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Volume 4 Issue 1

International Pharmaceutical Industry

Supporting the industry through communication

Peer reviewed

Amsterdam BioMet Building the Metropolitan Area for Life Sciences Early PK-PD Modeling Significantly Facilitates Identification of the Best Drug Candidates Manufacturing and Quality Control Of Liquid-Filled Two-piece Hard Capsules Automated Vision Inspection For Parenteral Closures

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PUBLISHER: Mark A. Barker EDITORIAL COORDINATOR: Jaypreet Dhillon jay@ipimedia.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Patrick Rhoden patrick@ipimedia.com DESIGN DIRECTOR: Ricky Elizabeth design@ipimedia.com CIRCULATION MANAGER: Dorothy Brooks dorothy@ipimedia.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Caroline Benton benton@ipimedia.com COVER IMAGE: iStockphoto © PRINTED BY: SW TWO UK print@ipimedia.com 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 May 2012. 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. 2012 PHARMA PUBLICATIONS Volume 4 issue 1 March 2012

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STRY IN U D

DIRECTORS: Martin Wright Mark A. Barker

Contents 6

Publisher’s letter

Regulatory & Marketplace

International Pharmaceutical Industry

Supporting the industry through communication

UTICAL IN CE

Supporting the industry through communication

PHARMA

International Pharmaceutical Industry

AL

RNATION E T

8 Patents for Stem Cells in Europe With the arrival of every dramatically new technology, patent law must evolve to keep up. When stem cell research first emerged, the law was not clear as to whether the fruits of this research could be patented. Jenny Donald, Senior Associate and Charlotte Teall, Associate in Biotechnology at Forresters discuss how the Court of Justice of the European Union (CJEU) handed down a landmark judgement which overrides all pre-existing national law on stem cell patentability in Europe 12 FlandersBio, Building Biotech Bridges FlandersBio is the umbrella organization for the life sciences and biotechnology sector in Flanders. This network brings together companies with innovative, R&D-driven activities in the life sciences sectors. Joke Comijn, Communications Manager at FlandersBio, provides an overview of Knowledge for Growth and an insight into Europe’s largest regional biotech convention. 14 ‘Molecules to Markets’ In any major pharmaceutical operation there are hundreds of different functions, departments and teams. Trying to understand how it all fits together can be a nightmare. Just to make it more complicated there are also different ‘views’ of the organisation – functional hierarchy, therapy areas, project structures, and so on. John Faulkes, Key Associate from PPMLD describes how the pharma business fits together. 20 Amsterdam BioMet: Building the Metropolitan Area for Life Sciences At the heart of European Life Sciences, the Netherlands offers a longstanding tradition of biomedical research. In the Amsterdam Metropolitan Area, scientific excellence is empowered by metropolitan strengths, turning the region into a unique hotspot for life sciences. Sandra Migchielsen, Senior Project Manager / Cluster Manager for Life Sciences at Amsterdam Innovation Motor, hosting BIO-Europe Spring® in March 2012, illustrates how the region is building its niche as the Netherlands’ only BioMetropolitan Area. Drug Discovery, Development & Delivery 26 Applying Multi-Parameter Optimisation in Drug Discovery: Explore Broadly but Focus Quickly on High Quality Compounds Finding a successful drug is a delicate balancing act. It is necessary to simultaneously optimise many, often conflicting, requirements to identify a compound that will ultimately become a safe and efficacious drug. Methods for guiding this process, commonly referred to as multi-parameter optimisation (MPO) have been developed. Matthew Segall, Director and Ceo at Optibrium explores how these can be applied in practice to improve productivity and efficiency in drug discovery. 34 De-risking Open Bioinformatics Open bioinformatics can be found in use throughout the pharma and healthcare research sectors. Anyone who has used BLAST to compare sequences, or has accessed information from GenBank or EMBL to research sequences of interest, has used open bioinformatics. Richard Holland, Operations and Delivery Director at Eagle Genomics Ltd, describes the main attraction of open bioinformatics and the ethos that ensures that it is easily adapted and modified to suit individual circumstances.

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38 A New Step on the Critical Path Revolutionary new diagnostic tools are fundamentally changing the ways in which drugs are developed and the ways in which clinical trials are conducted. Dr Clarke, Chief Scientific Officer at Lab21 Limited, looks into the significant changes in the ways in which two industries interface, and how this has led the regulatory bodies to play a leading role in shaping the ways in which future pharmaceutical development will be expected to progress. Clinical Research 44 Early PK-PD Modelling Significantly Facilitates Identification of the Best Drug Candidates Pharmacokinetics and pharmacodynamics are disciplines that can straddle discovery and development when considered in their complex physiologic relationship to one another using a sophisticated PK/PD model. Richard Slauter, Senior Director of Drug Metabolism/Pharmacokinetics and Senior Principal Study Director at MPI Research, describes how traditionally pharmacokinetics is placed in the preclinical discovery phase, because it is a series of studies that helps to narrow the number of molecules being evaluated for a particular therapeutic approach. 50 In Vivo Data – Earlier the Better – Meeting Demands for Better Data in Early Discovery Discovery scientists continually seek better data earlier to rapidly assess whether a new compound will be both effective and safe. Anthony S. Chilton, President & Chief Executive Officer at Basi, discusses how the earlier generation of relevant in vivo data, that minimises the number of animals, time and costs, would be an asset to a discovery group. 52 When It’s Documented, It Happened. A New Approach to Track Generic Drug Development Rigour of the health and medicine agencies worldwide has significantly increased over the past decade, and their scrutiny when inspecting one’s system-based approach and documentation is not a new thing any more. Public health benefits from generic drugs and agency diligence. Mihajlo Ceraj Cerić, Life Sciences Director, and Marijo Volarević, VP Business Services, at Infotehna, investigate how generic drug manufacturers can benefit utilising document management solutions in managing the drug development process. 58 Defining Pharmacometrics Pharmacometrics is an emerging science, defined as the science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions. PierreOlivier Tremblay, Associate Director of Pharmacometrics Clinical Pharmacology at Pharmanet I3, describes how pharmacometrics uses the application of mathematics to analyse vast amounts of data about disease progression, drug response, and clinical behaviour. The results help innovative drug companies and regulatory bodies alike make appropriate and well-informed decisions during the drug development process. 62 The Role of the Medical Photographer within Clinical Research Clinical research organisations are becoming more aware of the benefits of engaging with medical photographers, who are highly specialised in their profession, to ensure the accuracy, suitability and integrity of the visual data that supports or validates a clinical trial. Jo Truelove, Senior Medical Photographer at Illingworth Research, explains what was once seen as an optional extra is now being viewed as a service that has a substantial impact on proving or disproving a compound’s value in a study, potentially saving significant costs and, more importantly, lives. Labs/ Logistics & Cold Chain Supply

involves packing, insurance, customs regulations and controlling a range of risks along the way. Lucy Jenner, Marketing Manager at Charles Kendall explains why involvement in major government programmes or niche commercial contracts makes effective management of supply chains by air, sea, rail or road vital to controlling costs and maximising profit in any business. 68 Specialist Logistics for Controlled Room Temperature Shipments Many pharmaceutical products need to be kept in an environment with a particular temperature band. Temperatures of extreme cold can risk freezing products, while milder cold temperatures can still affect liquid suspensions. Similarly, heat from high temperature experiences can degrade medicines and affect the chemistry. Nathan Barnard, Cool Chain Manager at Biocair International, offers an overview of controlled room temperature. 74 Non-Invasive Method for Monitoring Real-Time Oxygen Concentrations during Hematopoietic Stem/Progenitor Cell (HSPC) Culture The SDR SensorDish® Reader has allowed for the quantitation of in vitro oxygen concentrations during the culture of hematopoietic stem/progenitor cells isolated from human umbilical cord blood. The influence of simulated physiological oxygen concentrations on HSPC proliferation, cell cycle status and expression of markers of stem cell phenotype or differentiated cell types were examined concurrently with the monitoring of real-time oxygen concentrations in the cell culture media. Timothy McKinnon, Postdoctoral Fellow at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, demonstrated the usefulness of this system for examinations of cell phenotype and function in conditions that effectively mimic the in vivo oxygen environment. Manufacturing 80 Drug Delivery: Thin Dissolving Films Begin to Come of Age Thin Dissolving Films have been in use for industrial applications for over 25 years. The first real public awareness of edible thin films was the high-profile launch of Listerine Breath Fresheners, which spawned many copycat products. Consumers decided these were imitation rather than innovation, and growth of this new technology stalled. Chris Hatton, Business Development Director at BioFilm Ltd, explains how, with the success of Suboxone Film, a unique thin film application of a controlled drug ensuring increased patient compliance; TDF technology is once again being taken seriously for pharmaceutical and consumer healthcare products. 82 Manufacturing and Quality Control of Liquid-Filled Two-piece Hard Capsules In the pharmaceutical market, hard capsules, together with tablets, are the most common dosage forms for oral administration. Concerning the manufacturing of solid dosage forms on an industrial scale, it is broadly recognised that powdered formulations are incorporated in two-piece hard gelatin capsules, while liquid or semi-solid formulations are incorporated in soft gelatin capsules, which are sealed during the filling process. Helton Santos, Head of the Department of Pharmaceutical Development at Labialfarma, explains how two-piece hard gelatin capsules can be accomplished, thus allowing the incorporation of liquid or semi-solid formulation. 86 What is Cleaning in Place? How Does it Work, and Where Should You Use It?....A Basic Primer Answers These & Many More Questions Cleaning in Place has been around for approximately 50 years, and is commonly used in hygiene critical industries, such as food, beverage and pharmaceuticals, to clean a wide range of plants. Timo Bleschke, Product Manager Pneumatic and Process Interfaces at Bürkert Fluid, explores Cleaning in Place within the pharmaceutical industry.

66 Supply Chain Management. It’s More than Just Freight Effective supply chain management requires more than the ability to transport freight from A to B. It starts with procurement and 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Volume 4 Issue 1


90 Robots Set for a Fruitful Future in Pharmaceutical Processes The food and beverage and pharmaceutical industries have often mirrored each other in the way they use similar technologies in their respective production processes. Automation is one such area, particularly when it comes to robotics. Having been embraced in increasing numbers by food manufacturers, robots are increasingly finding their way into many pharmaceutical manufacturing processes as well. Nigel Platt, Sales & Marketing Manager for ABB’s UK robotics business, explains the benefits robots have already been proven to deliver in pharmaceutical applications, and examines the scope for future application of the technology. Packaging 94 Industry-suitable Technologies to Protect Pharma Products against Counterfeiting These new measures, which improve the protection of public health, will be adopted by member states on January 2, 2013. As a result, implementing labelling, tracking and tracing systems for products will likely result in additional costs to the pharmaceutical industry. Fred Jordan, CEO of AlpVision, sheds light on several cost-effective product authentication processes and features, which can be easily deployed and implemented within manufacturing plants and laboratories worldwide. 98 Drug Product Manufacturers and Packaging Suppliers Working Together to Enhance Drug Product Quality: Automated Vision Inspection for Parenteral Closures Lynn Lundy, Regulatory Affairs Specialist at West Pharmaceutical Services, examines the use of vision inspection systems to mitigate the risk for particulates and defects associated with container closure systems. Vision inspection systems used by elastomer closure suppliers are automated, program-controlled devices that inspect all sides of elastomeric stoppers and pistons. Vision inspection allows suppliers to develop standardised procedures for improving the component manufacturing process upstream. The ultimate goal is for suppliers to work with pharmaceutical companies to provide a finished product that meets the needs of the healthcare industry. 104 Child-Resistant Packaging Accidental poisoning is common amongst young children. As a natural part of their early development children explore their environment using their senses to ‘play’ with items that are new to them. They cannot differentiate between items that are safe and items that may be harmful to them. Tim Bollans, Marketing & Sales Executive at Burgopak Healthcare & Technology, examines how child-resistant packaging has been a part of the pharmaceutical and healthcare industries for the last forty-five years, but only recently has the need for real innovation been at the forefront of the industry. Exhibitions PREVIEWS & Reviews 108 Growing Life Science Business in the Pacific Rim: BioPartnering North America The Pacific Rim refers to places around the edge of the Pacific Ocean, the world’s largest. On the northeastern rim are the US and Canada, with their vast innovation capabilities and natural resources. On the northwestern rim are the massive production capabilities and the expanding markets of Japan, Korea and China. Robert Lee Kilpatrick, Co-Founder and Partner of Technology Vision Group LLC, looks into the ways economies are also seeking to increase their global success through innovation, by harnessing science and technology, particularly the life sciences.

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Publisher’s letter Pharmaceutical companies are facing great changes to the industry — emerging science, new products and services, shifting demographics, evolving regulations, transforming business models and increased stakeholder expectations. The market for contract services in the pharmaceutical sector has been pegged back since the end of 2008, but looks set to bounce back in the next five years, with gains for contract manufacturing, research and packaging over the next five years. A report from BCC Research showed that the global market for contract pharmaceutical services was worth an estimated $177 billion in 2010, and should increase by a healthy 11.1% a year over the next five years to reach $299 billion. The lion’s share of the market is taken up by contract manufacture of over-the-counter medicines and nutraceuticals such as dietary supplements, which accounted for $103 billion of the total market this year and are tipped to grow at a rate of 11.4% to reach $177 billion in 2014. Contract manufacture of bulk- and dosageform drugs, the second-largest segment, was estimated to be worth nearly $44 billion in 2010, and is projected to increase at a compound annual growth rate of 10.8% to reach $73.1 billion over the same period. Contract manufacturers have been experiencing a lot of volatility in the market of late, as their clients adjust manufacturing capacity in the wake of the recent spate of consolidation, although this could present opportunities in the coming quarters. Big pharma is also wrestling with excess capacity at the moment, although that looks set to be offset by an uptick in new drug approvals compared to 2011. With the increasing demand to reduce capital expenditures and protect their margins, pharmaceutical companies are outsourcing their non-core activities, such

as active pharmaceutical ingredients (API) and intermediates manufacturing, to lowcost destinations like India and China. The third-largest segment, contract research, is expected to reach $40.6 billion in 2014, equivalent to a five-year CAGR of 10.7% over its present value of $24.4 billion. That comes against a decline in overall R&D spending for the industry as a whole, with smaller, research-stage companies affected by a drop in investment funding, and a decline in the value of licensing deals with larger drug-makers. The smallest segment, contract packaging, is projected to perform the worst, with a CAGR of 8%, increasing from $5.5 billion in 2009 to $8.1 billion in 2014. “Pharmaceutical and biopharmaceutical companies are dependent on the contracting companies due to increased generic competition, declining R&D productivity, rising drug development costs, constricting patent life, and fewer drug discoveries,” according to BCC. By 2016, the global pharmaceutical market, including pharmacy and hospital sales, is forecast to be worth around US$1.6 trillion at retail prices. High growth in emerging markets will leverage slow growth in developed markets. Cost-containment policies will be offset against market demands for more effective products. Health access will expand, due to increasing generic penetration. The local market is the operating environment in which companies have to work. Domestic priorities set the agenda that affects a company’s operations, therefore the prevailing macroenvironment needs to be both understood and planned for. In this way, pharmaceutical companies have strengthened their capabilities to increase sales in local and international markets. The USA will continue to be the first worldwide economy, but other emerging markets will perform well, led by China, India, Russia and Brazil. However, a second wave of emerging markets will arise, namely South Korea, Mexico, Turkey, Indonesia and Poland.

In an environment which is becoming more regulated, pharmaceutical producers are realigning their global strategies. Any investment in market information must make a real return in terms of market knowledge and business efficiency. That brings the demand that the articles we feature within IPI are of the highest quality, thoroughly researched with primary sources and with insightful analysis and forecasts. Our team of editorial co-coordinators work full time to source pharmaceutical market information from our peers that is second to none. With IPI you get comprehensive market evaluation on which you can rely. Our company motto is “Quality information = Business confidence”. With that in mind, we have brought you another set of thought-provoking articles. Jenny Donald and Charlotte Teall of Forresters look at Patents for Stem Cells in Europe. John Faulkes from PPMLD discusses ‘Molecules to Markets’. In the Drug Discovery & Development Section, Richard Holland at Eagle Genomics Ltd describes the main attraction of open bioinformatics and the ethos that ensures that it is easily adapted and modified to suit individual circumstances, in “De-risking Open Bioinformatics”. Starting the Clinical Research section, Richard Slauter from MPI Research describes Early PK-PD Modelling, whereas Mihajlo Ceraj Cerić and Marijo Volarević of Infotehna investigate how generic drug manufacturers can benefit from utilising document management solutions in managing the drug development process. Chris Hatton of BioFilm Ltd describes how Thin Dissolving Films have begun to come of age, and Nigel Platt of ABB’s UK robotics business explains why robots are set for a fruitful future in pharmaceutical processes. I hope you all enjoy this issue, and see you in May 2012.

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

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

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

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

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 & Market Place

Patents for Stem Cells in Europe With the arrival of every dramatic new technology, patent law must evolve to keep up. When stem cell research first emerged, the law was not clear as to whether the fruits of this research could be patented. In the UK and Europe, inventions which are “immoral” cannot be patented. The courts had to decide whether the use of stem cells fell inside this definition. Many national courts in Europe, including the UK, decided on this issue, but came to differing conclusions. Recently, however, the Court of Justice of the European Union (CJEU) handed down a landmark judgement which overrides all pre-existing national law on stem cell patentability in Europe. The European Patent Office (EPO), an organisation through which a patent can be obtained that is effective in all EU member states, has indicated that it will implement the decision, despite not being legally bound to do so. The content of this decision has caused widespread controversy, not least because it will have an extremely far-reaching effect and is likely to heavily impact upon the stem cell research sector in Europe. Before the Decision Prior to this decision, there were limitations on what could be patented in relation to stem cells. Human totipotent stem cells, adult or embryonic, were not patentable in the UK and Europe. This is because they have the ability to develop into a human. Pluripotent adult stem cells were patentable in the UK and Europe. However, whether human embryonic stem cells (other than totipotent cells) were patentable was open to debate. In the UK, such stem cells were patentable because those cells could not develop into a human. The focus of the EPO was on whether human embryos needed to be destroyed to obtain those cells, rather than their potential to develop into a human. The EPO applied the principle that stem cells were patentable only if no human embryos had to be destroyed in order to carry out the invention. For 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

instance, the EPO would consider an invention patentable if it used human embryonic stem cells obtained from an established cell line, and this cell line was available for use when the patent application was filed. The justification for this was that no new embryos would need to be destroyed in order to carry out the invention. Rather, the invention would provide a use for embryonic stem cells that have already been isolated and cultured, and that might otherwise go to waste. Background to the Decision The CJEU was asked by the German courts to decide upon stem cell patentability in respect of a German patent invalidity case. The patent in the case in question covered neural precursor cells derived from human embryonic stem cells, and their methods of production. The theory was that the neural precursor cells could be transplanted into the central nervous system where they would divide and replace tissue lost through degenerative diseases, such as Parkinson’s. The party contesting the validity of the patent in the German court was Greenpeace, who argued that

the patent was invalid because the European directive that governs the patentability of biotechnological inventions in Europe, known as the “Biotech directive”, prevents the patenting of technology involving the “use of human embryos for commercial or industrial purposes”. The German court was unable to decide on this matter because the meaning of the terms “human embryo” and “commercial and industrial processes” were not defined in the directive. Was the definition to include embryonic stem cells? Also, was it meant to apply to uses which are purely research-orientated, with no commercial goal? The Decision (Greenpeace and Brüstle) The CJEU decided to use a solely legal perspective, not taking into account the general consensus of the scientific world. It stated that the term “human embryo” covers any entity which has the capacity to develop into a human being, including any fertilised human embryo, and any non-fertilised human embryo that has been artificially stimulated so that it is capable of developing into a human being. Volume 4 Issue 1


Regulatory & Market Place The Court decided that scientific research is covered by the terminology “commercial or industrial processes”. It held that, if a patent has been applied for, commercialisation is a viable option. On the basis of these interpretations, the CJEU decided that if the invention required the use or destruction of human embryos at any stage in the history of the invention then it is not patentable. It stated that it is irrelevant if the stem cells can be obtained from a cell line, because at some point a human embryo was destroyed to establish the cell line. It is also irrelevant if the patent application does not specifically refer to the destruction of the human embryo. This decision leaves very little scope for patenting inventions involving embryonic stem cells. The general view is that, following this decision, in Europe an invention involving human embryos is only expressly patentable if it is beneficial to the embryo itself, for example because it improves its chances of life. Technology for treating infertility may fall into this category. The decision is binding on the national courts of all EU member states. UK legislation will therefore have to be revised to follow the directive, and the UK Intellectual Property Office (IPO) will have to take a much harder line than it has done previously when granting patents for this technology. The EPO is not bound to follow the decision, as not all of its member states are part of the EU. However, in a recent statement it has indicated that it will follow the decision. The footprint of the decision will be huge, and its effect will reverberate through medical research across Europe. Effect The upshot of the decision is that it will be considerably more difficult to obtain patents for technology involving stem cells in Europe. While prospects for stem cell patenting were limited before the decision, they are now very narrow. Inventions involving the use of induced pluripotent stem cells (iPSCs), artificially-produced stem cells derived from an adult cell that has been genetically re-programmed are likely 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

still to be patentable, because their production does not involve the use or destruction of a human embryo. Other embryonic stem cell substitutes which do not involve using human embryos should also be patentable. Nevertheless, there is no escaping the conclusion that this decision is a significant blow to Europe’s stem cell research sector. There are understandable fears that investors in this sector will cease to put money into Europe, without a patent to protect their investment. They may be more inclined to invest abroad in jurisdictions, like the US, where patents for this technology are easier to obtain. In addition, stem cell research companies may well relocate out of Europe, which would be a major setback for the biotech industry in Europe, since Europe is a leading player in this field of research. In addition, it is not clear what effect this decision will have on the validity of stem cell patents that have already been granted. It seems probable these are now unenforceable. If so, this may further injure the industry, if investors decide to pull out because they have lost patent protection for the technology in which they have invested. This decision will undoubtedly be bad news for research scientists in Europe. Greenpeace, and pro-life organisations, on the other hand, have hailed the decision as a victory for morality. Advice for Applicants If you intend to file a patent application for an invention involving stem cells, or you have already filed such an application, we recommend that you seek the advice of a patent attorney to assist you in the drafting of your application, to ensure it does not fall foul of this decision. If the invention necessarily involves the destruction of a human embryo in order to be put into effect, then it is unlikely that you can obtain a patent in Europe. For the affected cases in Europe, some protection can still be provided by the data exclusivity period afforded by a European marketing authorisation. This can be anything between six and ten years, which can keep generics companies out of the marketplace during that period. Patent protection can also still be

pursued in other jurisdictions, such as the US. If you would like advice on how this decision might affect your business, we at Forresters would be happy to discuss this with you. Our Life Sciences team are highly experienced in handling patent applications involving stem cell technologies at both the UK IPO and the EPO.

Jenny Donald S e n i o r Associate – Biotechnology J e n n y specialises in patent prosecution in the UK, Europe and elsewhere in the world. She mainly works in the fields of biotechnology, pharmaceuticals and medical devices. Jenny has particular experience of patent prosecution at the European Patent Office, including experience with opposition and appeal procedures. She also has comprehensive experience in obtaining Supplementary Protection Certificates. Jenny is primarily based in our London office, but spends several weeks each year in Munich for dealings with the EPO. Jenny is a UK and European patent attorney and is a member of epi and CIPA. Email: jdonald@forresters.co.uk

Charlotte Teall Associate – Biotechnology Charlotte specialises in biochemistry and is primarily involved in the drafting and prosecution of patent applications in the fields of biotechnology, pharmaceuticals and medical devices. She also handles Supplementary Protection Certificates in Europe, including in the new European member states. Charlotte is primarily based in our London office, but spends everal weeks each year in Munich for dealings with the EPO. Charlotte is a UK and Europeanpatent attorney and a member of epi and CIPA. Email: cteall@forresters.co.uk

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FlandersBio, Building Biotech Bridges FlandersBio is the umbrella organisation for the life sciences and biotechnology sector in Flanders. As a dynamic, non-profit, fee-based organisation with 245 members, our mission is to support and foster the sector’s sustained development. Our objective is to ensure that biotechnology remains a strong driver of economic growth in the region. By organising networking activities we build bridges between the different actors, and by actively stimulating innovation and R&D, FlandersBio creates added value for the sector as a whole. The FlandersBio network brings together companies with innovative, R&D-driven activities in the life sciences. Our corporate members are involved in a wide range of activities in red (healthcare), green (agricultural) and white (industrial) biotechnology. They develop biopharmaceuticals,

vaccines, medical technologies, diagnostics, bioIT products, genetically modified crops, enzymes, biofuels… Our network also welcomes companies with production activities based in Flanders, as well as academic research institutes and providers of capital, services and technologies to our life sciences community. And because we believe a good network provides a fertile soil for growth and development, FlandersBio is developing both a regional and an international network of medical, plant and industrial biotech actors. Direct contact between the biotech companies on the one hand, and service and technology providers, capital providers, research institutes, universities and government representatives on the other, offers clear strategic advantages. FlandersBio brings all these players together in one single network.

Knowledge for Growth, Europe’s largest regional biotech convention On Thursday 24 May 2012, FlandersBio will organise the 8th edition of its annual life sciences convention, Knowledge for Growth, in Ghent. Knowledge for Growth is Europe’s largest regional biotech convention, attended by over 1000 individual participants, representing 330 companies and organisations active in the life sciences (61% being representatives from the industry, and 39% academics). Consequently, Knowledge for Growth is the networking event of the year for the sector, featuring an extensive programme of business and scientific lectures (over 40), a space with company booths; and a poster exhibition. Last but not least we will also organise a job fair, giving companies and jobseekers in the life sciences the opportunity to get to know each other. www.flandersbio.Be

Joke Comijn has a university degree as biotechnologist and a Ph.D. in molecular biology. Interested in science and biotechnology communications, she started in 2005 a career in science communications at VIB, the Flanders Institute for Biotechnology. Since April 2009, she is communications manager at FlandersBio. She is responsible for the overall communication and the networking with the FlandersBio members, the biotech industry at large, the policy makers and the public. Email: joke.comijn@flandersbio.be

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Regulatory & Market Place

Molecules to Markets Jenny Allen is having a bad day. She sits at her desk, not knowing what to do next. For the first time since she joined this large pharma company, she’s regretting having left her successful IT role in a finance company. Her key role in this job is the review of systems for the commercial function and in particular she’s been tasked to replace two very similar current packages with one new one. The commercial guys are not motivated to change, so Jenny’s challenge is to present a convincing proposal. But there’s a big problem – she just can’t get her head far enough around what these systems do! One is something to do with ‘country reimbursement system intelligence’. The other is ‘market access plans’. They’ve been explained, but she still doesn’t get it! In theory, things should be easier for Paul Thomas. Unlike Jenny, who does not understand the vast tsunami of scientific and process jargon she’s met since she joined, Paul is a preclinical scientist with fifteen years’ experience in the industry, and understands most of how it operates. But he’s just returned from a project meeting where sudden changes in trial plans were announced. His clinical colleagues asked for urgent changes in the toxicology testing programme, seemingly without any acknowledgement of how much work has been done so far. Paul’s set up contractor agreements, schedules, timelines and up until this moment the whole programme has been virtually ready to start. It just can’t be changed that quickly. Why can’t they think it through? The Benefits of Knowing the Business Later in this short article, we’ll tell you a little bit about how the pharma business fits together. But first, why should you need to know that? The scenarios above describe situations typical in the pharma industry. To some extent, we’re always 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

going to be at risk of this degree of inefficiency, due to the complexities we deal with. But we may be able to minimise the damage, and the stress levels with a bit of education. There are four main benefits if we do: 1. Mutual understanding – Perhaps more than any industry, our products require the collaboration of a greatly diverse mix of specialities and disciplines. People who work in these functions are increasingly stretched. An attitude we all may be guilty of is thinking that our own jobs are complex, whereas others’ are straightforward. So why don’t they just get on with them and deliver what should be easy? Just what’s just happened to Paul Thomas. Well, it helps if we have a window into what others’ stresses are; what’s involved in doing what they do. It makes it much easier to collaborate, think in advance of sudden requests and make better decisions. 2. Engagement of support functions – As we saw above with Jenny, many of our people in HR, IT, finance and so on cut their working teeth in other industry sectors. They take jobs with us and are expected to deliver results quickly. They are however faced with internal customers who, try as they might, are not very good at translating their jargon into lay persons’ language! If Jenny could get a detailed grounding in how the business really works, she would be much better placed to achieve what might be very necessary improvements in business infrastructure. 3. Motivation – It’s well known that an understanding of ‘purpose’ is a key part of what motivates us. So for the guys in Paul’s toxicology team, even if the extra work necessary to meet the clinical deadlines is clear and agreed, it won’t necessarily motivate them. They know that a molecule must have a proven safety profile. But if they knew that the side-effect profile is a major part of a new drug’s unique

value; that the health authorities are particularly sensitive to this; that the safety profile is pivotal to achieving the best price when the drug goes to market, thus generating profit to keep the company secure, this may make a difference to how they view the task. Some business education would help them to grasp how they really fit in with the commercial imperatives of the company. 4. The aftermath of mergers and major changes – When the dust has settled, there frequently are new and changed ways of doing things. Decisions are made differently. Functions that weren’t there before, now are. Other functions that were there, have been outsourced. All of the players in research, development, marketing and supply may be reorganised, and may be spread over a network of collaborating companies. They can all benefit, and therefore the extended organisation can benefit, from a good knowledge of how things operate in the new world. So What Happens from ‘Molecules to Market’? In any major pharmaceutical operation there are hundreds of different functions, departments and teams. Trying to understand how it all fits together can be a nightmare. Just to make it more complicated there are also different ‘views’ of the organisation – functional hierarchy, therapy areas, project structures, and so on. Companies sometimes have 100+ page manuals that describe all of this. However these are impossible to use for most people, who have busy jobs and no time to wander through dense swathes of jargon. We can explain things at a reasonable level of detail, but using just three perspectives: 1. Essential functional groups 2. The key stages of activity 3. Therapy areas and cross-functional decision-making Volume 4 Issue 1


Regulatory & Market Place The best news is that all of these can easily be represented on one comprehensive diagram. This is shown in Figure 1. Figure 1: Molecules to Market – overview diagram This value-chain diagram shows (1) the key stages (at top) of a project leading from research work with molecules, right through to local market sales worldwide. (2) Key functions work in parallel to make this happen and these are shown as coloured bands. (3) At key milestones (the red chevrons), major ‘go / no-go decisions are made by senior crossfunction teams, shown as vertical shapes.

