Volume 6 Issue 1
International Pharmaceutical Industry
Supporting the industry through communication
Doesnâ€™t the Human Immune System Deserve Human Specific Vaccines? Where Does Controlled Room Temperature Fit in the Cold Chain? Beyond Asthma and COPD Elemental Impurity Analysis In Pharmaceuticals
06 Editor’s Letter REGULATORY & MARKETPLACE
International Pharmaceutical Industry
Supporting the industry through communication
DIRECTORS: Martin Wright Mark A. Barker EDITOR: Cecilia Stroe firstname.lastname@example.org EDITORIAL ASSISTANT Orsolya Balogh email@example.com BOOK MANAGER: Anthony Stewart firstname.lastname@example.org BUSINESS DEVELOPMENT: Madalina Slupic email@example.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks firstname.lastname@example.org FINANCE DEPARTMENT: Martin Wright email@example.com RESEARCH & CIRCULATION: Holly Barnes firstname.lastname@example.org COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: email@example.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 2014. 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. 2014 PHARMA PUBLICATIONS Volume 6 issue 1 - Spring - 2014
08 Making Life Sciences a Magnet for Talent in 2014 Following years of growth and favourable market trends, 2014 will see the global life sciences industry facing the so-called ‘new normal’. Markets are changing and life science companies must respond by adopting new business models. Dominic Graham of Kelly Services discusses the key challenges that these companies will likely face in terms of recruitment, along with suggestions on how they can meet these head on and attempt to mitigate risk. 12 SPCs and the CJEU – Latest Developments The Court of Justice of the European Union (the highest Court in Europe) has again been busy considering the law on SPCs. Charlotte Teall of Forresters is making sense of the recent CJEU decisions on Supplementary Protection Certificates (SPCs). In four important cases, the CJEU ruled that in most circumstances, multiple SPCs for different products may be obtained under a single patent. The CJEU also provided further guidance on the type of patent claims that can support an SPC. 16 Pharmaceutical Product Recall: Lesson Learned Product recalls and returns have become rampant and increased dramatically in recent years. However, product recall could significantly damage a company’s reputation, profitability and brand integrity. Sunil Shewale and Sameer Parakh of Serum Institute of India and Manisha Chavan of Alard College of Pharmacy, Pune, India explore the process of pharmaceutical product recall: various critical factors affecting product recall system implementation, the appropriate recall strategies, and key solutions to overcome it. 24 Realising Peak Performance of an Organisation The complexity and volatility of the environment in which organisations operate is increasing fast, and requires organisations to continuously adapt to these changes in order to create added value and remain relevant to their customers. Ruth Lachaert of UmamiFlow looks into a simple and practical approach, which removes barriers and boosts drivers, ensuring employees realise their full potential. 30 Scaling up Action to Meet the New World Cancer Declaration Targets Originally launched in 2006, the World Cancer Declaration has helped to bring the growing cancer crisis to the attention of government leaders and health policy-makers. Dr Julie Torode and Rebecca Morton Doherty of UICC explains how by more closely aligning the updated World Cancer Declaration with the emerging global NCD framework and post-2015 development discourse, the Declaration targets resonate more widely, allowing the cancer community to reach out to non-traditional partners in the development, disability, education, employment and many other sectors, for innovative partnership. 34 The Future of Life Sciences and the need to innovate – Edinburgh BioQuarter talks tactics Scotland has always been at the forefront of life science research with Edinburgh playing a key role. Dr Mike Capaldi illustrates the unique concept of Edinburgh BioQuarter: it brings together scientists from the University of Edinburgh and NHS Lothian with commercial research companies to collaborate and accelerate the development of new drugs, diagnostic tools and medical devices to treat diseases. This huge enterprise has made Edinburgh a leading European destination for translational medical research, fasttracking drug development from ‘bench to bedside’.
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DRUG DISCOVERY, DEVELOPMENT & DELIVERY
LOGISTICS AND SUPPLY CHAIN
38 Doesn`t the Human Immune System Deserve Human-specific Vaccines? Are murine in vivo models helpful as disease models for drug development? In at least two important therapeutic areas, oncology and allergy, the value of mouse models is, at the very least, questionable. Dr G.C. Mudde of S-TARget therapeutics GmbH outlines how, in the last decades, the need for humanspecific animal models has been realised and accepted by official regulatory authorities; several centralised primate research facilities are now available for testing human-specific drugs, but more money and effort should go into understanding the differences and similarities between the two species.
66 The New GDP Guidelines: A Year On The EU GDP guidelines created a yardstick by which logistics providers could be measured and compared. A year on from the first publication, they are now fully in force and there has already been an update from the EU. GDP 2013/C 68/01 has been superseded by 2013/C 343/01. Published and enacted in November, this corrected a couple of factual errors and expanded on the rationale. World Courier’s Sue Lee looks at the regulations’ impact on the pharmaceutical supply chain in Europe and beyond.
44 Why the Need for New Technology in Bio-pharma R&D? Companies need to manufacture their product candidate under current Good Manufacturing Practice (cGMP) conditions in order to conduct clinical trials. R&D cost in bio-pharma is high and there is a need for more efficient technology as biologics manufacturing is complex and highly regulated by the FDA. Puneet Ramaul of Beroe Inc discusses the challenges encountered by bio-pharmaceutical companies in product development.
70 Where does Controlled Room Temperature Fit in the Cold Chain? David Johnson of Intelsius argues that it was on the back burner, but you can now call it breaking news. Since the introduction of the new GDP guidelines last September, attention has begun to focus on CRT shipments and the requirement to ship within label conditions. CRT shipments that were shipped unmonitored and in uncontrolled packaging are now creating tension, as the need to demonstrate temperature compliance uncovers a hidden world of issues.
48 Beyond Asthma and COPD Although the global pulmonary drug delivery market is now so large that many players can profitably coexist for some time, as regulation evolves in order to push improvements and establish a baseline in inhaler performance, the optimal strategy is to innovate. Innovation allows the creation of new and better inhalers which can specifically address problems inherent in inhaler design, and David Harris of Team Consulting looks into the key drivers – commercial, technological and regulatory – fuelling current advances. 52 Modifying MDI Canister Surfaces to Improve Drug Stability and Drug Delivery Over the past few years, a number of surface coatings have been developed that can be applied to MDI canisters and valve components, to protect the contents from deposition and degradation. More recently, plasma processes have been developed to modify and improve the surface energy performance of an MDI canister. As Richard Turner of Presspart Manufacturing explains, this approach has a number of advantages over alternative coatings, but requires careful optimisation to ensure the highest quality finish and MDI performance CLINICAL & MEDICAL RESEARCH 56 CNS – Still Sending Out the SOS? Following up on an article written in 2006, Susan McGoldrick of QCTR Ltd is assessing the state of CNS drug development, looking into what progress has been made since. Has the world in CNS changed? What have been the breakthroughs and the changes for patients, and is the need any closer to being met? Currently, CNS drug sales are dominated by antipsychotics and antidepressants, and despite some leading drugs recently going off-patent, sales of branded drugs are still growing. However, despite the large sales there still remains unmet need for patients. 60 The Anticipated Clinical Effect of the new Alzheimer Drug ANAVEX PLUS in a Predictive Humanised Cortical Cognitive Model for Alzheimer’s Disease ANAVEX PLUS, the proprietary combination of ANAVEX 2-73 (AV273) with donepezil, the most prescribed Alzheimer’s drug, combines cholinergic pharmacology with muscarinic and sigma-1 receptor activity and can potentially combine symptomatic, neuroprotective and potentially disease-modifying properties, as illustrated in a paper by C. Missling of Anavex Life Sciences, T. Maurice of INSERM U710, University of Montpellier 2, France, A. Spiros of In Silico Biosciences, Lexington, MA, P. Roberts of OHSU, Portland, OR, and H. Geerts of University of Pennsylvania, PA.
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Spring 2014 Volume 6 Issue 1
BERLIN . NEW YORK . TOKYO
90 Developing a Lyophilised Portfolio Lyophilisation is one of the most effective ways of giving to biotechnologically produced drugs greater stability and a longer shelf-life, while still maintaining their effectiveness. For drug manufacturers, the challenge may at first appear daunting, but it is one that must be met if the compounds being developed are to be successful. Thomas Otto of Vetter Pharma takes a look at what makes lyophilisation and reconstitution viable: the wide range of available systems that can be used as primary packaging for the lyophilised substance, from simple vials to sWFI syringes for reconstitution and special dual-chamber cartridges for pen injector systems for the homecare segment. 96 The Importance of Critical Temperatures in Freeze-drying Katriona Scoffin of BTL addresses the importance of a well-designed freeze-drying cycle. In order to freeze-dry products thoroughly, and to ensure consistent quality and activity in the reconstituted product, it is vital that the freeze-drying cycle is designed specifically for each material. This also applies to different formulations of products, since the choice of excipient can have a marked effect on the thermal characteristics. PACKAGING
74 Cost of Quality Robert J Hayes of Seer Pharma provides an analysis of the cost of maintaining a state of compliance. Since the 1930s, famous quality gurus have promoted the use of quality tools and techniques to improve product quality and reduce operating costs, such as Cost of Quality (CoQ). Although used widely in many industries, the take-up in the pharmaceutical industry is low; symptomatic of an industry that is generally slow to adopt tools, techniques and methodologies from other industry sectors. 78 GDP and the Challenge of Protecting Controlled Ambient Pharmaceutical Freight The new GDP regulations are well documented, but what’s the operational reality? Peter Lockett of TP3 Global explains how there’s no getting away from the fact that protecting controlled ambient (CRT – controlled room temperature) freight, where there has been little or no previous budget, is a challenge. LABORATORIES 80 Elemental Impurity Analysis in Pharmaceuticals A method to identify the presence of heavy metals in pharmaceuticals was introduced in the United States Pharmacopoeia more than 100 years ago. Today, pharmaceutical companies are still using essentially the same method, the USP <231> Heavy Metals Limit Test. David Riches and John Welch of Butterworth Laboratories gives an overview of the current method limitations, considerations for the new methodology, and the risk-based assessments being carried out by manufacturers. MANUFACTURING 84 Antimicrobial Copper: An Engineering Approach to Reducing Cross-contamination Copper, as well as being man’s oldest engineering metal, is now recognised as a proven, broad-spectrum antimicrobial material. Well over 60 published papers support its efficacy against pathogens that cause healthcare-associated infections (HCAIs), both in the laboratory and the busy clinical environment. Angela Vessey of Copper Alliance delves into the latest research – including ongoing study of the mechanism by which copper exerts its antimicrobial effect and the implications for its use as an infection control measure – and investigates how and where it is being used in the healthcare field and beyond.
4 INTERNATIONAL PHARMACEUTICAL INDUSTRY
102 Interpack 2014: Fully Booked All the available spaces in the Düsseldorf exhibition centre with its 19 halls are booked out. From 8 to 14 May 2014, about 2700 exhibitors are expected, from industries ranging from food and beverages, confectionery and baked goods, to pharmaceuticals and cosmetics, non-food consumer goods, industrial goods and related services. 104 A New Type of Pharmaceutical Vial - Managing the Risk of Delamination On the FDA’s list of drug recalls and enforcement reports, the number of recalls due to delamination is on the rise. Pharmaceutical companies and packaging manufacturers are faced with the challenge of solving this problem as recalls on account of delamination can cost companies a lot of money. Dr Bernhard Hladik of Schott Pharmaceutical Systems presents a new solution: pharmaceutical vials that minimise the risk of delamination. 108 Space-saving Solutions The packaging is the first point of communication with the patient and it is imperative that it clearly communicates to the patient in a way that is easily understood. Bob Houghton of Chesapeake Corp outlines how, over the past decade, the amount of information required to support many healthcare products has dramatically increased due to legislation, consumer and retail demand. This has had several major repercussions that have led to various innovative packaging formats which offer space-saving solutions. 110 Get to Know Your Patient Justin Schroeder of PCI looks into compliance and adherence, a hot topic in the pharmaceutical industry these days. The challenges companies face in bringing products through their pipelines to commercialisation, coupled with healthcare reform, leave them looking at patient adherence to medication regimens as a new opportunity. 112 The Balancing Act of Pharmaceutical Packaging High-quality packaging is vital for any healthcare product. However, developing packaging can become challenging when specific factors are required, always with the end-user in mind. Glenn Svedberg of Nolato Medical Pharma Packaging explores senior-friendliness and child-resistance: there are a number of solutions on the market that satisfy each requirement, but the perfect solution that incorporates both does not yet exist. Optimising one factor will decrease the effectiveness of the other – a balancing act for the packaging industry. 114 Conferences & Reviews Spring 2014 Volume 6 Issue 1
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Editor’s letter The global pharmaceutical and life sciences industry is bouncing back, undeterred by the heightened regulatory scrutiny and pricing pressures. Forced to examine and respond to emerging market trends and challenges in recent years, it is now reinventing itself by adopting new R&D and business models designed to cost-effectively deliver innovation and ultimately, better patient outcomes. IPI`s Spring edition takes a look at many of the issues that keep executives in the pharmaceutical industry up at night: in the Labs & Supply Chain section, we cover extensively the new EU GDP regulations, which – compared to previous versions – places significant emphasis on temperature control and the safety and security of medicinal products throughout the entire supply chain, from the manufacturer to the patient. World Courier’s Sue Lee tackles the guidelines` impact on the pharmaceutical supply chain in Europe and beyond; David Johnson of Intelsius and Peter Lockett of TP3 Global delve into the operational reality of temperature compliance, with its `hidden world of issues`; finally, Robert J Hayes of Seer Pharma deals with quality tools and techniques meant to improve product quality and reduce operating costs, such as Cost of Quality. Markets are changing. It`s a fact. In his article, Dominic Graham of Kelly Services focuses on the key challenges that life science companies
will likely face in terms of recruitment to ensure they are countering slowing sales growth, keeping costs contained and meeting higher consumer expectations. Therefore, the biggest challenge for 2014 might turn out to be `the human factor`: the ability of each organisation to source the talent, regardless of where it is based; to spot, employ and train the right people for the job. Of mice and men: to find out how helpful murine in vivo models really are as disease models for drug development, don’t miss IPI`s Drug Discovery section. Dr G.C. Mudde of S-TARget therapeutics GmbH argues that in at least two important therapeutic areas, oncology and allergy, the value of mice models is questionable. Animal models have played a critical part in the in vivo evaluation of novel therapeutic agents and treatments, historically animal research having had a vital role in almost every medical breakthrough over the last decade. However, rodents are not furry little humans, and drugs that look promising when studied in mice, fail to do so in humans. Significantly, in the last decades, the need for human-specific animal models has been realised and accepted by official regulatory authorities. What areas of research are heating up? Respiratory drug delivery and inhaler technology for instance is at a turning point. David Harris of Team Consulting explains how decades of research, development, and user experience have created a body of knowledge which is leading to innovation in new and unexpected directions.
Recently published research has finally come up with the scientific evidence of something that has been long suspected: packaging can increase patients` adherence to their medication and positively impact on patient health outcomes. In the Packaging section, Glenn Svedberg of Nolato Medical Pharma Packaging focuses on the two increasingly important areas of senior-friendliness and child-resistance; both critical requirements on clients’ `wish lists` that are making developing packaging a true balancing act: there are a number of solutions on the market that satisfy each requirement, but the perfect solution that incorporates both does not yet exist. Still, as Justin Schroeder of PCI sees it, the challenges companies face in bringing products through their pipelines to commercialisation, coupled with healthcare reform, leave them looking at patient adherence to medication regimens as a new opportunity. Such as Bob Houghton of Chesapeake Corp`s innovative packaging formats which offer space-saving solutions, or Bernhard Hladik of Schott Pharmaceutical Systems’ pharmaceutical vials that minimise the risk of delamination. Cecilia Stroe Editor This year, IPI`s Spring edition will be at Interpack (Dusseldorf), running from 8th till 14th May, where about 2700 exhibitors are expected.
Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan
Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT
Catherine Lund, Vice Chairman, OnQ Consulting
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma
Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters
Jim James DeSantihas, Chief Executive Officer, PharmaVigilant
Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company
Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation
Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group
Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP
Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics
Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation
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
Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences
Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Spring 2014 Volume 6 Issue 1
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REGULATORY & MARKETPLACE
Making Life Sciences a Magnet for Talent in 2014 Following years of growth and favourable market trends, 2014 will see the global life sciences industry facing a ‘new normal’. By any means it is still a stand-out performer globally, and a key strategic area for the EMEA region. In Europe, for instance, it is the second largest market for pharmaceutical sales, and the sector directly employs more than 660,000 people in the region, and around four times this number indirectly. However markets are changing. Life science companies must respond by adopting new business models to ensure they are countering slowing sales growth, stemming profitability challenges, meeting higher consumer expectations and finally, but of equal importance, promoting the industry for future success and innovation. Individual companies will be responsible for making these adjustments, but to do this successfully they will need
8 INTERNATIONAL PHARMACEUTICAL INDUSTRY
to be able to find, engage and train the right people for each job. The challenge for 2014 and beyond is therefore ultimately about talent and the ability of each organisation to source it, regardless of where it is based. In this article I will explore the key challenges that life science companies will likely face in terms of recruitment, along with suggestions on how they can meet these head on and attempt to mitigate risk. The Future of R&D Pressure on public purses, coupled with regulatory constraints, continues to put pressure on R&D investment in Europe. Meanwhile, emerging economies are gaining a greater share of this investment worldwide. For life science companies in the Eurozone, the challenge is to invest wisely in R&D activities to combat some of the
other significant challenges facing the industry – whilst keeping costs contained and improving competitiveness. Although the Lisbon strategy target of assigning three per cent of EU gross domestic product (GDP) to research and development activity by 2010 was not met – largely due to broader economic factors – it remains one of five key targets in the Europe 2020 strategy. Government and businesses know that R&D investment is a clear determinant of the overall strength of the pharmaceutical market. However, even though some individual countries are investing heavily in R&D activities, namely Finland (3.87% of GDP in 2010), Sweden (3.42%) and Denmark (3.06%), the concentration of investment is disparate and inequitable across the region. Meanwhile emerging economies are gaining a greater share of investment.
Spring 2014 Volume 6 Issue 1
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Eurozone life science companies are facing constraints in some local markets given the large variations in investment across the region, and lifting the longerterm outcomes for the industry partly depends upon more effective and innovative R&D investment decisions. However, governments alone cannot change the dynamics associated with R&D investment across a region as diverse as Europe, and it’s up to individual companies to find solutions to the R&D challenge and therefore boost their competitiveness. Among these solutions must be inventive and original approaches to accessing R&D talent, that has traditionally been concentrated in the South-east, where investment has been high in the past. Better management of the R&D talent supply chain will require new collaborative models of research driven, for example, by the emerging bio parks and incubator hubs such as BioCity Scotland that we partner with to help start-ups secure their critical talent. Access to a global talent network that can deliver knowledge and insight across geographical boundaries can be exploited through non-traditional hiring processes and virtual workforces. Generics vs Big Pharma As we know, for some time big pharmaceutical companies have been losing patent protection and the generic market has boomed. Smaller, more niche companies are now benefiting from a more relaxed patent environment. In 2011, the global generics market was estimated to be worth approximately $225 billion. This is expected to grow to $358 billion by 2016, representing more than 18% of pharmaceuticals sales. Again, trends indicate that emerging markets are experiencing growth and generics are no exception. Nowhere is the generics market growing faster than in emerging economies, which creates a twofold challenge for many large pharmaceutical companies operating within the EMEA region. If the cheaper, generic drug market is to be dominated by companies in emerging nations, the model of relying on one or two ‘blockbuster’ drugs is no longer viable, and all organisations are challenged to find more diverse sources of revenue. To do this, they will need new strategies, and new skills sets to deliver them. 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY
For example, they will need to be able to analyse new technologies and use big data to identify emerging trends and business opportunities. They will also need to ensure they have the ‘softer skills’ required in their workforce, such as communication and management skills. Emerging Markets IMS forecasts show that global spending on medicines will reach $1.1 trillion by 2015 – but revenue growth will slow to 3% between 2010 and 2015, from 6% between 2005 and 2010. The combined US and European share of spending will fall from 61% in 2005 to 44% in 2015. Emerging markets will take much of this share, expanding from 12% in 2005 to 28% in 2015. The impact of $120 billion of product revenues losing patent protection in major western markets from 2011-2015 will be largely matched by on-patent brand growth, leaving emerging market growth and generic spending as the main drivers of global pharmaceutical spending. In fact, aggregate emerging market revenues are forecast to grow at a compound 14% between 2010 and 2015. If the pressure on the US and EU markets lessens after the ‘patent expiration cliff’ and low levels of growth return (say 3%), global growth would then be around 4% between 2015 and
2020. Either way, the gap between the two markets is clear. Essentially the global pharmaceutical market is still growing, just not as fast as in the past. Profit margins are declining and a larger share of growth is to be found in emerging markets. For life science companies the challenge is to balance growth and investment across emerging and developed markets, and to ensure that their access to the right talent and research (as well as other key capabilities) matches the market opportunities. The key question companies need to ask themselves now is “how well positioned are we to capture growth in emerging markets and are we adapting our staffing strategies to match?” Trust and Transparency For better or worse, the internet has fundamentally changed healthcare. Consumers now have far greater access to information about their healthcare options, the drugs available and treatments on offer. This has altered the task facing pharmaceutical companies today. Pharma organisations need to be far more transparent in the way in which they work.
Spring 2014 Volume 6 Issue 1
REGULATORY & MARKETPLACE
From horsemeat to energy price rises, 2013 was a year that saw huge issues with transparency and trust in many industry sectors and it’s a key theme that will remain in place for 2014 and beyond. Life sciences will be no exception, and pharma companies have to be transparent in the way they research, test and deliver drugs to market, as well as providing better, faster and more holistic health solutions. Communities and individuals now have higher expectations about what science can deliver – and the timeframes it will deliver on those. Building trust in pharma products complicates the communication and engagement challenge facing large pharma companies globally. They must open the dialogue with consumers, and enhance communication and transparency in the way new treatments are brought to market. They also need to deliver personalised health solutions in a timely and affordable way. As a result, pharma companies will increasingly be looking for talented people who have the softer communications skills, who will be able to tie this into their daily work. Consumers seek collaboration and detailed insight regarding the way their treatment is managed, and pharmaceutical companies need to be part of facilitating this. Industry leaders need to build relationships with medical practitioners and consumers to improve communication and deliver patientcentricity. Trust in the life sciences industry as a whole is a key reputational issue and as such, has a massive impact on attracting and retaining talent. Not only must companies address the key reputational issues that have occurred in communities over recent decades, they must also equip their workforces with new competencies to adapt to this new era of ongoing collaboration and communication. Smaller Entities Must Collaborate Life science companies across the world are united by their desire to lower costs – hence the focus of many of these businesses on emerging economies. As the populations in many developed countries are ageing, governments too are struggling to deliver high quality healthcare, and therefore demand better value, putting pressure on pricing. A key strategic response to this has www.ipimedia.com
been for SMEs to account for a larger share of total business sector R&D. Firms with fewer than 250 employees already account for some 22% of total business sector R&D in the EU, 14% in the US and 8% in Japan. The trend towards complex and specialist tasks being outsourced to smaller, niche organisations is increasing in the life sciences sector, as well as elsewhere, and the EMEA market looks well positioned to capitalise on that trend. Retaining focus on core business activities while reducing fixed costs on other tasks is something many organisations in other industries have been doing for some time – now life sciences businesses are adjusting their business models to do this too. How individual organisations engage with talent and restructure work to be able to raise productivity and lower fixed costs in this way is a key strategic issue going forward. It will critically challenge core concepts of intellectual property, competitive advantage and the role of talent in delivering return on investment. What does this mean for talent? It is clear that there are some key challenges facing the industry in 2014 and beyond. Life science companies are facing significant challenges to their existing business models. The market is growing, but not in the ways it did previously. The need for new business models – from mass market to niche and targeted – translates into the need for different skills sets, and new pools of talent across more diverse geographical locations. It also requires companies to change the way they operate, as well as how they engage with the communities they operate within. If the life sciences industry is to become the destination for talent that it simply must become to meet its challenges, it must engage the broader talent community in its mission to deliver better, faster and more personalised health solutions. There are of course issues in attracting and retaining talent in the industry. For a start, companies need to find ways to engage with specific talent clusters. R&D and STEM skills have formed regional and local clusters that are often self-reinforcing. Investment in a specific location often leads to more investment, which attracts more talent
– and as a result, more competition. Companies therefore need to find ways to access the talent within these clusters and consider new staffing models to avoid always needing to compete for the same talent in the same locations. Building their own talent pipeline requires longerterm planning and analysis, and new partnerships. Companies will also need to ensure they can distinguish between productivity and cost-cutting. Boosting productivity and output must be done through innovative workplace practices. Low staff ratios in critical R&D roles lead to high turnover and higher recruitment costs overall. Of course there is a need to keep costs under control, however this must be done in a sustainable way, so as not to impact the future talent pipeline for the business. We’ve talked a lot on the need for businesses to recruit people with softer skills, who have business acumen as well as a life sciences background. Consumer demands and expectations are changing, and the kinds of skills sets needed must adapt to these. Finally, competition must be balanced with community needs. Clearly, organisations need to maintain competitiveness while improving the ways in which solutions are delivered to communities – competition must not come at the expense of faster, better health solutions, and industry collaboration is critical to addressing this.
Having worked in the recruitment industry for over 15 years, specialising in engineering and scientific recruitment, Dominic Graham heads up the Professional and Technical division of Kelly Services, where he oversees the Kelly Scientific, Kelly Engineering and Toner Graham brands across the UK, ensuring they are positioned as the global recruitment supplier of choice. Email: firstname.lastname@example.org
INTERNATIONAL PHARMACEUTICAL INDUSTRY 11
REGULATORY & MARKETPLACE
Making Sense of the Recent CJEU Decisions on Supplementary Protection Certificates (SPCs) The Court of Justice of the European Union (the highest Court in Europe) has again been busy considering the law on SPCs.
the situations in which an SPC is possible: In those decisions, the CJEU stated
also cast uncertainty on how many SPCs are allowed per patent. For many
that the test for determining whether a product is protected by a basic patent is to ask if the product is “specified” or “identified” in the wording of the claims of the basic patent.
years national authorities have allowed multiple SPCs for single patents, based on the understanding that it is possible to have one SPC per product, per patent. However, the CJEU chose not to confirm whether or not this approach was correct, or whether national authorities should only allow one SPC per patent, regardless of how many products are protected by the patent.
In four important cases, the CJEU ruled that in most circumstances multiple SPCs for different products may be obtained under a single patent. The CJEU also provided further guidance on the type of patent claims that can support an SPC. Background Supplementary Protection Certificates (SPCs) exist to compensate patentees in Europe for the long time it can take to get pharmaceutical products to market. SPCs are available for medicinal products and can be extended when the product has been tested for paediatric use. This system allows a patentee for a patented pharmaceutical product to obtain an extension of protection, beyond the patent term, for up to five years. In order to obtain an SPC, the product of the SPC must contain an active ingredient or a combination of active ingredients. That product must be protected by a basic patent and be the subject of a marketing authorisation in the country or countries of interest. A number of prior CJEU decisions looked specifically at the situation surrounding products containing a combination of active ingredients. In some instances, the marketing authorisation related to a product which did not have the same active ingredients as those protected by the patent. The CJEU decided that, in cases of such a mismatch, an SPC can still be directed to the patented active ingredients. If the patent protects only A, an SPC can be directed to A, even if the marketing authorisation is for A + B. Where a marketing authorisation is for A + B + C, but the patent only protects A + B, the SPC can be for A + B, and so on. The table below provides a summary of 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY
However, the Court did not explain how much detail was needed for the product to be “specified” or “identified”. By way of example, prior to those rulings, the UK Intellectual Property Office (UK-IPO) has granted an SPC for the product A + B where the patent claimed A, together with a carrier and, optionally, other therapeutic ingredients. The UK-IPO deemed that the claims covered A + B even though B was not explicitly recited. It is questionable whether the UKIPO would now grant such an SPC, in particular whether it would deem B to be “specified” in that claim. Whether a claim to A in combination with an antibody (where B is a known antibody) would be considered to protect A + B is similarly uncertain. The CJEU did give some guidance, however. It stated that, if a patent claims a product having two active ingredients, but does not claim an active ingredient individually, an SPC cannot cover that ingredient alone.
These uncertainties led to the referrals, which resulted in the four important cases being handed down by the CJEU in December 2013: Actavis Group v Sanofi (C-443/12) Eli Lilly v HGS (C-493/12) Georgetown University (C-484/12) Glaxosmithkline Biologicals SA (C210/13) Does an Active Ingredient Need to be Identified in the Claims by a Structural Formula or will a Functional Formula Suffice? In the Lilly case, the CJEU was asked whether an SPC is possible where the product is an antibody which is defined in the claims of the basic patent in functional terms (antibody binding to a particular target antigen).
Since those decisions, a number of national Courts have tried to apply this test and found that serious questions still arose as to the boundaries of the test.
The CJEU decided that for a product to be protected by a basic patent in force, it is not necessary for the active ingredient to be identified in the claims by a structural formula.
In the prior decisions, the CJEU had
Where the active ingredient is covered Spring 2014 Volume 6 Issue 1
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the basis of the same patent, because the CJEU has previously ruled that an SPC for a single active ingredient can be infringed not only by a drug containing that ingredient, but also by a combination drug containing the ingredient. If they were not allowed to do that, they asked whether they could surrender their combination product SPCs in favour of the single product SPCs. In the Actavis case, Sanofi’s SPCs related to a combination of an antihypertensive agent (irbesartan) together with a diuretic (HCTZ). The patent claims included one directed to “irbesartan in combination with a diuretic”, but nowhere in the claims or the patent description was HCTZ specifically recited. Sanofi had already been granted an SPC for irbesartan alone and was seeking an SPC for the combination with HCTZ on the basis of the same patent. The marketing authorisation for the combination with HCTZ was granted some time after that for irbesartan alone, such that the combination SPC would expire 14 months later than that for irbesartan alone. by a functional formula in the patent claims, it may be possible to obtain an SPC, provided that the claims, when interpreted in the light of the description relate “implicitly but necessarily and specifically” to the active ingredient. The CJEU has left the interpretation of the claims to the national Courts. Therefore, we will have to wait and see how the national Courts decide whether the claims relate “implicitly but necessarily and specifically” to the active ingredient. For many cases, it is difficult to see how this should be interpreted at a general level and is thus likely to come down to a case-by-case basis. Is an Adjuvant an Active Ingredient? In the Glaxosmithkline case, the CJEU decided that adjuvants do not fall within the definition of “active ingredients” and so cannot be the product of an SPC. This is the case even if the adjuvant influences the therapeutic effect of an active ingredient, because the adjuvant has no therapeutic effect on its own and so cannot be the subject of an SPC either alone or in conjunction with an active ingredient, such as an antigen.
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Is it Possible to Obtain Multiple SPCs for Different Products based on the Same Basic Patent? In the Georgetown case, the CJEU was asked whether multiple SPCs can be granted based on a single patent for different products, and whether an applicant can surrender an earlier granted SPC if they are only allowed one SPC per patent. Similar questions were asked in the Actavis case. Georgetown’s SPC applications related to cervical cancer vaccines (Gardasil® and Cervarix®) comprising multiple antigens, where each antigen was described for the first time in the basic patent. Georgetown had applied for multiple SPCs on the basis of this single patent for the antigens alone and various combinations of the antigen, based on the same marketing authorisation. Therefore, all the SPCs would expire at the same time because the duration of the SPC is calculated by subtracting the filing date of the basic patent from the date of first marketing authorisation in the Community minus five years, with the maximum term being five years (plus a possible six-month paediatric extension). Georgetown had been granted SPCs to various combinations of antigens, but wanted SPCs to the single antigens on
In Georgetown, the CJEU decided that it is possible, in principle, to obtain multiple SPCs for different products where a single patent protects a number of different products, provided that each of the products is protected as such by the basic patent. Therefore, Georgetown should be allowed multiple SPCs for the single antigens and combinations of antigens that are protected as such by the same basic patent, with those SPCs all expiring on the same date. If the marketing authorisation for the single active ingredient had been granted after a marketing authorisation for a combination of actives including that single active, it seems that two SPCs could be granted on the basis of the same basic patent; one for the single active and one for the combination. However, those SPCs would both expire on the same date because the first marketing authorisation for the combination of actives which contains that active would be used to calculate the SPC duration, not the later marketing authorisation for the single active. The exception here would be where the active ingredient contained in the later marketing authorisation is different to that contained in the earlier Spring 2014 Volume 6 Issue 1
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marketing authorisation, and both fall within the limits of protection conferred by the basic patent. In the Georgetown case, the HPV-16 antigen contained in the earlier marketing authorisation for Gardasil® is different to the HPV-16 antigen contained in the later marketing authorisation for Cervarix®, and both forms appear to be protected by the basic patent.
the SPC applicant can convince the patent office that A + B is a “totally separate innovation” to A alone. The Georgetown decision provides some relief for SPC owners who, in situations like those in Georgetown, will not need to forfeit second and subsequent SPCs on the same basic patent. Active ingredients claimed in functional terms rather than purely structural terms, particularly antibodies defined by their binding to a particular antigen, should be sufficient for the purposes of SPC protection. More clarity is still needed on what is meant by “implicitly but necessarily and specifically” in terms of active ingredients other than antibodies, which are defined functionally.
