space, whether due to just starting out, being mainly based elsewhere or running a business that does not require a facility beyond occasional meeting-room space. Virtual clients have access to the LBIC facilities, services and networks but can be based anywhere, be that in another country, at a large facility elsewhere in the UK, or in a personal residence. LBIC currently has 35 virtual clients, ranging from start-ups to international companies. The total number of virtual clients has doubled over the past five years, featuring clients from 16 countries across Europe, North America and Asia, showing the increasing appeal of London and the UK as a base. A Global Business A key aspect of life science as an industry is its natural global applicability: the same health problems occur worldwide and so a solution developed in one place should be applicable elsewhere, subject to environmental compatibility and local regulatory approval. Many LBIC clients have international connections: for example, deltaDOT, a company specialising in high performance capillary electrophoresis (HPCE) instruments, has a distribution agreement in Japan as well as numerous links with the USA including supplying instruments to the Texas A&M Center for Innovation in Advanced Development and Manufacturing (CIADM)2. LBIC client iQur leads a consortium focused on the development of a novel universal influenza vaccine made up of institutions from Latvia, Luxembourg, Spain and the UK, funded by a €5 million European Union Framework 7 grant3. London in particular is well placed to facilitate international relations as well as attract overseas companies looking for a base, served by six international airports as well as Eurostar and domestic transport links. Four of the world’s top 50 universities are based in London, according to the Times Higher Education rankings 2014-154, while 28 of the Science Council’s ‘100 leading UK practising scientists’ work in London5. 2016 will also see the opening of the Francis Crick Institute, “a biomedical discovery institute dedicated to www.ipimedia.com

understanding the scientific mechanisms of living things”6 based beside St Pancras International station in London. A consortium of six leading UK scientific and academic organisations, the Francis Crick Institute will take a multidisciplinary approach to researching disease and illness, employing 1250 scientists and having an operating budget of £100 million per year6. The establishment of the Francis Crick Institute is part of the increasing commitment to life sciences in the UK. In March 2014, the UK government pledged £300 million for scientific projects, with the expectation of generating £0.50 in every subsequent year per £1.00 spent on research, representing a £150 million return annually. As part of its announcement, the government highlighted the fact that despite representing only 1% of the world’s population, the UK publishes 16% of the world’s top quality research. Recognising the importance of science to the UK economy, the government ringfenced a £4.6 billion science budget and guaranteed sustained capital investment of £1.1 billion each year until 20207. LBIC client Aqix benefitted from government funding through a grant from Innovate UK, enabling development of AQIX RS1®, which keeps donor transplant organs and tissues functioning outside the body for up to 72 hours8. In addition to the government’s contribution, $713 million of venture capital was invested in the UK life sciences sector in 2014, an increase of 41% compared to $503.89 million in 2013. Of this $713 million, $502.64 million went to companies in the ‘golden triangle’ formed by London, Oxford and Cambridge9. In April 2014 the Mayor of London’s Office launched MedCity London in collaboration with London’s three Academic Health Science Centres – Imperial College Academic Health Science Centre, King’s Health Partners and UCLPartners. The initiative is also supported by London & Partners and the Higher Education Funding Council for England (HEFCE). MedCity has set up the Angels in MedCity programme to build relationships between companies and potential investors, and is also partnering with the London Stock Exchange to publicise the diverse life science investment opportunities available

in the UK, as well as encouraging companies to consider flotation10. Businesses with a London address are further assisted by the Mayor’s Export Programme, set up with UK Trade and Investment (UKTI) to facilitate export relationships between London businesses and overseas organisations11. The Export Programme runs regular events focussing on worldwide locations: most recently, a delegation visited the East Coast of the USA to build links with leading investors and business figures there, with a particular emphasis on life sciences and technology12. The Evolving Biotech Sector As investment in life sciences grows and new technologies become available, innovative approaches to the business of biotech are developing, with a more multidisplinary approach to research and even increased flexibility in the way a business can be run. In future there is likely to be a significant increase in the number of companies working in ‘life science’ who do not perform regular lab work. In an article for the Guardian newspaper, Katie Erbs and Chris Duffey announced 2014 as “the year mobile became mighty in healthcare”, a trend that looks set to continue13. The two authors quote a study from Research2Guidance that identified 100,000 health apps worldwide, with 4 million free downloads daily. Mobile health app services are projected to grow to £15 billion by 2017, with uses including secure recording and transmission of personalised patient data, checking drug interactions and even using sensor technology to assist with diagnosis. Another emerging sector within life science that may not rely on standard laboratory space is synthetic biology, which was listed by the Department for Business, Innovation and Skills as one of the UK’s ‘eight great technologies’ in 2013. The global synthetic biology market is predicted to reach US$11.8 billion by 2018. Synthetic biology “aims to design and engineer novel biologically based parts, devices and systems, and redesign existing natural biological systems for useful purposes”14. A number of companies in this area are developing technologies that allow other users to streamline their processes to reduce the time spent in a laboratory. For example, INTERNATIONAL PHARMACEUTICAL INDUSTRY 29


Regulatory & Marketplace LBIC client Synthace utilises multifactorial experiments for systematic augmentation (MESA), which combines automated liquid handling with Antha, the company’s proprietorial programming language, to make “simple, reproducible and scalable workflows”15. This can accelerate the path to market for biological products by rapidly identifying the significant factors and interactions in a process early on, reducing the risk of unexplored interactions causing problems at a later stage. A recent development in scientific study is the emergence of scientific ‘hackerspaces’, such as the London Biohackspace, which is part of the London Hackspace facility, originally launched in 2009. London Hackspace is a nonprofit organisation that is owned and run by ‘members’, who pay a monthly fee that varies according to an individual’s circumstances and generosity16. The Biohackspace gives members access to donated laboratory equipment for “collaborative or individual projects for which it would be difficult to seek funding from traditional bodies”17. The Biohackspace is not limited to scientists, but is open to any member including designers, engineers and programmers, encouraging open innovation and novel approaches to biotechnology. This approach has close links to the rapidlygrowing synthetic biology sector, and participates in initiatives such as the annual Google-sponsored International Genetically Engineered Machine (iGEM) Foundation synthetic biology competition for students18. In line with the Hackspace’s focus on projects that may not secure “traditional” funding, the recent growth in ‘crowdfunding’ has begun to influence bioscience. While there are many unsuccessful attempts to secure crowd funding for biotech projects, a notable recent success was that of Glowing Plant, which raised US$484,013 against its original US$65,000 goal through the popular Kickstarter website. This project is based around creating plants that luminesce in darkness – “the first step in creating sustainable natural lighting”19. The funding success of Glowing Plant and the emergence of science hackerspaces is likely to bring about an increase in the number of bioscience companies following a non-standard path to commercialisation. Areas such as synthetic biology and mobile health 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

technology are particularly open to alternative business structures that may not revolve around a traditional laboratory base, as their recent advances allow users to develop products from any physical location. The Future The role of incubators is evolving alongside the biotech sector. Since it opened to clients, LBIC has supported well over 100 client companies, and is close to signing its 60th current client. The type of client has developed over time: LBIC’s client list now includes subsidiaries of large corporations such as Cancer Research UK and Johnson & Johnson, as well as more traditional SMEs. Elsewhere, some incubators have a formal link with a large corporation, as in the case of the Stevenage BioScience Catalyst, where GlaxoSmithKline (GSK) is a funding partner and encourages interaction between the incubator clients and scientists at the nearby GSK R&D site20. As larger companies create links with incubators, whether by becoming clients or through a partnership, smaller enterprises are finding new ways to structure a company and following novel paths to market. For these companies, a virtual office is more suitable, providing a professional front-of-house and networking opportunities without a commitment to physical space. References 1. QS World University Rankings by Subject 2015 - Veterinary Science http://www.topuniversities.com/ university-rankings/university-subjectrankings/2015/veterinary-science#s orting=rank+region=+country=+facult y=+stars=false+search= 2. http://www.deltadot.com/news.htm 3. Melanie Sena, 2013. iQur Leads Major European Project to Develop a Universal Influenza Virus Vaccine http://www.biopharminternational. com/iqur-leads-major-europeanproject-develop-universal-influenzavirus-vaccine 4. Time Higher Education World University Rankings 2014-2015 http://www. timeshighereducation.co.uk/worlduniversity-rankings/2014-15/worldranking 5. Science Council, 2014. 100 leading UK practising scientists http://www. sciencecouncil.org/content/100leading-uk-practising-scientists#top 6. http://www.crick.ac.uk/about-us/

7. Department for Business, Innovation and Skills, The Rt Hon David Willetts and UK Space Agency, 2014. £300 million investment to support growth and jobs in UK science https://www. gov.uk/gover nment/news/300million-investment-to-support-growthand-jobs-in-uk-science 8. Innovate UK, 2014. Organ donation: new technology preserves life at the margins https://www.gov.uk/ government/case-studies/organdonation-new-technology-preserveslife-at-the-margins 9. MedCity, 2015. UK life sciences ‘comes of age’ with 41% leap in investment http://www.medcitylondon.com/ news/uk-life-sciences-comes-age-41leap-investment/ 10. http://www.medcitylondon.com/ 11. h t t p s : / / w w w. l o n d o n . g o v. u k / priorities/business-economy/forbusiness/trade-missions 12. MedCity, 2015. MedCity joins Mayor of London’s US delegation http:// www.medcitylondon.com/news/ medcity-joins-mayor-londons-usdelegation/ 13. Chris Duffey and Katie Erbs, 2014. How mobile became mighty in healthcare http://www.theguardian. com/healthcare-network/2014/ jun/09/mobile-became-mightyhealthcare 14. Department for Business, Innovation & Skills and The Rt Hon David Willetts, 2013. Over £60 million for synthetic biology https://www.gov.uk/ government/news/over-60-millionfor-synthetic-biology 15. http://www.synthace.com/our-work/ 16. https://london.hackspace.org.uk/ signup.php 17. http://biohackspace.org/ 18. http://2015.igem.org/Main_Page 19. h t t p s : / / w w w. k i c k s t a r t e r. c o m / projects/antonyevans/glowingplants-natural-lighting-with-noelectricit/description 20. http://www.stevenagecatalyst.com/ about/

Lucy Garnsworthy has worked at the London BioScience Innovation Centre (LBIC) since 2010 and is currently the Communications Manager. Lucy is the editor of LBIC News (the biannual newsletter of LBIC) and is responsible for marketing and events at LBIC as well as working with colleagues on the daily operations of the Centre.

Summer 2015 Volume 7 Issue 2


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quality that today’s pharmaceutical carton makers need. and, if that wasn’t enough, a range of options that include the revolutionary aCCubraille Gt embossing system and, soon, the aCCuCheCK carton quality control device, mean that eXpertFOlD 50 is by far the most suitable folder-gluer for pharma carton manufacture.


Regulatory & Marketplace

The Cambridge/London Corridor: Its Strength and Impact on the UK In my role I am regularly asked what makes the Cambridge/London life science and healthcare corridor so vibrant, strong and supportive of the UK economy. There are, of course, fantastic examples of clusters or ecosystems around the world that are equally inspiring – in particular the East and West coasts of the US – but the question often asked is what makes our part of the UK so exceptional? There is, of course, the world-class science and academic base. Then add in the exceptional presence of risktaking entrepreneurs, the strength of the mentoring and coaching of those who have been there and done it already and are now giving back with their sage advice and wisdom, and of course brilliant companies, all against a backdrop of knowledgeable investors. This makes for a heady mix of the right ingredients in which the sector can be nurtured and flourish. It is of course not easy, but when has it been in this sector? Now more than ever, young and emerging companies, and the older, more established hands too are having to justify every penny spent and every hour used – and ensure that all they are doing is pivotal to the vision and mission of their organisation. So what is it specifically about Cambridge/London that means that we at One Nucleus (who are based in Cambridge) are inundated with requests to interact with, be profiled in front of and have contact with our R & D members.

exceptional’, and what in fact makes the UK exceptional? And we quickly came to the conclusion that it is the translation of research. When we really set about the detail of our initial view, it became more and more apparent that this is what differentiates the UK from other parts of the world – the company’s ability to collaborate, deal-make and translate an early-stage invention and idea into innovative healthcare treatments. So we created our one-day Cambridge-based ON Helix conference (this year to take place on 14 July at the Wellcome Trust Conference Centre www.onhelix.com). There are three key themes to what One Nucleus feels companies here do exceptionally well: • • •

de-risking of research, often by working in collaboration de-risking of partnerships – for example by having robust systems in place for the sharing of data de-risking of funding – with investors often having their interest piqued by being drawn to people who they know have been there and done it, and done it well, and by taking advice from peers on opportunities

Here the interaction between academia and business is incredibly strong, with partnerships springing up on an almost daily basis. Of course we are all basking

in the excitement of AstraZeneca moving its global headquarters to Cambridge – which is a fantastic move not only for Cambridge but for the UK – after all, Chief Executive Pascal Soriot could have decided to place his HQ anywhere in the world, and he chose the UK. In discussions with him, he has made it clear to me on several occasions the reasons were a) the strength of the science base and b) the collaborative spirit and opportunity. It’s important to remember that MedImmune, which is, of course, part of AstraZeneca, has long been involved in collaborations with academia, and AstraZeneca too here. The move to the BioMedical Campus in 2016 is already well under way with half of the 2000 reported team already in temporary situ around Cambridge, in advance of their lovely new building being ready. So this is all very positive, but what’s the statistical evidence for this region of the UK? Well, in describing the current activities and dynamics of this part of the UK, one needs to consider not just the immensely exciting growth of the Cambridge Cluster, but also how the M11 is shaping up to be a cash flow highway for our high-growth life science companies. Set out below are some of the key facts and figures about the greater CambridgeLondon axis, a world-leading base with two centres.

Three years ago we decided we would create a brand new Cambridge-based conference. Now there is clearly no good sense in creating an event for creating an event’s sake. Our R & D companies very much like and appreciate our therapyfocused one-day conferences, but they were missing interaction and dialogue with their peers in other parts of the sector; the opportunity to catch up over a coffee, chew the fat, share good news stories and share views on the state of the sector, barriers and issues in running what are often lean organisations. We had no wish to duplicate an event that others were already doing in the UK, so the obvious question to ask ourselves was ‘what makes this part of the UK 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2015 Volume 7 Issue 2


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Regulatory & Marketplace What is clear at a top-line level is that life sciences is thriving in the region with exciting growth, relocations, company formations (and exits), academiaindustry strategic collaborations and a strongly collaborative ecosystem. Key Facts and Figures • 239 biotechnology companies in the region (25% of the UK total) • 88 primary R&D companies developing novel therapeutics or diagnostics (38% of the UK total) • USD 143 million raised in the first 10 months of 2014 (43% of the UK total) From these key statistics it can be seen that the region is home to a disproportionate share of the primary therapeutics companies in the UK, and attracts an even more disproportionate share of raised capital. This illustrates not only the innovation strength of the cluster, but is also a reflection of the entrepreneurial ecosystem that exists locally where seasoned life science entrepreneurs interact seamlessly with more recent science graduates and PhDs with high aspirations and an appetite to learn. As well as the AstraZeneca news, there are also significant local expansions into new facilities underway for other exceptional companies including Dr Reddys, Takeda, BioFocus (now Charles River Laboratories) and Illumina. The last year has seen some truly mind-blowing financial and M&A activity too. The IPOs for Horizon Discovery and Abzena have demonstrated the tangible growing interest once more in the sector from the public markets, with Abzena electing to consolidate their previously Londonand Cambridge-spread activities at Babraham. There is also important in-region upsizing and relocations to accommodate expansion for companies such as Pathology Diagnostics, which beautifully exemplifies the fact that all parts of the sector are growing. Inward investment through acquisition is a welltrodden path over many years where we have seen purchases of the likes of Chirotech by Dr Reddys and Astex Therapeutics by Otsuka Pharmaceuticals. The innovative F-star-Bristol Myers Squibb deal late in 2014 and the even more recent acquisition of Convergence Pharmaceuticals by Biogen Idec (after announcing they were considering an IPO back in June 2014), again 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

demonstrate the premium value attached to Cambridge innovation by inwardinvesting corporates. So what does the future hold for this region? Well, there are challenges; that’s for sure. Cambridge city centre was created over 800 years ago, and that is not conducive to major construction or a heavy flow of traffic in and out on a daily basis. There is a clear need for more grow-on space for companies looking to expand both in London and Cambridge, and space available in the latter is being snapped up at a rate that is almost faster than the builders can build. At the JP Morgan conference in January at the FierceBiotech investor panel breakfast, US investors were talking about the next five years perhaps being the ‘Golden Age’ of biotech. We are certainly seeing a boom here, the likes of which has not been seen for years, and suggestions that this is not some bubble or blip, but potentially a long term and sustainable period of growth. So yes, we need more grow-on space (but we have exceptional science parks, incubators and business centres addressing this), and yes, we need more affordable housing and more housing for wouldbe employees, and yes, we need better transport infrastructure, but these matters are being seriously considered by those with the power – at Council, regional and national levels within Government. The UK has the only Minister for Life Sciences in the world – George Freeman MP, who just so happens to be MP for Mid Norfolk – not a million miles from here – and he is working hard to ensure that the UK remains a strong tour de force in life sciences and healthcare, and grows and flourishes. Finally, to prove it I shall end with some compelling statistics: •

• •

The UK has one of strongest and most productive life sciences sectors in the world, generating turnover of over £50 billion There are nearly 5000 companies in the wider health life science sector (including non-manufacturing and service companies) in the UK Employing an estimated 176,000 people £4.21 billion was spent on pharmaceutical R&D in the UK in 2012, 25% of the total industrial R&D spend and 34% of total manufacturing industry R&D Life sciences account for over 8.5%

of GVA in the UK manufacturing sector £2 billion in industry and private sector investment in the UK has been announced since December 2011

Harriet Fear joined One Nucleus as Chief Executive in February 2009. She previously worked as a Diplomat with the British Foreign Office for 21 years serving in over 17 countries around the globe. Half her career was spent in the commercial field, latterly heading UK Trade & Investments national life sciences trade team for over 5 years. During her varied Foreign Office career she was Deputy Ambassador three times, Private Secretary to the Minister for Europe, led an evacuation of Brits out of the Congo and worked in Khymer Rouge territory with Scotland Yard on a hostage crisis. She now enjoys a calmer life in the UK! In January 2014 Harriet became a UK Business Ambassador for the life science and healthcare sector at the invitation of the Prime Minister. This role sees her promoting the sector, briefing visiting dignitaries, leading trade missions overseas and advising the Government on its direction of travel in the sector. One Nucleus is an international membership organisation for life science and healthcare companies, based in Cambridge UK. A not for profit company, it is the largest of its kind in Europe by some way with over 470 members including pharmaceutical, biotech, medical device and diagnostic companies and associated technical and commercial service providers. The One Nucleus mission is to maximise the global competitiveness of its members. For their science and technology-based members, this means being global leaders in the research, development and commercialisation of healthcare innovations that radically improve the quality of people’s lives around the world. For their business and professional services members, it means delivering exceptional services that significantly enhance the business performance of their clients. Email: harriet@onenucleus.com Summer 2015 Volume 7 Issue 2


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Drug Discovery, Development & Delivery

The Virtual Elaboration of Fragment Ideas: Growing, Merging and Linking Fragments with Realistic Chemistry Fragment-based drug discovery seeks to identify relatively simple and low molecular weight molecules which interact with protein targets, then grow or link them into active leads. Molecular design software can be used to create realistic chemistry between and around fragments. Two key factors for success are: using computational techniques that are suited to handling small molecule fragments; and prioritising the results by evaluating each new potential molecule as a whole. Fragment-based drug design (FBDD), also referred to as fragment-based lead discovery (FBLD), has emerged as a successful new method in drug discovery for both lead identification and optimisation. Rather than starting out with screening compounds, which are typically drug-sized molecules, FBDD focuses on smaller molecules, referred to as fragments, that show some affinity to a protein target, then seeks to grow them into more drug-like and, therefore, larger active leads. One key advantage of FBDD is that it typically results in a lower molecular weight lead, which is likely to have a much better PK profile, including, for instance, higher oral bioavailability 1.

of fragments using a docking method. Computational methods are also useful once initial hits have been detected for growing and merging fragments. Example uses are for exploring additional features within a protein active site and for suggesting suitable linker chemistry between two fragments that have been found to bind in different positions within the active site. However, it is important that the computational chemistry software is suitable for use with fragments. Most drug design software has been designed to deal with drug-like molecules that have a molecular weight between 350 and 500 Daltons. Fragments are typically of the order of 200 to 350 Daltons. Therefore, algorithms that have been proven to work with larger molecules are not always successful when applied to fragments. An example of this is where a docking method utilises a scoring function to evaluate the binding energy for a given pose of a molecule. The algorithms typically use a functional group contribution, also known as a pharmacophore approach. In other words, features are identified on the ligand and on the protein then an

overall interaction energy is calculated by summing up pairwise ligand-protein feature scores. This works better for larger and more complex molecules as the approximations used tend to average out more. For smaller molecules, the errors in the approximations used do not get averaged so well, leading to less accurate results. Scaffold Hopping Methods Demonstrate Successful Fragment Handling The field of scaffold hopping has been developed over the last 15 years, coming from both ligand-based (LBDD) and structure-based (SBDD) approaches to the virtual screening of whole molecules. The techniques have been refined and modified to deal with the replacement of specific portions of a molecule. Scaffold hopping tools work by replacing a specific portion of a molecule with structurally different chemistry that is predicted to retain similar biological properties. For scaffold hopping, the portion of the molecule to be replaced is the core of the reference molecule. For other applications, the replaced fragment may be an R-Group or a core of a leaf group or substituent (Figure 1).

FBDD encompasses both experimental and computational methods. Fragments are relatively simple molecules with few chemical features. Their typical small size and low molecular weight mean that the affinity shown when binding to the target can be low in absolute terms. Hence expensive and sensitive biophysical techniques such as NMR, X-ray crystallography or surface plasmon resonance (SPR) are needed to detect the fragment interactions2. Experimental methods are, therefore, typically low throughput and high cost. Computational drug design techniques complement experimental methods and help researchers focus expensive lab resources on the areas most likely to succeed. Early in the discovery process, computational techniques are used to pre-screen fragments in order to focus on those most likely to bind. This is typically done by screening a database 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: The results of the fragment swapping experiments performed on the mGluR5 modulator MPEP using Spark5. Spark automatically searches internal database fragments for fit to a selected region of a molecule, rebuilds it and scores by field similarity back to the reference molecule and ranks the output6. Summer 2015 Volume 7 Issue 2


Drug Discovery, Development & Delivery In essence, scaffold hopping tools are fragment replacement tools. Scaffold hopping tools represent a proven method of working with fragments that are in wide use. They have been specifically tailored to handle fragments well and have enjoyed successful applications3, 4. Extending Fragment Swapping to Growing, Merging and Linking Scaffold hopping techniques, based on the identification and replacement of small sub-sets of a given molecule, are readily extendable to fragment growing, merging, linking and optimisation. Fragment growing is the process of building sensible chemistry around a fragment. Fragment growing typically starts with a single fragment hit. It proceeds by extending the molecule, typically in the context of an X-ray crystal structure, to explore further parts of the protein binding site in order to increase potency. Fragment merges start with overlapping reference molecules. method takes the decoration of molecule and substitutes it with the of the other. The output fragments therefore, a combination of both.

two The one core are,

For fragment linking, the starting point is two non-overlapping references. The first molecule is grown, then chemically linked to replacements that match the second. The challenge is to build successful bridging chemistry between the two fragments. Scaffold hopping methods have successfully been used to address the challenge of finding linker chemistry. This may be a case of merging adjacent pockets, or linking distant pockets. In either case, the chemistry has to be sensible, tractable and synthesisable, which requires an appropriate computational scoring of the entire proposed new molecule. Using Scaffold Hopping Software to Link Fragments Bound to P38 Kinase This P38 kinase example shows how scaffold hopping software can be used to link two separate fragment binding modes from X-ray crystal structures, combining them to form a series of druglike molecules. A scaffold hopping software tool was used to grow a fragment bound to P38 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

kinase. Two inhibitors that had been cocrystallised and deposited into the PDB as 3K3I and 3ROC were used as the starting points (Figure 2). The smaller inhibitor was grown to be ‘like’ the larger, DFG-in inhibitor.