1. Essential Functional Groups Any one pharmaceutical product that is supplied to the market has in its history been worked on by a great number of different experts. But in practice we can group these people into just eight, perhaps nine, key groups. These are shown below, but also as differently coloured bands in Figure 1.

16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To some extent, staff from each of these functional groups are going to be involved at most stages along the timeline of development for a product. But as we can see, there is a concentration of functional effort at particular times. So for example, for drug safety assessment activities – the yellow band on Figure 1 – most of these guys’ work is done in one of the key stages of activity. 2. The Key Stages of Activity Any one new product that is developed from molecules to market passes through several stages of activity, each one with a different focus. Essentially, there are four discernible periods – termed different things in different companies, but call them discovery, exploratory development, full development and commercialisation. Between them, there are pivotal decision points, where a project has to be assessed as to whether it has shown itself robust enough to continue. As we know, of all the projects that start out, some 3% or less will make it as successful products. A key part of the effectiveness of our project management is to coordinate the work done in each stage, so that all of the key functions work in parallel, communicate regularly and share knowledge. In many pharma companies there are many more smaller decision milestones than the three shown in this article, and a project team will have to prepare data for all of them. The four stages, with the milestone decisions that separate them, are shown below:

The above can best be described as ‘business’ stages, in that an asset – a potential product – increases in value as is passes each of the key milestones. But, there are some stages of activity within the overall development

chain that are used everywhere as the lingua franca of mid- and latestage development, and these are the clinical trial phases. How they fit into the whole is shown in Figure 2. Figure 2: Clinical Trial Phases Phase 1 – small studies on paid volunteers to see how the drug behaves in the body and identify any potential side-effects Phase 2 – with 100s of disease patients – to get an idea of if and how the drug works Phase 3 – large international studies, 1000s of patients – to prove to external bodies that the new product has value enough to be approved and attract a premium price Phase 4 – post-launch studies, conducted worldwide, to build new treatment uses and establish a wide base of safety data

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Regulatory & Market Place 3. Therapy Areas and CrossFunctional Decision-Making A traditional organisation chart is plotted ‘top down’ – but if the chart can be imagined turned on its side, we’ll have the functional view shown in Figure 1. Crossing this in a vertical slice is the ‘cross-function’ matrix.

At the project level, a team draws representatives from each of the functions to progress operational plans. At the senior level, companies typically group projects into ‘therapy areas’ – drugs for cancers, nervous system diseases, cardiovascular diseases, and so on. At the head of each is a cross-function group of senior execs, that make the ‘milestone’ decisions about each project. Sitting on these ‘portfolio teams’ are typically commercial, scientific and financial managers, to ensure that the most objective decisions are made. In our business, uncertainty is inevitable, but silly mistakes don’t have to be. How Can People Learn About All This? Going back to Jenny and Paul’s experiences at the start of this article, we should say that people require much more detailed exposure to this education than this brief overview. But we have three main challenges when we attempt to educate people about all this. Firstly, there’s an enormous amount of detail we could cover. In our experience, once you start talking to people about just one of the activities, they ask endless questions about how things work! This is on one hand very positive – it creates a dynamic atmosphere in the training room – but it means we’re going to run into the second challenge – almost always we’ll have less time available than we need to cover everything. Also it must be remembered that as well as talking 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

about our own ways of developing and marketing products, we have to explain something about the external world – the changes in the customer and regulatory environment, for example, to put our own strategies into context. We have found that in practice, most companies would not run such a training programme for anything longer than one-and-a-half or two days max, when three would be ideal. The third challenge is inevitable boredom. A good presentation about drug research, followed by an active Q&A session, is fine. But then we follow it with the same sort of thing, but about toxicology. Then another about patents. We can end up with a vast seminar, halfway through which most people are turning off.

2. Do it in smaller chunks As we’ve seen above, there are reasonably clear stages of development, each with their own distinct objectives. These can easily be addressed in halfday modules. Obviously some people are experts in certain functional work – they can attend some, but not all of the other modules.

We have found there are several ways that we can overcome these problems:

John Faulkes began his career as a scientist in the Pharma Industry, then in learning and development, specialising in project leader and team coaching. He helps companies to build collaboration and communication. Also he runs the ‘Molecules to Markets’ programme worldwide, as a training course with eLearning options, as needed. Email: john.faulkes@ppmld.com

1. Drive it with simulations We have found it enormously useful to create simplified, yet realistic, exercises that give people a window into the dilemmas encountered at stages throughout product development. Most of the learning comes through teamwork and discussion, maintaining energy and interest throughout a course.

3. Use an online / classroom mix Much of this sort of education is about absorbing information, and much of that is readily documented in online reference / eLearning media. Pharma people these days are constantly accompanied by their laptops, iPads and smartphones. Why not make the knowledge readily accessible, at any time?

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Regulatory & Market Place

Amsterdam BioMet: Building the Metropolitan Area for Life Sciences

At the heart of European life sciences, the Netherlands offers a longstanding tradition of biomedical research. In the Amsterdam Metropolitan Area, scientific excellence is empowered by metropolitan strengths, turning the region into a unique hotspot for life sciences. Hosting BIO-Europe Spring® in March 2012 illustrates how the region is building its niche as the Netherlands’ only BioMetropolitan Area. Biobusiness… The Netherlands is a vibrant and open life sciences & health (LSH) Cluster. Latest figures on the cluster, 2009 compared to 2010, show growth both in size and products 1. The number of companies within the innovative core of the Dutch LSH Cluster increased by 5% to 329, and the number of products grew 7% to 111. The Cluster is stimulated by increased public investments, and scored above average compared to other international key LSH clusters. Public investment went up 19% to €297m, due to an increase in credit available for innovation. With the help of MSD and Philips Healthcare, the Dutch LSH Cluster scored above average on revenue (€17.7bn in 2010). With many new companies originating from research institutes, excellent science is a key success factor of the Dutch LSH cluster. In the Netherlands, government, academia, companies, care professionals and patients work 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in close collaboration to achieve economic growth2,3. Founded in Scientific Excellence… The Netherlands has a robust academic system, with eminent scientists in biomedical life sciences. The Metropolitan Area contributes strongly with 8000 students and 5330 scientists. The city is home to two universities (University of Amsterdam and the Vrije Universiteit) with their academic hospitals (AMC and VUmc) and numerous specialised research institutes such as the highly respected Netherlands Cancer Institute (NKI), the Netherlands Blood Supply Foundation (Sanquin), the Netherlands Institute for Neurosciences (NIN) and ACTA, which recently opened the most advanced dental education and research facility in the world. Together they provide industry with easy access to many innovative technologies, standardsetting technological infrastructure, clinical trial capabilities, patient cohorts, bio-banks and centres of expertise. Life Sciences Center Amsterdam and Tracer Center Amsterdam are examples of how the Amsterdam Metropolitan Area integrates and positions its knowledge infrastructure for industry collaborative research. Life Sciences Center Amsterdam (LSCA) clusters and represents the full range of life sciences research in the Amsterdam Metropolitan Area, offering efficient access to a critical mass of translational and clinical research

opportunities for companies in search of innovation. One visit to Amsterdam provides access to translational research within many areas, including cardiovascular diseases, infectious diseases and immunology, CNS, oncology and a range of medtech opportunities. www.amsterdambiomed. nl/lsca Tracer Center Amsterdam (TCA) is a high-tech hub for collaborative R&D, focused on tracer design and development for biomedical imaging. It combines the strengths of Amsterdam’s key opinion leaders in the fields of oncology, neurology and cardiology with the cutting edge infrastructure and leading expertise in the field of tracer development. TCA is embedded within university medical centres, giving industry and other academic researchers access to the clinic experts and patient groups essential to translation. Unified in the Amsterdam BioMed Cluster… Within the Amsterdam Metropolitan Area, the Amsterdam BioMed Cluster is the unifying force in the region’s life sciences. It stimulates entrepreneurship by exploiting synergy between knowledge institutes, businesses and government, and opens up the regional knowledge and technology base to national and international partners interested in doing business. Today the Cluster counts over 370 partners, amongst which are 117 life sciences companies. Volume 4 Issue 1


Regulatory & Market Place Half of these belong to the innovative core, and a quarter are home-grown university spin-offs. The Amsterdam Metropolitan Area contributes 18% and 19% to the Dutch LSH Cluster in terms of innovative businesses and employees, respectively. While the region’s science parks offer start-up companies an environment to grow, (multinational) companies like Teva, MSD, Abbott and Genzyme, with headquarters, production, marketing & sales, or clinical trial functions, can be found distributed over the region. The Amsterdam Innovation Motor manages the Cluster and, together with cluster partners, bids for funds to undertake projects that stimulate innovation and growth. Under the direction of the Amsterdam Economic Board, Amsterdam BioMed Cluster works on completing and strengthening the overall life sciences innovation value chain with a focus on knowledge exploitation4. Empowered by the Amsterdam Metropolitan Area In line with the region’s metropolitan nature, it houses over 250 life sciences service providers, amongst which are multiple CROs, CMOs and VCs. Financial, business and supply services abound, a mature life sciences business chain exists. Moreover, the regional life sciences industry takes advantage of the many opportunities for cross-overs with other strong metropolitan clusters (Fig. 1). Close links with the Amsterdam ICT Cluster provide opportunities for testing the latest digital health applications in a living lab environment (see HealthLab example). Logistics and the financial and business services sector offer integrated services to foreign life sciences companies entering the European market (see BioPortEurope example). Health-Lab develops and tests, with the help of regional partners, digital health solutions in a living lab environment. The Amsterdam Metropolitan Area has an e-ready and diverse population, placing it at the forefront of testing new ICTbased, innovative (care) technologies. www.health-lab.nl The complexity of the life sciences market demands specialised knowledge and practical support. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure. 1 Amsterdam BioMed Cluster in the context of the Amsterdam Metropolitan Area: building the Life Sciences & Health Cluster on opportunities for cross-overs with other strong regional clusters. Some examples.

BioPortEurope is a professional life sciences expertise and trading centre providing integrated business services to Indian life sciences companies wishing to operate in the European market. Amsterdam inbusiness, the official foreign investment agency of the Amsterdam Metropolitan Area, assists international companies to get started in the Amsterdam Metropolitan Area. Services are free, confidential and without obligation. www.bioporteurope.nl BIO-Europe Spring® 2012 Ranking fourth in the European Cities Monitor 2011, Amsterdam is one of the most accessible locations in Europe, being well connected, both physically and digitally, to markets and customers. It has a strong international orientation, which makes it a magnet for talent and businesses and a focal point for (international) conferences. Building on its strong scientific heritage and metropolitan strengths the Amsterdam Metropolitan Area is quickly becoming a hotspot for life sciences in Europe. In this context we are very proud to host BioEurope 2012 in Amsterdam together with our national Cluster organisation LSH. This is our opportunity to showcase the Dutch LSH sector. We invite you all to partner and do business with us in the Netherlands. You will find a complete life sciences innovation ecosystem for success and growth in Amsterdam BioMet. References

1. L ife Sciences Health and The Decision Group, Dutch Life Sciences Outlook 2012, 2012 2. Topteam Life Sciences, Topsector Life Sciences & Health, For a healthy and prosperous Netherlands, 2011 3. Regiegroep Life Sciences & Health, First version of the innovation contract from the topsector Life Sciences & Health, Investing in research, development and innovation for a healthy and prosperous Netherlands, 2012 4. Amsterdam Economic Board Life Sciences kerngroep, Rode Life Sciences, Clusterstrategie Kennis & Innovatieagenda, 2011

Sandra Migchielsen is senior project manager/ cluster manager for life sciences at Amsterdam Innovation Motor. After obtaining her PhD at Leiden University (1996), she managed and developed Elsevier’s (In)Organic Chemistry portfolio (19972006). Currently, together with industry, academia and the public sector, Sandra initiates projects that strengthen the knowledge based economy of the Amsterdam Metropolitan Area in the life sciences field. See also www.amsterdambiomed.nl. Email: sandra@aimsterdam.nl

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Regulatory & Market Place

Biotechnology Unites the Central European Countries For some 11 years, the BioForum trade fair (www.cebioforum.com) has been attracting to Łódz, ´ in the centre of Poland, a number of biotech sector representatives. Attendees come not only from Poland and other Central European countries, but also from other countries from all over the world, where the biotech sector plays an important role in the creation of innovative biobusinesses. Last year, the BioForum organisers announced changes in the concept of the event. From 2012 BioForum will change its location and become a rotating event that is ‘moving’ within Central Europe. What does this mean in practice? In 2012 BioForum will be held in the Czech Republic, followed by Hungary (2013) and Poland (2014). “Observing the biotech sector development and the potential of the Central European biotech market, we have seen a great possibility for SMEs from the Central Europe (CE) region to attract the biggest players in this business sector. Acting individually, enterprises from CE have problems getting into the global market. By joining forces and acting as one team, they may become more attractive and visible players. BioForum is a place where biotechnology startups from the Czech Republic, Hungary and Poland can jointly present their activities. We believe that by working united, we may strengthen the CE biotech attractiveness and make our potential clearly visible to big biotech consortia, while at the same time facilitating the creation and development of a network between companies from the CE region. By organising BioForum 2012 in Brno, the Czech Republic, we also intend to attract companies from other parts of Europe which are geographically closer,” explains the main organizer of the fair, Bio-Tech Consulting Ltd. (www.biotechconsulting.pl). The strategic partner of the 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

upcoming edition of BioForum is the South Moravian Innovation Centre (JIC – www.jic.cz) – a Czech regional intermediary agency supporting the creation and development of innovative enterprises in the South Moravian region. The role of JIC is to assist the main organiser in the organisation of BioForum 2012 in Brno, and to promote the event in the Czech Republic. “BioForum is definitely one of the most important biotechnology events in Central Europe, presenting the potential of the biotechnology and life science sectors in this area. The event provides its participants with various opportunities for presentation and networking, combining matchmaking, exhibition and conference programme. Attending BioForum is a chance to get information about the latest technologies and trends in this field. This information and the valued contacts that can be established during the event may well lead to new opportunities for young biotechnology startups and commercialisation of new technologies,” says Jirí Hudecek, CEO of JIC. “Life sciences and biotechnologies have been identified as one of the four priority research fields and industrial sectors in the South Moravian region. JIC decided to take part in BioForum, since it is a great chance to highlight this dynamically developing sector and attract both academia and industry from abroad to Brno. We also believe that the shift of BioForum from Lodz (Poland) to Brno (Czech Republic) will make the event more easily accessible to participants from the countries of Western Europe. And, last but not least, increasing the critical mass of such an event in life science events, that will now combine representatives of this sector from both Poland and the Czech Republic, will certainly be of mutual benefit to the organisers and participants,” adds Hudecek.

South Moravian Innovation Centre (JIC) is a regional intermediary agency founded by the South Moravian Region, the City of Brno and four local universities. The mission of JIC is to effectively support the foundation and development of innovative companies and exploit the local R&D potential for the economic development of our region. The activities of the centre include support services for both startup and already established innovative companies, technology transfer, cluster development and internationalisation. JIC acts as a regional platform for coordination of technology transfer and internationalisation activities in the region. JIC has experience in supporting the creation of spinoff companies and its Innovation Park hosts nearly 50 technology companies, most of them based on strong collaborative links to local research teams. One of the incubators, Innovation Park INBIT, is specifically dedicated to life science, and represents a unique example of such a facility in the Czech Republic. BioForum is the biggest and the most important event in Central Europe dedicated to the biotech and pharma industry. Established in the year 2000, it has as a main aim the creation and development of a cooperation platform between companies from the life science sector in the CE region. The creator and the main organiser of BioForum is Bio-Tech Consulting Ltd. www.biotechconsulting.pl

BioForum – Central European Forum of Biotechnology & Innovative BioEconomy – together with accompanying events will be held on 23rd-24th May 2012 in the Conference Centre BVV Trade Fairs in Brno (Czech Republic). www.cebioforum.com Volume 4 Issue 1


Drug Discovery/ Development & Delivery

Applying Multi-Parameter Optimisation in Drug Discovery: Explore Broadly but Focus Quickly on High Quality Compounds Introduction Finding a successful drug is a delicate balancing act. It is necessary to simultaneously optimise many, often conflicting, requirements to identify a compound that will ultimately become a safe and efficacious drug. Methods for guiding this process, commonly referred to as multi-parameter optimisation (MPO), have been developed1 and in this article we will explore how these can be applied in practice to improve productivity and efficiency in drug discovery. When searching for a potential drug it is not sufficient to find a highly potent compound against the intended therapeutic target; selectivity against off-targets, appropriate pharmacokinetics and an absence of toxicity at the therapeutic dose are also necessary to reach the market and achieve a strong position. Unfortunately, these requirements are often conflicting; for example, increasing lipophilicity will often improve potency but this is also correlated with poor absorption, increased metabolic clearance and a higher chance of non-specific toxicity. The high rate of attrition in pharmaceutical R&D and the increasing cost attest to the challenge that this balancing act presents. One key to reducing costs and reducing late stage attrition is to simultaneously consider as many compound properties as possible from the earliest stages of drug discovery. By identifying high quality compounds with a good balance of properties as early as possible, resources can be focused on the areas of chemistry with a high chance of downstream success. An overly narrow focus on a single property, typically target potency, early in the optimisation process can be risky. Avoiding this reduces the chance of encountering a dead end, where a critical property cannot be achieved within a potent lead series, leading to many, long iterations in lead optimisation. 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The need to generate data on many properties for potentially large numbers of compounds has led to the development of high throughput in vitro assays and in silico models for a wide range of physicochemical, absorption, distribution, metabolism and elimination (ADME) and toxicity endpoints. However, the avalanche of data that these can generate poses a new challenge for drug discovery scientists; how to analyse this data effectively in order to make good, quick decisions regarding the selection and design of compounds. The human brain is not reliable when juggling complex data to make decisions. Unconscious biases can often impact on efficiency and productivity 2. Furthermore, this challenge is heightened by the fact that the data generated in early discovery almost always has significant uncertainty due either to experimental variability or statistical error in predictive models. This underlying uncertainty brings its own challenge; using even the best experimental or predictive methods in early discovery, it is impossible to say with confidence that a given chemistry will achieve the goals of a project. Furthermore, it is easy to incorrectly discard a compound based on an uncertain piece of data, leading to missed opportunities to find a good drug. Therefore, while it is important to focus quickly on the best chemistry for a drug discovery project, it is also necessary to first explore broadly. Where possible a range of possible avenues for exploration should be identified, which can be studied in detail to validate the initial hypothesis and confirm the direction the project should take. MPO methods that address these issues, have been used in a wide range of fields from engineering to economics and, more recently, drug discovery. In this article we will discuss how MPO can be applied

effectively in drug discovery to guide rigorous and objective decisions on the selection and design of compounds. Multi-Parameter Optimisation A wide range of MPO methods have been applied to compound optimisation in drug discovery; a detailed review may be found in reference 1. Probably the most common approach is the use of rules of thumb, such as Lipinski’s Rule of Five (RoF) 3, that provide guidelines for the characteristics of compounds that are similar to those of successful drugs. These are very easy to interpret and apply, which has led to their undoubted popularity and positive effect on the quality of compounds. However, these simple rules have significant limitations: the correlation between the simple characteristics employed by these rules and the complex biological endpoints are not strong; the rules are typically defined for a particular goal, e.g. oral absorption in the case of the RoF, and application to selection of compounds for other objectives may not be appropriate; and these simple rules are often applied to filter compounds making inappropriately harsh distinctions between compounds, for example a compound with a calculated logP of 5.01 is not significantly worse than one with a logP of 4.99, particularly given that such a calculation typically has an uncertainty of approximately 0.5 log units. These limitations can lead to missed opportunities and wasted effort. More sophisticated methods for MPO can bring together data of any type, experimental or predicted, allowing acceptable trade-offs to be defined and allowing for uncertainty in the underlying data to be rigorously taken into account. For example, the Probabilistic Scoring method, employed by the StarDrop™ software 4, allows a desired profile Volume 4 Issue 1


Drug Discovery/ Development & Delivery of property criteria to be defined by a user or project team as illustrated in Figure 1. This ‘scoring profile’ allows the requirements for each property to be defined along with the relative importance of each individual criterion to the overall success of the project. In addition to simple thresholds or ranges, more subtle relationships between the property value and a compound’s desirability can be defined as a ‘desirability function’ (also illustrated in Figure 1). Once this is defined, the data for each compound are assessed against the scoring profile, taking into account the uncertainty in the data due to experimental variability or statistical error in a prediction. The result is a score that estimates the likelihood of success of the compound against the ideal profile of properties and an uncertainty in the overall score. In turn this allows compounds with a good balance of properties to be easily prioritised and makes it clear when compounds can be distinguished with confidence.

www.ipimedia.com

In turn this enables the project team to focus effort on chemistries with the highest chance of success while avoiding missed opportunities when the data does not support confident rejection of compounds. This is

illustrated in Figure 2. Given the uncertainty in the data and hence in the overall assessment of compound quality, it may also not be appropriate to focus too heavily on a single series of closely related

Figure 1. An example of a multi-parameter scoring profile defining the properties of interest, the criterion for each property and the relative importance of those criteria. Underlying each criterion is a desirability function defining the relationship between a compound’s property value and how likely it is to achieve the project’s objective. An example is shown to the right, in blue, for the target potency (pKi). This indicates that ideally the pKi would be greater than 8 (Ki lower than 10 nM), below a pKi of 7 (Ki greater than 100 nM) the compound would not be of interest, and between a pKi of 7 and 8 the desirability increases linearly. The histogram in the background shows the distribution of pKi values in the data set.

Figure 2. Graph illustrating the output of probabilistic scoring. The compounds in a data set are ordered along the x-axis from the highest to lowest scoring. The score is plotted on the y-axis along with error bars showing the uncertainty (1 standard deviation) in the overall score due to the uncertainty in the underlying data.

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Drug Discovery/ Development & Delivery compounds. In particular, early in a project it is also important to explore a broad range of diverse chemistries to mitigate risk, investigate potential backup series and, where predictive models are being used, validate the predicted hypothesis. Achieving this balance between quality and diversity is also a form of MPO, and a number of approaches have been developed to assist the exploration of this trade-off. It is not possible to sort compounds by their diversity; the diversity is a property of a set of compounds, therefore achieving a good balance of diversity and quality requires many different selection strategies to be explored; for example there are 3×10 25 ways to select 30 compounds from a set of 100. Many of the methods to guide the exploration of this trade-off are based on ‘genetic’ algorithms that use the principles of evolution to ‘evolve’ a population of different selection strategies and identify one that achieves an appropriate balance 5. Examples of two such trade-offs can be seen in Figure 3, showing the effects of changing the Figure 3. Examples of two selections of 20 compounds from a set of 267. For each selection, the ‘chemical space’ is plotted to illustrate the diversity of the full data (the diversity is defined by Tanimoto similarity of 2D fingerprints) and each point is coloured by score from high (yellow) lo low (red). A similar graph to that shown in Figure 2 is also plotted for each selection. (a) illustrates a selection biased towards score in light blue. This shows that the compounds are selected from the highest-scoring, but that they are focused on a few small regions of similar chemistry. (b) illustrates a selection biased more towards diversity, selecting a wider range of both diversity and score.

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bias in the selection from quality (score) to diversity. Practical Application of MPO MPO algorithms provide a powerful basis to guide the efficient identification of high quality compounds. But how can they be applied in practice in drug discovery? The full value of these approaches can only be realised if they are easily accessible to all decisionmakers in a project. The majority of these are experimental scientists responsible for the design, synthesis and testing of compounds. Analysis by computational experts provides valuable insights into design decisions, however this analysis often introduces a delay before the results can be determined and reported back. The greatest impact on project decisions comes when many strategies can be explored, with instant feedback, before reaching a confident decision. Therefore, it is important that access is via a userfriendly interface through which it is possible to define multi-parameter objectives and then interpret the results in a visual way. It is also important that the algorithms are not ‘black boxes’

that accept data and output a result with little or no explanation. The objective is to provide tools to guide the decisions of experts not to automatically make a decision to be accepted blindly. Therefore, the output of the analysis must provide clearly interpretable results and guidance on potential issues or strategies for improvement. Some illustrative examples are shown in Figure 4. MPO methods may be applied throughout the drug discovery process. When designing libraries for use in high throughput screening it is important to cover a wide diversity of chemistry to ensure the greatest chance of finding a potent hit. However, even here, it is beneficial to select compounds with appropriate properties to provide good starting points for hit-to-lead wherever possible. In focused library design, the results of virtual screens can be combined with predictions of other important compound properties to provide good quality hits. During hitto-lead, the goal is to identify one or more high quality lead series; here it is important to find series with good ADME properties and no overt toxicity in order to give the best chance of rapid progress through lead

Figure 4. Two examples of visual feedback that help to guide the redesign of compounds in order to improve the overall chance of success. The histogram in (a) indicates the impact of each individual property on the overall score; a high bar indicates a high confidence that the property is good while a low bar indicates a significant negative impact of a property value (the colours correspond to the key in Figure 1). This suggests that the most significant risks for this compound are due to high logP and hERG inhibition. (b) is an example of the Glowing Molecule™ that shows the key structural influences on a predicted property of a compound, in this case logP. The red regions are those that have a significant impact increasing the predicted property, while the blue regions correspond to regions with a significant impact decreasing the property value.

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Drug Discovery/ Development & Delivery optimisation. At this hit-to-lead stage, it is important to explore as many options as possible to minimise the chance of getting locked into a lead series with a consistent problem. It can often be difficult to ‘hop’ to a new lead series in order to resolve a problem without sacrificing potency, which can lead to additional, timeconsuming iterations, increasing the cost and time of lead optimisation. Finally, during lead optimisation, MPO can help to optimise all of the required parameters simultaneously; too much focus on optimisation of a single property can lead to the sacrifice of other important factors which must then be re-optimised in turn, increasing the number of design-synthesis-test iterations. Early in the drug discovery process, when large libraries of compounds (virtual or synthesised) are often considered, little or no experimental data may be available. In this case, the design and prioritisation of compounds will be primarily guided by data from predictive models. This has been the most common way in which MPO has been applied, due to the quantity and complexity of the data that may be generated. MPO of predicted properties may also be used to guide the exploration of very large numbers of virtual ideas, automatically generated from a starting structure in order to increase the breadth of the search for optimisation strategies around hit or lead compounds 6,7 and prioritise the most interesting ideas for detailed consideration by an expert. However, with the increasing quantity of in vitro ADME and toxicity data that is now routinely generated, even in the earliest stages of drug discovery, MPO has become equally valuable for the effective use of these experimental data to select compounds for further investigation. An example application of MPO to a data set comprised only of in vitro data, to identify compounds with improved in vivo disposition in lead optimisation, is described in 8.

elsewhere 1,8. Here we will summarise two recent examples. MPO-Guided Automatic Idea Generation Reference 7 illustrates the application of MPO, coupled with automatic idea generation, to the lead compound that ultimately led to the discovery of the serotonin reuptake inhibitor Duloxetine, using the Nova™ tool in StarDrop™. A library of 206 ‘medicinal chemistry transformations,’ representing typical compound optimisation steps, were applied iteratively to the lead structure to create three ‘generations’ of related compounds. This could have generated approximately 1.7 million compounds if all possible combinations had been enumerated. Therefore, to control this, only the top 10% were selected from each generation, based on a probabilistic score calculated from properties predicted using quantitative structure activity relationship (QSAR) models of target potency and key ADME properties. After three generations this resulted in a total of approximately 2,200 compound ideas that explored the ‘chemical space’ around the initial lead and proposed a diverse

range of interesting structures, as illustrated in Figure 5. Among the top-scoring compounds in the final generation was the drug Duloxetine; its score was statistically equivalent to the top-ranked compound and was predicted to be better than the lead with a confidence of approximately 90%. Furthermore, the secondranked compound generated was very similar to another clinical candidate, Litoxetine, differing only in the substitution point of the side chain on the core naphthalene ring and the addition of a single methyl. This demonstrated that the combination of idea generation using medicinal chemistry transformations with predictive models and MPO can propose relevant and interesting structures for consideration during drug discovery. Quantitative Estimate of Drug Likeness Bickerton et al. 9 introduced a metric that estimates the similarity of a compound’s characteristics to those of known drugs. The quantitative estimate of drug likeness (QED) they propose is a generalisation of simple rules of thumb such as the RoF to

Figure 5 An illustration of the chemical space explored around the initial lead that led to the discovery of the drug Duloxetine. The points are coloured by score, from the lowest (0.29) in red to the highest (0.69) in yellow. The initial lead is shown as a dark blue diamond, Duloxetine as a green diamond. The top-three scoring compounds are shown as purple diamonds along with their structures. In this plot, each point represents a compound and the distance between two points indicates their structural similarity; close points are structurally similar while distant points are structurally diverse.