However, in the Actavis case, the CJEU outlined an exception to this principle, which arises in the situation of Sanofi’s SPCs. Where a basic patent protects both a first active ingredient and a combination of that active ingredient together with another, and an SPC has already been granted for the first active ingredient on the basis of a relevant marketing authorisation, an SPC for the combination product cannot be obtained under the same basic patent on the basis of a later marketing authorisation. The CJEU stated in the decision that a new SPC, potentially for a longer period of protection, cannot be obtained each time a medicinal product containing the principal active ingredient, protected as such by the basic patent and constituting the core inventive advance of that patent, is placed on the market in combination with another active ingredient which is not protected as such by that patent. Therefore, Sanofi should not be allowed a combination SPC as they already have a single active SPC under the basic patent. Thus, Sanofi cannot benefit from the additional 14 months of protection afforded by the later marketing authorisation for the combination. Instead, the SPC for the single active covers the single active product and combination product under the one SPC, but expires on the earlier date. At first, it may appear possible to circumvent this issue by filing separate patents (e.g. divisionals) to new active ingredients and related combination products. However, the CJEU specifically stated that each separate patent can only confer entitlement to a new SPC insofar as it covers “a totally separate innovation”. The CJEU failed to define what they meant by “totally separate innovation”, so it will be up to the national patent offices and Courts to determine this. Ultimately, another referral to the CJEU asking how to determine this is likely.
Conclusions The CJEU decisions were heavily based on the particular factual scenarios in which the references were made, making it difficult to extrapolate principles that can be applied more generally. What we can determine from the decisions is that adjuvants are not considered active ingredients and so cannot be the product of an SPC. With the exception of certain circumstances, such as Sanofi’s combination SPC, multiple SPCs for different products should be possible on the basis of a single patent. However, a decision on whether those multiple SPCs are worthwhile needs to be balanced with a determination of the SPC term. For example, where the patent protects A and A + B, the SPC term for SPCs to A and A + B will be the same if the first marketing authorisation encompasses A + B (e.g. A + B, A + B + C, etc.). In terms of infringement, the SPC for A can be infringed not only by a drug containing A, but also by a combination drug containing the ingredient, such as A + B. Thus in that situation, two SPCs may not be necessary. If the first marketing authorisation is only for product A, and the combination product A + B is later authorised, an SPC for A + B with a later expiry date seems to only be possible if
In terms of making sure the claims of the basic patent “protect” the product of the SPC, it is still difficult for SPC holders to formulate a strategy that deals with the increasingly confusing SPC decisions coming from the CJEU. One point that is clear is that patentees should aim to include claims to the product (whether that is a single active or combination of actives) on a general level, along with increasing levels of specificity before grant. Any likely commercial products should be specified in as much detail as possible in the dependent claims so that the national patent offices do not struggle to determine if the product is “implicitly but necessarily and specifically” claimed. Charlotte Teall graduated from Imperial College London with a BSc in biochemistry and subsequently obtained an MSc in the management of intellectual property from Queen Mary, London. During my studies at Imperial, Charlotte worked for a year as a research assistant at a major international pharmaceutical company, where she became particularly interested in stem cell technologies. Charlotte joined Forresters in 2006 and since then has specialised in all aspects of patent law in the UK and overseas. She is primarily involved in the drafting and prosecution of patent applications in the fields of biotechnology, pharmaceuticals and medical devices. Email: firstname.lastname@example.org INTERNATIONAL PHARMACEUTICAL INDUSTRY 15
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Pharmaceutical Product Recall: Lesson Learned Abstract The pharmaceutical industry is making every endeavour to comply with all current quality requirements. However, major challenges like increasing complexities of the design and manufacturing processes, intensive globalisation processes, more stringent inspection procedures, and product liability and regulatory burdens under which manufacturers operate, have increased drastically in recent times. This is due to the fact that product recalls and returns have become rampant and have increased dramatically in recent years. Product recall could significantly damage a companyâ€™s reputation, profitability and brand integrity, and hence the industry needs to cope with effective recall strategies. Moreover, safety must always be a concern of the people who manufacture, and are allied with, these pharmaceuticals. In this article, the authors have explored the process of pharmaceutical product recall, various critical factors affecting product recall system implementation, and appropriate recall strategies and key solutions to overcome it. Key Words: Pharmaceutical product recall, Recall issues, Recall strategies, Effective recall approaches 1. Introduction The pharmaceutical industry is at an important crossroads in medical innovations1 which develop cures for health conditions. Without this industry, many therapies would not be introduced to the market, and many health problems would remain unsolved. The pharmaceutical industry as a whole has traditionally been very profitable, and the global market is expected to grow 5-8% annually through 20142. Yet amidst the massive increase in the field, factors like product returns and recalls are giving the companies new challenges, such as litigation problems, negative publicity, loss of patent protection for many major drugs, and widespread efforts to contain drug spending3. On the other hand, increased competitiveness, fast-changing structure of competitors, complex strategic positioning, shrinking pipelines, counterfeit drugs and a fight for global market share are adding more burdens to the growth of the industry4, 5. 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY
A recall is a serious process. It highlights a dangerous situation that requires fast and effective action to protect the public from harm. Product recalls are becoming extensive and have increased radically 6. For example, the Food and Drug Administration [FDA] reported more than 1984 recalls with more than $700 million dollars manufacturersâ€™ penalties, and billions more in lost revenues since 20017,8. Nevertheless, companies are turning to set their strategic sight on future moves. In order to operate effectively in an increasingly competitive economic and commercial landscape, they are trying to adopt more formal business processes and stricter reporting methods9, as a way of navigating the risk and ensuring the drug safety and effectiveness. To be sure, the segment has yet to develop effective approaches that have progressed from inception to protection, and such events are likely to remain a few years or more away. 2. Pharmaceutical Product Recall To effectively manage a product recall, it is important to first understand what constitutes a recall and when it is necessary. It is a removal or correction of marketed products for reasons relating to deficiencies in quality, safety or efficacy, including labelling considered to be in violation of the laws10. Recalls can be either voluntary by the manufacturer, or can be initiated at the request of a regulatory authority. Depending upon the relative degree of health hazards involved, recall is classified as Class I, II, or III as shown in Table 1. A recall usually results from one or a
combination of the following situations: 1. Customer complaints: If a complaint reveals evidence of a critical or major defect, it can lead to a recall. E.g. precipitation in clear syrup, particles in injectables, off odour, stained labels due to leakage, etc. 2. Company discovery: Carrying out an investigation as a result of problems during processing of a particular batch might lead to the discovery of problems with earlier batches that were not detected prior to release. E.g. change in viscosity, caking in suspensions, etc. 3. Regulatory inspection: If a regulatory inspection uncovers a problem with the manufacturing process that casts doubt on the validity of the release for a given product. E.g. insufficient data on process validation. 4. Adverse drug reaction (ADR): ADRs, reported as part of a pharmacovigilance programme, can, but will not automatically, lead to a recall situation11. E.g. life-threatening effect, death or congenital anomaly due to drug products. Product recalls can be complex and will always involve many departments within the company such as production, quality control, quality assurance, marketing, R & D, as well as dealers, distributors and customers. Pharmaceutical recalls have grown faster per year from 2005-201112 (Figure 1) for many reasons, and the very survival of a firm may depend on how well and how quickly it can respond to the first notice that a product recall may be necessary. Product recalls are
Table 1: Classification of recall Spring 2014 Volume 6 Issue 1
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interactions; computerized physician order entry to reduce transcription errors; product ID scanning to reduce dispensing errors; bedside barcode scanning to reduce administration errors; electronic prescription to reduce ordering errors, etc. Added values could be attributed to the improvement of customer service leading to an increase in retaining customers and sales, in addition to reducing pharmacy cost, maximising manufacturer credit benefits and/or reducing cycle time16.
Figure 1: Recalled pharmaceutical products by FDA certainly expensive, but attempting them without adequate planning can be very costly13. 3. Issues Related to Product Recall 3.1 Multi-lisation of Pharmaceutical Companies Due to globalisation, fast emergence and the promising market in the healthcare sector, a veritable wave of companies have set up shop in different countries, eager to capture the global international clientele. In meeting various needs, companies are trying to match their promise as safe and effective medicine providers. At the same time, however, multi-lisation has added complexity to supply chains and the management of product quality. The industry continues to face problems of the flow of materials and information required for effective logistical management of the product14. Similarly, the supply chain may cause contamination of different product due to environmental factors, transportation problems, and personnel negligence, etc., causing outbreaks that affect large numbers of people. The issues related to the trading structure of the company have to be taken into account when deciding on the optimal multi-site investment strategy of the company, which in turn increases overall costing. The complex products and extended cross-border activities are difficult to manage and monitor with much lower costs. This in turn may impact the product quality, leading to product recall. 3.2 Lack of Value-added Capabilities Quick and efficient handling of returned products is critical in sustaining www.ipimedia.com
relationships and creating repeat purchases. A lack of value-added capabilities tends to create impact on product recalls. For example, medication errors may increase recalls, and difficulty in detection of such errors produces obscurity in effective implementation of product recall and can also cause risks to patients, including longer hospital stays, disability, and even death. At least 1.5 million people per year are harmed by medications, and around 100,000 people die each year as a result of medication errors15. Such events are related to medication process, prescription ordering, transcription, dispensing, and administration. Meanwhile, the addition of value-added capabilities may help to reduce medication errors, such as a clinical decision-making application which can suggest better dosing based on patient and product data, and avoid
3.3 Regulatory Complexity Regulations regarding product safety change frequently, almost always becoming stricter and more complicated. For example, regulatory bodies support their decisions on the desire to preserve individual safety against the risks associated with vaccines, rather than the adoption of a more robust approach in which the risks and benefits to the individual are judged in view of such vaccines in the society17. As the pharmaceutical industry expands into new territories, the compliance load increases and the complexity of any product recall multiplies. Each country has established its own regulatory system for dealing with product safety. For instance, in the United States, six federal agencies with vastly different jurisdictions regulate unsafe, hazardous or defective products. Of these, the FDA is responsible for food, drugs, cosmetics, animal health, biologics and medical devices. Meanwhile, the Ministry of Health & Family Welfare enforces the Drug & Cosmetic Act in India. Many of the steps involved in a recall are overlapping, and vary in urgency according to the severity
Figure 2: Breakdown of cost associated with recall INTERNATIONAL PHARMACEUTICAL INDUSTRY 17
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of the threat or breach of regulations involved. Because of stringent reporting requirements, companies are frequently obliged to report the product safety issue and decide on a course of action before they have investigated the nature and extent of the problem. New laws are giving governments in many parts of the world more power to intervene and order product recalls and withdrawals. Regulation, however, is not harmonised, and rules can be dense even within countries. 3.4 Consumer Power The easy distribution of information today allows customers to check whether they need to return a product which is defective, thanks to the internet, mobile phone applications and social media, although poor reading ability and healthcare education in the emerging world affects the adoption of such communication modes. For instance, while the current literacy rate shows satisfactory results in terms of educated population around the world, an estimated 20% of the world’s population, or about 800 million people, are still considered to be illiterate18, which affects effective handling of product recalls. Similarly, people generally do not ask sufficient questions when they lack knowledge about a subject, including medication. Some people think that new medicines are more effective or safer, but this may not necessarily be true. Even when patients choose their own drugs, they may lack the specialised knowledge to detect whether the product they are buying is of good quality. One of the largest drug recalls was for a combination therapy of diet drugs know as fen-phen (fenfluramine, phentermine, dexfenfluramine) which was approved for management of obesity through its appetite suppressant activity. It was found that this drug is associated with the development of serious cardiac valvular disease, and more than 6 million people used this combination before its recall19. Educating people is the only solution to these issues. 3.5 Competitive & Economic Pressure Even if the amount of activities for managing product recalls worldwide looks to be on an upward path for the foreseeable future, much of the nature and intent of the activity is changing below the surface. Globally, there is 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY
a pressure on pharma companies to reduce costs of drugs by government agencies20. In contrast, the increasing number of product withdrawals and recalls can run into losses of hundreds of millions or billions of dollars because of the overall cost associated with product recall (Figure 2). The high cost may cause pharmaceutical companies a significant loss of revenue. For example, the manufacturer of the brand Tylenol reported US$900 million in lost revenue from recalls of drugs, contact lenses and hip replacements, and underwent a lengthy shutdown of one of the factories involved during 201021. Pressure associated with economic risk can be transferred through the purchase of product recall insurance. As the blockbuster drugs lose patent protection and drug pipelines have run dry, big pharma seeks ways to limit profit erosion following generic entry22 which in turn leads to loss of earnings. Likewise, the generic drug industry lacks a more standardised approach which in turn may affect the quality of research and eventually the drug23. 3.6 Globalisation & distributorship Owing to globalization, a number of pharmaceutical organisations have started practising the loan licensing system or use of principal manufacturing systems. Even though the third party manufacturer has been monitored and audited by the parent company, and abide by legal agreements, it is difficult to find out the root cause and whom to blame in case of any defect occuring in product. In other situations, the organisations occasionally need to import certain component and raw materials. Several suppliers may provide raw materials or parts for one product. Equally, a single supplier may be providing a component or ingredient to many manufacturers, which can sometimes create problems in ensuring product safety and development of effective recall strategies. While reaching global patients, pharmaceutical companies have the support of the wholesaler and distributor chain, and
hence the company must rely on the distributors’ or wholesalers’ distribution information during a drug product recall. Depending on the geography in which it operates, the distributor may need to meet future regulations, e.g. on good distribution practices (GDP) in the EU, which will require (among other things) that distributors capture shipment lot numbers for potential recall processing24. But most distributors and wholesalers lack acceptable global standards. A pharmaceutical organisation taking proactive steps, rather than only comprehensive actions, seems to be the correct solution in such cases. 3.7 Bad Corporate Science Generally regulators do not conduct original drug medication safety research; they are reliant upon companies’ results which may be sometimes contain white lies and science fiction. For example, in a study conducted to know the effect of the Vioxx (Rofecoxib) drug on stomach tissue, the FDA approved it for the relief of arthritis symptoms based on data from trials lasting 3 to 6 months and involving patients at low risk for cardiovascular illness25. This has led to serious realworld consequences causing 88,000140,000 heart attacks, about one-third fatal, in the five years before its recall 26 . Afterward, it was found that the pharmaceutical company had ignored early warning signs, and employed an Spring 2014 Volume 6 Issue 1
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version of a new drug is faster than the call for drug recall. Zelnorm (Tegaserod maleate), a popular drug for irritable bowel syndrome and constipation approved in 2002, was subject to a FDA recall after Swiss scientists showed a higher chance of cardiovascular events, such as heart attack, stroke, or severe heartrelated chest pain in patients treated with Zelnorm28. It has taken five years for the FDA to recall the drug.
4.1.3 Communication & Course of Action As soon as risk assessment is performed, the firm should meet the regulator to discuss the agreeable and best recall strategy. A recall strategy based on the firm’s own interest will not be successful; rather, if it considers the regulator’s perspective to effectively defend the public it may help to get a quick response. Recall strategy includes the depth of recall. Recall depth is the level in the distribution chain to which the company will contact in order to retrieve the recalled product. There are three levels, viz. consumer, wholesalers and retailers. Consumer-level recall shall be executed when the product may have a chance of causing serious consequences and even death.
