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Volume 5 Issue 2

International Pharmaceutical Industry

Supporting the industry through communication

Peer Reviewed

Virtual Drug Development Vision, Oversight and Risk Management Optimising Short-Lived Isotopes For Quantitative Whole-Body Autoradiography in Drug Development Compensation for Research Injuries National Regulations and International Standards The Future Of Pharmaceutical Manufacturing Pharma Serialisation A New Challenge for Packaging Suppliers

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International Pharmaceutical Industry

Supporting the industry through communication

Contents 06 Publisher’s letter

DIRECTORS: Martin Wright Mark A. Barker PUBLISHER: Mark A. Barker EDITORIAL MANAGER Jaypreet Dhillon jay@ipimedia.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Madalina Slupic Ovidiu Terinte DESIGN DIRECTOR: Maria del Mar Alvarez Boloña maria@pharmapubs.com CIRCULATION MANAGER: Dorothy Brooks FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Maria Perez mariap@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 2013. 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. 2013 PHARMA PUBLICATIONS Volume 5 issue 2 - (Spring / Summer 2013) June 2013

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REGULATORY & MARKETPLACE 08 Grabbing Hold of the Bar of Success in Drug Development Globalisation and other recent developments such as stricter quality control criteria, evolving technologies, and the increasing stringency of regulatory standards, have imposed enormous pressures on biotechnology drug manufacturers. With such difficult basic conditions, only a limited few compounds will ever make it to Phase III, and even fewer will make it through to approval and to commercial manufacturing. Paul Nelles, at Vetter Pharma-Fertigung GmbH & Co. KG, explores whether a contract development and manufacturing organisation (CDMO) can help lower this bar? Or perhaps help to lift you higher, thus helping to improve a company’s odds of achieving success? 12  Some Practical Implications of the UP and the UPC for the Pharmaceutical Sector On 19 February 2013, 24 EU member states signed a supra-national agreement which is intended to bring into being a new court called the Uniform Patent Court. This agreement, together with two EU Regulations, the Unitary Patent Regulation (1257/2012) and the Translations Regulation (1260/2012), will finally bring into being something akin to a Community Patent and a Community Patent Court. Neil Jenkins at Bird & Bird LLP explains that to appreciate the implications of this to industry, and in particular the pharmaceutical industry, it is absolutely critical to understand the nature of both the new patent right and the new court. 18 Cancer: The Major Medical Challenge in Europe Today (Cancer Cures Made in Austria) Austria is at the forefront in the fight against cancer in Europe, and plays a leading part in the worldwide campaign, with several pioneering initiatives. Be it innovative immunotherapy, novel molecular targets or radiation therapy, researchers and oncologists throughout Austria are working to develop and commercialise diagnostics and treatments. Sonja Polan at Life Science Austria explains how at the core of Austrian cancer research, multidisciplinary research networks are bringing industry, healthcare and primary research together. 22 What the Unitary Patent Means for the Pharmaceutical Industry After nearly four decades in the pipeline, the countries of the European Union have finally signed an agreement that is expected to lead to a system of Unitary Patents. They will have pan-European effect and an associated Unified Patent Court to enable enforcement of the Unitary Patent across Europe. If the agreement is ratified by European member states, this will represent the most radical change to the patent landscape in Europe of the past 40 years. Martin MacLean at Mathys & Squire LLP examines the issues surrounding its implementation, and how it will affect the pharmaceuticals industry. 26 Compensation for Research Injuries: National Regulations and International Standards  Research regulations worldwide aim to prevent research injuries, as well as to provide remedies for injuries suffered by research participants, regardless of what or who may have caused those injuries. The ICH-GCP guidelines mandate that sponsors make provisions for compensation for research-related injuries, but largely leave compliance to applicable national or local regulatory requirements. Chitra Lele and Suhasini Sharma at Sciformix discuss the hotlydebated topic of how and why patients are to be compensated, and how worldwide regulations differ considerably.

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DRUG DISCOVERY, DEVELOPMENT & DELIVERY 32 Virtual Drug Development: Vision, Oversight and Risk Management The previous article examined how drug development has changed over the last century, whilst highlighting the theme of the increased complexity of drug development. In this follow-up article, Keith J. Williams and Bryan Hurst at Boyd Consultants looks at how many new drugs are being discovered within universities and start-up biotechnology companies. The general problems of sourcing and managing development resources, dealt with in this paper, apply to both of these types of organisations, though the actual development issues will differ. 36 Optimising Short-Lived Isotopes for Quantitative Whole-Body Autoradiography in Drug Development Quantitative whole-body autoradiography (QWBA), which has brought many improvements to the realm of tissue distribution, has itself been improved recently by the expanded use of short-lived isotopes. Andrea Knapp and Brian Knapp at MPI Research explain how this expansion increases options for better imaging and more specific data regarding tissue distribution due to increased resolution of QWBA images, as compared to PET or SPECT images. 40 Preactivated Thiomers: A New Generation of Mucoadhesive Polymers  Since the concept of mucoadhesion was pioneered in the early 1980s, various attempts have been made to improve the adhesive properties of polymers. These attempts include approaches such as mucoadhesion by a sustained hydration process, and the development of polymer-lectin conjugates and of polymer-bacterial adhesion conjugates. Andreas Bernkop-Schnürch at ThioMatrix GmbH looks into mucoadhesive polymers, and how they have in many cases not proven to be effective as ‘pharmaceutical glue’ in order to keep drug delivery systems for a prolonged time period on the target mucosal membranes.

This is particularly true when multiple companies run competing clinical trials. Adam Bianchi, Ryan McGuire & Rochelle Gagg at Cutting Edge Info, analyses the two main factors impacting duration are the level of difficulty of trial-specific patient recruitment and the number of patient visits required by a trial.

LABS & LOGISTICS 62 Ambient Temperature Profile Development: A New Approach for Qualifying and Defining a Shipping System’s Performance When developing an ambient profile for a temperature-controlled packaging solution to be qualified against, every temperaturecontrolled packaging (TCP) user has their own views on the best way to create a profile that accurately reflects a distribution process. Overall, each reaches the end result by a different method, meaning that companies often end up with very different ambient temperature profiles from each other. Richard Wood at DS Smith Plastics Cool Logistics discusses this burning issue. 68 Clinical Supply in Emerging Markets Over the last few years there has been a shift in conducting clinical trials away from North America and Europe and towards emerging markets, particularly the BRIC countries. Although the shift to perform clinical trials in these BRIC countries has increased, the majority of the drugs are still manufactured in North America or Europe. Rachel Griffiths at Biotec Services International explains why drug companies have been nervous to move new drug manufacturing to these countries, and how Brazil and India are expanding their development pharmaceutical manufacturing capability.

46 The Benefits of Bacillus-derived Hyaluronic Acid In Adding New and Improved Attributes to Existing Drug

Formulations, and Offering Opportunities for New Delivery System Development

 Jaypreet Dhillon, Editorial Manager at IPI, interviews Hans Ole Klingenberg at Novozymes Biopharma on the benefits and advances of the Bacillus-derived hyaluronic acid, and how this is adding new and improved attributes to the life-science industry, with progress in drug formulations and opportunities in new delivery system development. The interview highlights the potential of hyaluronic acid for drug delivery, and looks at concerns from the FDA, EMA and other regulatory bodies on its commercial availability; its advantages/ disadvantages; and how this technology is moving forward.

clinical research 50  Photostability Testing: Shedding Light on a Not Well Understood Guideline  The subject of pharmaceutical photostability testing often raises many questions for several reasons. Predominantly governed by ICH Guideline Q1B for small molecules, or ICH Q5C for biotechnology products, the standards are not particularly well written and often cause confusion. Q1B, in particular, provides options to use two non-equivalent light sources and additional variants. The standard also mixes radiometric and photometric light measurements for the ultraviolet and visible light dosages. Allen Zielnik at Atlas Material Testing Technology LLC explains the guideline options available, and provides some practical guidance. 58  Patient Recruitment Driving Length and Cost of Oncology Clinical Trials As prospective oncology drugs progress from Phase I to Phase III clinical trials, the difference between projected and actual patient enrollment durations typically increases. In most cases, oncology clinical trial delays are a direct result of patient recruitment challenges.

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manufacturing 74 Disposable Filling Needles For many years, biopharmaceutical production processes have been characterised by the cleaning and autoclaving processes of the existing systems, usually made of stainless steel. For some time, single-use systems have been making inroads more and more in the manufacturing companies involved in biotechnology. In almost all processes from upstream to downstream, to clean-up or storage, there are suppliers of disposable products nowadays who are placing their products on the market with a lot of success. Benedikt Knoch at Raumedic explores the ultimate user aims of reducing the cleaning and sterilisation processes. 78 The Future of Pharmaceutical Manufacturing According to a recent survey, global annual spending on pharmaceuticals is set to reach almost 1.2 trillion US dollars in 2016. The so-called pharmerging markets play an important role in this development. Growing population, rising incomes, and improved access to drugs are amongst the reasons for these markets reaching 30 per cent of global expenses by 2016. Jérôme Freissmuth at Robert Bosch GmbH explains how rapid development of emerging markets, progress in drug research, the rise in generics production, the availability of high-potency drugs, and innovations in manufacturing processes, will sustainably modify the global pharmaceutical landscape.

PACKAGING 88 Inner Strength Glass has established itself over the years as the most commonlyused primary packaging material for injectable drugs. And yet new drugs and sophisticated production processes such as lyophilisation have given birth to new challenges that high-quality glass containers must face. Florence Buscke at SCHOTT Pharmaceutical Packaging looks into how their geometries and special coatings help to make them stronger and minimise the risk of breakage, but also improve temperature transfer during the lyophilisation process.

92 A Highly Secure 2D Code to Protect Medical Drugs from Counterfeiting  The globalisation of production sites and distribution has led to a boom in counterfeit products and dysfunctions of systems and distribution networks. More and more pharmaceutical laboratories are choosing to go beyond regulation and adopt a new security device: a highly secure 2D code, allowing not only identification, but authentication. Jean-Pierre Massicot at Advanced Track and Trace explains that all sectors are concerned – the pharmaceutical sector included. Laboratories are reacting; authorities are implementing new regulations regarding medical drugs’ identification and authentication. 94 Pharma Serialisation: A New Challenge for the industry  Serialisation in the pharmaceutical industry is becoming a very important challenge, not only for the manufacturers but also for their packaging suppliers. According to the Directive 2011/62/EU, pharma companies have three years to implement a successful strategy in all their products to be distributed in the European Union. Saul Serrano at Nekicesa looks into similar regulations that are in place today in India, China, Turkey and some other countries.

special feature 100 Readying for a US FDA Inspection The Federal Food, Drug and Cosmetic Act states that domestic drug establishments can be inspected at least once every two years. The inspections can happen more frequently, such as if the drug you are producing is new, or if your facility has a history of cGMP problems. Joseph Pickett at Expert Briefings provides an overview of what you can expect the FDA inspector to do when he or she shows up.

PREVIEWS & REVIEWS

104 Pharmapack – Europe 2013 – A Great Success 106 BIO – Europe Spring® 2013 – Brought International Life Science Dealmakers to Barcelona, Spain for partnering


Publisher’s letter

The early success of a new class of cancer drugs, revealed in test results released here over the last several days, has raised hope among the world’s top cancer specialists that they may be on the verge of an important milestone in the fight against the disease. The excitement has spread to Wall Street. Shares in Merck and Bristol-Myers Squibb, which are developing such drugs, rose more than 3 per cent on Monday after data from their studies was presented over the weekend at the meeting of the American Society of Clinical Oncology. The drugs, still generally in early testing, work in an entirely new way, by unleashing the immune system to attack cancer cells much as it attacks bacteria. That could be an alternative to often-debilitating chemotherapy. Finding ways to use the body’s own defences has been a goal since the late 1800s, when a New York surgeon named William B. Coley noticed that cancer disappeared in a patient who had a severe bacterial infection. The new drugs work by disabling a brake on the immune system called the programmed death 1 receptor, or PD-1. And although the data presented at the meeting was from the earliest stage of testing only, the drugs were the centre of attention here, with some doctors predicting that cancer treatment was about to shift. Analysts, who predict billions of dollars in sales, are trying to determine which of the three front-runners — Merck, BristolMyers and Roche — have the best drug and how soon the drugs could reach the market. Some think it could be as early as a year-and-a-half from now.

Harnessing the immune system is appealing for several reasons. It might be applicable to many different types of cancer. It might produce longer-lasting remissions than can be achieved by chemotherapy or the newer targeted drugs. And it seems somehow more natural and holistic. Most of what is known about the PD-1 drugs is that they shrink tumours significantly in 15 to 50 per cent of patients. It is still not clearly established, though there are some hints, that the drugs will let people live longer. On this positive note, I would like to welcome everyone to this latest edition of IPI. We have brought you an exciting array of articles which will further assist you in your quest for global healthcare. In the Regulatory & Market section, Paul Knells, of Vetter Pharma-Fertigung GmbH & Co. KG, explores whether a CDMO can help to improve a company’s odds of achieving success. Sonja Polan at Life Science Austria explains how, at the core of Austrian cancer research, multidisciplinary research networks are bringing industry, healthcare and primary research together. Chitra Lele and Suhasini Sharma at Sciformix discuss the hotly-debated topic of how and why patients are to be compensated, and how worldwide regulations differ considerably. Within the Drug Discovery & Development Section, Keith J. Williams at Boyd Consultants looks at how many new drugs are being discovered within universities and start-up biotechnology companies, and Hans Ole at Novozymes Biopharma talks to IPI on the benefits and advances of the Bacillus-derived hyaluronic acid. Our Clinical Research Sections starts with Allen Zielnik at Atlas Material Testing

Technology LLC discusses Photostability Testing: Shedding Light on a Not Well Understood Guideline, and Adam Bianchi, Ryan McGuire & Rochelle Gagg at Cutting Edge Info, analyses the two main factors in patient recruitment which are driving length and cost of Oncology Clinical Trials. In the Manufacturing Section, Benedikt Knoch at Raumedic explores the ultimate user aims of reducing the cleaning and sterilisation processes during the production of Disposable Injectables, and Jérôme Freissmuth at Robert Bosch GmbH analyses the Future of Pharmaceutical Manufacturing. Our Packaging Section is quite extensive. IPI was a core sponsor of the Pharmapack Europe in Paris, and got a fantastic reception for all exhibitors and delegates alike. We kick off the Packaging Section Florence Buscke at SCHOTT Pharmaceutical Packaging looks into how geometries and special coatings on glass helps to make them stronger and minimise the risk of breakage, but also improve temperature transfer during the lyophilisation process. Jean-Pierre Massicot at Advanced Track and Trace and Saul Serrano at Nekicesa explains how laboratories are reacting to the menace of counterfeit drugs and regulations being implemented regarding medical drugs’ identification and authentication. I hope you all enjoy this issue. IPI will be present at the DIA Annual Meeting in Boston. I wish you all a wonderful summer, and look forward to seeing you again in September.

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 Pharmacy

Mark A. Barker Publisher

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP

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

Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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REGULATORY & MARKETPLACE

Grabbing Hold of the Bar of Success in Drug Development Today, companies that are in the business of developing highly complex biotechnology drugs know that they face a difficult task. Reaching for the bar of success is tough enough. Actually grabbing hold is even more difficult. Globalisation and other recent developments such as stricter quality control criteria, evolving technologies, and the increasing stringency of regulatory standards, to name just a few, have imposed enormous pressures on biotechnology drug manufacturers. And, because these compounds are subjected to many levels of risk during the early clinical phases, the bar is raised ever higher. At times, it seems as if the process is as difficult as trying to touch the stars. With such difficult basic conditions, only a limited few compounds will ever make it to Phase III, and even fewer will make it through to approval and to commercial manufacturing. But can a contract development and manufacturing organization (CDMO) help lower this bar? Or perhaps help to lift you higher, thus helping to improve a company’s odds at achieving success?

very high. Few can afford to fail grabbing hold of that bar of success, even once. For many, the very survival of the company itself can be at risk if the compound fails in development. Plurality of Issues Grabbing hold of the bar of success in drug development, particularly for the smaller biotechnology company, is hardly a simple undertaking. Unexpected challenges continue to impede the task, while complex decisions that are critical to move the project forward must be made and carefully addressed to avoid failure. Consider but a few of these decisions: How can it be ensured that packing materials will be compatible, and how can efficient process solutions be developed? Will lyophilisation be an issue? If so, how can it be realised successfully? How can consistent batch qualities be ensured? Can critical deadlines be met to move into clinical trial? Can the process be streamlined for scale-up and commercial manufacturing?

Before Reaching for that Bar, Some Awareness-stretching Exercises Let’s begin our task by taking a moment to consider but a few complex decisions to take along the clinical development pathway. The stretching exercise means knowing what to expect and finding the right solutions to specific problems. This step always begins with a clear understanding of a compound’s underlying technical and scientific requirements. Because compounds are becoming more and more complex, greater demands on primary packaging become more critical. In particular, biopharmaceutical drugs with their high sensitivity require drug-delivery systems that are optimally designed for them. Next to technical challenges, there are hurdles, such as growing cost pressures and increasingly strict rules from regulatory agencies. Thus, the need for a great deal of competence when calibrating packaging with the drug product is critical. Both the compound itself and its environmental conditions (reaction with certain materials, biological specifications, etc.)

What are Smaller Biotech Companies Really Reaching For? Small biotechnology companies by definition are extremely sensitive to any risk in early clinical phases. Unlike the large, well-financed biopharmaceutical company, the small biotechnology company is typically less resourced in both finances and personnel. Maximising the value of the compound in the very earliest stages of development, adding value that will assist in attracting investors, providing out-licensing opportunities, or in some cases even outright acquisition by a larger company, are their primary concerns. To such companies, little thought can be given to the later development or commercialisation efforts that must be applied to the compound and the myriad of interfaces between various partners that might be necessary as they move forward in their work. In drug development, the risks and rewards are 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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must be considered. Also, the evercritical time factor (time-to-market) and long-term market success (product lifecycle management) must also be factored in. Along with these issues, key decisions must be made, including the drug product’s compatibility with rubber stoppers, closure systems and other related components. The level of silicon that the substance can endure and a method for applying this silicon to the interior panels of the system must also be considered. Also, what materials are best suited for the components and do they have to be pre-treated? And, what materials are compatible for add-on systems (like safety devices), as well as decisions on the execution of washing and sterilisation? A Case Study Helps Illustrate How a Very High Bar was Reached and Success Achieved Because drug development has to be a well-defined process, the challenges of enabling the successful process are framed in the key steps and methods that will lead to a successful outcome. These challenges are well illustrated in the following vaccine case study: Multivalent vaccines are complex compounds that often present especially challenging issues, particularly in the early clinical phase. In our example, we look at a multivalent vaccine in clinical development that was at risk of losing biological potency during the filling process. It is important to understand that multivalent vaccines are comprised of several serotypical polysaccharide protein conjugates. Each serotypical conjugate must be prepared for filling so that the final mix of all serotypes retains its biological potency in elicitation of the appropriate immune response. Having 8 to 12 different peptide antigens conjugated in the final mix while retaining the biological potency is a major challenge. Highly sensitive biologics including vaccines, monoclonal antibodies and conjugated peptides are all affected by filtration in the scaling-up and filling processes. Many require complex multiple filtration steps that can involve Ultra, Dia and Q-filtration steps in a single run. And there are many critical variables to control, among them fill 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

concentration, viscosity and pumping pressure. To hold the biological potency of the final conjugated mix, the process design had to include several critical steps, namely: • Permanent recirculation during final filling to avoid unwanted volatility in concentration • Tailored pump and filtration technology to optimise bioactivity while preventing protein aggregation; designing an optimal pump filtration process was equally critical to protecting the bioactivity of the final product. In this example, a complex, multi-step filtration process had to be developed to prevent protein aggregation during filling and to eliminate leaching of any filter particles or extractable compounds in a final drug solution, as well as to maintain targeted viscosity and concentration during scale-up. Arranged specialised teams worked together to develop a novel, customised process design that delivered a high-yield, biologically potent vaccine, which afterwards was planned for a smooth scale-up from clinical to full commercial production. Through the benefits of working together with an experienced CDMO, the bar of success was reached. Some Thoughts on How to Reach your Bar and Achieve Success To help drug-developing companies reach the bar and so meet the growing number of challenges it faces to achieve

success, the biopharmaceutical industry has been using outsourcing models to CDMOs as a key strategic element. A partnering relationship is often beneficial, but selecting the right CDMO with whom to partner is not an easy choice. This fundamental decision must be made in the early phases of a drug’s development, when time is sufficient to find the right partner and develop a strong relationship. Chosen correctly, the partner you select will help you either lower the bar or help lift you higher so you can grab hold.

Paul Nelles Ph.D., Vice President Vetter Development Service, Vetter PharmaFertigung GmbH & Co. KG. Dr Paul Nelles is Vice President of Vetter Development Service and is responsible for Process Development, Process Implementation and Packaging Development. Before joining Vetter, Dr Nelles held a VP Position in Global R+D activities for Becton Dickinson, market leader for prefillable syringe systems and medical devices. Previously, he managed as VP the European and Asia Pacific R+D activities of West, market leader for elastomeric components for the pharmaceutical Industry. Dr Paul Nelles holds a PhD in Organic Chemistry and a degree as a Pharmacist. Email: info@vetter-pharma.com

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Some Practical Implications of the UP and the UPC for the Pharmaceutical Sector Introduction On 19 February 2013, 24 EU member states signed a supra-national agreement which is intended to bring into being a new court called the Uniform Patent Court1. This agreement together with two EU Regulations, the Unitary Patent Regulation (1257/2012) and the Translations Regulation (1260/2012), both of which had been adopted by the European Parliament the previous December, will finally bring into being something akin to a Community Patent and a Community Patent Court. To appreciate the implications of this to industry and in particular the pharmaceutical industry, it is absolutely critical to understand the nature of both the new patent right and the new court. As regards the new patent known as the Unitary Patent, it is not a Communitywide right (as is the Community Trade Mark and the Community Design) insofar as the Regulation was enacted via a procedure known as the Enhanced Cooperation Procedure, and both Italy and Spain have decided not to participate in it. As regards the new court known as the Unified Patents Court, it has been given not only exclusive jurisdiction over Unitary Patents but also exclusive jurisdiction over existing European Patents, subject to a transitional period where it may have either non-exclusive jurisdiction over European Patents or no jurisdiction at all depending upon the steps taken by patentees to opt their European Patents out of the new court system (and not opt them back in again). Unitary Patents can start to be granted after 1 January 2014 or the date of entry into force of the UPC Agreement, whichever is the later. The UPC Agreement will come into force three months after 13 of the contracting states, including the UK, Germany and France, have ratified the UPC Agreement (or possibly the third month after the date of entry into force of the amendments to Regulation 1215/2012 (the Brussels Regulation) concerning its relationship with the Agreement, whichever is the 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

later. It is anticipated that, because of the amount of work which needs to be done in order to set up the new court from scratch, the UPC Agreement will not come into force until early 2015. It remains to be seen how many of the remaining contracting states will have ratified the UPC Agreement at the point in time when it does come into force. The Unitary Patent (UP) The UP will be granted via an application for a European Patent (EP) to the EPO. On being notified of the intention to grant a patent by the EPO, applicants will have the option of obtaining a UP rather than a bundle of EPs if two conditions are satisfied: first, that the designated states include all of the member states who have participated in the UP Regulation (i.e., all of the EU member states other than Italy and Spain) and second, that the claims are the same for all those member states. If the applicant or prospective patentee decides that they want a UP then they have one month after the date of the publication of the mention of the grant of the EP to notify the EPO, and an entry is made by the EPO in the register of UP protection. The option to obtain a UP will apply to all pending applications for patents in relation to which the mention of the grant of the patent has not been published prior to the entry into force of the UPC Agreement (subject to the above two conditions being satisfied). The decision as to whether to obtain a UP or a bundle of EPs will therefore depend on several factors, but primarily translation costs, renewal fees and the effectiveness of the enforcement regime. The translation regime is known. During the transitional period of up to 12 years, if the patent is granted in French or German then a translation into English is required, and if the patent is granted in English then a translation into any other EU Official Language is required. The EPO will also provide free online access to automated translations of any European patent application and patent. Towards the end of the transitional period, the

Commission will review the effectiveness of automated translations and, if shown to be effective, human translations will not be required at all on grant. At the moment, the level of renewal fees is not known. This is likely to be decided later this year. The expectation is that it will be comparable to the equivalent of four – six EPs. What the proprietor of a UP will lose, however, over that of the proprietor of a bundle of EPs is the flexibility to lower that cost over the lifetime of the patent by jettisoning the protection in one or more of the contracting states in which the EP is in force. At the moment, the effectiveness of the enforcement regime is also not known. As explained in more detail below, the rules of procedure for the UPC are still work in progress and the court fees are not known. Both the rules of procedure and the court fees are also likely to be finalised and decided respectively later this year. How effective the UPC proves to be in practice will obviously not become apparent until it actually starts to deal with cases. The Uniform Patent Court (UPC) – Jurisdiction over UPs and EPs As mentioned above, although the intention is for the UPC to have exclusive jurisdiction over both UPs and EPs, this will not happen in respect of EPs in the short to medium term, mainly because of the transitional provisions. The transitional provisions have two dimensions to them. First of all, they provide that for a period of seven years (which in fact is likely to be extended to 14 and even up to 21 years), the UPC only has non-exclusive jurisdiction over EPs (both those that were granted before as well as those granted after the UPC Agreement comes into force). This means that a patentee contemplating an action for infringement or a third party contemplating an action for revocation or a declaration of non-infringement will have a choice as to whether to commence the action in a national court of a member state in which the EP is in force, or the UPC. Once an action in respect of an EP has been started in the Spring / Summer 2013 Volume 5 Issue 2


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courts of one system, then the courts of the other system will no longer have jurisdiction over the EP. Second, they also provide that the proprietor of an EP can choose at any time during the transitional period (seven/14/21 years) to opt the EP out of the UPC system altogether by notifying the UPC Registry of that fact. Although it is not clear on the face of the Agreement itself, it is understood that once an EP has been opted out then it remains opted out for the remainder of its life. If an EP is opted out then a third party who wishes to commence an action for revocation or a declaration of non-infringement has no option but to start the action in one or more of the national courts of a member state in which the EP is in force. The patentee however is in a more advantageous position in that (subject to an action for revocation or a declaration of non-infringement already having been started in a national court) they can decide to opt the EP back into the UPC system again and having done so, commence an action for infringement in the UPC. The upshot of the rather complicated position under the transitional provisions is that proprietors of both existing and future EPs need to take a positive decision whether to opt one or more or all of their EPs out of the UPC system. Given the ability to opt back into the UPC system, EPs that had previously been opted out, coupled with the fact that the jurisdiction of the UPC over EPs which have not been opted out is in any event non-exclusive, there would appear to be no good reason for proprietors of EPs not to opt all of their EPs out of the UPC system2. There is one further (mainly short term) complication for EPs and that is that as and when the Agreement is brought into force, it will not apply to EPs in force in Spain and possibly Poland, because Spain and as yet Poland have not signed the Agreement and it will not apply to EPs in force in those EU member states which have signed but not ratified the Agreement3. As regards the non-ratifying EU member states, they will presumably ratify the Agreement in the fulness of time and as and when they do, the UPC will then start to have non-exclusive jurisdiction over the EPs in force in those member states (unless in the meantime the EPs have been opted out). 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Uniform Patent Court – Structure, Language and Composition of Judicial Panels National patent enforcement systems around the world fall into one of two categories: those in which the issues of infringement and validity are heard by the same court, and those in which the issues of infringement are heard by one court and the issue of validity is heard by a different court. In Europe, most member states operate a unified system. Germany stands out as a European member state which operates a bifurcated system. The UPC has not adopted either the one or the other system but rather a hybrid version of the bifurcated system. The first instance courts of the UPC comprise two types of court division: the local or regional divisions which are primarily the infringement courts, and the central division which is primarily the validity court. Any contracting state can set up its own local division. A member state having more than 100 patent cases a year for each of the three years preceding the Agreement coming into force can set up additional local divisions (and indeed more than one for each additional 100 patent cases up to a maximum of four). In addition, any member state can join forces with one or more other member states and set up a regional division. The central division has its seat in Paris but also a section in London and a section in Munich. Cases are allocated to one of three locations depending on the subject matter of the patent being litigated – life sciences to London, electrical to Paris and mechanical to Munich. There is a detailed set of provisions governing the language of the proceedings before any given first instance court. In the central division, it is the EPO Official Language in which the patent was granted i.e., English, French or German. The local or regional divisions can choose whether, in the first instance, the language of the proceedings in their division is the OL (or one of the OLs of the country) or countries hosting the local or regional division respectively or one of the EPO OLs (i.e., English, French or German). The parties and the court are also given the right to propose the EPO OL in which the patent was granted and, failing agreement on the matter, a party is given the right to have the issue referred to the President of the Court. As matters stand at present, it seems

that there will be four local divisions set up in Germany, at least one local in each of the UK, Holland, France and Italy, and a regional division in Scandinavia (Sweden, Denmark and Finland). There are also indications that the language chosen by the Dutch local division and the Scandinavian regional division may be English rather than Dutch or Swedish/ Finnish/Danish respectively. Again, there is a detailed set of provisions governing the composition of the Judges in the first instance divisions. There will be a pool of both legal and technical Judges used to staff the central division as well as supply additional foreign legal and technical Judges to the local and regional divisions. The judicial panels have to be multinational. In the case of local divisions, if they have had more than 50 cases in each of the three years preceding the UPC Agreement coming into force, they are entitled to two local Judges and one foreign Judge from the pool, otherwise they are entitled to only