Key Factors for Success in Growing, Linking and Merging Fragments There are three key factors that are important to have in place in order for software to deliver a successful elaboration of fragment ideas into proposed

Figure 2. (a) P38 PDB: 3K3I DFG-out inhibitor (green) and (b) P38 PDB: 3ROC DFGin, hinge-flipped inhibitor (yellow). Initially the experiment was run starting from the 3K3I derived inhibitor as the fixed component and a dummy atom provided in the ortho position of the tetrahydro isoquinoline (TIC) moiety as the site for fragment replacement. The output field similarity score was weighted 80:20 between these two references derived from the two inhibitors – 3ROC : 3K3I.

molecules

A protein excluded volume was not used. The results were evaluated, and the examples shown (Figure 3) display a beautiful fit into the P38 protein. These results were found using a database derived from a commercial pool of compounds. Interesting output was also obtained using different reagent pools e.g., amines and alcohols which would involve the use of different chemical transformations but possibly via the same or a different starting chemical TIC

• •

with

realistic

chemistry:

Firstly, the electrostatics and steric calculations have to be right for small molecules; secondly, you have to have a good database of subsets of existing molecules to use as building blocks for growing, merging and linking the fragments; finally, it is important to assess each result molecule as a whole in its fully energy-minimised form.

Key 1: Get the Electrostatics Right for Small Molecules An accurate computational expression of the interaction potential of a fragment is vital for predicting the binding energy of the fragment with the protein target. This relies on a combination of calculations of electrostatic, hydrophobic

Figure 3. The results display a beautiful fit into the P38 protein. Left, Spark output example 8; right, Spark output example 84 from the thiol reagent pool. intermediate. This example shows how scaffold hopping software can be used effectively for fragment growth. The resultant candidate molecules in this example included interesting and sensible results, including highly selective p38 actives.

and shape properties. It is important that the underlying algorithms used by any modelling software translate to realistic results. Any errors in calculations will tend to be amplified when dealing with fragments. There is simply less margin for Summer 2015 Volume 7 Issue 2


Drug Discovery, Development & Delivery error since there are fewer atoms from which to calculate properties. Figure 4 shows the types of important detail that need to be calculated accurately when dealing with fragments.

Key 2: Use Subsets of Existing Molecules to Build Realistic Geometry and Realistic Chemistry

Figure 4: A correct calculation of the electrostatics of small molecules reveals details such as the sigma hole of chlorobenzene (left) and the complex electrostatics of amino acids histidine (centre) and tryptophan (right). These surfaces were calculated using the XED force field from Cresset7. A correct calculation of the electrostatics of atoms and molecules results in a significantly improved description of intermolecular interactions. For example, the interaction of aromatic groups, a common interaction in proteinligand complexes, is correctly predicted by the XED model to prefer an edgeto-face arrangement (Figure 5, right) whereas another algorithm incorrectly suggests that a face-to-face arrangement would be preferred (Figure 5, left).

The second key factor for success in growing, merging and linking fragments is to have a wide range of alternative pieces of chemistry available from which to build on the fragment. Rather than inventing de novo chemistry to add to the fragment of interest, successful fragment handling software makes use of databases of small sections of existing molecules with realistic geometries and chemistry.

Figure 5. The difference in interaction calculations that can result from an incorrect consideration of the electrostatics. Left: Benzene-benzene interactions as predicted using calculations suited to larger molecules incorrectly suggest face-to-face interactions. Right: Benzene-benzene interactions correctly predicted as edge-to-face using the XED model. www.ipimedia.com

Essentially, such a database is developed by breaking up existing molecules into ever smaller pieces, using chemical rules to identify the sensible bonds to break at each step. If a molecule has been synthesised before then we can have a high degree of confidence that the links can be synthesised again. For example, Cresset’s Spark application has a large database of molecular substructures that includes moieties derived from the CHEMBL and ZINC databases. The use of databases of moieties derived from real compounds also gives a high degree of diversity combined with reasonable probability of chemical synthesis. Further control over the chemistry that is employed can also be gained by the manual selection of connected atoms that form the new bonds to the existing fragment hits. Key 3: Assess Each Result Molecule in its Fully Energy-minimised Form The final key factor for success is that each result molecule grown from a fragment must be assessed in its fully energy-minimised form. Once it has been minimised, it can be scored for similarity to the ideal target, or for other criteria to ensure that only linking fragments that can truly work are progressed into the final results. The electrostatic and steric properties of each result molecule need to be considered in the chemical context in which it will be synthesised. In other words, it is really important to make sure that the added linker chemistry has not adversely affected the interactions from the parent fragments. The molecules need to be assessed in product space to ensure that the final molecule has retained the binding affinity for the target. This assessment considers both the final shape and the electrostatics, but in this case the emphasis is on the electrostatics. Generally the overall geometry of the molecule doesn’t change too much when linked to another moiety, but the electronic structure can be very different. If we take two active fragments bound to different areas of a binding site, then the linking chemistry is unlikely to radically alter the shape of the active fragments; however it could radically alter the electrostatics. The creation of result molecules that are fully energyminimised before computational scoring INTERNATIONAL PHARMACEUTICAL INDUSTRY 39


Drug Discovery, Development & Delivery ensures that only linking fragments that can truly work are progressed into the final results. The output molecules can be ranked towards protein pockets or surfaces (excluded volume) and by ranking their 3D field similarity against other bound ligands or substrates. Case Study - F-uracil as an Anti-cancer and Anti-viral Treatment8 Uracil DNA glycosylase (UDG) is a potentially interesting target for both cancer and anti-viral therapies. Recent efforts to produce synthetic inhibitors of this protein relied on an active fragment tethering approach, yielding some interesting bis-oxime linked active ligands. This case study describes an alternative method using molecular modelling software for the efficient elaboration of tractable fragment growing or linking chemistry. To illustrate the utility of scaffold hopping software for the reconnection of distant fragments, the bis-oxime linker was excised from a 1.5MicM active (PDB: 3FCI, Figure 6).

Figure 6. Active fragments originally tethered by a bis-oxime linker (disconnected for this experiment), shown embedded in UDG. In the modelling software, the protein is effectively employed as an excluded volume. The two fragment atoms to be joined were selected (i.e., the methyl groups of m-benzoic acid and uracil) and suitable fragments with appropriate vectors, which were capable of re-joining them, were inserted. Fragments were sourced from the software tool’s large internal databases, derived from ZINC and ChEMBL. The resultant molecules were automatically constructed in-situ, minimised and, in the simplest case, scored against the parent using a fieldbased 3D similarity metric7. The example results shown in Figure 7 show the diverse range of the output suggestions for new linking chemistry for the initial experiments. More importantly, each of the new fragments not only 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 7: Example outputs from a fragment linking experiment using the scaffold hopping tool Spark. satisfies the geometry and length required for the reconnection of the fragments, but also possesses features which are consistent with important interactions within the protein. Figure 8 shows the electrostatic surfaces of ‘Output 3’ sited in the protein target.

Figure 8. Spark output ‘entry 3’ with Cresset’s XED force field derived negative (cyan mesh) and positive (red mesh) electrostatic iso-potential surface

References 1. Murray CW, Rees DC, Nature Chemistry 1, 187-192 (2009). 2. Kumar A, Voet A, Zhang KY, Fragment-based drug design: from experimental to computational approaches, Curr Med Chem. 2012; 19(30): 5128-47. 3. Bioisosteric Replacements for the Neurokinin 1 receptor (NK1R), pages 259-278 of Scaffold Hopping in Medicinal Chemistry, edited by Nathan Brown, published by Wiley: a retrospective study. 4. Bioisosteric Replacements for the Neurokinin 1 receptor (NK1R), Francesca Perruccio, Scaffold Hopping in Medicinal Chemistry, 259-278. 5. www.cresset-group.com/spark. 6. Cheeseright T, Finding Potential New IP with Novel Bioisosteres of

mGluR5 Modulators, http://www. cresset-group.com/wp-content/ uploads/2013/11/FindingPotential-New-IP-with-NovelBioisosteres-of-mGluR5-Modulators. pdf. 7. Cheeseright T, Mackey M, Rose S, Vinter A, Molecular Field Extrema as Descriptors of Biological Activity: Definition and Validation, J. Chem. Inf. Model., 46, 665-676, 2006. 8. Slater M, Cheeseright T, Using Cresset’s Spark to grow and link distant fragment hits with sensible chemistry, Presented at Fragments 2015, Cambridge, UK.

Dr Robert Scoffin is CEO of Cresset. He is an expert in the fields of molecular modeling and cheminformatics, and his previous roles include CEO of Amedis and VP, Europe at CambridgeSoft. His DPhil is in Chemistry from the University of Oxford. Email: rob@cresset-group.com Dr Martin Slater is Director of Consulting Services at Cresset. He studied medicinal chemistry at the Universities of Huddersfield and Leeds, and spent 14 years in the highly dynamic pharmaceutical ‘fee for service’ environment at BioFocus in which he supported medicinal chemistry and a diverse range of programs. Email: martin@cresset-group.com Summer 2015 Volume 7 Issue 2


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Drug Discovery, Development & Delivery ISO IDMP Short Timelines and Limited Information: How Do You Solve the Challenges and Prioritise Your Efforts? ISO IDMP has been around since 2012, when the standards were initially published, and since November 2012 the implementing regulation 520/2012 has been in place. Now, four years later, information on how and what to implement is still scarce due to outstanding implementation guidelines from ISO and hence no implementation guidelines from EMA. Based on some of the main challenges outlined as part of a previous article on ISO IDMP1, I will outline some solutions to the challenges, what to prioritise and how to move forward. The four challenges are: 1. Information islands 2. Partial source, redundant source, EEA only? 3. Where are the clinical particulars? 4. Do you really want to tie your systems together? Challenge 1: Information Islands When data sources are identified for ISO IDMP and mapped to the respective applications, the next step is to map the information to the logical level. This means taking it one step further and actually identifying exactly where in the database the information is stored and what the keys are. Then you must design your full data architecture and identify or create the necessary keys to link your data together. This may sound trivial, however it is important to keep in mind how and where your keys are stored. For instance, it may provide business value to include the marketing authorisation number as metadata on your SmPC documents stored in your EDMS system. Therefore, this kind of consideration should be done not only from an IT perspective but from a business perspective as well. To avoid strong interdependencies of the applications, direct integration pointto-point should be avoided. It is generally advisable to take into account a data hub concept.

42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A high-level architecture could look like this:

your source systems, which should make you more agile and ready for changes.

By introducing a data hub to integrate data from your applications, you gain some benefits. Your current applications are GxP validated, currently fulfilling a business purpose, which in turn means that they are costly and time-consuming to update. ISO IDMP introduces a whole new set of controlled vocabularies that you need to adhere to. In the short run it will be difficult to respect these vocabularies in the source system; you might even discourage the adoption of vocabularies in certain systems, due to their impact on the current business process, or simply because legacy systems can be difficult to update.

Challenge 2: Partial Source, Redundant Source, EEA Only? In evaluating your systems, you will have to pay attention to what kind of source you are looking into – a global, partial or redundant source. Then you will have to work on the governance of the data being input, making sure that governance is at exactly the right level, not specifying that you need to input the product name, but that you need to input the product name (in EU) exactly as stated in the approved SmPC section 1, just as one example.

The data hub acts not only as an integration hub, but is in effect the spine of an IDMP setup, transforming the data based on rules, pre-processing values to extract IDMP relevant information, cleansing the data, etc. In the short run this may be a one-way street of consolidating the data and making it ready for the initial submission, but in a longer run this can be fed back to the source system to improve data quality. The data hub would be able to interact and extend a current master data management setup or make up the first wave of the implementation of such a setup in your organisation. The output of the data hub is IDMP-compliant data ready for hand-off to an application capable of exchanging the information with the authorities. By using the data hub as a layer between your applications for IDMP submission, you create a buffer or shield between the external requirements and

Furthermore, you must look into your redundant applications. Is there a specific reason why these are redundant; is the overlap 1:1, and should it stay like this? Ultimately you should strive to have one single source of truth and merge and decommission redundant systems. However, even if there may be good reasons for having an overall goal of achieving a single source of truth (and this should be your goal!), you should also evaluate each and every case carefully to make sure it makes sense and doesn’t compromise current processes. Challenge 3: Where are the Clinical Particulars? Clinical particulars are a specifically hard topic within IDMP, due to the natural source for this information being unstructured information found in the SmPC (EU) section 4 or the PI (US). This data requires an extensive effort to transform it into the structured format required. The information to be submitted Summer 2015 Volume 7 Issue 2


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Drug Discovery, Development & Delivery is specifics on2: • Therapeutic Indication • Contra-Indication • Population Specifics • Interactions • Interactant • Undesirable Effects

CCDS

In general, you can apply two approaches when solving this challenge. One is to just close the compliance gap and manually type in the information for each of your registrations in an IDMP application. However, this would be very time-consuming as each and every registration, independent of whether it is on the same product, will have to be updated separately. Furthermore, this will just be an add-on task and will not improve the current labelling process. The alternative route, which is the more complex in the short run, is to look into a structured authoring approach. This means not just looking into the SmPC but also the lifecycle of the information and creating a hierarchical structure of your content. Based on your company core data sheet (CCDS) you would structure and classify (e.g. MedDRA in Europe) the statements, then these will be associated with the SmPCs of that product, which will then inherit the information from the CCDS. This setup requires extensive work to establish the data baseline, but will generously pay off in the maintenance phase, where you will able to maintain most of your products directly based on the CCDS, making the change only once. Some SmPCs may not be aligned with the CCDS due to local variations, due to e.g. change request from the national competent authorities (NCAs). However, you will still be able to inherit the majority of the data and your data will be kept in a structured format. For coding the statements you may consider looking into assistance from semantic tools capable of evaluating current text and providing you with suggested MedDRA codes. This eases the process, but still requires a manual confirmation of the suggested codes. The benefits of this setup are that not only will you gain compliance if done according to the IDMP requirements; you will also improve the current labelling 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Undesirable Effects

4.8 Undesirable Effects

Undesirable Effect Text

Undesirable Effect Text

Undesirable Effect Classification

Undesirable Effect Classification

Frequency of occurrence

Frequency of occurrence

process and make it more efficient, leaner, coherent and flexible for meeting changes to requirements. Challenge 4: Do you Really Want to Tie Your Systems Together? In identifying source systems for your ISO IDMP submission, you should not only take into account whether the data is a match or not; you should evaluate the following as well: •

• •

SmPC

Could including the identified system in the IDMP scope compromise the current purpose of the system/ document? E.g. can missing or wrong data halt or stop current processes going forward? Will the data be available in due time for the IDMP submission? E.g. in an ERP system, data may not be entered upon approval of the product, but perhaps months later when production is initiated Is it worthwhile and economically sound to link the system with the remaining data? Maybe only little data is retrieved and no common keys are shared Will data be available for all registered products or only for products in production, or are there other limitations that must be taken into account? How large is the contribution of the system? Will the processes supporting the identified applications fit together

and are there natural handovers, owners and touch points identified? These may seem like obvious questions, but the fact remains that there is a tendency to stick to the source as soon as it is identified, independent of how the above questions are answered. These questions, among others, should be considered and act as part of the decision foundation when finally deciding to include a system in scope. How to Prioritise Your Efforts The challenges that lie ahead within IDMP are many and it may seem difficult to prioritise the efforts. Even though the official deadline is still July 1st, 2016, recent news from the EU IDMP Task Force states that IDMP may come in phases within the European Region. This then leaves the questions of what exactly will the waves be? This question remains to be clarified and agreed upon between EMA and EC; however, the following could be outlined as a possible first wave, making sure that efforts are focused on the right spot: Authorised Products xEVMPD data will have to be translated to the new ISO IDMP guidelines and the information surrounding this existing information would be a logical place to start. Furthermore the ISO ICSR implementation gudline3 specifies a certain sub-group of IDMP IDs of Summer 2015 Volume 7 Issue 2


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Drug Discovery, Development & Delivery of ISO 112387, and therefore provides a practical insight into what data is required, and how.

relevance (MPID, PhPID, SID, etc.) which would make sense to include. This means that the following areas would be logical to use as first wave: • • • • • • •

Medicinal Product (Name, Classification, Regulated Document, Country/Language) Marketing Authorisation (Procedure, Status, Application) Ingredient (Substance, Strength, Reference Strength, Specified Substance) Organisations (MAH) Clinical Particulars (Indication) Packaged Medicinal Product (PCID, Package Description) Pharmaceutical Product (PhPID, Route of Administration)

This would mean that in the current challenges, identifying the systems in scope for the first wave should be coordinated accordingly. Furthermore, it also means that the big task of structuring the clinical particulars may not lie just in front of us. However, it is important to recognise the effort needed to complete this task and not postpone until it is too late. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Investigational Products There is a big overlap between ISO IDMP and the data requested in the Clinical Trials Regulation5. The mandatory data set forth in the current draft implementation guidelines from ISO corresponds quite well with what is requested to be submitted to the EU Portal. The EU Portal will most likely not end out as the final implementation of IDMP in Europe; however it will be safe to assume that these two initiatives will align and integrate at some point. With the regulations receiving a lot of attention currently it would be a good prioritisation to connect these two initiatives and make the data available in a uniform way to support both requirements. Structured Substance Information For the remaining part, the substance information EMA has communicated that GInAS6 will be the application to use for maintaining and submitting the information. It would therefore be sound to look into the current mandatory sections of the ISO 112387, and invest in learning more on the GInAS application, how it is to be used, data input, etc. GInAS is designed to exactly fulfil the requirements

References 1. Bergendorff, R. ISO IDMP Four challenges in preparing Organisations for the July 1, 2016 EMA Deadline IPI Winter 2014 Volume 6 Issue 4, 32-33 (2014) 2. ISO 11615 Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of regulated medicinal product information, 2012-11-01, 79 3. EU Individual Case Safety Report (ICSR) Implementation Guide, 201412-04 4. COMMISSION IMPLEMENTING REGULATION (EU) No 520/2012 of 19 June 2012 5. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 6. http://tripod.nih.gov/ginas/, visited on 29 April 2015 7. ISO 11238 Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of regulated information on substances, 2012-11-01

Rune Bergendorff is responsible for NNIT’s ISO IDMP services. He has conducted numerous ISO IDMP assessments, is a member of the EU IDMP Task Force and ISO/TC215 WG6 and participates in this group’s ballots and reviews of ISO IDMP standards and implementation guidelines. Rune Bergendorff has worked with xEVMPD since 2011, advising on issues from requirements to the submission of data.He has written several articles and heads an ISO IDMP networking group for Danish pharma companies. Email: rrb@nnit.com Summer 2015 Volume 7 Issue 2


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Clinical Research Allergy Therapies: Tables and Figures Increasing the Probability of Clinical Development Success

Introduction The prevalence of allergic diseases is increasing sharply in both developed and developing countries. These diseases include: asthma; rhinitis; anaphylaxis; drug, food, and insect allergy; eczema; and urticaria (hives) and angioedema.1 Allergic asthma and rhino-conjunctivitis are the most common. Asthma incidence is rising, affecting some 300 million people worldwide.2 Allergic rhinitis (AR) affects an estimated 10-30% of the world’s population, with prevalence rates also increasing worldwide.1 Management of allergic diseases is based on trying to eliminate the trigger (there may be one or several) or to induce tolerance. Allergen-specific immunotherapy induces tolerance by redirecting the immune response away from the allergic pattern. Management of these patients also requires drug treatments focused on blockade of key mediators of inflammation. Antiinflammatory agents, which block the activation of key cytokines that augment and sustain airways inflammation, are also used. In addition, more targeted therapies are useful in selected patients.3 This paper discusses possible approaches to improving the probability of success for allergy and respiratory drug development programmes. To assist readers who are interested in this topic but may not be familiar with some of the nomenclature employed, Table 1 presents a list of abbreviations. Current Status of Clinical Trials in Allergy As understanding of allergic diseases has increased, the number of potential therapies in development has risen in parallel. As shown in Table 2, there are currently around 120 compounds being developed for asthma and 60 for rhinitis. The figures presented in Table 3 demonstrate that the number of clinical trials for potential allergy therapies has been rising sharply in recent years, growing from approximately 100 in 2009 to almost 400 in 2013. We carried out a search in June 2014 to determine the main geographic areas of activity: the results are presented 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 1: List of Abbreviations AHR AIT AR ATS CSMS EAACI ERS ESPIA HRQL IgE PAR PER PBI PIF QoL RQLQ RR SAR SF SPT TNSS VAS

Airway hyperresponsiveness Allergen immunotherapy Allergic rhinitis American Thoracic Society Combined total symptom score and medication score European Academy of Allergy and Clinical Immunology European Respiratory Society Satisfaction Scale for Patients Receiving Allergen Immunotherapy Health-related quality of life Immunoglobulin E Perennial allergic rhinitis Persistent allergic rhinitis Patient Benefit Index Peak inspiratory flow Quality of life Rhinoconjunctivitis Quality of Life Questionnaire Recruitment rate Seasonal allergic rhinitis Short-form health survey Skin prick test Total nasal symptom score Visual analog scale

Figure 1: Distribution of Allergy Trials in 2013

Figure 1: Distribution of Allergy Trials in 2013

Table 2: Number of allergy compounds in development

Number of compounds in development

Phase 1

Phase 2

Phase 3

Asthma

37

61

24

Rhinitis

8

35

19

Table 2: Number of allergy compounds in development

Table 3: Number of new allergy studies per year, 2009-2013 Number of new allergy studies per year

Summer 2015 Volume 7 Issue 2


Clinical Research Table 3: Number of new allergy studies per year, 2009-2013 Number of new allergy studies per year 2009

98

2010

138

2011

142

on investigational drugs from the top 50 firms in terms of pharmaceutical sales, including 812 compounds, which had 1369 failed indications; reasons were established for failure by clinical phase for 410 of these compounds and 659 indications. Key findings included:

• In Phase I, commercial reasons 2012 253 were the most common cause of failure, accounting for 40.9% of all 2013 387 failures. Efficacy and safety issues were approximately equally frequent, each accounting Table 3: Number of new allergy studies per year, 2009-2013 for slightly less than 30% of those failures. graphically in Figure 1.4 Although the • Efficacy main areas of activity are the United issues outnumbered commercial States (191 trials in 2013) and Europe considerations by 2 to 1 as the (115 trials in 2013), there is activity in leading reason for Phase II failure. all major regions and both hemispheres. This finding is consistent with the This is the result of new strategies to intent of Phase II studies, which is to advance studies by finding more trial obtain data on the effectiveness of participants and/or investigate exposure the drug for a particular indication to specific allergens. or indications in patients with the disease or condition. Efficacy A recent review by Citeline5 showed and commercial issues were that despite differences in sponsorship more prevalent than safety issues across therapeutic areas, the relative as reasons for Phase II failure, utilisation of the top 20 countries is accounting for 53.9%, 27.3% and generally consistent across therapeutic 17.2% of failures, respectively. areas, with the United States remaining • In Phase III, 52% of failures were the most-utilised country. It also is due to lack of expected efficacy; noteworthy that these top 20 countries safety issues accounted for nearly include Eastern European, Latin twice as many Phase III failures as American, and Asia Pacific regions. It did commercial reasons, at 30% vs. is clear that Eastern Europe has become 16%. an important region and that growth in utilisation of countries in Latin American More than half of development and Asia Pacific regions is likely in the discontinuations (54.3%) in respiratory future. In this competitive environment, trials globally were related to efficacy a high level of planning with accurate concerns. study design, strategic study setup, and high quality data capture is needed to An earlier Tufts study published in complete successful allergy studies. Nature7 identified a clinical approval success rate of 4.8% for respiratory In 2013, the Tufts Center for the Study of products originating within the Drug Development published a summary pharmaceutical industry that were first of clinical development failures for the tested in humans between 1993 and period 2000-09.6 The study was based 2004. www.ipimedia.com

Another study1 of clinical development success rates found the highest likelihood of approval from Phase I at 18.2% (n=720) in drugs for indications grouped together as “other”, which included allergy, gastroenterology, ophthalmology, dermatology, obstetrics-gynaecology, and urology.8 Improving Probability of Success Possible approaches to improve the probability of success for allergy and respiratory drug development programmes and their clinical trials centre around issues in study design, setup, and delivery: Study Design • Selection of primary outcomes should be based on current regulatory guidance, but there are discrepancies between regulatory guidance and science/clinical practice; in addition, there are regional regulatory differences. For example, although common dossiers are used, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have granted different summaries of product characteristics for some compounds, and one agency may ask for additional data despite the product having been approved by the other. • Patients’ phenotypes are important. Improved knowledge of disease pathophysiology has enabled identification of various inflammatory pathways and mediators. New compounds are now being developed addressing specific mediators. These require studies designed for the specific populations where each mediator plays a key role. Study Setup Strategy • Country selection is key, because for a new study the choice may contribute to several issues. For example, regulatory approval timelines may differ significantly by region, and even within regions they may not be fully harmonised, despite recent attempts under the new European Voluntary Harmonization Procedure.9 Recruitment rates may also depend on the structure of health services, and on local rules and practices. • Recruitment rate (RR) predictions need to be realistic. Overestimation INTERNATIONAL PHARMACEUTICAL INDUSTRY 49


Clinical Research

• •

of RR is a common issue in clinical trials. Estimates based on investigator interviews may be overly optimistic. Various factors play a role here, including interest from patients and investigators in participating (does the potential therapy address an unmet need?), the burden of the study for study participants and/ or investigator sites, and the safety of participants (is standard of care allowed, or is there a placebo arm?). Competition is intense for both participants and site resources. Operational strategy should be based on proactive risk-mitigation to help avoid issues such as recruitment delays. The main factors that may play a role in patient recruitment or compliance should be identified and remediation strategies should be ready to implement if needed. Protocol amendments result in study delays while they are being approved. Therefore, adequate multifunctional review of the protocol and the case report form is essential before regulatory submission takes place.