4 Strategies for Effective Recall 4.1 Basic Elements of Recall 4.1.1 Risk Assessment Figure 3: Flow chart: Recall process The pharmaceutical company needs to have aggressive promotional campaign of complete and accurate data in order for intimidation and misrepresentation which top management to decide whether to 27 caused this event . recall a product or not. It generally helps to evaluate the impact of failure on safety and efficacy of medicinal product. This 3.8 Reactive Approach for Safety is done by carrying out stepwise recall Despite strong efforts in scrutinising activities (Figure 3), and conclusions can drugs for safety purposes, the regulatory be drawn as to the chance that a consumer authority inadvertently may approve could be harmed by using the product in dangerous drug medications. Doctors question29. Creating a team as per cGMP unknowingly prescribe these expensive practice, comprising of representatives of drug medications and patients each discipline within the firm responsible suffer. Generally the regulator recalls for design, production, quality control, dangerous drug medications based on and marketing of the product, including complaints from patients, but until that hiring of a consultant and laying down time the manufacturer of the recalled SOPs for product recall, helps to mitigate drug medications gains astronomical product safety recalls. profits. If companies are asked to recall their product, they face the threat of 4.1.2 Records bad publicity and lawsuits. Once the Once the recall of a product is necessary authority demands the recall of the due to any of the reasons stated earlier, violated product, the company has to immediate action is required. The decide to remove its product, and keep pharmaceutical firm should establish the supervisory body updated about the communication between different status of drug medications remaining on departments. All necessary information the market. needs to be collected. The critical information includes records that will At the time of recall, regulators work enable it to quickly and accurately obtain with pharmaceutical companies and a violative product’s manufacturing lot doctors to alter warning labels until the history, including catalogue numbers, drug medication proves too dangerous to serial numbers, and quantities produced keep selling, followed by a ‘safety-based’ as per available SOPs. In addition to drug recall. This reactive approach records, the recaller must select a method means that the final test of safety is the of conducting effectiveness checks. public. Similarly, the regulatory approval for a new drug or an abbreviated
4.1.4 Disseminating of the Recall The next important step is the implementation of the recall through communication. As soon as the decision is taken for the recall of the product/ batch, the communication shall be sent stating the severity of the defect, using the fastest mode of communication (email, telephone, fax, SMS etc.) to the entire supply chain and also to the public if required. The communication should be concise and instructions detailed and easily understood. It should not be promotional. Similarly, incentives can be offered to encourage return of the recalled product. An effective recall also requires that the firm must create a strict quarantine.
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4.1.5 After Recall Termination Performing effective recalls also requires the company to take appropriate preventive steps so that similar problems should not occur in future. Implementation of such steps helps the firm to strengthen its brand. Similarly, companies should take the opportunity to build consumer confidence in the company brands, and positively influence customer satisfaction and loyalty with increasing profits30. 4.2 Regulatory Perspective Regulators play a major role in driving patient’s safety, no matter how it unfolds. Regulators should consider how they can begin working together with the public and private sector to develop a clear vision of global standards and how they will streamline the recall process. Although each country has their own regulatory framework and system, the vision of developing a global standard and internationally harmonised regulatory Spring 2014 Volume 6 Issue 1
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system could help manufacturers to effectively recall the product. 4.3 End User Perspective Whether literate or illiterate, the consumer needs to be proactive when it comes to medicinal product. If any particular product appears to be faulty, or if serious jeopardy has been found with any product, the user should log a concern or complaint with the local and/ or regulatory authority. These authorities will act on consumer concerns and may initiate a product recall if warranted. Their concerns may also prompt the manufacturer to make positive product design changes. When consumers hear news about a recall, they should try and obtain further details to see if the drug they are using is part of this recall or not. Consumers can have vital safety information available right on their mobile phone whenever and wherever required. For instance, downloading and installing the Recalls.gov (http://www.recalls.gov/ medicine.html) appliance on Android phones, consumers can now type a product’s name and learn immediately the status of the violated product; whether it has been recalled because of a safety concern31. 4.4 Use of More Robust Approaches 4.4.1 Tracking The TrackWise product recall solution improves response time to potential recalls by automatically tracking and managing the decision process to recall products from the initial recall request submission through the evaluation and resulting recall decision. Nowadays, many pharma companies are making investments in security measures, data systems and business processes to improve efficiencies in managing recalls. These include, among other things, barcoding on primary and secondary packaging for product identification, global location number (GLN) and healthcare identification number (HIN) for location identification and use of global data synchronization network (GDSN)24 which allows fast, accurate transmission 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY
of data from manufacturer to customers. Tracking provides a number of benefits for effective recall handling (Table 2). 4.4.2 Strategic Alliances Instead of following the long distribution chain for collecting necessary information, partnership by the pharmaceutical firm with a third-party contractor, especially for international sales and distribution of medicines, may support complete logistics management in product recall. These contractors could also provide the critical data, which allows pharma companies to better understand where their returns are coming from, the condition in which they arrive, and whether or not return instructions were followed. With all of this data, companies can get additional information on how their customers handle returns and recalls. Similarly, these third-party agents – as per the
decided terms – may carry out product destruction, saving time and cost. A strategic alliance makes sense when there is a need to offer more value. It is not only helpful in creating a stronger business relationship, but it also allows
the manufacturer to adapt its procedures to better suit customers’ needs, even leading to a more effective recall. 4.4.3 Staying Focused Our research suggests that the healthcare industry can create significant value from staying focused; both in terms of business value and in terms of meaningful improvements in patient safety and quality of care. Industry leaders who are convinced of the benefits of staying focused by adaptation of value-added capabilities (Table 3) are in a position to work across competitive and customersupplier relationship boundaries to agree on a common vision and approach. 4.4.4 One-touch Processing In an effort to reduce the complexity of recalling the product, there has been the development of one-step or one-touch programmes, which function as the single intermediary between manufacturer and downstream trading partners. In the traditional scenario, upstream manufacturer and the multiple downstream trading partners are engaged in handling routine returns. Using the newer approach, a single intermediary handles the entire return from initiation to final product destruction, acting as a partner to the drug maker, pharmacies or other retail partners. 5. Conclusion Recall is the antithesis of what a quality-conscious manufacturer seeks to achieve. Recalls happen, but an increasing and frequent trend could be expensive, may cause a shortterm embarrassment for a company, and is not good for the society as a whole, but in the long term it improves the quality and benefits the consumer. In today’s world it is technologically possible for a manufacturer to utilise an opportunity of a new kind of healthcare innovation. They should consider a culture, the context in which it happens, the practical and operational difficulties, the processes it will be used alongside, etc. It has become vital for industry professionals to increase their preparedness and be ready to develop tactical plans of action for risk assessment Spring 2014 Volume 6 Issue 1
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and management for recall. Similarly, other stakeholders, including consumers, doctors and regulatory authorities, need to be proactive so that patients can enjoy consistently safer and more effective healthcare systems. Finally, no one wants to be involved in a product recall. However, if the situation is unavoidable, proper training, planning, and execution of the recall can result in only minor operational and financial disruption. 6. Disclaimer: The article has been written in the authors’ personal capacities. All opinions expressed herewith are those of the authors and do not reflect the views of their organisation. 7. Conflict of interest None References 1. Shewale S., Parekh S. Reinventing Patient Recruitment in Clinical Studies. The Monitor. Oct. 2011. 2. Intercontinental Medical Statistics Health. 2010. 3. Folland S., Goodman A. C., Stano M. The economics of health and health care (5th ed.). Upper Saddle River, NY: Pearson Education, Inc. 2007. 4. CBR Pharma Insights: The New Pharmaceutical Sales Force - Key Trends Shaping Future Sales Strategies. Reuters online. 2009. 5. Edwards A. Manufacturing the future. Integrated
Sunil D. Shewale, B. Pharm, PGDCTM, MBA, M. Pharm (QAT) is an executive research officer at the Serum Institute of India Ltd. (SIIL), where he has more than six years of experience in clinical research and quality assurance of pharmaceuticals. He is a professional in product handling, documentation, trial monitoring, data management, medical writing, and overall project management. He has coauthored several original research publications for vaccine trials at SIIL. He has also published number of review articles. Email: firstname.lastname@example.org
collaboration between CMOs and Sponsors. Contract Pharma. May 2010. CNNMoney. Drug Recalls Surge. 2010. Available at: http://money.cnn.com/2010/08/16/ news/companies/drug_recall_ surge/index.htm (Accessed on 25th Feb. 2013) Kumar S., Dieveney E., Dieveney A. Reverse logistic process control measures for the pharmaceutical industry supply chain. International Journal of Productivity and Performance Management. 2009 (58): 188-204. D’souza A., Keeling D., Phillips R. Improving quality in pharma manufacturing. The McKinsey Quarterly. September 2007. Souza D., Danase J., Constatinou D. Business Efficiency and Regulatory Compliance. Pharmaceutical Technology. 2005. Guidelines on Recall and Rapid Alert System For Drugs; including biologicals & vaccines by CDSCO (draft version). Published on 22nd Oct. 2012. Shah D.H. Q.A. Manual, 1st Edition, 2000, Published by Business Horizons New Delhi, The Pharma Review, Congposh Publication Pvt. Ltd., August 2007 P.no.267. FDA Gold sheet. 2012. Risk topics; Product Recall Program by Zurich Service Corporation. Available From: zurichna. com/internet/zna/SiteCollectionDocuments/en/ media/inthenews/Risk TopicsProductRecall.pdf (Accessed on 28th Feb 2013). De la Fuente M.V., Ros L., Cardós M. Integrating Forward and Reverse Supply Chains: Application to a Metal-Mechanic Company. International Journal of Production Economics. 2008 (111): 782-792. Medication error statistics by Andrea Cook & Associates. Available from: http://www. alcooklaw.com/practice-areas/medicationerror-injury/medication-error-stats-examples/ (Accessed on 28th Feb 2013). Biederman D. Speeding Up, in Reverse. Journal of Commerce, New York. Jul. 2010. Parekh S., Shewale S. Understanding the Niche: the clinical development of vaccines. Journal for
Clinical Studies. 2012. Vol.4, (4): 52-56. 18. Lars Schmiedeberg. The challenges of cognitive testing in low-income countries. Journal for Clinical Studies: 2008: 32-34. 19. Edward Bauer. Drug Product Recalls: An overview of the process. Tablet & Capsules. May 2012. 20. Shewale S., Parekh S. Realizing the promise: India’s strategic shift from outsourcing to innovation. The Open Clinical Trials Journal. 2011, Vol. 3. 13-19. 21. Product Recall: The developing story, by Catlin group. April 2012. 22. The Pharmaceutical industry: The bitterest pill. The Economist. January 2008. 23. Parekh S., Shewale S. Understanding the reality: Is India losing standing for clinical research. Journal of Clinical Research & Regulatory Affairs. 2012. 1-6. 24. Strength in unity: The promise of global standards in healthcare by Mckinsey & Company. October 2012. 25. Juhana K., Topol E.J. The sad story of Vioxx, and what we should learn from it. Cleveland Clinic Journal of Medicine. 2004. Vol. 71 (12), 933939. 26. Snigdha P. The Cover-Up Artist. Slate Magazine. November 2011. 27. Birchfield A.D. Jr. Beasley, Allen, Crow, Methvin, Portis, Miles, P.C. The Vioxx story 2007. Available at: www.beasleyallen.com. (Accessed on 2nd Mar. 2013). 28. Zelnorm Recall: An overview. Available at: http://irritable-bowel-syndrome.emedtv.com/ zelnorm/zelnorm-recall.html (Accessed on 2nd Mar. 2013). 29. Cafmeyer N., Lewis J.M. How to Effectively Manage a Product Recall. Pharmaceutical Technology, 2011. Vol. 35, Issue 1. 30. Howard I., Humby S. Embedding Corporate Responsibility into Supply: A Snapshot of Progress. European Management. 2008 (26): 166-174. 31. Web link: http://apps.usa.gov/product-recalls-2. shtml (Accessed on 6th Mar. 2013).
Manisha Chavan, M. Pharm, Quality Assurance Techniques, is an assistant Professor at University of Pune. She leads the pharmaceutical chemistry department in college as a head of the department. She has more than seven years of academic and research experience. She has hands-on analytical method development experience with sophisticated instruments like HPLC, UV spectrometers, and FT infrared spectrometers. She has expertise in formulations of various types, i.e. tablets, capsules, liquid orals, etc. She has profound knowledge of GMP documentation in the pharmaceutical industry. Email: email@example.com
Dr Sameer S. Parekh, BHMS, MBA, CCRP is a clinical trial manager for the Serum Institute of India Ltd., who combines knowledge and experience from diverse fields such as research and clinical development, public health, and pharmaceutical management. He has over nine years of experience in the biopharmaceutical industry, with increasing responsibility in national and international research and clinical development efforts. With a primary focus on infectious diseases, pediatrics and oncology, his specialities include multifunctional team leadership, development of study design, drug safety and medical writing. He contributed to the conception and design, drafting and final approval of this article. Email: firstname.lastname@example.org
8. 9. 10.
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Realising Peak Performance of an organisation “By applying a simple and practical approach, which removes barriers and boosts drivers, this method ensures employees realise their full potential. The organisation is transformed into a dynamic and adaptive state and realises sustainable Peak Performance.” 1. The World is Changing Rapidly: Learnings from the Dinosaurs Rapid Change: Importance of Adaptivity The world was dominated for more than 150 million years by what we now call dinosaurs. They dominated water, land and air, and were able to adapt themselves to different climates on the planet. However, they disappeared, not because of lack of strength, but because other species were more able to adapt to a period of intensive climate changes than the dinosaurs. Now again, and fortunately not caused by external factors (such as meteors which speeded up the disappearance of the dinosaurs), multiple changes are occurring on the planet. Billions of people moved to middleclass status in a few decennia, a global economy without frontiers emerges, and information flows at the speed of light between all inhabitants of the planet. The speed of this is without precedents in human history and the speed of change is even accelerating. What does this mean? Who Benefits from the Rapid Change? While the dinosaurs disappeared from earth, the mammals replaced them very quickly and demonstrated their ability to adapt and prosper in all parts of the world. The complexity and volatility of the environment in which organisations operate is increasing quickly, and requires organisations to continuously adapt to these changes in order to create added value and remain relevant to their customers. The impact of this can be seen in several ways: 1. New, high-performing companies challenge the traditional leaders and often move fast to “star” positions in a few years, leaving the former leaders behind. On the other hand, companies that are believed to 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY
have a “sustainable competitive advantage” and enjoyed a leading position often appear to be no longer relevant in just a few years 1. 2. The traditional “MBA-style” management techniques still focus on improving efficiency with an organisational focus (reporting lines, outsourcing, and ICT applications) 2, while largely ignoring the human factors (team orientation, customer orientation, and level of personal involvement) as well as those factors which give people a sense of purpose and provide them with the right balance. Since these factors are not taken sufficiently into consideration, efforts to induce change often fail, leading to resistance. Also, middle management often resists change as they fear the possible reduction of hierarchical layers3. 3. The traditional success factors do not seem to work any more. Being large is no longer a guarantee for stability. People working in wellstructured organisations appear to resist change, while more chaotic companies function without hierarchical layers and adapt to a changing environment without instructions from “the top”4. Executives are fully aware that a wave of new organisations realise Peak Performance, adapt to new challenges very quickly, and create market after market. They are also aware that this Peak Performance is driven by highly motivated employees, who are empowered to respond to new situations, and are, more frequently than other companies, in a state of “flow”. However, they are not trained how to realise this in their own organisations and return to traditional management techniques once efforts to change mentality and increase motivation have failed. What is lacking here is the ability to combine new ways of thinking with the decisiveness to translate those ideas into reality.
2. Change and Adaptivity: Peak Performance through Transformational Change From the above section it is clear that rapid changes are challenging and require organisations and people not only to respond quickly to changes, but also to anticipate and prepare for what will happen. Can an existing organisation move to this required state of Peak Performance? The answer is yes, and what is needed is actually a combination of common sense, practical approach, but most important of all, focus on the human component in realising Peak Performance. Unlocking full potential includes: • •
Move from incremental thinking to transformational thinking. People orientation and focus on intrinsic drivers and barriers: move from top-down approach to bottomup flow of initiatives, implying the need for a non-hierarchical leadership style. Induce a process that attracts outside talent and customer focus realising a sustainable situation. Induce changes which aim at realising adaptivity and ability to cope with complexity: set a focus on the external world, breaking down the walls between the organisation and external stakeholders 5. Give people the feeling that they can really have an impact on society, customers as well as their team, by being innovative, creative and performant (see Figure 1).