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one local Judge and two Judges from the pool, of which at least one would need to be foreign. The regional divisions are entitled to two Judges from the countries making up the region and one foreign Judge from the pool. If validity is put in issue by way of a counterclaim and the local or regional court decides to hear the validity counterclaim (rather than transfer it to the central court) then a(n additional) technical Judge must be appointed from the pool. The Uniform Patent Court – Jurisdiction for Actions for Infringement, Revocation and Declarations of Non-Infringement The forum shopping opportunities within the UPC system are very much biased in favour of the patentee. An action for infringement may be brought in (1) any of the jurisdictions in which an act of infringement has taken place or (2) the jurisdiction of the principal place of business (PPOB) of the defendant, or failing that the place of business (POB) of the defendant or (3) if there is no PPOB or POB or the infringement is taking place in a jurisdiction which does not have a local or regional division, or a revocation action has already been started in the central division. If a revocation action is pending in the central division then although an infringement action may be started in a local or regional division, the local or regional division has to decide whether to do one of three things: (1) hear both the infringement action and revocation counterclaim, in which case it has to request the appointment of a technical Judge from the pool; (2) transfer only the revocation counterclaim to the central division and either suspend or proceed with the infringement action; and (3) with the agreement of the parties, transfer the infringement action and the revocation counterclaim to the central division. A pre-emptive revocation action can only be brought in the central division. Otherwise, if an action for infringement is already pending in a local or regional division then the defendant can only put the validity of the patent in issue by way of a counterclaim. However, as noted above, the local or regional division has to decide whether to transfer the revocation counterclaim to the central division or not and, if it is to be transferred, whether 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to stay the infringement action pending the outcome of the revocation action or proceed to hear it. A pre-emptive action for a declaration of non-infringement can also only be brought in the central division. However, if the patentee starts an infringement action in a local or regional division within three months, the infringement action takes precedence and the action for a declaration of non-infringement is automatically transferred to that local or regional division. As mentioned above, most of the national courts of the EU member states hear both the infringement and validity issues. The UPC Agreement allows for but does not mandate bifurcation as is the case currently in Germany. It seems unlikely that the local and regional divisions (including for that matter the German local divisions), if given the choice to bifurcate, will in practice decide to do so and deprive themselves of the ability to determine both the infringement action and the revocation counterclaim. If this does turn out to be the case then the central division is likely to have a lighter than anticipated workload. The only cases that will remain in the central division will be pre-emptive actions for revocation or pre-emptive actions for declarations of non-infringement where the patentee has been unable or unwilling to commence an infringement action in a local or regional division within three months or infringement actions where the defendant has no PPOB or POB or there is no act of infringement taking place, in a jurisdiction having a local or regional division. Costs As mentioned above, the court fees for initiating an action have yet to be decided. Given the need for the court to be self-financing coupled with the perceived benefit of obtaining a decision in one action which will have effects on a pan-European basis, it is to be assumed that the court fees will not be insignificant. The legal fees for running an action in the UPC are likely in most cases to be considerably greater than those for running an action in a national court, especially in the early years, given the uncertainties inherent in a new court system with a new set of rules of procedure. Given how much will be at

stake in a UPC action, one would expect the parties to throw everything at the litigation in order to secure a successful outcome. Overall, therefore, the parties to a UPC action cannot expect it to be a cheap exercise. Whether it proves to be cost-effective compared to the alternative of litigating national patents or opted out EPs before the national courts remains to be seen. The UPC Agreement provides that the winning party shall, as a general rule, be entitled to reimbursement of its reasonable and proportionate legal costs and other expenses (up to a ceiling yet to be decided). Interestingly, there is also a provision (familiar to English practitioners where the costs follows the event rule has been the norm) giving a defendant the right to apply to the Court for an order for security for costs. The Uniform Patent Court - Procedure The UPC Agreement sets out a number of (somewhat conflicting) general principles as to how cases should be tried and decisions taken – decisions should be of high quality, a fair balance should be reached between the legitimate interests of the parties, the courts are to be allowed a certain degree of judicial discretion although the exercise of that discretion should not impair predictability, the rules should be applied in a proportionate but also a fair manner, and the court should exercise active management of cases but without impairing the freedom of the parties to determine the evidence needed to decide their case. The UPC Agreement also sets out in broad terms the way in which an action is to proceed to trial with a first written stage for the pleadings, a second interim stage with a Case Management Conference, and then a third oral stage involving the trial or hearing. It also contains a mixed bag of procedural tools to enable the parties to gather or test the evidence needed to decide their case. These tools include the production of documents (akin to disclosure in the English system), the preservation of evidence (akin to a saisi in the French or Belgium system or a descrizione in the Italian system), the appointment of an expert (akin to that employed occasionally in the German system and to a greater extent in the Italian system), and cross-examination of expert witnesses (as used in the English system). Spring / Summer 2013 Volume 5 Issue 2


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The more detailed aspects of the procedure before the UPC are to be contained in the rules of procedure of the court. These however are still in draft – draft 14 to be exact. It is understood that draft 16 will be published later this year for public consultation. Given the array of procedural options made available to the first instance divisions, coupled with the likelihood that the judicial panels of most local and regional divisions will be staffed by a majority of local Judges, it seems likely that at least in the early years of operation the local and regional divisions are likely to be more amenable to doing things in the same way as their national courts have done them, i.e., they will show their couleur locale. For instance, one would imagine that the Italian local division would be more likely to grant a PI or order a court expert to be appointed, whereas the English local division would be more likely to order cross-examination of expert witnesses. At the same time, however, there will also be an opportunity for the local and regional divisions to do things differently to their corresponding national courts. Appeals to the Court of Appeal and the Role of the CoJ The Court of Appeal will be based in Luxembourg along with the Registry. No permission will be needed to appeal against a final decision in the action itself, nor will permission be required against orders made on certain interim applications, e.g., language, preliminary injunction. For all other orders made by a Court of First Instance, permission will be required to appeal immediately. Otherwise, the appeal has to be made at the same time as the appeal from the decision. On an appeal, the Court of Appeal is free to review matters of fact as well as law, which would suggest that the appeal may tend more towards a rehearing than a judicial review. There is also a provision prohibiting the use of fresh evidence unless the party wishing to file it can show that it could not have been obtained before the first instance decision. One of the issues which had prevented agreement on the UP being reached before now was the role of the Court of Justice of the EU as the ultimate arbiter of infringement. The experience of the www.ipimedia.com

CJEU in other areas of IP (especially trade marks and SPCs) has been seen by many to leave much to be desired. To avoid this outcome in the UP, the infringement provisions were removed from the UPC Agreement and the UP Regulation provides that infringement of a UP is deemed to be a matter of the national law of the EU member state where the patent proprietor had its PoP at the time of filing the UP (or if none then Germany). It remains to be seen whether in fact these provisions will achieve the desired effect and preclude the jurisdiction of CJEU on issues concerned with the infringement of a UP. Implications for the Pharmaceutical Industry There is no question that the opportunity in the UPC system for patentees to obtain pan-European injunctive relief and for third parties to invalidate weak patents for the whole of Europe will provide, in many cases, a significant advantage over the existing regime. Inevitably for a new court system, it will take time before the effectiveness of the new enforcement regime as compared to the existing regime will become known. Speed and a rational decision-making process are two of the most important prerequisites to a successful enforcement regime. The preamble to the rules states that the aim of the Court would be to make a decision within one year of an action being commenced. Other than in the most straightforward of cases, this seems optimistic. Much will depend upon the quality of the Judges and their ability to manage cases effectively. Much may also depend upon the ability of the Court of Appeal to impose its will on the first instance divisions. The pharmaceutical industry is different to many other industries in two important respects: first, drugs are most often protected by only one patent and if that patent is invalidated then the market is lost; second, geographical coverage is needed to protect the market in each country. Obtaining and maintaining EUwide patent protection is intended to be cheaper with a UP than a bundle of EPs. However, when it comes to enforcement, a finding of invalidity by the UPC will result in the entire EU market being lost. The decision at the outset to obtain only a UP for a pharmaceutical product for which a UP can only therefore be

enforced in the UPC system is one that should not be taken lightly. Furthermore, there seems no question that patentees should opt their existing and future EPs for pharmaceutical products out of the UPC system, bearing in mind that the jurisdiction of the UPC over EPs in the transitional period is non-exclusive, and a decision can always be made to opt them back in again. Despite the uncertainties, the fact that the UPC is due to open for business in early 2015 and has jurisdiction over existing EPs from the outset (unless steps are taken by patentees to opt their patents out) is something that both patentees and third parties need to take into account in their current litigation strategies. References 1. Bulgaria added its name on 5 March 2013, leaving only Poland and Spain outside the Agreement, although it is expected that at least Poland will sign in due course. 2. One possible reason may be the cost of opting a patent out of the UPC system. It is not known whether a fee will be charged for the privilege of opting out and opting back in again and if so, how much the fee will be per patent. 3. Even though Spain is currently challenging the basis on which UP and the Translation Regulations were made before the Court of Justice, it is certainly possible that it will eventually decide to sign up to both the UP and the UPC.

Neil Jenkins is a partner in Bird & Bird’s Intellectual Property group in London. He joined the firm in 1986 and became a partner in 1996. Neil is a patent litigator whose practice is focused on the pharmaceutical sector. He runs pharmaceutical patent actions in the UK and co-ordinates pharmaceutical patent litigation across Europe. He also litigates and advises on other IPRs including trademarks, copyright, designs, trade secrets as well as supplementary protection certificates and regulatory data exclusivity protection. Email: neil.jenkins@twobirds.com

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Cancer: The Major Medical Challenge in Europe Today (Cancer Cures Made in Austria) Austria is at the forefront in the fight against cancer in Europe and plays a leading part in the worldwide campaign with several pioneering initiatives. Be it innovative immunotherapy, novel molecular targets or radiation therapy, researchers and oncologists throughout Austria are working to develop and commercialise diagnostics and treatments.

Primary Research: The Frontiers of Oncology At the core of Austrian cancer research are multidisciplinary research networks bringing industry, healthcare and primary research together. It is these networks that have arguably helped Austria lead Europe in the fight against cancer. For instance, the Comprehensive Cancer Center Vienna (CCC) established by the General Hospital, the Medical University of Vienna, seeks to discover mechanisms leading to cancer development and progression with the goal of improving the prevention, diagnosis and therapy of malignant diseases, and reducing morbidity and mortality from cancer. Another example is the Austrian Breast & Colorectal Cancer Study Group (ABCSG), an important Austrian organisation that performs internationally successful clinical trials in breast and colon cancer. A radical treatment initiative for breast cancer patients with small tumours and nonaffected lymph nodes in ABSCG hospitals resulted in a remarkable 80% breast preservation. This is three times better than the similar statistic for Austria 25 years ago, and even exceeds preservation rates seen in the USA. There are currently 23,000 women participating in ABCSG studies, which is an astonishing number considering a small country like Austria. There are several pioneering research institutes in Austria that combine basic medical research and industrial partnership. One of them is the Institute of Molecular Biotechnology (IMBA), a basic research institute of the Austrian Academy of Sciences. There, an international team of scientists conducts 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

primary research to study molecular mechanisms of biological processes and to address questions in modern life sciences and biomedicine. The aim is to understand the elementary mechanisms of health and disease. To reach this goal, a wide array of model organisms, as well as advanced technologies in cell biology, structural biology, biochemistry, genomics and genetics are used. The CeMM Research Centre for Molecular Medicine is a flagship research institute of the Austrian Academy of Sciences which is pursuing a new medical focus. Driven by medical needs, CeMM integrates basic research and clinical expertise to pursue innovative diagnostic and therapeutic approaches focused on cancer, inflammation and immune disorders. The goal of CeMM is to assist in preparing the predictive, preventive and personalised medicine of the future. The Children’s Cancer Research Institute (CCRI) is nationally and internationally renowned for its multi-disciplinary approach to decoding pathogenesis mechanisms and for improving diagnosis, prognosis and treatment of cancers in children and adolescents. The Biobank Graz comprises populationbased and disease-focused collections of biological material, covering a huge variety of diseases. It is one of the world’s largest biobanks, containing more than 5 million samples from about 1.5 million patients. Its unique value comes from its collection of unselected pathological samples and clinical data from the entire Styrian population of the last 30 years, representing all detected diseases at their natural frequency of occurrence, such as common metabolic disorders like diabetes as well as cancer and noncancer diseases from all organs and all age groups. Tumour material is available for further research and biomarker development, enabling rapid scientific progress in the fight against cancer. In addition, Boehringer Ingelheim is pioneering innovative approaches to cancer therapy in Austria alongside its

research powerhouse, the Research Institute of Molecular Pathology (IMP) and industrial biotech partners . These collaborations support Boehringer Ingelheim’s team of 240 scientists in Vienna, enabling the company to be a key player in cancer research. Boehringer Ingelheim is also one of the leading companies for contract development and GMP production of biopharmaceuticals. The IMP, in particular, is a worldrenowned research facility, generating high-impact peer-reviewed research and attracting top scientists to focus on cellular growth regulation and the complex biological processes underlying disease.

Diagnosing and Screening for Cancer As with all cancers, early screening and diagnosis are vital for selecting an optimal treatment regime. Really accurate diagnostic tests that can pinpoint the disease in its very earliest stages can be critical to a positive outcome. Add to Spring / Summer 2013 Volume 5 Issue 2


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that companion diagnostics that can help detect patients who are likely to benefit from a treatment, and it is easy to see that cutting-edge diagnostic and screening technologies for common cancers can therefore really save lives! Austria has long been an engine of innovation in cancer diagnostics. Finding a way to tell which patients will benefit from a treatment and which will not, i.e. “personalised medicine�, is an important goal worldwide and a key driver behind the research of a consortium of scientists at Oncotyrol. This Centre for Personalised Medicine is using cutting-edge research to provide answers as to why cancer treatments work with some patients but not others. The efforts of the consortium are being further strengthened through its collaboration with the newlyestablished Austrian Drug Screening Institute (ASDI), where expertise is applied to both basic and translational research, with the aim of tailoring organotypic tumour modelling, cellbased assays, high-throughput screening and biomarker identification. The Department for Health Sciences and Biomedicine at the Danube University Krems is working in Health Service and Management. Furthermore it is working in clinical medicine with a special focus on internal medicine and regenerative medicine, including orthopaedics, sports medicine and complementary medicine. A privately-owned company with an innovative approach to an extremely quick and accurate cancer screening is Signalomics. Their proprietary technology allows for the highly-sensitive visualisation of tumour tissue and cancer cells by combining ligands specifically developed for this purpose with lightemitting nanoparticles called Quantum Dots. The resulting product is unique to Signalomics and is currently in advanced preclinical development for visualising colon cancer and the surrounding lymph nodes. therapies to treat tumour patients. For example, the department for Medical and Pharmaceutical Biotechnology at the FH-IMC University of Applied Science Krems is very well recognised in the identification of predictive biomarkers and personalised medicine, carrying out state-of-the-art research in 3-dimensional www.ipimedia.com

New Treatment Approaches In the last 50 years, cancer therapy has advanced considerably, but there is still much work to be done in order to find treatments that can improve quality of life and outcomes with minimal sideeffects. The following examples span a whole series of disciplines and detail where Austrian doctors, scientists and

businesses have been leading the way in the fight against cancer. Vaccines and immunotherapeutic approaches are important ways to combat cancer and to stop the spread of the disease within the body. APEIRON Biologics is an Austrian company developing innovative immunotherapeutics, signing, amongst others, an agreement with Merck KGaA on the rights to develop and commercialise a novel biological treatment for neuroblastoma and other cancers (currently in Phase III trial). Both Activartis Biotech, a spin-off from the CCRI, and CELLMED Research with its spin-out LifeResearch Technologies, are specialists in tumour-immunotherapy and are developing therapeutic cancer vaccines for unmet cancer needs. The approach is based on the use of antigenpresenting IL-12 dendritic cells which help the immune system to recognise and destroy tumour cells. Activartis, a subsidiary of AOP Orphan, is a specialist in cancer immune therapy. The company has developed a proprietary cancer vaccine technology using antigenpresenting IL-12 secreting dendritic cells which instruct the immune system to recognise and destroy tumour cells. Activartis’ technology is currently part of a randomised clinical Phase II efficacy trial with about 90 metastatic brain cancer patients. INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


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options for patients with more advanced stages of the disease. Chemotherapy and anti-cancer drugs will therefore continue to play an important and integral role in many cancer treatment regimes. New or modified anti-cancer molecules with improved potency and efficacy as well as reduced side-effects and toxicity are being discovered and developed by companies like Tube Pharmaceuticals who are cultivating powerful anti-cancer drugs called cytolysins. This new class of natural substances has demonstrated outstanding potency against dividing cells, including cancer cells in initial proof-of-concept studies by conjugations towards small molecule, polymers, peptides, proteins and antibodies. MedAustron is one of the most advanced centres for ion beam therapy and research in Europe and is based in Wiener Neustadt. The irradiation therapy will be performed with carbon ions or protons. The technical test operating will start in 2013 with the first treatments carried out by 2015. In the full operational phase, up to 1400 patients per year will benefit from this innovative treatment option. Overall, Austria offers both worldclass primary cancer research and dynamic therapeutic as well as diagnostic innovation and development. Considering the high quality of Austrian hospitals, it is perhaps unsurprising that Austria is leading Europe in the battle against cancer.

CELLMED Research, founded in 2006, is an Austrian Life Science Company focused on research and development of cellular therapies, in particular on the manufacturing and clinical application of cellular immunotherapy for the treatment 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of solid tumours. A clinical study in Phase I / IIa on the safety of PROCURE速 for the treatment of ovarian cancer is underway. While vaccines and other immunotherapeutic methods are important, there need to be treatment

Sonja Polan is the International Marketing Manager of LISA - Life Science Austria since 2009. Previously she worked as Account Manager at the European Commission, mainly in charge of marketing telecommunications policies to the European public. The most important campaigns were for the newly established roaming regulation and telecom reform. Before the European Commission, she worked for a major Brussels-based European public affairs consultancy, and also had short stints with the European Parliament and with trade federations. She speaks German, English and French. Email: s.polan@awsg.at

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What the Unitary Patent Means for the Pharmaceutical Industry After nearly four decades in the pipeline, the countries of the European Union have finally signed an agreement that is expected to lead to a system of Unitary Patents. They will have pan-European effect and an associated Unified Patent Court to enable enforcement of the Unitary Patent across Europe. If the agreement is ratified by European member states, this will represent the most radical change to the patent landscape in Europe of the past 40 years. Patent Attorney, Martin MacLean, examines the issues surrounding its implementation and how it will affect the pharmaceuticals industry. While other industries are likely to watch the development of the Unitary Patent system from the sidelines, the pharmaceutical industry is likely to see a more immediate impact (with potentially far-reaching effects) on daily operations and patent strategies, once the Unitary Patent system comes into force. While the Unitary Patent system will enable pharmaceutical companies to simplify maintenance and enforcement of their rights across Europe, and is also likely to reduce their patent costs in Europe, the Unitary Patent also comes with significant risks and uncertainties. Thus, the pharmaceutical industry will most likely be the first to test many of the new legal and procedural aspects of the Unitary Patent. It is therefore important for the industry to be aware of the issues surrounding the Unitary Patent and to monitor developments as implementation details of the system are revealed. Although full implementation of the proposed system is likely to be some years away, patent applications filed today are likely to fall under at least parts of the regime. Therefore, it is not too early to consider how the anticipated changes will likely affect your patent strategy and thus to consider how patent applications that are filed now might be enforced within the next few years. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What is the Unitary Patent? In summary, the Unitary Patent system will enable applicants to obtain a single patent with unitary effect across up to 25 of the 27 member states of the European Union. The agreement (of the UPC), which will bring the Unitary Patent into effect, has been signed but now needs to be ratified by at least 13 member states (including the UK, France and Germany). Under the current European system, grant of a patent by the European Patent Office (EPO) provides a “bundle” of national patent rights, requiring validation of the granted patent in each individual state in which the patentee requires protection. Translation requirements for each state in which the patent is validated can add significant costs for the patentee. By contrast, the Unitary Patent will cover all participating member states, with the aim of offering a pan-European ‘one in, all in’ approach. In addition, the translation requirements will be much reduced, and eventually eliminated altogether. The Unitary Patent will exist alongside the current, “traditional” European patent system, which will allow patentees to obtain patent protection in countries that are not party to the Unitary Patent (including Spain and Italy) and in the non-

EU territories that are also covered by the European Patent Convention (including Norway, Switzerland and Turkey). In addition, it will remain possible to pursue individual national patent applications outside of the European system entirely, by filing directly with national patent offices. Once granted, any revocation, transfer, or lapse of a unitary patent will take effect in all member states at once. However it will be possible to license a Unitary Patent in different territories. The Unified Patent Court Unitary Patents will be enforced and litigated in a new Unified Patent Court (UPC), which will have jurisdiction across all of the EU member states that sign the Agreement. London will host a branch of the UPC dedicated to hearing chemical and pharmaceutical cases. The rules and fee structures associated with the new court have not yet been finalised and are still under discussion. Many questions remain as to how the UPC will operate and what the costs of using the court are likely to be, but the basic structure is now clear. As well as litigating Unitary Patents, it is intended that the UPC will eventually also have exclusive jurisdiction over “traditional” European patents covering participating EU member states. Therefore, European patent applications that are filed today, and many that are already in existence, are likely to fall under the jurisdiction of the UPC. Ultimately, patentees will not be able to avoid the jurisdiction of the UPC even if they opt not to use the Unified Patent system. Once the UPC is brought into force, however, there will be a transitional period of at least seven years in which a patentee can opt out their traditional European patent from the jurisdiction of the UPC. It is expected that most patentees will wish to opt out their existing traditional European patents from UPC jurisdiction as soon as the UPC is brought into existence to avoid the possibility of competitors applying for central revocation of the patent. Under current proposals patentees will have the Spring / Summer 2013 Volume 5 Issue 2


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ability to opt back in and initiate litigation centrally, so it seems there is little disadvantage in opting out. However, there are rumours that a fee may be charged for opting out a patent. Due to a loophole in the current proposed regulations, there may be a short window in which a revocation action against a patent could be brought in the UPC before an “opt-out” for the patent is registered. If the proposals are not changed, this could provide an important window of opportunity, which is likely to be exploited in the pharmaceutical industry in particular, to bring central revocation actions against patents at the UPC. The UPC will consist of a central division split into specialist branches, to deal with infringement and validity actions, and several local and regional divisions. The central division’s specialist branches will be subjectmatter dependent, with pharmaceutical and chemical cases being heard in London. Although the details have yet to be agreed, it is likely that at least some European Patent Attorneys, who

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often have significant experience in both attacking and defending European patents in Opposition proceedings at the European Patent Office, will have rights of audience at the new UPC Courts. The UPC will also have jurisdiction to hear infringement cases for Supplementary Protection Certificates (SPCs), commonly used in the pharmaceutical industry to extend protection for medicinal products beyond the 20-year term of a patent. The Unitary Patent and the Pharmaceuticals Industry The pharmaceutical industry traditionally seeks to validate its European patents across as many European territories as possible. This is in part due to the nature of pharmaceutical products: while the costs incurred during research and development of a new drug can run into hundreds of millions of dollars, the manufacture of generic copies of a new molecular entity may be relatively cheap. Thus, it is vitally important to obtain as wide a territorial scope of protection as possible. By contrast, other industries often limit European patent protection

to major territories such as the UK, Germany, France and the Netherlands to capture the main markets and import/ export routes of Europe. The new Unitary Patent system will therefore provide obvious benefits for industries such as pharmaceuticals who seek the broadest patent protection across Europe. These benefits will include a streamlined grant and validation procedure, and the ability to enforce a patent across all territories participating in the Unitary Patent with a single crossborder injunction. The simplified process will mean the validation and management of European drug patent portfolios will be much more straightforward, as the system will be administered centrally at the EPO. Only one European representative will be needed, and a single renewal fee will be payable to cover all the member states. Although the fee levels have not yet been set, it is highly likely that the cost of obtaining and maintaining a Unitary Patent will be significantly less than the corresponding costs for patents in each separate European state.

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Risks and Rewards – Central Revocation and Enforcement A key feature of the Unitary Patent, which will have a significant impact on the pharmaceuticals industry, is the ability to enforce the patent across all Unitary Patent countries at a single court in a single action. For the first time, European-wide injunctions and damages will be available so, overall, enforcement procedures are likely to be cheaper, simpler and potentially also quicker. This may increase levels of patent litigation in Europe and reverse recent trends towards mediation and licensing. However, for all its benefits the Unitary Patent has one very major downside. The new UPC will have the power to revoke patent rights across the entire European Union in one blow. With the very real possibility of central revocation, the Unitary Patent route could involve serious risk for a drug patent of any serious value. This is quite evidently a major change from the existing European patent system, under which, once the centralised opposition period has passed, separate national revocation proceedings must be undertaken in the courts of the individual states. However, for any pharmaceutical companies typically engaged in opposition actions against their competitors, the ability to bring a single revocation action may prove very useful. It is likely that, at least at first, central revocation of a granted patent will be faster than the current opposition procedure, which typically takes around six years to conclude (three years at first instance, with a further three years when under appeal). In addition, there is no restriction on launching a revocation action against a patent that has already been successfully opposed in European Opposition proceedings. Therefore, there is a second opportunity for attack against a competitor’s patent. A Confusion of Languages and Legal Regimes Some of the most confusing and controversial aspects of the proposed UPC system are the complicated arrangements for determining where a case is to be heard, in which language and under which law. The proposed UPC system does not include detailed provisions on infringement, so the law that applies in a 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

particular case will depend on the place of business of the patent proprietor, with a default of German law for non-EU businesses. Infringement actions themselves will be heard either in a court present in the country where the infringer has a principal place of business, or in the country where infringement takes place. As a result, there is likely to be a wide choice of courts where the patentee may choose to bring infringement proceedings. The language of proceedings will depend on the language of the court in which the action is brought or the language in which the patent application was filed. While this sounds clear enough, it sets up a rather complicated system in which different legal regimes may be applied in different languages in various courts across Europe, even for a relatively straightforward infringement situation. For example, a US pharmaceutical company operating predominantly in Germany may file a European patent application in English. An infringement occurs in Portugal by a Dutch company. The US patentee could then bring an infringement action against the Dutch company in the Dutch regional division of the court in Dutch, on the basis of the English-language patent, but under German law. Alternatively, assuming there is no Portuguese local division of the UPC, the US company could bring the infringement action in the central

division in London in English, but also following German national law. In addition, many questions arise that will be particularly pertinent for international industries, such as pharmaceuticals. For example, will a US patentee that has many places of business throughout Europe be able to select which infringement laws apply to their patent? In theory, national infringement laws should be harmonised throughout Europe, however there are some crucial differences that will be critical in many pharmaceutical cases, for example with regard to the interpretation of the “experimental use” exception. At present, under national infringement laws countries such as the UK have taken a narrow view of the “experimental use” exceptions that pertain to trials conducted in order to obtain marketing authorisation for generic pharmaceuticals (so called “Bolar” provisions), whereas other countries such as Germany have taken a broader interpretation of the exemption. This raises the possibility that the scope of protection of a given patent might differ depending on the proprietor’s place of business. The complexity of the proposed rules, together with the lack of harmony of European patent law, means that ‘forum shopping’ by patentees to bring infringement actions in the most favourable courts is likely. Spring / Summer 2013 Volume 5 Issue 2


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Costs As yet there has been no public disclosure of the costs for the Unitary Patent, though requesting a Unitary Patent is expected to be as much as 80 per cent cheaper than validating patents in all countries. The translation requirements will also be reduced, ultimately to dispense with translations in favour of machine translations. Renewal fees for the Unitary Patent will be managed centrally by the EPO, requiring only a single renewal fee to be paid each year. Although the level at which renewal fees will be set remains to be decided, current expectations are that the renewal fee for a Unitary Patent (covering 25 European states) will be equivalent to somewhere between six and 15 national renewal fees. For the pharmaceutical industry, this represents a potentially significant cost saving, as patents for new drugs are typically validated in all available European states. Hurdles to Introduction Whilst there has been much fanfare from the European Parliament about its

approval of the Unitary Patent and its potential to dramatically reduce the cost of acquiring patent protection across Europe, there are still a number of hurdles to be overcome. With the requirement for the UPC agreement to be ratified by at least 13 member states including the UK, Germany and France, it is unlikely that the process of ratification will be complete by January 2014, the date predicted by the European Parliament. Formal proceedings are expected to delay implementation until late 2015 or even 2016, and elections in both Germany (in 2013) and the UK (in 2015) may also lead to delays in approval of the UPC agreement. Some member states, like Poland, have expressed concerns regarding the Unitary Patent’s effect on their economy and an increase in domestic competition. This very real concern may see more countries back out, reducing the scope and value of the Unitary Patent package before it is even introduced. If the Unitary Patent ever comes into being, it will undoubtedly change the patent landscape in Europe, whether

through the regulation of unitary and non-unitary patents or its ability to reduce the level of investment required to achieve pan-European patent protection. The extent to which the pharmaceutical industry may want to embark upon such a high-stakes gamble, in spite of the cost-saving benefits, remains to be seen. Dr Martin MacLean, Patent Attorney, Mathys & Squire LLP Martin is a qualified Chartered Patent Attorney and European Patent Attorney. He specialises in technologies including the retargeting of bacterial toxins, vaccines, expression systems, microbial detection assays, cytokine-based therapeutics, and agrochemicals. Martin is also a member of the Life Sciences Committee for the Chartered Institute of Patent Attorneys, and acts as a tutor for the UK and European Qualifying Examinations. Email: mrmacLean@mathys-squire.com


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Compensation for Research Injuries: National Regulations and International Standards Introduction Patients taking part in clinical trials may suffer from permanent or temporary harm as a result of their participation in the research. Research regulations worldwide aim to prevent research injuries as well as to provide remedies for injuries suffered by research participants, regardless of what or who may have caused those injuries. The ICHGCP guidelines mandate that sponsors make provisions for compensation for research-related injuries but largely leave compliance to applicable national or local regulatory requirements. Though there is no dispute that remedial measures are required for research-related injuries, how patients are to be compensated is a hotly debated topic, and worldwide regulations differ considerably in this respect. At one end of the spectrum are countries like the United States, the United Kingdom, and Taiwan that prefer to address compensation issues within their existing laws on accidents and injuries requiring the injured to establish evidence of negligence, misconduct, or wilful ignorance of procedure on the part of the research sponsors, investigators, or research institutions, though there is a strong public pressure “to do the right thing”. At the other extreme are European countries like France, Germany and Spain, where research sponsors are compelled by law to provide a no-fault compensation for research injuries through mandatory insurance requirements. Developing nations are faced with a peculiar dilemma – their court-based systems for securing compensation are slow and grossly inadequate for addressing the issue of research injury compensation, while the comprehensive no-fault compensation systems on Western lines would make the research enterprise unviable. International Law and Cross-Border Regulation Compared to national, i.e. domestic, enforcement systems, international law is a relatively weak source of authority since 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

it is not directly applied to individuals or institutions (Lauterpacht, 20111). For example, a patient in Malawi cannot directly file petition in any international court or tribunal like the International Court of Justice to enforce a specific provision of the Declaration of Helsinki (DoH). The Malawian government must do it on their behalf and is therefore more likely to want the issue to be resolved domestically. Nevertheless, instruments of international law, i.e. treaties, declarations, guidelines, etc., can be used by the international community to apply pressure on nations to formulate domestic rules on compensation for injuries sustained by research participants. This section explores three such documents of international law. First formulated in 1964, the World Medical Association’s DoH contains principles to protect the rights of research participants; however, until 2008, it contained no specific provision on compensation for injuries. The 2008 revision to the DoH contains a powerful acknowledgement of the principle that a provision for research injury compensation should be included in the study protocols, so that patients don’t have to seek expensive remedies through courts and tribunals. Another influential international instrument is from the Council for International Organizations of Medical Sciences (CIOMS, 20022) which states that “investigators should ensure that research subjects who suffer injury as a result of their participation are entitled to free medical treatment for such injury and to such financial or other assistance as would compensate them equitably for any resultant impairment, disability or handicap” (Guideline 19). However, a causal link must still be established to the experimental intervention, and compensation is not due when subjects suffer expected or foreseen adverse reactions which are similar to those seen in established interventions in standard medical practice. The Good Clinical Practice (GCP) guidelines of the International Conference

on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH, 19963) stipulate the following with respect to compensation for research injuries: • Ethics committees (ECs) are required to consider whether compensation is available to subjects when granting approval for a clinical trial. • The informed consent process must include explanations of the medical treatment and compensation options which may be available to participants in case of trial-related injuries. • Sponsors are required to make provisions for compensation for research-related injuries in accordance with applicable national laws. On the whole, the ICH-GCP guidelines adopt a deferential tone and largely exhort compliance with applicable national or local regulatory requirements. Therefore, they do not represent a standalone set of regulations that can govern the conduct of healthcare research, at least with respect to compensation for researchrelated injuries.