Study Delivery • Study compliance may be an issue in long-term studies, especially those designed to be carried out over threeto-five years’ duration, including periods of treatment. Special consideration should be given to studies that include paediatric or adolescent patients. • Recruitment challenges may include patients being required to undergo selection procedures out of season or within season, and/or excluding other concomitant allergens, depending on protocol definition. A good database of patients and pollen count availability in the area are key elements in pre-selecting participants and opening recruitment when pollen reaches a minimum level, for example. Some studies may benefit from support tools such as advertising: such tools should be selected with care for optimum effectiveness. Any patient-related documents must be approved by the ethics committee. • Screen failure and/or drop-out rate -- contingency plans, including alternative sites or countries, should be in place for higher-thananticipated rates. • Data issues – such as poor data 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

quality, lack of homogeneity in spirometry, or missing data – may result from the fact that most allergy clinical trials are designed and statistically powered using subjective measurements (symptom scores). In such cases, inter-participant variability tends to be wide, creating a need for large sample sizes, placing more individuals under evaluation, and increasing costs and timelines. Efforts to improve data quality are one of the most important elements in these studies. Investigator selection should be based on a history of proper management of diagnostic tools and previous experience in grading results and patient symptoms.

exposure units, and allergen chambers. The features of each are considered in turn.

Early Studies: Pharmacodynamic Models in Allergy Pharmacological approaches used to identify allergen sensitivities include challenge tests and a variety of models, such as skin prick tests, nasal provocation, ocular, bronchial, environmental

Skin prick tests are the subject of a European Academy of Allergy and Clinical Immunology (EAACI) position paper,12 representing a validated method that has been used as a surrogate marker in several clinical trials. In addition, recent data on skin tests support that

Skin Tests Skin prick tests represent a low-cost, rapid, and accurate method of identifying allergen sensitivity. These are used to confirm sensitisation in immunoglobulin E (IgE)-mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, atopic eczema and food and drug allergy.10 Such tests are often used in advance of nasal allergen provocation tests, due to the correlation between the dermal and upper respiratory effects of antihistamines.11 There is a long-standing tradition of extrapolating data from the skin to the airways in clinical practice.

Figure 2: EAACI recommendations for scores in allergy clinical trials

EAACI recommendation for scores in allergy clinical trials

Nasal

Daily Symptom Score (dSS)

Ocular

(in pollen allergic pat)

Daily medication score (dMS)

Combined symptom and medication score

0 = no symptoms

Itchy, sneezing, running and blockade nose

1 = mild symptoms (sign/symptom clearly present, but minimal 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but tolerable)

0-3 Watery, red eyes

3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping)

Oral and or topical non-sedating anti H1

1

Intranasal cortis (+/-) antiH1

2

Oral corticosteroids (+/- antiH1 +/nasal cortis)

3

dSS + dMS

awareness; easily tolerated)

0-6

(CSMS)

Summer 2015 Volume 7 Issue 2


Clinical Research suppression of the late skin response may be necessary, but not sufficient, for the therapeutic effect of allergen immunotherapy (AIT). Nasal Provocation Tests In nasal provocation tests, the allergen may be applied in powdered form, via sprays or nebulisers, from a syringe, topically using cotton wool, or by impregnation onto paper discs. An advantage of this test is the potential for critical evaluation of the kinetic response to stimuli, rechallenge and treatment. Response can be assessed both subjectively and objectively by a variety of methods: using baseline and study total nasal symptom score (TNSS); obstruction can be measured objectively using nasal peak inspiratory flow (PIF) or rhinomanometry; and rhinorrhoea can be quantified by measuring weight of tissues with nasal secretions. However, nasal PIF and rhinomanometry are not thoroughly standardised and have not been validated. Nasal provocation tests are the subject of an EAACI position paper,14 which notes that nasal provocation tests are useful in proof-ofconcept and dose-ranging studies, and to evaluate the mechanism of inflammation. Conjunctival Provocation Test In the conjunctival provocation test, the allergen concentration applied is usually higher than environmental levels, a factor that must be taken into account when determining clinical relevance. The EAACI position paper on this type of test notes that it is a validated method that documents conjunctival response to AIT, yielding similar results to nasal provocation testing and bronchial challenge. The conjunctival provocation test comprises mostly subjective parameters (using a scoring system for symptoms), but does not include parameters that can easily be measured objectively. Moreover, at present, there is heterogeneity in the scoring system for this type of test. Environmental Exposure Chamber The EMA requires justification for the use and validity of an environmental exposure chamber, and both the FDA and EMA restrict this to a limited role and provide no guidance on how to assess results. The use of an environmental exposure chamber is recommended in seasonal allergic rhinitis (SAR) prophylaxis trials. Useful properties include the ability to www.ipimedia.com

perform spirometry, pharmacokinetics, rhinometry, electrocardiograms, nasal PIF, tonometry, slit lamp exams, analysis of inflammatory biomarkers and skin prick testing. The EAACI position paper on this topic14 notes that several studies have shown the onset of AIT effects,25 and that there is good correlation between symptom responses of given patients to natural exposure and within the chamber. Relatively few environmental exposure chambers exist internationally, and the reproducibility of results among and within sites has not yet been determined. Pending results, an environmental exposure chamber is likely to be a good option as an adjunct to natural exposure studies for Phase III randomised clinical trials (RCTs). Bronchial Challenge The bronchial challenge is a wellcharacterised and useful tool for understanding the mechanisms of allergic airway inflammation and airway hyper-responsiveness (AHR). Epidemiologic studies demonstrate that environmental allergens are an important and increasing cause of asthma, resulting in bronchoconstriction, airway inflammation, and direct AHR. The bronchial challenge was used as the rationale for developing many of the animal and subsequent human models that have been used to study the immunology of allergic asthma and the efficacy of new therapies. The allergen challenge in allergic asthma is the only model of inflammation that accurately reflects the syndrome of asthma in a controlled clinical research environment. Allergen Provocation Tests For allergen provocation tests, the EAACI recommendations highlight the opportunity for more standardised procedures, the ability to control the environment (e.g., temperature, humidity), an avoidance of seasonal variation and the performance of single-centre studies requiring fewer participants.26 At present, there is no substitute for the clinical response to natural allergen exposure as the primary outcome in Phase III trials. Allergen provocation tests are recommended for understanding underlying mechanisms, biomarker discovery, proof-of-concept for onset of action, novel immunotherapy approaches, and allergen dose ranging.

Efficacy Clinical Trials in Allergic Rhinitis Study Designs: Regulatory Guidance & EAACI Position Paper The FDA13 and EMA14 have both issued guidance on the clinical development of medications for the treatment of AR, recognising multiple issues involved in conducting meaningful trials in this area. These include multiple allergenicities and comorbidities, subjective measures, the fact that subjects may be asymptomatic at recruitment, inter- and intra-subject variability, differences in pollen exposure, and the existence of multiple endpoints. A recently-published EAACI position paper on standardisation of clinical outcomes in allergen immunotherapy clinical trials outlines recommendations for nine domains of clinical outcome measures.15 As the primary outcome for future RCTs in AIT for allergic rhinoconjunctivitis, the paper recommends a homogeneous combined total symptom and medication score (CSMS) as “a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner.� The FDA and EMA recommend at least two adequate and well-controlled efficacy trials for approval of a rhinitis indication. According to regulatory guidance for these trials, the doseresponse should be evaluated using either clinical or validated pharmacodynamic studies. The protocol should involve randomisation, placebo and active control arms, including double-blind, parallel-group designs, ideally with a placebo run-in period. Non-inferiority trials are not possible because of lack of sensitivity, and superiority trials should be conducted against a well-established comparator with the same route of administration. Non-inferiority cannot be claimed from superiority trials in the absence of a placebo arm for internal validation. Regulatory guidance specifies that pollen counts should be measured at the different study centres. For SAR, randomisation of participants at each centre should be conducted over a short period to reduce variability in allergen exposure. For perennial allergic rhinitis (PAR), randomisation should take place outside the pollen season. According to the FDA, the study duration should be two weeks for SAR and four weeks for PAR. Under EMA guidelines, study INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Clinical Research Figure 3: Factors influencing strategy for allergy clinical trials

• •

duration may vary depending on the onset of action of the product, indication sought (treatment vs. prevention), and duration of allergen exposure expected: in general, the study duration should be 2–4 weeks for SAR, and 6–12 weeks for PAR. From a regulatory perspective, acceptable approaches to symptom evaluation include: • Subjective symptom scores on a diary card, using a scale from zero (absent) to three (severe), with recording of symptoms such as obstruction, sneezing, rhinorrhea, nasal itching and ocular itching. A visual analog scale (VAS) may also be used for persistent allergic rhinitis (PER); this is a psychometric response scale to assess global rhinoconjunctivitis discomfort. The VAS can also assess every symptom and its effect, with patients rating symptoms by placing a vertical line on a 10cm line representing severity from zero (no symptoms) to 10 (‘highest level of symptoms’).16 • CSMS, which is recommended by both the FDA13 and EMA.14 As the use of rescue medication has an effect on symptom severity, the EMA guidance notes that “therefore, the primary endpoint has to reflect both, symptom severity as well as the intake of rescue medication.”14 • The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ),17 an interviewer- and self-administered instrument that measures the functional impairments that are most significant to adult patients due to their seasonal or perennial rhinoconjunctivitis of allergic or nonallergic origin.18 The RQLQ has a seven-point scale, with higher scores reflecting lower quality of life. This approach has been validated and appears to be responsive to change; it is useful for measuring changes in health-related quality of life within a group, but not among groups. However, completing the RQLQ is a lengthy process, and might be cumbersome for clinical trial 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

participants if required repeatedly. In this case, use of a ‘mini-RQLQ’ may help reduce the burden. Days free of symptoms. Days free of medications.

Regulators will accept protocols that involve more than one primary endpoint (co-primary endpoints) if these are ranked and predefined for pan-European authorisation, but, in this scenario, outcomes for all endpoints need to be positive. The EAACI’s 2014 position paper15 includes recommendations for scores in allergy clinical trials as shown in Figure 2. The paper recommends the CSMS as the primary endpoint for allergen immunotherapy clinical trials for allergic rhinoconjunctivitis. Also included are recommendations on health-related quality of life (HRQL). For the EMA, an HRQL assessment can be included as a primary endpoint when improvement in quality of life is planned as a label claim, or as a secondary one. There are two main types: generic (SF36, SF12) and specific (RQLQ, as discussed previously). Other elements examined by the position paper include: • •

VAS: global assessment/individual symptoms, and secondary outcomes. “Well days” vs. “bad/severe days:” EMA recommends evaluation of ‘days with symptom control’ as ‘days without intake of rescue medication and a symptom score below a predefined and clinically justified threshold’; and “symptom-free days” as secondary endpoints. In clinical trials, ‘severe’ is defined in each day where a three is recorded for any symptom. Global assessments and patient satisfaction, including the Satisfaction Scale for Patients Receiving Allergen Immunotherapy (ESPIA),19 and Patient Benefit Index (PBI).20 Rhinitis control assessment tests, such as CARAT10,21 RCAT,22 and RAPP;23 these are quick, easy, validated, and available in multiple languages.

Recruitment in Allergy Trials With this dual approach – regulatory and updated science-oriented common study design – features in allergic rhinitis trials include: the use of a placebo control; entry criteria designed to identify diagnosed patients with at least two pollen seasons or two years’ history of

specific allergy; and with most studies allowing inclusion of mild asthmatics (controlled with minimal exacerbations, and potentially including periodic spirometry for studies that include asthmatic evaluation). Adolescents are often included in 'adult' studies. For inclusion, participants must have demonstrated sensitivity to a specific allergen based on the skin prick test and/ or IgE, and are required to complete daily symptom scores and periodic quality of life (QoL) questionnaires. They must have qualifying allergy symptom scores at screening and during the runin period, plus a positive skin prick test (the longest diameter of flare ≥ 10 mm and wheal diameter ≥ 5 mm, greater than the negative control). Subjects must be positive for specific IgE against study allergen (at least IgE Class 2) at the screening visit. Subjects may be excluded if they have clinically significant confounding symptoms of allergy to other allergens potentially overlapping the allergen-related season (for example, tree, grass and ragweed allergens, dust mites and moulds). The protocol may include serial blood sampling for PK, IgE, and repeat skin prick tests (SPT) and may exclude previous immunotherapy treatment in allergen-specific trials. There is usually a highly specific list of prohibited medications. Screen Failure The major reason for screen failure among potential allergic rhinitis clinical trial participants is the required SPT reaction and/or IgE level. Other factors include confounding allergies; prohibited medication use; lack of a documented two-year history of allergy; the need for clinical study site personnel to be trained to carry out and read SPTs, and to pre-identify qualified individuals; participants’ diary compliance/diary fatigue; and issues with including paediatric patients due to the requirement for SPTs and blood sampling. Screen failure rates can be reduced in several ways. For example, one is to develop a phone pre-screening questionnaire, and another is for clinical project managers to contact the sites with highest screening failure rates to offer education on pre-screening steps. Screen failure information can be included in site newsletters with suggested corrective measures, and clinical research associates can reinforce these messages Summer 2015 Volume 7 Issue 2


Clinical Research when interacting with sites. It can also be helpful to set up a webex site for training/ retraining of the principal investigator as needed, with continuous review and potential closure of screening at sites with high failure rates that do not improve after training. Recruitment of Patients In general, many factors influence recruitment rates for allergy clinical trials, such as study duration, treatment options, study interest and competition, patient access to physicians and healthcare providers, site capability, standard of care and physician access to patients (see Figure 3). Data Collection Potential issues related to data collection during allergic rhinitis trials include: • • •

The study outcomes depend on reporting by clinical trial participants. The rating of symptoms is subjective, and participants may not use scoring ranks appropriately. Paper diaries pose data collection hurdles, including: inability to track

compliance in real time; the fact that if the participant has ‘diary fatigue’, data can be lost over long periods; if a paper diary is lost, then all data are also lost; data are entered manually; there may be participant identifier errors; and diary completion may be inconsistent. Many of the issues related to paper diaries can be addressed using e-diaries, which provide one place for the trial participant to collect all required information, prevent data fabrication and late entry, and can be monitored closely for participant compliance. Despite being commonly performed in clinical practice, spirometry can be challenging in the research environment, as the results obtained require cooperation between the participant and the technician and are dependent on technical and personal factors. Calibration, reference equations, use of different types of equipment, and interpretation of flow-volume loops generally differs in clinical practice compared with research, thereby

resulting in variability. Attempts to standardise spirometry have included several publications including “Standardization of Spirometry” and subsequent American Thoracic Society/European Respiratory Society (ATS/ERS) updates.24 Centralised spirometry includes sites receiving the same equipment (e.g., spirometer and calibration syringe) loaded with study-specific software. Sites are trained in the proper use of the equipment and all data are sent to a central server database where the results are quality controlled by an external over-reader. The overreader analyses the spirometry results and reviews whether the proper volume flow loops have been selected according to ATS/ ERS guidelines, and are acceptable and reproducible. Feedback from the over-reader to the sites helps to correct errors and improve performance, thereby decreasing variability across the study. In summary, centralised spirometry reduces errors and discrepancies in data

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Clinical Research and helps to ensure the quality of the data for these key parameters. Concluding Comments In developing the right approach to clinical trials for potential allergy therapies, key points include the need for proper study design, appropriate participant selection, and high data quality. For proper study design, an integrated protocol should be developed to demonstrate proof-of-concept in the target patient group. Predisposing factors in the patient population should be taken into account, along with seasonal timing, variability in response, and potential for multiple exposures to allergens. Study design should specify the route of allergen administration – airway, dermal, nasal or ocular – and identify potential pharmacodynamic outputs and appropriate biomarkers. For appropriate participant selection, clinical trial sites with allergy experience should be selected, and backup sites should be identified as a contingency. Split SPT and IgE testing should take place prior to all other screening procedures, helping to reduce costs, and using commercial-strength SPT antigen coupled with an interactive voice response system to ensure classification of the shortform health survey (SF) is performed in a timely manner. Each site should use a detailed pre-screening questionnaire. For optimum quality, a retention plan should be implemented to minimise dropout rates, with a programme of disease education and clinical team training. An eDiary incorporating reminders and tools to maximise subject compliance should be used, along with best practices in monitoring and standardisation. References 1. World Allergy Organization White Book on Allergy 2011-2012. Available at: http:// www.worldallergy.org/publications/wao_ white_book.pdf (Accessed 11th March 2015) 2. Global Initiative for Asthma Global Burden of Asthma report, 2004. Available at: http://www.ginasthma.org/documents/9 (Accessed 11th March 2015) 3. Frew AJ. Overview: Avoidance, Treatment, Induction of tolerance. In: Global Atlas of Allergy. Published by EAACI 2014;27072. Available at: http://www.eaaci. org/globalatlas/GlobalAtlasAllergy.pdf (Accessed 11th March 2015) 4. Based on a search on ClinTrials.gov of: open studies; allergy; all study types; phase 1 to 4 (conducted on 18th June 2014) 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

5.

6.

7.

8.

9.

10. 11.

12.

13.

14.

15.

16.

17.

Marecki S. Is achieving trial success a roll of the dice? Dissecting trials with positive outcomes to identify strategies for success. Citeline, 2014. DiMasi JA. Clinical study failures vary widely by phase of study and therapeutic class. Tufts Center for the Study of Drug Development Impact Report, September/ October 2013. Available at: http://csdd. tufts.edu/files/uploads/Sep-Oct_2013_IR_ PR_v2.pdf (Accessed 11th March 2015) DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Nature. 2010; 87:272-277. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51. Guidance documents for sponsors for a voluntary harmonization procedure (VHP) for the assessment of multinational clinical trials applications. CTFG//VHP/2013/ Rev1 June 2013. Heinzerling L, Mari A, Bergmann KC, et al. The skin prick test – European standards. Clin Transl Allergy. 2013:3:3. Bousquet J, Lebel B, Dhivert H, et al. Nasal challenge with pollen grains, skin-prick tests and specific IgE in patients with grass pollen allergy. Clin Allergy. 1987;17:529536. Van Kampen V, de Blay F, Folletti I, et al. EAACI Position Paper: Skin prick testing in the diagnosis of occupational type 1 allergies. Allergy. 2013;68:580-584. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Allergic Rhinitis: Clinical Development Programs for Drug Products. Draft Guidance. 2000. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071293. pdf (Accessed 16th March 2015) European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases. 2008. Available at: http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003605.pdf (Accessed 12th March 2015) Pfaar O, Demoly P, Gerth van Wijk R, et al: European Academy of Allergy and Clinical Immunology. Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. Allergy. 2014;69:854–867. Canonica GW, Baena-Cagnani CE, Bousquet J, et al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62:317–324. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol. 1996;98:843-845.

18. American Thoracic Society. Rhinoconjunctivitis Quality of Life Questionnaire. Available at: http:// w w w. t h o r a c i c . o r g / a s s e m b l i e s / s r n / questionaires/rqlq.php (Accessed 12th March 2015) 19. Justicia JL, Cardona V, Guardia P, et al. Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire. J Allergy Clin Immunol. 2013;131:1539-1546. 20. Franzke N, Schäfer I, Jost K, et al. A new instrument for the assessment of patientdefined benefit in the treatment of allergic rhinitis. Allergy. 2011;66:665-670. 21. Fonseca JA, Nogueira-Silva L, MoraisAlmeida M, et al. Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma. Allergy. 2010;65:1042-1048. 22. Meltzer EO, Schatz M, Nathan R, et al. Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis. J Allergy Clin Immunol. 2013;131:379-386. 23. Braido F, Baiardini I, Stagi E, et al. RhinAsthma patient perspective: a short daily asthma and rhinitis QoL assessment. Allergy. 2012;67:1443-1450. 24. Miller MR, et al. Standardization of Spirometry. SERIES ‘‘ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING’.’ Edited by V. Brusasco, R. Crapo and G. Viegi (Number 2 in this Series). Eur Respir J. 2005;26:319–338. 25. Day JH, et al. The role of allergen chambers in the evaluation of anti-allergic medications: an international consensus paper. Clinical and Experimental Allergy Reviews, 2006; 6: 31-59. 26. Frølund L, Bonini S, Cocco G, Davies RJ, De Monchy JG, Melillo G, Pauwels R. Allergen extracts. Standardization of preparations for bronchial provocation tests. A position paper. (EAACI Sub-committee on Bronchial Provocation Tests). Clin Exp Allergy. 1993 Aug;23(8):702-8.

Dr Juan Gispert is Senior Medical Director and Head of Quintiles’ Allergy and Respiratory Center of Excellence. He received his M.D. from the University of Navarra, followed by a Ph.D. in Public Health, Statistics and Epidemiology from the University of Zaragoza, and post-graduate degrees in Pharmaceutical Medicine and in Design and Statistics in Health Sciences, both from Barcelona University, Spain. He is experienced in all aspects of clinical trials, from development and design to regulatory submissions and medical affairs. Email: juan.gispert@quintiles.com Summer 2015 Volume 7 Issue 2


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Clinical Research

The Present and Future of Non-Vascular Stents In our fascination for new-age medical devices such as smart pills and wearable health devices, we do not often pause to think about some of the less-fancy, but equally important medical devices. A class of devices in particular – nonvascular stents – receives much less attention than its 500 million dollar market size demands. At over 5 per cent compounded annual growth, they are a fast-growing market, underscoring their growing importance globally. It would be well worth our time to know a bit more about the device that we could one day end up using personally… The human body consists of a network of vessels and ducts that transport fluids necessary for physiological functions across the body. A block in these vessels can obstruct the flow of body fluids, resulting in serious physiological consequences; sometimes even death. It is therefore imperative that the patency of the vessel is maintained, or the crosssection of the vessel is unobstructed by hardening of the walls, calcified deposits, tumours or kinks.