This can only be realised by applying tools that assess the situation in terms of degree of readiness for Peak Performance, define areas of opportunity and barriers, and define the necessary actions to realise the desired state of the organisation.
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REGULATORY & MARKETPLACE life. We can no longer expect that young people who have been taught how to think will be able to adapt their teachings to the new world as it is emerging.
Figure 1: Performance, creativity and innovation triangle leading to Peak Performance 3. How Changes can be an Opportunity: The Force of New Thinking Paradigm Shift: Change as a State of Mind When the climate of the world changed 65 million years ago, there was little the dinosaurs could do. Dinosaurs as a species were indeed able to adapt to new the situation by means of forces of natural selection and adaptivity of the genes. However, climate changes created a real paradigm shift. Species such as mammals not only survived but started to dominate the planet by their intrinsic ability to adapt to changes. Being warmblooded, for example, they were able to live in different climates6.
This results in yet another paradigm shift. Waiting till our thinking adapts to new situations is no longer relevant. We need to change the way we think about ‘changing thinking’. To realise this, we need a deep understanding of how this works. But, even more importantly, we need to understand what drives new, creative, adaptive thinking, and we need to do all we can to create the right environment to do so.
Some observations from reality help to understand transformational thinking. We all have observed that people who are really good in something are not 10 or 20% better than their peers, but often 10 or 20 times better. We see that small teams in the biotech industry often are 50 to 100 times more productive in finding new advanced medicines than the traditional pharmaceutical companies. •
Second, we need to see our organisation as a team of individuals working together, rather than as a structure with departments and hierarchical levels. To change, we need to ask ourselves how this interaction really works. Are people working in a “flow”? What drives them? What do they think they contribute to society? To the team? Why do they fail to go “full blast”? This means we have to assess deeper motivations and use methods that are able to capture this in a systematic way8.
Third, we need to integrate the above way of thinking into a sustainable situation9. For example, an organisation that is built around people and teams will attract more people with the same spirit and value, reinforcing this culture and representing an asset in the “war for talent”. This will also lead to an increased level of customer intimacy, which will again reinforce and
Dynamic Environment and the Need for Dynamic Thinking If we understand this, the next steps are simple. But first, let us determine in a systematic way what impacts peoples thinking. Then, we can determine how to safeguard the environment in which people work, ensuring people can adapt their thinking. •
Only a few hundred thousand years ago, a new species emerged in the Savannah areas of Africa: the humans. They rapidly started to dominate the world because of a few “killer applications”, such as the ability to communicate and cooperate, which essentially require the capability to “think”, and the adaptivity which results from this. Humans rapidly dominated everywhere on the planet. They simply used their intelligence to adapt to whatever situation they encountered. Essentially, they were able to develop new thinking, when needed7.
First, there is a need to move from incremental thinking to transformational thinking. Incremental thinking remains valuable and relates to increasing productivity, enhancing internal communication, and good HR practices. However, incremental thinking will also lead to the traditional one-digit improvements, which are key for long-term success, but will not result in moving rapidly to a state of Peak Performance.
However, the changes we see now are unprecedented. The way of thinking which led to success one generation ago is now irrelevant, since the environment is so different. The need to adapt thinking increases together with the speed of external change. As a result, we can no longer rely on the traditional ways of adapting. We can no longer rely on our universities to teach young people new insights, and hoping that these learnings remain relevant during their working
26 INTERNATIONAL PHARMACEUTICAL INDUSTRY
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solidify this culture. Understanding these dynamics will lead to consistent actions that reinforce each other and create a situation where an organisation is growing based on culture rather than as a result of topdown actions. •
Fourth, we need to think of our organisation as a complex adaptive system. This means we have to see the organisation as a complex entity with both technological (techniques, tools, ICT, etc.) and social (interaction, leadership, communication, etc.) dimensions5. We also have to think of our organisation as needing adaptivity, implying it is able to respond immediately and adequately to external changes. As these changes are fast and complex, the traditional response method, where management is looking at the external environment and reorganises from time to time, is no longer enough. Management needs to create an organisation which is truly adaptive, meaning employees have the possibility of staying fully in touch with the external world and responding immediately to changes. This is often not possible in traditional companies as management layers regularly monopolise and filter information from the outside world.
4. Innovation: People Creating Value The term innovation is used in various contexts. In essence, however, it can be defined as the ability to rethink what the changing society is expecting from our organisation and be able to satisfy these changing needs with adequate products or services. We need therefore to think differently about how value is created and what the real drivers of this process are. We need to start from the way people think and function, rather than in terms of resources and production processes. In essence, we can define these drivers as the elements of the performance, creativity and innovation triangle (see Figure 1) which are intrinsically interlinked. Why is this way of thinking so important? These drivers relate directly with the way people in an organisation think and to what degree that thinking is aimed at creating value. Innovation is often considered as an activity which can be initiated by allocating a budget. However, innovation should be considered as a process, where people continuously think on how things could be better and move in this 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY
direction. This implies the need for a new forward-looking way of thinking: creating new approaches, services and products rather than improving existing ones. Creativity is part of being human. We all apply creativity in our homes, how we dress ourselves, how we cook or entertain each other10. It is creativity that causes innovation, provided we allow it to ourselves and our colleagues. Creativity no longer is a “nice to have”, but a fundamental requirement. So, create value and innovate! If we allow this out-of-the-box thinking for ourselves and others, we start a free way of thinking, and can leave existing thought patterns. Performance relates to the energy, the state of flow and dynamics of both teams and individuals. Essentially, it relates to meaning and impact11. What is the impact of what I do on society, the customer, my team and ultimately myself? Now that we have defined some components of what is needed to create an environment where people and teams can unlock their energy, and are stimulated to change and to adapt their thinking to the ever-changing environment, we can move to the methods by which this can be realised. 5. The Good News: All that is Needed to Adapt is Present in Every Human There is a universal principle that applies when we want to change the way people think and work. Everything that is in conflict with the essence of human nature is bound to fail. The past shows many examples of this phenomenon. Political systems - although often created with the best intentions - where these principles were violated failed completely. Let’s think of the events which resulted in the fall of the Berlin Wall and the realisation of democracies in the former Easter Europe area. Clearly, a system where a central government took the decisions did not prove to be sustainable. The system was not able to create added value, as it ignored the power of creativity, innovation and performance by individuals and teams. There are more examples of this. Consider, for example, the failure of the Western armies during the Vietnam war, where a high-tech hierarchically organised army was unsuccessful against a guerrilla army. Essentially, the success was based on the ability of smaller teams to adapt in a fast and flexible way to
different situations without the need for a hierarchy or central decision-making. Moving back again to the dawn of human history, we saw the same. Humans lived in relatively small groups and shared a common purpose; they had excellent communication and a flat hierarchical structure. The size of a hunting team was apparently around ten people, which is still the size of an operating unit in modern armies. We can ask ourselves what went wrong. Indeed, when the Industrial Revolution started, we saw the emergence of large organisations with a hierarchical structure that became leaders in the industries in which they operated. Examples are Ford, that became a leader by producing cars using assembly lines where every single task was defined in detail, as well as the time needed by employees to perform this task. The Charlie Chaplin movie ‘Modern Times’, released in 1936, was considered at that time as a comment on the situation of employees in large industrial corporations. Essentially, the concept of the assembly line, and the Ford philosophy of producing identical cars in large numbers, is in contrast with the situation most companies are facing right now. Indeed, there is significant volatility at all levels, and customers are increasingly demanding services and products that are customised to their needs. This relates to another mega-trend. People increasingly expect products and services that are adapted, or can be adapted, to their personal needs, even at different moments in time. For example, people prefer their mobile phones to have a different colour during working hours and during their free time. They want a home screen that is reflecting their moods and want different ring tones depending on who is calling12. In order to create an organisation that is creative, innovative and operating at Peak Performance, we need to go back to what made humans so successful to begin with: offer people a sense of meaning by giving them the possibility to impact society and customers with their decisions, and allow them to be close to themselves, society and their customers13. People also increasingly want to be able to express themselves and to be respected how they are. They also expect the company where they work to be authentic, and no longer accept that the company forces certain attitudes, or Spring 2014 Volume 6 Issue 1
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that outside communications are different from the reality in the company. This implies that companies need to accept the individuality of their employees and be honest and transparent in how they relate with them14. 6. Practical Approach: How to Create Peak Performance? If you search the internet on methods and tools that increase productivity or enhance creativity, you will find an uncountable and increasing amount of books, courses, tools, experts and companies that claim to be able to enhance performance. Actually, consulting on this has become a multi-billion dollar industry. PwC, for example, generated US$ 8.7 billion in various consultancy services in 2012. The fact that the best companies in the world spend substantial amounts of money to hire the most talented consultants to assist them in adapting to the environment confirms that this is a real issue. However, some observations suggest that there may be another approach to realise Peak Performance. All over the world, new companies emerge which are able to create new markets, and have highly motivated and creative employees, without help from outside consultants. Actually, while managers often desperately seek for solutions through external advisers or promising books written by the bestseller authors of the moment, most can be found just a few offices or a floor away: with their own employees. What is needed are just a few simple things: • Listen to what people working in your organisation have to say • Find out to what degree they feel their work impacts society, customers and their teams • Find out to what degree they know what the customers need • Ask them what they think the company expects from them • Find out their opinion on how good the company is in creating new services and products • Discuss with them why their performance is not always optimal Ask them who determines the future of the company. Customers? Management? The team? • Ask them if they would recommend young high talented people to work for the company. Why? Why not? • Ask them in what direction the www.ipimedia.com
company is going and how they feel about that Ask them if they feel appreciated by the company
These questions can be summarised in a simple sentence. First, there is a need to get insight (deep understanding) and then a need to provide foresight (perspectives, opportunities and respect) based on this insight. These questions generally provide a wealth of information on what is needed to remove barriers and boosts drivers, and how the full potential of your employees can be realised. This knowledge should provide the necessary focus to transform your organisation into a dynamic and adaptive state and realise sustainable Peak Performance. References 1. Wiggins, R. R. & Ruefli, T. W. Sustained competitive advantage: Temporal dynamics and the incidence and persistence of superior economic performance. Organization Science 13, 81–105 (2002). 2. Hansen, D. Why MBA programs don’t produce leaders. (2011). at <http://www.forbes.com/ sites/drewhansen/2011/10/04/ why-mba-business-school-notleaders/2/> 3. Mintzberg, H. Mintzberg on management: inside our strange world of organizations. 418 (Free Press, 1989). 4. Taleb, N. N. Antifragile: Things that gain from disorder. 550 (Penguin, 2012). 5. Beinhocker, E. The origin of wealth: Evolution, complexity, and the radical remaking of economics. 544 (Random House Business Books, 2006). 6. Crumpton, N. Mammals vs dinosaurs. (2013). at <http:// www.cam.ac.uk/research/features/ mammals-vs-dinosaurs> 7. The evolution of generosity: Welcome, stranger. (2011). at < h t t p : / / w w w. e c o n o m i s t . c o m / node/21524698> 8. Covey, S. R. The 8th habit: From effectiveness to greatness. 409 (Free Press, 2004). 9. Keller, S. & Price, C. Beyond performance: How great organizations build ultimate competitive advantage. 304 (Wiley,
2011). 10. Ready, D. A. & Conger, J. A. Make your company a talent factory. Harvard Business Review, June 2007, pp.68-77. Harvard Business Review 68–77 (2007). 11. Cranston, S. & Keller, S. Increasing the “meaning quotient” of work. 2013 at <http://www.mckinsey. com/insights/organization/ increasing_the_meaning_quotient_ of_work> 12. Fogliatto, F. S. & da Silveira, G. J. C. in Springer Series in Advanced Manufacturing 378 (Springer, 2011). 13. Davies, G. & Chun, R. To thine own staff be agreeable. Harvard Business Review 30–32 (2007). 14. Kotter, J. & Rathgeber, H. Our iceberg is melting: Changing and succeeding under any conditions. 160 (St. Martin’s Press, 2005).
Ruth Lachaert has over 12 years of healthcare (pharmaceutical and biotech) industry experience across different therapeutic areas and R&D functions related to Clinical Development, Critical Phase Project Management, Process Excellence, Regulatory Submissions and Market Access Health Economics, on global, EMEA and national level. During the last years she combined the above into an operational performance management concept, engaged in transformation and change management, and gained particular expertise in crisis management, entrepreneurship and innovation. She has her own management consulting company (UmamiFlow BVBA, Realizing Peak Performance) and recently founded Katara BVBA, to design and build ‘good companies’ and serve as a think tank for health. Ruth holds a Master in Biomedical Sciences (University of Antwerp), a Master in Project Management (George Washington University), a Process Excellence Green Belt, and an Executive MBA (Antwerp Management School). She is a certified business coach and Belbin team roles practitioner, and studies Comparative Philosophy (SCFA). Email: firstname.lastname@example.org
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Scaling up Action to Meet the New World Cancer Declaration Targets The World Cancer Declaration 2013 Originally launched in 2006, the World Cancer Declaration (Declaration) has helped to bring the growing cancer crisis to the attention of government leaders and health policy-makers, and to drive new government commitments in the global fight against cancer and other non-communicable diseases (NCDs). In 2011, heads of state and governments adopted the United Nations Political Declaration on the Prevention and Control of NCDs, which recognised NCDs as a global health and development priority. Success followed in 2012 with the adoption of a global target to reduce premature deaths from NCDs by 25% by 2025. In 2013, the foundations of a new global NCD architecture were put in place with the adoption of a Global Monitoring Framework for NCDs (GMF), a Global NCD Action Plan 2013-2020 (GAP), and a Global Coordination Mechanism for NCDs. In light of these groundbreaking developments in the fight against NCDs, and with the expiration of the Millennium Development Goals (MDGs) fast approaching, the Union for International Cancer Control (UICC) saw a growing need to more closely align the World Cancer Declaration with the emerging global NCD framework and the dialogue on the post-2015 development agenda. Figure 1: World Cancer Declaration 2013
Overarching Goal: There will be major reductions in premature deaths from cancer, and improvements in quality of life and cancer survival rates. Source: www.uicc.org/world-cancerdeclaration The language used in the Declaration has been updated to reflect current discourse in the public health and development arenas. Other specific changes to the Declaration include: •
Target 3, which relates to cancer risk factors, has been expanded to cover the known cancer risk factors which are common to NCDs, including tobacco consumption, overweight and obesity, unhealthy diet, alcohol intake, and physical inactivity. A new addition is the specific reference to UV radiation and exposure to asbestos made in the Declaration list of immediate actions. The text of the Declaration targets (specifically targets 7 and 8), and list of immediate actions have been enhanced to acknowledge the impact of distress among cancer patients, their family members and carers, and highlight the need for improved psychosocial and supportive care. The text of the Declaration targets (specifically targets 1 and 7) and list of immediate actions have been enhanced to acknowledge the importance of the quality of cancer care, and emphasise the principles of equitable access to effective, safe, patient-centred (supports active involvement of patients, their families and carers in the design and delivery of healthcare, and in decision-making about individual options for treatment) services.