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National Law and Domestic Regulation The regulatory regimes that govern compensation for research-related injuries for some key nations are described below. People’s Republic of China (PRC) Article 93 of the Drug Administration Law of the PRC states in broad terms: “drug manufacturers, drug distributors or medical institutions that violate the provisions of this Law and thus cause harm and losses to users of drugs shall bear the liability of compensation in accordance with law.” However, it does not discuss the issue of injuries for participation in medical research. Chinese research participants may file a case for compensation in a civil court in case of injury. However Zhang (20084) and Gourley et al. (20095) identified that in order to be eligible to receive any compensation, the fault between the medical treatment and the injury needs to be established and the compensation amount may not be adequate to cover the harm by the injury. India In 2011 the Indian Council for Medical Research (ICMR) provided specific guidance, introducing a ‘no-fault scheme’ including that the compensation is to be paid irrespective of (1) the cause of injury, (2) whether the injury was foreseeable, (3) whether consent was freely and appropriately obtained or (4) whether the injury was caused by a placebo or a treatment regimen in the control arm of the study (Pramesh & Badwe, 20125). To make the ICMR guidelines more stringent, the Central Drugs Standards Control Organization (CDSCO) amended and published the Draft regulations (2011, 2012a, 2012b6) in November 2011, July 2012 and August 2012 outlining the conditions in which compensation must be provided for research injuries. These regulations have now been finalised (30 January 2013) after a period of review during which strenuous objections were raised by the industry to some of the proposed provisions. The Ministry of Health and Family Welfare nevertheless decided to retain the most contentious of the provisions in the finalised regulations viz. compensation in case the investigational product or placebo fails to provide the intended therapeutic effect. 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Malaysia According to §5.8.1 of the Malaysian guidelines for GCP (National Committee for Clinical Research, 20117), the sponsor is required to provide insurance and indemnity in the form of legal and financial coverage for investigators and research institutions against claims arising from the trial, except for malpractice and negligence, but only “if required by the applicable regulatory requirement(s).” New Zealand New Zealand’s no-fault, taxpayer-funded compensation scheme for accidents and injuries has been in place since 1974. Since 2005, medical injuries have been included in the scheme under the revised definition of ‘treatment injury’ as a “personal injury suffered by a person seeking treatment or receiving treatment and caused by treatment…” (Wallis & Dovey, 2011, p. 2878).

bodily harm or death (in accordance with identified principles). United States As one of the most litigious societies, the United States makes available personal injury lawsuits filed in courts as the principal means of seeking compensation for research injuries. No-fault compensation systems have voluntarily been adopted by some research institutions, like the University of Washington, since the 1970s. However, at the federal level of regulation, the US research system has the following features per Beh (200511):

Taiwan (Republic of China) At present, Taiwan does not have any special guidelines for dealing with injuries arising from participation in healthcare research; general rules on civil liability apply. Uganda In the last two decades, the developing nations of Africa have become fertile sites for undertaking healthcare research, necessitating an examination of their laws on compensation for research injuries. In Uganda, the Uganda National Council for Science and Technology (20079) states that when a research injury is classified as “Definitely” or “Probably” related to participation in research, the subject is entitled to compensation that may consist of free medical treatment for the injury and financial and other assistance which compensates the subject equitably for the resultant impairment or disability (§7.5). United Kingdom The United Kingdom employs a classic courtroom approach to medical injuries, i.e. negligence or fault must be established in a court of law for compensation to be awarded to research participants. However, for many years, the Association of the British Pharmaceutical Industry (ABPI, 199410) has recommended that research sponsors voluntarily pay compensation to patient-volunteers in Phase II and III clinical trials suffering Spring / Summer 2013 Volume 5 Issue 2


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• Research institutions are not obliged to provide either compensation or reimbursement for medical expenses caused by research injuries. • ECs are required only to ensure that where more than a minimum risk of injury exists, participants are informed during the consent process if provision for treatment or compensation in case of injury has been made. • ICF cannot require participants to either waive their legal rights or release sponsors, investigators, and research institutions from liability for negligence. Other Countries Bioethics regulations in Brazil require that trial sponsors pay compensation to participants for trial-related injuries (PCSBI, 201112). No-fault compensation schemes for medical injuries were adopted in Sweden in 1975, Finland in 1987, Norway in 1988, and Denmark in 1992. The German no-fault compensation scheme differs principally from that of

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New Zealand in that it is sponsor-funded and therefore does not present a taxpayer burden. Sponsors are required to create an insurance fund to cover researchrelated injuries. However, the insurance only covers economic loss, not pain or suffering. The research participant, within three years of the conclusion of the research, must establish both that there is a causal link of the injury to the research intervention and that no other person has any liability for the injury. In the event of a research-related injury in France, sponsors are liable on a nofault basis for non-therapeutic research.

Interestingly, there is a presumption of fault and therefore liability on the sponsor in the case of therapeutic research. Therefore, the onus is on the sponsor to disprove fault and escape liability. The relevant Spanish law presumes that injuries to the health of a subject during and within a year of the research are caused by the research. In cases where a research injury is not covered by liability insurance held by the sponsor, the sponsor, principal researchers, and medical director of the research institution are jointly liable for providing compensation to the research participant.

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4.

5.

6.

Conclusion In order to prevent research participants against the harm to life and health involved in the research process, it is imperative for every country to adopt regulatory frameworks that are not only legally compliant but are also harmonious with the spirit of the instruments of international law like the DoH, the CIOMS guidelines, and the ICH-GCP guidelines. References 1. Lauterpacht, H. (2011). The Function of Law in the International Community. Oxford University Press. for International 2. Councils Organizations of Medical Sciences [CIOMS] (2002). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva, Switzerland: CIOMS and the World Health Organization (WHO). Retrieved from http://www.cioms.ch/ publications/layout_guide2002.pdf Conference on 3. International Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH] (1996). Guideline for Good Clinical Practice E6(R1). Geneva, Switzerland: ICH. Retrieved from http://www. ich.org/fileadmin/Public_Web_Site/ ICH_Products/Guidelines/Efficacy/ 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

7.

8.

9.

10.

E6_R1/Step4/E6_R1__Guideline.pdf Zhang, Q. (2008). Chinese Regulatory Licensing Regime for Pharmaceutical Products: A Law and Economics Analysis, The. Michigan Telecommunications and Technology Law Review, 15, 417. Gourley, S., Chen, Y., & Bass, S. (2009). China – compensation for drug and device-related injuries. In: PLC Cross-border Life Sciences Handbook 2008/09. London: Practical Law Company. Retrieved from: h t t p : / / w w w. s i d l e y. c o m / f i l e s / Publication/44f59dfe-70d9-4a9a8554-bf25e4589885/Presentation/ PublicationAttachment/a6c894838f6b-46b1-992e-c16c8ec946e6/PLC_ China_Compensation_Dec2008.pdf Pramesh, C. S., & Badwe, R. A. (2012). Compensation guidelines for research-related injury in India could destroy investigator-initiated research. The National Medical Journal of India, 25(1), 35–37. National Committee for Clinical Research [NCCR] (2011). Malaysian Guideline for Good Clinical Practice (3rd ed.) Petaling Jaya, Malaysia: NCCR, Ministry of Health, Government of Malaysia. Retrieved from http://ethicsrmi.uitm.edu.my/ ethicsrmi/images/stories/guideline/ gcp%20malaysia.pdf Wallis, K., &Dovey, S. (2011). No-fault compensation for treatment injury in New Zealand: identifying threats to patient safety in primary care. BMJ Quality & Safety, 20(7), 587–591. doi:10.1136/bmjqs.2010.047696 Uganda National Council for Science and Technology [UNCST] (2007). National Guidelines for Research Involving Humans as Research Participants. Kampala, Uganda: UNCST. Retrieved from: http://www.uncst.go.ug/ dmdocuments/Guideline,%20 Human%20Subjects%20 Guidelines%20Marc.pdf Association of the British Pharmaceutical Industry [ABPI] (1994). Clinical Trial Compensation Guidelines. London, United Kingdom: ABPI. Retrieved from http://www. a b p i . o rg . u k / o u r- w o r k / l i b ra r y / guidelines/Documents/Clinical-TrialCompensation-GLs.pdf

11. Beh, H. (2005). Compensation for Research Injuries. IRB: Ethics and Human Research, 27(3), 11–15. doi:10.2307/3564074 12. Presidential Commission for the Study of Bioethical Issues [PCSBI] (2011). Research Across Borders: Proceedings of the International Research Panel of the Presidential Commission for the Study of Bioethical Issues. Washington, D.C.: PCSBI. Retrieved from http://bioethics.gov/ cms/sites/default/files/PCSBI-IRP_ Research-Across-Borders_1.pdf Chitra Lele has been part of the leadership of Sciformix from its inception. Prior to this, she was with Pfizer for about 10 years, where she was Executive Director responsible for India operations of Pfizer Global R&D. Chitra established India’s first Biometrics Center, providing services in clinical data management, statistics, programming and medical writing, and successfully grew it to over 400 staff. Chitra has a Ph.D in Statistics from Stanford University and her prior experience includes work as a biostatistician in cancer epidemiology at Stanford University and University of California, San Francisco, and as a faculty member at the School of Statistics at the University of Minnesota and Indian Institute of Technology, Mumbai. Email: chitra.lele@sciformix.com

Co-author: Suhasini Sharma Dr Suhasini Sharma is a physician specialising in Pharmacology. She has over 25 years of experience working with Indian and multinational pharmaceutical companies, during the course of which she has headed medical affairs and handled medical information, medico-marketing, clinical research, drug safety and medical writing. Dr Sharma has also managed and overseen clinical trial operations (including a central ECG lab) for a global CRO, and an SMO. Email: suhasini.sharma@sciformix.com

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Virtual Drug Development: Vision, Oversight and Risk Management Following on from a previous article in which I examined how drug development had changed over the last century, we have developed the theme that I introduced about the increased complexity of drug development, increased outsourcing of projects or packages of work, the challenges of identifying and then managing multiple suppliers, and the concept of virtual developments. Until the last 15 years, most new drugs, even if discovered in academic units, were developed by what has come to be known as fully integrated pharmaceutical companies. Now, many new drugs are being discovered within universities and start-up biotechnology companies. They perform the initial target and drug screens, arrange for small-scale production, and then often outsource later aspects of the drug development process, leading to a virtual global development. Other small and medium enterprises (SMEs) may arise to develop traditional new chemical entities. The general problem of sourcing and managing development resources, dealt with in this paper, apply to both of these types of organisations, though the actual development issues will differ. Rather than use the cumbersome phraseology of start-up biotechnology and other SME pharmaceutical companies, the general term ‘biotechs’ is used, as it is often used in common parlance to embrace all such small companies attempting to develop novel drugs using new technologies. One of the concepts that some of the larger pharmaceutical companies, such as AstraZeneca, developed, was that of a fully integrated global project team involving all disciplines in research and development and led by a global product director (GPD), a single person with the authority to lead the team and to be responsible for the project costs, timelines and risk management. In addition to managing the team, the GPD, if having particular expertise in the therapy area under investigation, might also in parallel be a core member of the strategy team leading the vision for future projects, leading advisory 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

boards and being present and presenting at International meetings, and hence there is a continuity of management of projects. Many other companies had similar formats, but many others had fragmented leadership and the degree of integration varied (and still does) with independent leadership of the research, toxicology, chemistry and manufacturing control (CMC), clinical and commercial activities. The GPD would be supported by an experienced project manager that kept the integrated plans up to date. While many staff at ‘biotech’ companies have excellent previous experience, it is inevitable that since a company can only grow gradually, it cannot immediately secure staff with years of experience in regulatory affairs, manufacturing, toxicology, and clinical development. Project managers in the start-up phase will often have experience on the research and manufacturing issues, but they will rarely have led large-scale clinical drug developments. Some staff will have a part of the required expertise but most will not have led multi-functional teams and contractors for projects which have progressed from pre-clinical research to market, and particularly given the 10-15 years development times, there will not be many who have done so more than once. Situation Analysis of Drug Development Finding and Developing New Drugs There is good evidence that finding a blockbuster drug, or even a drug that will achieve a reasonable return upon investment is getting more difficult. Development times are increasing; aside from the improved review times following the PDUFA Act, attrition is rising and as a result so too are costs. Resources required to run trials in Europe have increased since implementation of the EU Directive. Pedro Cuatrecasas, who has an unsurpassed record of drug discovery, commented strongly on many of the internal reasons why large pharma companies are failing by not giving sufficient freedom to researchers and being too market-driven. Due to the

dearth of new drugs from the traditional large pharmaceutical companies, and because of imminent, major patent expiries, they are turning increasingly to universities and to biotechnology companies that are also accessing novel targets, developing new strategies and using novel technologies, particularly in gene therapy and biological drugs. Companies have had to also integrate new technologies such as combinatorial chemistry, genomics, proteomics, systems biology, and bioinformatics, along with improvements in fermentation technology, use of vectors and so on. Alongside a wide range of new technology, regulatory guidelines have had to be rewritten and continue to evolve. However, there is a danger that some of the lessons of the past will not be followed. We now have a very fragmented industry. Pharmaceutical companies are releasing large numbers of highly experienced staff. Small biotech companies start with limited staff, often with only limited or specialised drug development experience producing novel proteins or ligands with a good general concept of how they will be utilised in clinical practice, but without creating early in the process a fully integrated drug development plan (IDDP), partly because they do not see themselves performing, or have not the funding to perform, those activities. This is remarkable, as you would not consider building a motor vehicle or a home without such a template. Initial issues include hiring office space and staff to perform research and there are useful guidelines for funding and organising the early start-up period. There are of course books that can be read, but it is the assimilation of information and hands-on experience that adds real value. Our experience is that many companies do not develop an integrated drug development plan (IDDP) soon enough, and in particular do not develop their target product profile (TPP) sufficiently to make rational decisions on choosing the best lead compounds. They may be inhibited by the number of alternative chemicals they can make. It is all too Spring / Summer 2013 Volume 5 Issue 2


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easy to choose the most active agent from a series of assays without concerns about its likely toxicology profile, ease of manufacture and ‘developability’, in terms of solubility, physical properties and formulation, and with an eye to how the drug needs to be delivered, the shelf-life and how it will be used with other agents, and thus considerations of metabolism and drug interactions. This latter point is crucial, as many drugs will be used in elderly patients who do not have a single clinical problem and will be receiving multiple therapies concurrently. As the project progresses, much CMC, pre-clinical and clinical work is therefore contracted out to a large number of independent specialist companies, and there is a danger of loss of control. More than ever, the responsibility for the coordination of these complex studies falls on the shoulders of project managers. There must also be a close oversight by senior experienced staff with a longerterm vision of the product to ensure that research funds, timelines and risks are properly managed. They must also be aware of the inter-relationships between the studies such that manufacturing changes can negate the validity of toxicology studies which may in turn affect what can be done in the clinic. The main challenges are at the functional boundaries, and there is no substitute for employing or contracting with project managers who have previous experience in assembling and managing large multi-functional global projects and anticipating future issues and dealing efficiently with issues that arise. The success of early projects depends heavily on avoiding, mitigating and managing risks. Increasingly, in due diligence, large pharmaceutical companies will look to these processes before committing their funds to projects with delays, gaps of knowledge, and problems that were not adequately anticipated or dealt with. Those projects that are on a successful track will progress to clinical trials which are particularly expensive and there is a strong dependence on the use of clinical research organisations (CROs). The CROs each have excellent systems and processes and a global presence, but staff of variable experience and sometimes a high turnover of staff. While we recognise the funding issues and that companies cannot simply hire all of the staff needed, all too often they www.ipimedia.com

are not investing sufficiently in highlevel strategic consulting. They need to, because decisions made early in selection and in early development will define the likely success of the project. Taking the wrong track(s) can lead to a lot of ‘baggage’ later on, whether it be CMC modifications, repeated studies, additional tests required, longer time sorting out formulations and stability, longer time periods arising from regulatory and ethical committee questions, or in the worst cases may lead to failure. Knock-on effects might include more complex clinical protocols with more exclusions or additional tests required. The effect of these is to take longer to find suitable patients to perform studies, with further increased costs. The concept introduced here is similar to ‘a stitch in time saves nine’, referring to mending torn clothes before they get worse. Further challenges of the new technologies include the enhanced ability to predict individual patient responses, related to the genetics of the disease or drug absorption and metabolism, and hence propensity to some adverse reactions. There is the availability of novel biomarkers, and the increased biobanking of tissue samples. Parallel developments in techniques for measurement and imaging and the emergence of PK/PD analyses have dramatically improved the potential for dosing and monitoring drugs, as will nanotechnology. These all add further layers of complexity to creating the TPP and IDDP.

The ‘Biotech’ Model The previous model has been for biotech companies to develop their ideas, identify new targets and lead compounds and to take the drugs as far as they can, often constrained by the level of financial support such that data has to be collated, analysed, reviewed, approved and then written up in a call for funding. It is vital in the early stages of drug development that they get reliable advice relating to the long-term vision for the product. Most future issues with a project are defined by choices made early in the project cycle, relating to how good the target is, how specific the lead drug is, how much it was optimised, how carefully it was made and purified and its specifications, how doses were selected, and the choice and design of pre-clinical studies. These decisions ought to be, but are not always, made against a long-term vision for the compound, simply because the IDDP including the CMC plan, pre-clinical plan, the TPP and clinical development plan have not been adequately discussed, challenged and validated and then integrated as a single plan. It is only when such a plan is created and then externally validated by market research that the true potential of a new approach can be reliably estimated. Whereas with high technology products such as proteins, antibodies or gene therapies there are limited opportunities for improvement beyond the technical expertise of the research team, there are times when they might seek external expertise from other academics or

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specialised companies. Antibody therapies by definition will be highly specific. With new chemical entities, there are two main concerns. Firstly, how widely screens have been performed across the chemical possibilities, and secondly, what has been the decisionmaking process in selecting the lead compounds. When you see decisions being made on the basis of 2-4 animals that will then affect the whole future development of the agent, for which a TPP is not yet available, there will of course be concerns. Depending upon the route of administration, there can be various challenges. For the oral route, understanding the mechanism and site of absorption and how subtle chemical changes can alter this goes a long way towards optimising delivery. The same is true for the distribution of the drug to various body sites and in the case of a ligand, the receptor occupancy and the specificity for the target. Already at this stage we need to build in an understanding of potential consequences of off-target activity, the adverse effect that may result, and the dynamics of target concentration or enzyme induction. Tied in to this might be the binding of the drug to various proteins in the blood and the effect that has on the further distribution of the drug. Complexity and Challenges We face several irreconcilable factors moving forward. 1) Many of the easier targets and obvious therapeutic solutions have been addressed with replacement therapies and receptor targeted drugs and those based on available natural substances, though Cuatrececas cautioned this is not entirely the case. However, diseases now under investigation include rare and orphan diseases, chronic diseases and complex multi-factorial diseases, some of which remain incompletely understood, such as schizophrenia or Alzheimer’s disease, and many of which require long clinical trials with untested endpoints and hence increased risk. 2) The industry faces public pressure for more openness and for ‘safer’ drugs. 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In an increasingly litigious society there are increased penalties for mistakes or even unpredictable and unexpected events. Regulatory authorities have generally acted by demanding more of pharmaceutical companies with increased documentation pertaining to specifications, margins, dosing decisions, larger clinical studies, longer follow-up, more defined indications, and active controlled rather than placebo controlled studies where possible. 3) There is also the inevitability that as the population ages and as patients require more therapies in the last decades of their lives, it also gets more complicated in managing drug-drug interactions and changing pharmacokinetics in the elderly. 4) Technology has increased the amount of specialised input into studies. Developments in genomics, biobanking and biomarkers were already mentioned. For example, there are over 100 biobanks around the world and some are diseasespecific, some tissue-specific, some relate to stem-cells and some are country-specific. The possibility of using genetic profiles for the uptake and metabolism of drugs is already imminent, though not routine. In addition, there are companies offering tracked cold chain supply of drugs, interactive voice response systems (IVRS), translation services, electronic data management, specialised respiratory or cardiac function monitoring, and central laboratories, and the list goes on. As a result, drug development has become remarkably complex and the fact that it is not all managed in a fully integrated industry as previously adds significantly to the management challenges. Many of the above factors have a potential additive effect on the length and complexity of consent forms for patients. Sometimes it is valuable to work with patient groups to validate forms to keep them manageable and meaningful. They also have the potential to lengthen further drug development times if not properly managed, or if positively embraced can focus development, allowing better decisions to be made earlier. 5) In parallel, there is increased pressure on prices from government, health services and insurance companies,

and this leads to the need for more health economic studies, adding further to costs and complexity while the achievable prices are driven down, particularly in emerging markets with compulsory licensing. As many effective drugs have reached the end of their patent life, we have seen an increasing focus on generic medicines, which comprise up to 70% of the market in the USA, and are a rapidly increasing proportion also in other countries including India and China. All of the above factors have a knock-on effect on the use of new and novel drugs, that are held in reserve while off-patent and cheaper drugs are used first. This was first seen with anti-bacterials, and as a result of increased studies, more limited indications and generic substitution for what is often an acute therapy has led to many companies exiting certainly from antibacterial research. Those disincentives have extended more recently to other therapy areas such as CNS, particularly after there has been a class of adverse events discovered, or when indications have been restricted or when genomic data has led to a smaller than expected target commercial population. Examples of the latter are the restriction of indication for Herceptin positive breast cancer, EGRF and non small cell lung cancer, mutant B-RAF in melanoma. Thus certain sub-groups can be detected that are more likely to respond, and others can be detected that are more likely to have adverse events to slow metabolism, especially with drugs having a narrow therapeutic index such as warfarin. Other tests of genotype can predict hypersensitivity reactions such as those seen with Abacavir. Financial Support Resulting from the harsh economic climate globally and the risks involved and high attrition rate, funding for biotech research has become more challenging. The model for biotech drug development is often to progress a compound forward as far as possible with the available financial resources, with the aim that a large pharmaceutical company with global drug development expertise will come along, find the project attractive and purchase either the project or the company. They are more likely to do this if the project is Spring / Summer 2013 Volume 5 Issue 2


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novel, shows well described commercial potential, has been run efficiently, and the issues arising from manufacture and pre-clinical studies are not too onerous. In particular, they will not want to repeat studies that have been inadequate or inconclusive, whether by design or if the CMC processes have changed significantly since toxicology studies began. They will be attracted to projects that have been managed efficiently on timelines, and when they are secure that the work performed by contract research organisations and other providers is reliable. If some issues have arisen they will want to know that appropriate experts have been consulted. Large pharmaceutical companies will have to make difficult choices and will not want to expose themselves to projects that still involve a lot of risk. They will also be attracted to projects with sound project management and a smooth interaction with partners, as they themselves may wish to continue those relationships. One further consideration is that if particular companies are to be targeted, due consideration could be given to working with the CROs that they partner with, though care needs to be taken as a small biotech may not get the same quality team that looks after the larger client.

Staff Experience A consequence of increasingly complex and longer drug developments is that most people will have inevitably only seen a part of drug development and in recent times many will have been frustrated by early projects that have not run the distance. They may have only worked within one function, such as toxicology, or in only one stage of drug development, such as pre-clinical, and both these points may apply. Others will have had practical experience in a large pharmaceutical firm but then entered management positions, and have then not further experienced current issues first-hand but will have had to rely on feedback from the staff they managed. The same issues apply to therapy area experience if one has been limited to a single project or therapy area. In the second and concluding article of this series in the next issue, we will discuss in detail and with examples how experienced consultants can help with the long-term vision of development and secure initial funding, and advise on manufacturing, toxicology, regulatory affairs, project and risk management, market potential, and evaluating the best contractors to perform these tasks, and importantly to create the overall development and quality plan to make the project attractive to investors. References i. Keith J. Williams, Historic and Big Picture Views on Drug Development, International Pharmaceutical Industry 5.1 (February 2013) 34-41. ii. Rodney J. Y. Ho, Milo Gibaldi. Biotechnology and Biopharmaceuticals. Transforming proteins and genes into drugs.(2003: John Wiley, New Jersey). iii. Joseph A. DiMasi, Ronald W. Hansen, Henry G. Grabowski. The Price of Innovation: New estimates of drug Development Costs. J. Health Economics 22 (2003) 151-185 and various comments since see www. csd.tufts.edu Estimates by Pharma increased the 2003 figure from $802m to $1.3bn. iv. Recent press reports from AstraZeneca following similar losses from Pfizer see www.astrazeneca.com/Media/ Press_releases/18032103 v. www.eve.exa.com/resources/ EGBS4_Kolchinsky.pdf vi. High Staff turnover found in CROs.

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Judy Canavan HR+ Survey reported in www.pmlive.com/pharma_news/high_ staff_turnover-found_in_cros_470905 vii. Keith J. Williams, Richard P. Bax. Challenges in the Development of New Antibacterial Drugs. Current Opinion in Investigational Drugs (2009) 10: 157-163. viii.Pedro Cuatrecasas, Drug Discovery in Jeopardy. J. Clinical Investigation Volume 116, Issue 11 (November 1, 2006)J Clin Invest. 2006;116(11):2837– 2842. doi:10.1172/JCI29999.