56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Cholesterol and mineral deposits along the inner walls of coronary arteries reduce blood flow through the vessel, a condition known as atherosclerosis. Reduced blood flow to an organ results in the tissues being deprived of oxygen (ischemia), tissue death and depending on the organ which it vascularises – heart attack or stroke (brain). Likewise, obstruction of non-blood-carrying vessels such as the gastrointestinal and urinary tracts can have dire and fatal consequences as well. For example, tumours or calcifications can cause obstruction to the urinary tract, hindering the flow of urine through it, resulting in pain, infection, loss in renal function, and in extreme cases, death. Narrowing of the vessel cross-section is known as stenosis or a stricture. Stenosis is most commonly remedied by a minimally-invasive corrective procedure involving a device known as a stent. A stent is an implantable medical device that is used to maintain the patency of stenotic vessels. Stents are usually tubular in shape; they are

inserted into blocked vessels in order to “push out” the narrowing walls and to restore an unhindered cross-section for fluid transport. Depending on the type of vessel they are used in, they are classified as vascular and non-vascular stents. Non-vascular Stents Non-vascular stents are a family of devices for a variety of applications, including biliary, oesophageal, colonic, bronchial and tracheal implantations. The use of non-vascular stents in these applications is fuelled by a number of market drivers. Key among them is the benefit offered by the device and its way of implantation. Stents employ a minimally-invasive procedure for implantation, which is in contrast to an open surgical procedure that surgical treatment procedures require. A minimally-invasive procedure also ensures lesser pain; faster recovery period and a shorter hospital stay (and hence, lower medical bills). Non-vascular stents find increasing application in gastrointestinal, urological and pulmonary diseases, owing to an

Summer 2015 Volume 7 Issue 2


Clinical Research ageing population, changing lifestyle habits and environmental conditions. Besides these, ophthalmic and neural applications are fast-emerging as important non-vascular stent applications. A large addressable market underscores the importance of and the growing need for non-vascular stents. Large medical device companies such as Boston Scientific Corp., Covidien Ltd., and C. R. Bard, Inc. have recognised this market need, and developed a portfolio of non-vascular stent products. Gastrointestinal: The family of gastrointestinal (GI) stents includes biliary, duodenal, trans-hepatic, oesophageal and pancreatic stents. Globally, there is an acknowledged increase in the incidence of GI diseases. In 2014, the United European Gastroenterology Society, a not-for-profit professional society of digestive health professionals, conducted a survey on the changing trends in GI disorders. The pan-European survey, covering 28 European countries, revealed a marked increase in conditions such as upper GI bleeding, inflammatory

bowel disease, colorectal cancer and many other diseases, particularly among the elderly. The American Cancer Society estimates approximately 93,000 new cases of colon cancer and nearly 40,000 new cases of rectal cancer are diagnosed in the US every year. These new cases are in addition to the millions already suffering from colorectal cancer. Surveys conducted by the National Institutes of Health estimate that at least 10-15% of adults in the US suffer from gallstones in the biliary tract. These conditions and others such as bile duct injury, oesophageal perforations, and gallstones require non-vascular stenting either as a remedial procedure, or as a supplementary procedure. Urological: Obstructions in the ureter necessitate stenting procedures to alleviate the blockage or provide a shunt for fluid drainage. Ureteral stents are commonly used to alleviate obstruction in cases of nephrolithiasis (kidney stones), tumours, strictures, or retroperitoneal fibrosis.

Stents are also used in cases of prostatic obstructions or due to a complication of prostatectomy. The American Urological Foundation estimates that approximately 15 million Americans suffer from urinary incontinence (accidental loss of urine) and between 25 and 30% of American adults suffer from obstructive uropathy (blockage of urine). In such cases, particularly in cases of blockages, a ureteral (also known as or ureteric stent) is inserted into the ureter to bypass the blockage and enable urine flow from the kidneys. A ureteral stent varies in diameter and length, with some stents as long as 12 inches. These stents are often temporary stents, intended to provide relief from pain and difficulty in passing urine. Pulmonary: Pulmonary or airway stents are designed to keep the tubular structures in the pulmonary system (trachea-bronchial tree) open. Globally, there is a growing patient pool with airway obstruction along with the number of pulmonary surgical

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Clinical Research for different stent applications. Design Considerations

Coil geometry

Uses

Examples

Pros: Flexible and easily retrievable

• Esophacoil by EV3 Corporation • Silhouette® Ureteral Stents by Applied Medical with coil-reinforced technology

Cons: Limited strength

Woven or braided design

Used in self-expanding structures. Knitted Nitinol used in tracheo-bronchial stents as it can change its shape according to the contours of the airway as well as can exert pressure against acute compression forces

Anti-migratory design – Antimigration collar (with rings)

The designs are to prevent stent migration due to the peristaltic movement of the gastrointestinal tract or the urinary tract

Anti-reflux designstents with valves

The gastrointestinal stents are designed to decrease the risk of reflux and aspiration of the gastric juice

Stent coating

Hydrophilic coating which results in low friction, high ring stability and low tendency of encrustation. Antibiotic-coated stents prevents infection

Stent covering

Stents are covered with silicone or polyurethane to prevent tumour ingrowth and reduce food impaction

• Wallflex by Boston Scientific • Ultraflex tracheo-bronchial stent by Boston Scientific

• HV Stent Plus and SX-ELLA Stent Esophageal HV by ELLA-CS are equipped with a unique anti-migration collar. • Tracheal Stents with Posts or Rings by Hood Laboratories. • ALIMAXX-ES™ Esophageal Stent by Merit MedicaEndotek has anti-migration struts • Hanarostent by M.I.Tech with large flare ends for anti-migration effect • Esophageal stent Flexella plus by ELLA-CS has a special anti-reflux valve. • Esophageal Z-Stent by Cook Medical has a unique windsock design with Dua AntiReflux Valve • Hanarostent and Choostent by M.I.Tech, with anti-reflux esophagus valve • iStent - Teutaflex Ureteral Stent by Hospital Innovations • Percuflex™ Stent with HydroPlus™ Coating by Boston Scientific • INLAY OPTIMA® ureteral stent by BARD Medical with pHreeCoat to stabilize the PH. • Triclosan eluting stents Triumph® by Boston Scientific • Permalume covered WallFlex™ Esophageal Stents by Boston Scientific. • ATRIUM ICAST™ balloon expandable covered tracheobronchial stent

Tabular column 1: Non-Vascular Stents Design Innovations

Key properties of the materials used in the non-vascular stent are biocompatibility, resistance to corrosion, flexibility, expandability, and high strength. Some of the materials used to develop stents are given in the table below:

interventions. Conditions such as central airway obstruction, chronic obstructive © 2015 Frost & Sullivan pulmonary disease (COPD) and asthma necessitate the use of airway stents, to open up narrowed airways and ease the burden of respiration. The National Heart, Lung, and Blood Institute estimates over 23 million Americans currently suffer from asthma. Global health surveys peg this number around 350 million, with another 300 million suffering from COPD. Healthcare databases record that more than 500,000 procedures of bronchoscopy are performed annually in the US, showing the prevalence of pulmonary surgical intervention. The trachea-bronchial obstructions requiring pulmonary stents include complications relating to lung cancer, respiratory infection, tuberculosis, and so on. www.ipimedia.com

3

Depending on the nature of the blockage, pulmonary stents are either Y-shaped (to prop-up narrowed airway bifurcation), or are tubular in shape for relieving blockages further down the pulmonary system. Factors such as smoking and global environmental factors such as air pollution and exposure to inflammatory chemicals, particularly in developing countries, are expected to increase the market need for airway stents. Innovations in Design and Materials Non-vascular stents vary greatly in size specifications, materials and design. Depending on the nature of the stent, the length could be as much as 18cm (typically gastrointestinal or urological stents) or as low as microns in length (known as micro-stents, used in ophthalmic applications). Tabular Column 1 highlights a few design characteristics

Biodegradable Polymers: The use of biodegradable polymers such as poly acryl amine, poly lactic acid-glycolic acid, poly capro-lactone and others, in non-vascular stents, are recent material innovations. Biodegradable materials present the advantage of biocompatibility and eliminate the necessity of stent removal. The stent either degrades over time or gets assimilated into the body (bio-resorbable materials). Esophageal stents manufacturer ELLA-CS (Czech Republic) uses polydioxanone, a material used to manufacture sutures, in their oesophageal stents. Boston Scientific uses poly lactic acid for its bio-absorbable biliary wall stents. Self-Expanding Stents: In order to reach particularly narrowed vessels, self-expanding plastic stents (SEPS) and self-expanding metallic stents (SEMS) are used. These stents are present in deflated or collapsed state, so that they can pass through narrowed structures and they are expanded upon reaching the site of implantation. They find application as palliative or assistive devices during advanced stages of gastrointestinal cancer. These are some of the innovations that non-vascular stents have benefitted from in the last few years. Already device manufacturers are taking cues from coronary stent devices, which have a longer track record of innovation and market acceptance. Design improvements such as heparin-coating of stents to prevent blood coagulation, anti-microbial coating to prevent infection and addition of anti-restenotic drugs to the stents, are some of the design innovations already in development stages. Emerging Application Areas Ophthalmic and neural applications of non-vascular stents are among the new and niche markets that have opened up in the last few years. Both application areas – eyes and the brain – are sensitive areas for implantation of devices. They also necessitate a much smaller stent device (in the order of microns, or micrometres), known as a micro-stent. In most cases, these stents do not so much perform the role of opening up blocked vessels, as they act as the vessels themselves. In other words, the stents act as shunts for relieving an organ or a part of the organ from pressure due to fluid build-up. INTERNATIONAL PHARMACEUTICAL INDUSTRY 58


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59 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2015 Volume 7 Issue 2


Clinical Research

Materials

Silicone

Nitinol

Pros and Cons

Key Players

Cons: Less strength, migration

• Dumon stents by Novatech • Mini Monoka silicone monocanalicular lacrimal stents by FCI Ophthalmics • Mono Stent monocanalicular stent by Eagle Vision Inc.

Pros: Super-elasticity and shape memory, highly biocompatible, flexible, has excellent shape memory and is corrosion-resistant, MRI-compatible

• Ultraflex tracheobronchial stent by Boston Scientific • Niti-S Enteral Colonic stent by Taewoong Medical • Nitinella Plus biliary stent by ELLA CS

Pros: Non-adherent, highly flexible, and has shape memory; easy to insert and remove.

Cons: Tissue trauma by metals Pros: High strength, flexibility, cost-effective Stainless steel

Cobalt-chromium alloys

Cons: Not biocompatible, MRI incompatible, cause restenosis and thrombosis Pros: Super-elasticity, shape memory, MRI-compatible, corrosion-resistant, biocompatible

• Omnilink® .035 Biliary Stent System by Abbott Vascular • Visi-Pro® Balloon-Expandable Biliary Stent System by Covidien

• Resonance® ureteral stent by Cook Medical

Cons: Tissue trauma by metals

Tabular column 2: Non-Vascular Stent Material Innovations

While there are a number of reasons for hand are medical device giants such as Ophthalmic: Glaucoma is a group of a stroke to occur, a sizeable number – Boston Scientific Corp., Cook Medical, Biodegradable Polymers: The use of biodegradable polymers such as poly acryl amine, poly eye disorders that are caused due to an around 40,000 to 60,000 incidences Inc. and Covidien, Ltd. In addition to lactic acid-glycolic acid, poly capro-lactone others, stents,important are recent material increase in the intraocular pressure (IOP), per year in and the US alonein–non-vascular are due to being players in the nonmaterials present the advantage of biocompatibility and eliminate thecompanies or the innovations. pressure due toBiodegradable fluid build-up in the intracranial cerebral atherosclerosis. vascular stent market, these eye. The Glaucoma Foundation Similareither to the degrades plaque build-up coronary have a substantial necessity of Research stent removal. The stent overintime or getsalso assimilated into the global body presence lists glaucoma as the leading cause Esophageal of arteries, there is protein, cholesterol and in coronary peripheral stents. On the (bio-resorbable materials). stents manufacturer ELLA-CS (Czech and Republic) uses blindness in the world. An estimated 2.2 mineral accumulation along the vessels in other hand, companies such as ELLA-CS, polydioxanone, a material used to manufacture sutures, in their oesophageal stents. Boston million Americans and tens of millions the brain, resulting in narrowed ducts. s.r.o and South Korea-based Taewoong Scientific poly lactic acid for its bio-absorbable biliary wall stents. Medical Co., Ltd. focus exclusively on more worldwide,uses have glaucoma. When primary options such as blood gastrointestinal stents. There are also Self-Expanding order to reach particularly narrowed vessels, self-expanding plastic such as There is no cure for Stents: glaucomaIn as thinner medications and anti-coagulants single-product start-up companies of now, but the use of a micro-stent to do not effectively work, stenting becomes stents (SEPS) and self-expanding metallic stents (SEMS) are used. These are present Ivantis stents Medical, Aquesys andinTranscend reducedeflated the IOP, so the opticstate, nerve isso that a vitalthey go-to can option. Therethrough is an increasing (all based or that collapsed pass narrowedMedical structures andin California), they are material not damaged, is an approach that is most demand for minimally-invasive surgical and pharmaceutical companies that play expanded upon reaching the site of implantation. They find application as palliative or assistive commonly resorted to. At a maximum procedures to treat these patients. a crucial role in market innovations. during advanced stages of gastrointestinal cancer. lengthdevices of 1 millimetre and weighing Micron-sized neural stents, such as those a few micrograms, ocular stents are developed by Stryker Corporation, are The growing importance of nonThese area some of the innovations non-vascular stentsaneurysm have benefitted lastillustrated few fast becoming preferred glaucoma usedthat as implants to treat brain vascularfrom stentsin hasthe been with a management option. Ophthalmic stents and intracranial years. Already device manufacturers are takingstenosis. cues from coronary stent devices, which have a market, snapshot of the total addressable are also surgical diseases and market acceptance. Design improvements key growthsuch drivers, recent innovations longer track options record for of innovation as heparinlike monocanalicular trauma and for The different types of non-vascular in product design and coating of stents to prevent blood coagulation, anti-microbial coating to prevent infectionnew andapplication structurally correcting the irideocorneal stents that have received approval areas. In addition to these, the possibilities to clinical the stents, of the design innovations already in angle.addition of anti-restenotic drugs for use, orare aresome currently in the of partnerships, strategic alliances and development stages. process, are listed in Tabular Column 3. business partnerships make the nonNeural: With the increasingly ageing and vascular stent market an exciting space obeseEmerging population, Application the pool of ischemic Areas The Road Ahead to watch out for in the coming years. and haemorrhagic stroke patients is also The global non-vascular market increasing. The United States Centers landscape is a mix of large and small for Disease Control and Prevention lists companies, those with varied product stroke as the third leading cause of death, focus and others with focus exclusively 4 products. On one killing©more 140,000 people each year. on non-vascular stent 2015 Frost & Sullivan 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2015 Volume 7 Issue 2


Clinical Research

Product name

XEN 45 gel stent (Aquesys, Inc.)

Application Area

World’s first minimally invasive subconjunctival stent for the treatment of glaucoma

Product Status

Importance

Met the completion of enrolment in the US clinical trial

This 12-month, multicentre singlearm study data will facilitate the US FDA approval for this stent. This is an important milestone for obtaining US market clearance.

Receives Class 3 Medical Device License from Health Canada

With commercialisation existing in Europe, this approval expands Aquesys’s footprint into another large market of Canada. Company believes that these positive results will convince the surgeons to use the MicroShunt for treatment of glaucoma.

InnFocus micro shunt (InnFocus)

Ocular stent for the reduction in intra-ocular pressure.

This patented micro-stent showed good results. It showed 80% reduction in eye-drop medication use-over 70% off medications completely at 3 years

AEROmini Tracheobronchial stent (Merit Medical)

It is indicated for use in the treatment of tracheobronchial strictures produced by malignant neoplasms.

U.S. Food and Drug Administration approval under section 510(k)

The approval is expected to boost the growth of Merit Medical System, Inc.

WallFlex biliary stent (Boston Scientific)

Biliary stent for the palliative treatment of biliary strictures produced by malignant neoplasms.

Positive results in the trial showing the effectiveness and safety of fully covered self-expanding metal stents in the treatment of biliary obstruction in benign bile duct strictures patients.

The positive result substantiates the US FDA and CE mark approval. It showcases the strong presence of Boston Scientific in the gastrointestinal stent market.

WallFlex esophageal stent (Boston Scientific)

Fully-covered stent is used for treatment of refractory benign esophageal strictures.

Has received the CE mark approval in Europe.

The commercial availability of WallFlex in the European market promises revenue growth for Boston Scientific.

Evolution oesophageal stent (Cook Medical)

This stent is indicated for obstruction that is caused by malignant or benign oesophageal stricture.

Cook Medical initiates the first multicentre US study to evaluate the possibility of removing a self-expanding metal stent after malignant and benign strictures have been treated.

If this study shows the possibility of safely removing metal stents, it can widen the medical options for different varieties of patients and can increase their potential patient market.

Evolution® Biliary stent (Cook Medical)

Indicated to relieve symptoms associated with obstruction of the bile duct.

US FDA has granted 510(k) clearance.

With a CE mark already granted in Europe, this approval will expand its market into the United States.

Tabular column 3: Recent and Upcoming Product Launches

The Road Ahead

The global non-vascular market landscape is a mix of large and small companies, those with Bhargav Rajan is a Research Analyst working with Debarati Sengupta is a Research Analyst working varied product focus and others with focus exclusively on non-vascular stent products. On one the Healthcare Division of Technical Insights, Frost & with the Technical Insights Healthcare division of Frost hand are medical suchservices as Boston Scientific Corp., Cook Medical, Inc.innovations and Covidien, Sullivan. He tracks in medical devices, & Sullivan, device a growthgiants partnership company. Debarati graduated with the first class Master’s degree in medical imaging, clinical diagnostics and healthcare Ltd. In addition to being important players in the non-vascular stent market, these companies also pharmacy (pharmaceutical chemistry) from Birla Institute

©

of Technology. She has industry expertise in competitive intelligence and healthcare market research. She has an experience base covering sectors like pharmaceutical, biotechnology and medical devices. Email: debaratis@ 6 2015 Frost & Sullivan frost.com

www.ipimedia.com

practices. Bhargav holds a Master’s degree in Biomedical Engineering from the University of Florida, Gainesville, and has academic and industry experience in regenerative medicine and tissue engineering. He can be reached at bhargavr@frost.com. INTERNATIONAL PHARMACEUTICAL INDUSTRY 61


Logistics

Track-and-trace – A Challenge for IT

Although a few years ago the number of impressive reference projects and the price of a track-and-trace solution were the deciding factors when selecting a provider, the focus has shifted significantly towards integration capacity and the capability of providing comprehensive support with a strong local presence. By now, every serious provider has a long list of references in the market and can provide sufficient proof of knowledge of the subject as well as the market. Decisionmakers at pharmaceutical companies can choose from a broad range of established providers. A major deciding factor is the flexibility of a track-and-trace solution when it comes to integrating it into existing IT infrastructure. The implementation of different national track-and-trace requirements is still among the greatest challenges for the manufacturers of pharmaceutical products. Depending on the respective national regulation, different variations of marking and verification functions must be integrated into the packaging process. Tasks range from the checking of individual packaging steps to the inspection of complete fabrication lines. In addition to the installation of machines and modules for the application of product and identification data and their subsequent verification, the integration of required software into the existing IT infrastructure is surely among the most demanding tasks for providers of trackand-trace solutions. The wide variety of national regulations already demands a high degree of flexibility from a system in terms of the type and scope of product labelling, and this is even more true of the integration of track-and-trace software into the existing IT infrastructure. The depth of integration depends on the size of the company, as well as the aggregation steps and scope of manual post-processing needed in the warehouse and in the supply chain.   Different Requirements for Track-andtrace For pharmaceutical manufacturers with a manageable product range, serialisation 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

can often be implemented with a standalone solution that works offline, that is, provides serialised data outside the packaging line and can be extended as required to model aggregation levels. The needs of medium-sized pharmaceutical companies for track-and-trace solutions are already much more complex. Different products have to be labelled in their individual aggregation levels on multiple packaging lines and the labels subsequently verified. This requires a central administration of data such as serial numbers and product master data. It also includes the administration of batches, recipes and users, as well as audit trails. The most complex systems are implemented for global pharmaceutical companies who have to serialise and aggregate a large number of products on multiple packaging lines at different locations. If shipping orders are reworked or re-aggregated in the warehouse, the track-and-trace software has to model those processing steps along with the associated data flows. Along with the existing business IT (ERP/ MES), the software has to handle central data management, as well as process and order control. Predefined Cells Simplify Validation Processes To be able to model all these different requirements with just one system, one German company has developed a multi-level, modular track-and-trace solution that can control everything from individual packaging steps up to complete production lines, along with all the processes in the warehouse. Laetus GmbH, headquartered in AlsbachHähnlein, is part of the Coesia Group and the global market leader in GMPcompliant packaging inspection. For 40 years, the company has developed and produced inspection solutions for the pharmaceutical, medical technology, cosmetic, and FMCG industries. Secure trace & trace solutions, or S-TTS for short, consist of three software levels and have an extremely flexible system architecture that meets all national requirements. 'Cell control' is the lowest software level in the track-and-trace architecture. It

controls all the inspection devices used on the packaging line, such as cameras and printers. Here, every packaging step corresponds to an individual cell, each of which can be configured independently. Predefined cell types can be used for the flexible implementation of different configurations to meet specific requirements – from simple serialisation compliant with EU directives, to serialisation and single-level aggregation as required by the Turkish ITS, to serialisation with multi-level aggregation as required by California's e-pedigree. Simply by adding cells, an existing line configuration can easily be extended for future requirements. The use of predefined cells has the additional advantage of accelerating validation processes. Independent Line Communication Coordinates Cells The next-higher level of the software architecture, 'line control', synchronises an arbitrary number of cells along the packaging line. Control is provided by the recipe that is loaded. It includes specifications of the packaged goods, the packaging materials and all other process parameters. 'Line control' receives all order data, including serial data, and stores it locally. This allows the line level to manage and flexibly execute multiple orders, independently of any permanent network connection to the higher software level. 'Line control' also provides the functionality of supporting manual processes like rework and aggregation on the packaging line. Change Management for Core Systems Plant management is the highest level of the secure track & trace software architecture. It hosts central user administration and the main database for product data, device formats, line configurations and recipe management. At this level, orders are either entered manually or loaded through an interface from the connected business IT system (ERP/MES). External serial number generators are connected through an interface at the plant level, on a manufacturer-agnostic basis. The core software on the line and plant levels Summer 2015 Volume 7 Issue 2


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are GAMP 4 compliant in Class 4, while the interface to the higher-level business IT is Class 5. Adaptations to validated core systems are subject to a change management process, meaning that changes must be implemented as efficiently as possible while minimising risks to existing operating procedures. Top Flexibility in the Warehouse Data management, however, usually goes beyond the packaging process. In addition to processes in the packaging line, additional processing steps are carried out in the warehouse – frequently manually – that also have to be modelled in a track-and-trace system. Work steps like shipping, exception handling, the reworking or repackaging of closed orders or the reprinting of labels are typical tasks in the warehouse that are usually carried out at mobile workstations. Their integration into a track-and-trace system requires a high degree of flexibility.   Tested IT Connection for Investment Security The prerequisite for the close intermeshing of track-and-trace software with existing corporate IT is a precise knowledge of 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the company’s processes, IT landscape and associated data flows. Only that knowledge makes the exact specification of requirements possible. A workshop in which IT staff can work together with Laetus IT experts to define individual requirements and work out a sensible solution is helpful. Laetus can develop specific track-and-trace solutions based on the results of the workshop and the specifications. A test system permits the upload and download of real data between the ERP/MES and track-andtrace systems, permitting significantly more exact statements to be made about data trends than simulations can provide. If necessary, the test environment can even be used to test the entirety of the data traffic resulting from the generation and administration of serial and aggregated data. This procedure has two decisive advantages: first, large parts of the software architecture can be validated centrally. This minimises downtime in the packaging line. And second: the training of personnel can occur in the test environment, so it does not interfere with production performance. It has become apparent that the implementation of different national

regulations to increase counterfeit security of pharmaceuticals represents a great challenge, not only for engineers, but also for IT managers in the companies involved. Thus, in demand are track-andtrace solutions that can be integrated flexibly into the existing infrastructure and that can be scaled and adapted to changing requirements.

Barbara Schleper is a writer for Awikom Gmbh, a PR and advertising agency focused on b2b communication for technical products. awikom supports German mid-sized market and innovation leaders to communicate the technical and economical benefit of their products. Responsible for press relations and social media Barbara translates complex technical correlations into a common and comprehensible language. Email: barbara.schleper@awikom.de Summer 2015 Volume 7 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 65


Logistics

Obtaining European Regulatory Approval The aim of this article is to provide an overview of the European regulatory environment and to outline some of the main pharmaceutical regulations and requirements for companies to consider when bringing a new medicinal product to the European market. EU Regulatory Environment The European medicines regulatory system is made up of numerous regulations and directives set by the European Commission to ensure the quality, safety and efficacy of all human and veterinary medicinal products. These laws are then implemented by its member states through regulatory agencies/ bodies. The European Union (EU) is made up of 28 sovereign member states, with each member state having its own national regulatory agency; as well as the central European Medicines Agency (EMA). Each national agency is responsible for: • Assessing the quality, safety and efficacy (QSE) of medicines • Authorising the marketing and sale of medicines and medical devices • Post-marketing surveillance to report, investigate and monitor cases of adverse reactions • Regulations to clinical trials for medicines and medical devices • Operating quality control surveillance systems • Providing the public with authoritative information about medicines and medical devices The European Medicines Agency (EMA) is the EU body responsible for coordinating the existing scientific resources put at its disposal by member states for the evaluation, supervision and pharmacovigilance of medicinal products. Iceland, Liechtenstein and Norway are also part of the European regulatory environment. As members of the European Economic Area (EEA) they are allowed to trade in the single EU market without EU membership. Switzerland is not a member of the EU or the EEA but has a number of trade agreements with the EU. 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To be able to market a medicinal product within Europe, you must obtain a marketing authorisation (product license) from the relevant regulatory agency. Approval Routes There are four routes by which a medicinal product can be authorised for marketing in Europe: 1. 2. 3. 4.