Using Innovative Partnerships to Meet the Targets The World Cancer Declaration provides a shared vision for all that can play a role to take action and build collaborative partnerships to address the global cancer burden. Throughout 2013, momentum towards 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY
achieving the declaration targets has accelerated through a series of innovative multisectoral partnerships involving civil society organisations, governments, UN agencies, academia and relevant private sector: International Cancer Control Partnership The International Cancer Control Partnership (ICCP), formed in November 2012, is a group of organisations engaged in supporting country cancer control planning efforts. National Cancer Control Plans are a vital investment for all countries in understanding and responding to the cancer burden, and achieving clear plans for integration into NCD and broader health programmes. Through the ICCP, these organisations are committed to working together to ensure that all countries have a wellresourced, quality cancer control plan, integrated with non-communicable disease control efforts. The ICCP Portal, a one-stop shop for cancer prevention and control planning, was launched in November 2013 at the World Cancer Leaders’ Summit in Cape Town, South Africa. The ICCP Portal is a unique initiative that brings the experience and best practice knowledge of leading cancer organisations and experts, and offers policy-makers and cancer planners an online platform, dedicated to providing selected resources and tools on cancer control, all available in the convenience of one place. The ICCP Portal will shortly host topicspecific networks across the cancer care continuum that identify best practices, key resources and gaps in those fields. The UICC Cancer Prevention Network is the first network to bring this concept to life and encourages others to take a similar leadership role. To view the portal and provide suggestions for resources and/ or cancer plans, visit www.iccp-portal. org or contact email@example.com to find out more. Spring 2014 Volume 6 Issue 1
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Global Initiative for Cancer Registry Development This multi-agency initiative led by the International Agency for Research on Cancer (IARC) was launched in 2011 to expand the coverage and quality of data from population-based cancer registries (PBCR) in less developed countries, and to attain appropriate investment for such activities globally. National Cancer Control Plans should be based on accurate and reliable data sourced from population-based cancer registries. Currently, the existence of cancer registration worldwide shows large disparities between highincome and low- and middle-income countries; despite some good progress in registration activity in developing countries, the percentage of population covered by cancer registries in the reference publication Cancer Incidence in Five Continents, vol IX (2007), is 83% in North America and 32% in Europe, but only 6% in Central and South America, 4% in Asia and 1% in Africa1. Now in its operational phase, a series of IARC Regional Hubs for cancer registration are being rolled out in Africa, Asia and Latin America, with plans for the Caribbean and Pacific Islands. The objective of the hub is to ensure the sustained expansion of highquality PBCR by providing the necessary: • • • •
Mentorship and support Targeted training Guided research capacity; and Advocacy tools
For more information on the GICR: http://gicr.iarc.fr/ Palliative Care and Health Advocates’ Network Over the last three years, UICC has been working closely with a coalition of palliative care and health advocacy groups to highlight the urgent need for palliative care to be prioritised in the global health agenda. The World Health Organization estimates that there are 5 billion people living in countries with little or no access 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY
to pain medicines, including 5.5 million terminal cancer patients and millions of others suffering from acute or life-limiting illness, or approaching the end of life. The disparities between high- and lowand middle-income countries are vast and unacceptable. UICC therefore welcomed the recent decision to include palliative care in discussions at the 134th WHO Executive Board Meeting, and the ongoing efforts to develop a resolution for consideration at the 67th World Health Assembly. UICC will be working with its members and partners over the coming months to push for a comprehensive resolution to be adopted that will drive action at the national level to reduce barriers to the availability and accessibility of palliative care for cancer patients, including opioids for pain management. Evaluating Progress Towards the Targets Recent advocacy successes in the NCD arena have reaffirmed the importance and need for establishing a mechanism for monitoring and evaluating progress against the World Cancer Declaration targets. As such, UICC recognises that there is further work to be done in developing an agreed framework for measurement. Recent developments in the NCD arena have, however, provided us with a strong foundation on which to build. UICC members and partners welcomed the inclusion in the GMF and GAP of cancer-specific targets, indicators, and actions that are closely aligned with the Declaration; it represented a significant win for the cancer community. The nine global voluntary targets set out in the GMF, to be achieved by 2025, include: • A 25% relative reduction in risk of premature mortality from NCDs • At least 10% reduction in the harmful use of alcohol • A 10% relative reduction in prevalence of insufficient physical activity • A 30% relative reduction in prevalence of current tobacco use in persons aged 15+ years • Halt in the rise in diabetes and obesity • An 80% availability of affordable basic technologies and essential medicines
In addition to indicators for each of the above-mentioned NCD risk factors, the GMF outlines a set of cancer-specific indicators, including: • Cancer incidence, by type of cancer per 100,000 population • Access to palliative care assessed by morphine-equivalent consumption of strong opioid analgesics (excluding methadone) per death from cancer • Proportion of women between the ages of 30 and 49 screened for cervical cancer at least once, or more often and for lower or higher age groups according to national programmes or policies • Vaccination coverage against hepatitis B virus monitored by number of doses of Hep-B-vaccine (HepB3) administered to infants • Availability as appropriate of costeffective, affordable, HPV vaccines, according to national programmes and policies The emergence of new initiatives and partnerships in cancer prevention and control, including the GICR and ICCP, provide new opportunities for monitoring progress globally and have provided governments and the broader cancer community with mechanisms to monitor and evaluate progress against the Declaration targets 1 and 2 in particular. Nevertheless, in order to drive government action across the full cancer care continuum reflected in the Declaration, there are still a number of areas in which further work is needed by the cancer community to develop, agree and advocate for global recognition of additional quantifiable targets and indicators, particularly in relation to health systems strengthening, quality treatment and care, and human resource development for cancer prevention and control. In order to advance this work, UICC plans to draw on the wealth of expertise and knowledge across the breadth of its membership and partners, to develop a comprehensive framework for the monitoring and evaluation of all Declaration targets. At the World Cancer Congress in 2016, UICC plans to share an Interim World Cancer Declaration Report, highlighting progress since the launch in 2006 using targets and indicators that have now been secured in the GMF, and pressing for improvements and additional measurables where needed. Spring 2014 Volume 6 Issue 1
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Work is already beginning in key areas: The Global Task Force on Radiotherapy for Cancer Control UICC’s Board of Directors has approved the convening of a Global Task Force on Radiotherapy for Cancer Control (GTFRCC) to bring together cancer leaders, radiotherapy professionals, industry partners, cancer control organisations, patient groups, economists, and enablers of healthcare change, to quantify the investment needed to provide equity in global access to radiation therapy, an essential technology that all cancer patients must be able to access. Radiation therapy is recognised as an essential tool in the cure and palliation of cancer, and is recommended in 52% of new cancer patients1. The task force will report on progress at the 2014 World Cancer Congress taking place in Melbourne, Australia.
Priorities for 2014 By more closely aligning the updated World Cancer Declaration with the emerging global NCD framework and post-2015 development discourse, UICC believes that the Declaration targets will resonate more widely, allowing the cancer community to reach out to non-traditional partners in the development, disability, education, employment and many other sectors for innovative partnership. The onus is now on the cancer community to build on this momentum and continue to expand its sphere of influence to push for national accountability for existing commitments within the Political Declaration on NCDs and the GMF, and to push for cancer to be mainstreamed in the post-2015 development agenda. More specifically, UICC encourages its members and partners to use the 2013 World Cancer Declaration: • To urge governments to implement policies and programmes that the cancer community knows will be successful if they are adequately resourced and embedded within national cancer and NCD plans. • To reach out beyond health ministries to gain the political backing of all sectors of government – using the Declaration together with resource-appropriate and culturally relevant examples of successful implementation of policies outside of health is critical to ensuring a whole-of-government response to the cancer crisis. • To continue pressing for cancer and other NCDs to be embedded within the next generation of internationally agreed development goals. About UICC UICC unites the cancer community to reduce the global cancer burden, to promote greater equity, and to integrate cancer control into the world health and development agenda. A membership organisation founded in 1933 and based in Geneva, UICC’s growing membership of over 800 organisations across 155 countries features the world’s major cancer societies, ministries of health, research institutes and patient groups. Together with its members, key partners, the World Health Organization, World Economic Forum and others, UICC is tackling the
growing cancer crisis on a global scale. For more information visit: www.uicc.org.
Dr Julie Torode, Deputy CEO / Director of Advocacy & Programmes, Union for International Cancer Control (UICC) In addition to managing the UICC flagship publications, the TNM classification series and the International Journal of Cancer, Julie has been instrumental in developing and instigating the UICC road map spanning global advocacy and five lead programmes. Julie also leads UICCs strategic relationships with key partners IARC (Global Initiative on Cancer registry Development), IAEA (PACT partnership) and WHO (joint work plan as NGO in official relations). Prior to joining UICC, she spent the last 10 years in Germany working in the pharmaceutical industry including Phase I-IV clinical research – with a particular focus on breast and ovarian cancers, professional relations management and working with patient groups in oncology. Dr Torode holds a PhD in organic chemistry from the University of Liverpool. Email: firstname.lastname@example.org
Rebecca Morton Doherty joined UICC in 2011 as Advocacy and Programmes Coordination Manager, and continues to coordinate UICC’s advocacy efforts in the non-communicable diseases (NCD) arena, with an increasing focus on the post-2015 development agenda. Rebecca has a BA Honours degree in political sciences from the University of Warwick, and a Masters degree in gender and development from the London School of Economics. Prior to joining UICC, Rebecca spent six years working in London and Geneva-based NGOs in advocacy and communications roles. Email: email@example.com
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The Future of Life Sciences and the Need to Innovate - Edinburgh BioQuarter Talks Tactics Edinburgh BioQuarter is a unique concept. It brings together scientists from the University of Edinburgh and NHS Lothian with commercial research companies to collaborate and accelerate the development of new drugs, diagnostic tools and medical devices to treat diseases. This huge enterprise has made Edinburgh a leading European destination for translational medical research, fast-tracking drug development from ‘bench to bedside’.
Sir Michael Woodruff in Edinburgh over 50 years ago.
companies, venture capital funds, and contract research organisations.
Today, there continues to be a strong and vibrant life science sector in Edinburgh and the Lothians, which together account for almost half of Scotland’s biotechnology industry. The development of the Edinburgh BioQuarter over the last few years perhaps epitomises the direction which the life science sector needs to take if Scotland is to remain a significant player on the world stage.
Since then the team has created eight new life science businesses. These include BioQuarter’s most recent spinout Edinburgh Molecular Imaging, i2eye Diagnostics - developers of the world’s first visual field analyser for children and vulnerable adults, and Aquila BioMedical, a pre-clinical contract research organisation for certain inflammatory and neurological disorders which has already won major contracts with global pharmaceutical companies. Only last month (February 2014), Epidarex Capital, a leading international early-stage life science venture capital fund, announced a £4 million Series A investment in Edinburgh Molecular Imaging (EMI). Scottish Enterprise’s investment arm, the Scottish Investment Bank, also participated in the round. EMI, an Edinburgh BioQuarter spinout company from the University of Edinburgh, is developing a pioneering optical molecular imaging (OMI) technology with the potential to address unmet needs in the diagnosis and monitoring of several major diseases.
Scotland has always been at the forefront of life science research, with Edinburgh playing a key role. From Lister’s discovery of antiseptic, Simpson’s discovery of chloroform, the creation of the first genetically engineered vaccine (for hepatitis B) to the cloning of the world’s first mammal, Dolly the sheep, Edinburgh has continued to deliver over the centuries. Medicine has always been strong in Edinburgh. Following the introduction of the NHS in 1948, Edinburgh University pioneered teaching for general practice; it was also the first university to enable nurses to gain degrees. A new way to administer anti-tuberculosis drugs known as the “Edinburgh Method” saw TB almost eliminated in Edinburgh within six years, while the UK’s first successful kidney transplant was carried out by Professor 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY
About six years ago the University of Edinburgh joined forces with Scottish Enterprise and NHS Lothian to create the Edinburgh BioQuarter. Its aims were to foster deeper links with industry through collaborative research, to create new companies based on Edinburgh’s research base, and to encourage a culture of commercialisation in the NHS and among academic researchers. A critical element in delivering these aims was to assemble a team of industrialists to work hand in glove with Edinburgh University’s College of Medicine and Veterinary Medicine and NHS Lothian. The Edinburgh BioQuarter Commercialisation team was subsequently born in 2010, pulling in experienced executives from international biotechnology and pharmaceutical
EMI’s highly innovative OMI technology revolves around the development of fluorescent imaging reagents that detect harmful processes deep inside the human body, at the bedside, in real time and at molecular resolution. The company’s initial focus is on lung conditions, but the technology is applicable to a wide spectrum of disease. The company’s approach has the potential to transform clinicians’ ability to diagnose and manage a number of serious respiratory conditions, including lung cancer, fibrosis, lung infections and acute respiratory distress syndrome (ARDS). EMI’s technology will address the pressing need for tests which can rapidly provide diagnostic certainty and reduce healthcare costs. Respiratory diseases kill one in five people in the UK and cost the NHS over £6 billion per year, with lung cancer being the most significant cause of mortality. Spring 2014 Volume 6 Issue 1
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EMI is based upon the worldclass translational research (spanning chemistry, biology, and medicine) of its three founders from the University of Edinburgh: Professor Mark Bradley (School of Chemistry), Professor Chris Haslett and Dr. Kev Dhaliwal (College of Medicine and Veterinary Medicine). These leading scientists and clinicians have already secured major translational research funding from the Medical Research Council, Wellcome Trust and the UK Department of Health to develop their highly novel discoveries. Funder Epidarex Capital’s close partnership with the University of Edinburgh and the Edinburgh BioQuarter is typical of its investment model of providing early-stage risk capital to top researchers and entrepreneurs who are developing highly innovative solutions for the global healthcare market. i2eye Diagnostics Ltd - winner of Scottish Enterprise’s ‘Best New Life Science Company in Scotland’ award in 2013 - has commercialised a visual field analyser invented at Edinburgh University and the Royal Hospital for Sick Children in Edinburgh. Visual field analysis is used to assess problems with the eye, visual pathways and brain. It can help in the diagnosis and management of a variety of conditions from stroke to head injury and brain tumour. The new device uses a technique called SVOP, or saccadic vector optokinetic perimeter, to monitor eye movement, which makes it easier to test those patients who struggle with existing tests that require a degree of patient input and understanding, such as young children or vulnerable adults. The US is an important and high priority market for i2eye. There are already research and evaluation instruments installed at key hospitals in Boston and Cincinnati, and the company is looking forward to rolling out its product to the mainstream US market during 2014. And these spin-outs are just the start, as the BioQuarter Commercialisation team’s pipeline of new life science companies continues to grow, with a further 13 potential spin-out businesses being created over the next couple of years. These include FibromEd which generates hepatocytes, liver cells, for drug toxicity testing based on Edinburgh’s excellence in www.ipimedia.com
stem cell biology. Also in the pipeline are firms focused on drugs for the treatment of rare kidney diseases, an enterprise pursuing new drug formulations to treat cancer pain, and a medical imaging company developing a next-generation clinical diagnostic imaging technology. On the industrial collaboration front, the team has also delivered a number of key research agreements with major international biopharmaceutical companies including UK-based GlaxoSmithKline and Astra Zeneca, USbased Biogen Idec and Belgium-based Galapagos. Collaborations are also in place with the Crack-it consortium, led by Johnson & Johnson (US), as well as a research programme for fibrosis with Galecto Biotech AB (Sweden) and with Indianapolis-headquartered Eli Lilly And Company to develop novel screening tools. Biogen Idec is working with experts from the University of Edinburgh to seek greater insight into the biological causes of multiple sclerosis and motor neurone disease. This three-year collaboration will combine the University’s expertise in inflammation, neurology and regenerative medicine with Biogen Idec’s strength in drug discovery and development to seek new cures for these devastating diseases. An additional partnership with Eli Lilly in oncology was also recently announced. This brings the company together with Edinburgh University researchers to collaborate on novel cancer mechanisms. The Edinburgh Cancer Discovery Unit (ECDU) will provide Lilly with access to
the EDCU’s highly specialised biology models to potentially gain additional insight into the mechanism of action of some of Lilly’s anti-cancer drugs in development. And only last month (February 2014), the University of Edinburgh and GlaxoSmithKline agreed a collaborative partnership to discover and develop medicines with the potential to treat liver disease – the fifth biggest killer in the UK. This alliance – the second of its kind between the University and GSK - will see University researchers working alongside GSK scientists to develop new treatments for liver disease. Through a number of experimental approaches, University researchers have identified a mechanism important in the treatment of chronic liver disease (fibrosis or cirrhosis of the liver) – and in partnership with GSK, the aim is to expedite this into drug discovery and translation of a new medicine into the clinic. Both the liver collaboration and an ongoing collaboration between the University and GSK on pancreatitis were formed through GSK’s Discovery Partnerships with Academia (DPAc) initiative. The goal of this initiative is to bring together the complementary skills from academia and GSK into partnerships that could translate innovative academic research into medicines for patients. In addition, Johnson & Johnson Innovation has established a network of partnering offices across UK life science INTERNATIONAL PHARMACEUTICAL INDUSTRY 35
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which we tackle healthcare needs and treat disease – provided we put in place processes and resources to identify and support it. Scotland is a small country, but punches well above its weight in the life sciences. Major projects such as the Edinburgh BioQuarter not only help Edinburgh, but act as a window to the rest of the country helping to ensure that Scotland remains at the forefront of medical science and that the discoveries and innovations made by Scottish scientists continue to deliver benefits to patients around the world.
clusters – including a base at Edinburgh BioQuarter.
difficult airways in anaesthetised patients during surgery.