Dr. Keith J. Williams Keith is a Strategic Advisor and Project Manager at Boyd Consultants, which is led by Prof. Alan Boyd who offer high level strategic and operational support for early development projects. Clients include universities and biotechnology companies. He was previously a Global Project Director and Clinical Project Director at AstraZeneca, and is also a medical historian. Keith has a PhD and HonFICR, and has published widely in infection and product development. Email:keith.williams@boydconsultants.com

Co-Author Bryan Hurst Bryan has almost 30 years’ experience in drug development starting as a CRA before progressing to global project management. His experience includes all phases of drug development and latterly contributing to the development and operational strategy and project management of major drug developments including Merrem, Seroquel and Crestor. In addition Bryan has extensive experience in professional development and preparing and delivering training material for clinical research. Bryan has been successfully running his own project management and training consultancy company for the last 10 years and for the last 4 years he has worked in close collaboration with Boyd Consultants as a hands-on Project Manager. Email: bryan.hurst@boydconsultants.com

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Optimising Short-Lived Isotopes for Quantitative Whole-body Autoradiography in Drug Development Even the most reliable tools in the research laboratory can benefit from continued refinement. Radioisotopes have long been a dependable means for studying the absorption, distribution, metabolism, and excretion (ADME) of drug candidates in non-clinical studies. Over the years, new technologies have made better use of these radioisotopes. Quantitative whole-body autoradiography (QWBA), which has brought many improvements to the realm of tissue distribution, has itself been improved recently by the expanded use of short-lived isotopes. This expansion increases options for better imaging and more specific data regarding tissue distribution due to increased resolution of QWBA images as compared to PET or SPECT images. Radioisotopes in Tissue Distribution Radioisotopes, also known as radionuclides, are atoms with an unstable combination of protons and neutrons. This instability causes the atoms to give off radioactivity in the form of gamma rays or beta particles. Radioisotopes are common in daily life, finding use in smoke detectors (Americum-241), electric blanket thermostats (Promethium-147), and radio-carbon dating of dinosaur bones (Carbon-14). Certain radioisotopes are valuable in discovery, and non-clinical and clinical drug development, as a means of tracking how therapeutic molecules interact with biological systems. They can help researchers identify distribution or efficacy issues early in a compound’s development life, an issue that remains critically important as drug discovery and development becomes increasingly complex and expensive. Use of radioisotopes dates back to the 1920s, when George de Hevesy1, a Hungarian radiochemist at the University of Freiburg (Germany), conducted studies with radionuclides to study metabolic pathways in rats. A compound is tagged 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

with a radioisotope, administered to an animal or human, and studied by various means as it makes its way through the body, including how the compound is distributed in tissue. There are three common methods of determining tissue distribution of drug candidates with radioisotopes: • Tissue excision. After administering a compound to an animal model, entire tissues or organs are excised as a function of time, homogenised with water or buffer, and weighed aliquots of the homogenate are analysed. For gamma emitters, samples can be counted directly via a gamma counter. These samples are collected based on time points specified in the study protocol that are related to the pharmacokinetic profile of the therapeutic agent under study. This typically involves three animals per time point, for statistical relevance, with terminal necropsy required to excise the tissues. • Quantitative whole-body autoradiography. As the name indicates, QWBA provides a whole-body image that shows the tissue distribution of total radioactivity while distinguishing the regions of tissues or organs in which the radioactivity is found. Typically conducted with one animal per time point, animals are euthanised at specified time points and frozen in a hexane/dry ice bath. After freezing, the carcass is frozen in a block of carboxymethylcellulose (CMC) solution and cut into thin sections using a cryomacrotome. Sections that are approximately 40 µm thick are collected from the sagittal plane and captured on adhesive tape. Appropriate sections selected at various levels of interest are collected to encompass all major tissues and organs. By keeping the entire animal intact, discrete anatomic regions of tissues may be distinguished – kidney

medulla versus cortex, for example, or spleen red versus white pulp. Additional advantages include multiple data points within the same tissue or organ, lessened risk of contamination in sampling, and fewer animals needed. QWBA can be conducted in conjunction with other ADME functions, by collecting blood and excreta, for absorption and routes of excretion, or as a stand-alone procedure solely for tissue distribution. • Molecular imaging. Use of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are more recent developments. PET and SPECT provide three-dimensional images of how radioisotopes are distributed in tissues, as well as a complete time course for ADME in the same animal. Molecular imaging provides a good first look at tissue distribution of isotopes. Both imaging techniques are widely used in the medical field to study metabolic activity. Spring / Summer 2013 Volume 5 Issue 2


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Utility of Short-lived Isotopes The radioactive decay of an isotope is measured in half-life, the average length of time required for a substance to lose half of its radioactivity. This rate of decay can vary widely between isotopes, from milliseconds to millions of years. Carbon-14 (14C) – that of the aforementioned dinosaur bones – has traditionally been the isotope of choice for ADME studies because it has an exceptionally long half-life, some 5,730 years, and thus presents no risk of negatively affecting a study’s analysis due to loss of radioactivity through decay. Since the collection of meaningful data can be limited by a very short halflife, a longer half-life can be beneficial. However, 14C does have disadvantages. Because of its relatively low energy, more of the isotope is needed in order to supply measurable activity in the tissues. On the other hand, short-lived isotopes typically deliver a more concentrated energy signature in a shorter period of time. The shortened half-life of these isotopes greatly reduces disposal costs as they can simply be stored for 10 halflives, allowing the radioactivity to decay to background levels which can then be disposed of in the regular trash – after the appropriate confirmatory wipe tests. Most of these isotopes are used clinically and are relatively abundant. Of course, short-lived isotope is a relative term. (Carbon-14 is “short-lived”

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compared to Iodine-129, which has a half-life of nearly 16 million years.) For the purposes of this article, “short-lived” refers to isotopes with a half-life of days or hours. The ideal is to select an isotope that can be attached to a compound effectively, radiates at an adequate energy level to accurately determine tissue distribution, and has a half-life close to the time needed to complete the study. PET imaging can capture a single isotope type to a resolution of about 1.2 millimetres. PET is used in rodent models, with a typical dose of 250-500 microcuries (μCi) per rodent. SPECT is capable of imaging multiple isotopes to a resolution of about 0.8 millimetres, with models including rodents (typical dose up to 1.5 millicuries, or mCi) and nonhuman primates (up to 4 mCi). With the benefits of using shortlived isotopes in molecular imaging understood, expanding their use to quantitative whole-body autoradiography offers great potential in streamlining and improving non-clinical ADME studies. Optimised for QWBA The biggest challenge to using isotopes with shorter half-lives is time constraint. If study duration is longer than the marker’s half-life profile, the isotope will decay to levels of radioactivity below the limit of quantitation before the study concludes.

We began with an in vitro study using isotope-spiked standards to determine proper phosphor screen exposure duration for each isotope. Eight exposure time points were selected between two and 96 hours, with each isotope yielding varying results. Each isotope from each exposure was evaluated for variables such as background radiation, intensity of signal, and number of visible standards within acceptable ranges. After the evaluation, an optimal exposure duration was chosen for each isotope. The next step was in vivo studies involving rodent models, using QWBA in concert with PET or SPECT. When using short-lived radioisotopes, the QWBA process differs slightly from the standard approach. In both cases, animals are dosed and euthanised at a specified endpoint. Specimens are then frozen in a hexane/dry ice bath, blocked in CMC, and sectioned using a cryomacrotome. In the revised process, sections are collected at both 20μm and 40μm, with the thinner sections freeze-dried for 24 hours (as opposed to 36-48 hours in the standard process). Depending on the half-life and energy output of the isotope, the amount of radioactivity on a particular section should be balanced with how long it takes to freeze-dry. Phosphorimaging screen exposure time will vary depending on the isotope used. Care must be taken to manage coexposure with other sections; we used lead shielding between screen cassettes in a lead box to avoid contamination. The phosphor screen is scanned and an image is produced for analysis. INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


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For this in vivo stage, 123I (Figures 1a and 1b), 111In (Figures 2a and 2b), and 64Cu (Figures 3a and 3b) are used and each proved to have unique attributes that would prove useful in a variety of studies:

2b

Figures 1a and 1b: Uptake of 123I was found in the thyroid and stomach, with elimination via urine. Thyroid uptake was particularly large because no potassium iodide was added to the rodents’ water.* 1a

1b

3a

Figures 3a and 3b: Tissue distribution of 64Cu mostly involved the kidneys, liver, and gastrointestinal tract, with elimination via faeces. QWBA concentration data correlated extraordinary well with PET concentrations data.*

3b

Figures 2a and 2b: Post-dose images were taken at one, four, eight, and 24 hours, yielding quality images for 111In. Wide distribution was noted throughout the entire animal, with a large quantity of radioactivity found in the blood and kidney.* 2a

*

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Evolving Better Applications Traditionally, QWBA has relied on 14C, 3 H (Tritium), and 125I. Each of these longer half-life isotopes has its advantages; for example, 125I is frequently used in studying large molecules, and 14C remains a standard among long half-life isotopes. Now, given the positive results generated through QWBA and molecular imaging using short-lived isotopes, drug developers can expand the application of these tools to maximise data generation and reduce the number of animals used. To that end, we continue to identify and test isotopes to further equip the QWBA toolbox. To date, we have optimised 123I, 64 Cu, 111In, 201Tl, 99mTc, and 18F, meaning we have a complete picture of optimal exposure times and standard curves. We are now pursuing studies with 124I, Strotium-85 (85Sr), and Calcium-45 (45Ca), with an eye on testing other candidate isotopes as opportunities arise. Short-lived isotopes were once considered unsuitable for QWBA. As noted, time constraints have been the biggest challenge – a challenge that can be surmounted through careful avoidance of process delays and in the selection of isotopes based on the timeline needs of a particular study. This is where close communication between the various disciplines involved in a study is paramount so that the process is clearly understood and any anomalies can be identified quickly. Balancing the decay halflife of an isotope with the pharmacokinetic profile of the compound is important as

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well; a drug candidate with a longer halflife of elimination from the animal will either require an isotope with a longer half-life or a higher dose of radioactivity. Our research has shown that, with proper adjustments in the process, use of short-lived isotopes is quite feasible in this setting. Further, pairing QWBA with another molecular imaging modality can provide a “bigger picture” into the distribution of the compound being studied. Generating more data quickly, reliably, and cost-effectively is the mantra

of modern drug development. Enhancing the tools at hand, including more effective use of imaging techniques, remains an area ripe for innovative solutions.

Andrea Knapp, BS, is an Associate Research Scientist of QWBA services at MPI Research. Ms. Knapp received her BS in biology from the University of Wisconsin, Stevens Point. She joined MPI Research in 2009 and was instrumental in establishing the QWBA laboratory. Ms. Knapp started her career at Covance (Madison, WI), where she helped implement the safety pharmacology plethysmography technique and created a formal QWBA training and mentorship programme. She is a member of the Society for Whole-Body Autoradiography (currently serving as secretary and webmaster), the European Society of Autoradiography, and the Great Lakes Drug Metabolism Discussion Group. Email:andrea.knapp@mpiresearch.com

Brian Knapp, BS, is an Associate Study Director in ADME at MPI Research. Mr.Knapp received his BS in medical microbiology and immunology from the University of Wisconsin, Madison. Before joining MPI Research in 2008, he was a research assistant at Covance (Madison, WI) working in the in vitro, in vivo, and QWBA groups within the drug metabolism department. Mr. Knapp is a member of the Society for Whole-Body Autoradiography (currently serving as treasurer), the European Society of Autoradiography, and the Great Lakes Drug Metabolism Discussion Group. Email: brian.knapp@mpiresearch.com

References 1. N  obel Lectures, Chemistry 19421962, Elsevier Publishing Company, Amsterdam, 1964 2. Values provided by the Health Physics Society, North Carolina chapter, www.nchps.org

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Preactivated Thiomers: A New Generation of Mucoadhesive Polymers 1. Introduction Since the concept of mucoadhesion was pioneered in the early 1980s, various attempts have been made to improve the adhesive properties of polymers. These attempts include approaches such as mucoadhesion by a sustained hydration process, and the development of polymer–lectin conjugates and of polymer-bacterial adhesion conjugates. However, all these concepts are based on the formation of non-covalent bonds such as ionic interactions, hydrogen bonds and hydrophobic interactions providing only relative weak mucoadhesion. As a matter of fact, mucoadhesive polymers have in many cases not proven to be effective as ‘pharmaceutical glue’ in keeping drug delivery systems for a prolonged time period on target mucosal membranes. In the late 1990s a new generation of mucoadhesive polymers was introduced in the pharmaceutical literature1. Thiolated polymers – designated thiomers – were the first mucoadhesive polymers capable of forming covalent bonds. The bridging structure most commonly encountered in biological systems – the disulfide bond – was discovered for the covalent adhesion of polymers to the mucosa. Thiomers are polymers exhibiting thiol-bearing side chains. Based on thiol/disulfide exchange reactions and/or a simple oxidation process, disulfide bonds are formed between such polymers and cysteinerich subdomains of mucus glycoproteins mimicking the natural mechanism of secreted mucus glycoproteins that are also covalently anchored in the mucus layer by the formation of disulfide bonds. Meanwhile, there are more than 350 peer-reviewed research articles about thiomers available, demonstrating their potential both in vitro and in vivo. Drug delivery companies offer the development of thiomer-based formulations targeting mucosal membranes. Moreover, the first products based on thiomers such as chitosan-N-acetylcysteine eye drops (Effecoat®) for treatment of dry eye syndrome2 have already entered the market. 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Thiomers, however, are unstable, particularly in solutions and gels as they are subject to thiol oxidation at pH ≥ 5 unless sealed under inert conditions. This too-early oxidation of thiol groups prior to getting into contact with the mucus layer deteriorates the interactions between thiomer and mucus layer, substantially lowering their efficacy. In order to overcome this shortcoming, recently a second generation of thiomers – namely preactivated thiomers – has been established. 2. Mode of Action The concept for preactivated thiomers is based on principles of covalent chromatography, where, for instance, peptides and proteins exhibiting at least one cysteine subunit in their amino acid sequence are very efficiently linked to thiol-bearing resins, when they are preactivated via pyridyl substructures3. Pyridyl disulfides react very rapidly and quantitatively with sulfhydryl groups over a broad pH range to form disulfide bonds. During this reaction, a disulfide exchange occurs between the molecule’s –SH group and the pyridyl thiol group, i.e. the thiomer forms new mixed disulfides with the pyridyl thiol moiety as leaving group. Due to the toxic nature of the pyridyl leaving group, this technology, however, has so far not been applied for thiomers. By utilising nicotinamide (vitamin B3) instead of the pyridyl group, such toxic effects can be excluded4. 2-Mercapto-nicotinamide, for example, showed no cytotoxicity at all. If thiol groups of thiomers are entirely transformed to nicotinamidyl disulfides

as illustrated in Fig. 1, they will no longer be subject to oxidation. Consequently, preactivated thiomers are stable in solutions and gels over a broad pH range, providing a clear advantage over firstgeneration thiomers. Furthermore, based on theoretical considerations, preactivated thiomers are even more reactive then firstgeneration thiomers.

Figure 1. Schematic presentation of the mode of action of preactivated thiomers with the mucus gel layer

3. Mucoadhesive Properties The mucoadhesive properties of firstgeneration thiomers were verified by numerous research groups for various polymer backbones, showing even more than 100-fold improved mucuadhesive properties. Due to the immobilisation of thiol groups, the mucoadhesive properties of chitosan, for instance, were

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Figure 2. Comparison of the mucoadhesive properties of unmodified, with cysteine (Cys) modified thiolated and with 2-mercaptonicotinic acid (2-MNA) preactivated poly acrylates with an average molecular mass of 450 kDa (PAA 450 kDa) as determined by the rotating cylinder method. Thirty milligrams polymer tablets were attached to excised porcine intestinal mucosa, which was spanned on a vertical cylinder rotated with 100 rpm in 100 mM phosphate buffer pH 6.8 at 37 °C. The indicated time of adhesion represents an average of at least three experiments (± S.D.). Adopted from Iqbal et al.7.

improved 140-fold5. A good comparison and overview of the mucoadhesive properties of various mucoadhesive polymers and their corresponding thiolated versions is provided by Grabovac et al.6. Due to preactivation, the mucoadhesive properties of thiomers are significantly further improved. Iqbal et al. showed that the mucoadhesive properties of a polyacrylic acid-cysteine conjugate are even improved a further twofold, when the thiol groups of this thiomer are preactivated with 2-mercaptonicotinamide7. Results are illustrated in Fig. 2. Similar results were obtained for a thiolated chitosan, whose mucoadhesive properties were raised due to preactivation with Whether mercaptonicotinic acid8. this effect is exclusively based on the comparatively higher reactive thiol groups on the thiomer because of preactivation or additionally also on the exclusion of an oxidation of thiol groups before they can react with cysteine-rich substructures of the mucus gel layer, has so far not been investigated. Taking into account that preactivated thiomers are still not optimised regarding the type of polymer backbone, polymer chain length, type and degree of thiolation and type and degree of preactivation, their mucoadhesive properties will certainly be substantially further improved within 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the coming years. The development of comparatively much more efficient drug delivery systems providing, for instance, a prolonged residence time in certain gastrointestinal segments, or on the intraoral, nasal or vaginal mucosa, will likely become feasible utilising this novel technology. 4. Mucosal Uptake-enhancing Properties Mediated by mucoadhesion, an intimate contact between the drug delivery system and the mucosal membrane can be achieved, and consequently the drug can be released on the absorption membrane in a comparatively much more highly concentrated manner. The steeper the concentration gradient the membrane is on – representing the driving force for passive drug absorption – the higher is the systemic drug uptake. According to these considerations, mucoadhesive drug delivery systems can improve drug absorption. In addition, in case of oral drug delivery, a presystemic metabolism of therapeutic agents such as peptide drugs on the way between the delivery system and the absorption membrane can be excluded by mucoadhesion. But apart from improved mucoadhesive properties, thiomers also exhibit per se permeation-enhancing and efflux pump-inhibiting properties.

The permeation-enhancing effect is based on a thiol-mediated inhibition of protein tyrosine phosphatase leading to a reversible opening of tight junctions9. According to this mechanism, the paracellular absorption of drugs can be improved. In contrast, the efflux pumpinhibitory effect seems to be a result of a covalent attachment of thiomers in the channel-forming unit of efflux pumps such as P-gp via the formation of disulfide bonds10. These mucosal uptakeenhancing properties of thiomers have been demonstrated in various in vivo studies. The oral bioavailability of the therapeutic peptide antide, for instance, was tremendously improved by the coadministration of thiolated chitosan in pigs11. In another study in pigs, systemic uptake of the therapeutic peptide PACAP was only achieved when the peptide drug was intraorally applied together with a thiomer12. Worldwide, there are meanwhile over 50 different in vivo studies available demonstrating the strong permeation-enhancing and/or efflux pump-inhibitory effect of thiomers. Both the permeation-enhancing and efflux pump-inhibitory properties of thiomers are further improved by preactivation. Dünnhaupt et al. showed for the P-gp substrate rhodamine 123 a 4.1-fold improved membrane permeation in the presence of a thiolated chitosan. Utilising the preactivated version of this thiomer, however, led to a 6.7-fold improved absorption4. Similar results were obtained for liposomal formulations being coated with a preactivated thiomer13. As the permeation-enhancing as well as efflux pump-inhibitory properties of thiomers depend on the reactivity of their thiol groups, this further augmented effect of preactivated thiol groups fits very well in this concept. In particular for hydrophilic macromolecular drugs such as therapeutic peptides, DNA-based drugs and therapeutic polysaccharides, as well as for efflux pump substrate drugs, these mucosal uptake-enhancing properties are certainly advantageous. A proofSpring / Summer 2013 Volume 5 Issue 2


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of-principle could already be provided by Dünnhaupt et al. showing a 421-fold improved oral uptake of the peptide drug antide in rats, when the drug was co-administered with a preactivated thiolated chitosan14. Results of this study are illustrated in Fig. 3. 5. Conclusion Thiolated polymers – designated thiomers – were demonstrated to be the most mucoadhesive polymers available. As they are unstable towards oxidation, they exhibit limited storage stability, and their full mucoadhesive potential is in many cases not reached. These shortcomings led to the development of the second generation of thiomers, namely preactivated thiomers, being stable towards oxidation and exhibiting more pronounced mucoadhesive properties. Utilising these novel polymeric excipients will likely result in highly efficient mucosal drug delivery systems in the near future.

Figure 3. Plasma concentration curves of antide after oral administration of unmodified (♦) and preactivated thiolated chitosan (■) tablets as well as antide solution (+) of 8 mg/kg to rats. Indicated values are means ± SD of five rats; adopted from Dünnhaupt et al. [14].

References A, Schwarz 1. Bernkop-Schnürch V, Steininger S. Polymers with thiol groups: a new generation of mucoadhesive polymers? Pharm Res. 1999 Jun;16(6):876-81 2. http://bmctoday.net/ crstodayeurope/2011/12/article. asp?f=chitosan-n-acetylcysteine-eye-drops 3. Norris R, Brocklehurst K. A convenient method of preparation of high-activity urease from Canavalia ensiformis by covalent chromatography and an investigation of its thiol groups with 2,2’-dipyridyl disulphide as a thiol titrant and reactivity probe. Biochem J 1976, 159, (2), 245-57. 4. Dünnhaupt S, Barthelmes J, Rahmat D, Leithner K, Thurner CC, Friedl H, Bernkop-Schnürch A. S-protected thiolated chitosan for oral delivery of hydrophilic macromolecules: evaluation of permeation enhancing and efflux pump inhibitory properties. Mol Pharm. 2012 May 7;9(5):1331-41 5. Bernkop-Schnürch A, Hornof M and Zoidl T. Thiolated polymers – thiomers: modification of chitosan with 2-iminothiolane, Int. J. Pharm. 2003 260, 229 6. Grabovac V, Guggi D, BernkopSchnürch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev. 2005 Nov 3;57(11):1713-23. 7. Iqbal J, Shahnaz G, Dünnhaupt S, Müller 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

8.

9.

10. 11.

12.

13.

C, Hintzen F, Bernkop-Schnürch A. Preactivated thiomers as mucoadhesive polymers for drug delivery. Biomaterials. 2012 Feb;33(5):1528-35. Dünnhaupt S, Barthelmes J, Thurner CC, Waldner C, Sakloetsakun D, BernkopSchnürch A. S-protected thiolated chitosan: synthesis and in vitro characterization. Carbohydr Polym. 2012 Oct 1;90(2):765-72. Clausen AE, Kast CE, BernkopSchnürch A. The role of glutathione in the permeation enhancing effect of thiolated polymers. Pharm Res. 2002 May;19(5):602-8 Bernkop-Schnürch A and Grabovac V. Polymeric efflux pump inhibitors in oral drug delivery. Am. J. Drug. Deliv. 2006 4, 263-272. Bernkop-Schnürch A, Pinter Y, Guggi D, Kahlbacher H, Schöffmann G, Schuh M, Schmerold I, Del Curto MD, D’Antonio M, Esposito P, Huck C. The use of thiolated polymers as carrier matrix in oral peptide delivery--proof of concept. J Control Release. 2005 Aug 18;106(1-2):26-33 Langoth N, Kahlbacher H, Schöffmann G, Schmerold I, Schuh M, Franz S, Kurka P, Bernkop-Schnürch A. Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system. Pharm Res. 2006 Mar;23(3):573-9. Gradauer K, Dünnhaupt S, Vonach C, Szöllösi H, Pali-Schöll I, Mangge H, JensenJarolim E, Bernkop-Schnürch A, Prassl

R. Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties. J Control Release. 2013 Feb 10;165(3):207-15. 14. Dünnhaupt S, Barthelmes J, Iqbal J, Perera G, Thurner CC, Friedl H, Bernkop-Schnürch A. In vivo evaluation of an oral drug delivery system for peptides based on S-protected thiolated chitosan. J Control Release. 2012 Jun 28;160(3):477-85.

Dr. Andreas Bernkop Schnürch; Univ.-Prof. Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; Head of the Institute of Pharmacy; Chairman of the Department of Pharmaceutical Technology; Research Interests: mucoadhesive polymers; mucosal delivery of macromolecular drugs; nucleic acid delivery; peptide/protein delivery; efflux pump inhibition; oral drug delivery; Original Research Articles and Reviews: >250; Founder of the following companies: ThioMatrix GmbH; MucoBiomer GmbH; Green River Polymers GmbH; Email: andreas.bernkop@uibk.ac.at

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The Benefits of Bacillus-derived Hyaluronic Acid in Adding New and Improved Attributes to Existing Drug Formulations and Offering Opportunities for New Delivery System Development Hans Ole Klingenberg is Director for the Global Marketing group in Novozymes Biopharma. 1. Can you explain the potential of Hyaluronic Acid for drug delivery? Hyaluronic acid (HA or hyaluronan) is a natural, high molecular weight, linear polysaccharide composed of alternating N-acetyl glucosamine and glucuronic acid disaccharide units. HA is ubiquitous in human and animal tissues. It is found in the vitreous body, in the extracellular matrix of soft connective tissues, and in the synovial fluids. By supplementing the body’s level of glycosaminoglycan and providing water-binding, viscoelastic and biological properties, HA serves as a major ingredient in medical devices and pharmaceuticals. HA exhibits significant structural, rheological, physiological, and biological functions. These, coupled with its lack of immunogenicity and toxicity, make HA a very attractive carrier for drug delivery applications: 1. Due to its amphiphilic nature, HA forms a large coiled meshwork even at low concentrations that can be used for the solvation, stabilisation and entrainment of smaller molecules. 2. Specific HA cell receptors, namely CD44 and RHAMM, are upregulated on malignant tissues, where activation of the CD44 receptors within the tumoral environment mediates HA internalisation. 3. The relatively simple chemical structure allows HA to be modified to create a wide range of possible biocompatible and bioresorbable materials for use as drug delivery carriers. 4. HA is non-toxic and non-immunogenic and considered as biologically inert material by the regulatory authorities. The potential applications of HA in drug delivery can be segmented based on needs. These needs include targeted therapies, localisation of drugs, controlled 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

release of drugs and finally also use of HA for stabilisation of labile drugs. 2. The FDA, EMA and other regulatory bodies expressed concern about commercially available HAs traditionally used in osteoarthritis applications. Could you explain how Bacillusderived HA, or Hyasis, overcomes these issues? The popularity of animal-free ingredients is continuously growing. For example, regulatory authorities are beginning to enforce tighter quality controls on products used in ophthalmic applications to improve safety and minimise risk to patients. Traditional commercial sources of HA are primarily derived from either rooster comb extraction or various attenuated strains of Streptococcus bacteria. However, these sources can potentially result in contamination risks from animal-derived proteins, viruses or endotoxins. In addition, these sources of HA are purified using organic solvents, which pose further health issues to patients and make them a concern for regulatory agencies. Until recently, the course of a specific HA product has not been considered to be clinically important. However, with its growing use in health technologies and interventions, and the spotlight on potential contamination risks, demand is increasing for safer alternatives. The Bacillus-derived fermentation process for the production of HA has been developed to overcome both the manufacturing and safety challenges associated with animal-derived sources. Through this we use minimal medium, no animal-derived raw materials and a water-based technique, which removes the use of organic solvents at any stage during the manufacturing process. The Bacillus-derived fermentation process allows HA to be released from the cell naturally so it is able to achieve high levels of purity, as well as controlling the molecular weight of the end product. When HA is torn from a cell to extract it,

as with the Streptococcus fermentation process, it results in a heterogeneous mix of polymers without the ability to distinguish between high and low molecular weight. From the outset, it was essential that a technique was found to modify all elements of filtration including flow, process times and temperature, to enable a highly viscous polymer such as HA to be moved through a system, while at the same time removing impurities. It is true that in current clinical trials, the data in support of efficacy for HA in treatment of osteoarthritis does not show a very substantial effect versus placebo. However, there are likely to be many reasons for this, including the fact that the placebo treatments used are in fact not placebo (placebo is often a saline injection treatment, which is believed to help flush the knee joint of synovial fluid and inflammatory cytokines, thereby reducing inflammation and pain at least temporarily). It also follows from this that we today do not have any data to suggest that Bacillusderived HA, or Hyasis, can improve or change the treatment paradigm here, when it comes to efficacy. We do however believe that the high purity of Bacillusderived HA can support the opportunity to reduce the number of adverse events occurring in knee treatments, where there in some cases have been reports of increased swelling and sensitivity post HA injection (which may stem from the use of HA materials that are not pure enough). 3. What are the advantages of Hyasis in combination with active pharmaceutical ingredients (APIs)? HA can be combined with most APIs, including both small molecules and peptides or proteins. However, the compatibility will depend on the hydrophilicity of the API, HA being most compatible with hydrophilic compounds. One specific advantage of formulating HA with suitable APIs is the resulting slower-release time in an HA concentration-dependent manner. Spring / Summer 2013 Volume 5 Issue 2


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In the case of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) used in conditions such as acute injury and arthritis, experiment results showed the formulation without HA exhibits a complete release after ten minutes, which reflects a reasonable water solubility and a quick distribution in the dissolution system. By adding Hyasis to the formulation, the release time was extended to three, six and nine hours in an HA concentration-dependent manner. The slower release time is attributed to the increased viscosity of the formulations containing HA, resulting in a slower diffusion of the API. As a result, the diclofenac containing 3% HA showed a steady release profile with a 50 times slower release compared to formulation without HA. Another example of this can be seen in dexamethasone phosphate, which is a corticosteroid with an anti-inflammatory effect. Similar to diclofenac, the formulation without HA exhibits a fast distribution in the dissolution system, and a complete release was obtained after just ten minutes. The inclusion of

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HA in the formulation is again similar to diclofenac, where a complete release of dexamethasone phosphate is obtained after 9-10 hours when formulated with 3% HA. 4. Diclofenac and dexamethasone phosphate are highly soluble APIs. Could you explain how HA affects the sustained release of a poorly soluble API? Data indicates that the higher the hydrophobicity, the longer the release time using HA in its non-modified form. The exact release mechanism for poorly soluble drugs from an HA carrier is not known. However, factors including local retention of the drug at the site of injection, slow dissolution rate, polymer erosion and diffusion from the HA matrix may all play a role. 5. As both APIs are used in the treatment of osteoarthritis, could you evaluate the requirement for HA as a treatment option? Yes, it could certainly be considered

to combine HA and diclofenac as a combined treatment. Both are compatible with each other from a formulation perspective. The question is then whether this would lead to an improved therapeutic (the latter would need to be tested in clinical trials). 6. Could you explain the HA-based therapy for osteoarthritis? The exact mechanism by which HAbased therapies for OA are effective is not known. However, use of viscosupplementation with HA is believed to help improve the physiologic environment of the osteoarthritic joint and restore the shock absorption and lubrication properties of the synovial fluid. As a consequence, HA helps to “cushion� the joint and thereby reduce pain. Moreover, some studies have shown that the analgesic effect of viscous HA solutions is due to: (i) the ionic interaction of HA with positively charged Ca2+ channel activators; (ii) a detoxicating effect, i.e. the interaction of HA with the nociceptors or with pain-producing

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molecules, resulting in protection of the receptors by inactivation of these agents and in downregulation of the inflammatory response. 7. Arethe 1%, 2% and 3% concentrations of HA (% w/v) convenient for practitioners in offering good injectability? In general, the meta-analysis studies that have been done on HA osteoarthritis therapies have not been able to show any statistically significant difference between current marketed therapies, based on concentrations, number of injections or molecular weight. Hence it is not clear today that any one formulation is better than another. 8. What benefit does Bacillusderived HA offer to eye care? We have published a report highlighting the superiority of Hyasis for topical ophthalmic formulations, based on their physico-chemical and biological properties, tolerance and handling (including at industrial scale). Such solutions are expected to enhance tear film stability, to allow maximum comfort and to exhibit high residence time, while being biocompatible and easy to filter. As a result of its viscosity-enhancing properties, HA can be used as an efficient carrier for ophthalmic therapeutics. In this respect, Bacillus HA presents good compatibility with a variety of drugs such as ciprofloxacin, diclofenac and dexamethasone. Increased lacrimation and tear turnover following the application of ocular formulations most often lead to short precorneal residence time and, as a result, poor drug bioavailability. According to gamma scintigraphy, the precorneal residence time of Bacillus-derived HA is similar to that of Streptococcus-derived HA of higher molecular weight at the same concentration. Furthermore, the incorporation of HA in drug-containing ophthalmic solutions can increase drug retention in the tear fluid, along with drug contact time with the ocular surface, consequently improving drug bioavailability. The underlying mechanisms for drug retention are believed to be largely related to viscosity, bioadhesion (mucoadhesion) and physical attachment. 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

9. Looking ahead, what research is currently being conducted in this area, and how do you see the technology moving forward? There is certainly a lot of research effort to improve the performance of HA-based material for biomedical applications but also for drug delivery. With regard to OS, there is an attempt to increase the residence time of the injected HA in the joint to decrease the frequency of injections. Parameters such as the form of HA (hydrogel vs. particles), concentration, modification technology (e.g. degree of cross-linking), injected volume etc. are being tested to find the optimal combination. Finally, the use of HA as a drug delivery vehicle has not been fully exploited yet and tremendous research efforts are being conducted in this area and in the coming years will no doubt see an increase in its use.