Examples Many examples of the application of MPO to the challenges of drug discovery have been discussed 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Drug Discovery/ Development & Delivery provide a single numerical measure of ‘drug-likeness’. The QED was constructed by examining the frequency distributions of molecular weight, lipophilicity, numbers of hydrogen bond donors and acceptors, polar surface area, number of rotatable bonds, number of aromatic rings and number of structural alerts (i.e. undesirable substructures) for 771 known drugs. Desirability functions were fitted to each of these distributions, such that compounds with a value for which a high frequency of known drugs are observed will receive a high desirability score. The overall QED can then be calculated for a compound by combining the desirability scores for its individual characteristics into a single desirability value by taking a weighted geometric mean, which indicates the similarity of the compound to known drugs. Unlike rules of thumb which classify compounds as ‘good’ or ‘bad’, the QED provides a measure of ‘drug likeness’ on a continuous scale. The authors found that the value of the QED correlated with the subjective view of medicinal chemists on the suitability of a compound as a starting point for a medicinal chemistry project over a set of 17,117 diverse compounds. Furthermore, a benchmarking study also found that drugs were, on average, more likely to have a high QED than a general set of small molecule protein ligands. However, while avoiding ‘non-druglike’ compounds will reduce the risk of failure, it should be noted that a ‘drug-like’ compound is far from guaranteed to have suitable physiochemical and biological properties to be a successful drug. Conclusion The application of MPO to drug discovery can help to efficiently explore many potential avenues for research and quickly and confidently focus synthetic and experimental efforts on those areas of chemistry most likely to yield a high quality drug. This, in turn, reduces the cost and time for drug discovery while improving the chance of downstream success and reducing the chance of missing valuable opportunities. 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For MPO to have a strong impact on key decisions in drug discovery, it must be accessible to all members of a drug discovery project team to provide intuitive guidance on design and selection of compounds. Software that supports MPO in a visual and user-friendly environment can facilitate collaboration between computational scientists, chemists and biologists to bring consistency and objectivity to decision-making in order to quickly achieve the objectives of a drug discovery project. References 1. S  egall, M. D. Multi-Parameter Optimization: Identifying high quality compounds with a balance of properties. Curr. Pharm. Des. 2012, (in press), Preprint may be downloaded from http://www. optibrium.com/community. 2. C  hadwick, A. T.; Segall, M. D. Overcoming psychological barriers to good discovery decisions. Drug Discov. Today 2010, 15, 561-569. 3. L ipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23, 3-25. 4. O  ptibrium. http://www.optibrium. com/stardrop, visited on 8th February 2012. 5. F  onesca, C. M.; Fleming, P. J. Genetic algorithms for multiobjective optimization: formulation, discussion and generalisation. Genetic Algorithms: Proceedings of the Fifth International Conference, San Mateo, CA, 1993; 416-423. 6. S  tewart, K.; Shiroda, M.; James, C. Drug Guru: a computer software program for drug design using medicinal chemistry rules. Bioorg. Med. Chem. 2006, 14, 70117022. 7. S  egall, M. D.; Champness, E. J.; Leeding, C.; Lilien, R.; Mettu, R.; Stevens, B. Applying medicinal chemistry transformations to guide the search for high quality leads and candidates. J. Chem. Inf. Model. 2011, 51, 2967–2976. 8. S  egall, M.; Beresford, A.; Gola, J.; Hawksley, D.; MH, T. Focus

on success: using a probabilistic approach to achieve an optimal balance of properties in drug discovery. Expert Opin. Drug Metab. Toxicol. 2006, 2, 325-337. 9. B ickerton, G. R.; Paolini, G. V.; Besnard, J.; Muresan, S.; A.L., H. Quantifying the chemical beauty of drugs. Nature Chemistry 2012, 4, 90-98.

Matt Segall has an MSc in computation from the University of Oxford and a Ph.D. in physics from the University of Cambridge. As Associate Director at Camitro, ArQule and then Inpharmatica, he led a team developing predictive ADME and decision-support tools for drug discovery. In 2006 he became responsible for Inpharmatica’s ADME business and then, following acquisition, BioFocus’s ADMET division. In 2009 Matt led a management buyout of the StarDrop software business from BioFocus to found Optibrium. Email: matt.segall@optibrium.com

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De-risking Open Bioinformatics Bioinformatics software usually takes the form of a data processing tool with optional backend storage. Biological data is input by the user and results are generated by analysing and comparing the data against relevant datasets. The combination of this open-source software toolkit or algorithm plus any supporting public datasets is known as open bioinformatics. This definition also includes provision of standalone biological datasets which can be freely accessed in their raw form. Open bioinformatics can be found in use throughout the pharma and healthcare research sectors. Anyone who has used BLAST 1 to compare sequences or has accessed information from GenBank 2 or EMBL 3 to research sequences of interest has used open bioinformatics. Popular tools and datasets include the Ensembl genome browser 4 which includes a highly annotated complete human genome and plenty of population data. Ensembl can be used to research genetic factors of disease by visualising areas of the genome and superimposing the research data of interest, such as the genotype of a patient, in order that diagnostic hypotheses can be made based on the correlations observed. Other commonly found tools include Taverna 5 which can be used to construct simple bioinformatics workflows to analyse, for instance, DNA sequencing data. The main attraction of open bioinformatics is that it is always at the cutting edge of research with access to the very latest data and the most advanced technologies for analysing it. The open-source ethos ensures that it is easily adapted and modified to suit individual circumstances, whilst the community development aspect allows the development process to actively pursue the direct interests of the end users. Such flexibility and adaptability is rarely found in closed34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

source projects. The downside, and the main risk, is that open bioinformatics projects are rarely supported by their developers and communities to the level that commercial users would require. The lack of any realistic service level agreements (SLAs) does not reassure companies that they can get urgent help exactly when they need it. The lack of SLAs is usually down to four main reasons: 1. M uch open bioinformatics is produced by individual postdocs in academic labs who then move on to other positions, leaving their project behind with nobody in charge. 2. T hose same academic labs do not see support as a priority, as it interferes with their research and is simply not an interesting thing to do. 3. Funding agencies don’t generally provide grants to labs to support tools after they have been published. 4. A cademics who do offer support rarely accept code or feature ideas from commercial users, as they do not wish to see their projects influenced by commercial requirements that do not necessarily align with their own research requirements.

Despite this risky lack of support and the occasional bit of poor quality code, open bioinformatics is still wildly popular and used in almost every biotech lab in the world, in every sector from healthcare to agriculture. The reason is simply that it is very hard to make commercial alternatives, as the potential market for each individual tool is tiny and cannot hope to recoup the cost of development. The free solutions provided by academic researchers are therefore often the only option for anyone wishing to do serious bioinformatics research. As an added bonus, the lack of restrictive licences and the flexibility of being able to adapt the code yourself is invaluable. For most academic users, the level of risk is acceptable. They do not expect or need to get instant replies to their support queries, and if they have problems with the code they can just get a student to fix it for them. However this does carry a price in lost time and overheads, and the more canny academics soon realise that like their commercial cousins they would be making much better use of their resources, and reducing the overall risk of using open bioinformatics, by getting in external help. Commercial users Volume 4 Issue 1


Drug Discovery/ Development & Delivery meanwhile are always very conscious of their overheads and the value of their own time, and are very keen to find ways of reducing risk by getting expert help. A parallel is easily drawn with web designers. Most companies realise that although their IT staff might know HTML and CSS and can do an average job with the company webpage, it would be much more cost-effective and vastly increase the quality of the site itself by bringing in professional web design consultancies to do the work instead. Users of open bioinformatics can therefore make equivalent savings and improvements in the tools they use in their research by looking to use expert bioinformatics assistance from outside rather than try to make-doand-mend with whatever spare time they and their usually overworked bioinformatics staff have. An additional way of reducing the risk in open bioinformatics is to pool and share resources. Where two people want to use the same resource, it makes sense to install it just once and for them both to share access to it. Doing so removes the duplication and redundancy of installing a copy at each site, along with the expense of hiring specialist bioinformatics and systems administration staff at each site to keep it up and running. The more people that can share a single resource, the lower the per-person cost of that resource becomes. In parallel, the reduced number of installations means that more time can be spent concentrating on perfecting the single shared installation which will raise the quality of service and significantly reduce the risk of it failing. The pooling, sharing and outsourcing of the installation and maintenance of open bioinformatics tools and data is therefore of great importance in reducing the risk of using these resources. In addition, the investment of time in attending commercially available training courses and reading (and if necessary commissioning) good-quality documentation will naturally pay off as users spend less time poking around in the dark trying to find the features they need. For commercial 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

users, being able to obtain an SLA from a third-party support vendor can be all it needs to take the open bioinformatics resource from being a useful but informal reference resource to becoming a core part of their research pipeline upon which they can rely totally. The overall benefit of a de-risked open bioinformatics environment is clear. Money can be saved by reducing system redundancy and personnel duplication, and using expert assistance to reduce internal time commitments and related overhead costs. The options to customise the open solutions are endless and most systems can be tweaked to meet exact individual requirements. The openness of the code and less restrictive licensing means that the problem of commercial vendor lock-in is eliminated, as when a resource becomes de-supported or otherwise expires there is nothing stopping users from fixing the code themselves or bringing in third parties to do it for them. To summarise, the resources available under the open bioinformatics umbrella do carry a risk from the perspective of locating the expert support and advice required to make the most of them, but if managed correctly the risk can be mitigated and open bioinformatics can become as robust, reliable and dependably supported as any commercial solution. References 1. A ltschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403-410 (1990). 2. B enson, D.A., Karsch-Mizrachi, I., Lipman, D.J., Ostell, J., & Wheeler, D.L. (2007) GenBank. Nucleic Acids Res. 36, D25-D30 (2008). 3. C ochrane, G., Akhtar, R., Bonfield, J., Bower, L., Demiralp, F., Faruque, N., Gibson, R., Hoad, G., Hubbard, T., Hunter, C., Jang, M., Juhos, S., Leinonen, R., Leonard, S., Lin, Q., Lopez, R., Lorenc, D., McWilliam, H., Mukherjee, G., Plaister, S., Radhakrishnan, R., Robinson, S., Sobhany, S., Hoopen, P.T., Vaughan, R., Zalunin, V. & Birney, E. Petabyte-scale innovations at

the European Nucleotide Archive. Nucleic Acids Res. 37, D19-D25 (2009). 4. F licek, P., Ridwan Amode, M., Barrell, D., Beal, K., Brent, S., Chen, Y., Clapham, P., Coates, G., Fairley, S., Fitzgerald, S., Gordon, L., Hendrix, M., Hourlier, T., Johnson, N., Kähäri, A., Keefe, D., Keenan, S., Kinsella, R., Kokocinski, F., Kulesha, E., Larsson, P., Longden, I., McLaren, W., Overduin, B., Pritchard, B., Singh Riat, H., Rios, D., Ritchie, G.R.S., Ruffier, M., Schuster, M., Sobral, D., Spudich, G., Tang, Y.A., Trevanion, S., Vandrovcova, J., Vilella, A.J., White, S., Wilder, S.P., Zadissa, A., Zamora, J., Aken, B.L., Birney, E., Cunningham, F., Dunham, I., Durbin, R., FernándezSuárez, X.M., Herrero, J., Hubbard, T.J.P., Parker, A., Proctor, G., Vogel, J. & Searletaverna, S.M.J. Ensembl 2011. Nucleic Acids Res. 39, D800D806 (2011). 5. O inn, T., Addis, M., Ferris, J., Marvin, D., Senger, M., Greenwood, M., Carver, T., Glover, K., Pocock, M., Wipat, A. & Li, P. Taverna: a tool for the composition and enactment of bioinformatics workflows. Bioinformatics. 20, 17:3045-3054 (2004).

Richard Holland BSc MBCS, Chief Business Officer, Eagle Genomics Ltd. Richard is a founder member of the Open Bioinformatics Foundation, the organisation that backs most of the key open-source bioinformatics programming toolkits such as BioPerl and BioJava. Richard was also lead developer on BioJava, the primary resource for Java developers working in bioinformatics, and he is first author on the original BioJava paper. Richard has been working in bioinformatics for over 10 years in both industry and academia in the UK, Singapore, and New Zealand. Email: richard.holland@ eaglegenomics.com Volume 4 Issue 1


Drug Discovery/Development & Delivery

A New Step on the Critical Path The pharmaceutical development paradigm has been completely overhauled during the past 10 years, as it has become possible to classify patients who are likely to respond to investigational (or previously marketed) drugs and to differentiate/ exclude those patients who might be susceptible to adverse drugrelated events. So successful has the development of new technology been that revolutionary new diagnostic tools are fundamentally changing the ways in which drugs are developed and the ways in which clinical trials are conducted. In the past, the diagnostics industry has represented a parallel-track business sector to the pharmaceutical industry, but now it is becoming a fully-integrated component of drug development, and in many cases is becoming the rate-limiting step in the critical path of drug development. The emerging critical roles that diagnostics play in drug development have resulted in significant changes in the ways in which the two industries interface and, furthermore, has led the regulatory bodies, particularly the FDA, to play a leading role in shaping the ways in which future pharmaceutical development will be expected to progress. Although personalised medicine, i.e. the tailoring of a particular drug to a particular patient, has been evident in the anti-viral therapeutic area for many years, the driver to actually require a specific diagnostic test to be provided before a drug can be prescribed has largely been driven within the oncology area. The example of the use of herceptin as a therapeutic agent in breast cancer cells expressing the her-2 receptor is well recognised, but the companion diagnostic concept really accelerated with the clear clinical evidence from Amgen, Merck Serono and AstraZeneca that their new agents for colorectal and non-small-cell lung cancer, respectively, were more efficacious in patients with specific 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

genotypes in their KRAS and EGFR genes. These drugs were subsequently licensed with the clear indication on their labels that the appropriate KRAS and EGFR analysis was required before the drugs could be used. For the pharmaceutical companies, this stratification of their target market could have represented a clear threat to their potential revenues. However, they also came to realise that the availability of these new clinical tools was hugely beneficial to their clinical development plans because it meant they could pre-screen their trial cohorts to select those patients who were most likely to respond to their drugs. This would have a significant effect on the numbers of patients required in their cohorts, and would mean the trials could be conducted more quickly and at much reduced cost. Similarly, for the healthcare providers, there was a huge pharmacoeconomic benefit in this model, since some of these very expensive drugs would not be used in patients who were unable to derive any therapeutic benefit. For diagnostic companies, the close alignment of these diagnostic tests with the pharmaceutical development clearly opened new markets, but also presented new challenges, particularly with respect to regulatory authorities

and re-imbursement of these in vitro diagnostic (IVD) devices. Apart from the clear evidence provided in the oncology setting regarding specific biomarker profiles and the associated requirements for co-development of companion diagnostics, the clinical development of pharmacogenetic tools which can be equally useful in determining the optimal use of therapeutics is now evolving. It is clear that every individual patient is different in the ways that they metabolise drugs, and this can be affected by multiple factors including environmental, such as diet, and genetic. Leading the way in this area has been warfarin – a drug which is clearly metabolised by the Cytochrome P450 pathway, and in which specific variants of the P450 pathway exhibit diminished or, in some cases, enhanced ability to metabolise the drug. Another example of pharmacogenetics in clinical practice is demonstrated in the case of Clopidogrel, an anti-platelet drug used extensively in the cardiovascular area, the use of which is hampered by its variable biotransformation into the active metabolite. Metabolism of clopidogrel is a complex process (see Figure 1).

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Drug Discovery/Development & Delivery Within the liver, the majority of the clopidogrel oral dose is rapidly hydrolysed by hepatic carboxylesterase 1 (CES-1) into an inactive metabolite. At the same time, the parent molecule is activated by the activity of a variety of different enzyme systems (including CYP450 isoforms) into its final active form. It is likely that there are numerous subtle interplays between the components of these pathways which will profoundly affect the kinetics of appearance of the active metabolite. Further complication occurs in the presence of genetic polymorphisms in the CES-1 molecule which profoundly suppress the activity of the CES-1 enzyme. In patients possessing these particular variants, the ability to produce the inactive metabolite will obviously be diminished so that significantly more effective active metabolite will be produced per unit dose. Ultimately, it may be possible to correlate specific genotypes of all the components of the clopidogrel metabolic pathway into an algorithm which can accurately direct the required dose in an individual patient. Given the significant clinical progress made in pharmacogenetics, and now in the development of companion diagnostics, the FDA and other regulatory bodies are now providing new guidelines and advice as to how these new requirements should be introduced into clinical trials and, ultimately, into new product registrations. For example, the FDA has offered specific recommendations that pharmacogenetic testing be carried out in the case of patients on warfarin, even though it is not actually included on the drug label as a true companion diagnostic. More recently, in 2011, the FDA released draft recommendations regarding companion diagnostics - how and when these should be developed, and how and when these will be reviewed by the FDA. The key factor in this process is that the potential diagnostic needs to undergo the same rigid review as the drug itself and, ideally, within the same timelines – it is clearly in no-one’s interest to have a drug complete clinical trials and not be available for prescription because a robust, fully validated companion diagnostic is not 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

commercially available. The FDA has therefore issued draft non-binding recommendations aimed at both pharmaceutical companies and IVD companies that are developing drugs and devices for specific therapeutic products. They have made it clear that, if use of an IVD companion diagnostic device is essential for the safe and effective use of a therapeutic product, the IVD companion diagnostic device and therapeutic product should be approved or

cleared contemporaneously by FDA for the use to be indicated in the therapeutic product labelling. Product development plans should produce sufficient data to establish the safety and effectiveness of the IVD companion diagnostic device/ therapeutic product pair. The key factor in this process is that the correct diagnostic result must be assured every time a patient is tested, since healthcare professionals will rely on these results to make Volume 4 Issue 1


Drug Discovery/Development & Delivery important clinical decisions. If the test is unreliable or inaccurate, the drug could be used in patients who will derive no benefit and have severe therapeutic consequences. Therefore the implementation of an IVD device with inadequate performance characteristics could expose a patient to preventable risk. Consequently, the FDA will assess the safety and effectiveness of the IVD companion diagnostic device as used with the therapeutic. Ideally, a therapeutic product and its corresponding IVD companion diagnostic device would be developed contemporaneously, with the clinical performance and clinical significance of the IVD companion diagnostic device established using data from the clinical development programme of the corresponding therapeutic product. In fact, it is entirely possible that the IVD companion diagnostic device and the therapeutic product together meet the definition of a combination product, and may potentially be reviewed as a single entity. From the perspective of the diagnostic industry, these developments have positive implications in two respects. Firstly, an issue that has plagued the industry for many years has been the widespread use of so-called home-brew assays, which sometimes have inadequate quality controls, and in many cases infringe valuable intellectual property around the specific biomarker. Given the increased importance of the diagnostic test to the correct use of the new drugs, there must be more rigid regulation on the quality and clinical validation of the new assays. These stringent regulatory guidelines should have significant impact on the development and implementation of these home-brew assays which do not have regulatory approval. The second opportunity is provided to the new breed of so-called vertically-integrated diagnostics companies. These are still globally a rare commodity but describe those diagnostic companies that offer both fully accredited clinical diagnostic services and the ability to develop, obtain regulatory approval, manufacture and commercially distribute the IVD companion 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

diagnostic end-product. The FDA have clearly suggested that ‘If a diagnostic device and a therapeutic product are to be studied together to support their respective approvals (or clearance as appropriate for the diagnostic device), both products can be studied in the same investigational study, if the study is conducted in a manner that meets both the requirements of the IDE regulations and the investigational new drug (IND) regulations. This will enable a more focused and in-depth discussion about the validation of the IVD companion diagnostic device and will aid in planning for a device PMA or 510(k) that is complete and timely.’ From a pharmaceutical company’s perspective it would be much more favourable, efficient and cost-effective to have their clinical trials analysed within the service laboratories of the same company that can ultimately produce the regulatory-approved IVD. Currently several pharmaceutical companies possess their own diagnostics partners e.g. Roche, Abbott and Novartis, but the growing opportunity lies in those independent companies that can both service the trials and ultimately produce the IVD and distribute it to the global markets where the pharmaceutical will be sold. In particular, these types of partnerships should ensure that the drug and the IVD are developed and approved by the FDA within the same

timeframe wherever possible. In conclusion, the emergence of companion diagnostics as a major factor in drug development programmes offers huge benefits to both the pharmaceutical and diagnostics industries, but requires much closer interfacing between the two industries than has previously been the case, and an integrated relationship with regulatory bodies such as the FDA. Most importantly, the emergence of stratified personalised medicine and the fruits of these developments should be major benefits for the patients who receive the right drug, at the right dose, at the right time.

Dr Berwyn Clarke is the Chief Scientific Officer of Lab21 Limited. After a career in the pharmaceutical industry he moved into diagnostics in 2000 and is a specialist in translational and personalised medicine. In 2005 he co-founded Lab21 to provide high quality molecular diagnostic services and products for the healthcare and the pharmaceutical industry. Email: berwyn.clarke@lab21.com Volume 4 Issue 1


Clinical Research

Early PK-PD Modelling Significantly Facilitates Identification of the Best Drug Candidates Pharmacokinetics (PK) and pharmacodynamics (PD) are disciplines that can straddle discovery and development when considered in their complex physiologic relationship to one another using a sophisticated PK-PD model. We traditionally place pharmacokinetics in the preclinical discovery phase, because it is a series of these studies that helps to narrow the number of molecules being evaluated for a particular therapeutic approach. But in conjunction with pharmacodynamics, it also has the capacity to more accurately predict success in clinical phases. This approach has already contributed to a significant change in the traditional drug development model – helping to reduce the extensive time and significant cost involved in the development of a new drug. Leveraging the PK-PD relationship and its predictive potential will help mitigate the primary stumbling blocks for new therapies reaching the market. PK is essentially a mathematical way to describe the appearance and subsequent disappearance of a drug in an organism. It’s typically done by looking at the plasma concentration of the drug of interest as a function of time. A viable therapeutic has a certain temporal profile in the organism. Every therapeutic entity has a unique, optimal temporal profile. In simple terms, if you dose an antibiotic and it’s only there for threeand-a-half minutes, it doesn’t have much time to impart its therapeutic effect. Similarly, if you dose it and it stays there for three months, it can lead to toxicity by interacting with other targets. PD is a discipline that goes handin-glove with pharmacokinetics. PD describes the physiological response to the drug of interest as a function of time in much the same way that 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

PK describes the time-course of drug concentration. For example, if a human with an elevated core body temperature takes two aspirin, and two hours later the temperature has been reduced, that reduction in core body temperature represents the pharmacodynamic response. At one time, pharmacodynamics wasn’t viewed in the same way as it is increasingly today. Pharmaceutical companies and contract research organisations (CROs) would conduct pharmacokinetic studies, and pharmacodynamics was considered interesting, but nobody spent a lot of time on it. Now, using a series of simultaneous differential equations, it’s possible to create a model that incorporates the time course of appearance and subsequent disappearance of the drug in the body, and how that time course correlates with the appearance and subsequent disappearance of whatever physiologic response takes place. So who cares about this? Well, in small molecule drug discovery, it’s common to start with a lot of molecules – maybe thousands – that might affect the molecular target. So we need a set of criteria against which we can measure the suitability of any given one of those molecules as a drug candidate. Having an understanding of the pharmacokinetic–pharmacodynamic relationship and the ability to express it mathematically enables identification of molecules that will be a viable drug candidate. We are looking for a desirable PK-PD relationship. Pharmaceutical companies and CROs are using knowledge of pharmacokinetic-pharmacodynamic relationships to narrow the field of potential candidate molecules until arriving at the one that has the

most desirable pharmacokinetic properties, the most desirable pharmacodynamic properties in relation to those pharmacokinetics, and the best pharmacology – meaning it hits the target hardest and/or most effectively. As a CRO, MPI Research is continually working on developing an increasingly sophisticated understanding of PK-PD models so that it may be possible to take what we understand about the molecules we’ve already tried, roll that information into the PK-PD modelling methodology, and predict which molecules are going to give us what we’re looking for. The significant benefit of this approach is that it can cut the number of molecules needed in the first place. This approach should be applicable to small molecules, proteins, peptides, and nucleic acids, so it could be used across a spectrum of therapeutics and disease indications. As we get better at understanding and refining the mathematical model, we will also get better at being able to predict the molecules that are going to give the best results. This will be a significant move forward from the shotgun approach of taking 10,000 molecules and testing all of them to see which ones do best. A certain amount of testing will always be necessary, of course, which will also contribute to continual building of the database. We need information about how the structure of the molecule relates to its PK-PD performance, but we should be able to be continually more efficient. It should become increasingly possible to simulate a good chunk of the process accurately in a computer, rather than in animal models. So this will serve an objective both inside and outside the industry, to see less work with live animals. Volume 4 Issue 1


Clinical Research From an overall pharmacology and toxicology perspective, we will almost certainly never completely eliminate the need for testing in the whole organism, as whole organisms are extremely complex biological and biochemical entities. What we are working toward is on a more superficial level, where we can put together a checklist that comprises a profile of desirable characteristics for any given therapeutic. The list includes the PK-PD relationship, certain physico-chemical properties, oil/water partition coefficient, measures of the relative permeability of molecules across biological membranes, CYP profiling and other comparative metabolism-related data. Then we can test thousands of molecules in vitro in the lab and by computer against the checklist to narrow down to 10% of the original number of candidate molecules. At the next level of screening, we go from that 10% to 1%. The knowledge that we obtain using the tools of pharmacokinetics should be applicable across any disease indication. The pharmacodynamic parameters that we care about will vary, based on disease indication. For example, we might be studying molecules for their potential to affect Alzheimer’s plaques, but we notice that every time we dose it, blood pressure goes down in the organism. So then we’re motivated to look at the pharmacodynamics of the antihypertension characteristics of this drug. It’s fair to say that most of the PK-PD characteristics of a molecule that we come to understand relative to one disease indication will be applicable in any number of disease indications. There is also a downstream benefit to the pharmacodynamic modelling exercise. It has the potential for much better understanding of what to expect when the drug candidate moves into the clinical phases. When we’ve done this work in the nonclinical phase, we’ve constructed a descriptive, predictive PK-PD model. We can identify what it does to the pharmacodynamic response if administration is switched from once a day to twice a day. This also goes for changes in the formulation of the 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Clinical Research drug, dosing route, administration of the drug, etc. Data like this can be hugely beneficial later in the clinic. At MPI Research, we are interested in maintaining a high level of expertise in pharmacokineticpharmacodynamic modelling because it will help our Sponsors choose their candidates most effectively. And we don’t believe that very many CROs are doing this to a high level of sophistication, if at all. So it’s an important opportunity for us, and for the development of the industry. What it focuses on are not only the obvious reductions in time and costs that represent efficiencies the whole industry is seeking, but also identification of better therapeutics that are less likely to fail in the later stages of development. So it potentially contributes significantly to a more robust pipeline and more drugs making it to market at less cost and in less time – delivering therapies that are needed. With larger pharmaceutical companies, a lot of the nonclinical studies will be going on at the same time, and not necessarily at the same contract company or under the same roof. The order of studies can vary, too. So for the model to work for these companies, the scientists must have an understanding of the desired physiology and pharmacology. The checklist of ideal characteristics mentioned earlier should originate with the Sponsor company – it really shouldn’t come from the CRO. It depends on the individual company and the approach they have formulated for their model of development. Then we, as the CRO, can integrate these ideal characteristics in our screening programmes and bring tremendous value to the Sponsor We have been discussing the discovery aspect of PK-PD modelling, which is why it is positioned in the Discovery Center at MPI Research, but the beginning of this article mentioned the development phase potential. This aspect speaks to predicting the clinical outcomes once you’ve done your nonclinical work with a small-molecule, protein or peptide and you’re moving forward into the clinic. We can create ways 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to simulate what happens in patients when there is a change in the route of administration, frequency of administration, etc. – as indicated earlier. PK-PD modelling can also straddle discovery and development inside the CRO. When we understand the PK-PD relationship early enough, we can use it to help us select the most appropriate species in which to conduct the FDA-required safety and efficacy testing. Remembering that everything we do is designed to predict what is going to happen to people; for example, if canines don’t have a high level of a particular enzyme and humans do, then canines are not going to be a very good predictive model for what’s going to happen in people. Some Sponsors have selected canines because of cost benefits over primates, but then they’ve ended up having to do a primate study as well, due to the aforementioned problem. When we have done early PK-PD modelling that includes metabolism data, we can prevent this time-wasting and costly mistake. One of the factors enhancing this endeavour is the fact that a few speciality companies have sprung up, having recognised the tremendous potential in PK-PD modelling. They have developed software platforms that utilise enormous, intelligent relational databases of chemical structures and long-term scientific literature, and they’ve designed sophisticated information recognition algorithms that can search numerical data, biological data, and textual information to enable us to see relationships in all of the activity that has ever been observed with particular molecules. One platform, based on chemical structures, does a risk assessment to evaluate the toxicologic risk of certain molecules or molecular structures. Another uses historical metabolism literature to predict the metabolites of any given compound. MPI Research is partnering with companies such as these to leverage the enormous legacy of study data we have, bringing even greater value to our work and to our Sponsors. Twelve years and close to $2 billion to develop a drug is not something

we want to sit back and accept. These efforts in pharmacokinetics and pharmacodynamics are part of many converging strategies to enable positive change in the process. As a CRO, we are conducting this work every day, which gives us a great level of expertise in a focused area. We’re motivated to work seamlessly with partner companies to advance our efforts, with the view that this will result in those efforts bringing greater value to Sponsors and ultimately to the drug development process. From a regulatory perspective, a CRO’s impartiality – and that impartiality being inherent in study data provided – is a further advantage. We’re not only looking to reduce the cost and time involved in development, but also believe we can mitigate failures later in the clinical stages by understanding more earlier on, which can only succeed in bringing more therapies to market.