Further deals are on the way and bit by bit, Edinburgh is building its reputation as a world-class academic medical centre that the pharmaceutical industry wants to work with. People see the deal flow that comes out of the University and recognise that because Edinburgh BioQuarter is working with large multinationals such as GSK there must be something here. The buzz about what BioQuarter is doing and achieving is helping secure more collaborations. It also means the venture capital community sees these partnerships and the company spin-outs, and is increasingly finding Edinburgh a place of interest.
A key part of BioQuarter’s strategy to translate research into patient benefit is the availability on the BioQuarter campus of a business incubation centre, ‘Nine’, which opened in 2012. It offers office and laboratory space for both newly-formed companies and established leaders in the biopharmaceutical industry seeking close proximity to the clinical research assets on site. Nine is now home to 13 companies and that number is set to grow as the research community at the BioQuarter continues to expand.
The Commercialisation Team also supports an annual BioQuarter Innovation Competition which was launched in 2011 to generate new ideas from staff and students within the University of Edinburgh and NHS Lothian for products and services that benefit human health. The competition has already produced more than 100 new product or business concepts. Tissuestik, a company proposition with a new concept for reducing contamination in human tissue samples, won the first prize in Edinburgh BioQuarter Innovation Competition in 2012, while the winners of the 2013 Innovation Competition were a team of anaesthetists based at the Royal Infirmary of Edinburgh. Their concept was the introduction of novel safety features to a commonly used medical device, to improve the management of 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The BioQuarter Commercialisation Team is part of a larger, 25-year project of expansion on the site involving the University, NHS Lothian and industry as the biocluster grows. Over the next five years, BioQuarter expects to be home to more than 2000 researchers, working in areas such as stem cell therapy at the Scottish Centre for Regenerative Medicine, and on new therapies for MS and related conditions at the Anne Rowling Regenerative Neurology Clinic. New research centres planned on site include The Brain and Body Institute and the new Royal Hospital for Sick Children from 2017. Edinburgh BioQuarter’s ultimate vision is to build a community, where scientists, clinicians, industrialists and patients come together to create an ecosystem where innovation and commercialisation go hand in hand. The scale of innovation within the health service and academia is vast and could transform the way in
Dr Mike Capaldi followed his PhD in Medical Biophysics (Manchester), with a two year post-doc at the RPMS, Hammersmith Hospital, eventually moving into industry in 1984 joining Ciba Geigy’s Advanced Drug Delivery Research Unit. In 1987 he moved into sales and marketing at SmithKline & French and has followed a commercial career in the biopharmaceutical industry working in the UK, USA and Europe. He has since held board positions in listed and start-up companies including Nycomed Amersham plc, Core Group plc, Oxford Asymmetry plc, Synaptica Ltd, Scancell Ltd, Hunter-Fleming Ltd and CMP Therapeutics Ltd (in the latter four companies as CEO). Dr Capaldi is also currently Chairman of Stealthyx Therapeutics and a director of Synaptica, Roslin Cells and Support4Bio. Mike has extensive experience of raising capital from private and public markets having helped raise over $60M since 1997 including an IPO of Core Group plc on the LSE. He also has extensive deal making experience most recently having completed the sale of HunterFleming to Newron Pharmaceuticals in 2008. He joined Edinburgh BioQuarter as Director in early 2010. Email:mike.capaldi@edinburghbio quarter.com Spring 2014 Volume 6 Issue 1
WELCOME TO EDINBURGH BIOQUARTER
Designed to foster scientific creativity and encourage entrepreneurship among clinicians and researchers, BioQuarter combines world-class research from Edinburgh University’s College of Medicine and Veterinary Medicine with the long tradition of clinical excellence at NHS Lothian. Building one of Europe’s most significant concentrations of clinical and research assets, BioQuarter brings together a major teaching hospital, medical school and three leading research institutes in one location. Over the last three years our experienced Commercialisation Team has spun out seven new life sciences businesses and negotiated a number of major industrial collaborations, as well as generating 100 new product or business concepts from its Innovation Competition.
To find out more about how this commercialisation partnership is building on Scotland’s successes in life sciences, visit www.bioquarter.com
EDINBURGH LAUNCHES WORLD’S FIRST VISUAL FIELD ANALYSER FOR CHILDREN
In March 2012, Edinburgh BioQuarter launched i2eye Diagnostics Limited, creators of the world’s first visual field analyser for children and hardto-test patient groups. Based on research undertaken at the
University of Edinburgh and NHS Lothian, this device enables young children’s field of vision to be tested accurately for the first time, helping to pick up retinal and optic nerve defects as well as certain forms of brain cancer. Backed by private venture capital, the company, which has taken up premises in our incubator building – Nine, the BioQuarter – is already generating lots of interest and is looking to roll out its product to the mainstream US market during 2014. www.i2eyediagnostics.com
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Doesn’t the Human Immune System Deserve Human-specific Vaccines? For obvious reasons the human immune system is probably the most studied immune system of all species. Tools are available to detect almost any known cell and almost any known protein or receptor on the cell surface and inside these cells. The second most studied immune system is probably that of the mouse, not because of homology with the human system, which is only 75% (www. eupedia.com), but because this species allows for easy access to in vivo models. Murine models are available as inbred mouse strains with special features and/ or as transgenic and knockout models. Clearly such models are not readily available in other non-rodent species. Are murine in vivo models helpful? Yes, they are indeed very helpful, e.g. to study basic interactions between genes, proteins and phenotype, e.g. to support basic research that goes beyond in vitro interactions. They are also useful to generate tools such as (human-) monoclonal antibodies. But are they also helpful as disease models for drug development? Well, this question is much more difficult to answer, because it depends on the disease of interest and on the type of drug that will be developed. However, in at least two important therapeutic areas, oncology and allergy, the value of mouse models is at least questionable. In general, development of biologics specifically interacting with human receptors/proteins is difficult in rodents. One would need to create a transgenic model of each individual receptor type that is being studied; in addition the animals are not allowed to make an immune response against the foreign proteins, limiting the model to be expressed in immune-deficient animal strains. Very complicated and rather un-physiological models are the result. However, not only are biologics difficult to develop in mice, but also the development of classical “small molecule” compounds is limited by the differences between rodents and man. More than 70% of all “small molecule” drugs reaching in vivo proof of concept in rodents, and subsequently moving forward into clinical development, fail in clinical Phase II. The
statistics for biologics are a little better. Companies developing drugs that fail in clinical Phase II lose at least 10 million € spent on research to develop the drug up to Phase II, and 4-5 years of patent life. Very often drugs are abandoned at this stage; they don’t get a second chance. Clearly this calls attention to the need for better in vivo models - models which are much more predictive of human response in the clinic. In some cases these models are available, but they require the use of a species evolutionarily close to humans: non-human primates. Obviously the use of these higher animals needs very careful evaluation at every level, not only ethically and scientifically. Before starting in vivo trials, alternative in vitro assays need to be explored. In the last decades the need for humanspecific animal models has been realised and accepted by official regulatory authorities such as the FDA and the EMA and with the help of the EU and local government grants specific research centres, such as the Biomedical Primate Research Centre (BPRC) in Rijswijk, the Netherlands, are able to offer support for (biotech) companies focusing on humanspecific medication. Human-specific Vaccines for Allergy: In order to understand why mouse models are of little clinical value in the field of allergy, the immunological differences between humans and rodents have to be highlighted. a. Allergy, pathology and immune deregulation: Allergies affect up to 30% of the Western population (www.waojournal.org). Allergic diseases are predominantly hereditary and based on an unbalanced immune response to otherwise harmless environmental stimuli, usually proteinbased antigens. Antigens that cause allergy are called allergens. In many cases, allergic diseases increase in severity over time while, in addition, spreading from one allergy to multiple allergies1, a process called the “allergic march”. Therefore, when an allergy is diagnosed, therapeutic intervention is required as early as possible to maximise therapeutic success rates and to stop this “allergic march”.
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Strictly, allergy comes as immediate (type I) and delayed (type IV) hypersensitivity. Type I allergy, which is dominant in e.g. hay fever, is characterised by excessive activation of certain white blood cells, mast cells and basophiles, by a type of antibody known as IgE, resulting in an immediate and extreme inflammatory response. In other, more severe, allergic diseases such as allergic asthma and atopic eczema, type IV hypersensitivity is more important. Type IV reactions are caused by IgE-mediated allergen uptake by dendritic cells (DCs)2 and leads to long-range activation of the local T cell compartment. In the lungs this leads to allergic asthma, whereas in the skin, IgE-mediated allergen presentation will cause atopic eczema3. Allergic diseases are controlled by allergen-specific T helper 2 (Th2) cells, which induce the production of allergenspecific IgE by B cells. The amount of IgE produced against allergens is directly correlated to the severity of the allergic disease (Figure 1); the more IgE, the more severe the allergic symptoms. Allergic reactions range from mild (allergic conjunctivitis, itchiness, and runny nose) and severe (allergic asthma, atopic eczema), to life-threatening (allergic asthma and anaphylactic reactions induced by e.g. wasp or bee venom). Patients may have mixed forms of allergic diseases, e.g. atopic eczema together with allergic asthma, and they also may be allergic to more than one allergen at the same time. In the Western world, the most important allergen for allergic asthma is found in the excrement of house dust mites (HDM). When an allergic asthma patient inhales HDM particles in his/her lungs, the inflammatory response caused by the release of histamine by mast cells and basophiles and/or by IgE-mediated allergen presentation by DCs will cause lower airway constriction and swelling of the lining tissue, leading to airway obstruction. In the early 1990s it was discovered that the binding structure for IgE on DCs was the high affinity receptor for IgE, which is also expressed on mast cells and basophils4.
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DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Figure 1: Relationship between serum IgE levels and allergic disease. b. What is wrong with mice? From the above it is clear that IgE is crucial for the pathogenesis of allergic disease. IgE binds to high-affinity IgE receptors and is important in effector functions as well as regulatory functions by means of antigen uptake and presentation by DCs. The DCs are the key players in the immune system. These cells determine the fate of T cell responses, polarising into Th1 / Th2 or reactive / tolerant. Mice do not express the high-affinity IgE receptor on DCs. Therefore, a human disease such as allergy that is largely mediated through this receptor expressed on antigenpresenting cells cannot be mimicked in this species. Very recently Sallman et al.5 produced a transgenic mouse that expresses the high-affinity IgE receptor on DCs. Indeed, the allergic responses in this mouse are much closer to the reactions seen in humans; still there are additional differences which have to be taken into account. For instance, where humans produce IgE together with IgG4 when B cells are stimulated with aCD40 + IL-4, mice produce IgE and IgG1. The difference between mouse IgG1 and human IgG4 is that the former can interact with CD32b on B cells, mast cells and basophils, whereas IgG4 does not bind to this receptor. CD32b is a low-affinity IgG receptor that provides negative feedback signals to the expressing cells, by downregulating the signalling of other receptors when they are co-crosslinked with CD32b. So, in case of an allergen being recognised by both IgE and IgG antibodies, each binding to a different epitope, the IgG1 of the mouse will prevent mast cell degranulation by co-cross-linking the high-affinity IgE receptor with CD32b, whereas human www.ipimedia.com
IgG4 will be not be able to do this. As a result the mast cell will degranulate as if no IgG was bound to the allergen. Hence mice are not truly allergic. Even in balb/c mice which are known for their Th2-biased immune responses, true allergic reactions do not occur. An example: three subcutaneous injections with a foreign protein formulated on alum will induce enormous IgE titers against the protein in this mouse strain, but at the same time very high IgG1 titers will be induced as well. Further contact with the antigen in these mice, e.g. by means of a fourth booster injection will not lead to a deadly anaphylactic shock thanks to the presence of the co-induced IgG1 antibodies. Humans with such high IgE titers would undergo life-threatening anaphylactic shock reactions when the immune system gets in contact with the protein, e.g. as can be seen in bee sting allergy. It is impossible to study the efficacy of disease-modifying drugs in complicated multi-factorial diseases such as allergic asthma, if the central cells of the immune system - the DCs - are left out of the equation and additional negative feedback loops exist which are not present in humans. In other words, mice are evolutionarily too far away from humans to give meaningful results. Mice are easy to get and relatively cheap, and there are many tools available, but this does not mean that the available models are good enough and that their use in drug development is justified. One has to be very careful in selecting the disease that can be addressed by a mouse model.
c. Alternative models? After having disqualified murine models for allergy, what is left? The most closely related species to humans are nonhuman primates. The immune system is >95% homologous to that of humans6;7. However, tools are limited and basic knowledge on specific immunological aspects in monkeys is still largely missing. Most tools (e.g. monoclonal antibodies) are human-specific tools which happen to cross-react with their monkey equivalent. Although this confirms the close homology between the species, it also hampers basic research. Many similarities are taken for granted without actually having been studied. In order to set up the right human disease models in non-human primates, and also understand their strong and weak points, basic research needs to catch up. As indicated above, several centralised primate research centres are now available for testing humanspecific drugs, but more money and effort should go into understanding the differences and similarities between the two closely-related species. Nevertheless, a decade ago three groups published realistic allergic asthma models7 in nonhuman primates6;8;9. This was the basis and a prerequisite for founding S-TARget therapeutics in 2010, which develops vaccines on the basis of the human specific S-TIR™ technology platform (Specific T cell Immune Remodeler). Without an in vivo model to obtain in vivo proof of concept, there would be no point in developing drugs with this platform. Human-specific Vaccine in Practice S-TIR™ vaccines are comprised of active ingredients that work together in a twomodule system: a proprietary generic module (“warhead”) and a proprietary disease-specific module (“immunogen”) linked by high-affinity connectors. In short, the warhead ensures specific delivery of the immunogen in a non-toxic manner to those cells that adjust and (re-)programme the patient’s immune response: plasmacytoid DCs (pDCs). In addition, the warhead strongly boosts and defines the therapeutic effect of the drug. The immunogen, loaded with the disease-specific information, stimulates specific T cells which, in the case of allergy, are consequently converted from allergic Th2 cells into healthy normal Th1-cells triggering a normal immune reaction in future contact with the natural allergens. In the case of tumourspecific information being packed into the immunogen, tumour-specific T and INTERNATIONAL PHARMACEUTICAL INDUSTRY 39
the automation solution
AS A worlD leADer in AUtomAteD ASSemBly mikron oFFerS A level oF eXpertiSe UnmAtcheD in the phArmAceUticAl AnD meDicAl Device inDUStrieS. we mAnAge proDUction proceSSeS AnD gAmp 5 certiFicAtion StAnDArDS For Both high AnD low volUmeS
AmericA: Denver (USA) - ASiA: SingApore , ShAnghAi (chinA) - eUrope: BoUDry (SwitzerlAnD)
Mikron Automation is a world leader in automation solutions
for assembled products you can hold in your hand. Its mission is to deliver the most reliable, precise and productive assembly solutions to keep its customers one step ahead of the competition. Renowned companies around the world place their trust in Mikron – for precision, performance and success. Grown from the same roots as the Swiss watch-making industry, the story of Mikron Automation starts at the beginning of the 20th century with the foundation of Haesler, a company specialized in the construction of machining systems for the watch industry. Following its takeover by Mikron in 1961, the company began producing its first assembly systems back in 1976. Since 1991, the Mikron Automation division has focused completely on assembly automation.
Close to 40 years’ experience and 3000 installations, with a long history of delivering successful customized automation solutions and it also has the crucial advantage of being close to its clients, wherever they are. We serve global customers in different markets: Pharma/ Medical devices, automotive, Electric/Electronics, Industrial/ Building and Consumer goods. Mikron Automation: The assembly solution for pharmaceutical and medical devices Mikron Automation continuously innovates to supply the best automated assembly and test solutions for devices such as inhalers, safety syringes, pen injectors, auto-injectors, e-devices, test and diagnostic kits, lancets and pumps. Mikron Automation is a leading manufacturer of customized, highly productive automation solutions for high-precision assembly and testing from the pilot line up to the automatic line. Mikron’s core competencies are the use of highly standardized manual, semi-automatic and fully automatic modules through its Mikron G05 and Mikron EcoLine platforms and its expertise in complex process integration. Mikron adds value with the use of Polyfeed, the flexible feeding system, and the Tray Handler, for loading and unloading parts from trays.