Hans Ole Klingenberg is Director for the Global Marketing group in Novozymes Biopharma. Hans Ole has been with Novozymes for more than 10 years and has through his time at Novozymes held various positions in the area of corporate business development, with a focus on establishing new business entities for Novozymes in the biopharmaceutical industry. Hans Ole has since 2007 been working in Novozymes’ Biopharma business with a focus on marketing, and is commercially responsible for establishment of Novozymes’ new Hyaluronic Acid business franchise. Hans Ole has a background from Copenhagen University, with a bachelor in chemistry and master in economics. He is based in Denmark. Email: biopharma@novozymes.com Spring / Summer 2013 Volume 5 Issue 2


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Photostability Testing: Shedding Light on a Not Well Understood Guideline The subject of pharmaceutical photostability testing often raises many questions for several reasons. Predominantly governed by ICH Guideline Q1B for small molecules, or ICH Q5C for biotechnology products, the standards are not particularly well written and often cause confusion. Q1B, in particular, provides options to use two non-equivalent light sources and additional variants. The standard also mixes radiometric and photometric light measurements for the ultraviolet and visible light dosages. Following one of these options, which specifies the spectral power distribution of the light source, will require different exposures in order to conform to the guideline minimum requirements. This article will attempt to explain the guideline options available, and provide some practical guidance. ICH Q1B guideline “Photostabililty Testing of New Drug Substances and Products”1 was introduced in 1997 and has provided necessary guidance to pharmaceutical applicants about the regulatory requirements for photostability testing. It has provided a valuable framework for harmonising global laboratory practice, and provides a sequential approach when identifying protective packaging requirements for photosensitive pharmaceutical products. It also contains a forced degradation provision to help validate stability indicating assays. Prior to the introduction of the guideline, photostability protocols varied considerably with regard to the types of photolysis sources and their spectral characteristics, specimen presentation, exposure duration, etc. Exposures often vary by several orders of magnitude, making comparative studies difficult. The adoption of Q1B set minimum requirements for test protocols and duration, and comprises one element of a larger set of environmental stability testing guidelines, and has been adopted by the majority of pharmaceutical producing country regulatory bodies. 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

However, the Q1B document is not without its critics. At a high level it primarily pertains to the photostability of active pharmaceutical ingredients (API) and manufactured final pharmaceutical products (FPP) and does not address the photostability of a product under inuse conditions. It also does not address specific photochemical characteristics or quantitatively determining rates of photochemical degradation. At a practical level the vagueness of the language, and the mixing of scientific and lay terms - which are either unfamiliar to the pharmaceutical laboratory or not used in photochemistry - to describe the radiation output can lead to misunderstanding. The implication is that the various photolysis source options are technically or effectively equivalent, which is not the case.

Terminology of Photochemistry To better understand photostability testing a brief guide to photochemistry terminology is useful: • The photolysis source provides the flux (optical power). º

º

Radiant flux is a radiometric unit of the total rate of emitted radiation from the source and is expressed in watts. Luminous flux is similar, except that it is a photometric unit of visible radiation only, as viewed by the spectral sensitivity of the human eye, and expressed in lumens.

• Irradiance is the total rate of energy (radiant flux, all wavelengths) incident upon a given surface area and commonly expressed in W/m². • Illuminance is analogous to irradiance

but only for the visible region of the spectrum, and is expressed as lumens/m², or more commonly, lux. • Spectral irradiance is irradiance expressed at a specific wavelength or integrated over a range of wavelengths, (e.g., 320-400nm), usually expressed as W/m²•nm where the wavelength(s) is (are) specified. • Spectral Power Distribution (SPD) refers to a continuous plot of the wavelengths over a specified range versus the irradiance at each point, and is useful for visualising or comparing the source spectral output. • Dose is the measured irradiance or illuminance over time. For example, the Q1B 200 W•h/m² UV (320400nm) minimum dose would be achieved with a spectral irradiance of 20 W/m²•320-400nm for 10 hours. Following Newton’s inverse-square law, this holds true for point sources or for specimens greater than five times distant than the diameter of the source. ICH Q1B Exposure Dose The guideline sets required confirmatory testing minimum doses for the UV and visible light exposures. Note that these are dose minimums and not exposure endpoints, so “overexposure” is technically not possible. In fact, as the majority of photolability issues can be resolved with appropriate packaging, a common practice is to expose to 5-10X the ICH confirmatory minimums and first determine if there is a potential stability problem. If photolability is found, further studies may be implemented to identify the amount and rate of photodegradation. The developers of the guideline assumed that light exposure could occur anywhere during manufacturing, packaging, warehousing and distribution, or in a pharmacy or home setting. Light sources would most commonly be various types of fluorescent lamps, indirect sunlight filtered through window glass, or a combination. The product should be expected to withstand a minimum of: Spring / Summer 2013 Volume 5 Issue 2


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• Three months of continuous exposure to visible light without protective packaging, as a 90-day supply could be transferred to a nonprotective package. This exposure was estimated to be at 500 lux (about normal office lighting) for 24h x 100 days = 1.2 x 106 lux•h. • During this same time, indirect sunlight filtered through window glass was estimated at 200 W•h•m² (~320-400nm), roughly the equivalent of 1-2 days of windowsill exposure where the glass attenuates the lower wavelength UV.

As photon energy is inversely proportional to wavelength, the lower UV cut-on and higher low wavelength spectral irradiance of D65 compared to ID65 (Figure 1) can be significant in terms of photolytic effects. Although either SPD is permitted in Q1B for confirmatory studies, the results may be dissimilar. Note that the key point is that both UV and visible exposures are conducted simultaneously under one full spectrum source.

variation between sources, however. The source for visible light is “cool white” fluorescent as specified in ISO 10977, although window light does contain visible wavelengths not found in cool white lamps. These two fluorescent lamps may be used in combination or in sequential exposures. Depending on the manufacturer, however, there may be an emission gap between the two sources

In order to provide these conditions, while providing testing flexibility, the guideline provides for two laboratory testing options using different photolysis sources. Option 1 and Option 2 Sources for Confirmatory Requirements Option 1 sources may be xenon or metal halide arc discharge lamps that are appropriately filtered, or “full spectrum” fluorescent lamps providing both UV-A/ UV-B and visible energy to provide a D65 (outdoor daylight) or ID65 (behind glass indoor daylight) SPD. In practice, however, fluorescent lamps of this type are difficult to source and the UV content ratio in specific wavelength bands can vary. Likewise, metal halide lamps providing the proper spectra are also limited. Therefore, optically filtered long arc xenon lamps are predominantly used; they have a high-fidelity spectral match to D65 and ID65 sunlight and are the “gold standard” for simulating sunlight.

Figure 1. Comparison of xenon arc SPD for D65 and ID65 requirements.

Option 2 radiation sources attempt to mimic indoor (fluorescent) lighting conditions of a windowed room. This is provided by two separate fluorescent sources. The one for UVA emission is to have a spectral distribution from 320400nm with a maximum energy emission of 250-370nm, with a “significant” portion of the UV in both the bands 320-260nm and 360-400nm. The term “significant” may lead to considerable

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between 390 and 430nm. If this is the case it is important to verify that the API or drug substance does not absorb in this region to avoid an incorrect test result. A dichotomy exists in meeting the specified SPD and the exposure durations required to attain the minimum confirmatory requirements for UV and visible. For an Option 1 xenon source, the 200 W•h•m² (~320-400nm) dose corresponds to about 0.45 million lux•h of visible radiation. Therefore exposing to 1.2 million lux•h would result in exceeding the UV minimum by a factor of 2.5 to 3 times by using D65 or ID65 sources respectively. The “overexposure problem” can be avoided in one of two ways in Option 1: • Exposing two sets of specimens simultaneously, removing the first set when the UV minimum is met, and the second when the visible exposure minimum is met. Of course both specimens receive the full spectrum, but for different dose minimums. ICH does not require that the UV and visible exposures be separated; in fact, using Option 1 they can’t be separated. Spring / Summer 2013 Volume 5 Issue 2


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• Combine Option 1 and Option 2. Use an Option 1 source for the UV confirmatory minimum and Option 2 cool white fluorescent for the visible. Another possibility is to use appropriate UV cut-on and cut-off filters between the Option 1 source and the specimens to isolate the UV and visible exposure bands. While this may be possible for small individual specimens, it is not practical for the larger area of a typical exposure chamber. However, the use of sharp cut on or bandpass filters may be useful for determining the actinic wavelengths responsible for photodegradation. Irradiance Levels, Exposure Time and Dose Another aspect of Q1B is that the irradiance levels are not specified, only the radiant energy dose. However, high irradiance levels can alter the degradation response of the product if reciprocity is not obeyed. Fluorescent lamps can be operated over a relatively narrow power and irradiance range, although the number of lamps can be increased or the distance to specimen decreased to provide higher irradiance. Xenon arc lamps can be operated over a wider power range, but the infrared heating effects become disproportionately larger. In general, Option 1 xenon sources are higher output and result in relatively short exposure times, often as short as 3-9h for the minimum confirmatory UV requirement, or 7.5-22h for the visible exposure, by varying the irradiance. Forced Degradation Requirement While the minimum confirmatory requirements for UV and visible exposure may seem confusing, the forced degradation requirement is more straightforward, though less defined. The Q1B guideline has a sequenced structure with a flowchart and qualified exit points. This leads the researcher through testing requirements first with the API and then, if needed, to the API with excipients through to product with packaging. The guideline also specifies retest requirements, such as a change in synthesis or plant. The result helps determine any protective packaging requirements to prevent photolability resulting in toxicity, loss of efficacy or physical changes such as dissolution or friability. 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Forced degradation, on the other hand, attempts to force the API or FPP to degrade by any means necessary. For photostability, performing testing to 5-10X the confirmatory minimums often serves this purpose. Sometimes more extreme measures are required. This may include performing the more severe D65 rather than the low UV-filtered ID65 source tests, or using other photolysis sources. The main purpose is to achieve some degradation, then to validate the ability of the stability-indicating assays, such as HPLC, to detect the change. Due to minimum detection levels or interferences, a sufficient level of degradation products need be created to validate the assay method (5-15% API loss is often used). However, care must be taken when degradation is forced using wavelengths more damaging, such as UV-C germicidal lamps, as this may force degradation mechanisms that would not occur under normal conditions. An important aspect of validating the assay method is the concept of mass balance, where a decrease in the API must be accompanied by a reasonable accounting for the mass of the degradation products. Loss of API without detecting degradants is of limited value. If using Option 2 or Option 1/ID65 sources for confirmatory testing, switching to D65 is usually a reasonable

technique as direct sunlight exposure can occur in the real world. Other Considerations for Testing Option 1 sources generally provide more specimen heating effects than Option 2, especially at higher irradiances. With both options, a “dark control” specimen (e.g., wrapped in aluminum foil) shielded from light is recommended during exposures. The guideline specifies “room temperature” testing, but in practice most chambers provide some specimen heating. The confounding effects of temperature (and, in some instances, humidity) can then be evaluated relative to the light-exposed specimens. Sometimes the higher near-infrared wavelengths present in xenon sources may cause “greenhouse effect” heating of sealed specimen containers, so some air exchange should be permitted. The higher chamber cooling airflow requirements of Option 1 sources may also be problematic when testing powders. Powders should be maintained at a controlled depth during exposure, covered with appropriate UV transmitting quartz, for example. This will allow uniform sampling of a degraded surface relative to the bulk material; some commercial powder testing apparatus are available for this purpose (Figure 2).

Figure 2. Example of powders and tablets under Option 1 exposure. Spring / Summer 2013 Volume 5 Issue 2


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The spectral transmittance of any specimen container is an important factor, especially for the UV exposures. Many common glass vials and some plastic foils do not transmit low wavelength UV. Liquid specimens should usually be tested with as large an exposed surface area and short path length as is reasonable, like powders, to account for the BeerLambert Law. FPPs should be tested in their final dosage form as well as in final packaging. Specimen containers should be positioned so as to avoid shading or reflective effects, and special care should be taken regarding container closures shielding the specimens. Commercial Photostability Chambers A number of testing chambers are commercially available. These vary in photolysis source, optional optical filtering, thermal and humidity control, irradiance control and geometry. Regardless of design, the user should be aware of spatial variations in spectral irradiation (and temperature) and verify through mapping studies; some chambers have considerable variability near the edges and corners. This may be accomplished with a radiometer or spectroradiometer with a positionable sensing head. A calibrated luxmeter may be used for the visible range, but neither it nor a UV filter radiometer is suitable to obtain an absolute measurement of the irradiance, or to compare irradiance between sources. Various sources, while appearing continuous in output, may be driven by square or sine waves, or rapidly pulsed; unless calibrated for the specific light source, erroneous readings may result. One should always consult the source manufacturer for proper measurement and calibration techniques. Many chambers have an integral measurement or control system to provide the proper irradiance. The use of chemical actinometers, such as quinine hydrochloride, is problematic2 and should probably be avoided, especially with Option 1 sources. Some photostability exposure apparatus are equipped with active cooling to mitigate temperatures, a consideration when testing thermally labile compounds such as biotechnology products (Figure 3). A Note on ICH Q5C The primary difference between ICH Q1B for 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3. A commercial Option 1 photostability chamber with auxiliary cooling system for thermally labile specimens.

small molecules and Q5C3 for biotechnology products such as peptides, proteins, monoclonal antibodies, etc., is the lack of a confirmatory minimum requirement. Many of these products are light-sensitive, such as protein disulfide bond linkages, which can lead to loss of conformation and bioactivity. In essence, only the forced degradation requirement, and subsequent stability assay verification, is required.

Conclusion The ICH Q1B guideline is the principal document governing photostability testing. It is, however, an imperfect one and can result in some confusion, especially regarding the choice of Options 1 or 2 light sources and their equivalence. Further, the measurement of irradiance and timing of exposures is often a source of confusion. Hopefully these, and others, will be addressed in future revisions. In the meanwhile, the Q1B guideline, and

its Q5C corollary, provide a reasonable structure for testing to ensure that potential pharmaceutical photostability issues are suitably managed. References 1.

International Commission on Harmonization, ICH Guideline Q1B, Stability Testing: Photostability Testing of New Drug Substances and Products, Nov. 1995. 2. Baertschi, S., Alsante, Tønnesen, H. A critical assessment of the ICH guideline on photostability testing of new drug substances and products (Q1B): Recommendation for revision, J.Pharm.Sci, Vol. 99(7), Jul 1 2010. 3. International Commission on Harmonization, ICH Guideline Q5C Stability Testing of Biotechnological/ Biological Products Allen Zielnik is a Senior Consultant within Atlas Material Testing Technology’s Global Consulting Group. He has been with Atlas for 19 years. Prior to Atlas his career spanned 19 years with analytical instrument companies, principally in pharmaceutical chromatography and spectroscopy. He is a frequent conference speaker and has authored over 100 publications. Email: al.zielnik@ametek.com.

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Patient Recruitment Driving Length and Cost of Oncology Clinical Trials As prospective oncology drugs progress from Phase I to Phase III clinical trials, the difference between projected and actual patient enrolment durations typically increases. In most cases, oncology clinical trial delays are a direct result of patient recruitment challenges. This is particularly true when multiple companies run competing clinical trials, an increasingly common situation. Oncology research is the most active therapeutic area, with 10,303 drug programmes in process, accounting for 18% of all development programmes, according to BioPharm Insight. Cutting Edge Information’s study, “Oncology Clinical Trials: Drug Development Resources and Case Studies,” found that across all phases of oncology clinical trials, the two main factors impacting duration are the level of difficulty of trial-specific patient recruitment and the number of patient visits required by a trial. Patient recruitment difficulties have become widespread as companies struggle to meet their trial enrolment targets. If a particular therapeutic area is already competitive, with a number of companies performing similar clinical trials, enrolling patients becomes even more challenging. Depending on how competitive a specific indication is, many potential patients may already be participating in other investigative trials. In regions with more available treatment options, patients may favour current standard of care regimens above investigative trials. Patient recruitment may be less challenging in regions where clinical trials may represent one of only a few cost-efficient treatment options available for patients.

a harder time developing participant criteria during Phase I — which explains patient recruitment difficulties present during some of the Phase I trials that Cutting Edge Information studied. By the time a compound enters Phase II investigative trials, companies have better refined and streamlined their enrolment criteria. The number of patient visits required by investigative trials also influences the duration of profiled trials across Phases I, II and III. For trials requiring multiple patient visits, the amount of time trial participants must wait before undergoing additional monitored visits may skew the actual trial duration. Increased Duration, Increased Cost Clinical development groups continue to dedicate the considerable resources necessary to bring investigational treatments to market — and considerable may be an understatement. Based on the trial data that Cutting Edge Information collected, advancing an oncology treatment through Phase I, Phase II and Phase III clinical trials costs a combined average of $56.3 million and eight years. These data do not include time spent in pre-clinical testing and regulatory filing that add to both development cost and time.

On the surface, Phase III trials are much more expensive than Phase II trials. In one study, the average total cost for Phase III trials ($41.7 million) stood four times higher than the average cost for Phase II trials ($10.2 million). But much of those cost differences are the result of the larger patient enrolment required during Phase III. On a per-patient basis, Phase III trials cost only 7% more than Phase II trials, according to interviews for a recent benchmarking study. As oncology products successfully progress through each stage of clinical development, the stakes grow higher and higher. Theoretically, a drug failure in late-stage trials is exponentially more costly than an early-stage failure. The pharmaceutical company not only loses the monetary investment made in clinical research, but also the opportunity to invest in other pipeline candidates. Significant Variation Across Indications During Phase I and Phase II trials, oncology clinical trial durations average 27.5 and 26.1 months, respectively. The longest trial durations during these phases fall between 48 and 50 months. By comparison, the average length of a Phase III trial, according to surveyed trial

Average Trial Duration by Phase Phase I trials averaged a 7.8-month delay between projected and actual end dates. Phase II trials reported an average of a 5.1-month delays and Phase III reported 6.4-month delays. Companies may have 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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profiles, is approximately 41 months; the longest Phase III trial topped 81 months. More common diseases such as breast cancer and prostate cancer have been studied extensively and the pharmaceutical industry has made significant breakthroughs, including 188 and 99 approved treatments in both indications, respectively. Developing treatments for other types of cancer has proven more challenging — particularly liver cancer and melanoma, which only have 11 and 15 approved treatments respectively. But the pharmaceutical industry seems up to the challenge with a host of promising drug programmes being tested in those areas of critical need. Melanoma has 158 active drug programmes in either Phase II or Phase III testing, while liver cancer has 92 drug programmes in late-stage testing. Another highly active area of oncology research is solid tumours, with 845 active drug programmes. The total cost of an oncology trial varies greatly depending on the specific indication, required medical procedures in the protocol, and location. One Phase III trial reported a total cost of $88 million, while another Phase III trial reported a cost of only $3.4 million. The most obvious factor that sets these two trials apart was a difference in patient enrolment of approximately 700 patients. The number of patients enrolled is the greatest driver of overall trial cost, according to Cutting Edge Information’s study. To more accurately compare the 29 oncology trials examined in this report, analysts relied heavily on metrics such as per-patient trial costs, patients per clinical research associate, and patients per site. Patient Recruitment Challenges Oncology clinical trials’ patient recruitment difficulties are not caused by a lack of patients. The US National Cancer Institute estimated that, in 2012, there were 1.6 million newly diagnosed cancer cases and a total of 577,000 cancer deaths in the United States alone. These numbers grow several times higher when the rest of the world is included. Incidence rates of prostate cancer in US men have risen to 1.4 for every 1000; a commonly held theory asserts that one out of every nine women will develop breast cancer at some point in their lives. Patient recruitment goals are achievable 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

because the disease state is so prevalent: 1,756 solid tumour trials were registered in the United States from 2003 to 2012. Depending on the specific area of oncology being studied, some targeted patients may already be participating in other clinical trials. In the areas where there are more available treatment options, patients may prefer the current standard of care as opposed to unproven investigative clinical trials. Cutting Edge Information found that drug companies can lessen the patient recruitment challenge in geographic areas where clinical trials are one of the few low-cost treatment options available for afflicted patients. Patient recruitment is easier for Phase I oncology trials because trial protocols generally require fewer patients, and the combination of cancer patients and healthy volunteers makes recruitment easier, yet. Phase II and Phase III trials have much smaller patient groups at each investigator site. The requirement of patients with a very specific disease state slows patient recruitment, causing trial managers to depend on more sites to reach enrolment targets. Although average overall enrolment is much greater for these later-phase trials, enrolment is spread over many more sites. The ratio of patients to investigator sites is a revealing metric in comparing

trial phases. Cutting Edge Information’s research shows a strong correlation between number of patients and number of sites (correlation coefficient = 0.85). Fewer sites with larger patient groups are characteristic of Phase I trials while Phase II and Phase III trials tend to have more sites with fewer patients at each. These metrics are useful to trial managers deciding how many sites a trial will need to reach the target patient enrolment. Patient Recruitment Strategies Working in the healthcare industry’s favour is that patients’ altruistic feelings drive many of them to participate in clinical studies. One company surveyed by Cutting Edge Information conducted a survey of its patients and found that 90% of patients who have participated in clinical trials would do so again. The challenge is to gain access to these willing participants. To do this, it is crucial that trial sponsors diligently evaluate sites and build strong relationships with highperforming investigators. Using CROs or large networks of clinical trial sites can open the door to the desired patient populations. Performing patient demographic research can aid in site selection and protocol design, ensuring the best chance for recruitment success. Evaluating patient populations can both pinpoint Spring / Summer 2013 Volume 5 Issue 2


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geographic concentrations of disease and improve the diversity of trial sites to better meet regulators’ requirements. Other market research can allow a trial manager to accurately identify which motivators will work most effectively; for example, what might motivate a senior citizen is likely not the same for a 19-yearold. Likewise, different reimbursement and communication tools may motivate patients in densely populated areas and rural settings. A keen understanding of patient demographics can aid trial protocol designers in both motivating participation and improving retention. One successful strategy is to design trials that will make participation easier and more convenient, such as requiring fewer return visits and allowing for some treatment follow-up by phone. These techniques are simple and inexpensive to implement, and they protect the study from losing its most valuable asset: patients. Nevertheless, patient recruitment strategies and motivators also present challenges. Successful patient recruitment requires an investment of time and money that many drug companies rarely consider when setting a study budget. To save money, sponsors may choose to skip important aspects of the recruitment process, including patient demographic research. The same occurs with patient retention strategies; once patients are recruited, study sponsors may think the job is complete. But extra investment during the patient recruitment and retention phases rewards forward-thinking trial managers. Taking adequate time to evaluate sites and spending money on additional tools will speed patient recruitment, eliminate delays, help to meet target enrolment and, in many cases, save money. Other Cost-saving Strategies In an effort to save money, many companies have turned to contract research organisations (CROs) for a large portion of their clinical trial activities. But these cost-savings occur because CROs have developed highly efficient clinical operations. CROs have collected performance measurements on clinical trial operations for years, and the drug companies have caught on. Now the average clinical trial tracks 14.6 performance metrics. Along with these rising costs, companies are increasing www.ipimedia.com

the percentage of their clinical budgets allocated to outsourced organisations. One contributing factor is a move toward more full-service clinical vendors. Fullservice vendors allow companies to minimise internal FTE contribution and avoid over-resourcing during clinical downtimes. Despite the trend of increased outsourcing, companies have found ways to limit outsourcing while continuing to reap the benefits by building internal CROs. Another solution that several drug companies at the forefront of clinical efficiency have explored is adaptive clinical trial design. Adaptive design allows clinical teams to adjust the parameters of a trial midstream, shifting patients and resources to treatment arms with greater probability of success. Although the concept of adaptive design has been around in different forms for several years, an FDA guidance set forth in 2010 finally addressed some of the life science industry’s key questions on the topic. Despite the guidance, drug companies’ apprehensions remain, preventing the industry from widespread adoption of this efficient clinical technique. A more widespread adoption of adaptive design into clinical trials is held up by three main obstacles: statistical challenges, operational challenges and executive-level acceptance. The statistical and operational challenges can be solved with rapidly advancing technologies that allow clinicians to avoid introducing bias into their studies. Finding acceptance, however, is still a work in progress. Adaptive design is a marked departure from the tried-and-true clinical trial design, leaving pharma executives cautious about implementing it into expensive and critically important latestage trials. Instead, pharma is more comfortable applying adaptive design to early-stage trials, where companies can more easily mitigate risks. The FDA’s guidance provided a loose framework within which late-stage registration trials could successfully use adaptive design. But until some high-profile, successful registrations occur, the industry will continue to be lukewarm to the practice. Many clinical development groups still suspect that the FDA, despite its encouragement, is less likely to approve a drug studied under an adaptive design protocol.

There is, however, strong incentive for pharma to expand the use of adaptive design in all phases. When implemented properly, adaptive design offers many advantages. It can cut down trial costs by helping investigators realise that a drug will likely be unsuccessful, allowing the decision to terminate trials early. It can also get drugs to market faster, extending the critical time a drug has to generate revenue. Adaptive trial design allows investigators to make important adjustments to an ongoing trial that could improve the trial’s probability of success and/or approval. But the scope — and indeed the very existence of these advantages — depend on numerous variables. The one consistent, reliable advantage offered by adaptive design is saving time. By allowing investigators to make better choices about treatment arms, dosage levels and sample size, adaptive design can bring a trial to conclusion several months earlier than a traditional trial design would allow for. Even if the company terminates the trial early, the sponsor is still saving time that would have otherwise been wasted on an unsuccessful endeavour. The time saved can be significant; survey respondents reported saving as much as one year on trial duration through the use of adaptive design.

Adam Bianchi serves as Cutting Edge Information’s chief operating officer and has provided support for pharmaceutical executive decision-makers for over 15 years. Email: adam_bianchi@cuttingedgeinfo.com

Ryan McGuire is a research team leader with extensive knowledge of the clinical development and medical affairs functions.

Rochelle Gagg is a special projects coordinator supporting the company’s thought leadership and commercialisation efforts.

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LABS & LOGISTICS

Ambient Temperature Profile Development: A New Approach for Qualifying and Defining a Shipping System’s Performance When developing an ambient profile for a temperature-controlled packaging solution to be qualified against, every Temperature Control Packaging (TCP) user has their own views on the best way to create a profile that accurately reflects a distribution process. Overall, each reaches the end result by a different method, meaning that companies often end up with very different ambient temperature profiles from each other. But shouldn’t all profiles be created in the same way? Why do they differ so greatly? And is it actually possible to have one universally accepted formula, which could be used to help standardise the process? Richard Wood from DS Smith Plastics Cool Logistics discusses this burning issue. The design and development of a packaging solution to manage products that require a temperature-controlled environment during transit, depends upon a comprehensive understanding of the distribution territory and challenges it could face during its journey. This knowledge will not only maximise the packaging’s performance and minimise cost, it will maintain the quality of the product being shipped. In order to build this picture, many healthcare companies collect temperature data and may take information from identical environments, on matching routes, with the same transportation method - but end up developing completely different ambient profiles. This is because there are many methods for establishing profiles, ranging from empirical analysis (direct or indirect observation or knowledge) to theoretical models (such as geography or historical weather data). When taking into consideration geographic zones, seasonal variance and anticipated temperatures throughout the shipping process, many TCP users lack sufficient evidence-based temperature data within their supply chain. This can hinder the development of a profile or 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

may lead engineers to adopt a ‘worst case’ approach; planning to extreme geographic ambient highs and lows. The use of a ‘worst case’ methodology in the design of TCP leads to ultimately increasing the packaging size and logistics spend. This is because it requires a higher level of thermal performance to overcome the external ambient stress in order to sufficiently protect the products being shipped. As a result, the added materials lead to heavier, larger systems, higher costs and increased freight spends.

what constitutes the ‘right’ method for creating an ambient temperature profile for any given shipper.