The centralised procedure The national procedure The decentralised procedure The mutual recognition procedure

Applications must be made in the language of the national agency, except for the EMA, which requests all submissions to be in English (however patient and labelling information must be provided in the specific language(s) of the countries that your marketing authorisation is for). All application dossiers must follow the common technical document (CTD) format which has been mandated since 2003. More detailed information about the CTD can be found in the EMA Notice to Applicants, as well as providing a detailed insight into how each procedure works, the deadlines and requirements; EudraLex - Volume 21. The eCTD is the electronic version of the CTD and is the mandatory submission format in the centralised procedure. Compilation of an eCTD can be timeconsuming and requires specific software to create it. However, it offers easy tracking of any updates that are made to the dossier sections during life-cycle management of the product. (CP)

• •

It is compulsory to register certain medicinal products via the centralised procedure; otherwise pharmaceutical companies are able to make a decision as to the best route of action for their product depending on the target audience and time constraints. It is worth considering long-term goals as well as immediate marketing plans, as this can facilitate quicker approval of future applications.

Centralised Procedure The centralised procedure

compulsory for human medicines that are:

derived from biotechnology processes, such as genetic engineering intended for the treatment of HIV/Aids, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases officially designated ‘orphan medicines’ (medicines used for rare diseases) advanced-therapy medicines, such as gene therapy, somatic cell-therapy or tissue-engineered medicines

The centralised procedure is also applicable if it can be demonstrated that the concerned medicine is a significant therapeutic, scientific or technical innovation, or if its authorisation would be in the interest of public health. The centralised procedure allows the marketing of a new product in all European Union (EU) and European Economic Area (EEA) countries simultaneously. The marketing authorisation (MA) assessment is coordinated by the EMA in London, governed by European Regulation No. 726/20042 and then the MA is issued by the European Commission based on the EMA’s recommendations. The National Procedure This is the route taken when a company launches a new product, which does not already have a marketing authorisation in place in the EU, for distribution in a single country (also known as a 'member state'). This route cannot be taken if: a) The applicant has a product MA in place (or an application is under consideration) through another member state of the European Union (EU) or European Economic Area (EEA) - (in which case they must follow the mutual recognition procedure).

is Summer 2015 Volume 7 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 67


Logistics b) The medicinal product comes under the compulsory centralised procedure list. When a marketing authorisation is issued by an agency via the national procedure it is only valid in that single member state, however this can then serve as the first phase of a mutual recognition procedure where the 'national state' serves as the reference member state (RMS). The Decentralised Procedure This may be used to simultaneously obtain a marketing authorisation in several member states when the applicant does not already have an MA in the EU. This procedure allows marketing roll-out in a number of member states at the same time, resulting in much shorter timeframes and reducing administrative burdens. The coordination group for mutual recognition and decentralised procedures (CMD(h)) is the European consultative body responsible for the correct functioning of the decentralised and mutual recognition procedures. Each member state, plus Norway, Iceland and Liechtenstein, has one representative in the group which was set up to examine any objections raised on the grounds of a potentially serious risk to public health relating to an MA of a product in two or more member states. After consultation with the company making the submission, one of the member states is given the role of the reference member state (RMS). The competent authority of the RMS undertakes the product assessment and coordinates the procedure on behalf of all the other states known as 'concerned member states' (CMS). The company receives identical MAs for its medicinal product in all the markets reducing future administrative burdens involving renewals and variations, etc. Once a decentralised procedure has been completed, the company can subsequently follow the mutual recognition procedure to obtain MAs in any additional EU/EEA member states. The Mutual Recognition Procedure This procedure may be used to obtain a marketing authorisation in another member state, or in several member states simultaneously, when the applicant already has an MA for the product in an EU/EEA country. 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In this procedure, the country's competent authority who issued the first marketing authorisation for that product offers its assessment reports to other member states. Rather than conducting their own assessment procedure, those member states are instead requested to recognise the evaluation already done and grant an MA on the basis of expanding the area of authorisation. The country who issued the original MA for the product acts as the 'reference member state' (RMS) whilst the countries the company wishes to introduce the product into become the 'concerned member states' (CMSs). The original quality, efficacy and safety assessment reports, produced by the RMS agency, are made available to the CMSs, and this forms the basis for requesting mutual recognition of the original MA (including the SmPC, PIL and labelling text). Unless the CMSs have grounds for rejection, almost identical MAs are subsequently issued by the corresponding agencies. The RMS coordinates the entire procedure between the CMSs and the pharmaceutical company. Pre-application Considerations Before applying for a licence there are some key points that need to be considered: Legal Basis A pre-submission agency meeting is a key tool to identify the legal basis for the application. This assesses the type of application that is required: full, generic, hybrid or similar biological, well-established use, fixed combination and informed consent. However, for a truly innovative product, the legal basis is most likely to be a full application. In this case, the results of pharmaceutical tests (physico-chemical, biological or microbiological), pre-clinical tests (pharmacological and toxicological), and clinical trials must be submitted. Further information on the legal basis of an application is available in the EMA pre-submission guidance3. Product Naming It is essential to carefully consider the naming of a medicinal product. For the centralised procedure the product must have the same name in all EU countries, bar where an exception is made due to trademarks. The EMA and individual country regulatory authorities publish

guidance on the acceptability of names to be used for medicinal products4. A non-confusing invented name or a common/scientific name along with a trademark of the applicant can be used. The international non-proprietary name (INN) in accordance with World Health Organization (WHO) guidance is often accepted as the common name. An invented name may be desirable in order to make the innovative medicinal product stand out from other marketed drugs when the product falls out of protection and generics can be marketed. For the centralised procedure, the invented name must be submitted to the Naming Review Group at the EMA. An invented name will be subject to evaluation in order to assess if there is any safety risk or potential concern for public health if the name was used on the market. The created name should not be confusing in respect to its printing, writing or pronunciation with an existing product. The name cannot be misleading, in that the user may believe it has a perceived therapeutic or pharmaceutical effect, or the composition of the product is different to its intended use. Packaging Design Packaging may have already been considered during product development. However, there are guidelines in order to assure that it is user-friendly, effective and safe. The packaging mock-ups and hard copies of the outer and immediate packaging have to be reviewed by the regulatory agencies before the product is marketed. The immediate packaging and outer packaging specimens also have to be accompanied by the package inserts and leaflets. A mock-up is a presentation of the artwork design so that the layout and text of the labelling is clear: it can be provided in paper or electronic format. Member states may request that some further market-specific information is included on the packaging. This can include pricing information, legal status, identification and authenticity information. These additional requests are known as blue box requirements and more information can be found in the Notice to Applicants1. All labelling must be easy to read and understand and must not be able to be Summer 2015 Volume 7 Issue 2


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Logistics removed or changed once applied to the package. The language on the packaging must be in the official language(s) of the member state; however, multi-lingual packaging is sometimes acceptable. The name of the medicinal product, including the strength, must also be in braille format on the packaging for blind and partiallysighted patients. Risk Management and Pharmacovigilance A pharmacovigilance qualified person (QPPV) for the application is required, and it is the responsibility of this person to ensure that due diligence and pharmacovigilance of the product is followed according to EU legislation throughout the product lifecycle. In absolutely no case will a marketing authorisation be granted without an established pharmacovigilance system for the drug product. The pharmacovigilance system must have a risk management plan in place to identify, characterise, prevent and minimise safety risks concerned with the product. The risk management system also includes interventions that can be made against those risks and assessment of their effectiveness against measurable targets. Benefits to the public health system and/or patient must outweigh the risks associated with the drug. The pharmacovigilance system has to have in place a process to report adverse events in EU member states (and in any other countries where the product is marketed). Pharmacovigilance is likely to be already in place from the clinical trials stage, but it is essential that all points are thoroughly covered as detailed in the Notice to Applicants. Environmental Risk Assessment An Environmental Risk Assessment (ERA) must be submitted with the application. The assessment analyses the risk to the environment that the use, manufacture, storage and disposal of the medicine may cause. There are two phases; the first phase is the calculation of the predicted environmental concentration, whereas the second phase is only performed when the first phase is above a threshold. The EMA provides guidelines on how to perform the Environmental Risk Assessment. GMP Compliance and QP release Another important factor to consider early 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

on is inspection of the manufacturing facilities for good manufacturing practices (GMP) and good distribution practice (GDP). Whilst assessing the application, a regulatory authority may request the applicant to be inspected and they can do this without giving any prior notice. If the manufacturing site is located outside of the EU/EEA, consideration needs to be made to check if there is a mutual recognition agreement (MRA) of GMP inspection between the country of manufacture and the EU/EEA. Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation of the principles and guidelines of good manufacturing practices5. Finally, after being granted a marketing authorisation, the product is ready to be launched on the market. The product has to be certified by a Qualified Person (QP) before it is released into the EEA. The site where this batch certification occurs acts as the importing country.

2. Annex I of (EC) No. 726/2004 http://eur-lex.europa.eu/LexUriSer v/LexUriSer v.do?uri=OJ:L:2004:136:0001:0033:en:PDF accessed 12th May 2015 3. European Medicines Agency http://www.ema.europa.eu/ema/ index.jsp?curl=pages/regulation/ general/general_content_000197. jsp&mid=WC0b01ac058002251c accessed 12th May 2015 4. EMA – Guideline on the acceptability of names for human medicinal products processed through the centralised procedure http://www. ema.europa.eu/docs/en_GB/ document_library/Regulatory_and_ procedural_guideline/2014/06/ WC500167844.pdf accessed 19th May 2015 5. Eudralex – Volume 4 Good manufacturing practice (GMP) Guidelines http://ec.europa.eu/ health/documents/eudralex/vol-4/ index_en.htm accessed 19th May 2015

If the product is manufactured and imported from outside the EEA, each batch of product has to be retested upon entering the EEA unless an MRA exists for the GMP of the exporting country. However, batch release must take place inside the EEA, regardless of the existence of MRA. If any of the processes are contracted out to a third party, e.g. batch testing, it is the QP of the applicant who is still responsible. Conclusion Bringing a new drug product into Europe is achievable, although it requires a great deal of planning. Understanding from the beginning what is expected can help to make the process smoother. While the essentials have been described briefly in this article; further advice can be sought from regulatory experts and the EMA website. Other agency websites such as the UK’s Medicines & Healthcare products Regulatory Agency (MHRA) are also helpful in understanding the role of regulatory agencies in assessing and approving marketing authorisation applications. References 1. EudraLex - Volume 2 http:// ec.europa.eu/health/documents/ eudralex/vol-2/index_en.htm accessed 12th May 2015

Graham Donaldson is a Regulatory Affairs Project Manager for TRAC Services. He has 10 years’ experience of working in European Regulatory Affairs. E-mail: gdonaldson@tracservices.co.uk Summer 2015 Volume 7 Issue 2


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LIMS as an Enabling Technology for the Pharmaceutical Industry In the pharmaceutical industry, just as in many other industries, the purchase of a laboratory information management system (LIMS) is not a trivial exercise and requires a good deal of involvement from both the customer and the vendor. In view of this process, the resultant LIMS is frequently viewed as a ‘system’ that has been designed to meet the needs of the customer and is then set in stone. However, the range of potential applications for LIMS and the fast-moving pace of the pharmaceutical industry means that rather than having a ‘fixed system’ LIMS, pharmaceutical laboratories need to be highly agile and build flexibility into their systems to cope with change. Change can come about for a multitude of reasons - new ideas surface, new departments are introduced to the system, overseas locations are added often through acquisitions or mergers, new business requirements emerge, new regulatory requirements are enforced etc. This article looks at how the wideranging opportunities for LIMS within pharmaceutical organisations such as QA/QC, stability studies, pre-clinical pathology, clinical trials, biobanking and environmental can benefit from a flexible approach to LIMS. In fact, it can be much more beneficial to view the LIMS as an ‘enabling technology’ which can evolve and adapt, often under direct control of the user, as the requirements change. For this to be the case, the front end of the LIMS has to be truly configurable, by the vendor and the end user alike. In fact, from a regulatory viewpoint configuration is actually preferred to custom coding according to the GAMP levels. Whilst most LIMS are configurable to some degree, depending on the particular system, a programmer or other IT person would need to write scripts or new custom programs to design new screens or link menus in different ways to support different workflows. Some LIMS, however, use exactly the same core program suite but feature a configurable ‘layer’, or set of configuration tools, that allows each system to be set up to exactly match user requirements. This makes the process of configuration much simpler and truly embraces the ‘enabling technology’ concept. 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

QA/QC Pharmaceutical quality control laboratories have an important function in both raw material evaluation and production, and can significantly impact overall manufacturing performance. Enhancing laboratory productivity leads to improved manufacturing efficiency, and information management in laboratory operations is essential to improving laboratory efficiencies. Using a LIMS to control, manage, organise, document, analyse and report information leads to improved efficiency and functionality of data storage and manipulation. The system is likely to be required to manage data for a wide range of analytical techniques for both the raw materials and finished products. Raw materials and finished products have to conform to pharmacopoeia and relevant product licenses. The LIMS must be compliant with all of the relevant regulations and practices such as cGLPs and cGMPs, including audit trails, time- and datestamping of all actions, version control of all reference data such as test definitions, and provide features to help with 21 CFR Part 11 compliance such as data entry authentication and comprehensive password management capability. The software could be used to generate certificates of analysis and monitor lab efficiencies whilst trending results for the finished products. A configurable LIMS solution can create a system that matches the specific requirements, such as customer-specific tables/modules and multiple screens for the same function (e.g. different login screens for different product classes, such as raw materials and finished products). Stability Studies Stability studies to measure the shelf life of a given product by testing a series of samples stored in environmental chambers to simulate accelerated testing is an essential part of the drug development process. The requirements for stability testing are described in 21 CFR 211.166 (Revised as of April 1, 2012). The application of LIMS to stability testing ensures that approved protocols are followed precisely, with “pulls” made on schedule and the appropriate tests completed, while providing the necessary

security and audit trail to comply with FDA regulations, including 21 CFR Part 11. This requires change control, validation and audit trailing of changes to the system and the data that it holds. Yet today’s laboratories must be able to offer the flexibility to adapt and change their processes and workflows when necessary, and their LIMS must stay in step with these changes. Stability testing requires the management of significant amounts of data from a variety of sources. In addition, clear, cohesive reporting of stability testing results is required, both for dossier submission and for ongoing studies. The use of an appropriately configured LIMS can automate and control the entire operation of the stability study including: • • • • • •

Protocol creation Study initiation and management Inventory management Sample login scheduling Future workload reporting Stability study reporting

This approach simplifies the whole study management process. While a LIMS can make a considerable contribution to managing stability studies, given the sheer range of studies that may be required, the system requires the flexibility to be configured to the particular application. Pre-clinical Pathology Pre-clinical pathology applications continue to be an important part of the pre-clinical evaluation of drugs to ensure that they are safe and effective before moving to the clinical phase of drug development. Pharmacokinetic studies are very important to reveal the safety and efficacy parameters in terms of absorption, distribution, metabolism and excretion. The implementation of a LIMS can create an almost completely paperless system for tracking laboratory samples and accounting for individuals performing the tasks (tests) on these samples. In multi-site organisations, this can require many users across multiple locations. A complex querying function, rapid registration of thousands of samples, and customised menus and options can all be created using a configurable LIMS. This allows saving Summer 2015 Volume 7 Issue 2


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Figure 1. LIMS Workflow for stability testing

Figure 2. LIMS workflow for a clinical trial showing how data entry is mapped to the sequence of actions taking place in the laboratory of cycle time, which is essential when thousands of samples may be registered per day. Clinical Trials The development of novel pharmaceuticals requires rigidly regulated clinical trials. Competent authorities (those tasked with enforcing legislation) need to be able to verify that all analyses during the trial were carried out without bias. This means that each step must be securely recorded 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

at the time and there must be evidence that these records have not been tampered with after the event. For each sample, the audit trail may extend to hundreds or even thousands of entries; starting with the nature of sample collection and storage, which may dramatically alter the results of analyses, potentially ending with complex data sets such as those from next generation DNA sequencing or mass spectroscopy. A trial may involve many thousands of samples,

so handling of these records in accordance with the regulatory requirements is challenging. Conducting clinical trials in the EU is tightly regulated. This is to uphold the rights and ensure the safety of clinical trial participants, as well as the reliability and robustness of the data generated. A LIMS is capable of tracking clinical trial collection kits/ supplies, managing and tracking specimens, managing laboratory testing workflows and recording quality performance, creating laboratory reports and managing study-specific documents. A configurable LIMS can log each step in the workflows for each trial and store the log in a readily accessible format that allows audit in minutes rather than days. The database can be created and updated, with audit points for each sample being added from workflows in the LIMS that mimic the wet lab processes used in the trials. A configurable LIMS means that the system can be readily modified in the event of any future changes to the official statutes. Biobanking Biobanks play an important role in biotechnology, pharmaceutical and medical research. The ability to manage an ever increasing number of biosamples (blood, tissue, DNA etc.) and to comply with the regulatory requirements, such as HTA, GCLP, MHRA, FDA 21 CFR Part 11 and other similar requirements, is a high priority for all organisations working in this area. One of the challenges faced when implementing a biobank management system is how the system can evolve with time. A LIMS that can offer flexible configurability can keep the system in step with user requirements and regulatory change moving forward. This both extends system life and reduces overall cost of ownership of the system. Samples need to be tracked at all times and it is essential to be able to record the complete genealogy for all samples and track the aliquots, pooled samples and derivatives of each sample. Typical requirements that a biobank management system should be capable of handling include management of the documents, study plan and standard operating procedures (SOPs) with change control. Since samples could easily be taken at distributed sampling points, patient consent forms, sample collection, tracking and inventories for sampling kits, local sample storage and sample delivery will all need to be considered. Once the samples are received at the Summer 2015 Volume 7 Issue 2


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Figure 3. Overview of all the samples within a Biobank central facility, accessioning, sample storage, and sample distribution, transfer and return all need to be handled. With regard to sample testing, consideration must be given to screening tests, results entry, storage, aliquots, derivatives and sample processing. At the end of the testing, final sample disposition may be required and, of course, reports must be produced. Biobank management systems therefore need to be configured to deliver a solution that meets the specific requirements in a clearly understandable way. Environmental Environmental monitoring is an essential part of any pharmaceutical manufacturing process. It is essential to show that the microbial and particulate content of all cleanroom air and work surfaces is within acceptable levels. Any utilities used in product manufacture, such as purified water or compressed air, must also be shown to be free of contamination. Implementation of an effective EM programme allows corrective action to be taken to ensure that the manufacturing process remains in control and safe from dangerous contaminants. Testing includes air sampling, settling plates, surface sampling, water monitoring (USP <1231> (TOC & conductivity)), and heterotrophic plate counts (microbial levels). A configurable LIMS can be used to define a complete environmental monitoring protocol, including sampling plan and testing 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

schedule. The collected samples can be associated with particular analysts, control samples, instrumentation and in/out of incubation dates. In addition, observational monitoring documentation can be associated with testing of a particular controlled environment. Trend plots and summary reports can be produced. The user can optionally associate morphology data with the batch of collected samples. Contract Laboratory Testing Away from the pharmaceutical manufacturing sector, there are also opportunities for flexible LIMS usage in business contract laboratory testing. Here the opportunities for a configurable system are even greater as, in addition to laboratory information management, there is the possibility of extending the system to handle an extensive range of management functions, from invoicing to consumable inventory control. In the traditional laboratory environment, the configurable LIMS offers all the capabilities needed to capture, store and report on a very wide range of materials and tests for small or large contract laboratories, and introduce new protocols and tests as demanded by individual customers. A freely configurable LIMS could also provide the functionality for management of a variety of activities essential to running the actual business, such as the creation of quotations, order booking, allocation of appropriate prices, generation of

results and customer reports and the production of invoices, either directly or in conjunction with a corporate accounts system. By having a fully configurable pricing capability, business profitability can be monitored right down to the test level. With such an extensive range of applications within the pharmaceutical industry, the concept of LIMS as an â&#x20AC;&#x2DC;enabling technologyâ&#x20AC;&#x2122; is an important one. The rich and diverse requirements from organisations both large and small make it essential that the LIMS can be adapted to the needs of the laboratory, rather than laboratory workflows being adapted to fit into a restrictive LIMS structure.

John Boother, Managing Director at Autoscribe Ltd, has had involvement in around 5000 LIMS projects. Autoscribe is a UK-based, global supplier of LIMS to both the laboratory and the wider business markets with distributors in every continent offering localised technical support. Visit www.autoscribeinformatics.com for more information. E-mail: john.boother@autoscribe.co.uk. Summer 2015 Volume 7 Issue 2


PREDICTING CLINICAL BEHAVIOR Attana systems measure target accessibility and off-target interactions in biologically relevant environments. By mimicking in vivo conditions we enable customers to study their drug candidates using cells, blood plasma and other biologically active agents, resulting in enhanced clinical success rates and efficiency of the R&D process. To learn more about our contract research services and our label free cell-based biosensors, please visit attana.com or contact our sales department sales@attana.com


Manufacturing

Syringe Siliconisation Trends, Methods and Analysis Procedures Ready-to-fill, i.e. sterile, prefillable glass syringes, are washed, siliconised, sterilised and packaged by the primary packaging manufacturer. They can then be filled by the pharmaceutical companies without any further processing. These days the majority of prefillable syringes are made of glass and the trend looks set to continue. The siliconisation of the syringe barrel is an extremely important aspect of the production of sterile, prefillable glass syringes because the functional interaction of the glass barrel siliconisation and the plunger stopper siliconisation is crucial to the efficiency of the entire system. Both inadequate and excessive siliconisation can cause problems in this connection. The use of modern technology can achieve an extremely uniform distribution of silicone oil in glass syringes with reduced quantities of silicone oil. Another option for minimising the amount of free silicone oil in a syringe is the thermal fixation of the silicone oil on the glass surface in a process called baked-on siliconisation. Plastic-based silicone oil-free or lowsilicone oil prefillable syringe systems are a relatively new development. Silicone oil-free lubricant coatings for syringes are also currently in the development phase.

Figure 1: polydimethylsiloxane Fig.1 In light of this development, there is an obvious trend towards optimised or alternative coating techniques. Attempts are being made to achieve the most uniform possible coating with a reduced quantity of silicone oil and to minimise the amount of free silicone oil by way of baked-on siliconisation. In this context, reliable analysis technologies that can be used to make qualitative and quantitative checks on the coating are absolutely essential. Alternative coating techniques are also being developed. Silicone Oils and their Properties Silicone oils have been used for half a century in numerous pharmaceutical 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

applications. For example, they are used as lubricants in pharmaceutics production and as inert pharmaceutical base materials (e.g. soft capsule walls)5. Trimethylsiloxy end-blocked polydimethylsiloxane (PDMS, dimethicone) in various viscosities is generally used for siliconisation (Fig. 1). The most frequently used silicone oil for the siliconisation of primary packaging components is DOW CORNING®360 Medical Fluid, which has a viscosity of 1000 cSt. PDMS is produced by reducing quartz sand to silicone metal. In the next step, the silicone reacts directly with methyl chloride in a process called Müller-Rochow synthesis to create methyl chlorosilanes. In this process, a mixture of different silanes is produced, the majority of which (75% 90%) are dimethyldichlorosilane (CH3)2 SiCl2. After distillative separation, the dimethyldichlorosilane is converted by hydrolysis or methanolysis into silanols which condense into low-molecularweight chains and cycles. In an acidic (cationic) or alkaline (anionic) catalysed polymerisation, polydimethylsiloxanes with hydroxy functions are generated. After the addition of trimethylchlorosilane they are furnished with trimethylsiloxy end groups. The short chain molecules are removed from the resulting polydisperse polymers by way of vaporisation, leaving deployable PDMS. The characteristic aspect of the PDMS molecule is the Si-O bond. With a bond energy of 108 kcal/mol, it is considerably more stable than the C-O bond (83 kcal/ mol) or the C-C bond (85 kcal/mol). PDMS is accordingly less sensitive to thermal loads, UV radiation or oxidation agents. Reactions such as oxidation, polymerisation or depolymerisation do not occur until temperatures exceed 130°C. The molecule also typically has a flat bond angle (Si-O-Si 130°C) which has low rotation energy and is especially flexible (Fig. 2). A high bond length (1.63Å Si-O as compared to 1.43Å for C-O) makes the molecule comparatively gas-permeable6.