Richard Slauter, PhD, DABT is Senior Director of Drug Metabolism/ Pharmacokinetics and Senior Principal Study Director at MPI Research. Dr. Slauter was most recently a Principal at Bay Therapeutic Development Solutions, where he designed and managed preclinical development programs for new drug candidates in oncology, metabolic, cardiovascular, anti-infective, and autoimmune indications. Before that, he was Director of Nonclinical Development at Exelixis, Inc., where he was responsible for nonclinical development of lead compounds through Phase I. He served as Vice President of Preclinical Development of Oncocidex, Inc., and held various scientific leadership positions at Battelle. He holds a PhD in pharmacology from Wayne State University School of Medicine and completed post-doctoral work at the University of Michigan Medical School. Email: richard.slauter@mpiresearch.com

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Clinical Research

In vivo Data – Earlier the Better – Meeting Demands for Better Data in Early Discovery Discovery scientists continually seek better data earlier to rapidly assess whether a new compound will be both effective and safe. Generating relevant in vivo data earlier that minimises the number of animals, the time and the costs would be an asset to a discovery group. An appropriately designed protocol using an automated dosing, data and sample ® collection experiment, e.g. the Culex in vivo sampling system, facilitates a scenario to maximise the information on a new drug from one animal in one experiment. It’s an opportunity to decrease capital outlay, increase the quality of information and satisfy the 3R principle (reduce, refine, replace). Better quality data can be generated in about one-third of the time and cost. The demand for drug companies to maintain strong drug discovery pipelines against a backdrop of falling revenues as blockbusters hit a ‘patent cliff’ has forced management to review research strategies. In particular, company leaders are considering their R&D expenditure and resetting expectations on costeffective investment in discovery. It is not surprising that this has initiated a change in philosophy and approach to discovering new medicines. Large companies are reducing their internal overhead expense on R&D and focusing their internal expenditure on novel therapeutic areas. To supplement their strategy, large companies are looking more toward smaller, more focused and cost-effective organizations, both commercial and academic, to research and discover compounds for their future development pipelines. The ripple effect of this has hit the small innovative companies who recognised the potential opportunity to be acquired by large pharma for their programmes or to out-license 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

their discoveries for royalty payments downstream. In turn, they are seeking faster and cost-effective means of generating the appropriate portfolio of information and data that increases the value of their discoveries to the large pharma companies. To avoid significant investments in overheads, and retain the ability to stay focused on their core attribute of understanding diseases and designing new therapies, they are aiming to generate the relevant information in a shorter timeframe and be costeffective. Scientists are revisiting the ‘classical’ processes in discovery

and are looking at new technologies to evaluate the efficacy and potential toxicity of their new discoveries. Discovery scientists strive to identify the lead candidate as soon as possible and knock out the contenders that do not meet the candidate criteria, including poor efficacy, potential toxicity or ADME/PK issues. The quick-win, fast-fail drug development paradigm makes the identification and development of a new therapy more cost-effective. There is a greater emphasis on early-stage clinical and biomarker development to avoid the high costs of Phase II-III failures. Volume 4 Issue 1


Clinical Research The objective is to discover an active drug that is safe to administer. It is important to understand its in vivo efficacy and its potential to produce unwanted side-effects. In vivo animal efficacy models are increasing as a means of assessing efficacy in vivo and potential toxicities such that a better prediction of the effects can be extrapolated to the ultimate target species – man. Contract research organisations (CROs) are changing too to respond to the rapidly changing needs of their discovery customers. Companies are creating discovery support services resourced with discovery scientists, many of whom come from pharmaceutical companies. These scientists understand the paradigm and very different expectations from traditional development programmes that classic CROs have been accustomed to. CROs are expected to provide staff along with new technologies and techniques. However, it is not enough to provide an operational service and process compounds through a series of in vitro and in vivo screening programmes and generate a set of data. Much more can be gained by an active collaboration between both the discovery customer and the CRO. Where the CRO can provide fast highthroughput turnaround screens, it is the appropriate interpretation of the information that is critical in designing the next experiment. In vitro data is arguably more susceptible to overinterpretation and over-prediction than in vivo data. However, gathering in vivo data can be time-consuming and expensive, and uses lots of animals. Discovery scientists should look for CROs that work with them to understand the therapeutic target, the compounds series under investigation and to interpret appropriately the information generated. The sooner in the process new compounds can be investigated in a suitable animal model, the sooner more relevant and useful information can be considered. The challenge is how to generate this information quickly, cost-effectively, and use fewer animals. If discovery scientists could run an experimental protocol that enables multiple series of data to be collected www.ipimedia.com

from a single conscious freely-moving animal and facilitate automated dosing regimens and automated sample collection, then they would have a very flexible and powerful, relatively high-throughput in vivo screening protocol. In an appropriate animal model, a protocol would measure, for example, efficacy, behaviour, ADME and PK all from a single conscious freely-moving animal. Consider further the opportunity to monitor blood-brain barrier transport in vivo in real time, to monitor vital signs automatically during the experiment and the ability of the test compound to reach the target site or organ. The potential to generate the calibre and range of in vivo data on a number of compounds is of great value to discovery scientists. Large pharmaceutical companies can afford to make the significant investments into the resources required to maintain an infrastructure and facility to provide this expertise and capability. Small to medium-sized companies do not necessarily want to invest to this extent, but would benefit significantly from the cost-effective and relevant in vivo information at a relatively early stage in their discovery process. As drug development scientists look for more efficient ways to understand the dynamics and fate of their compounds through efficacy, metabolism and excretion, automated sampling creates the quality controls and reduced intervention that simply aren’t possible with manual plasma sampling. Animals and scientists are less stressed when conducting the experiment. The real advantages are realised when using animals that are difficult to manage and handle for repeat sampling. Serial sampling from mice, a common and expensive therapeutic model, is much easier with this technique. Drawing frequent samples for PK or biomarker measurements from monkeys can be easier and safer for both the animal and the scientist. The animal is not aware that a sample is being drawn. This approach can build to a productive and cost-effective in vivo screening programme that provides valuable, tight and relevant data. With automated collection of all timepoints from a single subject, animal use in

an individual study can potentially be cut by half or more. Considering the sheer volume of discovery animal studies conducted today, the acrossthe-board reduction seems to be the ‘right’ thing to consider. This presents an opportunity for the innovative CRO that can provide not only the scientific partnerships with their discovery customers, but provide the cost- and time-effective in vivo data that can considerably expedite the discovery process for them, and gain a comprehensive portfolio of more relevant in vivo information on their new compounds. As CROs continue to play a key role in working with companies to develop discovery programmes, the need to expedite the acquisition of relevant in vivo data needed to select the lead drug candidate is paramount. Discovery scientists are looking to discovery service providers who have the experience and expertise in all aspects of automated in vivo sampling to build models and screening programmes, and benefit from the advantages of in vivo discovery data to help identify better lead candidates for their discovery pipelines.

Anthony S. Chilton, Ph.D. President & Chief Executive Officer Dr. Chilton has more than 30 years of experience as a scientist and executive in leading life sciences companies in England, Canada and the United States. At BASi, he oversees drug development services at three locations in the U.S. and one in Europe, as well as the development of analytical and in vivo sampling instrumentation. Prior to joining BASi, Dr. Chilton was in charge of early development programs at Atherogenics, Inc. in Georgia and provided consulting and advisory services to various pharmaceutical companies. Dr. Chilton received his Bachelor’s Degree in Chemistry from the University of East Anglia in 1981, and his Ph.D. in Analytical Chemistry from the University of Hertfordshire in 1993. Email: tchilton@basinc.com

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Clinical Research

When It’s Documented, It Happened A New Approach to Tracking Generic Drug Development Rigour amongst health and medicine agencies worldwide has significantly increased over the past decade, and their scrutiny when inspecting one’s system-based approach and documentation is not a “new thing“ any more. “What has not been properly documented, did not happen.“ We know that public health benefits from generic drugs and agency dilligence. However, can generic drug manufacturers benefit as well from the new “normal“? Yes, indeed. Drivers While it is somewhat challenging to control an R&D project over a typical timespan of 30 months, it is quite feasible to control key deliverables - DOCUMENTS. What hasn’t been documented did not happen, remember? There are many drivers that make us take a close look at every stage of that process. New Chemicial Development

entities

(NCE)

Generic Drug Development

Unlike brand-name manufacturers that invest upwards of $1 billion and spend, on average, ten years to bring a new drug therapy to market, generic developers and manufacturers operate on a much more limited development timeframe. Their focus is on two critical business metrics: 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• t hey must demonstrate clinical bioequivalence to the innovator drug and • they must be the first to file their dossier for review and approval. A generic pharma company will have months, not years, to reverseengineer the performance of a brand product and demonstrate its bioequivalence. In-depth knowledge of IP, monitoring data exclusivity and demonstrating superior formulation and the overall development process is not enough. Project management becomes a key ingredient. Some Documents Are Gatekeepers The process is long, but it also produces thousands, if not hundreds of thousands of documents. These documents are either archived or used for different purposes (development reports, quality control, registration dossier, purchasing and production). It is therefore of paramount importance that the right versions of these documents are readily available to authorised persons, that all of the changes are immediately propagated, and that the person in charge of the development process can track the life-cycle of each of the relevant documents. But there is more to it: Some of these documents are milestone marks; they represent the end of a particular development process phase. A stability report or bioequivalence study clearly marks the end of the corresponding phases. Every phase, standard or customised for a particular method/product/company has such a document. By tracking these outputs, we can easily monitor the whole process against set deadlines. These requirements can only be achieved by use of modern electronic

document management system (EDMS) and reporting tools, and it is therefore strange that there are so few dedicated development solutions in the market. In this article, we will discuss the important features of such a solution using the example of one commercially available solution. Although the solution is also applicable for the development of innovative drug products, we will concentrate on development of generic drug products. R&D Project Management Support The development of a generic drug product usually starts with a strategic marketing decision on the desired product’s characteristics International Nonproprietary Name (INN), form, dose, markets, referent product, targeted launch date...). In most companies, the development process is project-oriented, so the next step is choosing a project manager and project team. The project manager then puts together the project plan (usually with MS Project or a similar tool), in which all project-related information is available (start and finish date of each activity, milestones, usage of resources...). The result of each project activity is usually a document, so in order to complete the project, the project manager has to gather all of the relevant documents and compose them into the project report. But the real problems begin with the actual start of the project, since in most cases real life does not follow the plans. Dates shift; people are not available any more; new reminders have to be sent out for commencement of activities. Information on all executed actions has to be entered in the project management application. This puts a tremendous strain on the project Volume 4 Issue 1


Clinical Research manager and his limited timeframe, and it often fails to perform these duties in timely manner. In addition, the project management tool makes only one piece of information available on the project deliverables, namely if the document in question is finished or not. For all of the other information (if the work on the document has commenced or not, which life-cycle stage the document is on, if there is a new version of the document in preparation...) the project manager has to consult other applications (most frequently a large Excel spreadsheet), which again is only as good as it is diligently updated. These problems can only be solved by combining the project-oriented approach with document management. The project plan is put together in the usual way (using MS Project), but after the approval, it is transferred to the document management solution. The project is represented as a virtual document, and each of the project activities automatically creates a binder, in which the relevant project information (start date, finish date) are represented as document attributes (metadata) (Fig. 1). Fig. 1. 1. A  t the predetermined start date, the project manager gets a reminder from the system to start the task. The project manager determines

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the roles on the document (author, reviewer, approver) and starts the task. 2. T  he author gets the task in his inbox, writes the document, and finishes the task by sending the document to the reviewer. 3. T  he reviewer performs the review and finishes the task by sending the document to the approver. 4. A  fter approval, the document becomes effective, and the project manager gets the information in his inbox that the document is available. This information can be e-mailed as a follow-up action, but also a colour-coded scheme to visualise the progress on each dossier (Fig. 2.) Fig. 2. It is worth mentioning that the document is automatically stored in a predetermined place in the database (based on the document attributes), and it is linked to the appropriate binder in the virtual document structure. In this way, there is always only one valid document in the system, it is transparent where this document is used, and if the new version of the document is available, all users of the old version are able to see it. Fig. 3. During the whole document creation

process, the project manager is able to check where the document is, who is in charge, whether the process is on time, and even the content of the document. When the due date of any activity is approached, the task performer will get a reminder, and if the activity is not finished by the due date, the reminder goes to the project manager. In this way the project manager can see the status of all project activities at a glance, and get information on all overdue activities all from one solution, without manually entering all the status changes. A consolidated view of several projects by management is also possible, even on the level of activity or group of activities comparison. This can than help in increasing the overall process performance (Fig. 4.). When all of the project activities are finished, all of the documents can be merged into a single PDF file by a simple command, and published with a table of contents (ToC) and hyperlinks, forming the so called Development Dossier. The final document (in PDF, or both PDF and virtual document form) is then made available to all of the relevant departments, to be perused in whole or in parts. If an individual document is to be used for other purposes (for example, the specification in purchasing,

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Clinical Research Fig. 4. As described above, there are a lot of advantages in utilising document management solutions in managing the drug development process. The process is transparent, the project manager and the management are able to monitor all of the activities, documents are stored only once in the system and are reusable and, last but not least, the whole process is well documented in compliance with 21CFR11 and EU GMP Chapter 4 and Annex 11 requirements. All of this together guarantees a smooth and efficient development process, improved time-to-market and fewer worries about regulatory compliance. It is also a very powerful infrastructure to build on, either for management reporting, process improvement or interfacing other systems using business intelligence reporting tools. Here are is one example a) T  racking multiple projects using an slice & dice tool quality control and registration dossier), and other solutions are available, the document is not copied, but again linked in the appropriate virtual document (registration dossier, analytical procedure...).

b) Drill-down: delayed projects

Mihajlo Ceraj Ceric, MSc. Pharm. – Life Sciences Director at INFOTEHNA He was 3 decades associated with PLIVA (Teva Group member) where he held a number of managerial posts. Serving on such diverse positions as R&D director, Head of pharmaceutical investments, RA director and Deputy to QA/QC director enabled him to achieve comprehensive and indepth understanding of business critical processes in pharmaceutical company. After leaving Pliva (Teva Group member) he has joined INFOTEHNA Group as Life science Director. Mr. Ceric has particular interest in enterprise content management, and is one of the industry’s top experts in document and processes management. As a consultant he specializes in business process analysis, pharmaceutical procedures streamlining and optimization of electronic document management systems. Mr. Ceric is also a very prolific author, who has written numerous articles on enterprise content management issues in modern pharmaceutical organizations, and is regular presenter or chair at pharma conferences. Email: mihajlo.ceraj@infotehna.com

Marijo Volarevic, MSc. - VP, Business Services at INFOTEHNA n his 17 plus years of rich international experience Marijo most recently served as CEO of Comminus, a Business Intelligence company. For more than a decade he has held numerous IT executive positions in both headquarter and subsidiaries of a global Pharmaceutical company (Teva US/Barr Labs/PLIVA), and later provided services for few other Pharma companies. Mr. Volarevic has developed strong leadership and analytical skills he effectively couples with astute business acumen. Email: marijo.volarevic@ infotehna.com 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Clinical Research

Defining Pharmacometrics Pharmacometrics uses the application of mathematics to analyse vast amounts of data about disease progression, drug response, and clinical behaviour. The results help innovative drug companies and regulatory bodies alike make appropriate and wellinformed decisions during the drug development process. Perhaps one of the best definitions of pharmacometrics is one provided by the US Food and Drug Administration (FDA)1: “Pharmacometrics is an emerging science defined as the science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions.” The FDA emphasises the broader role of pharmacometrics in drug development. Pharmacometrics includes a collection of model-based approaches used to1 extract from data and organise our understanding of a system’s behaviour in a concise manner; and do so in a language (i.e., mathematics) that allows simulation of the system output. These models can be divided into three classes: • exposure-response models that specifically describe the relationships among dose, drug concentration in blood (or another matrix), and clinical response (effectiveness and undesirable effects), as stated in the ICH-E4 guidance document2; • disease models that, as the name implies, aim to describe disease progression; and • clinical trial models that describe patient demographics, adherence, drop-out rates, trial structure and so on. The purpose of pharmacometrics is also expressed in the International Conference on Harmonization ICH-E4 Guideline2 titled, “DoseResponse Information to Support Drug Registration”: “Knowledge 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of the relationships among dose, drug concentration in blood, and clinical response (effectiveness and undesirable effects) is important for the safe and effective use of drugs in individual patients. This information can help identify an appropriate starting dose, the best way to adjust dosage to the needs of a particular patient, and a dose beyond which increases would be unlikely to provide added benefit or would produce unacceptable side effects.” While exposure-response models are the most commonly used pharmacometric applications in the pharmaceutical industry today, the future should see greater use of clinical trial simulation applications. The Use of and Need for Pharmacometrics in a Regulated Industry Several regulatory documents address the use of and need for pharmacometrics in drug development. The ICH, followed by the FDA, produced scientific guidance on exposure-response studies emphasising the use of concentrationeffect relationship modelling in individualising therapy, in preparing dosage instructions, and in providing primary evidence of effectiveness2,3. The FDA and European Medicines Agency (EMA) guidances on population pharmacokinetics outline specific provisions on the conduct, context and use of non-linear mixedeffect modelling in drug development and regulatory submissions4,5. One pertinent document is the FDA guidance titled “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products”6, published after the Food and Drug Administration Modernization Act (FDAMA) of 1997 to clarify what constitutes “confirmatory evidence” of effectiveness (as per the Food, Drug, and Cosmetic [FD&C] Act, Section 505. [21 USC §355])7. The guidance

makes provisions for the use of extrapolation from existing studies to support effectiveness. In this regard, pharmacometrics is an undeniably potent tool. The 2009 FDA guidance on the end-of-phase 2A (EOP2A) meetings for sponsors of investigational new drug applications (INDs)8 closes the loop by unequivocally advocating the use of pharmacometrics in drug development and regulatory evaluation: “The purpose of an EOP2A meeting is to facilitate interaction between FDA and sponsors who seek guidance related to clinical trial design employing clinical trial simulation and quantitative modeling of prior knowledge (e.g., drug, placebo group responses, and disease), designing trials for better dose response estimation and dose selection, and other related issues.” In 2010, the FDA received 10 EOP2A meeting requests9 and is expecting an increase in requests in the coming years as pharmacometrics becomes integrated in clinical drug development. Pharmacometrics in the Development Pharmacometrics’ full potential can be realised when data are modelled from the start of development at the nonclinical level, up to the confirmatory Phase III and post-marketing trials. During the non-clinical development phase a major concern is the prediction of human exposureresponse behaviour from animal data. Two modelling strategies often applied to circumvent this problem are allometric scaling and physiologicallybased modelling. Allometric scaling is based on the relationship that exists between animal size and metabolic rate, and is generally used to extrapolate appropriate doses to humans from other species data 10,11. Physiologically-based modelling works by dividing the system into Volume 4 Issue 1


Clinical Research organised anatomical compartments and using physiologically-oriented parameterisation; this approach has intrinsic between-species scaling proprieties that allow for exposureresponse modelling in various species12. In Phase I and IIA clinical trials, several doses will generally be tested, and safety data will be collected as well as preliminary efficacy data. This stage often involves the quantification of dose dependence in PK, along with the effects of food, concomitant drugs, and exposure in certain populations. Exposure-response modelling should be performed to relate blood concentration to safety outcomes of interest, such as QT interval prolongation and relevant biomarkers, if available. The resulting model, along with appropriate trial model components, can be used prospectively to simulate laterphase trial designs and predict drug exposure, adverse events expectancy and efficacy. The FDA had this very intention in mind when it issued the EOP2A meeting guidance. Late-stage trials also benefit from pharmacometrics integration, not only to extract knowledge from observational data (as is often the case for late-stage PK sampling, for example) but also to complement the early phase-models to the more diverse patient population encountered in those trials. Combining the models built using extensive drug exposure data from early phase trials with the extensive efficacy and safety data of late phase trials bridges the gaps in exposure-response characterisation. With a thorough knowledge of the dose-response behaviour in specific patient populations, adequate dosing recommendations can be made. Having an incomplete characterisation of the shape and location of the exposure-response profile can lead to significant dosing errors. For example, in a 2002 paper by Cross et al.13, it was found that of 499 new molecular entities approved by the FDA from 1980 to 1999, one in five had a postmarketing dosage change and for four out of five, the change resulted in a decrease in dose. Clinical development for pediatric indications is a field where 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

pharmacometrics is gaining increased momentum because studies in this population are generally not as extensive as with adults. Knowledge gaps in the pediatric pharmacology must be bridged by means that allow precise quantitation of beneficial and adverse effects, and permit sound extrapolations to the intended age groups. A pharmacometrics example in pediatric applications is the FDA’s Written Requests for pediatric studies. It is the FDA’s goal to have 100% of Pediatric Written Requests designed by simulation studies by 2020. CRO’s Role In Pharmacometrics In the past, CROs usually did not have access to the entire body of data from sponsors. Only large pharmaceutical companies typically had the means to assemble pharmacometrics teams within their organisations. The opportunity to help pharmaceutical companies reduce development costs, the FDA’s increasing interest in predictive analysis methods, and the existence of commercially available analysis tools are making the offering of pharmacometrics services attractive to CROs. A range of pharmacometrics services are now offered by CROs, from non-clinical to post-marketing applications. Pharmacometrics service providers, such as PharmaNet/ i3, are best used for circumscribed analyses that require handling data from one or a few selected trials. When deciding to outsource pharmacometrics services to a CRO, certain criteria should be considered. First, assess the CRO’s ability to handle data. Pharmacometrics typically involves analysis datasets that have been built from one or several study databases. This represents a challenge because study databases are typically classoriented (e.g., interventions, events, findings), while pharmacometrics analysis datasets are subject- and chronology-oriented. Second, evaluate the scope of work that will be provided. The modelling tasks to be undertaken by the CRO should be clearly established from the start, and ideally should not be modified substantially over the course

of work. Timelines tend to elongate significantly as the tasks increase in complexity. Additional tasks or changes in orientation may arise, but to the extent possible, these should be covered in the initial contract by allowing for changes in timelines and scope. Third, the type and level of quality control for the data and the model(s) should be clearly stated in the contract. Pharmacometrics analysis is typically not linear so the quality of inputs and outputs should be reviewed regularly. The level of quality control should depend upon the task (descriptive vs. predictive modelling) and the intended use (internal vs. submission). For contractual pharmacometrics services, it is prudent to consider entering into a functional service partnership. Sponsors need to ensure service providers have appropriate data management capabilities, sufficient resources with the right skills, and the ability to offer independent quality assurance services. Pharmacometrics in the Future Although clinical trial simulation (CTS) may be a well-implemented practice in some organizations, it remains a challenging and resourceintensive endeavour at all levels: CTS requires computational capabilities, demonstrated expertise and diversity in personnel backgrounds, making it an activity essentially reserved to a few, well-organised pharmaceutical heavyweights 14. Access to the critical data required to simulate some components of clinical trials (i.e., data on the natural progression of diseases) are often not easily accessible. With the advent of concerted efforts aimed at making disease data and models publicly available, it now becomes possible to envision a broad use of CTS in drug development. One has only to think about the Alzheimer’s disease model from the Coalition Against Major Diseases (CAMD) 15, the OpenDiseaseModels. org initiative of the Metrum Institute 16, or the FDA’s Specific Disease Model Library 1. By the continued Volume 4 Issue 1


Clinical Research development and sharing of such models among the industry and regulatory stakeholders, it will become easier for scientists to build and for regulatory bodies to review larger, more complex trial simulations that may eventually replace some of the existing live clinical trials. References 1. Pharmacometrics at FDA.www. fda.gov/AboutFDA/CentersOffices/ CDER/ucm167032.htm (last accessed: 2011-02-16) 2. ICH Harmonized Tripartite Guideline. Dose-Response Information to Support Drug Registration. E4. Current Step 4 version. 10 March 1994. http:// www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/ Efficacy/E4/Step4/E4_Guideline. pdf (last accessed: 2011-02-16) 3. G  uidance for Industry ExposureResponse Relationships — Study Design, Data Analysis, and Regulatory Applications. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Apr 2003. www. fda.gov/downloads/Drugs/ GuidanceCompliance RegulatoryInformation/ Guidances/ucm072109.pdf (Last accessed: 2011-02-21) 4. G  uidance for Industry: Population Pharmacokinetics. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Feb 1999. www. fda.gov/downloads/Drugs/ GuidanceCompliance RegulatoryInformation/ Guidances/ucm072137.pdf (Last accessed: 2011-02-21) 5. C  ommittee for Medicinal Products for Human Use (CHMP). Guideline on Reporting the Results of Population Pharmacokinetic Analyses. CHMP/ www.ipimedia.com

EWP/185990/06. Jan 2008. www.ema.europa.eu/docs/ en_GB/document_library/ Scientific_guideline/2009/09/ WC500003067.pdf (Last accessed: 2011-02-25) 6. G  uidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). May 1998. www. fda.gov/downloads/Drugs/ GuidanceCompliance RegulatoryInformation/ Guidances/UCM078749.pdf (Last accessed: 2011-02-25) 7. w ww.fda.gov/Regulatory Information/Legislation/ FederalFoodDrug andCosmeticActFDCAct/ FDCActChapterVDrugsand Devices/ucm108125.htm Last accessed: 2011-03-11) 8. G  uidance for Industry: Endof-Phase 2A Meetings. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Sep 2009. www.fda. gov/downloads/ Drugs/GuidanceCompliance RegulatoryInformation/ Guidances/ucm079690.pdf (last accessed: 2011-02-21) 9. D  ivision of Pharmacometrics – Annual Report 2010. Office of Clinical Pharmacology, Office of Translational Sciences Center for Drug Evaluation and Research, FDA http:// www.fda.gov/downloads/ AboutFDA/ CentersOffices/ OfficeofMedicalProductsand Tobacco/CDER/UCM248099. pdf. (last accessed: 2012-02-19) 10. S  harma V, McNeill JH. To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol. 2009 Jul;157(6):907-21. 11. A  nderson BJ, Holford NH.

12.

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Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25-36. M ager DE, Woo S, Jusko WJ. Scaling pharmacodynamics from in vitro and preclinical animal studies to humans. Drug Metab Pharmacokinet. 2009;24(1):16-24. C ross J, et al. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf. 2002 Sep;11(6):439-46. H olford N, Ma SC, Ploeger BA. Clinical trial simulation: a review. Clin Pharmacol Ther. 2010 Aug; 88(2):166-82. C oalition Against Major Diseases (CAMD). Work Scope 1.1. Critical Path Institute. Jul 2009. http://www.c-path. org/pdf/CAMDWorkScope.pdf (Last Accessed: 2011-02-25) w ww.opendiseasemodels.org/ (Last accessed: 2011-02-25)

Pierre-Olivier Tremblay, MSc, Associate Director, Pharmacometrics Clinical Pharmaclogy Mr. Tremblay has been working in the field of pharmacometrics for the past ten years. He is the pharmacometrics team manager, supervising the development of tools and processes aimed at streamlining pharmacometric and statistical data analysis and output. Mr. Tremblay’s primary areas of interest are population PK/PD analysis (non-linear mixed effect modeling) and applied modeling and simulation methods. Email: potremblay@pharmanet.com

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Clinical Research

The Role of the Medical Photographer within Clinical Research Introduction Advances in consumer digital cameras combined with falling prices have led to researchers and other healthcare professionals untrained in medical photography increasingly taking their own photographs. With this comes inherent limitations and even risks; this often leads to poor quality images, resulting in a loss of vital data and inconsistent handling of consent and confidential images. But more recently, clinical research organisations are becoming more aware of the benefits of engaging with medical photographers, who are highly specialised in their profession to ensure the accuracy, suitability and integrity of the visual data that supports or validates a clinical trial. What was once seen as an optional extra is now being viewed as a service that has a substantial impact on proving or disproving a compound’s value in a study, potentially saving significant costs and more importantly lives. Why Take Photographs? The first known clinical photograph was taken over 150 years ago, ca. 1847, and photography has been used extensively within the healthcare environment since, providing visual evidence for patient records of the progress of a patient’s disease or treatment, as a teaching aid for medical practitioners and for illustrative purposes in publications and promotional material. Within clinical research, standardised, high quality medical imaging can provide visual evidence of a treatment or the effectiveness of an investigational medicinal product or medical device. The blinded review of photographs is an essential element in dermatology clinical trials 1 as well as other disciplines, including plastic surgery and ophthalmology. In 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

practice, if the results of any study can be seen, they can be photographed. A significant number of studies have been undertaken using photography within the area of wound healing. A recent US study found that a blinded assessment of pressure ulcer photographs taken by a research co-ordinator was found to be a 97% effective method of diagnosis 2. The reporting of this study is impressive given both the finding of the ability of photography to recreate what can be seen visually, and also the poor quality of the images that are used to illustrate the article. The removal of intentional or unintentional bias from a clinical trial can only help ensure the credibility of study conclusions 3. When taken consistently, images can be compared over a period of time to provide an unbiased perspective from an appropriate panel of experts, rather than subjectively by different site investigators. Numerical data of objective colour and dimensions can be gained from such standardised images, through the use of specialised image analysis software. Such blinded statistical data can effectively be used as a primary endpoint in a clinical trial. In addition, images can provide secondary endpoint data relating to study events or outcomes as well as for promotional purposes. From the subjects’ perspective, a professional medical photographer may provide extra reassurance regarding the use of their images. A survey was carried out in 2009 looking into the perception of medical photography, with the aim of promoting “healthy doctor-patient relationships”. This survey found that there was a low level of acceptability to the use of personal cameras (16%) and phones (12%) compared to hospital equipment (75%) 10.