A Pivotal Role Indeed, successful product distribution for today’s complex global healthcare industry begins with the sophisticated design and configuration of TCP, which ensure that the products inside maintain their efficacy during transportation. As such, creating an ambient temperature profile is no trivial matter, and is actually the most important factor when TCP manufacturers test their shippers for a customer. Ultimately this relationship between time and temperature is designed to replicate what the shipping system may be exposed to in a real world transit. It lays down the building blocks for the design and dictates how much phase change material the manufacturer has to put into a shipper to absorb the heat energy that it is exposed to on its journey. The development of a realistic profile is essential in ensuring the right packaging solution is devised to maintain the correct temperature control that these products require. But, there are many views on

configuration of energy-absorbing phase change materials, the TCP may not offer the required level of thermal protection for the duration of their journey, which could result in temperature excursions within the packaging payload and could compromise the temperature-sensitive product’s quality and efficacy. It stands to reason that the more challenging the profile, the more robust the packaging needs to be, but as previously mentioned, the availability of ‘real-world’ data needed to create ambient profiles varies considerably. For example, when regularly shipping along predefined distribution lanes, such as Europe to America, there is an abundance of temperature data to support the way in which an ambient temperature profile is designed. However, when creating a profile for less familiar routes, such as Europe to remote parts of Africa or the Asia, TCP users often work with their TCP vendor to build an ‘ambient challenge’ that they feel will satisfy the new route.

Understanding the Challenge Professionals who design and qualify TCP solutions for healthcare products continually face a multitude of challenges in developing systems that suit the many demands of a distribution route. Exposure to extreme temperatures needs to be taken into consideration and can impose a significant hazard. Without the correct

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Building the Picture The largest user of TCP with the least amount of variability within the distribution channels includes the large pharmaceutical product manufacturers. When transporting products from the main manufacturing site to a predefined distribution hub, the shipping lanes are well mapped for times and temperature, plus the freight service is of a high standard. On these routes, it is possible to control certain temperatures; for example, packages could be stored in a controlled room temperature environment or a refrigerator. Likewise on flights, temperatures that the aircraft hold is controlled at can be prescribed, so therefore this distribution model faces a ‘lesser challenge’ in the industry. The next stage of the route (from the distribution hub into clinics, pharmacies and hospitals) becomes a bit more challenging. While the duration of the shipment may be shorter, as delivery may be within the same country, the variables become a lot more inconsistent. For example, it could be transported via a standard delivery network, in a truck or van, where temperatures could vary if it is curtain-sided or has a solid wall and/or air conditioning. So this is where a shipper perhaps needs to have more robustness built into it, because there are more variables involved. However, it is the clinical trial sector that faces the biggest challenge of all TCP users. This is due to the fact that clinical trials for particular products have to be conducted in extremely remote areas of the world in order to assess ‘naïve patient groups’ who haven’t already been exposed to certain types of pharmaceutical products. It is on these distribution routes that some of the greatest ambient temperature profile design challenges are faced. Here, it is not just the time duration of getting clinical trial material from Europe into countries such as West Africa or Africa, which generally speaking could take around 48 hours. One of the main issues faced is its management during customs clearance, where it could be held (and potentially mis-managed) for up to a week.

industry standardisation. Standards organisations have attempted to address this issue by developing generic ambient profiles, whose objective was to function as a universal test profile for insulated shipping systems. Whilst these projects have been run in partnership with several pharmaceutical companies, packaging suppliers and global logistics providers in order to conduct this study, unfortunately these profiles have not fulfilled the demands of all regions. This meant that ultimately, the shipper designs were not robust enough or were over-engineered for the particular purpose they served. Historically, these organisations that have created a ‘one size fits all’ approach to developing an ambient profile have always focused on the external temperature and the duration of the shipment. This information is then used to build an ambient challenge for a shipper to be qualified against. However, this puts forward the question of whether we are looking at this the wrong way, and is it indeed possible to challenge

this method with a new, completely different approach? Instead, rather than focusing on what could be happening outside the shipper, why not look at the capabilities of the shipper itself… A Different Approach By using new virtual development design tools such as Multi-Physics (MP), which are beginning to be adopted by the industry, we can assess the energyabsorbing capabilities of a TCP system and match it to the average thermal stress that is going to be experienced during a distribution process. This can be applied to any region in the world and, based on certain key parts of information being made available by the industry, in theory perhaps offers a new way of looking at qualifying and defining a shipper’s performance. Firstly, by obtaining the temperature lane data and understanding the heat/ thermal challenges faced whilst trying to distribute a product (information which is

Setting a Standard While in previous years, data-based standards by which to qualify a TCP have been created, currently there remains an absence of a reliable globally accepted 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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likely to already be in the hands of many pharmaceutical companies), a single database of ambient statistics could be developed to build an accurate global map of distribution lane data. For instance, if a TCP needed to be shipped from North America to Asia, the actual data collected in the field provides a very accurate view of what temperatures will be experienced during that distribution route and off the back of that, an average thermal stress score could be created that the shipper would be exposed to during its distribution. Secondly, TCP providers would qualify shippers to demonstrate their basic performance and ability to withstand the external ambient conditions (either hot or cold) during transit. What this means is that the qualification style would change and stress tests would provide a Thermal Stress Score that the shipper would be able to overcome. TCP manufacturers could then take the Thermal Stress Score based on the real-world data (database) and match it to the Thermal Stress Score that the shipper can accommodate. That would give healthcare companies a clearer view of what configuration of passive shipper they should be using and thus remove the uncertainty from distribution chain challenges. Let me explain, using cycling to illustrate (bear with me). In recent years it’s become possible to measure a cyclist’s overall performance (power output) when riding a bike. This helps these athletes train more effectively and understand what stresses they put their bodies under during competition. Special power-measuring cranks are attached to the bikes that constantly monitor the power output they are producing. This data, along with the heart rate, speed etc. are recorded on the bike using a data logger (cycle computer). After a training ride or race, the data is downloaded to an application that analyses and interprets the data. The software reviews the power output and the heart rate by using a special algorithm that produces a Training Stress Score. This offers a very simple way of assessing how hard the cyclist has worked during that event and is a training method that has been put to excellent effect in recent years by Team Sky, culminating in the success of Sir Bradley Wiggins at last year’s Tour de France. In a similar way, by understanding the 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

stresses that a shipping system will be exposed to during shipments, we can use technology like MP simulation to design TCP that is specifically intended to overcome these stresses by means of controlling the amount of heat-absorbing material (power) designed into the shipper. Like the subjective nature of ambient profiles for TCP, cyclists used to determine how hard they were working based on feel. The introduction of a system by which they can empirically assess the work they have done on the bike has significantly changed the way most cyclists now train. Perhaps by introducing such a ‘data-based’ system to the pharmaceutical industry it too can realise the benefits of looking outside the box! Conclusion This theoretical, fact-based approach is supported by a TCP system’s capability to absorb and release energy in the form of heat over a time period. This is very different to the way ambient temperature profile development has always been approached previously in the industry.

For the most part, certainly around domestic and clinical trial distribution, it has been built around perception of what the requirements might be, and not necessarily based on accurate data of what the challenge actually is within those particular lanes. This would mean that customers could approach TCP manufacturers and select a shipper based on a Thermal Stress Score they expect to see on a particular route, and manufacturers would match their requirements with the appropriate system. This single tool could be used to define challenges that need to be overcome by a TCP shipper, and would potentially simplify and standardise the way in which packaging systems are designed to perform, as well as regulate the selection method for the shipper. But in order for this approach to work well,the primary information needs to be sourced from as many different points in the industry as possible, and requires the collaborative working of the industry, as well as with academics, to understand and coordinate the collation and interpretation of data. Perhaps this would then create a global thermal map of distribution lanes that would be far more comprehensive and fact-based that any previous universal formula for the development of ambient temperature profiles. The debate continues… Richard Wood has worked in various design and manufacturing engineering functions during his career. He currently holds the position of Design Manager at DS Smith Plastics Cool Logistics, where he has worked since 2005. During this time, Richard has been involved in literally hundreds of bespoke, customer-defined projects. Richard has also helped to ensure that manufacturing practices are standardised across the Cool Logistics partners network. Richard’s current role within DS Smith Plastics Cool Logistics is focused on standardising development, qualification and manufacturing practices to help support the company’s global customer base. Email: richard.wood@dssmith.eu Spring / Summer 2013 Volume 5 Issue 2


CORPORATE CAPABILITY

Sofrigam working hard and innovating for laboratories New technologies in 2013

Leader in the design of customised temperature-controlled packaging, Sofrigam is an essential and innovative cold chain partner for pharmaceutical laboratories. Today, its services also cover flow optimisation and hospital and dispensary staff training. With twenty years of experience, the company stands apart through its ability to anticipate tomorrow’s requirements in healthcare. With an increasing number of drugs being transported under controlled temperatures (between +2 and +8°C), particularly vaccines, cancer and diabetes drugs and also blood derivatives and biotechnological products, the laws and regulations associated with heat-sensitive products have become stricter over the last few years. This trend will continue next year to include room temperature transportation (between +15 and +25°C). At the same time, the arrival of new market players complicates the game. For laboratories, mergers have been the driving strategy for optimising purchasing and finding standard solutions for world logistics circuits. All these changes are today leading to more precise specifications and high value-added solutions that respect the cold chain. By adopting Sofrigam’s solutions, laboratories can save up to 15% of their cold chain logistics management costs.

Sofrigam, European Leader in Insulated Packaging Systems 212 Avenue Paul Doumer 92508 Rueil-Malmaison Cedex - France +33 (0) 1 46 69 85 00 www.sofrigam.com www.coldshop.com

Managed by R&D engineer Gilles Labranque, Sofrigam quickly integrated these new demands, confirming its lead ahead of the competition. Today, the company generates more than €20 million in sales, 90% of which is in export, with fifty employees in France. On the healthcare market, it has set itself apart through innovation and vision. Its team of five R&D engineers specialises in high added-value solutions and their development. 2,000 tests are carried out every year in a metrology lab to certify its packs and packaging; the lab became an independent entity in 2011. Sofrigam also annually invests 5% of its turnover in innovation. On the back of its success, the company has extended its range of solutions for the pharmaceutical industry which today stretches from clinical trials to internal transfers and for the last four years has included “last mile” solutions for hospitals and dispensaries. “We are currently working with American partners finetuning new technologies that will be released in 2013. The aim is to double our number of references every two years,” announces Laetitia Perche, Sofrigam’s Marketing Director. In terms of services, efforts have been focused on the Monchy-le-Preux site which covers 10,000 square metres and produces 250,000 cases every year. Since August, the site can boast a new storage area (3,000 square metres) for finished products and raw materials. “We have also improved our reaction times and flexibility for managing just-in-time laboratory production,” comments Laetitia Perche. Other developments include recycling large containers and processing online orders with “SofriWeb” to optimise logistics and traceability. Sofrigam puts every effort into making heat-sensitive product transportation safe, secure and easy for its laboratory partners.


LABS & LOGISTICS

Clinical Supply in Emerging Markets Over the last few years there has been a shift in conducting clinical trials away from North America and Europe and towards emerging markets, particularly the BRIC countries (Brazil, Russia, India and China). In a survey conducted by Pharma IQ1 the main reasons given for this shift were the reduced costs of performing the trials and the availability of suitable patients. The population of the BRIC countries is approximately 3 billion; many of these patients are drug-naïve and therefore provide the pharmaceutical companies and CROs a far greater opportunity to recruit the required patients and in a much quicker timescale. Additionally, the number of clinical trials being performed in these countries is much lower compared to North America and Europe, therefore the competition for clinicians and patients is much lower. Although the shift to perform clinical trials in these BRIC countries has increased, the majority of the drugs are still manufactured in North America or Europe. Drug companies have been nervous to move new drug manufacturing to these countries as the risk of the product being copied was too high. However, out of the four BRIC countries, Brazil and India are expanding their development pharmaceutical manufacturing capability. Brazil and India have recognised the concerns of the pharmaceutical companies, and in the last years have taken considerable steps to improve their patent legislation, whereas legislation in Russia and China is still weak. Product Manufacture in Emerging Markets The globalisation and outsourcing of IMP (investigational medicinal product) manufacture and clinical trials has resulted in new demands upon the supply chain. The pharmaceutical companies are responsible for the quality and safety of their products. Although material may be manufactured and trialled outside of North America or Europe, it is most 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

likely destined for sale in these markets. Therefore the manufacturer must meet the strict regulatory and compliance requirements laid down by these countries. As a result, manufacturing sites across the globe are required to operate to US and EU GMP standards as well as their own local standards. India has some advantage over the other BRIC countries in this regard, as it has a highly educated English-speaking workforce. This makes the transfer of processes and standards far simpler, as the requirement for translation is reduced and with it the risk of mistranslation and misinterpretation. As a European-based clinical supply company, we have found one consequence of the globalisation of manufacture is the increasing demands placed upon our QPs (qualified persons) to not only audit manufacturing plants in South America and India, but to provide consultancy on how a product with an API manufactured in one continent, formulated and fillfinished in another, and tested in a third, can be released for use in the EU. The physical transfer of these ‘in process’ products around the globe must be very tightly controlled to prevent loss of material from temperature excursion and damage and also counterfeiting. A greater number of new drugs are biologics or require very strict temperature control. Loss of the material during transport can result in huge commercial loss for the pharmaceutical company, both in terms of drug production costs and in delays in clinical trials and time to market for the product. Therefore an increasing focus is being placed on the logistics of the manufacturing process, not just the manufacture itself. Smaller companies may look to outsource not just the manufacture of product, but also the co-ordination of the logistics of the manufacture, to specialist companies or hire consultants to oversee their supply chain to ensure all possible risks are minimised. For example, a country may have an excellent manufacturing facility which can produce high quality product at a lower cost, but if the Customs

requirements and infrastructure at the country’s airports result in long delays to shipments and they cannot provide temperature-controlled storage capable of holding large temperature-controlled pallets of material, the costs due to loss of product may quickly outweigh any benefits. Consultants should identify these issues during a risk assessment of the supply chain and make recommendations accordingly. Conducting Clinical trials in Emerging Markets As already mentioned, conducting clinical trials in emerging markets is becoming increasingly popular due to the availability of suitable patients and the lower costs of performing trials in these countries. Clinicians are often very keen to be involved in research and the study sites are usually well managed. However there are also drawbacks. The sites need to have high quality, reliable and secure internet and IT infrastructure, as most larger trials are controlled by IRT (integrated response technology) and EDC (electronic data capture) systems in which patients are recorded, randomised and tracked, and the drug supply is controlled. Often receipts and drug dispensing at site need to be recorded directly into the IRT along with the temperature graphs for the receipt of material. Upload of temperature graphs at site directly into the IRT system enables a faster release of the product, as there are minimal delays in receiving the information and sending a response (particularly across time zones), and there is greater GCP compliance at site as the risk of temperature graphs ‘going missing’ at site is greatly reduced, since they can be flagged up immediately in the system. Companies use these systems to control global trials, and having to implement an alternative system for a particular country or hospital due to poor internet access would be costly and inconvenient. Other concerns are language and local regulations. Companies who have primarily conducted trials in the US and Canada may not be used to Spring / Summer 2013 Volume 5 Issue 2


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supplying drug, investigational manuals and other documentation in multiple languages. Even companies experienced in conducting trials in Europe, who are used to booklet labels and multiple translations, need to take into account the country-to-country variations in language. For example, in South America several versions of Spanish may be required. Also, the education level of patients should be considered. Although the clinicians and trial professionals are well educated, the level of education in the general population may be lower and so a direct translation of a patient consent form used in Europe may be inappropriate. Additionally religious and local customs need to be taken into account, as information required for patient screening may be deemed as inappropriate and unacceptable to a local ethics committee, and consent to perform the trial will not be granted. An experienced consultant or CRO within the countries is essential to support the regulatory and recruitment requirements of trials in emerging markets. In Europe, for example, there are CRO companies who specialise in Eastern Europe. The benefits of conducting trials in Russia, Ukraine and Belarus are the availability of patients, lower costs, and proximity to Western Europe which enables them to sit under the European supply umbrella. However, the authorities within these countries at government and local level are very difficult to deal with. A Western European approach – where the rules are clear and must be complied with – does not necessarily work, and a local specialist is essential to determine what is required and negotiate with the authorities to obtain approval for the trials. Obtaining approval to conduct the trial in a country is one step in the process; recruiting sites and patients is the next step. However both of these have a reduced value unless the drug can be delivered to the patient on time and in compliance with the protocol. This is one of the largest hurdles to pharmaceutical companies conducting trials in the emerging countries, as the import requirements for each country can be different and complex. The ‘triangle’ formed between the sponsor of the trial, the CRO and the clinical supplies provider is key to the success of the clinical supply chain to trial sites. (There may be other companies 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

involved in the chain, for example IRT and EDC providers, couriers, storage depots and procurement companies. But each of these additional companies is usually under sub-contract to one of the three companies. For some very large companies the CRO and the clinical supplies company may be the same, but usually operate as separate departments.) In my experience, the most effective supply chains have been achieved when the sponsor, CRO and supplies company have developed a close, open working relationship at an early stage of the project. From the supplies provider point of view, a good understanding of the protocol is essential. This ensures that input into the kit design regarding labelling and quantity of material per kit can be optimised to meet the dispensing needs of the trial, and minimise packing and shipping costs. Input on label design and language requirements can be provided to minimise the language variations needed to meet the regulatory requirements. Shipping routes to the countries and trial sites can be identified and fed into the IRT specification. Most importantly, issues or special requirements regarding imports or exports to the countries in the trial can be flagged at an early stage and effective measures to minimise their impact put in place, or in some cases the decision to remove the country from the trial may be made.

The clinical supplies company must work very closely with the couriers, depots and CRO to identify the import requirements for each country and the timelines required. Generally the CRO will arrange the import licences and permits for the clinical trial, and the supplies company will produce the Customs and proforma invoices, however there may be additional requirements for the import of animal products, and some countries require additional test certificates which may not be readily available. The importer of record for each country should also be identified in advance of any shipments, as in some countries the procedure to appoint this is quite lengthy. For emerging markets, an understanding of the local requirements is essential. In recent years many of the specialist clinical trial couriers have set up depots in South America, India, China and Russia. This has enabled them to have local knowledge available to global customers. It also minimises the supply chain risk of importing material into the country as fewer shipments are required to stock the depot compared with shipments to each site, and the time between order and delivery for shipments to site is minimal. Critically, these depots operate to a global standard, therefore the shippers, monitors and inventory systems are the same for all depots regardless of the country they are situated within.

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Additionally they are experienced with interacting with IRT systems, and will readily receive orders from IRT, register receipts and despatches and load temperature records. The use of depots in emerging markets is often essential, but may add additional cost to the project for additional storage and project management. However the use of a depot usually means that stock at site can be kept to a minimum as resupply is from within the country, thus reducing the level of drug waste. Careful management of depot stock levels needs to be considered, particularly for short shelf-life products, as there are often duties and taxes to be paid at import and so unused stock will not only incur the loss of manufacturing costs but also the additional taxes and storage fees. In theory, materials stored at a depot are still within the GMP supply chain and so could be returned and used elsewhere in the study. However re-export of clinical trial material from depots in some countries can be virtually impossible. Although the individual companies involved in supplying clinical materials to emerging markets are working hard on their innovation and levels of cooperation to support the clinical trials, the governments may still impose a large number of regulations which can have a great impact on the cost and timelines of a trial. Some examples of these are discussed below. A very large number of trials currently taking place in Europe have sites in the Ukraine. It meets all the requirements for patient recruitment and trial execution that a sponsor is looking for. However, the duties for importing material into the Ukraine are extremely high. Unlike most countries, who recognise the commercial value of clinical trial material as minimal as it will not be sold, the Ukraine authorities determine the value of the clinical trial material as the same as an ‘equivalent’ commercial product. VAT at import in the Ukraine is 20%, which must be considered when budgeting for trials in the Ukraine. Ukraine Customs will set a value for the product, and 20% of this value must be paid at import to release the material from Customs. In addition, the authorities require a C of A for any imported materials. For comparator drugs this can be very difficult to obtain and must be built into the comparator procurement procedure. 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Where possible the depots within the Ukraine will try to source local comparators and ancillary supplies that are equivalent to those used throughout the rest of the world, as this greatly reduces the import fees and sometimes is the only way for the sites to obtain the required material. Import of ancillary materials is often one of the last requirements considered in the supply chain. However in some countries the requirements for the import of these materials are significant and may result in large delays in trials. An example is Argentina, where a signed certificate of origin is required for needles and syringes, and nutritional drinks (often required for diabetes trials) are classed as food and require a separate import licence. Changing the nutritional drink to an alternative available within Argentina may affect the clinical trial results as the sugar content is different. These are not insurmountable issues, but add significant time to the shipping times and must be factored in to the supply chain. In summary, emerging markets can provide excellent, value for money manufacturing opportunities, and reduce the cost and time of clinical trials. However, in order to achieve these benefits, an integrated, well informed supply chain is essential, with the risks

identified and minimised wherever possible. This requires good local knowledge teamed with high levels of co-operation between the sponsors, CROs and clinical supply providers to ensure all the individual requirements can be met. References 1. Pharma IQ “BRIC Clinical Trial Report: Clinical Trials: Opportunities and Challenges.” Rachel Griffiths is an Associate Director at Biotec Services International. Rachel joined Biotec Services in 2004 and is responsible for Operations and the Technical Team. Part of her role involves overseeing supply routes and innovations in the supply chain for Biotec Services controlled temperature storage and distribution worldwide. With a degree in Microbiology and Virology, Rachel has previous experience as a development scientist, a technical support scientist and a product support specialist. www.biotec-uk.com Email: online@biotec-uk.com

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Disposable Filling Needles For many years, biopharmaceutical production processes have been characterised by the cleaning and autoclaving processes of the existing systems, usually made of stainless steel. For some time, single-use systems have been making inroads more and more in the manufacturing companies involved in biotechnology. In almost all processes from upstream to downstream, to clean-up or storage, there are suppliers of disposable products nowadays, who are placing their products on the market with a lot of success. The demands on these products are clear. The ultimate user aims at reducing the cleaning and sterilisation processes. Moreover, the flexibility of production should increase, and the risk of cross-contamination should be reduced significantly. As a rule, the user receives these systems configured, gamma sterilised and thus ready to use already. Compared to the traditional design, the space required in the manufacturing sector is reduced with this concept. The pharmacist can store the sets for many years and need not permanently transport entire assembly groups for sterilisation or cleaning. However, if the expanding branch of biopharmaceutical disposables is looked into in greater detail, it will be noted that no standard solution has been found for the branch yet in the area of final filling, and in particular for the issue of disposable filling needles. So far there are only a very few suppliers who have dealt with this subject. For this reason, end users are still largely relying on traditional solutions. Apart from distribution systems (stainless steel “rakes�), this applies for multi-use filling needles in particular. Among other things, the reason is, of course, that a very critical application is involved, and that no risk may be taken in this area. In this step, the product is filtered in sterile condition only to subsequently be filled into the final container. Correspondingly high standards have been set for this final process step. In no way should a single-use solution jeopardise the purity of the final 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

product. Otherwise, of course, the use of disposable filling needles would be grossly negligent and not permissible. In addition, the filling accuracy, in case of small volumes in particular, plays a decisive role on account of the monetary value of the active substances. Another prerequisite for a single-use needle is that transfer tubing can be connected to the needle safely and tightly. True, the pressure requirements in this step are not very high, but nonetheless the connection should work without cable ties. The demands presented for such a solution produce several challenges at the same time for potential suppliers: Firstly: The material of a disposable filling needle has to have a sufficient hardness in order to ensure the stability of the needle. If this is not the case, the tube will start moving during raising and lowering movements. This in turn leads to inaccuracies or even to the medium

being squirted out of the container. Moreover, the material has to be procured and processed inexpensively in order to make a one-time use sensible. These facts seem to indicate that polymers exclusively can be used. Secondly: During the production of the needle it has to be ensured that no particles can get inside. Any contamination by disposable polymer needles is not acceptable. Thirdly: A disposable needle may not deform at all, or minimally only. In order to ensure that the container can be penetrated, only a certain circumference / bottle neck can be used to warrant clean filling. Fourthly: In order to be able to build a single-use tube in a set, it is imperative that the polymer material can be gamma sterilised. In addition, it would be advantageous if the needle material could be autoclaved as well. In particular, Spring / Summer 2013 Volume 5 Issue 2


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if the user does not use a completely disposable system, the needle has to withstand vapour sterilisation with at least 121 deg. Celsius without changing chemically or mechanically. Fifthly: As already indicated, a suitable connecting means for a tubing has to be provided. At the same time the holder has to be designed in such a way that the needle can be attached in the filling line. In an ideal case, this receptacle should be so flexible that the needle can be attached universally in any filling device. Sixthly: The inside diameter of a polymer needle has to coincide with that of a stainless steel needle in order to warrant the filling accuracy. This, however, requires that the disposable tube can keep very tight tolerances. If all these requirements are met by the disposable version, only the material of the disposable needle has to be safe with regard to regulatory aspects. 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Relevant standards of the FDA, USP or of the European pharmacopoeia have to be observed here, of course. If this aspect has been cleared, a massive advantage for production is ensured. Filling needles made of a regulatorily correct polymer material increase the efficiency considerably. Similar to the systems already existing for other steps, pre-fabricated gamma sterilised filling assemblies could be included in the filling system, and the manufacturing staff would have to connect it only. These assembly groups can be designed individually to suit the conditions of a company and could include all required components, such as tubing, bags, filters, distributing connectors and filling needles as well. On account of such systems, the cleaning processes and vapour sterilisation are no longer required in this area. Consequently, no validation has to be carried out for these steps as

the pre-fabricated systems are used one time only. In addition, manual fabrication by the end user is not required any more either. This fact not only saves costs, but also eliminates the risk of faults during the assembly. Another advantage is also that no WFI water has to be used in the manufacturing process. Today’s multi-use systems have to be flushed with WFI water after every batch. Given the new method, the flushing process itself (including the equipment required) as well as the outlay for providing the WFI water is no longer required. The disposable concept is a distinctly more environmentally-friendly process (despite the disposal of the sets after each batch) than the reusable systems. In closing, it can be substantiated as follows: Independently of which range of disposable systems has been implemented individually, single-use filling needles definitely minimise the risk of cross-contamination. As the efficacy of the filled media is further increasing and as there is a tendency to reduce the batch sizes, a disposable needle offers an effective approach to minimise risks. In case of contract production in particular, disposables permit a fast change and qualification of new production of substances. The introduction of a single-use filling needle is a further step towards converting the biopharmaceutical production process completely to an efficient and safe disposable concept. Benedikt Knoch is 28 and Product Manager in the Business Team Marketing and Sales within the strategic business unit Extrusion / Tubing of RAUMEDIC AG. Within this role, he takes care of RAUMEDIC’s products which are used in the pharmaceutical production; i.e. silicone or thermoplastic tubing, molded parts or fully sterilised assemblies. Before he started at RAUMEDIC in 2009 he studied business administration with the focus on marketing and sales. In parallel he worked for diverse industrial enterprises like Bosch Thermotechnology or ZF Sachs. Email: benedikt.knoch@raumedic.com

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The Future of Pharmaceutical Manufacturing The pharmaceutical industry today is witnessing major changes and challenges, and will continue to do so in the near future. Rapid development of emerging markets, progress in drug research, the rise in generics production, the availability of high-potency drugs, and innovations in manufacturing processes will sustainably modify the global pharmaceutical landscape. According to a recent survey1, global annual spending on pharmaceuticals is set to reach almost 1.2 trillion US dollars in 2016. The so-called pharmerging markets play an important role in this development. Growing population, rising incomes, and improved access to drugs are amongst the reasons for these markets reaching 30 per cent of global expenses by 2016. Due to increasing cost pressure and higher local demand, production is being relocated to the emerging markets. While the share of the industrialised nations in global pharmaceutical expenditure will continue to decline, spending on

generics2 will increase due to expiring patents, accompanied by higher generic use for off-patent molecules. Cutting-edge developments in personalised medicine have led to sophisticated solutions tailored to stratified groups. We observe a global trend towards combining pharmaceuticals with medical technology applications. The development of new drug delivery devices increasingly focuses on patients’ individual needs. Some of the devices, such as inhalers, are necessary applications to transport the active substance to where it is needed. Tools such as insulin pens have been optimised, in particular with respect to convenience and ease of use, while the equipment generally tends to be smaller and much safer to handle. The availability of high-potency treatments has also exploded in the past decade. High-potency active pharmaceutical ingredients (HPAPIs), for example, is a fast growing segment, and is projected to grow at a compound annual growth rate (CAGR) of 9.9 per cent through 20183.

To keep pace with these advances, engineering expertise is required to design equipment that can handle, package and secure such substances. Pharmaceuticals, biopharmaceuticals, vaccines and anti-virals must be manufactured and packaged with the utmost caution and attention-to-detail. It is with these requirements in mind that we see the following trends emerging in the field of pharmaceutical processing and packaging equipment, namely: • a rising demand for pharmaceutical quality and safety through inspection technology • the ability to handle potent substances; adapting lines for small batch sizes and research purposes • an increasing use of single-use components • the necessity to combat pharmaceutical counterfeiting on different levels the need to improve productivity by • optimising manufacturing processes with respect to Overall Equipment Effectiveness (OEE). Product Quality for Patient Safety In order to comply with strict pharmaceutical quality and safety standards such as the FDA, PAT and GMP, the industry requires reliable and high-end inspection technology equipment to be integrated in their production lines. Manufacturers are continuously challenged to increase output and improve efficiency, as well as inspection accuracy, placing their main focus on fully automated solutions. Manual and semi-automated devices remain in use for research purposes, customised smaller batch applications and the re-inspection of rejects from fully automated machines. Physical inspection via spectroscopic methods, pressure decay or high voltage can be used to detect leakages and fissures of containers. Quality control is essential for liquid and solid pharmaceuticals such as syringes, ampoules and vials, as well as tablets and capsules. One of the

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most common and reliable methods for particle inspection is the “static division� (SD) technology. It derives its name from the ability to differentiate static from moving objects, using light transmission to detect moving particles by measuring dynamic light fluctuation. Projecting light through the liquid onto an optical SD sensor enables the differentiation between particles contained in the liquid and immobile objects. The SD technology is also suited for inspecting filling levels. Ultramodern high-speed cameras in turn allow for the reliable detection of particles and cosmetic container defects. The combination of these two inspection methods provides for best inspection results.