Figure 2: 3D-structure of polydimethylsiloxane Fig. 2 The spiral shaped (and therefore easily compressible) molecule is surrounded by CH3 groups which are responsible for the chemical and mechanical properties of PDMS. The molecule’s methyl groups only interact to a very limited extent. This ensures low viscosity, even with high molecular weights, which simplifies the distribution of PDMS on surfaces and makes it a very effective lubricant. PDMS is also largely inert and reactions with glass, metals, plastics or human tissues are minimal. The CH3 groups make PDMS extremely hydrophobic. It is insoluble in water, but soluble in non-polar solvents6. Siliconised Syringes As already explained, the syringe system only works if the glass barrel and plunger stopper siliconisation are homogenous and optimally harmonised. For needle syringes, siliconisation of the needle is also essential to prevent it sticking to the skin, thereby minimising injection pain. For the so-called oily siliconisation of the syringe glass barrel, DOW CORNING® 360 with a viscosity of 1000 cSt is used. The DOW CORNING® 365 siliconisation emulsion is often used in the bakedon siliconisation process. The needle is siliconised using a wipe technique during ready-to-fill processing. DOW CORNING® 360 with a viscosity of 12,500 cSt is used. Another option is the thermal fixation of silicon oil on the needle during the needle mounting process. The goal of syringe barrel siliconisation is to obtain the most even anti-friction coating possible along the entire length of the syringe in order to minimise break loose and gliding forces when the plunger stopper is deployed (Fig. 3).

Summer 2015 Volume 7 Issue 2


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Manufacturing

Figure 3 : Definition of break loose Fig. 3 Inadequate siliconisation of the syringe barrel, particularly the existence of unsiliconised areas, can cause slip-stick effects that impair the syringe’s function. The forces in the injection process can then be too high or the entire system can fail. Since inadequate siliconisation and gaps in the coating are often found on the lower end of the syringe (luer tip/needle end), it is possible that the syringe will not be completely emptied. Such defects can remain undiscovered, particularly in auto-injectors since these are closed systems. The result could be that an inadequate dosage of the medication is administered. The obvious solution is to increase the amount of silicone oil used to achieve a homogenous

80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

coating. However, as already mentioned, increasing the amount of silicone oil used is also associated with higher quantities of silicone particles in the solution. With protein-based drugs, in particular, undesirable interactions with silicone oil particles cannot be ruled out. Sub-visual silicone oil particles are thought to promote protein aggregation, which can increase the severity of immune responses and reduce the drug’s tolerability. However, the underlying mechanism is not yet fully understood. There is a discussion as to whether protein aggregation is influenced by additional motion, e.g. shaking the syringe7. Experiments have also shown that when silicone oil in excess of 1mg/syringe is

used, the additional silicone oil does not further reduce gliding forces. The interior siliconisation of glass syringe barrels has another advantage. It prevents the drug solution from interacting with the glass surface and rules out related problems such as the loss of active ingredients through adsorption or pH value changes due to alkali leaching. Prefillable glass syringes are only manufactured from high quality type 1 borosilicate glass. However, sodium ions can still leach out of the glass surface if the syringe contains an aqueous solution and is stored for a long period of time. This leads to higher pH values, which could be problematic in unbuffered systems. Acidic environments foster this process. Si-O-Na + H20 ↔ SiOH + NaOH. In alkaline environments, on the other hand, an etching process is observed. 2NaOH + (SiO2)X → Na2SiO3 + H2O Aqueous solutions with a high pH value cannot therefore be stored for long periods of time in borosilicate glass containers. They have to be lyophilised and reconstituted before use. In extreme cases, the etching of the glass surface can cause delamination.

Summer 2015 Volume 7 Issue 2


Hydrophobic deactivation of the container by siliconisation effectively protects the glass surface.

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Optimised Siliconisation For the above-mentioned reasons, the main objective in siliconisation is to achieve the most homogenous possible coating with the minimum possible quantity of silicone oil. Initially it is necessary to establish the minimum quantity of silicone oil which will reliably satisfy the quality requirements of the application. In the production of ready-to-fill syringes, siliconisation generally takes place after washing and drying. Fixed nozzles positioned at finger flange level under the syringe barrel spray the silicone oil onto the inside surface. In long syringes, the silicone oil is sometimes unevenly distributed and the concentration of the silicone oil is lower at one end of the syringe (luer tip/needle end). The use of diving nozzles can considerably improve the evenness of the coating across the entire length of the syringe body. In this process, the nozzles are inserted into the syringe to apply the silicone oil (finely atomised) in motion. The result is practically linear as is shown by the closely-bundled gliding forces in the force path diagram (Fig. 4).

Figure 4: Comparison of extrusion

to swiftly respond to changing markets and production needs, reliably provide top quality drugs while meeting regulatory compliance?

Fig. 4 Studies on 1 ml long syringes have revealed considerable potential for reducing the amount of silicone oil required. In the experiment, the quantity of silicone oil per syringe could be reduced by 40 % without any impairment of the systemâ&#x20AC;&#x2122;s functional properties (Fig. 5).

We can help you to have them. Contact us.

Figure 5: Extrusion force profile Fig. 5 In practice the calculation of the optimum quantity of silicone oil has to take syringe volume, plunger stopper type (coated/ uncoated), plunger stopper placement method (seating tube/vacuum) and application requirements (injection systems) into account. Plunger stoppers from different suppliers not only www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 81

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Manufacturing differ in terms of the type of rubber used and their design; they are also coated with silicone oils of different viscosities. The siliconisation methods also differ considerably. These variables can have a bigger impact on the syringe systemâ&#x20AC;&#x2122;s functional properties than the syringe siliconisation of different suppliers, as shown by Eu et al.8.

permanent hydrophobic layer is created (Fig. 6).

Fig. 7 In addition, the average molecule weight increases as a result of polymerisation and the vaporisation of short chain polymers. The resulting, extremely thin, layer of silicone in conjunction with the low quantity of silicone oil used in the emulsion Baked-on Siliconisation minimises free silicone in the syringe and Another key advancement in siliconisation ensures that the required quality of finish technology is the baked-on siliconisation is achieved. The layer thickness measures technology. It involves the application of 15 - 50 nm. By comparison, the average silicone oil as an emulsion, which is then layer thickness with oily siliconisation is baked on to the glass surface in a special 500 - 1000 nm. Baked-on siliconisation kiln at a specific temperature and for a reduces the measurable quantity of free specific length of time (see Fig. 6). silicone oil to approx. 10 % of the normal value. As a result, there are fewer subFig. 6 In the baked-on process, both visual and visual silicone oil particles in hydrogen and covalent bonds form the solution. This siliconisation process between the glass surface and the is therefore recommended for use with polydimethylsiloxane chains. The bonds sensitive protein formulations. It is also are so strong that part of the silicone oil advantageous for ophthalmological cannot be removed with solvent and a preparations which are associated with very stringent requirements as regards particle contamination. To investigate the differences in particle load for spray and baked-on siliconised syringes, a study has been performed using 1 ml long SIN syringes with oily and BoS filled with WFI and Tween Figure 6: Baked on siliconization 0.03% solution.

Figure 8: Glass Dust Test Fig. 8 (1-4) Results from the study did prove that Gx Baked-on RTF syringes show much lower particle loads. Analysis Methods The optimisation of the siliconisation process necessitates reliable qualitative and quantitative analysis methods. Online methods for the one hundred per cent control of siliconisation during production are not currently available. In process control, random samples are taken and several destructive and nondestructive methods are used. In the glass dust test, the siliconisation is made visible by dusting it with finest glass particles (Fig. 8). Fig. 9 This destructive method is simple

Figure 9: gliding force measurement but time-consuming. It is also associated with the problems that the quality of the siliconisation is subjectively evaluated and the results are affected by temperature and air humidity. Measuring the gliding force is an indirect method of determining the evenness of the siliconisation (Fig. 10). Figure 7 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2015 Volume 7 Issue 2


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Manufacturing very experienced person to interpret the results properly.

Figure 10: Silicone Layer Fig. 10 This process is also destructive and associated with problems. For example, the results are influenced by the positioning of the plunger stopper and there is no standard for extrusion speed. A value of 100 mm/min is often taken for empty syringe systems; and up to 380 mm/min. for filled systems. Relatively fast quantitative and non-destructive results can be obtained with reflexometry. For example, the Layer Explorer UT (Fig. 11), which is manufactured by rapID, scans the syringe body line-by-line. It can measure layer thicknesses of 15nm to several thousand nm with a precision of 5 nm (Fig. 11.1). Scanning a 40 mm syringe with the Layer Explorer takes approximately one minute.

Figure 11: Zebra Science

Figure 11.1: Visualsation of syringe barrel Fig. 11 and Fig 11.1 Another nondestructive technique such as the one developed by Zebra Science is based on digital image processing. The entire inside surface of the syringe barrel is imaged to visualise typical siliconisation surface structures. The technology captures these visual cues as a direct indication of silicone oil presence and poorly siliconised areas. It delivers fast qualitative results and is suitable for empty and filled syringes. However, empty syringes should be measured immediately after siliconisation because even just half an hour after siliconisation the distribution of the silicone provides a completely different picture and it takes a 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Outlook There is a trend towards reduced-silicone systems or baked-on siliconisation in glass syringe finishing. Improved analysis techniques and a better understanding of the phenomena involved support optimised use of silicone oil. New issues are arising as a result of the use of innovative materials or coatings. In light of the increasing complexity of devices and the more widespread incidence of biopharmaceuticals with specific requirements, new alternative materials for primary packaging products are becoming increasingly interesting. For example, the inside surfaces of vials and syringes can be coated with pure SiO2 in a plasma process to minimise their interaction with drugs. Plastic systems based on cyclic olefins (COP/ COC) are also gaining in significance for prefilled syringes and vials. COP syringes such as the ClearJect TasPack™ by Taisei Kako Co. Ltd have glass-like transparency. Additionally, they have a higher break resistance, their pH stability range is larger and there is no metal ion leaching. Excellent dosage precision is also very important in packaging for bio-pharmaceuticals. In most cases siliconisation is also essential in COP syringes. Silicone oil-free systems are also offered. The gliding properties of plunger stoppers with proprietary coatings eliminate the need to siliconise plastic syringes. References 1. United States Pharmacopoeia 35 NF 30. Dimethicone, The United States Pharmacopeial Convention Inc, Rockville, USA, 2011 2. Pharmacopoea Europaea. 7th edition. Dimeticon, Deutscher Apotheker Verlag, Stuttgart, Germany, 2011, p. 2788 3. Pharmacopoea Europaea. 7th edition. 3.1.8 Silicon oil for use as a lubricant, Deutscher Apotheker Verlag, Stuttgart, Germany, 2011, p. 486 4. Jones LS, Kaufmann A, Middaugh CR. Silicone oil induced aggregation of pro teins. J Pharm Sci 2005; 94(4):918-927 5. Colas A, Siang J, Ulman K. Silicone in Pharmaceutical Applications Part 2: Silicone Excipients. Dow Corning Corporation, Midland, USA, 2001

6. Colas A. Silicone in Pharmaceutical Applications. Dow Corning Corporation, Midland, USA, 2001 7. Thirumangalathu R, Krishnan S, Speed Ricci M, Brems DN, Randolph TW, Carpenter JF. Silicone Oil and agitation-induced aggregation of a monoclonal antibody in aqueous suspension. J Pharm Sci 2009; 98(9):3167-3181 8. Rathore N, Pranay P, Eu B. Variability in syringe components and its impact on functionality of delivery systems. PDA J Pharm Sci and Tech 2011; 65:468-480 Mrs. Petersen did study bioprocess engineering at the Technical University of Berlin. After two years postgraduate work in the field of oncology research she joined in 1998 company Life Sciences Meissner & Wurst working finally as a lead validation engineer. From 2000 – 2007 she held different positions at West Pharmaceutical Services (a leading supplier of elastomer components for the pharmaceutical industry) European Technical Support and Marketing department finally as Senior Manager Biotechnology. In Dec 2007 she started to work as Director Business Development for the Tubular Glass Division at Gerresheimer . Since Dec 2014 she is the Global Director Business Development for the Gerresheimer Medical Systems business unit. E-mail: c.petersen@gerresheimer.com

Bernd Zeiss studied biology, microbiology and chemistry at the University of Göttingen, Germany. After several years working in the fields of contract research, clinical sales management and automated laboratory equipment, he today is a member of the Gerresheimer Bünde business development team. He works in the Gerresheimer Center of Excellence for prefillable syringes as Technical Support Manager. His main areas of work are technical customer support, investigating possible interactions between syringe components and drug substance as well as the evaluation of innovations like COP syringes in comparison to glass. Email: b.zeiss@gerresheimer.com

Summer 2015 Volume 7 Issue 2


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Manufacturing

Freeze-drying with Collapse is Not Necessarily Bad for Stability and can Reduce Cost Lyophilisation is often used to increase the stability and shelf life of proteins which are physically and/or chemically unstable in aqueous solution. Freeze-drying removes water protein solutions, including water from the protein surface which plays a major role within the protein structure, and this frequently causes damage. An appropriate choice of stabilising additives is necessary to protect the protein from denaturing, during both the freezing and the dehydration. The components of the excipients displace water by replacement, which makes drying possible without causing damage to the proteins. In addition, the solidification of the excipients forms a matrix around the particles which keeps the proteins in their native structures. Concerning the process, the cycle is usually running below collapse temperature to avoid a loss of physical structure, incomplete drying (high moisture content), a decrease of solubility (or increase of aggregation), or a decrease of activity and/or stability. In addition, the best freeze-drying cycles are those that have been optimised to be as short as possible: run at high temperature to run fast. In that case, formulation should have a high glass transition temperature to facilitate freezedrying. Some disaccharides like sucrose are often good stabilisers for proteins, but unfortunately they have a low collapse temperature. Recent studies seem to indicate that drying above the collapse temperature is not necessarily bad; the protein stability is not always damaged. Our objective was to study the activity and stability of a freeze-dried protein in vials which shows signs of collapse. The protein selected was alkaline phosphatase (from Sigma Aldrich) which is used to help in detecting liver disease. The enzyme may catalyse the hydrolysis of various monophosphate esters at alkaline pH; the method for the measurement of alkaline phosphatase specific activity was based on the conversion of para-nitrophenylphosphate (p-NPP) to para-nitrophenol and the colorimetric determination of the resulting coloured product. 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A formulation by combining alkaline phosphatase, Tris HCL buffer and sucrose was defined. The collapse temperature (Tcoll) was measured using freeze-drying microscopy (cf. Figure 1). Figure 4: Macroscopic view of freeze-dried formulation by combining alkaline phosphatase, Tris HCL buffer and sucrose, on the left collapse structure; on the right no collapse structure

Figure 1: Microscopic observation of formulation by combining alkaline phosphatase, Tris HCL buffer and sucrose collapse area shown.

The formulation was poured into a vial and loaded in a freeze-drier. Two cycles were running: one with a “conservative” freeze-drying protocol which maintains the product temperature below collapse temperature (time of cycle: 72 hours, cf. Figure 2), and an “aggressive” freeze-drying protocol carried out at higher temperature and higher pressure which does not maintain the product temperature below collapse temperature (time of cycle: 48 hours, cf. Figure 3). In the first case, the appearance of the freeze-dried products was good, and in the second case they showed signs of collapse but the cycle was shorter (cf. Figure 4). 

° °

 °

° °  

 

 

Figure 2: Conservative cycle

against denaturing, but more particularly the results suggest that the freeze-dried product with signs of collapse did not damage the alkaline phosphatase quality. The specific activity recovery of alkaline phosphatase is the same with a collapse macroscopic structure and with none.

Figure 5: Specific activity recovery of alkaline phosphatise as a function of the storage with or without collapse structure

This presentation is for informational purposes only and it is not about new guidelines for stabilisation of proteins by freeze-drying, but it suggests that in some cases, not generally speaking, we can freeze-dry above the collapse temperature to have a short cycle which implies lower costs without causing damage to the product if we do not care to have an inelegant product, if the product aspect is not that important.

 °

freeze drying above the collapse temperature

°

 °

° °

 

 

 

Figure 3: Aggressive cycle

Figure 2 and 3

These measurements are performed in accordance with a TO and after storage at 25°C temperature conditions. The results of storage stability in dried state (cf. Figure 5) confirm that sucrose stabilises the protein conformation

Sophie Declomesnil is the manager of Research and Development at LYOFAL (groupe SYNERLAB) leading collaborative research activity of client projects. Over the past 19 years, she has been working at LYOFAL and is responsible for the lyophilisation development of the company focusing on formulation, freeze drying cycle development and thermal properties of the products and also tech transfer. Email: sophie.declomesnil@synerlab.com Summer 2015 Volume 7 Issue 2


Manufacturing

Accelerating and Automating Sterility Testing in Microbial Quality Control In 2009 the influenza A (H1N1) pandemic struck the United States and, according to CDC estimates1, affected approximately 60.8 million people, with 274,304 hospitalisations and 12,469 deaths. While this strain of the flu virus continues to circulate worldwide, the rapid and significant impact of this pandemic revealed the need to find ways to speed response to future events. One area of opportunity is the sterility test. The traditional sterility test used by pharmaceutical manufacturers based on guidance in the European Pharmacopeia is a time-consuming test that includes potential risks. First, sample test results are measured using turbidity, a presence/absence technique that can be considered subjective, since the microbiologist must make a decision based on experience as to whether the solution incubated does contain growth. This can potentially lead to errors and requires that the sample itself does not exhibit turbidity. If the sample does cause either of the traditional media fluid thioglycollate medium or soybean casein media to become turbid, then the lab must perform a subculture step and an additional four days’ incubation to declare the product sterile. This extra time added to the original 14-day incubation can either cause significant delays in manufacturing or drive the business to manufacture product at risk with an expectation that the sterility results will be negative.

unobserved within manufacturing for up to two weeks, providing more time for contamination to become widespread, with more potential product waste and also potential patient risk of a supply chain shortage. The length of the test is directly related to the need to capture slow-growing bacteria. These can come in two forms: those with a long lag period such as stressed bacteria, or the true slowgrowers i.e. those with a slow generation time. Pharmaceutical manufacturing environments are very harsh for bacteria and lead to a large amount of stress from desiccation, disinfectants, temperature, etc. This can lead to damage and hence a slower and longer lag phase, as the cells repair any injured components prior to the start of replication. Slowgrowing species, however, such as Propionibacterium acnes, have a slow generation time (5.1 hours)2, therefore it can take 4-5 days for a non-stressed P. acnes to be visualised (and much longer in stressed systems). Accelerating the Test New technologies are available to reduce the incubation time for sterility testing by nearly half. These methods take advantage of the traditional sample preparation, but use advanced imaging and detection technology to detect

growing colonies at a more rapid pace. An example of such a technology is the Growth Direct™ System. The Growth Direct System mirrors the traditional sterility incubation regimen. The test still relies on the filtration of the sample using the current sterility pump system, and a liquid media is still used, mirroring the traditional test. As seen in Figure 1, to replicate the existing testing environment, each test kit comes with three cassettes; two to provide aerobic testing at both 20-25°C and 30-35°C, and one for anaerobic testing at 30-35°C. After the sample is prepared, the technician releases oxygen scavengers to create the anaerobic environment. As with the traditional test, the product is filtered using a peristaltic sterility pump and tubing. Liquid growth medium is then added using the same device. To ensure a closed environment, the cassettes are sealed. For the anaerobic cassette, the oxygen scavenger is activated in order to create an anaerobic environment. The cassette and system are designed for monitoring to ensure the anaerobic state has been reached and maintained throughout the assay. Once samples are prepared, they are

In addition to turbidity, the manual sterility test, like all manual tests, has the potential for errors such as incubating for the wrong time or at the wrong temperatures, or incorrectly recording results. Not only can this create incorrect results, it can generate costly investigations. The sterility test is one of the most critical tests performed in the microbiology laboratory, and has a direct effect on patient health. It also has one of the longest incubation times and can create a bottleneck in terms of production. The length of the test can also result in a sterility failure potentially remaining 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 Sterility Test Summer 2015 Volume 7 Issue 2


Manufacturing loaded into the detection technology, which leverages robotics, imaging, incubation and detection technology. Samples are distributed between two incubators at the appropriate temperatures. At regular time intervals, the samples are automatically taken from the incubator to the imaging chamber where a blue light is shone onto the surface of the sample at a particular wavelength. An image of the cassette is registered by a CCD chip camera (Figure 2). While the blue light illuminates the sample, any living cells will autofluoresce and be captured on the CCD chip. This process is repeated at measured intervals to generate a library of images over the course of the incubation. Software algorithms analyse the library of CCD images to differentiate a growing colony from any background fluorescence. The positive/negative results are reported to the lab by LIMS, allowing for the lab to respond quickly to any positive results. The use of natural autofluorescence for colony detection offers several advantages. First, imaging is able to detect growing colonies of as little as around 100 cells, rather than the 5x106 cells needed for the human eye. Second, at the end of the test the colony remains intact, and can then be ready for identification. Because of this, a further step is eliminated in that a spread plate for purification may no longer be required. Thus, in the case of true slowgrowing organisms such as P. acnes, days can be saved over the standard method. The rapid sterility method can detect growing colonies starting in hours, with comparable results to the traditional method in about half the time – seven days versus 14. Studies have shown this detection rate even with stressed organisms. Automating the Test Beyond rapid results, the automation of incubation, detection and reporting of sterility results can have a significant impact on both the lab and production environment. Because the technology is examining samples at regular time intervals, positive results are available as soon as they are detected. This can allow the lab and production area to prepare for an investigation ahead of the final sample result. In addition, integration of the automated technology to a laboratory information management system (LIMS) 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

eliminates the risk of any keying errors of results and the potential investigations that follow. Stakeholders will have access to sample results in half the time and updated to their LIMS system. The technology contains a full audit trail of user actions on the Figure 2 Detection of Natural Autofluorescence instrument, which can be accessed as needed. In conclusion, utilising a Rapid Automated System for sterility testing can dramatically reduce the time to results for the sterility test and increase Figure 3 Comparison of the Time to Result using Automated the efficiency of Imaging vs. Manual Counting. the microbiology lab and the 2. Growth curve for Propionibacterium acnes, manufacturing of a sterile product. • •

The test is a presence absence/assay which means that no subjective turbidity judgment is relied upon. Automation of the process minimises any risk of errors caused by the manual handling involved in following traditional SOPs such as incubation of samples at the wrong temperatures and times. The risks of poor handwriting and transcription errors are eliminated due to the software and LIMS interface, which means that test results can be immediately available in the LIMS system at the end of an assay.

Results can be achieved in about half the time of the traditional test, and an email/text warning can be provided the moment a sample becomes positive, meaning that many days can be saved in the event of a sterility failure. Such time savings can have a direct impact on the production of pharmaceuticals such as the flu vaccine. References 1. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010), Shrestha SS, et al., Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S75-82.