A professional medical photographer is able to put the subject at ease by capturing images efficiently with the appropriate equipment. In addition to reassuring subjects and making them feel at ease when participating in trials, a medical photographer can help in eliminating the need for recall visits to re-take images due to poor quality, which can be of great benefit in enhancing patient retention. Who Should be Taking Medical Photographs? Traditionally, medical photography was viewed as a highly specialised, technical profession, and medical photographs were only taken by skilled medical photographers. However, the availability and cost-effectiveness of easy-to-use consumer digital cameras and mobile phone cameras has, as Berle describes, ‘democratised clinical photography’4. Whilst this may be a quick fix for some CROs, it can ultimately result in inferior quality images, which could have a detrimental effect on the results of a clinical trial. Whilst it may not always be possible to have a medical photographer capture all trial images due to cost, availability or feasibility, it is advisable to involve those professionally experienced or qualified initially to provide input into your study protocol, ensuring all imaging requirements are met. It is also preferable that those involved in taking the images undertake some training on the capture of standardised and consistent images and relevant confidentiality procedures. Not only will this input provide guidance and reassurance to those involved but, most significantly, it will help ensure that the high quality images needed to support a clinical trial are achieved. Volume 4 Issue 1


Clinical Research Consent & Data Protection Although obtaining fully informed written consent is now a legal requirement within clinical research, specific consent to clinical trial photography can often be overlooked. There is a general lack of guidelines available regarding specific clinical trial photography consent. However, it is advised that the patient consent form should specify not only that photographs are going to be taken, but more specifically what they are to be used for, for example purely for trial data, for publication or for promotional material etc. Given the lack of governance regarding clinical trial photography, the Institute of Medical Illustrators (IMI) was set up to create and maintain standards for the medical illustration profession. The IMI Code of Responsible Practice is in place to ensure that all members follow its guidelines, including those on consent to photography and patient confidentiality. It is advised that anyone undertaking clinical trial photography is fully aware of these guidelines, otherwise, as Samuels stated in March 2011, ‘it is only a matter of time before serious litigation with regard to sensitive images will occur’5. Six months after Samuels made his prediction, five lawsuits were filed against a US physician. Dr Koo allegedly posted ‘before and after’ images of women on her website. It is alleged that she had not only failed to gain appropriate consent for this, but she had also attached the patients’ first and last names to the images 6, resulting in a complete lack of patient privacy and confidentiality. The number of legal cases is sure to increase, in line with the increase in those taking medical photographs and the ease with which they can be disseminated, given the lack of knowledge or regard for what is second nature to a professional medical photographer. Image Quality and Colour Management If images are to be used as a primary or secondary endpoint within a clinical trial they should be of a consistently high quality. Medical photographers are trained and qualified to take high quality medical www.ipimedia.com

photographs, whilst a study nurse or doctor is understandably not. Out-offocus, inconsistent, poor quality or missing images due to technical/user faults will, obviously, in no way help in creating viable, useful clinical trial data. A recent internet search highlighted the issue that a large number of doctors are increasingly taking their own photographs, worryingly without the appropriate knowledge or training. A doctor who was taking medical photos on a daily basis sought help with his medical photography through an online forum, and whilst some of the advice he received was relatively ineffectual, one useful comment he did receive suggested he consult a medical photographer for the imaging and concentrate his time on seeing more patients 7. There is literature available on medical photography and how to achieve consistent images, and those qualified in the subject would rather provide help and guidance to those unsure of procedures than risk the integrity of what is essentially a specialised, technical profession. Whilst the subject of colour management could form a lengthy article in itself, it is particularly important to note that without carrying out any colour management the images produced will not be perceived as consistent and will not be a true representation of the original subject matter. If you require consistently high quality, objective image data or validation of the smallest changes in colour then colour management can, and should, be applied appropriately from capture through to output.

of misleading ‘before and after images’ 8,9. The use of image manipulation software and techniques, such as airbrushing, are widely used in the advertising world, and people are understandably, and with good reason, cautious of believing what they see. Images taken within a clinical trial should be treated in the same respect as any other source data, therefore there should be a clear and detailed audit trail from capture to output and analysis, whether it is through printing or expert panel review. If ‘before and after’ images are used as promotional material to market an IMP or medical device, only through following standard operating procedures and through observing best practice is it possible to prove that the images, and therefore the clinical trial data, are authentic. Lighting Whilst ‘point and click’ cameras may indeed be easier to use than professional SLR cameras they, of course, have their limitations. Options for lighting a subject, for example, are restricted to simply flash on, off or arbitrarily on auto. With the appropriate knowledge, different lighting techniques can show various attributes of the skin, in a number of ways, and can be repeated consistently throughout a study with the manual settings that professional SLR cameras permit. The results obtained through using different lighting of the same scar (see Fig. 1) can show what would be seen under Figure 1. Example of how lighting techniques can show different attributes of the skin.

Before and After The role of a professional medical photographer is to provide accurate, standardised images that reflect conditions or diseases as accurately as can be seen by the human eye, whilst providing the written documentation and operating procedures to support these images. A professional medical photographer does not produce images that have been manipulated with the intention of misleading people. Recently a number of articles have been submitted online on the subject INTERNATIONAL PHARMACEUTICAL INDUSTRY 63


Clinical Research diffuse (A) and oblique (B) lighting. Different lighting techniques can also be used when photographing open wounds, for example ulcers, which generically have a very shiny surface. These can prove difficult to capture using a ‘point and click’ system, especially if specific detail of the wound is required for analysis purposes. The appearance of a mole or lesion on the skin can also differ depending on the lighting techniques used. Figure 2 shows the same mole Figure 2. The appearance of a mole and the surrounding skin appears different due to specialised lighting techniques

lit under oblique (A), direct (B), diffuse (C), and cross-polarised lighting (D). Less traditional methods of photography can also be used within clinical trials, using wavelengths outside of the visible spectrum. Infra-red and ultraviolet light sources enable the capture and potential measurement of conditions such as psoriasis, fungal infections of the skin and vascular patterns in varicose veins and varicose ulcers, amongst other specialist applications that some researchers may not be aware of. Image Measurement By including both physical and colour scales into an image at the point of capture, the calibration of content can be demonstrated. There are countless measurements which can be achieved from the original image, including both numerical measurements and colour information. In addition to this, images can be adjusted consistently, in accordance with written procedures, to emphasise certain traits or characteristics, so allowing for secondary objective analysis. At every stage the original calibration, adjustment actions and measurement parameters can be saved to provide a robust audit trail throughout.

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Summary Whilst it may not always be feasible to use the expertise of a professional medical photographer to take all clinical trial images, it is advised that as a minimum, it should be ensured that those taking images are professionally advised and trained by a specialist medical photographer. Before undertaking any medical photography the process should be fully explained to the patients and/or subjects, sufficient specific consent should be given for the photography undertaken, and the stated usage of images should be adhered to. It is also crucial to determine the need and the final use of your images, then consult a specialist medical photographer to select the correct equipment to achieve the desired images. Images may not only be used purely as visual evidence, but if taken correctly and consistently configured they can enable objective, unbiased trial data suitable for both primary and secondary endpoints. If you are unable to show an audit trail for your images, then you cannot prove their authenticity, or any subsequent trial results. If in doubt ask the professionals. References 1. B ikowski J, Evolving Technologies for Clinical Photography, Practical Dermatology: 17-19 2011 2. B aumgarten M et al., Validity of Pressure Ulcer Diagnosis Using Digital Photography, Wound Repair and Regeneration: 17(2): 287-290 2009 3. D ay S and Altman DG, Blinding in Clinical Trials and Other Studies, British Medical Journal: 19-26, 321:504 2000 4. B erle I, Clinical photography and patient rights: the need for orthopraxy, Journal of Medical Ethics: 34:89-92 2008 5. D ’Sa P, 2011, Medical Photography with Mike Samuels: Part 2, available at http:// www.medicalhealthwriter.com/ medical-photography-with-mikesamuels-part-ii accessed 18 Nov 2011 6. D aily Mail (online) 2011, Patients’ horror as they find pictures of

7.

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their breasts online after plastic surgeon ‘posted images on web... and put their names next to them’, available at http:// w w w. d a i l y m a i l . c o . u k / n e w s / article-2042827/Patients-horrorfinding-naked-pictures-breastsonline-plastic-surgeon-postedpictures-internet--names-them. html#ixzz1eWuabN6A accessed 18 Nov 2011 O  zzu Webmaster forum 2008, available at http://www.ozzu.com/ photography-forum/medical-picst94151.html accessed 18 Nov 2011 F  rentzen J, 2011 Is it Real or is it Photoshopped?, Available at http:// www.plasticsurgerypractice.com/ issues/articles/2011-09_08.asp accessed 18 Nov 2011 K  otler R, 2011 Secrets of a Beverley Hills Surgeon, available at http://blogs.webmd.com/ cosmetic-surgery/2011/08/ m i s l e a d i n g - b e f o r e - a n d - a f t e rphotos.html accessed 18 Nov 2011 L au C, Schumacher H, Irwin M, Patients Perception of Medical Photography, Journal of Plastic, Reconstructive & Aesthetic Surgery 63:6 e507-511 2010

Jo Truelove, is a senior m e d i c a l photographer at Illingworth Research, a UK based CRO. Jo has a photography degree and is one of only a small number of people in the UK to have an MSc in Medical Illustration. She has over twelve years experience working as a medical photographer within the NHS and within both the biopharmaceutical and CRO company settings, where she has provided primary endpoint images for over thirty clinical trials. Jo is also a member of the Institute of Medical Illustrators. Email: jo.truelove@illingworthresearch.com

Volume 4 Issue 1


Labs/ Logistics & Cold Chain Supply

Supply Chain Management It’s More than Just Freight Effective supply chain management requires more than the ability to transport freight from A to B. It starts with procurement and involves packing, insurance, customs regulations, and controlling a range of risks along the way. Whether you are involved in major government programmes or niche commercial contracts, effective management of your supply chains, by air, sea, rail or road, is vital to controlling costs and maximising profit in any business. Supply chains can be vulnerable to more than just the financial pressures of the global downturn. As well as the possibility of a supplier defaulting, there are the risks of trade compliance, ethical responsibility, cultural and political issues and supply chain disruption, such as physical or natural disasters. Freight forwarding companies are increasingly asked to produce significant cost savings through tailored risk management and compliance programmes. It has been said that a supply chain is only as strong as its weakest link, and nowhere is that maxim more important than in the matter of security. Particularly when your cargo is highvalue, the emphasis on supply chain integrity and security is paramount. Typically supply chain security relies on a combination of traditional supply chain measures such as traceability, and increasingly the use of sophisticated software-based techniques such as tagging and tamper-proof seals. In addition, you should always work with an Authorised Economic Operator (AEO) and send advanced shipment notification to your customers, so they are fully aware of what they are expecting. Sounds obvious, but a surprising number of businesses send goods without advance paperwork, or even matching paperwork, on occasion. A similar initiative which has been running in the US since 2001 is the Customs Trade Partnership Against Terrorism (C-TPAT). This voluntary 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

organisation works with private companies to help them improve the integrity and security of their supply chain. The overall aims of frameworks AEO and C-TPAT are the same; by helping companies to understand the wider implications of lax security, it has been possible to build a more secure network with reduced border delays and customs inspections. If you’re working with transatlantic suppliers or customers, this is certainly something to consider. Peter Sunderland, the MD of Charles Kendall Freight, comments, “Compliance advice for customs is particularly in demand, as there are penalties for making errors with customs requirements. If businesses get these wrong, they will be fined, so they appreciate any expertise in steering them through the regulatory maze.” Flexibility to respond quickly to market demand is now seen by many to be more valuable than price alone. One significant development is the move by shipping lines to shelve fast but fuel-hungry container vessels –built for rushing Chinese goods to the US – and instead use slower-moving, larger and more economic container ships. The net result however is longer lead times. In uncertain times companies want greater flexibility not longer lead times. The geopolitical risks associated with countries such as Greece are causing more companies to review their manufacturing locations. “The logistics and risks of getting supplies to customers on time from a plant close to Greece may outweigh the cost benefits of manufacturing in the region,” says

Mr Sunderland The informed-compliance culture, established in the US in the 1990s through the Customs Modernization Act and successive amendments by the Federal Maritime Commission of the Shipping Act of 1984, has been adopted globally post 9/11 and is being aggressively implemented in the EU currently. The customs regime is increasingly complex and the penalties for non-compliance can be severe. UK Customs are increasing the number of audits and visits, with fines of up to £2500 for each individual error. Even so, few organisations have inhouse compliance experts. Serious infractions, such as rebating or illegal discounting, regularly incur severe penalties. A multinational was fined $1million in 1980 for accepting illegal rebates from ocean carriers. Events affecting companies’ supply chains in 2009 Source: Economist Intelligence Unit

Interesting Statistics • “ 8 Million. The size of Toyota’s carrecall programme due to faulty component” (Dec 2009) • “ $1.25bn. BP’s clean-up costs from Deepwater Horizon oil spill (BP, June 2011) Volume 4 Issue 1


A Handy Guide to Exhibition Shipping If you’re going to be exhibiting at a conference or exhibition this year, you’d best be prepared. Lots of exhibitors make common mistakes. We can show you how to make the most of your time and money by guiding you through the minefield of logistics.

Make sure your marketing materials make it onto your stand on-time and in one piece by using the right logistics supplier.

Common Mistakes! • Foodstuffs can be tricky. Avoid sending them if possible, or let your agent know so they can be properly declared. There is no escaping Customs & Revenue! • Leaving it too late. Seems obvious, but it’s a pitfall many an exhibitor has fallen into. And you could get stung by late fees. Find out the deadlines as early as possible and set yourself reminders. Never underestimate how long it could take to gather your materials and pack them. • Mislabelling can trip even the most experienced marketing executive up. Always refer to instructions, or better still – ask for help from your event logistics supplier. • Don’t over-pack or under-pack. The contents could be damaged if overstuffed, and equally if there is not enough padding or wrapping used in under-filled boxes. • Brief your stand staff fully on what is expected from them setting up and breaking down the stand. A Solution in the UK? • Use a freight forwarder who specialise in event logistics. They understand the marketing requirements of an event over general Freight Forwarding. • Find a company who are experienced in bio-logistics as they will know the life science industry best. • Ask if your logistics supplier can consolidate shipments. This can often mean savings through economies of scale. Find out more at www.charleskendallbiologistics.com or call 0208 831 1376


Labs/ Logistics & Cold Chain Supply

Specialist Logistics for Controlled Room Temperature Shipments Introduction Many pharmaceutical products need to be kept in an environment with a particular temperature band. Familiar examples are frozen product and Cool Chain (+2°C to +8°C). Both of these temperature requirements are based on keeping product cold or frozen while the external environment is hotter. Other pharmaceutical product needs to be kept within a warmer environment than the typical ambient temperatures in transport routes. Some medicines and healthcare products are distributed and shipped to patients without temperature control – examples are transdermal patches, many overthe-counter medicines, tablets, etc. While many of these products are very stable, some do risk quality degradation if they are subjected to certain extremes of temperature. Temperatures of extreme cold can risk freezing products while milder cold temperatures can still affect liquid suspensions. Similarly, heat from high temperature experiences can degrade medicines and affect chemistry, through crystallisation in medicinal patches for example. Some of these products can be shipped without temperature control. However, where there is a risk of degradation in extreme temperature environments, they are often distributed in shipping systems or environments that maintain a warm, yet not hot, temperature environment. Such distribution is called Controlled Room Temperature (and is often abbreviated to CRT). Often the temperature range specification of these shipments is +15°C to +25°C. Sometimes these temperature thresholds might be wider, for example up to +2°C to +25°C where a cooler temperature is acceptable or +15°C to +30°C where a hotter temperature is OK. Wider temperature bands are beneficial as this gives 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

greater flexibility for the temperaturecontrolled logistics solution. As an alternative to simply shipping with or without CRT temperature control, a decision can be made on each shipment depending on the likely external temperatures that will be experienced on the route. Given increasing regulatory requirements, more and more pharmaceutical products and research samples are being sent using CRT shipping technology. Controlled Room Temperature Shipping Options Once a decision has been made that a research sample or a finished pharmaceutical product needs to be shipped under Controlled Room Temperature conditions, the next step is to determine the method for shipping. A climate-controlled vehicle can be selected, thus providing an actively controlled environment for the

shipped goods, along with a trained driver to monitor progress. For many routes, this is not practical as the shipment’s route will require a flight as part of the journey. A vehicle can also quickly become uneconomic when distributing individual patient medicines over a wide geographical area. Self-contained temperaturecontrolled packaging and containers then take over as the best options. Packaging Technology for Controlled Room Temperature Shipping A pharma industry manufacturer may make the decision that one of their product lines needs to move from ambient shipping to Controlled Room Temperature. Similarly this could be imposed by a healthcare regulator if there have been problems associated with temperature damage. It’s worth being aware of the implications of this on the likely shipping solution, particularly Volume 4 Issue 1


Labs/ Logistics & Cold Chain Supply when geographical and distribution requirements are such that selfcontained shipping systems have been chosen. The product line will likely be contained within individual patient packs and multiple packs contained within grouping cartons. With no temperature control, these cartons can be stacked directly onto pallets for distribution. The ratio of the volume on the pallet taken up by product compared to the total volume available is an important measure in shipping. Excellent efficiency can be achieved if the grouping cartons are designed to give a good fit to the dimensions of the shipping pallet. After moving to a Controlled Room Temperature shipping solution, the configuration of a pallet commences with the components of the temperature-controlled shipping system. Usually this means starting with an insulated outer container – this enables the internal environment to be shielded from outside temperature risks and slows down the rate at which these can affect it. Within this container space, eutectic plates of Phase Change Material (often abbreviated to PCM) are located as determined by the validated shipping system design. This PCM is used to maintain the correct temperature range. The space remaining inside the layout of eutectic plates can then be filled with product grouping cartons. It is not unusual for the product volume available in the design to be less than 50% of the outer volume of the complete pallet. Figure 1 gives a demonstration of what this change might look like. On the left a pallet is shown loaded directly with product cartons. On the right is a similar Controlled Room Temperature pallet system. Inside the insulated walls and PCM plates (shown in purple), fewer product cartons can be fitted. A wide range of self-contained packaging options are obtainable and it is worth exploring these in some more detail. The simplest of systems is based on the theory of thermal mass and components commonly used in Cool Chain shipping systems. Thermal mass is a concept which describes the inertia against temperature 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

changes that objects may possess. Water-filled cool packs contain a significant amount of thermal mass, that is, because of their weight and some of the physical properties of water, they slow down temperature changes within their environment. Thus, in the simplest of CRT shipping solutions, cool packs containing warm water are packed around the shipped product in an insulated container. Of course a specialist packaging supplier will have conducted appropriate qualification testing on the design in the usual pharmaceutical validation process. However, most Controlled Room Temperature packaging takes a step up from this and uses the phase change of a specialist material to give a powerful temperature-maintaining effect. These specialist phase change materials work in the same way as a water-based cool pack works in a Cool Chain shipping system. In Cool Chain, frozen ice cool packs melt to water at 0°C and provide a cooling effect at this constant temperature as they do so. Ice is going through a phase change at this temperature – changing from one state (solid ice) to another (liquid water). Indeed, this is the ‘magic’ of most temperature-

controlled shipping options – they use the energy ‘storage’ capability of a phase change to maintain a tight temperature range around them. Consider a specialist phase change material that might be used in a CRT shipping system. A typical PCM used might have a melting point of +20°C – a temperature safely within the +15°C to +25°C shipping temperature range. The PCM material has a latent heat energy at +20°C as the material changes between solid and liquid. In a shipping system, this can be used to keep the internal temperature close to +20°C while the outside environment varies. There are two approaches to using this phase change material. The first is to prepare it in its liquid state – for our hypothetical material this would mean a little above +20°C in temperature. When the shipping system is exposed to cold external temperatures and this cooling effect travels through the walls of the insulated shipper, the PCM freezes at a constant +20°C, thus maintaining the internal temperature. The payload is then kept in the required +15°C to +25°C environment. The second approach is the opposite of the first. The phase change material is then prepared in its solid state (i.e. a little below +20°C).

Figure 1. Diagram of a pallet loaded directly with product cartons (shown on left) next to a Controlled Room Temperature pallet system (shown on right) into which fewer product cartons can be fitted

Volume 4 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 73


Labs/ Logistics & Cold Chain Supply Now, in the opposite temperature risk situation – in other words, when the shipping system is exposed to hot external temperatures – it is a heating effect that travels through the walls of the insulated shipper. Yet when this happens, the PCM melts at a constant +20°C, thus maintaining the internal temperature. Again the payload is kept in the required +15°C to +25°C environment. These two methods of using the PCM are similar to having ‘summer’ and ‘winter’ systems with Cool Chain solutions. The two options are designed for performance in different external environments. Of course, CRT packaging used in shipping will be sourced from a specialist packaging or logistics provider. They will supply an appropriately validated design with a packing instruction that describes how the PCM eutectic plates should be prepared. A Risk Management Approach to the Selection of CRT Logistics Solutions Many specialist CRT packaging solutions can be quite costly, while the risk of product damage through temperature excursion is often only confined to some shipping routes and times of year. Because of this, a pragmatic approach to purchasing and using CRT logistics can be followed. By making a risk-based assessment of each shipping route, a decision can be made on which specialist logistics option is chosen. The three options that have been discussed are: 1. N o temperature control – the goods are packed in grouping cartons and sent through a normal logistics process 2. A climate-controlled vehicle giving a temperature-controlled solution 3. T he use of PCMs in self-contained temperature-controlled packaging giving a temperature-controlled solution Consider a hypothetical product that is normally stored in an uncontrolled warehouse environment but for which it is undesirable to experience extremes of hot or cold temperature. If this product is to be distributed from the UK to international destinations 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 1. An assessment of example logistics routes for a hypothetical pharma product with proposed specialist logistics solutions

there will be a variety of temperature risk factors. These will vary by destination and over the course of the year as ambient temperatures fluctuate. By assessing these risks, the best logistics solution can be chosen for each eventuality. In this hypothetical example, consider that it is undesirable for the product to experience temperatures, say, below 0°C or above +30°C. Table 1 shows possible outcomes from an assessment process on various shipping routes. Different logistics solutions have been proposed depending on the nature of each route. A Specialist Logistics Provider can offer these options to a shipping site. When actually shipping, temperature monitors can be used to add confidence that unexpected environments have not been experienced. They can also be used to validate routes over the seasons to measure actual temperature experiences. At Biocair, we see requirements for Controlled Room Temperature packaging and logistics vary over the year. Requirements increase during the winter as colder temperatures give more concern over cold temperature risks. Similarly, some hot emerging market destinations justify a CRT logistics solution in the summer, especially if there are potential delays in an uncontrolled Customs warehouse. In conclusion, specialist logistics solutions for Controlled Room Temperature shipping are available. For some products and research samples, a CRT option must always

be selected as a specific temperature band such as +15°C to +25°C is required. With many other products and samples, the risk of degradation is limited and an assessment can be made as to what level of logistics solution is required. By using support from their specialist logistics provider, smart decisions based on a risk assessment of the route can be used to ensure the solutions chosen are appropriate and efficient.

Nathan Barnard, Cool Chain Manager, Biocair International Nathan Barnard is the Cool Chain Manager at Biocair International, a leading specialist courier to the Biotechnology, Pharmaceutical and Scientific Research Industries. He is responsible for directing and developing Biocair’s temperature controlled logistics services worldwide. This includes improving temperature performance and giving customer support where needed. Prior to Biocair, his experience includes medical device and pharmaceutical packaging roles, in particular for specialist packaging companies who supply Cold Chain and other temperature controlled shipping solutions. Email: nb@biocair.com

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Non-Invasive Method for Monitoring Real-Time Oxygen Concentrations during Hematopoietic Stem/Progenitor Cell (HSPC) Culture Summary The SDR SensorDish® Reader has allowed for the quantitation of in vitro oxygen concentrations during the culture of hematopoietic stem/ progenitor cells (HSPC) isolated from human umbilical cord blood. The influence of simulated physiological oxygen concentrations on HSPC proliferation and cell cycle status, as well as expression of markers of stem cell phenotype or differentiated cell types, was examined concurrently with the monitoring of real-time oxygen concentrations in the cell culture media. This study has demonstrated the usefulness of this system for examinations of cell phenotype and function in conditions that effectively mimic the in vivo oxygen environment.

Alterations in oxygen concentration are known to have direct effects on the differentiation of trophoblast and vascular cells. Furthermore, pathological placental development has significant effects on in utero oxygen tensions. Abnormal placental oxygen concentrations likewise affect growth and development of the fetus and could eventually lead to an increased risk of fetal and maternal morbidity and mortality. For this reason, it is extremely important that investigations into the effects of oxygen concentration on placental growth and vascular development continue. An in vitro culture system that effectively mimics these alterations in physiological oxygen concentrations during in vitro cell culture would prove irreplaceable in future studies.

Oxygen Concentrations Rise during Embryonic Development Oxygen concentrations change dramatically during human embryonic development. These alterations in oxygen concentration are most striking in the developing placenta as it grows and invades maternal uterine tissue and ultimately taps into oxygenated maternal blood (reviewed in 1. Trophoblast cells are one of the earliest cell types to form in the human placenta and, thus, must develop in a variety of oxygen concentrations. Similarly, hematopoietic and vascular progenitor cells can first be found within the early placenta in a low oxygen environment2. As development proceeds, oxygen tensions rise and both trophoblast and progenitor cells adapt to the rising oxygen concentrations3,4. Interactions between trophoblast and vascular cells are extremely complex and have not been adequately described.

HSPC Culture in Physiological Oxygen Concentrations For the analysis of cellular processes during placental vascular development, an in vitro model was developed using CD133+ cells isolated from human umbilical cord blood, called hematopoietic stem/progenitor cells (HSPC). Two different oxygen concentrations were used for this in vitro model to simulate physiological oxygen tensions at specific timepoints during placental development. Traditional cell culture conditions in ambient oxygen were likewise examined and compared. Crucial to this investigation was a non-invasive method for monitoring real-time oxygen concentrations in the HSPC culture media during experimentation. To that end, the SDR SensorDish Reader from PreSens Precision Sensing GmbH was effectively employed to measure oxygen concentrations while conserving

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the sterile in vitro environment. Low oxygen environments in this cell culture study were achieved using a hypoxia chamber (Billups-Rothenburg, USA) inserted into a traditional CO 2 incubator (Figure 1). Prior to cell Figure 1: The SDR SensorDish® Reader from PreSens Precision Sensing GmbH was to monitor in vitro oxygen concentrations during HSPC culture. HSPC were cultured in OxoDish® 24-well plates in a hermetically sealed, humidified cell culture chamber containing low oxygen gas mixtures (1% or 8% O2, 5% CO2) or atmospheric oxygen (20% O2) (A). OxoDishes® were placed on the SDR SensorDish® Reader and the chambers incubated at 37°C for the specified time. Connection of the SDR to computer (B) allowed for non-invasive, real-time measurements of oxygen concentrations in HSPC culture media during the experimental period.

culture, the chamber was infused with gas mixtures containing either 1% or 8% O 2 according to the manufacturer’s protocol. HSPC cultures in ambient oxygen concentrations (20%) were also compared. This setup allowed for specific physiological oxygen concentrations to be monitored and Volume 4 Issue 1


Labs/ Logistics & Cold Chain Supply maintained in vitro (Figure 2). HSPC culture dynamics in physiological Figure 2: Actual oxygen tensions measured in the HSPC culture media during a two-day experimental period in atmospheres containing low (1% or 8% O2) or atmospheric oxygen (20% O2). A representative graph demonstrating in vitro oxygen tensions measured with the SDR in combination with OxoDishes® during two-day HSPC culture in various oxygen environments. An average oxygen tension of 10.2 (± 5.5 mmHg) was encountered when HSPC were cultured in 1% O2. In 8% O2, the average oxygen tension in the media was 65.0 (± 7.5 mmHg). When HSPC were cultured in ambient oxygen (20% O2) the average oxygen tension in HSPC culture media was 157.9 (± 9.2 mmHg). To obtain a relatively stable low oxygen environment, the atmosphere was replaced one time per hour for three hours at 24-hour intervals.

Similarly, apoptosis levels were quantified using the FITC-Annexin V Apoptosis Kit (BD) in combination with flow cytometry. At the protein level, expression patterns of extracellular markers of stem/progenitor or differentiated cells were analysed using multi-parametric flow cytometry. The following characteristics were observed from HSPC cultured in the described oxygen concentrations. In hyperoxic environments, HSPC displayed an increased rate of proliferation. HSPC growth curves decreased in an oxygen concentrationdependent manner, with the lowest cell proliferation seen in environments containing 1% O2 (Figure 3).

Figure 4: Flow cytometric cell cycle analysis of expanded HSPC (Day 7) and HSPC cultured in physiological oxygen concentrations. HSPC were expanded in HSPC-GM for 7 days, fixed and stained with propidium iodide (PI). Stained cells were then subjected to flow cytometry. Live cells (R1) were gated based on FSC and SSC (A). Single cells (R2) were gated and cell aggregates resulting from fixation were excluded (B). Cell ploidy was determined based on the stochastic integration of PI into HSPC DNA (C). Results from this experiment demonstrate that following expansion 65% of HSPC were 1n (G0/G1) while 2% of HSPC were 2n (G2/M). The remainder of the cells were in the S phase of the cell cycle (33%). HSPC were grown in 1%, 8% or 20% O2 and cell cycle status determined on days 7, 8, 10, 12 and 14 (D). Low oxygen dose-dependently increased the number of resting G0/G1 HSPC over the test period. Subsequent reductions in cycling G2/M and S cells were measured.