Machines based on x-ray technology serve as systems for comprehensive quality and weight control of capsules. These technologies are advancing rapidly due to software development and new imaging capabilities. Most recently developed inspection units are able to simultaneously check all quality features like weight, foreign particles, deformation of capsule top and bottom, as well as length in real time and at high throughput rates. The exact process control adopts several functions of visual systems for error identification and provides significant benefits, such as reduced reject rates and the prevention of packaging errors.

of highly potent and cytotoxic substances in the treatment of cancer, and hence new challenges in the containment of these substances. In the supply chain, both workers and the drugs themselves are at risk if containment technologies are not applied effectively. Also, for high potency drugs such as hormones, GMP guidelines require dedicated facilities to minimise the risk of cross-contamination. Handling highly potent drugs is therefore built around the principle of protecting drugs and employees from contact with each other, with as little manual intervention as possible. The latest equipment solutions favour the use of automation and robotics technology to reduce human contact with any

substances that are being manufactured. As a result of the increasingly strict guidelines from regulators, manufacturers increasingly rely on the use of barrier technology such as isolators.

Barrier technology allows fully enclosed, sealed and pressurised units completely separated from operators. They offer far greater sterility assurance than conventional cleanrooms, and can significantly lower costs associated with more traditional filling and finishing methods. The most advanced, closed restricted access barrier systems (cRABS) contain toxic compounds, usually in their use of positive pressure and air filtration systems within the chamber. Technological advances in air suits, gloves and sleeves further diminish the risk of cross-contamination. Automated cleaning features allow for machine parts to be cleaned without manual disassembly, and give employees greater protection from potentially harmful substances. Ever Smaller Batch Sizes Personalised medicine will continue to demand ever more flexible and versatile processing and packaging solutions. Smaller batch sizes shift the emphasis from speed and mass production of standard dosage products to more individualised products packaged in highquality materials. Short start-up times, easy changeovers and a high degree of automation are key considerations. Before being introduced to the market, personalised medicine requires a great deal of R&D effort. Devised on very small laboratory equipment, the recipes need to finally be transferred to production-scale machinery. However, manufacturing lab equipment is highly complex and costly. From research and development via scale-up to industrial production scale, manufacturers strive to reduce time

Handling High-potency Substances Particularly in the past ten years, containment has steadily moved up the agenda for drug manufacturers and will continue to do so. Advances in oncology and immunology have led to increased use 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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to market. Laboratory processes can be optimised by implementing small and flexible machinery with scale-up possibilities to production size. In the fast-paced pharmaceutical market, it is difficult for manufacturers to anticipate which products will be required next. Therefore new machinery must be future-proof, have scalable and flexible platforms, and be adaptable to new products, characteristics and formulations. With their flexible platforms, state-of-the-future machinery is capable of processing many different containers. Moreover, equipment providers will be well-advised to increase their services in terms of formulation and development support. Rising Demand for Single-use Components The demands for greater flexibility and the elimination of possible contaminants will find another effective ally in the form of single-use components. This trend is a consequence of industry safety regulations, growing use of highly potent substances, and a shift towards smaller batch sizes. The time-consuming process of cleaning, sterilisation and validation of product contact parts, particularly during changeovers, has long been a hindrance in achieving operational efficiency. Single-use, pre-validated, pre-assembled and pre-sterilised parts, including hoses, product bags, filling needles and tubingÂŹ, remove this inefficiency and can eliminate the loss of capacity resulting from lengthy cleaning validation, as well as the risk of contamination between batch runs. Pharmaceutical manufacturers will be increasingly drawn to the simplicity and speed of single-use systems, which easily meet industry standards. Assembled in DIN ISO 14644-1 class 7 cleanrooms, the latest single-use components are connected to the product stream via sterile plug-andplay connections and are easily removed, bagged and disposed of without breaking connections and exposing the environment to the product.

was linked to the deaths of 81 people and hundreds of allergic reactions in the United States during the first half of 20084. Amongst other factors, wider use of the internet for pharmaceutical purchases plays a major role in this trend, which threatens both public safety and brand image. Counterfeiting also constitutes unfair competition, and damages research and development activities by lowering pharmaceutical companies’ return on investment. Lately, international organisations such as the World Health Organization (WHO) have worked alongside governments and producers to help curb this damaging practice. In June 2011, the European Union published its Directive 2011/62/ EU5. In addition to the introduction of serialisation standards for prescription medicines, the directive initialises the search for appropriate safety features. It also provides for stricter regulations regarding the import of active substances and the improved control of the supply

chain, including wholesale. Regulations for Internet trading of medicines, the harmonisation of Good Manufacturing Practice (GMP) inspections and the introduction of a pan-European early warning system are also an integral part of this Directive. Track-and-trace equipment already provides a quick and flexible way to protect brands from counterfeiting. The most advanced systems allow faultless, individual product traceability with no compromise in line speed. They allow numerous systems based in different processing and packaging plants to be linked to the same database. Marketleading packaging experts offer Carton Printing Systems (CPS) modules that are both unfailingly accurate and easily integrated - minimising their impact on overall production and reflecting the current shift towards greater manufacturing flexibility. Customised CPSs ensure total compliance with regulatory bodies such as the FDA.

Fighting Pharmaceutical Counterfeiting Counterfeit products are currently thought to account for around 10% of the global medicines market and are responsible for many instances of serious illness and death. For example, counterfeit heparin, a drug used primarily to treat blood clots, 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Improving Productivity In general, rising cost pressure in production will press manufacturers to further improve productivity with respect to Overall Equipment Effectiveness (OEE) over the next few years. Large-scale production of generics will increasingly be relocated to the emerging markets, calling for durable and highly productive machines. To maintain and improve a plant’s OEE, aftermarket services are becoming more and more important. A processing and packaging specialist who wants to keep pace with the industry needs to offer comprehensive consulting services all over the globe. OEE is equally important when it comes to the development and market introduction of new pharmaceuticals. So far, the production of small batches has been quite an expensive venture. But with the optimisation of machines in terms of flexibility, automation, easy changeover and scale-up, the situation has changed significantly – and will continue to do so in the future. These improvements enable manufacturers to develop new drugs with short time to market, while complying with strict regulations. Pharmaceutical companies that offer machinery and services along the pharmaceutical value chain clearly lead the way into an exciting future of changes and opportunities.

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References 1. http://www.pharmaceuticalonline.com/ doc.mvc/bosch-presents-enhancedinspection-technology-portfolio-0001 2. http://www.boschpackaging.com/ Boschpharma-us/eng/3414.asp 3. http://www.contractpharma.com/ issues/2011-06/view_features/single-usedisposable-systems-for-aseptic-fill-fin/ 4. http://www.boschpackaging.com/ boschpackagingservices/eng/OEE_ Consulting_69722.asp Dr Jérôme Freissmuth studied technical chemistry at the Technical University of Vienna, Austria. He holds a doctorate in technical science and has worked as a management consultant focusing on strategy and organisational projects for the pharmaceutical machinery industry and process industry for several years. In 2010, Jérôme Freissmuth joined Robert Bosch GmbH as Director of Business Development, Product Management and Marketing in the Packaging Technology division, Business Unit Pharma. From June 2013, he will take over the position of Plant Manager Pharma in Hangzhou/China. E-mail: Jerome.Freissmuth@bosch.com

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ADVERTORIAL

Vetter Development Service Filling Your Clinical Development Needs in Chicago Vetter, a leading provider of aseptically prefilled drug-delivery systems, operates a state-of-the-art facility at the Illinois Science + Technology Park in suburban Chicago. The site offers a central US location with a domestic and international airline hub. It is uniquely situated in a thriving biopharmaceutical region that offers an established infrastructure and prominent research institutions. The company’s Chicago site supports preclinical through phase II development projects. The 27,000 ft2 facility’s functional areas include microbiology and chemical analysis laboratories; materials preparation; compounding; aseptic cGMP filling for vials, syringes, and cartridges; quality assurance; and seamless transfer to Vetter Commercial Manufacturing. DeveIoped at the urging of Vetter’s North American clients, the Chicago site supports small-batch, early stage products. Vetter has extensive experience working with biologics, including monoclonal antibodies, peptides, interferons, and vaccines. Supporting a Faster Time to Market The Chicago facility provides the Vetter approach to product development, which enables a smooth continuum throughout a product’s lifecycle. Project Management: Across functions and facilities, throughout the development effort, Vetter teams communicate and coordinate using project-management principles. Such a process-driven approach helps keeps projects on track and timelines tight. Experienced project managers steer all tasks and processes, which is especially critical in early phase work. Technology Transfer: Development and commercial teams closely coordinate a product’s transfer from Chicago’s small-scale site to Vetter’s large-scale manufacturing facilities. The Chicago facility already replicates commercial-stage processes to help prevent surprises at market production. Partnership: Client collaboration is one of Vetter’s distinguishing hallmarks. Vetter works closely with its clients to plan not only for the present, but to set a successful course through registration and long-term market production. A full menu of Development Services Vetter’s Chicago facility is an expansion of Vetter Development Service, which employs more than 150 personnel in Europe and the United States and supports customer products from preclinical development through market launch. Its service portfolio includes:

Formulation support: In early clinical development, preformulated compounds may sometimes require a higher level of support prior to process development. Vetter can work side by side with your development team to optimize preformulated API for clinical trial – as well as identify the strongest of several prequalified candidate drug formulations through compounding and filtration studies, API/material compatibility analysis, and lyophilization cycle testing. Transfer, optimization of analytical methods, and validation is also provided. Process development: The goal of process development is to enable fast, smooth transfer of your project to commercial manufacturing. Tailored to your product’s specific requirements, process development services include: siliconization methods studies for the appropriate drug delivery system; filter compatibility testing; lyophilization cycle development; feasibility studies; engineering batches; stability and clinical batches; method transfer and clinical batches; and method transfer and scale-up for commercial, as well as validation batches. Clinical trial manufacturing: Following confirmation of successful scale-up, clinical production begins. Key steps include compounding, filtration, preparation of primary packaging materials, and filling. Additional steps may include lyophilization, terminal sterilization, and visual inspection. Precise indicators are also generated for the master batch record. Analytical service: Validation of all raw materials, bulk solutions, in-process materials, and finished product is determined by sophisticated analytical techniques. Vetter’s highly trained analytical quality control staff also provides expert support for the critical transfer of analytical methods. All instruments and methods are aligned with current international requirements. Regulatory support: Vetter provides support through all phases of regulatory submission. Expert technical writing and dossier preparation begins in parallel with clinical production to streamline the regulatory submission process, supported by in-depth knowledge of global regulatory requirements, including FDA, EMA, PMDA (Japan), and RP (Germany). Vetter at a Glance Vetter is a leading contract development and manufacturing organization (CDMO) that specializes in the aseptic filling of syringes, cartridges and vials. With approximately 3,000 employees worldwide, Vetter holds numerous patents and has longstanding experience in working with regulatory authorities around the world. Vetter’s international success arises from its three interdependent divisions: • • •

Vetter Development Service specializes in taking complex compounds from preclinical development through Phase lll. Vetter Commercial Manufacturing provides Phase lll clinical manufacturing through global market supply. Vetter Packaging Solutions helps clients match their drug substance with the appropriate drug-delivery system for a product’s life cycle.

For US inquiries please contact +1-847-581-6888 or infoUS@vetterpharma.com For EU inquiries please contact +49-751-3700-0 or info@vetterpharma.com


PACKAGING

Inner Strength Glass has established itself over the years as the most commonlyused primary packaging material for injectable drugs. And yet new drugs and sophisticated production processes such as lyophilisation have given birth to new challenges that high-quality glass containers must face. Their geometries and special coatings help to make them stronger and minimise the risk of breakage, but also improve temperature transfer during the lyophilisation process. In the pharmaceutical field, lyophilisation is used to extend the shelf-life of highly sensitive drugs with new composition of agents, e.g. biotechnological components. Currently, there are about more than 300 biopharmaceutical products approved in the US and EU, and about 46 per cent of them are manufactured by freeze-drying. The interests of both the pharmaceutical industry and patients are rather obvious. They are interested in achieving the highest possible protection for their precious and costly medications and making sure that they remain effective for as long as possible. This explains why lyophilisation is so prevalent and yet a challenging issue. There are two reasons for this. First, new compositions of agents lead to completely different interactions between the drug and its container. Common challenges that are of great interest today include unintentional adsorption, i.  e. when active ingredients become attached to their containers, or how to deal with so-called “extractables” and “leachables.” These compounds from the glass can detach themselves from pharmaceutical packaging over time and have a direct influence on the formulation of modern APIs (active pharmaceutical ingredients) based on biomolecules. They also react quite sensitively to any changes in the storage conditions. Protein adsorption kinetics can take place very quickly; in other words, the surface can become completely saturated within only a few hours. All of this obviously also impacts the effectiveness of the medication stored inside. 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Applying extremely thin coatings to the inside surface of a pharmaceutical container represents one very effective approach to improving the chemical stability and smooth surface of the respective packaging materials. Here, five letters have really made a name for themselves in the industry: PIVCD, which stands for “Plasma Impulse Chemical Vapour Deposition.” The first mass application was in so-called cold light reflectors. When coated on the inside, these devices are capable of increasing the efficiency of halogen lamps quite considerably. Today, plasma coatings are also opening up new possibilities in the pharmaceutical industry. The first step is to wash the finished vials in a pharmaceutical washing machine and then dry them inside an electric heat tunnel. Next, the containers are placed inside a plasma reactor. Several layers of silicone dioxide molecules are then applied to the inside surfaces of the containers with the help of the pulsed plasma technique. The resulting layer is only about 40 nanometers thick and thus has no effect whatsoever on the dimensions of the pharmaceutical container. It remains stable when

exposed to pharmaceutical processes like washing, sterilisation and depyrogenisation which often involves heat treatments at temperatures of up to 300°C. The coating that is applied as part of a validated and permanently inspected process is so smooth and homogeneous that freeze-dried drugs cannot adhere to the inside of the container walls. As a result, the lyophilisation cake shows a better appearance, with less disruption of the dry material as well as reduced breakage during the lyophilisation process due to a special geometry of the glass vial. The method has been tested scientifically for extractables and leachables. The toxicology profile and calculation for the cyclic siloxanes – in fact only four extractables found by qualitative analyses – showed that the acceptable daily exposure could be 60- to 600-fold higher than the amount found in the vial. Moreover, the coating has a “magnifying” effect on the lyophilisation cake: with hydrophobic coatings, the cake finds it difficult to adhere to the inside walls of the vials. This results not only in a more attractive visual appearance with a more elegant (in pharmaceutical terms) and mechanically stronger lyo

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cake that doesn’t collapse, but also medications that dissolve more quickly in water. The drug can also be removed from the container more easily, and less residual volume remains. At the same time, this makes it much easier to inspect the product. All of this obviously contributes to the cost-effectiveness of manufacturing. As an alternative, one could use silicone oil as a hydrophobic coating inside the vial. This, however, can also cause interference with the drug. Problems range from droplets in the solution to hazing of the lyophilised product. The silicone droplets can attract proteins from the medication and cause protein-related aggregates. This affects the effectiveness of the drug – and ultimately even the health of the patient. The reason why the silicone layer interacts with the drug is that its bonding to the glass container is of a noncovalent nature. Non-covalent bondings involve more dispersed variations of electromagnetic interactions. A covalent bond, on the other hand, is characterised by the sharing of pairs of electrons between atoms – and is therefore more stable than non-covalent bonding. While the coating significantly adds to the “performance” of a vial used for lyophilisation, each step of the process poses further challenges for the stability of the container. During freezing, the formulation begins to expand, and radial as well as tangential tensile stresses are exerted on the inner wall of the vial. During sublimation, heating the vial from the bottom side can cause glass breakage due to enormous local temperature gradients. Later on, sterilisation and filling of the glass vials can damage the surface (glass-to-glass or glass-to-metal contacts, chatter marks, etc.). Due to the characteristics of its manufacturing process, the bottom of a glass vial is 35 to 45 per cent thinner than its wall. And this explains why a glass container usually breaks at the bottom of a vial. Aware of this weakest spot, a new production method for tubing vials has been developed. It is regularly improved by the FEM (Finite Element Method) according to new requirements, and ensures an improved, more resistant geometry of the glass vial. This not only reduces breakage, but also improves temperature transition during each step of the lyo process. In summary, lyophilisation places high demands on a drug container. It 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

must be able to withstand mechanical and thermal stresses, guarantee low chemical and physical interaction of the container walls with the drug and, last but certainly not least, complete removal of the dosage. A solution that features a special geometry of the glass vial and an ultrathin hydrophobic coating has been developed. As a result, the lyophilisation cake has a better appearance, and there is less disruption of the dry material and a lower risk of breakage during the lyophilisation process. At the same time, the customer also benefits from a lower rate of rejects caused by collapsed lyophilisation cakes and the fact that breakage is less likely to occur. Because both effects obviously have an impact on processing costs, there is definitely a financial advantage to using this product.

Florence Buscke is Global Product Manager, Vials and Coatings for Pharma Packaging at SCHOTT Pharmaceutical Packaging. Florence joined SCHOTT in 2001 and has worked for several business units in various fields, including Marketing Management and Key Account Management roles for SCHOTT’s Laboratory Glassware, Medical, Cosmetics and Dental applications. Florence holds a French and German Diploma in Economy and Business Administration. Email: florence.buscke@schott.com

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A Highly Secure 2D Code to Protect Medical Drugs from Counterfeiting The globalisation of production sites and distribution has led to a boom in counterfeit products and dysfunctions of systems and distribution networks. More and more pharmaceutical laboratories are choosing to go beyond regulation and adopt a new security device: a highly secure 2D code, allowing not only identification, but authentication. A Need for Authentication Production sites and distribution’s globalisation has led to a boom in counterfeit products and dysfunctions of systems and distribution networks. All sectors are concerned – the pharmaceutical sector included. Laboratories are reacting; authorities are implementing new regulations regarding medical drugs’ identification and authentication. Whether using data matrix codes, other public codes or radio frequency, the new regulations impose batch identification on each drug pack. This should be serialised for each pack. Laboratories can really distinguish identification from authentication: if the unitary identification enables tracing of each packaged product, it does not make it possible to authenticate it – and even less to authenticate its content. A data matrix or any public code is easily copied and reproduced. As it is visible, it is also vulnerable to destruction and alteration, much like the RFID chip, that can be cloned. It prevents the tracing back of a product’s history or path. Though they meet the needs for traceability – which is a huge step forward – the new regulations do not answer authentication and secure traceability issues. New solutions for strong authentication and secure traceability, compatible with all standardised codes, including ECC200, are being commercialised. If traceability is subject to regulation, the choice of a reliable authentication and traceability solution belongs to the laboratories, which have to take into account the security level required. EU Directive to Guarantee High-level Protection Against Counterfeit Drugs In Europe, a new directive is to make 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tamper-evident sealing compulsory on medical packages. Adopted on June 8th, 2011, the European Parliament and Council 2011/62/UE directive amends the 2011/83/CE directive introducing a common code concerning medical products for human use, and relates to protection against the introduction of falsified medicines on legal supply chains. Applicable from July 2013, the directive plans the set-up of security and tamper-evident devices in order to check up on the authenticity and identification of individual medicine packs. The application of those is compulsory for all medicines delivered on prescription.

containing capacity: information related to traceability, production operations, product-related data. This is usable to authenticate any type of item or physical support on which information is printed or marked – blisters, directions for use, cases, pill boxes, labels, etc. – and compatible with all printing or

French company Advanced Track & Trace® uses highly secure 2D codes on tamper-evident stickers in order to comply with the new EU regulation

Unbreakable 2D Codes A fundamental breakthrough in the fight against counterfeiting and secure traceability has been carried out by operating a technological break between security-through-obscurity and the new digital security technologies. The latest technology, currently used by an increasing number of international pharmaceutical groups, is a new type of authenticating 2D code, physically, scientifically and mathematically impossible to copy.

marking processes (offset, heliography, flexography, inkjet, laser, in-mould…) and all materials (cardboard, paper, aluminium, PP, PET, metal…). This code is auto-authenticating, readable on field with only a smartphone, and can be either visible and/or invisible. It brings a robust private traceability and strong authentication, enabling the security needs of production and distribution operations to be answered, and to compile strategic information about a product’s components: who did what? Where? How many? Why? Whom for?

This authenticating code assumes the shape of a high-resolution, copysensitive data matrix, with a high data-

The integration in production processes is simple and rapid, with no additional costs. The main asset of these solutions Spring / Summer 2013 Volume 5 Issue 2


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is that they do not require specific means; they can be operated with smartphones and have the same unit price for multi-component products (e.g. case, blister and directions for use), thus meeting laboratories’ needs and expectations. They can also be printed on product-related or shipment-related documentation. A Wide Range of Applications The industrial integration of such codes is operated on the suppliers’ and packaging sites, as well as the different integration protocols: quality, security and operation. Information, log-ins and passwords can be transferred onto the products via the existing processes, depending on the strategy implemented. They are used for security and secure traceability, from production to dispensaries or hospitals, and sometimes to the end-patient for patient relation management, especially for observance-related needs.

authenticated, as well as the sticker and secondary packaging. The strategic components thus are authenticated, traced and correlatively assembled so as to be able to proceed to coherence check-ups on field, if necessary. A centralised database gathers up the different pieces of information, which are then associated to the ERP. The reading can be done as a stand-alone, directly on field and with no access to an external database, using a smartphone. The authenticating codes can also be read from a simple office scanner. The management of configurable rights of access enables one to define authorisations to check or receive the different levels of information. Advanced management tools for counterfeiting and dysfunctions, which meet the different needs of market surveys, are also supplied: traceability and geolocalisation of controls, counterfeit

An example of a digital high-capacity, copy-sensitive 2D code Concerning products, for a pill case under blister for instance, all the components of a product are traced and authenticated, such as: flat paperback case, directionsfor-use booklet, and blister. Production sites, whatever their location, are secured to integrate these codes. Production operations and componentrelated information are registered in the databases, and made available to the laboratories’ departments. For vaccines, glass bottles are directly traced and www.ipimedia.com

products’ characterisation, etc. This information enables optimisation of downstream investigation operations led by the laboratories. The documentation coming along with the products is protected by authenticating it, and permitting the control of its integrity at any given time. New developments have enabled the rolling out of the pills’ straight authentication without modifying them or adding extra material.

The highly secure 2D codes are also integrated on labels and tamper-evident security stickers. They can be embedded into a hologram, thus making it possible to design a very high security hologram out of a standard one, with the most competitive price on the market. These codes can be visible, for easy and direct access, and invisible, with no consumer goods, for authorised personnel. ‘This technology is versatile; there is no inherent limit to the type of object, support or surface on which it can be applied,’ explains Jean-Pierre Massicot, CEO of Advanced Track & Trace, a French expert company in authentication solutions. ‘This technology offers the pharmaceutical industry solutions that easily integrate into existing processes; they are secure and tamperproof, even in unsecure environments, and render it possible to know all the operations related to a product’s and its components’ life cycle, from manufacturing to distribution, complying to an efficient cost-performance ratio.’ Jean-Pierre MASSICOT, CEO of Advanced Track and Trace® since 2003 and former CEO of Nutrinova Company, has a long experience of the pharmaceutical Industry and holds several patents in the field of authentication. As a member of the AFNOR consortium, he was involved in the ISO 12931 standard “Performance criteria for authentication tools for anticounterfeiting in the field of material goods”. Email: info@att-fr.com

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PACKAGING

Pharma Serialisation: A New Challenge for the Industry Serialisation in the pharmaceutical industry is becoming a very important challenge, not only for the manufacturers but also for their packaging suppliers. According to the Directive 2011/62/EU, pharma companies have three years to implement a successful strategy in all their products to be distributed in the European Union. Similar regulations are in place today in India, China, Turkey and some other countries. Every member of the industry knows the benefits of serialisation: • Supply chain synergies – the unique code of each package can be accessed by pharmacists, the brand owner, officials or even consumers, providing the ability to track and trace products along the chain, from the pharma facility to the consumer’s home. • Brand protection – fight against counterfeiting is a very big challenge for healthcare authorities and pharma companies. Serialisation, as well as other anti-counterfeiting measures, will be a useful tool to reduce the impact of this problem.

platforms with serialisation equipment, and have the knowledge and experience to work properly with databases and different codification standards. The process to become a packaging supplier with the capability to serialise carton boxes brings some important challenges for the whole organisation, as serialisation enforces a traceable production process, controlling and reducing production losses. Serialisation does not only consist of printing a code on a box, but leads to a deeper collaboration between the packaging supplier and the pharmaceutical company. To be part of the serialisation process, the packaging supplier has to: • Know and manage serial number definitions and formats. • Improve the quality standards to take care and inform of every single loss of a batch • Integrate the serialisation procedures in the IT systems, for associating serial numbers with orders, shipments, invoices, etc.

Source: HDMA, 2012.

The process to introduce serialisation in the packaging lines is very complex and needs an important investment to print, read and verify the serial numbers. An appropriate procedure for handling exceptions, reworks, returns and any other issues is also a must. Very few pharma companies have already prepared their lines and processes to introduce serialisation and, as this requirement is no longer avoidable, reliable packaging suppliers will support their customers introducing serialisation as a new part of their process. Innovative packaging suppliers must have the capability to adapt their 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Meanwhile, serialisation regulations are pending in developed countries (US, Canada and EU), and have already been implemented in several other countries like Turkey, India, China, Brazil, Argentina and South Korea. Brazil launched a three-year roll-out for Track & Trace requirements in 2009. In India regulations went into effect in the middle of 2011, and a barcode is mandatory on every medicine that will be exported from this country. On the other hand, since 2010 China mandated printing a drug supervision code on the smallest package by March 2011.

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can be guessed should be a minimum of 1 in 10,000. Therefore, in order to avoid the opportunity for a counterfeiter to estimate the randomisation pattern from two or more samples, two aspects will be taken into account: •

• •

Source: Domino.

In Europe, several countries have their own drugs, in addition to those pending from the EU. However, in 2006, EFPIA (European Medicines Verification System) in collaboration with GS1, the global organisation dedicated to the design of global standards and solutions to improve efficiency and visibility in the supply chain, recommended the adoption of a unique standard for the coding of pharmaceutical product across Europe, based on the 2D (2-Dimensional) Data Matrix ECC-200, to be introduced on all secondary packaging of prescription products sold in Europe. While other coding standards, such as the PPN1, are available, EFPIA recommends the globally used GS1 standard. EFPIA considers this the most effective and technological system for the current time. Despite this, the adoption of a 2D Data Matrix system does not mean that in the future, the adoption of other technologies such as RFID (Radio Frequency Identification) at a later stage will be a solution. In fact, nowadays, RFID costs double the amount and is not easy to introduce and operate, but it would probably be a natural progression of the system.

Example 2D Data Matrix ECC-200

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EFPIA knows that national numbers in specific situations are needed, and have worked with GS1 to deliver an enhancement to the GS1 General Specifications that allows the accommodation of national product identifiers. In a number of countries in Europe, these national numbers are used to facilitate the reimbursement processes and are embedded into IT systems, business processes and even legislation; it would present significant challenges for these countries to move to a GTIN. GS1 have therefore issued an amendment to the General Specifications that describes how these national codes can be accommodated. This code structure would make use of the Application Identifiers (AI) already in use throughout the supply chain today. The EFPIA preferred structure uses only four of the many Application Identifiers available to define: 1. The product code. 2. The serial number. 3. The expiry date. 4. The lot number (batch code). The serial number will be unique per product code and should preferably only contain either lower case or upper case letters, not a mixture. On the other hand, the alphanumeric range can include the digits 0-9 and the letters of the western alphabet, but excludes the following letters: i, j, l, o, q and u (I, J, L, O, Q and U). In order to provide a reasonable level of complexity within the serial number, the probability that a valid serial number

The randomisation substrings must be equally distributed, e.g. the serial number substring should not contain fixed blocks of fixed digits. Any randomisation substring must be independent of other substrings. The randomisation substrings must not be built using an algorithm that is easy to find out from knowing the given set of serials or a subset thereof.