Gerri S. Hall, Kathy Pratt-Rippin, David M. Meisler, John A. Washington, Thomas J. Roussel, Darlene Miller, Current Eye Research 1994 13:6 , 465-466

Anna Mills, Senior Validation Specialist at Rapid Micro Biosystems. Ms. Mills has more than 12 years of experience in the Life Sciences industry. Prior to joining Rapid Micro Biosystems as a senior field application specialist, Ms. Mills worked for BD Diagnotics systems, providing technical training and support for the European Sales organization across a wide range of products from dehydrated culture medium to rapid detection and identification systems. Prior to that, Ms. Mills managed southern European technical support at Celsis, where she provided regulatory support for the Celsis pharmaceutical team throughout Europe, and served as an application specialist for Becton Dickenson. Anna holds a Bachelors of Science with honors from Plymouth University, and a Masters of Philosophy in the research of Campylobacter from the University of Northampton. Summer 2015 Volume 7 Issue 2


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Pierre FABRE CDMO: Pierre FABRE is one of the leading pharmaceutical companies rooted in France, which sells its pharmaceuticals, healthcare and dermo-cosmetic products all over the world1. With more than 50 years of activities and an annual turnover exceeding 2 billion euros, Pierre FABRE is a well-established player, firmly anchored in the south-west of France and with a growing footprint in Africa and Asia, as well as in America, either on its own or through strategic partnerships. For more than 30 years, the Pierre FABRE Pharma division has offered CMO activities to clients, mostly in the field of injectable products. Recently, the initiative to turn to a CDMO model was launched, with a new team and a redesigned organisation, in the frame of a global strategic plan “Trajectoire 2018”2. « Manufacturing for your Health » is the watchword for the Pierre Fabre CDMO newly-organized franchise, and they are words the CDMO team members have taken to heart in developing their new business activities. The global pharma outsourcing market is growing fast, with an estimated market value of about $300 billion this year, thanks to the contribution of contract research organisations (CROs), contract manufacturing organisations (CMOs), and contract development and manufacturing organisations (CDMOs). After more than 30 years of CMO activities, CDMO has now become an integral part of the development and manufacturing strategies of the Pierre FABRE Pharma division. The turn from CMO to CDMO is not new in the pharma & biotech industry. A trend towards outsourcing earlier-stage analytical and formulation capabilities was already noticed in the past 5-10 years. Small biotechs are particularly eager to get their products into the clinic more quickly and raise value earlier in their development, with the assistance of global service providers. Pierre FABRE follows this CMO-to-CDMO evolution, with the objective to reinforce its competitiveness within three specialised poles of activity: 1. injectable products, including conventional cytotoxic and biotechnology products; 2. API chemistry, in particular for natural products; 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Manufacturing for your Health

3. the niche market of pharmaceutical lozenges. Each of these three business lines is associated with technical innovations and linked to R&D knowledge (Figure 1).

R&D operations

Development activities (chemical and biological products)

Partners

External innovation (alliance, partnership)

Demands

PF CDMO team

Injectable & Biotech Products

PCC

API chemistry

Filled aseptic vials, syringes

SCF

Natural products Plant/animal extracts HP-cytotoxic drugs

CDMO Division for Injectable and Lozenges Biotech Products Pharmaceutical lozenges Pastilles One of our main services focuses on manufacturing (+/- packaging) of very Raw materials, ingredients, components, etc large batch sizes of marketed products Figure 1: Illustration of Pierre FABRE CDMO business owned by medium and big pharma capabilities and outputs. Innovation platforms, such as Fluid (SCF) and Plant Cell Culture (PCC) function in partner companies essentially. This is the Supercritical a semi-independent mode from core mainstream activities recognised expertise of our agenciesaccredited site located in Pau (PFMP, shop for their product. Whatever the France). This site, organised around perception of the so-called “shop”, which nine independent workshops, specialises may propose activities from “Gene to in aseptic processing and isolator Syringe” or from “Compound to Clinic” manufacturing of anticancer and biotech or from “Bench to Market”, the objective products in vials, syringes and infusion is always to offer a broader service bags, liquid or freeze-dried (Figure for our clients. In this context, and as a 2). Each workshop provides customer- typical example, we are a key partner oriented innovations, such as ATEX for the fill and finish of a registered compliance for sterile processing and immuno-conjugate owned by a US big freeze-drying processes with organic pharma company relying on our highsolvents, compact loading/unloading capacity manufacturing capacities, systems, sterile capping, laser printing as well as the strategic partner for an devices, etc. The onsite service also emerging European biotech developing includes purchase and control of raw a new generation of antibody-drug materials/components, cold storage conjugate. Both ADC companies, the of active ingredients, manual or semi- large and the small ones, request from automatic visual inspection and specific us a high-quality organisation and packaging in bulk or finished products, good people and infrastructures to and delivery. In addition, we now offer handle their products, with guarantee a broader service linking manufacturing to respect their timeline and financial to product development services for constraints. We demonstrated a costboth chemical and biological entities, effective partnership for quality services via two R&D facilities based in Toulouse from development to manufacturing, and Saint-Julien-en-Genevois (France). based on our solid expertise of sterile This CDMO model thus integrates key components of drug development (process development and validation, formulation and analytical support, stability storage and testing, clinical batches production, etc) into the manufacturing process at early stages. Clients - be it a large global pharmaceutical company, a mid-sized biotech, or a virtual firm - are particularly Figure 2: Manufacturing of injectable products (Pau, France) keen to find a one-stopCDMO divisions & industrial plants

Summer 2015 Volume 7 Issue 2


Advertorial injectable products. In this domain, the international competition is fierce and the market tends to concentrate around a few big players selected by large/mid-sized pharmaceutical companies. A full product offering is key to keep our partners and bring newer, smaller players which tomorrow will be the leaders through their novel drugs. Said in another way, there is no choice but to offer our present and future clients the D they demand, in addition to the M we are mandated to do. With an agile organisation and adapted equipment, we can be brought in on a new project, let’s say a new vaccine for example, at the early stage of protein development with a small batch scale-up to the late stage of registration with a commercial dimension, depending on the wish and strategy of the partner. Needless to say, in this domain of highly-active products (generally for oncology and inflammatory diseases), our production processes are subject to rigorous quality control procedures and testing, and are GMP-compliant in accordance with requirements of international agencies (ANSM, FDA, PMDA, ANVISA…). The Pierre FABRE CDMO division for injectable cytotoxic and biotech products is the partner of choice for a number of European, US and Japan pharma companies. All our partners are different; we adapt to their need and profile. Our perspective is to broaden our international presence and to be continuously pioneers in the manufacturing process. CDMO Division for Pharmaceuticals Lozenges For more than 30 years, the Pierre FABRE plant in Aignan (France) has offered a cost-effective service for the manufacturing of hard-boiled lozenges and pastilles/gums that are sucked in the mouth and traditionally used for cold and throat OTC preparations, but also for smoking cessation or other nutraceutical applications. A variety of well differentiated products can be made, based on our custom formulation and taste-masking capabilities. Different production lines offer variable capacities, from batches of 65kg to large volumes of 5000kg using a fully automatic continuous manufacturing process (Figure 3). This later up-to-date technology of continuous flow enhances the production capacity as well as product quality and security. Our R&D teams provide the necessary support to create new products or to modulate lozenges formulation www.ipimedia.com

or product stability, to optimise local exposure of the active ingredient in the oral cavity for a predetermined period of time, for example. We offer a full CDMO lozenge service to our clients, from product development to product launch. The service can include both manufacturing and packaging, with a variety of packaging solutions: blister packing, bag in box and flow wrap. The development service is broad: optimisation of formulations, scale-up services (pilot batches, clinical batches, registration batches), biological tests, stability testing, validation batches, regulatory support, technical transfer for commercial production, and other custom services. Our dedicated plant in Aignan produces a variety of lozenges, from Drill® Pierre FABRE’s famous brand of cough relief lozenges, renowned for their unique flavour and active qualities, to a range of partner products with different forms and applications (pastilles to soothe and relieve sore throats, coughs or colds; lozenges containing flavour modulators, nicotine, etc...). We currently produce more than 300 million lozenges per year. Electronically controlled, automated, high-performance machines carry out all the processes right from weighing the raw material, to cooking, blending, flavouring, cooling and forming the hard candy. The Pierre FABRE CDMO division for Pharmaceuticals Lozenges can assist you in the manufacturing and supplying of medicated and herbal lozenges in various sizes and types of packaging. We are engaged to complete projects at a reasonable cost and to deliver expeditiously according to stringent timelines. Our dedication to our clients and their business contributes to a differentiated product capable of competing in both domestic and international markets (European and US markets). Our Aignan facility is robustly implanted in the pharmaceuticals lozenges niche market. We are upgrading the plant to ensure that it meets

the rigorous requirements demanded by both our customers and the health authorities. Facility expansions are also planned for the near future and further down the line. This CDMO division will continue to grow sweetly. CDMO Division for API Chemistry The Pierre FABRE company was founded more than fifty years ago and it is today a firm of international repute, renowned for its high-quality and innovative products, in particular natural substances extracted from plants. For example, Pierre FABRE is the world leader for the extraction of vinca-alkaloids from the tropical periwinkle (e.g. the cytotoxic products Navelbine® and Vinflunine®, both prescribed in oncology). The group has an incredible culture of natural substances, used in the pharmaceutical field and even more extensively in the dermo-cosmetic domain. Located in Gaillac (F), the dedicated site “Plantes & Industrie” offers high technologies for the extraction, purification and chemical synthesis of APIs (Figure 4). A speciality of our operators is the handling of high potent APIs, in particular naturallyoccurring cytotoxic agents manipulated in specific workshops to enable their extraction and purification, and in specific cases their chemical modulation (e.g. low-temperature fluorination in superacidic media). Another site located in Bagnère-de-Bigorre (France) is dedicated to the preparation of floral waters, and two other complementary plants in Virey-del-Pino (Argentina) and Palézieux (Switzerland) provide specific expertise in animal extraction, with the production of chondroitin sulphate sodium (extracted from chicken wishbones), hydroxyapatite (from bone extracts) and other animal specialities. These plants operate in full compliance with current good manufacturing practices (GMP, ICHQ7A) and are regularly inspected by international agencies, including EMA and FDA. Gaillac’s core capabilities

Figure 3: Manufacturing of pharmaceutical lozenges (Aignan, France): batch production (left) and continuous flow (right)

INTERNATIONAL PHARMACEUTICAL INDUSTRY 93


Advertorial technologies in order to provide customers with the highest levels of development, quality, productivity and reliability of health products. Our engineers adapt and optimise key technologies to broaden our services. Here are two segments, both related to green chemistry, which we have significantly investigated and invested in over the past ten years:

Figure 4: Extraction (top) and chemical synthesis (top) of active pharmaceutical ingredients (Gaillac, France)

include controlled substances, plant alkaloids, complex amino acids, and many other technically complex APIs. The specific and independent workshops allow manufacturing for clinical trials or commercialisation, either for defined chemicals or natural extracts. The expertise for purification and extraction is large, using counter current continuous extraction (multi-solvents) and batches, also using industrial HPLC purification and specific technology innovations (e.g. supercritical fluids, see below). The CDMO Division for API chemistry provides pharmaceutical chemistry services to large and emerging pharma and biotech companies across the globe, helping accelerate candidates from discovery to production. We support clients from medicinal chemistry services through Phase I-III to large-scale commercial API production, with a focus on natural products and highly potent 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

cytotoxic products. Our specialisation in natural products chemistry (extraction, analytics, hemisynthesis) and compound classes that require strict regulatory and safety controls, such as potent compounds and controlled substances, differentiates us from our competitors. CDMO officers provide a centralised approach to project management, to ensure on-time and onbudget completion of API development projects for both clinical trials and commercial supply. Over the past five decades, Pierre FABRE has carved out a groove in the natural products market, offering capabilities for several classes of molecules such as amino acids, biopolymers, cytotoxic agents and more recently immuno-conjugates (ADC, see below). Technology Innovations Another key aspect of Pierre FABRE CDMO is to offer a palette of innovative

Plant Cell Cultures (PCC) Biomanufacturing is a major activity to ensure flexible and low-cost production of complex biomolecules using microbial, cell cultures or transgenic technologies. In this context, based on its 50 years of botanical expertise, Pierre FABRE has developed a plant cell culture technology platform and leading know-how to manufacture plant biomass, extracts and secondary metabolites. The PCC technology is based on the isolation of stem cells from a given plant, which are then grown in a bioreactor (Figure 5) to produce an optimised biomass. A modulation of the production of secondary metabolites (elicitation and/ or addition of precursors) can be applied to stimulate the production of the desired product(s). The biomass is then treated, purified and formulated to obtain the whole active mixture of active ingredients. Our flagship commercialised product is Cell CapitalÂŽ from GalĂŠnic brand (FABRE dermo-cosmetic), a potent antiageing lifting elixir from native argan cells. This preparation derives from an in vitro culture of dedifferentiated, nonelicited cells of the argania tree (Argania spinosa, endemic to Morocco but today under threat), used for treating skin ageing, inflammation and scarring. A specific industrial process to ensure the cultivation of these argan plant cells has been designed and implanted within a dedicated workshop, equipped with various incubators and wave bioreactors, under GMP conditions3. This bioprocess can be tailored to produce other active substances on demand in a humancontrolled environment, independently of the original plantâ&#x20AC;&#x2122;s ecosystem, while respecting green chemistry principles (e.g. limited solvent use). It is particularly adapted to plant species that are difficult to cultivate on a large scale, that grow slowly or that have not been domesticated, or are protected or threatened with extinction, without endangering them. This is the case for the diterpenoid epoxide triptolide, an investigational anticancer agent4, usually isolated from the traditional Chinese Summer 2015 Volume 7 Issue 2


Advertorial being produced at the commercial scale under GMP conditions. Our scalable, GMP-compliant and cost-effective supercritical fluid technologies can bring high value to challenging health projects. The CDMO supercritical fluids division has been recognised by international experts and has been awarded with a CPhI Innovation prize for its innovation.

Figure 5: Plant cell culture in a wave bioreactor (Gaillac, France)

medicinal plant Thunder God Vine (Tripterygium wilfordii Hook. f.) and for which we have established a specific PCC process to facilitate the production of the drug and analogues5. The PCC technology is well adapted to produce highly certifiable, environment-friendly products, free of micro-pollutants like heavy metals, aflatoxins, pesticides and herbicides. The goal of our CDMO PCC team is to supply new active substances using various plant cells for use in the cosmetic and pharmaceutical fields. Pierre FABRE has registered several patents in this breakthrough R&D area and offers a full PCC service. Super Critical Fluids (SCF) Over the past 12 years, Pierre FABRE has extensively developed the use of supercritical carbon dioxide as a solvent-free (green) approach to improve the formulation of APIs. Several patented processes have been set up to help the development of products, lifecycle management or formulation: Formulcoat® (particle-coating for taste-masking), Formulplex® (inclusion complex with cyclodextrin), Formuldis P® (solid dispersion in excipient matrix). Our supercritical fluid experts operate in a state-of-the-art and independent SC CO2 platform (Figure 6), using topquality equipment and infrastructure (high pressure pumps 20 kg/h to 500 kg/h; Cyclonic separators 10 and 20 litres; mixer dryer, high potent drug area; etc) in compliance with cGMP to manage a large diversity of therapeutic classes of APIs, including poorly bioavailable www.ipimedia.com

and insoluble APIs, from a few grams to commercial batches (reactors from 0.25 to 50 litres), within our EMA-certified and FDA-inspected site in Gaillac. For example, the supercritical process has been used to improve the dissolution rate of eflucimibe, a cholesterol acyltransferase inhibitor, used to lower serum cholesterol concentration6. More recently, the methodology was used todevelop and to produce a taste-masked Ibuprofen for orodispersible tablets. We also work on the purification of a polymer. Several phase III batches have been manufactured and the polymer is now

These two examples, PCC and SCF, illustrate our efforts to promote green chemistry by complementary approaches. They demand a long-term vision and commitment to yield results, but innovation is clearly not just about technical research and development. Innovation is not the technique itself, it is the output, such as a new natural product obtained by PCC or a valuable polymer purified by SCF. Moreover, we also rely on organisational innovation, with the aim to improve processes and workflows. Solid functional capabilities are important to develop technical knowledge. We are largely open to external innovations to bring in new methods, principles and ideas (Figure 1). Networks, alliances of customers, suppliers and competitors are also source of innovation. Integrative, functional and organisational capabilities are the pillars of our CDMO franchise. Today, at its heart, Pierre FABRE CDMO is essentially an engine for the manufacturing of injectable products, for “fill & finish” operation via its Pau site facility. This activity represents more

Figure 6: Manipulation of supercritical carbon dioxide (Gaillac, France)

INTERNATIONAL PHARMACEUTICAL INDUSTRY 95


Advertorial than 70% of the current annual CDMO revenue, and the most competitive service. Our objective is to maintain a sustainable international position in this domain, including more biotech products, through additional capacities and equipment and workshops, robustness of processes, and a strong link with drug development teams. But we are not committed to one dominant technology. In parallel, we intend to reinforce our competitiveness in API natural products chemistry and develop the pharmaceutical lozenges branch. In the field of API chemistry, we face a major challenge – the requirement to innovate, not just occasionally but often, quickly and with a solid success rate. For lozenges, hand in hand with our clients, the goal is a continuous stream of new products at low price, high quality and for a mass market. In the short term, our position will be reinforced via novel production and packaging lines and development capacities to touch new markets and new therapeutic applications. Clearly the company takes a specialised approach, making investments in the three above mentioned business lines and a few technology platforms, such as PCC and SCF. A key aspect is also to cross this know-how with a clear articulation between services, platforms and organisation. An example of that is given below. A Case Study in Translational Capability: Manufacturing of Antibody-drug Conjugates (ADC) With two products on the oncology market (Adcetris® and Kadcyla®), ADCs may still be considered as an emerging class of anticancer products, although the concept of attaching a potent cytotoxic agent to a cancer cell delivery vector is quite old7. The first ADCs were proposed more than 30 years ago. Now, technologies have evolved and the field is mature, with more than 50 ADCs under clinical development8,9. ADCs are complex molecules, not only intrinsically with three designed and joined components (antibody, linker, cytotoxic), but also in terms of chemistry, manufacturing and controls. The supply chain for a given ADC usually requires multiple partners and a tight management of suppliers, manufacturers, delivery processes, etc. The continuum in the process, from initial synthesis to the finished dosage form is key and few companies can offer the full service. 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

On the one hand, we do perform the fill & finish operation for ADC clinical batches and commercial supply. Pierre FABRE Medicament Production (Pau site) is Seattle Genetics’ operator for cGMP fill/finish manufacture of commercial quantities of brentuximab vedotin (Adcetris®)10. On the other hand, our different R&D teams possess the necessary skills and pilot units to prepare non-GMP and GMP batches of monoclonal antibodies, (high potent) cytotoxic natural products, and hemisynthetic analogues with appropriate linkers. Most importantly, they know perfectly how to handle these individual components, assemble them into effective ADCs, and how to analyse such complex and costly hybrid molecules and characterise integrity, activity, stability, etc… API chemistry, with an emphasis on high potent natural products is a core competence at Pierre FABRE (see above). Our chemists are also engaged in the synthesis of linkers (cleavable, noncleavable) which require traditional small molecule technology for production. Discovery and early development of antibodies, and more recently ADC, is a speciality of the Pierre FABRE Immunology Center, based in SaintJulien-en-Genevois11. With the CDMO franchise, we have now created fully permeable business boundaries between the different entities in R&D and industry, to offer the full service. Cross-functional exchanges encourage innovation and performance. Manufacturing of ADC is considered as a strategic initiative for Pierre FABRE, requiring a good combination of chemical synthesis with biologics engineering. There are several leading companies which best combine the art of chemical synthesis and biological technologies. We jump into the field with a competitive offer based on our reputation in cytotoxic natural products and excellence in performing fill & finish operations. The goal is to provide a full service (Figure 7) to ADC-owners, from biotechs at early stages of development

to mid-size and big pharma requiring essentially terminal manufacturing of their drug products. We see our role as a pure service provider and wish to offer a simplified supply chain from early drug synthesis and antibody production to ADC linking services and fill & finish operation (Table 1). We manufacture the cytotoxic agent and linker at one facility (Gaillac site). We produce the antibody from mammalian cells and provide drug conjugation at our SaintJulien facility. And then we offer terminal aseptic filling and packaging at our Pau site. All steps are realised in high containment environments. Detailed analytic investigations of ADCs can also be proposed, based on a state-of-the-art analytical platform and experts12-15. Conclusion The outsourcing service industry is playing a significant role in moving the entire pharmaceutical industry forward. Along with CROs and CMOs, CDMO players can help with their specialised know-how and deep experience, but players are numerous and specialisation is necessary. Pierre FABRE CDMO offer concentrates on three specific axes, with the aim of capturing a significant share in R&D and in commercial production. The new CDMO team is up and running, with division-dedicated business developers, technical experts and project managers. Strong orientations are fixed (including ADCs, biotech products) and we are in the process of establishing partnerships and alliances to promote our position within the worldwide CDMO arena. Looking forward to the future, we expect to see even more connectivity between pharma R&D and manufacturing industry to facilitate the productive use of knowledge and to best answer the needs of our partners.

Manufacturing capacities for antibody-drug conjugates (ADC)

HP-API production & linker chemistry

Antibody production

ADC conjugation

Aseptic filling

clinical batches (R&D) Commercial scale (Industry) Figure 7: Pierre FABRE CDMO manufacturing capabilities for antibody-drug conjugates (ADC). At present, HP-API production and aseptic filling can be performed for both (pre)clinical batches and commercial use, whereas antibody production and ADC coupling are realised for (pre)clinical batches only.

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Advertorial Table 1: Pierre FABRE ADC capabilities __________________________________________________________________________ 1. HP-API production and • >30 years natural products extraction/purification linker chemistry • Synthesis of HP-cytotoxic agents • API sourcing support • R&D and commercial production • Synthesis of cleavable or conditionally stable linkers • Diverse small molecule chemistry technologies (e.g. superacid chemistry, large-scale chromatography, etc) • Supercritical fluids technology platform • Plant cell culture platform and botanical expertise • GMP-compliance, FDA-approved facility 2. Antibody production

• Process development and scale-up • Master and working cell bank manufacture • Mammalian cell culture (up to 1000L single-use bioreactor) • Fully single-use downstream platform (clarification, chromatography, viral filtration, SU TFF…) • Non-GMP and GMP grade production (kg scale) • Analytical methods development and validation • Formulation development, stability studies • Technology transfer • ANSM-approved facility

3. ADC conjugation

• Aseptic biological manufacturing environment with safe manipulation of highly cytotoxic drugs • Cystein and Lysine coupling technologies • Pilot scale and GMP scale production (up to 100L ADC/batch) • Formulation development, stability studies • Analytical methods development and validation • State-of-the-art ADC analytical characterisation

• >30 years sterile cytotoxic injectables expertise • Wet and dry vials, prefilled syringes • Nine independent workshops • Large lyophilisation capacity • R&D and commercial production • Packaging service • Conform to US/EU/Japan regulatory requirements __________________________________________________________________________ Different R&D and industrial sites are implicated, in Gaillac (API chemistry), Saint-Julien-enGenevois (antibody production and ADC coupling), Pau (fill & finish) and Toulouse (R&D and CDMO offices). 4. Aseptic filling

Table 1: Pierre FABRE ADC capabilities

Acknowledgements: I am grateful to Ms Corinne Alaux for useful comments and corrections to the manuscript. I also wish to thank several Pierre FABRE CDMO, Industry and R&D colleagues for providing me with their insights into the processes mentioned here. References 1. http://www.pierre-fabre.com 2. http://www.pierre-fabre.com/en/ news/pierre-fabre-laboratories-presenttheir-new-strategic-plan-trajectoire-2018 3. Steward N, Mandeau A, Castex Rizzi N. (2010) Préparation issue d’une culture in vitro de cellules dédifférenciées non élicitées d’arganier, leur utilisation pour le traitement du vieillissement cutané, de l’inflammation et de la cicatrisation, et leur obtention. Patent FR2958163 – A1. 4. Meng C, Zhu H, Song H, Wang Z, Huang G, Li D, Ma Z, Ma J, Qin Q, Sun X, Ma J. Targets and molecular mechanisms www.ipimedia.com

5. 6.

7.

8.

9.

10.

11. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010, 10, 345-352. 12. Wagner-Rousset E, Janin-Bussat MC, Colas O, Excoffier M, Ayoub D, Haeuw JF, Rilatt I, Perez M, Corvaïa N, Beck A. Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. MAbs. 2014, 6, 173-184. 13. Wagner-Rousset E, Janin-Bussat MC, Colas O, Excoffier M, Ayoub D, Haeuw JF, Rilatt I, Perez M, Corvaïa N, Beck A. Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. MAbs. 2014, 6, 273-285. 14. Debaene F, Boeuf A, Wagner-Rousset E, Colas O, Ayoub D, Corvaïa N, Van Dorsselaer A, Beck A, Cianférani S. Innovative native MS methodologies for antibody drug conjugate characterization: High resolution native MS and IM-MS for average DAR and DAR distribution assessment. Anal Chem. 2014, 86, 10674-10683. 15. Janin-Bussat MC, Dillenbourg M, Corvaia N, Beck A, Klinguer-Hamour C. Characterization of antibody drug conjugate positional isomers at cysteine residues by peptide mapping LC-MS analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2015, 981-982:9-13.