Figure 3: Growth curve demonstrating the effects of physiological oxygen on HSPC cell number. HSPC (Day 7) were cultured in low oxygen environments (1% or 8% O2) or

oxygen concentrations could also be compared to traditional HSPC culture in the hyperoxic environment of ambient oxygen. The effects of oxygen concentration of HSPC function and differentiation were likewise compared in this study. Analysis of the Effects of Physiological Oxygen Concentrations on HSPC Cultures CD133+ HSPC cells isolated from umbilical cord blood were cultivated for up to one week in special 24-well OxoDishes®. Every 2-3 days, cells and culture media were removed, briefly centrifuged (1500 rpm; 5 min) and cells were carefully resuspended in media that had preincubated for 1 h in the appropriate oxygen concentrations (1%, 8% or 20%). Real-time oxygen concentrations were monitored online with the SensorDish Reader during the entire incubation period. Concurrently, HSPC cells were cultivated in either 24- or 6-well plates, depending on assay, under identical conditions. When media was exchanged, an aliquot was removed and cell number determined using a Casy® Counter. Flow cytometric measurement of DNA content allowed for the examination of HSPC cell cycle status following culture in physiological (1% or 8%) or ambient (20%) oxygen concentrations.

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ambient oxygen (20% O2). HSPC cell number was quantified on Days 10, 12, and 14 with a Casy ® Counter. HSPC number expanded in ambient oxygen (open triangles). On the other hand, HSPC growth dose-dependently decreased in low oxygen with the greatest decrease in proliferation seen in 1% O2 (grey diamonds). HSPC culture in 8% O2 (black squares) significantly decreased cell number when compared to hyperoxic conditions.

Flow cytometric analysis of HSPC DNA content allowed for the analysis of cell cycle status. Results from this investigation clearly demonstrated that the number of cells either resting (e.g. G0) or in G1 increased significantly when oxygen concentration in the environment decreased (Figure 4). Flow cytometry was also used to measure apoptosis levels in HSPC cultured in decreasing oxygen concentrations. Oxygen concentration appeared to have no significant effect on HSPC apoptosis in this experiment (data not shown). Taken together, these results suggest that when HSPC are cultured in conditions that mimic the in vivo environment, cell proliferation decreases, most likely

due to an increase in the number of resting cells (G0) and without any significant effects on cell death. Multiparametric flow cytometry was employed to examine HSPC lineage marker analysis. Expression of the stem/progenitor cell markers (e.g. CD34, CD133, and CD117) were not significantly changed during

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Labs/ Logistics & Cold Chain Supply culture in physiological oxygen concentrations (data not shown). Conversely, based on the expression of four extracellular markers (CD11b+CD13+CD14+CD31+), the percentage of monocytes in the culture was greatly increased with decreasing oxygen concentration (Figure 5). Figure 5: Representative flow cytometry dot plots demonstrating the expression of extracellular markers for the monocyte lineage during HSPC culture in physiological oxygen concentrations. Expanded HSPC (Day 7) were incubated with fluorescently-labelled antibodies and subjected to multiparametric flow cytometric analysis. Live cells were gated based on size (FSC) and granularity (SSC). Cells coexpressing the monocyte markers CD11b and CD14 (CD11b+CD14+) were further gated. The majority of CD11b+CD14+ cells were contained within a population of CD13+CD31+ cells (monocytes). On Day 7, less than 1% of cells expressed all four markers (A). Cells expanded a further seven days (Day 14) were similarly analysed. The percentage of monocytes increased with decreasing oxygen concentration over this period (B).

Furthermore, the expression of important factors for vasculogenesis (e.g. chemokines) was affected by oxygen concentration. For example, when expression of the chemokine receptor, CXCR4, was examined in HSPC cultures grown in low oxygen it was noted that the number of CXCR4+ cells increased with decreasing oxygen concentration. In addition, the ligand for CXCR4 was shown to be expressed by placental stromal cells in low oxygen environments in vivo and in vitro 5. Results from this study provide one of the first descriptions of HSPC culture conditions that effectively mimic the in vivo oxygen environment of the developing placenta. Furthermore, this study demonstrates evidence that oxygen concentration has a definite effect on 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Labs/ Logistics & Cold Chain Supply stem/progenitor cell phenotype and function, and further substantiates the idea that oxygen plays a key role during placental development. New Perspectives for Non-invasive Oxygen Monitoring with the SDR Physiological oxygen concentrations during distinct time-points in human placental development could be effectively mimicked with surprising precision using two different gas mixtures, containing either 1% or 8% O2 (5% CO 2). Measurements made in this study with the SDR SensorDish® Reader paired with OxoDishes® provide additional proof that traditional cell culture in atmospheric oxygen (20% O2) creates a clearly hyperoxic environment with oxygen tensions well above normal pO2 found in human tissues. The use of low oxygen gas mixtures is not novel in placental research, and oxygen-reduced environments have previously been used to assess trophoblast development and functions6-8. One important difference, however, is that previous investigations did not include non-invasive, realtime oxygen monitoring. As clearly demonstrated in this investigation, oxygen concentrations in low oxygen cell culture systems are in a constant flux and are difficult to maintain at physiological levels. Accordingly, standardisation of experimental parameters (e.g. cell number, media depth and composition, gas replacement intervals, etc.) and extensive testing was required to ensure that actual physiological oxygen concentrations were reached and subsequently maintained. Using standardised protocols, variability between experiments was reduced. Furthermore, and in contrast to previously published results 6-8, the SDR oxygen monitoring system provided reliable data concerning in vitro oxygen levels during the entire experimental period. The above-described study illustrates a successful attempt to analyse hematopoietic stem/ progenitor cells functions in conditions that precisely mimicked physiological oxygen concentrations in their placental environment. Reproducible results from this study 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

have demonstrated a clear connection between oxygen concentration and cell proliferation and cell cycle status. The significance of these results on stem/progenitor cell culture and function will be examined in further detail in the future. The SDR SensorDish® Reader has opened up the possibility of further in vitro studies in which defined, physiologicallyrelevant oxygen concentrations play an important role.

4.

5.

6. Future Directions for Research Involving the SDR SensorDish ® Reader In combination with in vitro experimentation, the SDR SensorDish® Reader has opened up additional application fields in defined oxygen environments. For example, tissue engineering for regenerative medicine or in vitro toxicology studies to test for cytotoxic agents could prove more useful when taken in the context of physiological oxygen concentrations. The SDR SensorDish® Reader could also be used to monitor oxygen concentrations while testing for useful pharmacological molecules. In addition, the pH sensor HydroDish ® has made the SDR SensorDish® Reader an alternative for measuring pH values in the culture media under sterile conditions. With these applications, the SDR SensorDish ® Reader has provided a new scale for instrumentation that allows stable cell culture conditions to be maintained. Furthermore, media changes or alterations in oxygen concentrations can be monitored and altered according to experiment. Using this system, research objectives will be reached in a timely manner, thereby reducing research costs. References 1. H  err, F., et al., How to study placental vascular development? Theriogenology, 2009. 73(6): p. 817-27. 2. R  obin, C., et al., Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell, 2009. 5(4): p. 385-95. 3. J auniaux, E., et al., In-vivo measurement of intrauterine gases

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and acid-base values early in human pregnancy. Hum Reprod, 1999. 14(11): p. 2901-4. R  odesch, F., et al., Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol, 1992. 80(2): p. 283-5. M  cKinnon, T., et al., CXCL12 homes fetal progenitor cells to sites of placental vascular development. (submitted) C  aniggia, I., et al., Hypoxiainducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest, 2000. 105(5): p. 577-87. G  enbacev, O., et al., Regulation of human placental development by oxygen tension. Science, 1997. 277(5332): p. 1669-72. G  raham, C.H., T.E. Fitzpatrick, and K.R. McCrae, Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood, 1998. 91(9): p. 3300-7.

Timothy McKinnon, PhD is a Postdoctoral Fellow at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, Canada. He is currently working in the laboratory of Rebecca Gladdy, MD, PhD where they use functional genomics in conjunction with novel mouse models to develop targeted therapies against pediatric sarcomas. Email: mckinnon@lunenfeld.ca

Co-authors: Nelli Baal and Prof. Marek Zygmunt

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Manufacturing

Drug Delivery: Thin Dissolving Films Begin to Come of Age Thin dissolving films (TDFs) have been in use for industrial applications for over 25 years. The first real public awareness of edible thin films was the high profile launch of Listerine Breath Fresheners, which spawned many ’copy cat’ products which consumers decided were imitation rather than an innovation, and growth of this new technology stalled. However, with the success of Suboxone film, a unique thin film application of a controlled drug ensuring increased patient compliance, TDF technology is once again being taken seriously for pharmaceutical and consumer healthcare products.

insoluble actives can be suspended in films for release on dissolution in the mouth. TDFs are an ideal dosage format for the elderly, children or patients with nausea, or anyone who will not tolerate conventional tablet/ capsule dosage formats, and are now substantially cheaper to produce than ODT. Recent formulation advances are also allowing much higher dosages of API to be included in TDFs. 2) Fully Dissolving Dental/Buccal Films: Controlled release into the oral cavity or onto the teeth/gums Dental Films: Films are applied to teeth/gums and release ingredients over 10-15minutes before dissolving away e.g. teethwhitening strips, teeth re-mineralising/ sensitivity.

TDF is a unique technology with a very broad range of product applications for oral and topical controlled release. By using the wide range of high-grade film-forming polymers now available, it is possible to produce films with an enormous range of dissolution and film characteristics. Examples of product applications for TDF are:1) Edible Oral Films:

Fast dissolve in the mouth within 3-10 seconds. New taste-masking techniques allow bitter ingredients to be successfully formulated, and water80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Buccal Films: Applied to the roof of the mouth the film dissolves slowly, releasing ingredients into the oral cavity and nasal passages. Ideal for volatile, decongestant ingredients. This film format is commercially marketed as Snore-eze, an antisnoring device.

be adapted to adhere to the mucosal wall and provide controlled release directly into the bloodstream with rapid absorption and avoidance of first pass metabolism.

3) Dermal Films: Advanced Wound Dressings: TDFs are incorporated as part of a multi-layer dressing, usually the skin contact layer, to provide controlled release of actives such as antimicrobials, antibiotics and haemostats onto the wound. TDF dissolution rates can be adjusted from rapid release into the exuding wound, or very slow titration using polymer films which are water-based but, once formed, are virtually insoluble so that after wetting they become porous to release actives very slowly over a 1-3 day period.

Temporary Skin “Plaster”: these are “stand-alone” skin coverings applied to wet skin. The TDF dissolves onto the skin surface and dries to form a temporary protective layer adhering to skin. Ingredients such as antimicrobials or anti-inflammatory agents can be included in these skin films which wash off with soap and water, and can be easily re-applied as required

Sublingual/Mucosal Absorption: There are only a few of these mucosal and sublingual films currently marketed, but TDF technology can Volume 4 Issue 1


Manufacturing

Conclusion: After a slightly hesitant start, thin dissolving films are beginning to come of age as a drug delivery mechanism with potential for many unique applications in pharmaceutical and healthcare products. For more information: please contact Chris Hatton, Business Development Director, BioFilm Ltd tchris.hatton@biofilm.co.uk. www.biofilm.co.uk

Sticky Ingredients: Natural antimicrobials such as honey have been used in wound dressings as pastes for several years. Honey can be formulated into a dry film which is much easier to handle during manufacture and in patient application, but releases at the wound surface.

4) Cosmetic Films & Soaps: Face Mask: Dry thin films can be a very convenient method of applying ‘messy’ ingredients to wetted skin, releasing cleansing, emollient and lightening agents.

Packaging: Automated packing techniques have introduced pharmaceutical-style, peelopen, unit-dose, hygienically-sealed foil sachets to replace plastic multistrip dispensers. Thin Film Soaps: Surfactants, with suitable antimicrobials such as bioactive silver and emollients, can be formulated into a neat dry thin film soap which, when water is added, provides a hygienic hand and arm cleansing ‘dosage’ form for medical professionals and hospital visitors. Manufacture: Techniques have evolved significantly since the early thin films launched over 10 years ago with the advent of close control of dosage and gentle drying of film which allow the formulation of heat-sensitive API’s and new tastemasking methods. www.ipimedia.com

Chris Hatton is an experienced sales and marketing professional with a proven track record of business and product development in major f.m.c.g. companies and SME’s in the consumer healthcare and life science sectors. Chris was with SmithKilne Beecham (now GSK) for 20 years in senior marketing positions in the UK and overseas and was responsible for major brands such as Lucozade and Night Nurse Cold remedy. Chris moved to Scotland with RohtoMentholatum (Deep Heat, Oxy & Rohto eyecare), where he was Sales & Marketing Director for 12 years developing business through major retailers such as Boots, Tesco and leading pharmacy groups, before joining BioFilm in 2010. Email: chris.hatton@biofilm.co.uk

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Manufacturing

Manufacturing and Quality Control of Liquid-Filled Two-piece Hard Capsules In the pharmaceutical market, hard capsules, together with tablets, are the most common dosage forms for oral administration. Concerning the manufacturing of solid dosage forms on an industrial scale, it is broadly recognised that powdered formulations are incorporated in twopiece hard gelatin capsules, while liquid or semi-solid formulations are incorporated in soft gelatin capsules, which are sealed during the filling process. However, sealing of twopiece hard gelatin capsules can be accomplished, thus allowing the incorporation of liquid or semi-solid formulation. The use of two-piece hard capsules for the purpose of carrying liquid or semi-solid formulations appears to be an attractive strategy, but its potential has been poorly explored by the pharmaceutical industry. The current perspective presents a promising future for this “new” dosage form intended for the delivery of drugs or other substances which may be incorporated into a liquid or semisolid matrix of lipophilic or hydrophilic nature. The technology for obtaining twopiece hard capsules filled with a liquid or semi-solid formulation is relatively simple. The production of the dosage form is carried out in appropriate facilities with specialised equipment, under suitable and controlled conditions of temperature and humidity. Basically, the manufacturing process includes multiple steps, namely content preparation, filling, sealing or banding of the filled twopiece hard capsules, followed by drying of the sealed/banded filled two-piece hard capsules. The process for the production of liquid-filled twopiece hard capsules is also simpler as compared with that used to obtain soft gelatin capsules and, regarding the filling of powders, the problems of weight variation are reduced, and cross-contamination is virtually eliminated. The use of two-piece hard 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

capsules proves to be suitable for substances showing low melting point, hygroscopic and oxidation sensitivity, or those requiring an oral absorption optimisation. Today, the vast scientific literature presents that this dosage form, in addition to promoting an increase in bioavailability as compared to the tablets, constitutes a simple way to obtain different release profiles from a unit dosage. Some products presented as liquid-filled hard capsules are already available worldwide, namely in Europe, USA, Middle East, Australia and Japan. Today, two major companies are investing in this dosage form by providing two-piece hard capsules, machinery and technical advice: Shionogi Qualicaps and Capsugel. Other midsize companies working in the development and manufacturing of finished products are LiqFillCaps (Portugal), Encap Drug Delivery (Scotland), RentschlerPharma (Germany), and Pharmaceutics International, Inc. (United States). The two-piece hard capsules intended to be filled with liquid or semi-solid formulation have the same composition as conventional hard capsules. Conventionally, the gelatin hard capsules are the first choice, although gelatin/polyethylene glycol (gelatin-PEG) and hypromellose (HPMC) hard capsules could be used depending on the nature of the material to be filled. In spite of the fact that the ordinary two-piece hard capsule could be filled with liquid or semi-solid formulation, it is preferable to have a specifically designed hard capsule for secure containment of liquids and semi-solids. This design is found in LiCapsTM developed by Capsugel. What could be derived from the extensive experience of LiqFillCapsTM in manufacturing this type of dosage form is that the ordinary two-piece hard capsules (gelatin or HPMC) are perfectly feasible when the filling material is liquid at room temperature and viscous enough to not leak from capsule before applying sealing or

banding, or liquid and viscous enough at elevated temperature but semi-solid at room temperature. The preparation of the hard capsule content includes steps common to any manufacturing process, namely weighing of the formulation components, and the mixture of the components in a predefined sequence and under predefined conditions of temperature, pressure, and agitation. The mixture can be processed at room temperature (25oC) or higher, and on agitation or ultrasonication, depending on the characteristics of the formulation components and the desired type of lipidic system. In order to obtain a robust process, thermal and rheological characteristics of the filling mixture are to be considered. Generally, the viscosity of the filling material should be between 0.1 Pa×s and 25 Pa×s, thus filling can be achieved with accuracy and precision. However, the maximum viscosity is determined by the characteristics of the filling pumps of the filling equipment. Concurrently, the viscosity of the filling mass should allow a clear break from the dosing nozzle and the absence of stringing. The temperature of the filling mass should not exceed 70oC, a requirement particularly important in the case of semi-solid formulations. When the filling formulation consists of a dispersion, it is recommended that the particle size of the suspending active component should be smaller than 50 μm, however manufacturing practice confirms that a particle size smaller than 180 μm (the same as the size range required in the case of soft capsules) is perfectly feasible. The process of two-piece hard capsule filling with liquids/semi-solids should employ suitable machinery. It is said that most capsule-filling equipment could be modified so as to enable filling of hot or cold liquids into two-piece hard capsules. The fact is that this argument is not entirely valid or feasible, but was true when in early times engineering adapted powderfilling machines for the purpose of Volume 4 Issue 1


Manufacturing liquid-filling. Nowadays, appropriate machines are available for the filling of liquids or semi-solids into two-piece hard capsules. With respect to the lipidic composition of the filling material for two-piece hard capsules, it is observed that formulations are susceptible to oxidation to a greater or lesser degree. The process of filling the liquid material into the body of the hard capsule is very fast, especially when using a machine that could work at a high liquid-filling rate (e.g., 80,000 capsules per hour), leading to a very short time exposure to the air. Nevertheless the air bubble at the head of the liquid-filled hard capsule (since only approximately 90% of the hard capsule total volume could be filled) could be detrimental to the stability quality of the formulation itself. Only recently, LiqFillCaps developed and validated a system capable of ensuring a nitrogen-saturated environment at the liquid container and, most important, at the liquidfilling station of the equipment. The system developed by LiqFillCaps was able to decrease oxygen in the head space of the liquid-filled hard capsule to values below 5% depending on the nitrogen purge. For that purpose, the oxygen and nitrogen levels were measured using a needle-type oxygen microsensor suited for measuring oxygen distribution profiles. This nitrogen purge system for the liquidfilling of hard caps was shown to be essential when a highly sensitive to oxidation oil was filled into two-piece hard gelatin capsules. Measurement of the oxidative parameters (peroxide value and p-anisidin value) for the filled oil, with and without the nitrogen purge system, was compared. Evidence showed that the oxidative parameters were kept low and constant throughout the stability study under ICH conditions when applying the nitrogen purge system. The sealing process is another critical step in the manufacturing process. Sealing prevents the leakage of the content of the hard capsules. The processes of filling and sealing of hard capsules may occur in separate operation units or by a continuous process. Within the methods described for that purpose, the most used is 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

banding technology. According to this technology, the equipment performing banding is fed with liquid-filled hard capsules. The capsules are positioned and guided to pass over the sealing disk that rotates in a sealing solution, transferring the solution on to the capsules, thus coating the junction between the cap and body. The Hicapseal速 is an example of a device developed by Shionogi Qualicaps for the technology described above. Right after banding, filled hard capsules are directed to a continuous-loop conveyor belt of a drying unit. The drying unit allows the freshly applied band to dry while keeping its integrity. This sealing process has the advantage of allowing a good seal and easy scale-up. With regard to the sealing solution, it has the composition of the two-piece hard capsule, i.e. if gelatin hard capsules are used then the sealing solution is a gelatin solution which is kept warm at controlled temperature during operation (attention must be paid to the viscosity of the solution during operation due to solvent evaporation). If HPMC hard capsules are used, then an HPMC solution is employed, in which case it is an ethanolic solution which is kept at room temperature during operation (the same attention must be paid concerning viscosity of the solution during operation due to solvent evaporation). Another sealing technology is the one developed by Capsugel, designated as LEMSTM (Liquid Encapsulation by Micro Spray). This technology involves the application of a micro spray water-alcohol solution within the gap between body and cap of the capsule, which lowers the melting point of gelatin, promoting the junction between the two pieces. Each capsule is individually sprayed, and drying occurs smoothly in a revolving cylinder. The quality control of the finished product has to be held in appropriate facilities and conditions and through approved procedures for the various tasks. Manufacturing of hard capsules containing liquids or semi-solids starts with quality control of raw materials, including the hard capsules. During the manufacturing process, it is also necessary to implement control systems for intermediates as well

as in-process control (IPC) being fully validated, since these are an integral part of quality assurance. Thus, after preparing the filling mixture it is necessary to perform the IPC by analysing and determining the following parameters: viscosity, pH and drug content. After filling of hard capsules follows the process of sealing and banding. At this stage, assessments are made of the visual appearance (optical clarity/turbidity, and presence of particulates), sealing, and weight uniformity of the capsules. A usual and practical method to assess sealing effectiveness is to visually inspect a sample of sealed capsules submitted to negative pressure on a bed of soft paper after a predefined period of time (the test is only positive if oily spots are observed on the soft paper). The moment before the primary packaging, packaging material should be properly checked for identification and printing. The semi-finished product (hard gelatin capsules containing liquid) should be subjected to a microbiological control and assay for the drug content. After the secondary packaging, it is important to verify the following aspects: the number of capsules per carton, batch no, expiry date, label, and print literature. The subsequent analysis of the finished product consists of the determination of parameters such as identification and determination of the active substance, disintegration test, and dissolution test.

Helton Santos Head of the Department of Pharmaceutical Development at Labialfarma S.A. Graduated in Pharmaceutical Sciences at The Federal University of Bahia (Brazil). PhD degree in Pharmaceutical Technology (2005) at the University of Coimbra (Portugal). Joined Labialfarma in 2004 as a member of the Department of Pharmaceutical Development. Member o the Center for Pharmaceutical Studies, from the University of Coimbra. Email:heltonsantos@labialfarma.com

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Manufacturing

What is Cleaning in Place? How Does it Work, And Where Should You Use it? A Basic Primer Answers These & Many More Questions Cleaning in Place (CIP) has been around for approximately 50 years, and is commonly used in hygiene-critical industries, such as food, beverage and pharmaceutical, to clean a wide range of plant. CIP refers to the use of a mix of chemicals, heat and water to clean machinery, vessels or pipework without dismantling plant. The process can be one-shot, where everything goes to drain, or recovery, which recycles most of the liquid. Overall, CIP can be a very efficient way of cleaning. The principles of CIP can be applied to any industry and plant where hygiene is critical; and the process is usually an integral part of any automated plant. Increasing Health and Safety legislation is set to make CIP more common, which is a good thing because a shiny surface on the outside of plant is no guarantee of cleanliness on the inside. CIP is principally concerned with soil removal: soil being anything that should not be present in a clean vessel. Soil can cause tainting and can often be smelt. It can be visible (scale, foreign bodies), or invisible in the form of bacteria, such as E. coli, or yeast spores. The time needed to remove soil is at least 15 minutes using a suitable chemical (strength dependent on chemical supplier and product) at temperatures above 50 degrees C, but no greater than 75 degrees C because there is no advantage to be gained above this temperature. Cleaning Agents Commonly used chemicals for soil removal include caustic soda, and phosphoric and nitric acids, sodium hypochlorite (hypo) and peracetic acid (PAA). Caustic soda is an alkali typically used at 0.5% - 2% volume. It reacts with the fats in the soil and softens it for removal. One downside is that caustic soda is not effective for removing scaling. In addition, 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sequestriants are often added to keep soiling in solution. Phosphoric and nitric acids are used in detergent formulations for scale removal, often at lower temperatures than caustic. These acids must be used with care as they can attack valve and pump seals. They are often used in dairies for one week in every six weeks to remove milk scale, and

can be used after commissioning to remove installation debris. Sodium hypochlorite (hypo) offers the advantage of a very low cost. It is used primarily for disinfection because its ability for soil removal is poor. The active ingredient of hypo is chlorine (bleach). This can corrode stainless steel in high concentrations and will attack seals and personnel. It will also Volume 4 Issue 1


Manufacturing taint if not rinsed out, and is dangerous if mixed with acid, forming chlorine gas, which is poisonous. PAA is an equilibrium mixture of acetic acid and hydrogen peroxide. It is a powerful oxidising agent with an oxidation capacity higher than sodium hypochlorite and chlorine dioxide, and is comparable to the oxidative capacity of ozone. PAA at 75 mg/L is reported to successfully kill 100% of a 10(7) cell/ ml yeast or bacterial population in 30 seconds. CIP Line & Vessel Cleaning When cleaning lines in process equipment using CIP, the correct fluid velocity must be achieved to obtain good cleaning. Laminar flow, from velocities below 1.5 m/sec does not give good cleaning characteristics. What is required is turbulent flow at velocities between 1.5-2.1 m/sec. There is no gain at velocities above 2.1 m/sec. In the cleaning of vessels two main methods are generally employed. The first uses high-pressure cleaning heads to remove soil by mechanical action: the vessel surface being contacted in a series of passes. The second method employs low-pressure cleaning heads that rely purely on chemical action to remove the soiling. CIP Return The majority of problems with CIP can be attributed to poor CIP return. This causes excessive CIP times, excessive use of detergent and heat with high effluent discharge. To overcome these problems the system for return must quickly and efficiently return the cleaning solutions back to the CIP set. Critical in this respect is the choice of scavenge pump. Poor scavenge allows back-up of cleaning solution and poor cleaning of the lower part of the vessel. In contrast, effective scavenge allows fresh cleaning solutions to contact the vessel walls and carry away soil effectively. CIP Optimisation Most CIP sequences are never altered from post-installation settings; these are usually a set of “defaults” which are set on commissioning. However 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

CIP operators can optimise their systems by monitoring a number of key parameters. These are: •W  hat temperature and concentration (conductivity) are the caustic tanks set to? - often set too high with no added benefit. •C  onsider the pre-rinse – does it run clear and then keep going? •C  austic fill – how high are the return conductivity and temperature transmitters set? • Intermediate rinse – is it removing caustic solution and temperature prior to sterilisation? •S  terilisation – what strength is the sterilising agent and how long is the contact time? Finally all changes resulting from the CIP monitoring process should be documented and validated to meet any statutory regulations, and/or specific client requirements. Burkert saves £120,000 per annum - or 40% - in CIP costs for major pharmaceutical manufacturer Converting a manual CIP process to automatic across 80 reaction vessels, using pressure transmitters, condition sensors and flow meters, has enabled Burkert to achieve savings of £120,000 per annum for a major UK pharmaceutical manufacturer. Prior to the installation of the Burkert system, the reaction tanks were each cleaned for six hours, constantly flushed to drain with hot water at 70oC. This was a purely manual process based upon operator experience, rather than positive signals from the process that the cleaning procedure was complete. The weekly costs for the manual cleaning procedure were substantial: energy costs were running at around £4000, with water at approximately £1000 and effluent costs approaching the same figure. In total, the combined weekly figure across all activities included in the cleaning was £5900; or a considerable £295,000 per annum.

Keen to reduce these costs, engineers at the pharmaceutical manufacturer contacted Burkert. This resulted in a site visit to view the manual CIP process. Following the visit Burkert suggested a solution for each reaction vessel based upon a Type 8311 pressure transmitter, a Type 8222 condition sensor and a Type 8041 flow sensor. These products were installed on a test group of the vessels and linked to the plant SCADA system. The CIP process was then undertaken in an automatic mode, with the 8222 condition monitor providing effective feedback of when the water in the vessel was clean – and hence the vessel itself – to the SCADA system, which terminated the process. On the basis of the initial tests, engineers at the pharmaceutical plant calculated that their CIP costs would be reduced by 40%, or £120,000 per year, using the Burkert equipment. “This application highlights the savings that can be achieved on even the simplest of processes, as a result of consulting our specialist engineers,” said Burkert UK Sales Manager, Neil Saunders. “All business sectors today are incredibly competitive, so all opportunities to exploit so-called ‘lowhanging fruit’ have to be taken and optimised upon. With our specialist knowledge and leading-edge product range this is exactly what we do: and the results speak for themselves, as evidenced by this application.”

Timo Bleschke is product manager of pneumatic and process interfaces at Bürkert Fluid Control Systems since 2010. Before he was resonsible for trainings and for management of new product launchings for six years in the department „Marketing Services“. Email: timo.bleschke@burkert.com

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Manufacturing

Robots Set for a Fruitful Future in Pharmaceutical Processes The food and beverage and pharmaceutical industries have often mirrored each other in the way they use similar technologies in their respective production processes. Automation is one such area, particularly when it comes to robotics. Having been embraced in increasing numbers by food manufacturers, robots are increasingly finding their way into many pharmaceutical manufacturing processes as well. Nigel Platt, Sales & Marketing Manager for ABB’s UK robotics business, explains the benefits robots have already been proven to deliver in pharmaceutical applications, and examines the scope for future application of the technology Although the characteristics of food and beverage and pharmaceutical products may be very different, they do have several things in common. First of these is the over-riding need for hygiene, with both industries operating equally high standards that must be met to eliminate product contamination. There are numerous examples of process techniques that are common to both industries, including aseptic filling, sanitisation, sterilisation, isolator technology, containment and cleaning in place. Both industries are also governed by very similar standards for validation and traceability, particularly when it comes to ensuring that their production processes meet strict regulatory requirements. Food and Drug Administration (FDA) requirements, for example, whilst originating in the US, impact any company importing food or pharmaceutical goods into the USA, consequently affecting companies worldwide. Meeting these standards can be a challenging and time-consuming process, particularly as technically, 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

there is no such thing as an FDA approved or compliant product. Instead, the FDA reviews the validation of each production process and looks at the combined ability of all the equipment, manufacturing and quality systems employed to ensure that the end product will be safe for human consumption. In meeting these requirements, it makes little sense for companies to develop solutions from scratch, making the availability of a proven production solution from a closelyrelated industry highly attractive. With robots still largely considered as new technology in many quarters, even despite their over 50 years of heritage, it has taken a while for robotic equipment to be accepted as part of the Good Manufacturing Processes (GMP) set out for the production of food and pharmaceutical products. In recent years, however, there have been major advances in robotic technology that have made it increasingly suitable for both food and beverage and pharmaceutical processes alike. Foremost amongst these has been the development of specific hygienic design models for these industries, rather than just adaptation of existing models developed for other applications. This targeted focus has been partly driven by the need for robot suppliers to look for alternative markets to the traditional bastion of automotive manufacturing, particularly in the last two years when many large automobile manufacturers have had to downscale their operations. As new specific models have become available, such as stainless steel versions for use in clean-inplace processes, so too have new applications been found for them, which in turn has helped to secure their acceptance. The following are just some of the key processes where robots are already being deployed.