On the other hand, the so-called National Healthcare Reimbursement Number (NHRN) is usually assigned by a national authority to healthcare brand owners for specific trade items, and should only be used for compliance to regulatory requirements where the GTIN alone in a barcode symbol will not meet the requirements. When a regionallyspecific NHRN application identifier is approved (as above), the overall variable length is specified by the national authority, with a twenty alpha-numeric characters maximum, as noted in the general format above if applicable. In this regard, it is important to point out that including the batch number and/or expiry date within the unique identifier would be to lead to manufacturers incurring additional costs. Some manufacturers, particularly SMEs, may decide to print the codes and unique identifier where required offline and associate individual packs with the identifier and, if appropriate, the batch number and expiry date via a reader on the production line. The batch number and expiry date would still be available via a database or repository, and could be read by online scanners, even though not within the identifier itself. Where this approach would be more cost-effective, particularly for smaller manufacturers, it appears to be inappropriate and discriminatory to prevent those manufacturers adopting it. On the other hand, standardisation of the unique code across Europe appears more efficacious in order to avoid difficulties in managing the database. The issue about applying elements that are not mandatory but nice to have, which can imply an extra cost, could be Spring / Summer 2013 Volume 5 Issue 2


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discriminatory for some generic suppliers to enter or even remain in the market. Apart from that, this would potentially damage the resilience of the low-cost generic supply chain, and reduce the availability of medicines to patients. The extra cost associated would favour more established suppliers and reinforce market dominance of incumbent suppliers. As well as being discriminatory, this would have cost consequences for member states and possible implications for security of supply to patients across the EU.

by wholesalers to be reasonable and proportionate. However, many medicines are administered in the hospital environment from stock held in clinical areas such as wards, theatres, accident and emergency departments, and intensive care units. In these areas it may not be practical or in the patient’s interest to scan medicines for authenticity. It is not possible to always identify in advance which packs of medicines received are destined for dispensing direct to patients and which

Source: EMVS

Likely, from the point of view of the wholesalers, they have argued in some countries that it would be practically impossible for them to verify all medicinal products by scanning them on arrival, so they cannot meet the requirements. Additionally, they need to have batch numbers in the unique serial number to enable them to collect the data. These arguments are, of course, mutually contradictory. Checks earlier in the supply chain have several benefits, but also have disadvantages. Doing it at the dispenser level would also create workload and systems at this point of the supply chain which will be less likely to cope with this, and introduce greater costs overall to systems of medicines supply across the EU. Article 80(e) of amended Directive 2001/83/EC requires wholesalers to maintain records of the batch numbers, at least in products with safety features. The sort of focused risk assessment for which we argue below would result in only those few products of truly high risk of falsification bearing the safety features, thus making the task faced www.ipimedia.com

are destined for clinical areas. It would be unreasonably burdensome to scan stock twice (on receipt and at the point of dispensing) and may not be possible if the database holding the information on the unique identifier only allows an organisation such as a hospital to verify the medicine once. Concerning the recalls, the EU argues that verification by wholesalers and dispensers facilitates recall of medicinal products from patients. Nevertheless, today, manufacturers control product recall by lots, which can consist of thousands of items. Instead of sending out up to thousands of notifications for each recall, the industry looks forward to the day when it can send out specific notifications based on knowledge of where each serialised item in the affected batch/lot was distributed. Further, from a manufacturer and regulatory perspective, it would be helpful to see what percentage is actually returned and what product remains in the marketplace. The inefficiencies surrounding the current market recall process, and the inability to confirm that the affected medicines have

been recalled, highlight the need for a targeted process based upon serialised data. Further, from the consumer’s point of view, despite the fact that any information identified by the EU as commercially sensitive should be protected, as proposed by some associations, it does not mean that data generated by meeting the requirements or in a way associated with the implementation of the Directive 2011/62/EU should not be used for commercial purposes. Finally, sustainability plays an important role and, with this requirement, the unwanted effect of this legislation could well be an increase in medicines wastage with consequent environmental and cost implications. If repackaging is not allowed except when unique identifiers and tamper-proofing are reapplied after repackaging, repacking of medicines within some hospital pharmacies will be discouraged. This will result in whole packs being issued (e.g. 28 tablets) when only a few doses are required. The patient would then be directed to throw the rest of the pack away. It may also encourage the issue of excess medicines which pose a threat to patient safety or a risk of diversion and abuse. Unused ward stock medicines are returned to the hospital pharmacy for examination and potential re-issue. In conclusion, taking into account the several aspects from the point of view of the different players within the supply chain (consumers, multinational companies, contract manufacturers, institutions, hospitals, etc), serialisation becomes an abstract problem to solve, in which many contrary interests make it difficult to find a standardised solution that complies with all requirements.

Saul Serrano is currently South Plant Manager in Nekicesa and has been working in the graphic industry for 15 years. He is member of the Nekicesa Innovation Comittee, created to analyze and implementing new techonologies and processes concerning tamper evident, anticounterfeiting features and serialization in Nekicesa. Email: sserrano@nekicesa.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 97


SPECIAL FEATURE

Readying for a US FDA Inspection If your company produces drugs, medical devices or nutraceuticals that fall under US cGMP regulations, your facility is eventually going to be inspected by the US Food and Drug Administration (FDA). The Federal Food, Drug and Cosmetic Act states that domestic drug establishments can be inspected at least once every two years. The inspections can happen more frequently, such as if the drug you are producing is new, or if your facility has a history of cGMP problems. Here is what you can expect the FDA inspector to do when he or she shows up. They can enter, observe, gather samples, interview your employees and review records that are related to the production of the drug or device product. However, the investigator cannot have access to personnel data other than training records, any type of financial statements, pricing or sales information or research records. What is the FDA Investigator Looking For? One of the best places to get a good idea about the inspection is to read the FDA’s Investigations Operations Manual, or IOM. This document is the primary guide for FDA audit policy and procedures for investigators. Generally, the investigators are looking for the following: • Is the facility following cGMPs? • Does the facility have proper SOPs for all operations and are they being followed? • Is the staff fully knowledgeable about and familiar with both FDA regulations and cGMPs? • Is proper documentation available that shows proper training, monitoring and compliance? A Word About Attitude You can look at an FDA inspection as an intrusion and an inconvenience to normal business operations, or as a chance to show the FDA what you are doing and a chance to improve your processes. Your inspection will go more smoothly if you take the latter approach! 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It is only human to be resistant to an FDA inspection. After all, it does involve some amount of criticism. But that criticism can really be a good thing. FDA feedback will help you to better follow the regulations that ensure you are producing products that are of high quality, safe, profitable and will do what they are advertised to do. SOP Tips The FDA regularly issues 483 inspectional observations regarding failure to keep accurate records and to establish and maintain SOPs. Often, the failure to create and maintain such records is due to having procedures that do not support your operational processes, or do not even exist at all. A common mistake pertaining to SOPs is copying the FDA regulation word for word. This results in an SOP that does not give the employee any instruction for doing essential tasks. Your SOPs should consist of several sections, including purpose, scope, definitions, background, reference documents, responsibilities, revision histories and then the steps of the procedure.

Assemble a War Room If you know an FDA inspection is coming, you absolutely need to assemble a war room. This is a strategic office that should be entirely devoted to giving all of the needed evidence that is requested by an FDA inspector during an audit. Having a war room is going to help your company in many ways, but most importantly, it will speed your responses to FDA inspectors. One of the most important things that an FDA inspector is going to notice is how long it takes you to find requested documents. A fast response is always going to be very favourable for you. A well organised war room is what makes this possible. And if you take an hour to find a requested document…well, let’s just say the FDA is going to notice the lack of organisation. They also will wonder what else in your organisation is not well organised. Your FDA inspection war room should have the following: • Desktop documentation • Good records of data and recorded information • Pre-selected auditees and backups • Your quality system manual, or the master plan for the site. • Your organisation chart that shows how the quality and regulatory departments relate • Important SOPs that manage your compliance and quality systems. This includes CAPA, internal audits, record control, change control, master batches, and also process flow diagrams • Proper permissions for file access, or people who can access all critical information In addition to a war room, below are some of the most important tips to follow before, during and after your inspection: Pre-Inspection • It is important to practice inspection readiness on a daily basis. Run a mock audit often and review the findings. This way, you will have uncovered any potential FDA compliance problems. Spring / Summer 2013 Volume 5 Issue 2


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And, your quality team will be calm and confident on the day of the real FDA inspection. • Try to get your hands on FDA 483s and warning letters, that are readily available from the FDA. This will give you a good idea what they are stressing in current inspections. During the Inspection • On the day of the audit, you will want to only answer questions that FDA asks. There is one drug company out there that trained their employees like this: If the FDAer asks you if you know what time it is, you just say ‘yes.’ The moral is to keep every answer as simple as possible, and only directly answer the question asked and no more. • Have your senior management be the point people during the inspection. You don’t need to have a whole crew of people tailing the FDAers all day. Make sure you select people who are calm and confident. If you have some grumpy quality people, send them on a fishing vacation during the inspection (seriously, our recent webinar speaker recommended just that to one client!). • Use the all-important close-out meeting with the FDAer to clarify any items that are not clear. This will help you to understand what the investigator is thinking. Sometimes you may be able to clear up any misunderstandings and avoid some FDA 483 observations. You should not use this close-out meeting to argue with the inspector. If there were any corrective actions taken during the audit, ask the investigator if these actions were enough. • Remember that the exit interview is critical many times to establish that senior management will do corrective actions. This can help to minimise further FDA actions. The FDAer on the inspection has much input into the compliance division decision on how to classify the audit. If senior management seems like they don’t care, you can expect the district will try to upgrade your 483 to a warning letter. After the Inspection • After the audit, a good way to avoid a 483 is to respond to the observations www.ipimedia.com

as quickly and completely as you can. Demonstrate that you have your stuff together. FDA is not very understanding if you have repeat violations from an earlier 483. Key – remember you MUST respond to 483 observations in 15 days, or the FDA will not even open your response. You can easily flush $100,000 in consultant fees down the toilet if you do not respond within the 15-day timeframe. • Just because the auditor wrote the observation does not mean that you cannot dispute it. You may dispute the facts upon which the observation is based, or you can argue whether the observation rises to the level of a 483 observation. • This has been heard directly from the mouth of the Director of the Office of Compliance: “We know within 30 seconds of scanning your 483 response if you ‘get it’ or not.” Did we mention that answering a 483 quickly and thoroughly is really important? Random Tips • We find that quality is mostly dependent upon the culture of your company. If people from all of the departments have a shared feeling of ownership of quality, the quality of the company will be much better. If people think that only the quality department should worry about quality, you could have trouble brewing. We hope that by following the tips and guidelines outlined here, your next FDA inspection will be a much more successful and positive experience. Joseph Pickett is Owner and President of Expertbriefings. com, a leading provider of regulatory teleconferences in clinical trials, pharmaceuticals, medical devices and biological products. For more information, please visit www.expertbriefings.com. Email: communications@expertbriefings.com


PREVIEWS & REVIEWs

PRA Invests in Clinical Informatics, Expands European Footprint via Welsh Investment PRA, a leading clinical research organisation (CRO), officially opened its new facility in Swansea, Wales on Wednesday 8th May 2013. The new building, located on the Swansea waterfront, is a significant investment for PRA in Wales. The company is expanding its Clinical Informatics team in Swansea by creating more positions in the Data Coordination, Clinical Programming, and Safety groups as well as establishing a new multi-lingual Help Desk. It is planned that the expansion will create 100 new graduate-level jobs. PRA is keen to recruit high quality graduates from Swansea, Cardiff and Aberystwyth

next two to three years this recruitment drive will look to take the total Swansea group up to 200 employees, recruiting a further 100 graduates. Skills needed by the Clinical Informatics team include a knowledge and background in the biology sector, medical sector and understanding of general sciences such as mathematics. Steve Powell, PRA executive vice president, Clinical Informatics and Late Phase Services, said, “We are delighted to officially open our expanded location in Swansea. The new site has received substantial funding from the Welsh government which will mean significant job creation and support for the local

economy. As a leading CRO, we are committed to the growth of our Swansea team and to transforming clinical trials across all phases of drug development; the new building and jobs demonstrates PRA’s commitment to offering a more dynamic service to our customers, both locally and internationally.” “A number of other locations were under consideration for this important expansion project so I am delighted that support from the Welsh Government helped secure it for Wales,” said Mrs. Hart. “This investment is particularly welcome as PRA is a strategically important company within the Life Sciences sector – one of our priority economic sectors with high growth potential.” She added that the expansion will create a significant number of highlyskilled jobs across a range of disciplines over the next three years and reaffirms PRA’s commitment to Wales. Formerly based in Matrix Court, Swansea, PRA moved to Llys Tawe on Swansea’s SA1 development. The move supports PRA’s key strategic objective of creating seamless logistics from data collection through information submission for its global customer base. Clinical Informatics The new facility sees PRA doubling

Universities and the University of South Wales, for a range of jobs from programmers to data managers. PRA’s new Welsh home office was officially opened by Edwina Hart AM MBE OStJ, Minister for the Economy, Science and Transport, who announced the expansion is being supported with £1.29 million of business finance from the Welsh Government. Swansea Footprint This year marks PRA’s 17th year in Swansea, as a Welsh Government development grant in 1996 enabled the business to get five people on the ground. Over the past 17 years this has developed to a team of 100. Over the 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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its efforts in Clinical Informatics. In Swansea, the focus is on the collection and management of the data from clinical trials, managing the safety and efficacy profiles of the drugs and the trials that PRA is running. The Clinical Informatics team, focused and established, ensures that the data is efficiently collected, managed and then quickly presented to regulatory bodies around the world, like the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) to secure approval for PRA’s customers. PRA has the technology to streamline the process of data management to provide efficiencies, and is committed to transforming clinical trials with an innovative approach to pharmaceutical and biotech drug development and highly skilled teams of dedicated personnel. From data collection to submission PRA uses a standard tool to get outputs as quickly as possible. The EXACT tool ensures data is managed as quickly and appropriately as possible

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and offers significant process savings on multiple task items from data extraction to statistical reporting through the use of unique industry processes and software. Global Footprint PRA, headquartered in North Carolina in the United States, currently employs more than 5000 employees in over 50 global offices, with the Swansea operation currently providing 100 Clinical Informatics and administration staff who collect, analyse and interpret data from clinical trials. The planned expansion will double the size of the office and ultimately employ close to 200 people in the Swansea area. PRA expanded its entire global footprint this year with an announcement in January of a joint venture with WuXi PharmaTech, a leading CRO with operations in China and the USA. The joint venture facilitated PRA’s ability to offer a broad platform of Phase I-IV clinical trial services in China, Hong Kong and Macau. Since then they have also acquired ClinStar, a privately

held CRO that provides comprehensive trial and logistics services in Russia and Eastern Europe. Furthermore, in April they had received a $400,000 grant from the Kansas Bioscience Authority (KBA) to create 80 new jobs this year in Kansas. The Kansas graduates will be part of The PRA (Preparing for Research Advancement) Program, an innovative career opportunity for new college graduates interested in clinical research and the CRO industry.

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Pharmapack Europe 2013 - A Great Success!

The twelfth edition of Pharmapack Europe, which promised to be a great success, took place in Paris on 13 and 14 February 2013, fully living up to all expectations and recording its best ever level of attendance. More than 3000 visitors and 305 international exhibitors, representing key names in the healthcare industry, convened at the Grande Halle de la Villette for a comprehensive overview of the latest trends and innovations in the packaging and delivery of medicinal and healthcare products. Pharmapack Europe is the largest event in Europe dedicated to technological innovation in packaging and delivery systems for medicinal and healthcare products. The event is going from strength to strength, attracting an even greater audience this year. Visitor attendance increased by 9% compared with 2012. The trade fair exceeded its forecasts (290 exhibitors) by bringing together 305 suppliers of packaging solutions for healthcare products. This represents an 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

increase of 16% on the previous edition. The vast majority of these companies came from outside France, with nearly 60% of exhibitors representing 27 countries, including India, Finland and Tunisia, which took part for the first time. The internationalisation of the trade fair is also evident in terms of visitors, with the participation of high-level professionals from 63 countries: specialists from healthcare institutions and organisations, and key decision-makers from pharmaceutical, biopharmaceutical and veterinary laboratories (managing directors, R&D directors, purchasing managers, and others). As many visitors and exhibitors have pointed out, this edition was extremely beneficial both in terms of the wealth of participants and the quality of the programme on offer. Top-level Conferences and Workshops to Promote Innovation for the Benefit of Patients The central theme of Pharmapack 2013 was “putting the patient at the heart of

innovation�. This theme, which conveys a new approach to the development of treatment solutions, was well received by participants. A number of presentations and case studies on this topic served to highlight the features of medicinal delivery devices and pharmaceutical packaging that increase compliance with treatment requirements and result in greater safety for patients and healthcare workers. These sessions also demonstrated how the creation of innovative solutions in response to public health issues constitutes a significant lever for competitiveness and development for manufacturers of healthcare products. In the conference room, which was full to bursting during both days of the trade fair, more than 40 semi-scientific presentations and numerous debates led by a panel of international experts took a comprehensive look at regulatory changes, the latest technological advances, and current market trends, over the course of five themed sessions: • Patient safety and packaging compliance Spring / Summer 2013 Volume 5 Issue 2


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• Innovation in parenteral administration and packaging process • Innovation for pulmonary and nasal forms of drug delivery • Targeted drug delivery via convergent technologies • Sustainable packaging and materials For the first time at Pharmapack Europe, a programme of four technical workshops was organised to enable participants to discuss, with specialists and in detail, issues relating to the following subjects: • Drugs and isothermal packaging • Serialisation: Track & Trace • Medical packaging sterilisation and validation • Innovative combination products: Challenges and Approvals, EU-USA Pharmapack Awards 2013: Innovations for Better Compliance and Ease of Use Held at the end of the first day, the Pharmapack Awards 2013 ceremony revealed the most innovative solutions in packaging and delivery systems for

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medicinal and healthcare products to reach the market between November 2011 and December 2012. The panel of judges paid particular attention to innovations that resulted in real benefits for patients in terms of improved compliance with treatments. • “Compliance” category, NovoPen Echo by Novo Nordisk. This is the first insulin delivery device to combine a memory function and half-unit dosage system. The memory function displays how many units of insulin were last delivered and when, enabling children to manage their own treatment autonomously and self-inject their insulin more easily. This new device introduces an element of fun into the patient experience with a variety of stickers that can be used to personalise the pen. “Ease of use and process • simplification” category, Arnica RH (Radix) DIS by Weleda. This cardboard packaging system comprises a tamperproof closing device. Once opened, the vials (or other pharmaceutical products) can

be removed easily. The box also offers the added advantage of being resealable. • “Easy use for ambulatory care” category, blister pack carrying case, STI Plastics. This range of blister pack carrying cases has been designed to store, transport and protect plasters, blister packs, patches, etc. The packaging is made from 100% recyclable plastic and is available to suit all products of all sizes. It is quick and easy to open, and practical to handle. It is available with a day/night opening system for medicinal products packaged in a single blister pack. The thirteenth edition of Pharmapack Europe will take place on 12 and 13 February 2014 at the Porte de Versailles in Paris. This new venue will enable the trade fair to host an even greater range of expertise within an ever-more convivial atmosphere.

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PREVIEWS & REVIEWs

BIO-Europe Spring® 2013 Brought International Life Science Dealmakers to Barcelona, Spain for Partnering The seventh annual BIO-Europe Spring® international partnering conference was held in Barcelona, Spain, March 11–13, 2013, at the CCIB Convention Centre Barcelona. The event is the springtime counterpart to EBD Group’s flagship conference, BIO-Europe®, and welcomed more than 2000 participants representing over 1200 companies from 50 countries vying for an estimated 2148 licensing opportunities. Close to 11,000 one-to-one meetings took place at that event between companies across the life science value chain, from large biotech and pharma companies to financiers and innovative startups. Spain was selected as the 2013 event host based on the strength of their infrastructure that supports a dynamic life science discovery cluster. Carola Schropp, President of EBD Group, stated “Barcelona’s biotech hub is interested in new public-private partnerships with international companies, and they are committed to the global pursuit of innovation in clinical research and human health. And the role of Biocat in promoting collaboration and discovery in the Catalan region is a model of innovation.” The Host Committee for the 2013 edition was coordinated by http://www. biocat.cat/enBiocat and the http:// www.bcn.cat/en/ihome.htmBarcelona City Council —through Barcelona Activa — and through support from other sector organisations and companies from the BioRegion of Catalonia, including Almirall, Amgen, Biokit, ReigJofré, and Ysios Capital. The Barcelona region features 20 science and technology parks and 60 research centres focused on life science, notably the state-of-the-art National Genome Analysis Center, and over 450 companies in the sector. The purpose and tradition of BIOEurope Spring is in providing life science companies with high-calibre partnering 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

opportunities. In addition to productive partnering, BIO-Europe Spring offers high-level workshops, panels, http:// www.ebdgroup.com/bes/presenters/ prs_comps.phpcompany presentations, and a lively http://www.ebdgroup.com/ bes/exhibitors/index.phpexhibition. The 2013 http://www.ebdgroup.com/bes/ program/index.phpprogramme featured executive-level panellists who openly shared their insights and opinions on many important industry issues. The company presentation tracks provided a

forum for innovative startups, established biotech companies, and large and midsize pharma to present information on products, partnering opportunities and corporate strategy. Parallel workshop topics ranged from alternative financing models to personalised oncology and next-gen cancer drug development, to ways to avoid a failed POC. There were also three parallel panel discussion tracks. The business development track focused on hot topics for dealmakers Spring / Summer 2013 Volume 5 Issue 2


PREVIEWS & reviews

such as an examination of major deals from 2012, a review of 2012 IPOs and operationalising R&D. The second track, In The Spotlight, featured specific topics of interest to the industry such as market access issues in Europe, stem cell discovery and collaboration opportunities, and overcoming challenges to commercialisation of cancer immunotherapies. A popular feature of the BIO-Europe Spring programme returned in 2013. Therapeutic Insight by Defined Health was a specialised track for industry executives that provided an unparalleled understanding of transformational challenges and opportunities across the industry. Within selected disease and platform technology areas, the forum was intended to connect decisionmakers with the “big picture” of realworld drug development, partnering and commercialisation issues. The Therapeutic Insight by Defined Health track included a presentation on balancing scientific and commercial risk in the pursuit of relevance and key industry opinion leader panel discussions focused on oncology, antibiotics, and orphan CNS diseases. BIO-Europe Spring 2014 will be held in Turin, Italy, March 10–12, 2014. www.ipimedia.com

One-to-one partnering meetings for BIO-Europe Spring were scheduled prior to the event utilising partneringONE®, EBD Group’s leading conference networking solution. As the leading conference networking solution for the life sciences, the system generates over 40,000 one-to-one meetings annually at EBD Group’s six life science partnering events held around the world. With partneringONE, pharma and biotech dealmakers can create a partnering profile and begin efficiently

identifying and requesting meetings with potential collaborators. For more about partneringONE and how to log on to an existing account, go to www.ebdgroup. com/bes/partnering/index.php h t t p : / / w w w. e b d g ro u p . c o m / b e s / partnering/index.php More information for BIO-Europe Spring can be found online at http:// www.ebdgroup.com/beshttp://www. ebdgroup.com/bes or follow us on Twitter at @ebdgroup, hashtag #BES13.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 107


NEWS

Boehringer Ingelheim pioneers biopharmaceuticals move to China Boehringer Ingelheim has signed with Zhangjiang Biotech & Pharmaceutical Base Development Company in Pudong, Shanghai a strategic alliance agreement and contract to build a cGMP biopharmaceuticals facility. The new site will provide full range of development and clinical services to Chinese and multi-national customers. It will become the first facility established by a leading international biopharmaceuticals manufacturer in China utilizing mammalian cell culture technology. The facility set up will include technical process development and cGMP manufacturing which will be ready for operations early 2016. Boehringer Ingelheim plans an investment of over 35 million EUR. The project will create up to 65 job opportunities with high qualification standards. Source: Jaypreet Dhillon – IPI Staff Writer Big multiple sclerosis breakthrough A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research. In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them. The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no 110 INTERNATIONAL PHARMACEUTICAL INDUSTRY

adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens. As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin. This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. The research was supported by the German Federal Ministry for Education and Research and the Cumming Foundation. Source: Jaypreet Dhillon – IPI Staff Writer Available drugs may have a dramatic impact on children stricken with TaySachs disease A team of researchers has made a significant discovery which may have a dramatic impact on children stricken with Tay-Sachs disease, a degenerative and fatal neurological condition that often strikes in the early months of life. Available drugs may dramatically ease a child’s suffering, say scientists. “There is hope for this disease,” says Suleiman Igdoura, lead researcher of the study and an associate professor of biology at McMaster University. “Imagine what that could mean for parents who have a child diagnosed with this incurable condition, who may have only a few years with their child.” Tay-Sachs is a genetic disorder caused by the absence of vital enzymes which are involved in the breakdown of waste within cells. Without those enzymes, waste accumulates and eventually destroys healthy cells, leading to blindness, paralysis, mental retardation and eventually death. Igdoura and his team have found that when a key protein in the brain—known as TNFa—is removed, some of the devastating symptoms of Tay-Sachs and

its close relative Sandhoff, were much less severe when tested in mice. Those symptoms include spasms, muscle wasting and loss of neurological function. The findings are significant because the protein can be managed by FDAapproved drugs, readily available on the market. Source: Jaypreet Dhillon – IPI Staff Writer Faster, more potent antithrombotic drugs recommended for high-risk heart attack patients The Cardiovascular Research Laboratory of the Bellvitge Biomedical Research Institute (IDIBELL) led by the cardiologist of the Bellvitge University Hospital JosLuis Ferreiro has conducted a study on the effect of antiplatelet drugs given to high risk patients suffering from acute myocardial infaction (heart attack) in the context of the Infarction Code. The study concludes that when patients arrive to the hospital, in most cases the administered antiplatelet drugs have not worked yet. Therefore, in high-risk patients, the researhers recommend the use of faster and more potent antithrombotic drugs. The results of the study have been advanced in the online edition of Thrombosis and Haemostasis journal. Source: IDIBELL Aflibercept drug used for AMD shows no added benefit over current standard therapy The drug aflibercept (trade name: Eylea) has been approved in Germany since November 2012 for the treatment of wet age-related macular degeneration (AMD). In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG) the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether this new drug offers an added benefit over the current standard therapy. Such an added benefit cannot be derived from the dossier, however, as the manufacturer did not submit any suitable data for this comparison. The Federal Joint Committee (G-BA) Spring / Summer 2013 Volume 5 Issue 2


NEWS

specified the drug ranibizumab as appropriate comparator therapy. In its dossier the pharmaceutical company cited two approval studies of aflibercept that directly compared aflibercept with ranibizumab. But in these studies, ranibizumab was not used according to its approval status. For instance, the continuation or discontinuation of treatment was not made dependent on whether the patients had achieved stable visual acuity or not. Although the manufacturer cited other documents in its dossier, these cannot be used for the benefit assessment, as they do not allow any reliable conclusions to be drawn on the comparison of aflibercept and ranibizumab. Overall, no added benefit of aflibercept can be derived from the data presented in the dossier. The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer’s dossier and IQWiG’s assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment. Source: Jaypreet Dhillon – IPI Staff Writer Avandia Vote Ends An Era Of Drug Safety Scandals Avandia, once the most-used diabetes pill on the planet, was all but finished. After concerns emerged that it might cause heart attacks, the Food and Drug Administration in 2010 put severe restrictions on Avandia, forcing doctors and patients to register and fill out paperwork to show they understood the risks. The number of patients taking Avandia in the U.S. rapidly fell from 120,000 to 3,000. Now a panel of advisers to the FDA says that the restrictions should be eased so more patients can get the drug despite still unproven risks. An overabundance of caution can hurt patients. Seven panelists voted to remove all restrictions, arguing the evidence for any heart risk was weak; five voted to leave www.ipimedia.com

all the restriction as they currently are. Thirteen voted to change the restrictions, and described various ways of loosening them, including not forcing patients to register or to sign informed consent forms. Source: Jaypreet Dhillon – IPI Staff Writer AstraZeneca Expands in Australia to Meet China Demand UK-based pharmaceutical company AstraZeneca is investing more than A$20 million in its plant in Sydney to expand production of a key asthma medicine ahead of an expected rise in demand from China. The A$20.2 million investment, earmarked for a third manufacturing line, will nearly double production of the medication from 240 million units a year to 435 million units by 2015. It is the latest leg of AstraZeneca’s production expansion in Australia following its global sole supplier agreement reached last year with China and Japan. The move builds on Australia’s reputation as a global centre of medical innovation and proximity to China, where investment-led economic growth is expected to give way to consumer-led growth, including demand for health and medical care. The company has invested $250 million in Australia over the last decade. According to the online version of Australian Manufacturing, it has invested $80 million in production over the last five years to meet growing demand for its medicines. AstraZeneca Australia is one of Australia s largest private-sector investors in medical research and development. It is also Australia s country s largest producer of medicines. It exports AS$254 million worth of products every year, a figure it expects to rise to AS$340 million by 2015 when the manufacturing equipment is fully installed. AstraZeneca is a global biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines for a range of disease including heart, cancer, autoimmune and respiratory conditions. It employs 51,700 people worldwide,

including 1000 in Australia. Source: Astra Zeneca (India) Valeant Pharmaceuticals Announces Filing Of Preliminary Base Shelf Prospectus Valeant Pharmaceuticals International, Inc. announced that it has filed a preliminary base shelf prospectus in Canada. The preliminary base shelf prospectus was filed with securities regulatory authorities in each of the provinces of Canada. Once receipts for the final base shelf prospectus are obtained from provincial securities regulators, the final base shelf prospectus will be valid for a 25-month period during which time Valeant Pharmaceuticals International, Inc. (the “Company”) may, from time to time, offer and issue common shares having an aggregate offering price of up to US$3.0 billion. The specific terms of any offering of common shares will be contained in a shelf prospectus supplement filed in connection with each offering. As previously disclosed by the Company, the Company has entered into a definitive agreement under which the Company will acquire Bausch + Lomb Holdings Incorporated (“Bausch + Lomb”). The Company confirms its expectation that such transaction will be financed with debt and approximately US$1.5 - $2.0 billion of new equity. No securities may be sold nor may offers to buy be accepted prior to the time at which receipts for the final base shelf prospectus are obtained from provincial securities regulatory authorities. This news release does not constitute an offer to sell securities, nor is it a solicitation of an offer to buy securities, in any jurisdiction. This news release does not constitute an offer of securities for sale in the United States and the securities referred to in this news release may not be offered or sold in the United States absent registration or an exemption from registration. Source: Valeant Pharmaceuticals

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