Christian Bailly is the Pierre Fabre CDMO Director. Contract Development and Manufacturing Organization, CRDPF, 3 Avenue Hubert Curien - BP 13562, 31035 Toulouse cedex 1, France. Email: christian.bailly@pierre-fabre.com

of triptolide in cancer therapy. Chin. J. Cancer Res. 2014, 26, 622-626. Steward N, Chomarat N, N’Guyen, N.T. (2009) Method for producing triptolide. WO 2011/054929 – A2. Rodier E, Lochard H, Sauceau M, 9 Letourneau JJ, Freiss B, Fages J. A three step supercritical process to improve the dissolution rate of eflucimibe. Eur. J. Pharm. Sci. 2005, 26, 184-193. Beck A, Haeuw JF, Wurch T, Goetsch L, Bailly C, Corvaïa N. The next generation of antibody-drug conjugates comes of age. Discov Med. 2010, 10, 329-339. Gerber HP, Koehn FE, Abraham RT. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat Prod Rep. 2013, 30, 625-639. Chari RV, Miller ML, Widdison WC. Antibody-drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl. 2014, 53, 3796-3827. http://www.seattlegenetics.com/pdf/ SGEN_AR_2011.pdf INTERNATIONAL PHARMACEUTICAL INDUSTRY 97


Packaging Inspection Technology Patient Safety and Product Quality Come First Thorough inspection is a key quality safeguard for pharmaceuticals, and contributes significantly to patient safety. With the advent of new and highly potent drugs, quality requirements have dramatically increased. Stricter guidelines and the demand for faster and more flexible processes have triggered the development of sophisticated new technologies for both liquid and solid dosage forms. One single technology is no longer sufficient to inspect all drugs at the highest standards. By offering a combination of highly innovative inspection systems, leading equipment manufacturers enable pharmaceutical companies to achieve the highest product quality with flexible processes. The demand for highly potent medicines is rising continuously1. They cover a wide range of therapeutic areas such as cancer and hormonal therapy, and are administered in many different forms. Since any container defect or change in the drugsâ&#x20AC;&#x2122; structure poses a serious threat to patient safety and product quality, these medicines and their primary packaging require especially thorough inspection. The progress in drug and container development calls for the use of different inspection technologies to meet the highest quality levels at all times. Technologies range from manual and semi-automated to fully-automated inspection systems for liquid and solid dosage forms. They are used either for the detection of productrelated contamination, container defects, leakages or all of them.

range of highly individualised medicines will require a combination of different technologies to ensure consistent product quality and patient safety. From Manual to Fully Automated Inspection When performing manual inspection, each container is carefully inspected with fluorescent light against a black and white background. As manual systems remain subject to human errors and do not offer the speed required for larger batches, they are mainly used for customised applications and stability surveys. Semiautomated inspection systems can achieve more accuracy and reduce the need for manual handling. Automatic feeding, sorting and discharging functions enable inspectors to focus entirely on the quality control of containers. Automated particle inspection systems have their origins in the 1970s. One of the original automated inspection principles is the static division (SD) system, which was developed by Eisai Machinery (now part of Bosch Packaging Technology). The SD system derives its name from the ability to differentiate static from moving objects. It transmits light through the solution onto an optical SD sensor. The container is rotated and then suddenly

stopped, while the liquid continues to rotate in the immobile container. The insoluble foreign particles block a portion of the transmitted light and cast a shadow, which is detected by the SD sensor. These changes in light intensity are only caused by moving particles. Highly Sophisticated Combinations Automated camera-based systems are used for both particle and cosmetic inspection. Depending on the type of container, application and defect, camera systems are either based on CMOS (complementary metal oxide semiconductor) or on CCD (charge coupled device) sensor technology, and are used in area or line scan cameras. Combined with specially-designed optics and lighting such as LED, camera-based systems ensure highly accurate inspection of product defects such as particles stuck to the sidewall, fill levels and product colour, as well as container flaws such as cracks in syringe flanges, or crimp or sealing defects. New CMOS-based systems test containers at elevated speeds. In addition to cosmetic defects, they even identify particles inside medium- to highly-viscous products, oils and suspensions. While the containers are rotated, cameras take a sequence of images. By comparing these images with sophisticated algorithms,

Product contamination implies the undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter into or onto a raw material, intermediate, or API during production, sampling, packaging, storage or transport2. Cosmetic container defects, on the other hand, can occur during handling, either by human intervention or by incorrectly adjusted machinery. Container or closure leaks might entail microbial ingress and reduced shelf life. The choice of inspection methods depends largely on product consistency, product type, and form and size of the containers. Pharmaceutical companies producing a 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Packaging the system identifies target defects while ensuring a low false reject rate. Productspecific parameters determine whether the container is rejected or accepted. To meet the industry’s rapidlychanging requirements, new high-end machines offer a hybrid approach by integrating both SD and camera-based inspection technology in one flexible platform. This enables pharmaceutical manufacturers to adapt their inspection items and processes to their individual production and product needs. These machines aim at high detection rates, even for suspensions and viscous products. Moreover, a modular machine design facilitates the expansion of existing systems by additional inspection units or an extra inspection module. A combination of transmitted and reflected light furthermore allows for the simultaneous detection of light- and darkcoloured particles on the same inspection station, thus leading to significant space savings. An Increasing Focus on CCI In recent years, container closure integrity (CCI) has steadily moved up the agenda3. A trend towards 100 per cent CCI can be observed throughout the industry. Studies show that not only ampoules are prone to CCI defects, which might be even more hazardous than particles when they lead to a change in the API. A container and closure system refers to the entirety of packaging components that together contain and protect the product4, such as containers, stoppers or seals. While sterility testing was deemed sufficient to verify microbial integrity of container closure for a long time, non-destructive CCI methods have now established themselves as the most efficient procedures. They allow pharmaceutical manufacturers to detect sterility breaches prior to product contamination, and prove to be less time-consuming than most sterility test methods. CCI inspection comprises an array of physical testing methods, such as highvoltage leak detection (HVLD) of plastic or glass containers, headspace analysis (HSA) and vacuum leak detection (VLD). Depending on the container and closure system, these methods may still be complemented by microbial testing5 . The choice for the appropriate leak detection technology is dependent on the specific characteristics of product and container, such as conductivity,

headspace parameters, alcohol content or API. To date, systems using HVLD are most commonly applied. They measure the electrical resistance of containers with conductive solutions at up to 25 kilovolts. In case of a leak, the resistance diminishes significantly. Headspace analysis, in turn, is applicable to lyophilised products and medicines filled under vacuum or purged with gas. It measures the quantity of light passing through the headspace region via laser spectroscopy. New solutions are able to inspect both standing and nonstanding containers at outputs of up to 600 containers per minute, and offer a combination of headspace analysis, NIR (near infrared) measurement and coding. In order to ensure highest reliability and accuracy, an automatic (re-)calibration of the measurement modules is continuously performed by using certified reference containers. In case neither HVLD nor HSA is applicable, VLD can be used by measuring vacuum or pressure decay in a dedicated chamber. Solid Dose Inspection Software developments and new image processing capabilities also contribute to a rapid progress of solid dose inspection technologies. Machines that identify defects such as colouration, breakage and foreign particles as small as 50 micrometers at an output of up to 600,000 tablets per hour add to the flexibility of tablet inspection. Their highly accurate camera-based imaging systems ensure a 360-degree inspection of each tablet, thus avoiding blind spots or dead angles. The tablet surface and its peripheral edge are inspected with an RGB line scan camera, while the opposite side is inspected after flipping over the tablets during transportation. This highspeed tablet inspection technology from Bosch was first developed exclusively for the Japanese market, where customer requirements regarding patient safety and product quality – including aesthetic features – are particularly high. Developed with these requirements in mind, such technologies can also benefit solid tablet production in other regions of the world by fulfilling all current and most future needs. Partners Beyond Installation Leading machine manufacturers, who carefully analyse the market and include customers’ experience in their new developments, have already

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established a modular inspection portfolio. The offer ranges from highspeed equipment with a large number of inspection features to low- and midrange solutions with a pre-defined scope. Some of the latter nonetheless combine different technologies such as particle and cosmetic inspection, as well as leak detection at highly economic conditions, while ensuring efficiency and product safety through gentle in-feed and loading solutions. As competent partners to the industry, these providers also support pharmaceutical producers in improving their entire production process, for instance by integrating inspection equipment into complex production and packaging lines. Depending on API, dosage form, container type and size, each product requires one or more very specific inspection methods. The possibilities of inspection technology are continuously growing in order to fulfill the needs set by therapeutic advances. The keys to higher patient safety and product quality lie in the effective combination of state-of-the-art technology. Together with continuous development, these technologies are ready to meet the future requirements of increasingly complex pharmaceutical products. References 1. IMARC Research Inc.: Global Biopharmaceutical Market Report (2012-2015) 2. h t t p : / / w w w. g m p - c o m p l i a n c e . org/elements/PDF/19_Glossary_ GMP2020.pdf 3. Michael J. Akers, Sterile Drug Products: Formulation, Packaging, Manufacturing and Quality (2010), p. 455. 4. US State Food and Drug Administration (2008). Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, p. 3. 5. http://www.pharmacopeia.cn/ v29240/usp29nf24s0_c1207.html

Joachim Baczewski, President of Bosch Packaging Technology K.K. in Japan and Head of Inspection Technology Email: joachim. baczewski@bosch.com Summer 2015 Volume 7 Issue 2


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Packaging Global Traceability: From Factory Floor to Pharmacy An Update on Progress as the Final Countdown to Compliance Begins With only three years until the EU Falsified Medicines Directive (FMD) is enacted into law in each EU member state in 2018 as a response to the global threat of counterfeiting, a number of pilot programmes are now in force across Europe. The journey is not easy, and the complexities that come with the integration of a serialisation system into an existing line mean that manufacturers need to adapt quickly to issues and to modify their approach if challenges arise. Craig Stobie, head of the Life Sciences team at Domino Printing Sciences, and Bart Vansteenkiste, EU Life Sciences sector manager, look at current progress, exploring how some of the greatest concerns for manufacturers around serialisation can be remedied as the deadline for compliance edges closer. Serialisation compliance requires a complete review of the pharmaceutical industry and will become a fundamental, behavioural and culture change in the way that the life sciences industry conducts business. Manufacturers who have embarked on their compliance journey will be under no illusion about the complexities of the FMD, but there is no doubt that new legislation will significantly improve patient safety. Similar schemes in force or in implementation globally – including ANVISA in Brazil, ANMAT in Argentina and MHW in South Korea – are driving item-level serialisation to become the global standard for proving the origins of every pharmaceutical pack. And despite counterfeiters’ efforts to imitate authentic packaging and branding, item-level serialisation will make it much harder for criminals to subvert the legitimate supply chain. “Item-level serialisation will certainly have a positive effect,” explains Vansteenkiste. “The number of falsified products making their way into the hands of patients will be dramatically reduced, as all the legislations that are emerging are imposing unique numbers for each pack of medicines – something counterfeiters won’t be able to re-create.” For the manufacturer, while patient 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

safety is the foremost benefit, there are many more besides. “The industry will be able to handle the management of expired and recalled products much more quickly and effectively when the Directive comes into force,” explains Stobie. “And while improving patient safety is a huge driver for governments and authorities, brands will also be protected from an association with low quality or dangerous products and less money will be lost through counterfeiting. The European industry is therefore very supportive of the legislation.” The Wait Continues With only three years until the compliance deadline, the pressure is building for companies to ensure they can continue to operate within the EU. However, after a recent compliance deadline extension from 2017 to 2018, the Delegated Acts that mandate the obligatory authenticity features on the outer packaging of the medicines are still to be published. Despite the widely-shared expectation that this feature will take the form of an ECC200 2D matrix code, some manufacturers may still be reluctant to invest in changes that have not yet formally been requested. But Stobie stresses this delay should not be a reason to wait. “We already have a good idea of what the Delegated Acts will specify and this largely matches the European Stakeholder Model,” Stobie says. “The European Medicines Verification System is very close to completion, so there really are no excuses to wait to implement serialisation systems. “The Delegated Acts have been drafted and scheduled for adoption in the coming weeks,” he continues. “Once they are published, this will signal the three-year mark before the ultimate compliance date. If manufacturers aren’t ready by then, quite simply, they will not be able to continue to sell their products in the European marketplace.”

Learning From Those in the Know Legislative compliance will require a complete review of the entire business for pharmaceutical manufacturers and serialisation will affect every aspect – from the hardware and the IT systems to the way third parties are managed. So for the manufacturers who have given themselves enough time to create a flexible solution, they will have the knowledge that other companies may be lacking. As serialisation legislation around the world calls for a broadly similar approach, some countries are already broadly versed in the technicalities that come with item-level serialisation – such as France – which had already embarked on the CIP 13 legislation before the EU Directive was announced. “France’s experience of implementing 2D codes for CIP 13 has provided valuable national experience of the challenges of serialisation, and France has been one of the first to start implementing serialisation programmes and pilots for the EU FMD,” says Stobie. “In fact, there are pockets of mature systems across the entire EU, where manufacturers have been aware of the time constraints associated with implementing serialisation and have started pilots as early as possible.” However, Stobie stresses that even these manufacturers may not be entirely prepared. “If manufacturers have used one of their best lines with their best operators in a leading plant to implement a pilot programme, this will not reflect the result that serialisation may have on more challenging lines. It is these lines that will really impact a compliance programme and cause the most problems.” The Serialisation Silver Bullet As the global marketplace shrinks, serialisation legislations are developing to incorporate this and to enable manufacturers across the globe to be able to package products for different markets. “Site culture, geographical location and the local environment can require adjustments to any system. Software serialisations generally offer different reporting options, so that when you run a production order for China for example, Summer 2015 Volume 7 Issue 2


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Packaging the software will not only automatically print the data on the pack in the right format required, but will also produce the report as specified by the authorities to allow you to upload data correctly,” says Vansteenkiste. Despite these developments, however, no single technology or provider will have a solution that will cover all aspects of serialisation. “Although standard best practice approaches should be adopted, a single package will not be suitable for every eventuality,” adds Stobie. “The current requirements might share common themes, but the fact that individual country requirements are still emerging means that any system must remain agile and flexible. “Each company has to adopt a strategy to integrate serialisation capability into their existing business processes as smoothly as possible,” Stobie continues. “And as this affects every business area from the hardware, the IT systems, the people and the management of third parties, a holistic approach is key here. Manufacturers will have to consult multiple specialist companies, from coding and vision companies to software solution companies, to create a solution that works for them.” In a new development, while manufacturers are busy running pilot projects in line with the Directive, ISO standards are now being finalised for the identification of medicinal products (IDMP). Concerns have been raised about whether companies may have to modify their approach in light of these in respect to code generation, but Vansteenkiste is keen to reassure those that have concerns. “It doesn’t matter which standard you adhere to, as long as you use one,” Vansteenkiste says. “The standards will reflect industry best practice, so it should not impact anyone who is doing the right things already.” Beyond Item-level Serialisation A significant difference between approaches is that some legislatures will mandate aggregation beyond item level, which the FMD does not. Although this brings additional challenges, Vansteenkiste and Stobie explain why aggregation

beyond item-level can be beneficial. “Creating a hierarchy that links all the individual numbers on the pack to the number or barcode on the outer case or on the pallet, will simplify the logistics when shipping products through the supply chain. It will also allow better track and trace of products at any time, as serialised individual packs are only seen again at the end of the supply chain when they are dispensed and checked out of the repository,” Vansteenkiste explains. “Although adopting aggregation from day one does add some further challenges, it is much easier than trying to retrofit aggregation into an existing system.” These challenges, Stobie says, mean that manufacturers must be very careful about ensuring the system stays in step. “Aggregation means manufacturers will have multiple stations along the production line that will print and read codes to record the numbers and create relationships between them,” he explains. “If the system gets out of step because of a pack being removed from the line or replaced by another after the data file is created, the whole pallet could be considered as counterfeit and lose all its value. Data files accompanying a pallet or a shipper case are not always visible and hard to check, which forces companies to look at every possible procedure that could disrupt the correct registration of the data throughout the entire process of packaging medicines.” Equipment Efficiency For manufacturers in varying stages of compliance, a concern for many is how overall equipment effectiveness (OEE) can be maintained after integration of a serialisation solution. According to Stobie, the answer lies in the improvement of every element of the packaging line, including the coding equipment. “By choosing the right equipment that ensures the best code grading and guarantees the lowest possible product rejection rates, manufacturers can avoid delays in an already pressurised environment.” Purchasing systems with speciallydesigned features will also help, says Stobie. “Inkjet systems that have been developed to enable a line to continue while ink is replenished are simple but effective measures to up OEE,” he

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explains. “The same applies for the other components that will be added to the line. Manufacturers must look at all elements – people, packaging and equipment – and ensure that any system is viable and robust. Optimising many of the current procedures to ensure that no mistakes are made in aggregating products will in itself lead to an eventual increase in equipment effectiveness as serialisation becomes business as usual.” Key Learnings on the Journey to Serialisation At this point in the journey, manufacturers have a good opportunity to learn from early and current projects that can factor into their eventual serialisation strategies. For Stobie, lessening the pressure through time-scales is essential. “The companies who have started projects have realised how time-intensive it is to create a tailored solution. Start early and involve all departments in this project from the very start,” he says. For small and medium-sized businesses, the task may be more daunting. “Smaller companies need to reduce the size and complexity of the data footprint that serialisation will create,” Stobie adds. “Starting as early as possible means companies can learn and adjust while they have the luxury of making mistakes that don’t yet have a legislative implication.” For Vansteenkiste, forward-thinking is imperative. “A flexible system is really important,” he concludes. “Because sooner or later you will be confronted with new legislations and changes as the pharmaceutical industry continues to adapt. Serialisation is not the end – it’s the beginning.”

Craig Stobie has worked for Domino for over 18 years in technical, operations service and commercial roles. Craig has a broad view of the legislative and commercial pressures facing the healthcare sectors and is well versed in current and impending global legislation. Email: craig.stobie@domino-uk.com Summer 2015 Volume 7 Issue 2


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Chapter Title News China Rejects Sovaldi Patent China has denied Gilead a patent on its blockbuster hepatitis C drug Solvaldi, paving the way for cheap generic versions to appear in the country. Sovaldi (sofosbuvir) is a highly effective medicine, but Gilead has faced backlash across the world for its high price – a full twelve weeks of treatment costs $84,000. The patent application was rejected following a pre-grant challenge filed by the Initiative for Medicines, Access & Knowledge (I-MAK). “China’s rejection of a key patent on Sovaldi goes to show that there are serious questions about whether this drug merits patenting, and sends a strong signal to other countries that are currently reviewing patent applications for the drug,” says Rohit Malpani, director of policy and analysis for Médecins Sans Frontières’ access campaign. “China could prove to be an important supplier for the raw materials as well as the finished product of Sovaldi. Increased competition from manufacturers in China could help push the price of the drug down, so that more people can access it. We hope that other countries where Gilead is seeking patents are watching closely.” Rejections and Challenges This is not the first time Gilead has faced patent difficulties with Sovaldi – it has also been rejected in Egypt and India. A number of additional challenges have been filed in Argentina, Ukraine, Russia, and Brazil. GSK sells Meningitis Vaccines to Pfizer GlaxoSmithKline will sell its meningitis vaccines Nimenrix and Mencevax to Pfizer to satisfy regulatory conditions for its assetswap deal with Novartis. The European Commission and other antitrust regulators were concerned because GSK acquired two rival meningitis vaccines – Menveo and Bexsero – from Novartis as part of the deal, which could have given the company too much power in the market. Nimenrix and Mencevax are older vaccines that had combined sales of £34 million last year. The total value of the transaction with Pfizer is £82 million. “Adding these two innovative and complementary vaccines to our current portfolio will allow us to more completely respond to meningococcal disease outbreaks as well as proactively address a critical public health need – the prevention of meningococcal disease across all ages,” says Susan Silbermann, president of Pfizer Vaccines.

A $10 per-pill generic of the drug has also appeared in Bangladesh, and its manufacturer Incepta plans to market it in other nations where Gilead does not hold a patent. The charity Doctors of the World has even filed a challenge in Europe, saying that the drug “is not sufficiently innovative to warrant a patent”. England First Country to offer Meningitis B vacc Programme England will be the first country in the world to offer all newborn babies a meningitis B vaccine as part of its national immunisation programme. From September, babies aged two months will be offered GlaxoSmithKline’s Bexsero, followed by a second dose at four months and a booster at 12 months, after months of wrangling between the vaccine’s maker and health officials on its price came to an end earlier this year.

“Acquiring these quadrivalent vaccines will broaden our ability to address the burden of meningococcal meningitis – an uncommon but serious and sometimes fatal disease.”

Bexsero was recommended by the Joint Committee on Vaccination and Immunisation in March 2014, but negotiations on price only started in August, finally leading to an agreement in March this year. Campaigners slammed the lengthy process, claiming that lives could have been lost as a result of the delay to the jab’s widespread availability.

Last year Pfizer purchased another meningitis vaccine, Baxter’s NeisVac-C, and had its own serogroup B meningococcal disease drug Trumenba approved. The sale is expected to be completed by the end of the year.

Meanwhile, Health Minister Jane Ellison also announced that to help combat the rise in meningitis W cases in adolescents, all 17 and 18-year-olds will receive a combined meningitis vaccine offering protection against A, C, W, Y strains of the bug from August.

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Summer 2015 Volume 7 Issue 2


ChapterNews Title The vaccine is particularly important for those who are heading off to university, as they are at greater risk, and thus will also be available to older students aged 19 to 25 who are starting university this year, the Department of Health confirmed. 'Not Beaten' Meningitis B chief executive Sue Davie said while the two new immunisations programmes are good news “we’re keen to ensure that people don’t take it to mean that meningitis is now beaten”. “Our message is ‘Don’t become complacent about meningitis’ - there are still strains for which there is no vaccine available and there will still be people who are not protected by these vaccine programmes,” she stressed, adding that the charity will continue its Beat it Now! campaign to extend the availability of the Men B vaccine to other at-risk groups. Teva Buys More Mylan Shares as Takeover Fight Continues Teva has raised its stake in Mylan to 4.61%, which will allow it to take its acquisition bid to court “should it become necessary”. Mylan reincorporated in the Netherlands last year, and under Dutch law owning this amount of shares allows Teva to legally challenge the company’s continued rejections of its $40 billion takeover offer. In a letter last month, Mylan claimed that Teva purchasing these shares violates US antitrust laws, but Teva has countered by saying that such laws should not matter for a company who has moved its domicile abroad. "We note that you have been saying you are a Dutch company when you believe it helps you create unprecedented governance structures, a UK company when it helps you lower your US taxes and a US company when you believe it helps you prevent Teva from purchasing Mylan shares," CEO Erez Vigodman and chairman Yitzhak Peterburg say.

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Merger triangle Mylan itself is in the process of attempting to buy Perrigo, but has also been rejected multiple times. The company has accused Teva of using its bid to try and distract from this purchase. In May Mylan implored the Israeli firm to make its intentions clearer before a planned special general meeting where shareholders will vote on whether to endorse the Perrigo offer. Teva has now said that it will limit its shares in Mylan to less than 5% if this meeting is held before September. Tekmira's Ebola Jab Unlikely to Show Benefit Shares in Tekmira have taken a downturn after it emerged that its experimental Ebola vaccine was unlikely to hit efficacy goals in a mid-stage trial. The Vancouver, Canada-based group said it has stopped enrolment in the Phase II, Sierra Leone-based trial after a predefined statistical endpoint indicated that there was not likely to be an overall therapeutic benefit from its jab. However, “final conclusions on the efficacy and tolerability of the drug must await full analysis of the data,” noted Peter Horby, Associate Professor of Infectious Diseases and Global Health, University of Oxford, Chief Investigator on the study. Data analysis is ongoing and full results will be made available as soon as possible, the firm said. Tekmira’s RNAi therapeutic - designed to switch off certain genes responsible for the virus’ proliferation - was being tested by Oxford University researchers against the Ebola-Guinea strain behind the current outbreak in Africa, with funding help from the UK’s Medical Research Council.

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