Research and Development The research and development stage has historically been a complicated, time-consuming process that has invariably led to delays in time to market, and increased costs to cover testing and evaluation. With steady advances in robotic technology over recent years, this situation has now changed, such that thousands of potential pharmaceutical products can now be developed and tested in a fraction of the time previously required. One example is High Throughput Screening (HTS). Using robotic technology, coupled with data processing software, liquid handling devices and sensitive detection equipment, HTS enables research teams to conduct millions of tests, in turn leading to much faster discovery and development of new pharmaceutical products. The improvements that this technology has brought has meant that up to 100,000 samples per day can now be tested and evaluated, as compared with the 30 samples per day previously achievable with manual screening. With ultra High Throughput Screening (uHTS) now also in development, robots could soon also have a part to play in processing even greater numbers of samples. Another important benefit of utilising robotic technology has also been the elimination of the negative impact of human tedium on test results. Today’s robots can handle the full range of tasks inherent in the screening process, spanning everything from sample preparation and shaking samples through to transporting samples between different experiment points. Robots have also proved useful in temperature-controlled processes, where samples need to be incubated in special ovens for specific periods of time. In these applications, the Volume 4 Issue 1


Manufacturing

robot can automatically insert and remove samples to ensure they are incubated under the correct conditions. Production There are several areas in which the demands on robots in pharmaceutical processes differ from those in standard industrial applications. One key difference is the need for faster cycle times. Time constraints on the screening processes, for example, where each part of the experimentation process needs to be performed for a set duration, mean that robots have to move at faster speeds without any negative impact on precision. With recent developments in robotic control technology, coupled with advances in handling accessories, such as grippers, robots have proven highly adept at delivering fast, repeatable performance with few or no production errors. Developments in vision technology, such as the arrival www.ipimedia.com

of colour and three-dimensional capabilities, have also helped to add an extra element of intelligence. Areas where this is proving beneficial include the scanning of barcodes to enable recognition and tracking of specific batches through production and packaging, crucial for meeting traceability requirements. Vision capabilities can also assist at the packaging stage, where the ability to ‘see’ enables robots to visually weigh and fill products much more effectively, greatly reducing packing errors. As mentioned earlier, another pressing requirement inherent in pharmaceutical production is the demand for the highest levels of hygiene and cleanliness. With a choice of specially designed robots now available, of which ABB’s own Flexpicker robot is just one example, it is now increasingly possible for pharmaceutical companies to find new ways of achieving the ideal situation of a production process

where products are ‘untouched by human hands’. Packaging The benefits that robots can bring in the packaging of pharmaceutical products are well illustrated by an ABB installation at Novartis in Italy. The plant produces and packages up to 35 different vaccines for shipment to over 70 different countries worldwide. Various robots are used at the plant. The first of the robots to be supplied to the plant handles the palletising of packaged products, with the flexibility to handle different package sizes and shapes when required. This robot uses two scanners to read barcodes on boxes arriving via a conveyor belt and sorts them according to their shipment destination. The robot proved so fast and reliable that it was subsequently moved to a larger area where it now loads up to six pallets at a time. The improvements brought by INTERNATIONAL PHARMACEUTICAL INDUSTRY 91


Manufacturing this robot led to the acquisition of a second robot which is used mainly for packaging oral vaccines for polio. Incorporating an advanced vision system, this robot ensures that each individual polio cartridge is correctly lifted and placed into boxes of 20 cartridges at a time. The most innovative robotised application at the plant, however, is a robot de-nester, which came into operation in 2008. The robot is part of a 40-metre packaging line for flu and meningitis vaccines that handles up to 500 syringes a minute. This process entails three separate stages, which were previously handled manually, risking potential contamination and repetition-induced error. The process begins with ‘nests’ of 100 flu syringes arriving from the aseptic department in lidded plastic tubs. The robot removes the lid of each tub by vacuum, before lifting each nest and placing them individually on a conveyor belt, ready for the next stage. With each nest costing potentially thousands of euros, it is critical that any errors are avoided. Once the contents of the tubs are emptied, the robot places each tub and its lid onto a pallet. This placement too has to be carefully controlled to meet pharmaceutical GMP requirements, which stipulate strict separation of packaging materials and products. Since several million tubs and lids will be handled over the course of a year, it is therefore critical that the robot ensures the correct procedures are followed. The robot also incorporates a telecamera, which matches each tub and its contents through datamatrix code reading, to ensure that the correct vaccines have arrived in the correct tubs and eliminate the risk of potential cross contamination. As a security measure throughout the entire process, the system performs three verifications on the tub contents, with any irregularities immediately reported to the operator. Dispelling the Myths Despite the many benefits that robots have been proven to bring, and a heritage spanning over 50 years, 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

robots are still often deemed to be ‘new technology’ by many users, anxious about perceived complexity or cost. Smaller companies especially, which have limited financial and technical resources and are consequently more risk-averse, often tend to see robots as the preserve of larger companies. In fact, it is precisely these smaller companies at which the developments in robotic technology, particularly in the areas of programming and operation, have been aimed. Over time, the technology has been steadily tweaked with a whole raft of improvements aimed at reducing complexity and increasing the range of applications where robots can be used. Simplified Ownership For users of robotic equipment, a key development has been in the area of remote monitoring technology. With developments in communications, it is now possible for a robot to relay upto-the-minute data on its performance which can be used to identify any potential issues before they occur. When coupled with a remote service agreement where a robot supplier takes total responsibility for robot maintenance, this technology can yield considerable benefits in terms of asset availability and maintenance resource allocation. Summary Compared with even five years ago, when the role of automation in pharmaceutical processes was still being widely debated, the progress made by robots in the pharmaceutical market has already been impressive. Indeed, the 2010 International Federation of Robotics (IFR) report identifies the ‘tremendous potential’ for growth in the pharmaceutical sector between 2011 and 2013 as more manufacturers embrace the possibilities of the technology. The rate of adoption of automation in general, and robots in particular, is likely to continue to grow dramatically both up to and beyond 2013. The benefits of improved product quality and consistency, coupled with enhanced profitability and product throughput, provides a strong case

for the implementation of robots that often far outweighs any lingering concerns over their introduction. For both UK and European companies, it is also worth considering the impact of the longterm demographic, which shows an ageing population with fewer younger people filling the employment gap as older workers retire. Already there are concerns about a shortage in the availability of skilled pharmacologists. Automation is an ideal insurance policy against the consequences this will have on both skills and resource availability. With robots also in the ascendancy in the food and beverage industry, it will also be interesting to see whether some of the projected growth in both the food and beverage and pharmaceutical sectors might stem from greater collaboration on developing shared solutions. All in all, the future for robotics in the pharmaceutical sector is likely to be a fruitful and interesting one.

Nigel Platt As ABB Robotics’ Sales and Marketing Manager for the UK, Nigel is responsible for developing and driving the sales and marketing strategy, in line with ABB’s global strategy and business plan. He joined ABB in 1990, where Platt began his career with ABB as Account Manager for the South East Region. Nigel holds a Higher National Certificate (HNC) in Mechanical & Production Engineering from De Havilland College in Hertfordshire and is a member of the British Automation and Robotics Association Council, serving as the ‘Industrial Robot supplier representative’. He is trained in advanced team selling, contract law and negotiation skills and is Institute of Leadership and Management (ILM) accredited. Email: robotics@gb.abb.com

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PACKAGING

Industry-suitable Technologies to Protect Pharma Products against Counterfeiting As clearly stated in the new European directive 2011/62/EU¹ relating to medicinal products for human use, as regards the prevention of the entry into legal supply chain of falsified medicinal products, patient safety will be achieved with the combination of three components: - verify the authenticity of the medicinal product, - identify individual packs or batches - verify whether the outer packaging has been tampered with. These new measures, which improve the protection of public health, will be adopted by member states on January 2, 2013. Because implementing labelling, tracking and tracing systems for products will likely result in additional costs to the pharmaceutical industry, this paper hopes to shed light on several cost-effective product authentication processes and features, which can be easily deployed and implemented within manufacturing plants and laboratories worldwide. Authentication and Identification Several organisations have reported that individual product coding can be used to identify counterfeits. However, more and more experts agree that visible product codes, batch numbers and expiry dates cannot be used reliably for product authentication because they can be copied by counterfeiters². Banknotes, for example, have been serialised for decades and are still widely counterfeited. Of course, the cost invested to secure a banknote is far greater than that of medicines. However, we believe that some lessons learned in the field of high security documents can contribute to finding solutions to counterfeit pharmaceutical products. 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Visible (Overt) or Invisible to the Naked Eye (Covert) Security Features Traditionally, pharmaceutica lcompanies have added visible security features to their packaging to prevent counterfeiting. These include, for example, holograms, kinegrams, embossing, micro printing, moiré or special ink such as optical variable ink. However, these visible features only provide minimum security and require training for effective authentication Fig 1. By the same token, if a company Figure 1 Overt security features examples (hologram)

manufacturing company, an approach that restricts consumer access Anti-counterfeiting literature also suggests that a specialised scanner or a distinctive analysis is required in order to identify covert security features, making the “genuine-orfake” verification a costly and timeconsuming process. However, as in other industries, the digital or software revolution has opened up new and exciting possibilities. For example, the Cryptoglyph® on-packaging3 (e.g. folding boxes, blister packs, labels) achieves invisible protection by using normal visible ink or varnish. Fig 2 Digital security features simply Figure 2 Covert security (Alpidrin box)

suddenly decides to discontinue the use of visible security features, consumers might mistake a genuine product for a fake. Today, counterfeiters have the best printing equipment and components at their disposal in order to perfectly replicate the visual aspects of a packaging, including its visible authentication features. By contrast, the use of “covert” features – security features that are invisible to the naked eye – provides a higher level of security. For example, “good” counterfeit banknotes always include a replication of the visible security features, but rarely of the invisible ones. To prevent leaks, however, covert security features should never be disclosed. These features should only be shared with a limited number of trustworthy persons of the branded

require an off-the-shelf office flatbed scanner or an iPhone 4 smartphone device to perform a “genuine-or-fake” verification. In this case, the covert feature scanner can be purchased on the consumer electronics market anywhere, while proprietary hardware is the rule when security substances, taggant or dedicated invisible optical effect are used. Replacing security consumables with software has also had a significant impact on the cost of implementing an anti-counterfeiting programme for multi-brand companies using multiple production plants. For example, when using security consumables, it is necessary to provide the various production plants with the right quantity of security features in relation to the number of packaging Volume 4 Issue 1


PACKAGING elements to produce, plus extras for the overs. If poorly managed, this procedure can encourage theft during transportation and misuse of the overs to produce counterfeits. The use of security components can also affect the packaging printing equipment if special ink is used or if extra features such as hologram or taggant should be inserted in the production run. By contrast, digital security features using normal ink will not alter the printing process or production speed; this is an important cost-saving benefit. Human Sensory Perception-based or Machine-based “Genuine-orFake” Verification When selecting a security feature, it is not only important to assess the cost of purchase, implementation, global deployment and management, and resistance to replication, but also how a “genuine-or-fake” verification is performed. In this case, the various anticounterfeiting features can be placed in two main categories: - features which use human sensory perception; - features which are machinereadable. When using human sensory perceptionbased verification (visual, tactile, oral), a person will be required to undergo adequate training to be able to distinguish a genuine security feature from a fake replication, when displayed side-by-side. By contrast, when using machine-based verification, a person will only be required to follow a stepby-step process. If properly described, the latter can be performed by anyone without any specific knowledge or training. Some methods combine a human visual decision with a device, such as the Raman Spectroscopy analyser, which is capable of analysing the chemical components of a tablet and comparing them with the analysis result of the genuine production stored in the device. Such a device may cost dozens of thousands of dollars and require some training to properly manipulate. In addition, only a few analysers are generally available within a given company at a given time, 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

forcing the manufacturer to send the suspected tablets to a dedicated lab. As mentioned earlier, other visual features include the form factor packaging, that is its facial appearance, display surface, size and shape, and other printing details that counterfeiters may not have identified. A discrepancy between a genuine pack and a counterfeit can therefore also be identified with the help of a detailed description, stored in and provided by an online database. But this data can only uncover counterfeits until attempts are made to remedy these discrepancies. So, an important question arises as to the cost of performing a machine-readable “genuine-or-fake” verification. Because some existing digital authentication processes use off-the-shelf office scanners or iPhonelike devices to verify the authenticity of the packaging components (folding box, blister pack or label) and because these supplies are often part of an office setting Fig 3, performing a Figure 3 Medicine container authentication via iPhone 4

machine-based verification using digital authentication processes results in virtually no added costs to the branded manufacturing company. Local vs. Remote Verification Process In order to perform a machine-based “genuine-or-fake” verification, there are two distinct methods: a local process using the appropriate hardware, or a remote identification using an online server. Local verification could be seen as advantageous as it does not require any data connection. However, in the

case of covert security features, using a local verification process requires that the equipment be rid of sensitive information, which, if stolen, could fall into the hands of counterfeiters. By the same token, if the pharmaceutical manufacturing company needs to carry out verifications at multiple locations, it will need to have the appropriate equipment, provide training, and perform maintenance and calibration onsite. These added costs should not be neglected, especially when taking into account employee turnover, and equipment upgrades and refills. Because internet and mobile connections are widely available around the world today, a security feature enabling remote “genuine-orfake” verifications via a central secure server is a major advantage. A remote verification process not only eliminates the need to share sensitive information with the operator, but also enables consolidation of all the verifications performed worldwide, thus facilitating the detection of any correlation between various fraudulent sources within the supply chain. As for all criminal acts, the quicker you uncover them the more you are well positioned to identify the criminal source to stop it. Security Level and Protection against Leaks A recent FDA report4 shows that organised crime is active in counterfeit medicine, as this industry represents a very lucrative and less risky criminal business compared to others. The use of corruption and coercion is therefore seemingly prevalent to obtain security features or programmes. An important question then arises as to the number of people and companies that should be involved in the security chain. In the case of consumable security elements, suppliers are involved in the security chain on a recurring basis, exposing the recipient company to theft or misuse of the overs necessary to produce the secure packaging. Consequently, the less suppliers are involved in critical security elements, the less leaks. Web-based Secure Server Solutions There are two fundamental ways web servers can be used. The first Volume 4 Issue 1


PACKAGING approach consists of using the server as a data repository system. This method is used to detect the different anti-counterfeiting features used in a given packaging or production batch. For example, the IPM system – Interface Public-Members of the World Customs Organisation – is a secure communication tool for the exchange of information between right holders and customs administrations. By using the IPM system, field customs officers have access to the ‘genuine/fake’ database to check imported goods for counterfeits. The second approach uses the secure server to analyse different parameters of a packaging in order to automatically assess its authenticity5 using a digital image captured with a regular office scanner, a digital camera or even a smartphone device. In this case, the secure server is also capable of managing the deployment of anti-counterfeiting features. Because these features are digital elements, there is no need to involve additional security suppliers in the security chain. The branded pharmaceutical manufacturing company has in turn full control over the generation of digital security elements, and can allocate individual profile and password authorisations online to automate “genuine-or-fake” verifications worldwide. This second approach appears to be the best protection against leaks, especially if very few high-level employees are authorised to access critical security elements, such as an encryption key or security patterns. The security elements are then digitally routed via encrypted and secured data networks to local markets and their related production plants. Of course, costs related to software licenses and software customisation for the deployment of the application within an existing information technology environment, as well as royalties, have to be taken into consideration. However, if the web-based system is well conceived, access to a free internet browser should be all that is necessary to use it. This approach also frees very large organisations from having to perform complex computer validation processes while updating local PCs with new pieces of software and, in www.ipimedia.com

turn, from disrupting the production of medicines. Could Smartphones be used to Uncover Fake Medicine? Smartphones, such as iPhone-like devices, are continuously evolving with increased functionalities and computing power, as well as image and video capabilities. Smartphones can therefore benefit the development and expansion of digital authentication features based on invisible marking, allowing mobility and “on-the-fly” genuine-or-fake verification. However, these advancements do not mean that mobile verifications should be placed in the hands of patients because of many unanswered questions related to the legal responsibility of a genuine-orfake verdict. Given these uncertainties, we believe that mobile product authentication should stay in the hands of professionals in the pharmaceutical industry, and undergo further research before being extended to the patient level. In summary Covert (invisible to the naked eye) security features provide higher security compared to overt (visible) ones. Digital solutions based on software are easier to deploy compared to security consumable-based solutions. Machine-readable security features are less expensive and more reliable for authenticating genuine-or-fake items compared to human sensorybased features, as no specific knowledge is required, only a step-bystep process that, if well described, can be performed by anyone. Remote online verification using a web application does not require specific software at the verification side, only a free internet browser. Moreover, this approach will reduce the risk of leaks, especially if very few people are involved in managing the sensitive security data elements. Digital solutions for product authentication based on software are less costly compared to security consumable-based solutions, especially when considering large production volumes. Medicine counterfeiting is flourishing. In fact, trade in counterfeit medicines

appears to be growing faster than the market for legitimate drugs6. Factors like global business exchanges, e-commerce, aging population and growing medicine consumption are all naturally leading counterfeiters to enter the pharmaceutical market. This growing tendency can at least be partially counteracted with technological progress. Indeed, increased computing power and the ease with which people can use handheld devices to access networks and exchange data will lead to developing effective web-based authentication solutions and fighting back. 1. D  irective 2011/62/EU of the European Parliament and of the Council of 8 June 2011 2. International Pharmaceutical Industry, August 2011, volume 3 issue 3, “Should we Leave it to Patients to Identify Counterfeit medicines?” 3. Cryptoglyph digital security solution, http://www.alpvision.com/ cryptoglyph-covert-marking.html 4. FDA Conducts Preliminary Review of Agency’s Diversion and Counterfeit Criminal Case Information September 2011. 5. Krypsos Web Application, http:// www.alpvision.com/krypsos-onlineauthentication.html 6. United Nations Office on Drugs and Crime, http://www.unodc.org/ documents/data-and-analysis/ tocta/8.Counterfeit_products.pdf, June 2010. Dr. Fred Jordan – CEO of AlpVision SA Dr. Jordan is co-founder of AlpVision and has served as CEO since June 2001. He is the author of numerous publications and patents and co-inventor of Cryptoglyph and Fingerprint, the core technologies currently being used by AlpVision. Dr. Jordan has work experience in the USA and France. In 1999 he obtained his PhD title from the “Ecole Polytechnique Fédérale de Lausanne (EPFL)” Signal Processing Institute (ITS). Email: fred.jordan@alpvision.com

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Drug Product Manufacturers and Packaging Suppliers Working Together to Enhance Drug Product Quality: Automated Vision Inspection for Parenteral Closures Abstract: The healthcare industry is challenged with meeting stringent quality requirements regarding the manufacturing of drug products. Packaging components are critical to this operation. Because of these requirements, each final container processed for parenteral preparation must be inspected thoroughly for the presence of visible particulates. According to USP 32-NF 27, “Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter in its contents. The inspection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates.”1 A survey regarding industry practice related to visual inspections of injectable products was generated in 2008. Twenty-one companies responded and the survey results identified particulate as the most common defect found in parenteral finished products.2 Due to USP 35NF30 <1> requirements and the occurrence of particles at low frequencies and randomness, each finished injectable drug must be inspected.3 Additional challenges facing the healthcare industry include reducing product and process variation, meeting Japanese defect-free quality expectations and minimising product rejects. According to Good Manufacturing Practices (GMP), “sterilized container/closures must be sterile as to not alter the purity of the drug product” - 211.67 and 211.113.4 Further direction regarding the manufacturing of sterile drug products, provided in Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing,5 recommends excluding particulate matter and 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

container closure defects. Additionally, packaging suppliers can contribute to reducing particulate matter in finished drug products by supplying components virtually free of embedded and adhered particles. This practice will assist in reducing the risk of rejecting drug products caused by visible particulates. An attempt to proactively address these challenges in the healthcare industry would require all packaging components to be inspected for defects prior to shipment. This procedure would expedite the pharmaceutical industry process, while maintaining more stringent safety standards. This article will examine the use of vision inspection systems to mitigate the risk for particulates and defects associated with container closure systems. Vision inspection systems used by elastomer closure suppliers are automated, program-controlled devices that inspect all sides of elastomeric stoppers and pistons. Vision inspection allows suppliers to develop standardised procedures for improving the component manufacturing process upstream. The ultimate goal is for suppliers to work with pharmaceutical companies to provide a finished product that meets the needs of the healthcare industry. A quality drug product has been defined by Janet Woodcock of the FDA as a drug product free of contamination that delivers the therapeutic benefit promised in the label to the consumer.6 Particulate matter in finished drug products is a concern, since a product’s quality can be affected by the presence of various degradation materials, including particulate.7 The foreign particulate matter in parenterals comes from a combination of intrinsic and extrinsic sources. Extrinsic sources may include

hair, cellulose, polyester, etc. Intrinsic sources are derived from processes and container contact surfaces such as rubber, silicone or glass.8 This article will explore regulatory expectations and methods for inspection of finished drug products. It will also examine the use of vision inspection systems to mitigate the risk for particulate and defects associated with container closure systems. Visual Inspection of Foreign Particulate in Finished Drug Product The particulate matter burden of an injectable product has been taken by some healthcare practitioners, academic investigators and regulatory personnel as an indicator of the overall finished drug product’s quality.9 Several regulatory guidance documents exist to inspect and control particulate in finished drug product. The manufacturing of sterile drug product requires visual inspection of the final drug product in filled, sealed containers. The inspection is intended to ensure the quality of the packaged drug product by rejecting any container that is defective or contains particulate. Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects.10 Inspection for visible particulate may take place when inspecting for other critical defects, including cracked or defective containers or seals.11 An inspection system can identify, isolate, trend and address particulate and other critical defects of container closure components, thus augmenting the quality expectations for sterile drug products. This type of preventative action will not only avoid nonconformance, but also will identify areas for improvement in component manufacturing, which results in higher Volume 4 Issue 1


PACKAGING be used to perform automated visual inspection of sterile drug products are Defects Associated with Container available.16 Closure Systems With regard to packaging Vision inspection by the manufacturer components, automated vision for embedded and adhered particulate inspection is preferred. Typically, in packaging components reduces component manufacturers who inspect the risk of finding particulate in manually will pull components based finished drug product. In addition to on a sampling plan. As a result, only a inspecting for particulate, component portion of the component is inspected, vision systems also detect defects on and specifications are set using closures. Defects may include trimming Acceptable Quality Limit (AQLs). AQLs or molding defects, such as those seen can be defined as the worst-case per in Figure 1. Any damaged or defective cent defects that are allowable by the container closure systems should customer. If component manufacturers be detected and removed during the were to eliminate sampling plans and inspection of final product. Container inspect each component manually, or closure deficiencies can cause loss then the process would increase of container closure system integrity.12 the amount of time humans come in In the event that a nonconformance contact with a packaging component. is observed, the vision system shall Automated vision inspection is be capable of detecting that defect preferred by packaging suppliers because it is capable of inspecting category at a high level. every component and reduces contamination from humans. Automated inspection systems Figure 1: Molding and Trimming Defects on Rubber Closures can be qualified to assure that large volumes of products are consistently inspected, thus improving throughput and reproducibility. Vision inspection machines (Figure 2) are currently used by some Vision Inspection Methods Because of the various compendia elastomer component manufacturers and regulatory requirements and to inspect all sides of elastomeric the implications to the safety and stoppers and pistons. The machine effectiveness of the drug, there are is programmed to distinguish an component from a a variety of methods for inspecting acceptable parenteral finished drug products. defective component. Each vision inspection machine The primary method is manual inspection, which can be subjective consists of multiple cameras that use and relies on adequate training of Figure 2 - Automated Vision Inspection Machine human inspectors.13 Differences in visual acuity, personality and fatigue levels for each inspector may vary, and can lead to dissimilar levels of particulate detection. The subjectivity involved with manual inspection not only impacts effectiveness, but also may decrease the speed at which the inspection is completed.14 With regard to vision inspection, regulators expect improved methods to ensure better precision and consistent sensitivity.15 Because of the limits of manual inspection, automated inspection systems have been implemented for finished drug products. Currently, various light transmission and camerabased commercial systems that can quality packaging components.

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bright, dark and diffused illumination for the detection of defects. These defects include stains, marks, foreign matter and rubber inclusions embedded or protruding from the elastomer surface. Additional defects may be detected based on a specific component or customer specification. The end result is a quality component that is designed to meet or exceed the needs of the pharmaceutical manufacturer. Automated Vision Inspection Process Automatic vision inspection of rubber components occurs after the components are washed through a ready-for-sterilisation process. The end result is a washed product that meets specified limits for bacterial endotoxin, particulate matter and bioburden. After the ready-to-sterilise process, stoppers are unloaded from the washer in an ISO 5 clean room. The stoppers are passed from the ISO 5 clean room into a second ISO 5 clean room for vision inspection. The components are loaded into the vision inspection machine, inspected and packaged in sterilisable bags or rapid transfer port bags. Bags of product are removed from the vision inspection machine, sealed and labelled in the second ISO 5 clean room. Depending on customer requirements, the sealed and bagged products are either placed in final cartons or sent to be sterilised outside the ISO 5 environment. To test the reliability of the vision inspection machines, a capability study is performed. For the purpose

Volume 4 Issue 1


PACKAGING

of the study, a defect library is created to aid in the programming, debugging and testing of the device. The library can be populated based on extrinsic and intrinsic sources. The component supplier may create defect references, typically evidenced in the industry by dispersing defects throughout the rubber mix. Defects used to challenge a vision inspection machine include hair, fibre, loose particulate contamination, embedded and adhered foreign material, moulding defects, and cosmetic defects. The goal is to obtain one defect per component (Figure 4) to establish a representative defect reference. This assures that the vision inspection machine is consistently detecting the lone defect. To perform capability testing, component sample sets from the defect library consisting of known good product and known rejected product www.ipimedia.com

are run through the vision inspection machine. The defects are used to optimise the vision software and challenge the vision system. Finally, the rates of acceptance and rejection are determined for each component. After capability testing is performed, the defect library is used to verify that the vision inspection machine can detect the standard defects

appropriately. Prior to production, a known set of components passes through the machine to verify that the machine meets requirements. The defect library has been found to be an acceptable method for challenging the vision inspection machine and assuring that defects are consistently detected.

Figure 4: Camera View of Foreign Matter

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PACKAGING Strategies to Enhance Quality of Component Manufacturing Creating a defect library advances manufacturersâ&#x20AC;&#x2122; knowledge regarding reasons why component defects occur. To understand these causes further, all component defects are reviewed and trended. Statistically analysing each type of defect allows manufacturers to gain an enhanced understanding of the defects that occur during manufacturing. That knowledge can be used to improve processes throughout the of the manufacturing cycle and prevent recurrence of a particular defect. For example: process improvement may result from component rejection

due to fibres found upon vision inspection. The outcome of the process improvement event requires manufacturing employees to wear new and enhanced gowning during closure moulding and trimming steps (Figure 5). The enhanced gowning further reduces the chance of hairs, fibres from clothing or other human-generated particulate from contaminating the product during manufacturing. Ultimately, the implementation of the new gowning requirements reduces particulate found during inspection and improves the overall quality of the components. Component suppliers have been viewed as focusing on end control

Figure 5: Enhanced Gowning Requirements for Closure Moulding and Trimming

Figure 6: Results of a study performed on finished drug product before and after vision inspection of elastomer components

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rather than preventing defects through process improvements.17 If properly utilised, vision inspection systems can not only detect defects, but also can analyse, determine the source of and prevent defects from recurring. As suppliers increase the amount of packaging components sent through vision inspection systems, they continue to drive toward better detection and understanding of defects occurring in the manufacturing process. Vision inspection can be used to assure that quality is built into component manufacturing that can meet and exceed the increasing standards of the healthcare industry. Studies have been performed on vision inspected components to determine if healthcare industry needs have been satisfied. In one case study, a drug product manufacturer inspected finished drug product before and after the implementation of vision inspected packaging components. The goal of the study was to determine if the vision inspected components reduced reject rates. The results of the study demonstrated improvements in the overall quality of the finished product (Figure 6). Conclusion Currently, the pharmaceutical and biotechnology industries are challenged with meeting stringent quality requirements for parenteral products and maintaining integrity throughout the manufacturing process. Visual inspection of drug products is mandated, and includes performing 100% vision inspection of final product. Reducing product and process variation facilitates quality-by-design initiatives and minimises product rejects. Manufacturing efficiencies benefit suppliers and manufacturers, and ultimately help to ensure adequate supplies of needed drug products reach the market. In an attempt to address the challenges of the healthcare industry, component manufacturers have introduced vision inspection for their products. Elastomeric closures for parenteral products, including serum stoppers, lyophilisation stoppers and syringe pistons, are vision inspected by automated machines designed to examine the external quality attributes Volume 4 Issue 1


PACKAGING of elastomer components. Knowledge gained from closure defects detected by vision inspection machines can be used to improve closure manufacturing quality. Automated vision inspection used in conjunction with continuous improvement techniques creates multiple opportunities for preventative action. Such action should be deployed when an inconsistency is identified from trending the inspection data. Manual inspection cannot achieve the same consistent high-quality results. In addition, manual inspection cannot catalogue data for improvement events. Product offerings using automated vision technology can reduce the risk of defects and provide pharmaceutical manufacturers with improved compliance and risk mitigation. The ultimate goal for a component manufacturer is to build a relationship with the pharmaceutical manufacturer to provide a finished drug product that efficiently and effectively meets the needs of the patient. References: 1. USP 32 – NF 27. General Chapters: <1> Injections, (2009), Pharmacopeial Forum, 35(3), 4133. 2. Leversee, R. L., & Shabushnig, J. G. (2008). A survey of industry practice for the visual inspection of injectable products (preliminary report), PDA, Bethesda, MD. 3. Cherris, R. T., Hunt, D. G., Madsen, R. T., & Shabushnig, J. G. (2009). Visible Particles in Injections – A history and a proposal to revise USP General Chapter Injections <1>. Pharmacopeial Forum, 35, 13831387. 4. EC Guide to Good Manufacturing Practice Revision to Annex 1. (2003) Manufacturing of Sterile Medicinal Products (EC Ad Hoc GMP Inspections Services Group). Brussels. 5. U.S. Department of Health and Human Services Pharmaceutical CGMPs. (September 2004) Guidance for industry: Sterile drug products produced by aseptic processing – current good manufacturing practice. Retrieved from:DGuidanceComplianceRe gulatoryInformation/Guidances/ UCM070342.pdf www.ipimedia.com

6. Y u X, L. (2006). Implementation of Quality-by-Design: QuestionBased Review. Drug Information Association: 42nd Annual Meeting. Philadelphia. 7. M  cAuley, A., Rathore, A. S., Rathore, N., & Singh, S. (2009). Best practices for formulation and manufacturing of biotech drug products: How to maintain product stability and prevent particles. BioPharm International, 22(6), retrieved from: http://biopharminternational. findpharma.com/biopharm/ Downstream+Processing+Articles/ Best-Practices-for-Formulation-andManufacturing-o/ArticleStandard/ Article/detail/601406 8. C  ao, S., Freund, E., Law, R., & Milne, G. (2009). Studies of Particulates in the cGMP Manufacturing Environment, Amgen. 9. B  arber, T. A. (2000). Control of Particulate Matter Contamination in Healthcare Manufacturing. Englewood, Co: Interpharm Press. 10. E  C Guide to Good Manufacturing Practice Revision to Annex 1. (2003) Manufacturing of Sterile Medicinal Products (EC Ad Hoc GMP Inspections Services Group). Brussels. 11. USP 32 – NF 27. General Chapters: <1> Injections, (2009), Pharmacopeial Forum, 35(3), 4133. 12. U.S. Department of Health and Human Services Pharmaceutical CGMPs. (September 2004) Guidance for industry: Sterile drug products produced by aseptic processing – current good manufacturing practice. Retrieved from:GuidanceComplianceReg ulatoryInformation/Guidances/ UCM070342.pdf 13. Benedek, K., Cao, S., Jiang, Y., Narhi, L. O., & Shnek, D. (2009). A critical review of analytical methods for subvisible and visible particles. Current Pharmaceutical Biotechnology,10, 373-381. 14. Chen, C., Gonzales, O., Rathore, N., & Wenchang, J. (2009). Challenges and strategies for implementing automated visual inspection for biopharmaceuticals. Pharmaceutical Technology. Retrieved from: http://pharmtech. findpharma.com/pharmtech/

Analytics/Challenges-andS t r a t e g i e s - f o r- I m p l e m e n t i n g Automat/ArticleStandard/Article/ detail/638760 15. Cao, S., Freund, E., Law, R., & Milne, G. (2009). Studies of Particulates in the cGMP Manufacturing Environment, Amgen. 16. McAuley, A., Rathore, A. S., Rathore, N., & Singh, S. (2009). Best practices for formulation and manufacturing of biotech drug products: How to maintain product stability and prevent particles. BioPharmDowns tream+Processing+Articles/BestPractices-for-F ormulation-andManufacturing-o/ArticleStandard/ Article/detail/601406 17. Scheidegger, P., (2010). Rubber stoppers: Customer requirements v. supplier performance. Parenteral Drug Association Presentation.

Peggy Frandolig holds a Bachelor of Sciences in Biology from the University of Pittsburgh at Johnstown and has nearly 20 years of experience within the pharmaceutical industry. She currently is the Manager of Technical Customer Support with responsibilities for working with customers to guide decisions for appropriate container closure systems for their drug products. Peggy joined West Pharmaceutical Services in 2000, as Project Coordinator for the Analytical Laboratories; Peggy was promoted to Associate Manager of Project Management and Document Control in the Analytical Labs. Her most recent position at West was Quality Assurance Manager, Customer Relations where she was responsible for managing the customer complaint handling process and facilitating corrective action and route cause analysis for issues surrounding production. She was the customer liaison between the manufacturing facilities and customer as it relates to product complaints and other related quality interactions.Email: peggy.frandolig@westpharma.co

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PACKAGING

Child-Resistant Packaging Accidental poisoning is common amongst young children. As a natural part of their early development children explore their environment using their senses to ‘play’ with items that are new to them. They cannot differentiate between items that are safe and items that may be harmful. This responsibility lies with the child’s parent or carer to ensure that proper precautions are in place to avoid a child gaining access to harmful substances. Most cases of child poisoning happen within the home when items are left ready to be used, in sight or unattended by adults. Other cases occur when a child has climbed up somewhere high or got into a cupboard and inadvertently accessed harmful substances. In this case a certain level of responsibility lies with manufacturers to ensure their hazardous products are as difficult as possible for young children to open. Children accessing medication is one of the major causes of accidental poisoning. The rise in adults taking medication, such as anti-depressants or sleeping aids, has contributed to the increased incidences of accidental poisoning in children. The amount of drug poisonings among children rose 22% between 2001 and 2008. Researchers believe that this dramatic rise is purely because there are more drugs in the home that can be accessed by curious children. Researchers from Cincinnati Children’s Hospital Medical Centre and the University of Cincinnati recently analysed data on 544,133 children that had visited the emergency department between 2001 and 2008 after accidental medication poisoning. In 95% of the cases the child had gained access and ingested the drug by themselves, rather than receiving a dosage error from their parent or guardian. Prescription drugs were a bigger problem than over-thecounter too. In all, prescription drugs accounted for 55% of these cases, with 43% of these children admitted into intensive care after going to accident and emergency. Again, the researchers attributed this to the fact that more and more adults are using prescription drugs to combat a variety of diseases 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and conditions. The authors of the research also suggested that the best method to combat these high numbers would be to design new packaging for both adults and paediatric drugs, that is not only difficult to open, but would also make it more difficult for young children to ingest large quantities. The World Health Organization (WHO) concurred in their Report On Child Injury Prevention in 2008: “Child resistant packaging is one of the best-documented successes in preventing the unintentional poisoning of children.” In 1967, Dr Henri Breault invented the first locking device for medical containers. According to WHO, unintentional poisoning deaths amongst children fell from 151 per 100,000 in 1968 to 23 per 100,000 in 2000 after this introduction. There is plenty of evidence to suggest that childresistant packaging is directly related to a reduction in accidental poisoning amongst children. However, with the rise in cases being reported since 2001, there has to be more the industry can do to ensure their packaging is difficult for a child to get into. It is impossible to completely ‘child-proof’ a product, but with medicine becoming more commonplace in every household, the pharmaceutical and healthcare industries are realising the necessity of child-resistant packaging, particularly in America where the market is more prevalent than here in Europe. A history of accidents involving children opening household packaging and ingesting the contents led the US Congress to pass the Poison Prevention Packaging Act (PPPA) of 1970. This gave the US Consumer Product Safety Commission the authority to regulate this area. The regulations are based on protocols of performance tests of packages with actual children, to determine if the packages can be opened. The PPPA law of 1970 specified that nearly all prescription drugs (and certain OTC drugs) intended for household use be shipped in ‘child-resistant’ formats. The increased number of people taking medication in the US has led to developments in child-resistant

packaging since the first locking device for medical containers was introduced in 1967. All innovations are subject to the rigorous testing mentioned above, which they can either pass or not, but we can also assess their effectiveness in everyday use by the consumer. Which innovations offer the highest level of child- resistance whilst being convenient and easy-to-use for the adult consumer? Traditionally, medication is packaged in two formats, blisters and bottles, both of which are available in child-resistant versions. More recent child-resistant packaging is delivering better solutions for the patient through ease-of-access, portability and increased compliance. Push and twist child-resistant bottle caps are probably the format that people are most familiar with. This child-resistant design has been on the market for a while, and it is an effective barrier against children accessing potentially poisonous medication. With the bottle format, the room for innovation is quite limited beyond the push and twist design. In terms of compliance, there have been a number of studies that have shown child-resistant blister packaging outperforms bottles. The child-resistant features used in bottles often become disabled. Their caps can unintentionally be left off the bottles, thus invalidating their child-resistant features. Bottled child-resistant medication can also prove difficult for elderly consumers to open, particularly those who suffer from arthritis or have reduced dexterity. Child-resistant variations of blister packaging are more successful at achieving patient compliance. Another advantage of blister packs is that they allow for single cavity storage of medication, decreasing the likelihood of contamination or incorrect dosing. A good example of a child-resistant blister on the market is GP Solution’s Dose Guard™. Dose Guard™ is a secondary barrier that, when applied to the back of a blister pack, will render it child-resistant. At the same time it also offers improved senior access, by incorporating a peel-and-push Volume 4 Issue 1


PACKAGING Burgopak Healthcare and Technology’s child-resistant pack is a good example of a solution that delivers just that. Their pack achieved the US Consumer Product and Safety Commission’s F=1 child resistance effectiveness, in conformity with US regulatory standards for poison prevention packaging. The pack’s functionality is based upon two pressure-point locking devices at either side of the pack that, when pushed together, release the blister and patient information leaflet at opposite ends. Once the patient has accessed the medication they simply push the blister back, locking it into place. By keeping the blister, patient information leaflet and outer carton permanently connected, the pack encourages compliance from the patient, as all-important information about the product is available every time they access the medication. This feature also keeps the pack compact and portable, which enables the patient to easily carry the product with them at all times. But a key feature in a package which protects the blister and achieves child-resistance is the package’s ease-of-access for seniors and the dexterity-restricted patient; this a key advantage of a good packaging design such as the Burgopak Slider.

design. The self-adhesive barrier can be applied to any blister and requires the user to peel away a perforated tab before pushing the medication through the blister; the design comes in single or double layers. Although child-resistant blister packs can be more effective compared to bottled versions, certain blistered solutions can still have their own limitations. Through directly protecting the blister, some manufacturers may force the patient to access the medication by other means than those instructed, for instance with scissors. Solutions that directly protect the blister whilst achieving child-resistance are not the easiest of solutions to access packaged medication. This can prove both problematic and frustrating for the consumer who needs access to their medication when in different environments, like an aeroplane for instance. This phenomenon even has its own name, ‘wrap rage’ or ‘package rage’, the common name given to the feeling of heightened anger resulting from the inability to open hard-toremove packaging and access its contents. Pharmaceutical and healthcare companies find themselves in a situation where they are required by law to produce packaging that is child-resistant, but they have to ensure that the medication is easily accessible to the consumer or patient who needs access to it. Finding this happy 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

medium is what makes a successful child-resistant package. Child-resistant packages that are able to offer ease of access to patients whilst keeping young children out will be successful within the marketplace. But child-resistant packs need both to offer increased portability, for those who need their medication on the move, and also to encourage compliance from the patient. Those that also have these attributes will have more chance of being successful in the market. For instance, a design that permanently connects the outer carton, product and patient information will offer maximum opportunity for the patient to comply with their course of treatment. Keeping the medication and information together reduces the risk of dosage mistakes or the patient incorrectly following the information provided by the manufacturer. Packaging that provides the above can also be more compact in comparison to traditional pharmaceutical and healthcare packaging. This makes it easier for the patient to carry their medication with them, which again increases the likelihood of them complying with their treatment. Child-resistant packaging has been a part of the pharmaceutical and healthcare industries for the last fortyfive years, but only recently has the need for real innovation been at the forefront of the industry. The increased number

of people taking medication has led to a rise in potentially harmful drugs being commonplace in households across the globe. Unfortunately, with this rise, there have also been more reported cases of accidental child poisoning, which is pushing the need for innovation in the pharmaceutical packaging industry. There are a number of new solutions on the market that are effective barriers to stopping children accessing potentially harmful medication. Products that combine this safety element yet still provide ease-of-access to the user are gaining a good command in the marketplace. Conversely, packaging companies need to look at the portability of their packaging and whether their products encourage compliance from the patient. A packaging design that encompasses all these components will have the greatest opportunity for success in the pharmaceutical and healthcare industries.

Tim Bollans Since graduating university Tim Bollans has worked exclusively on the marketing and selling of intellectual property and innovative products. During his final year and immediately after graduation Tim worked for Nottingham University, turning academic ideas and research into commercially viable products across the food, health and pharmaceutical industries. Since joining Burgopak Healthcare and Technology, Tim has been responsible for developing awareness of the company’s products in the pharmaceutical industry through various channels, whilst also personally driving the development & product launch of the Chrysalis Carton solution in partnership with Medica Packaging. Tim has in-depth understanding of the challenges faced when trying to market innovative products and has a proven record in successfully implementing marketing strategies to maximise the success of products Email: tim.bollans@burgopak.com

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Exhibitions Previews & Reviews

Growing Life Science Business in the Pacific Rim: BioPartnering North America The Pacific Rim refers to places around the edge of the Pacific Ocean, the world’s largest. On the northeastern rim are the US and Canada with their vast innovation capabilities, and natural resources. On the northwestern rim are the massive production capabilities and the expanding markets of Japan, Korea and China. These economies are also seeking to increase their global success through innovation, by harnessing science and technology, particularly the life sciences. The southwestern rim is home to the “Asian Tigers” such as Malaysia, Singapore, Vietnam, and Indonesia, together with Australia and New Zealand – all major centres for the development of the life sciences. The southeastern rim is home to half of Latin America, where the life sciences are increasingly being used in agriculture and energy development. This is a massive region and there is a lot going on. Asia is now the fastest-growing region in the world. The west coast of the US and Canada remain the most innovative region in the world. This is especially true for the life sciences, with large clusters in the San Francisco Bay Area, San Diego, Los Angeles/Orange County, Portland, Seattle, Vancouver and Alberta. After 10 years of success, TVG is focusing its BioPartnering North America (BPN) on the Pacific Rim because this is where a lot of life science business will be taking place in the years to come. We plan to build on close ties with industry leaders in the Pacific Rim to create a unique opportunity for the US, Canada, and Europe to meet leading life science companies from Asia. In previous 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

years, we have had delegations from Japan, Korea, China and India, which have greatly expanded networks, and it is our intention to expand this aspect of BioPartnering North America (BPN). Vancouver is strategically placed to be able to play a three-pronged role in this plan: 1) a s a gateway from North America to Asia; 2) a s the top of the Pacific Biotech cluster in North America – Vancouver in the north to San Diego in the south – the largest concentration of life science institutions in the world; 3) t apping into Canada, which is the fourth largest biotech cluster in the world. Europeans, such as the Italian Trade Commission (ITC), UBI France and UKTI will be able to assist their client companies to greatly expand their business connections. BioPartnering North America is scheduled for February 26-28, 2012, and sits in the calendar between the JP Morgan investor event in San Francisco in January, and the BIO CEO & Investor meeting in New York City in March. What makes BPN different is that delegates can have quality meetings with potential partners, from over 30 countries. Using TVG’s partnering software product, ‘biopartnering.com’, all delegates can pre-arrange meetings up to two months prior to the event, and during the event. Follow-up is possible using the system, after the event has concluded. TVG’s biopartnering.com software product is widely viewed as the “gold standard” of the industry, and is used with success by thousands of life

science companies each year. TVG acknowledges that a global life science industry is forming, and not just in the world of biopharmaceuticals, but also all areas of the economy, what is termed the “bioeconomy”. Wikipedia defines the bioeconomy as “all economic activity derived from scientific and research activity focused on understanding mechanisms and processes at the genetic and molecular levels and its application to industrial processes.” The next phase in the evolution of BioPartnering North America is to further develop the Pacific Rim network because all aspects of biotechnology are being advanced in this region. BPN will remain a biopharmaceutical event in 2012, and as our network expands, we will include other industry categories in future. All events must serve a purpose. The purpose of any event changes over time. When BioPartnering North America was launched in 2003, many people were not aware that there was a vibrant biotech community in British Columbia. Now, BC has many leading institutions, including the CDRC, Genome BC, UBC, Simon Fraser University, plus large and small life science companies, which are worldrenowned. TVG and the stakeholders in BC have experienced how an event such as BPN can catalyse business growth and development. This is true for government institutions as well as private sector groups. There is no shortage of opportunities in the world. Perhaps at a time when the internet has created virtual networks of all kinds, people are discovering two immutable facts: 1) there is no substitute for face-to-face Volume 4 Issue 1


Exhibitions Previews & Reviews meetings, particularly at the start of business relationships; 2) there is not enough time to travel around the world to have face-toface meetings, as required. The most efficient way to have many meetings is to attend an event that delivers the right people to one venue. BioPartnering North America has been doing this for 10 years. Looking ahead to 2012, TVG believes that there has never been a greater need for events that help small and large companies get deals done. BioPartnering North America delivers the people, delivers the products and technologies, and delivers the infrastructure to facilitate deal-making. In 2012, we will showcase the west coast biopharma cluster (west of the Rockies); the best that Canada has to offer; more and better Asian companies; and a growing roster of investors from all of these parts of the Pacific Rim who want a piece of the action. BioPartnering North America is evolving to meet new needs which

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reflect the changing world realities. It represents a cutting-edge solution to the major problem faced by busy executives: “who should I meet with today?” A recent marketing campaign puts it succinctly: Get Your Deal and Ski. Come to Vancouver, ski at Whistler (home of the 2012

Winter Olympics) the weekend before BioPartnering North America, and invite colleagues and potential partners to join you. Have fun, get your meeting, and get your deal. It doesn’t get any better than that.

Dr. Robert Lee Kilpatrick is a Co-Founder and Partner of Technology Vision Group LLC (TVG). Since 1992, Dr. Kilpatrick along with TVG has been connecting innovators and leaders in the life science industry across the US, Canada, China, Europe, Australia, Latin America, India, and Asia. The 20-year track record of success is founded by a deep industry knowledge, integrity in business, and powerful network of valuable relationships. His contact list is extensive and includes key people around the world. Dr. Kilpatrick was educated at the University of California, Berkeley and Cambridge University, where he received a Doctorate in the History and Philosophy of Science and Medicine. He has served on the Board of Directors of the BayBio Institute, a non-profit organization focused on education and entrepreneurship and education. He currently serves on the Scientific American Worldview board of advisors and the Board of Camphill Properties, a non-profit organization serving the residential needs of disabled people living in Camphill California. Dr. Kilpatrick writes a blog under the name of “Biotech Gadfly”. Email: rlkilpatrick@techvision.com

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NEWS

Quantum Pharmaceutical Appoints New Commercial Director Quantum Pharmaceutical, the UK’s leading unlicensed medicines manufacturer and supplier, is delighted to announce the appointment of Brian Fisher as Commercial Director.

With extensive experience of the pharmaceutical industry built over many years in wholesale and distribution, Brian has a wealth of knowledge of the healthcare market, across pharmacy, hospitals, dispensing doctors and manufacturer services. Previously responsible for sales and customer engagement across all business channels as Head of Sales at Alliance Healthcare (Distribution) Ltd, Brian has a strong reputation and proven track record in business development, change management and implementation of programmes which enhance and improve customer value and experience. Brian’s knowledge and experience will ensure that Quantum Pharmaceutical continues as market leader within the specials industry by developing its core service and valueadded offerings to lead its customers through the ever-changing world of unlicensed medicines. In his role as Commercial Director, Brian and his team will drive and develop close working relationships with key customers, pharmacies, wholesalers, healthcare providers, hospitals, healthcare commissioners, the NHS and other organisations to 120 INTERNATIONAL PHARMACEUTICAL INDUSTRY

further shape the service offering available from Quantum. Commenting on his appointment, Brian said: “I am delighted to have joined the board of directors at Quantum and I look forward to developing strategies and working with my colleagues to ensure Quantum Pharmaceutical leads the way in delivering great value and leading edge service excellence to the NHS, our customers and their patients.’ Source: Smith & Smith PR. ASLAN Pharmaceuticals Selects PharmaNet/i3 as Strategic Partner for Oncology Development PharmaNet/i3, inVentiv Health’s clinical segment, and a leading provider of clinical development services to pharmaceutical, biotechnology, generic drug and medical device companies, announced today that ASLAN Pharmaceuticals has selected PharmaNet/i3 as a strategic partner supporting the development of their oncology portfolio in Asia, and conducting Phase I and Phase II clinical trials for two of ASLAN’s compounds. PharmaNet/i3 has been conducting clinical studies for innovative oncology products since 1996, and has an experienced team, including on-staff oncologists, dedicated to the development of cancer treatments. The company has extensive experience in the development of a variety of cytotoxic chemotherapies, monoclonal antibodies, pathway inhibitors and therapeutic vaccines. More than four hundred local, regional and global oncology clinical trials have been awarded to PharmaNet/ i3 in the past five years, including more than a dozen registration programmes, seven of which resulted in NDA/MAA approvals. “Clinical development of oncology therapeutics requires a special understanding of the mechanism of action and the different approaches to cancer therapies,” commented Dalvir Gill, PhD, President, Phase

II – IV Development, PharmaNet/ i3. “ASLAN has a novel and creative approach to personalised medicine and combination therapy. We will work closely with ASLAN to address the unique methodologies needed to evaluate the efficacy and safety of their innovative products, and look forward to a long and productive relationship.” Source: IPI Staff Reporter – Jaypreet Dhillon Schwartz Center Receives $500,000 Grant from the Amgen Foundation The Schwartz Center for Compassionate Healthcare, a Boston-based non-profit dedicated to strengthening the relationship between patients and their healthcare providers, today announced it has received a $500,000 grant from the Amgen Foundation. This grant will go toward the planned expansion of Schwartz Center Rounds® and to support the launch of a National Consensus Project. These initiatives aim to make compassionate, patient-centred care a national healthcare priority. The Schwartz Center Rounds allow care-givers from multiple disciplines to come together on a regular basis to discuss the most challenging emotional and social issues they face in caring for patients. The National Consensus Project will convene a broad range of stakeholders to define compassionate care, develop best practices to ensure that this type of care is provided, and develop a plan to implement these core principles and best practices. The Amgen Foundation, based in Thousand Oaks, is the philanthropic arm of Amgen, the world’s largest biotechnology company. A key area of focus for the Foundation is ensuring quality of care and access for patients, with an emphasis on patient empowerment and reducing healthcare disparities. Through its National Consensus Project, the Schwartz Center will launch a national conversation about Volume 4 Issue 1


NEWS

the importance of compassionate care by convening healthcare professionals, patients, policymakers, educators and researchers to reach expert consensus on a definition of compassionate care, develop a set of organisational and institutional best practices to ensure that this type of care is provided, and develop a plan for disseminating these core principles and best practices. Source: Schwartz Center for Compassionate Healthcare Video Games lead to New Paths to Treat Cancer In a research lab at Wake Forest University, biophysicist and computer scientist Samuel Cho uses graphics processing units (GPUs), the technology that makes videogame images so realistic, to simulate the inner workings of human cells. “If it wasn’t for gamers who kept buying these GPUs, the prices wouldn’t have dropped, and we couldn’t have used them for science,” Cho says. Now he can see exactly how the cells live, divide and die. And that, Cho says, opens up possibilities for new targets for tumour-killing drugs. Cho’s most recent computer simulation, of a critical RNA molecule that is a component of the human telomerase enzyme, for the first time shows hidden states in the folding and unfolding of this molecule, giving scientists a far more accurate view of how it functions. The results of his research appear in the Journal of the American Chemical Society. Cho worked with colleagues from the University of Maryland and Zhejiang University in China for this study. The human telomerase enzyme is found only in cancerous cells. It adds tiny molecules called telomeres to the ends of DNA strands when cells divide – essentially preventing cells from dying. “The cell keeps reproducing over and over, and that’s the very definition of cancer,” Cho says. “By knowing how telomerase folds and www.ipimedia.com

functions, we provide a new area for researching cancer treatments.” A new drug would stop the human telomerase enzyme from adding onto the DNA, so the tumour cell dies. Cho, an assistant professor of physics and computer science, has turned his attention to videogaming technology and the bacterial ribosome – a molecular system 200 times larger than the human telomerase enzyme RNA molecule. His research group has begun to use graphics cards called GPUs to perform these cell simulations, which is much faster than using standard computing. “We have hijacked this technology to perform simulations very, very quickly on much larger biomolecular systems,” Cho says. Without the GPUs, Cho estimated it would have taken him more than 40 years to program that simulation. Now, it will take him a few months. Source: IPI Staff Reporter – Jaypreet Dhillon Preventing and Treating Drug Use with Smartphones Clinical researchers at the University of Massachusetts Medical School (UMMS) are combining an innovative constellation of technologies, such as artificial intelligence, smartphone programming, biosensors and wireless connectivity, to develop a device designed to detect physiological stressors associated with drug cravings and respond with user-tailored behavioural interventions that prevent substance use. Preliminary data about the multi-media device, called iHeal, was published online first in the Journal of Medical Toxicology. According to the study’s authors, many behavioural interventions used to treat patients are ineffective outside of the controlled clinical settings where they are taught. This failure can be attributed to several factors, including a patient’s inability to recognise biological changes that indicate increased risk of relapse, and an inability to change their

behaviours to reduce health risk. Edward Boyer, MD, PhD, professor of emergency medicine at UMass Medical School and lead author of the study, worked with colleagues at UMMS and at the Massachusetts Institute of Technology to design a mobile device using so-called “enabling technologies” that could be used to make behavioural interventions for substance abusers more effective outside the clinic or office environments. The result of their work, iHeal, combines sensors to measure physiological changes and detect trigger points for risky health behaviours, such as substance use, with smartphone software tailored to respond with patient-specific interventions. Individuals with a history of substance abuse and post-traumatic stress disorder were asked to wear an iHeal sensor band around their wrist that measures the electrical activity of the skin, body motion, skin temperature and heart rate all indicators of stress. The band wirelessly transmits information to a smartphone, where software applications monitor and process the user’s physiological data. When the software detects an increased stress level, it asks the user to annotate events by inputting information about their perceived level of stress, drug cravings, and current activities. This information is then used to identify, in real-time, drug cravings, and deliver personalised, multimedia drug prevention interventions precisely at the moment of greatest physiological need. Boyer and his teams examined the iHeal system architecture, as well as preliminary feedback from initial users, to identify key attributes and assess the device’s viability. Their analyses suggest a number of technical issues related to data security, as well as the need for a more robust and less stigmatising version before the device could be worn in public. Source: IPI Staff Reporter – Jaypreet Dhillon INTERNATIONAL PHARMACEUTICAL INDUSTRY 121


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Page 41 Almac Group IFC Amsterdam Biomed Cluster Page 7 Analytical Biochemical Laboratory BV Page 33 Angel Biotechnology Page 111 9th Anglo Nordic Biotech Conference Page 39 Bioanalytical Systems, Inc. (BASi) Page 112 Biotrinity 2012 Page 9 Biowin Page 93 Burkert Fluid Control Systems Page 3 Catalent Page 29 Cellgenix GmbH Page 57 Centrical Global Ltd. Page 67 Charles Kendall BioLogistics Page 85 Colder Products Company Page 113 DIA – 24th Annual EuroMeeting Page 115 EBD Group Page 71 Envirotainer AB Page 49 ERT Page 27 Excard Research GmbH IBC ExpreS2ion Biotechnologies Page 59 EXTEDO GmbH Page 105 Faubel & Co. Nachf. GmbH Page 99 FeF Chemicals A/S Page 13 FlandersBio – Knowledge for Growth Page 107 Flexible Medical Packaging Ltd Page 17 Forresters Page 37 Glycotope Biotechnology GmbH Page 73 GoPlasticPallets.com - All Pallets Ltd Page 55 Health Protection Agency Page 95 Helapet Limited Page 89 Hospira: ONE2ONE Page 45 Illingworth Research Ltd Page 43 INFOTEHNA Group Page 19 LC Patents Page 65 Ludger Ltd Page 87 LYOFAL S.A.S. Page 11 Midfield Media – 2012 Immunogenicity Page 35 Midfield Media – Orphan Drugs Summit 2012 Page 15 Miller Insurance Services Ltd. Page 117 Mindstream – Biomedica 2012 Page 5 MPI Research Page 83 Patheon Inc. Page 47 Phage Consultants Page 25 Qualogy Ltd Page 31 Sanbe Pharma OBC SCA Cool Logistics Page 23 Scottish Development International Page 109 SMi Group – 8th Annual Conference on Imaging in Cancer Drug Development Page 114 SMi Group - 6th Annual Conference on Paediatric Clinical Trials Page 114 SMi Group - 6th Annual Conference on Clinical Trial Logistics Page 116 SMi Group 12th Annual Conference on Pain Therapeutics Page 69 Sofrigam Page 110 Terrapinn - World Orphan Drug Congress USA 2012 Page 79 Vindon Scientific Ltd Page 77 West Pharmaceutical Services Page 21 Wiborg ApS Page 53 Woodley Equipment Company Ltd.

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IPI - International Pharmaceutical Industry. Journal looking into the best outsourcing practice by the pharma and biotech industry

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