The solutions operate at speeds of up to 100 cycles/minute with outputs up to 500 parts/minute. The entire family of Mikron products takes into account the special conditions for cleanroom ISO 7 (class 10,000) applications. Customer Service - After installation, our customized training and production assistance introduces your people to the feel and function of the new system, increasing productivity by improving the learning curve. Our support continues with remote maintenance tools, a service hotline, and the expertise of our technicians who arrive at your site to personally provide support throughout the entire service life of your assembly solution. Pharma and Medical Competencies The pharmaceutical and medical device industries are governed by exceptionally stringent regulations and production processes which need to be verified by means of strict procedures. To meet these specific needs, Mikron offers full qualification support in accordance with GAMP-5. Specific emphasis has been put on ergonomics and cleaning of tooling to meet the GMP norms. Mikron has a dedicated and skilled team with medical project expertise to support the project team from design to delivery. Mikron produces a set of documentation in accordance with FDA, GMP and GAMP-5 guidelines, to support the customers in their validation process. At a glance • Mikron Automation is a leading global manufacturer of automation solutions for cost efficient manufacturing of products in high quantities • Worldwide presence to support our clients locally • Facilities in Boudry (Switzerland, headquarters), Berlin (Germany), Denver (USA), Singapore and Shanghai (China). • 554 employees • CHF 101 million in annual sales revenue (2012) • Close to 40 years of experience • 250 customers worldwide • 3000 installed systems • Over 40 projects a year • 4 to 12 months delivery time • Every day 45,000,000 components are assembled on Mikron solutions Web: www.mikron.com/automation Key Contact: Jean-François Bauer / Head of Marketing & Business Development Mikron Automation Email: firstname.lastname@example.org
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
B cells will become activated. Under normal conditions, these tumour-specific T and B cells are anergic or tolerant to the tumour-associated antigens - in fact they are auto-antigens - but thanks to the warhead, tolerance to these tumourassociated antigens is transiently broken. The T cells will provide help for the (re-) activated tumour-specific B cells leading to IgG antibody production as well as to the induction of cytotoxic T cells (Tc) which will differentiate into Tc effector cells, and in addition will contribute to eradicating the tumour. How does this work in detail? The generic module “warhead” is designed to combine three major elements and functions 1. Binding to pDCs through specific interaction with FcγRII (CD32), which facilitates enhanced and specific uptake of the vaccine by the relevant professional antigen-presenting cells (APCs). pDCs are a rare subset of circulating DCs which can be found in blood and in peripheral lymphoid organs and which express both CD32 and TLR9. 2. Triggering of pDCs to produce large amounts of Th1-inducing cytokines through a specific interaction with the Toll-like Receptor 9 (TLR9), which therefore serves as intrinsic “adjuvant”. 3. High-affinity binding to the immunogen through a specifically designed dimerisation motive that connects with its counterpart in module 2. The disease-specific module “immunogen” combines two basic elements which are similar but not identical in oncology and allergy vaccines. In allergy, these functions are: 1. Stimulation of allergen-specific Th1 cells by pDCs, through the presence of “shuffled” allergen epitopes. The epitopes are shuffled to prevent interaction with allergen-specific IgE, which may otherwise lead to the induction of an anaphylactic shock. 2. High-affinity binding to the warhead through a specifically designed dimerisation motive that connects with its counterpart in module 1. In oncology there are three functions for the immunogen: 1. Re-activation of (anergic) Th and Tc cells by presenting the auto-antigens
on HLA class I and II molecules on the surface of simultaneously TLR9 activated pDCs. 2. High-affinity binding to the warhead through a specifically designed dimerisation motive that connects with its counterpart in module 1. 3. Recognition of the auto-antigen by auto-antigen-specific (anergic) B cells. So far two human-specific vaccines based on the S-TIR™ technology platform have been tested in vivo in Cynomolgus monkeys: first, S-TARget’s SG100 was able to significantly improve early- and late-phase clinical asthma symptoms induced by house dust mite inhalation in 5 out of 8 animals suffering from chronic severe allergic asthma. Second, OncoQR’s TYG100 (product outlicensed to TYG Oncology Ltd) was able to induce very high titers of neutralising antibodies against autologous gastrin (G17) in Cynomolgus monkeys. Neutralising G17, the growth factor for pancreatic cancer cells, was validated in clinical trials about 10 years ago by Aphton Inc10. Unfortunately their vaccine (Insegia) was not approved at the time, because immunogenicity was found to be too low with only 40% of the treated patients producing clinically relevant antibody titers that correlated with survival prolongation. In addition there was a dose limitation for Insegia due to adjuvant-related severe local injection site side-effects. TYG100 induced 200fold more anti G17 IgG than Insegia ever did, and had a 100% immunogenicity score, in the absence of side-effects. In addition, the high IgG titers against G17 were reversible and renewable, indicating that it is possible to fine-tune the immune response induced by the human-specific vaccines based on the S-TIR™ technology platform. References 1. Mudde,G.C., R.Bheekha, and C.A.F.M.Bruijnzeel-Koomen. 1995. Consequences for IgE/CD23 mediated antigen presentation in allergy. Immunol. Today 16:380-383. 2. Mudde,G.C., F.C.Van Reijsen, G.J.Boland, G.C.De Gast, P.L.B.Bruijnzeel, and C.A.F.M.BruijnzeelKoomen. 1990. Allergen presentation by epidermal Langerhans’ cells from patients with atopic dermatitis is mediated by IgE. Immunology 69:335-341. 3. L a n g e v e l d - W i l d s c h u t , E . G . , P.B.Bruijnzeel, G.C.Mudde, C.Versluis, A.G.Leperen-Van Dijk, I.C.Bihari, E.F.Knol, T.Thepen, C.M.Bruijnzeel-
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Koomen, and F.C.Van Reijsen. 2000. Clinical and immunologic variables in skin of patients with atopic eczema and either positive or negative atopy patch test reactions. Journal of Allergy & Clinical Immunology 105:1008-1016. Rieger,A., B.Wang, O.Kilgus, K.Ochiai, D.Maurer, D.Födinger, J.-P.Kinet, and G.Stingl. 1992. FcRI mediates IgE binding to human epidermal Langerhans cells. J.Invest.Dermatol. 99:30S-32S. Sallmann,E., B.Reininger, S.Brandt, N.Duschek, E.Hoflehner, E.GarnerSpitzer, B.Platzer, E.Dehlink, M.Hammer, M.Holcmann, H.C.Oettgen, U.Wiedermann, M.Sibilia, E.Fiebiger, A.Rot, and D.Maurer. 2011. Highaffinity IgE receptors on dendritic cells exacerbate Th2-dependent inflammation. J Immunol. 187:164-171. Van Scott,M.R., J.L.Hooker, D.Ehrmann, Y.Shibata, C.Kukoly, K.Salleng, G.Westergaard, A.Sandrasagra, and J.Nyce. 2004. Dust mite-induced asthma in cynomolgus monkeys. J.Appl.Physiol. 96:1433-1444. Coffman,R.L. and E.M.Hessel. 2005. Nonhuman primate models of asthma. J.Exp.Med. 201:1875-1879. Yasue,M., S.Nakamura, T.Yokota, H.Okudaira, and Y.Okumura. 1998. Experimental monkey model sensitized with mite antigen. Int.Arch.Allergy Immunol. 115:303-311. Schelegle,E.S., L.J.Gershwin, L.A.Miller, M.V.Fanucchi, L.S.Van Winkle, J.P.Gerriets, W.F.Walby, A.M.Omlor, A.R.Buckpitt, B.K.Tarkington, V.J.Wong, J.P.Joad, K.B.Pinkerton, R.Wu, M.J.Evans, D.M.Hyde, and C.G.Plopper. 2001. Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae). Am.J.Pathol. 158:333-341. Gilliam,A.D., P.Broome, E.G.Topuzov, A.M.Garin, I.Pulay, J.Humphreys, A.Whitehead, A.Takhar, B.J.Rowlands, and I.J.Beckingham. 2012. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 41:374379.
Dr. Geert C. Mudde received a Ph.D. in immunology from the University of Utrecht in 1985 and joined the pharmaceutical/ biotech industry in 1992. Dr. Mudde (co-) founded f-star GmbH in 2006 and is founder and serves as CSO of S-TARget therapeutics GmbH (2009) as well as OncoQR ML OG which was founded in 2013. Email: email@example.com Spring 2014 Volume 6 Issue 1
FROM THE GENE TO THE DRUG Over 30 Years of Experience in GMP
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GLYCOTOPE Biotechnology is your one-stop service provider for the development of biotherapeutics with a dedicated focus on glycosylation.
GLYCOTOPE Biotechnology GmbH | Czernyring 22 | D-69115 Heidelberg | Germany | phone: +49 (0) 62 21-91 05-0 fax: +49 (0) 62 21-91 05-10 | email: firstname.lastname@example.org | www.glycotope-bt.com
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Why the Need for New Technology in Bio-pharma R&D? New molecule development requires pilot-scale studies which need small volumes of material to support drug product development. The batch size for the manufacture of the clinical trial material is typically a few litres and the quantity of the bio-pharma active ingredient required is also small, but due to operational inflexibility in the traditional process, cost-saving is not possible. Traditional technology upgrading is also insignificant for scientists designing or upgrading systems for improving processing efficiencies and throughput time.
take an additional four hours or more.
Drug companies nowadays are focusing more on bio-pharma product development. Currently, there are close to 400 biotechnology drug products and vaccines in clinical trials, which are targeting more than 150 diseases. Companies need to manufacture their product candidate under current good manufacturing practice (cGMP) conditions to conduct clinical trials. R&D cost in bio-pharma is high and there is a need for more efficient technology as biologics manufacturing is complex and highly regulated by the FDA.
Facilities Maintenance A biologics plant is extremely complex, and requires continuous investment in infrastructure for maintenance and cleaning of traditional equipment, which would add to overall costs. Bio-
“Bio-pharma R&D efficiency will be improved with the implementation of single-use technology through risk contamination [and] fast changeovers, as well as reduction in overall costs for running a facility.” Director, large bio-pharma company Major Challenges Encountered by Biopharma Companies: Process Inefficiency In the traditional process, fluid transfer has been handled through product piping, stainless steel vessels, routing manifolds and valves. Such equipment needs to be cleaned and sterilised for validation before being re-used in the upstream and downstream process. i) A CIP (clean in place) process cycle for vessels ranging from 100 to 1000 litres takes between two and four hours. ii) An SIP (steam in place) process cycle with steaming, vessel cooling and hydrophobic filter integrity testing will
Process Safety Large bio-pharma companies are losing critical time; in some cases it has resulted in a delay of six to 12 months, leading to disruption in large pharma R&D and manufacturing facilities. There has been an increase in warning letters to major bio-pharma companies in the past three years. GMP (good manufacturing practice) deficiency from biopharmaceutical plant audits is linked to cross-contamination, which represents 15% of total deficiencies.
pharma raw materials include active pharmaceutical ingredients which are very costly, and most of the time remaining material is left in the bottom of vessels, pipes or filling lines, which adds to the overall maintenance cost. Long Construction Time The time required to develop new biomanufacturing capacity for a particular therapy requires huge investment, therefore there is need for new technology which reduces the time for a new facility to become operational. The average construction time is 2 - 3 years or more for a bio-pharma facility. The validation process for the new facility also takes several months for regulatory
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approvals, which will further delay the operations. Lack of Flexibility Plants are designed for specific product processes, i.e. in the traditional equipment process, flexibility is minimal in terms of designing or upgrading systems for improving processing efficiencies and throughput product time. A lot of time gets wasted in batch transformation for the cleaning and sterilisation of vessels to be next batch-ready for different products. “In future, single-use technologies (SUTs) would make up a large percentage of clinical testing in research and development (R&D).” Bioprocess International
Major Solutions by Adoption of Singleuse Technology are:1. Capital Investment Equipment: It will reduce the requirement of vessels for media buffer and product cleaning of containers for the bags and tube welders with single-use technology. E.g. a large Fortune 500 pharmaceutical company was able to save USD 1 million by implementing Xcellerex 2000L SUB in its Lexington plant in the US. Reduced floor area in the facility: The requirement for contained room areas is reduced with the use of tube fusing systems for making aseptic connections from bag to bag instead of making connections under laminar air flow (LAF) Spring 2014 Volume 6 Issue 1
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
achieving greater adoption in biopharma R&D. â€œContract research organisations (CROs) spent ~25% while biopharmaceutical companies spent ~15% on purchasing single-use bioreactors in 2012.â€? Bioprocess International
cabinets. E.g., disposable containers can be stacked up for maximum space saving within the facility.
just in time, thereby eliminating the raw material wastage for different batch products.
Validation Requirements: Installation, operational and performance qualification (IQ/OQ/PQ) time required for disposable technology in the commissioning phase of a new facility is considerably less than the time required for traditional equipment.
Safety: The single-use system bag technology eliminates the risk of crosscontamination. The bag technology functions in a closed circuit; there is no need for an air-vent filter moving towards the total-containment concept that the FDA prefers.
2. Operation Productivity: The disposable bag technology allows fast equipment turnaround time by fully utilising the cleaning, sterilisation and revalidation time being wasted in the traditional vessel cleaning process.
3. Regulation Global regulatory agencies (FDA, EMA etc.) are helping to promote adoption and understanding of single-use technology as SUTs enhance manufacturing efficiency with improved quality management systems in the bio-pharma production process.
Utility Consumption: With disposable technology there is no cleaning required, therefore the requirement for utilities such as water for injection, pure water, clean steam (only required for specific process equipment) and CIP chemicals is significantly reduced.
In the upstream process, there has been major adoption of disposable bioreactors, while in the downstream process, tangential flow filtration is
Large Bio-pharma Adoption Large bio-pharma companies want to reduce their production cost while also reducing the risk of over-production. Single-use equipment gives this flexibility to the pharmaceutical company. E.g. A large bio-pharma, which uses single-use technology in its manufacturing plant, has achieved operational effectiveness of 87% less expenditure on water and 30% less on energy through partnering with Xcellerex. Regulatory Development The FDA (US) and EMA (European Union) are encouraging single-use technologies from R&D to commercialscale as the risk of cross-contamination can be controlled with the help of specific single-use technology tools. Regulatory bodies are working on standardising single-use technologies for productive use, sustainability, acceptance and better evaluation criteria for leachables and extractables in the disposable equipment life cycle. Equipment Improvement There has been an increase in bundling between single-use disposable bag technologies and sensor technologies to provide customised solutions to the
Maintenance: The stainless steel vessels require regular maintenance, which is not required with single-use technology such as bag technology; also, annual validation requirements for CIP and SIP processes are greatly reduced. Labour: The labour costs for cleaning (CIP) and sterilising (SIP), as well as the utility cost for water, steam production for autoclaving, and cleaning chemicals, are significantly reduced or completely eliminated. Flexibility and Efficiency in Process: The size of the disposable bags can be adapted to a variety of batch sizes depending upon the different requirement in the buffers that can be made available www.ipimedia.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 45
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
General Manager, company
Consultant: “Enhanced operational and process monitoring capabilities benefit process development scientists by enabling operations such as perfusion and monitoring of additional cell culture parameters such as carbon dioxide, viable cell density, or optical density.” Director, Single-Use Processing Systems
end-users. In the upstream process there are new technologies being developed for increasing the scale of single-use bioreactors up to 10,000L along with increased level of development for system-based solutions, together with increasing the level of sophistication in the future. The use of single-use technologies in downstream processing is also gaining prominence, e.g. filtration, purification etc., due to significant improvements in process control techniques.
Supplier Capability Evolutions The suppliers are looking to reduce the risk of handling critical process operations and contamination, and reducing cycle time. Suppliers are scaling up their capability in the US and Europe as large bio-pharma companies are concentrating the majority of R&D and manufacturing in these regions. Catalent has replaced six stainless steel reactors with single-use reactors, mixers and tangential flow filtration skids in current and new manufacturing locations. Gallus has adopted a single-use XDRbioreactor for commercial manufacturing capacity expansion, and a small-scale 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY
bioreactor for the development lab. Single-use technologies (SUTs) now make up a large percentage of biopharmaceutical manufacturing, particularly in clinical testing and research and development (R&D). The industrial suppliers of disposable equipment are looking to reduce the risk of handling critical process operations and contamination risks, and save time.
Expert: “Service providers are starting to offer small- and large-scale equipment constructed of the same product contact materials. This helps to simplify the scaleup process and reduces the compatibility testing required.” Director, Product Development Services, CMO Procurement Manager: “Single-use manufacturing allows for dedicated equipment per batch to minimise the infrastructure requirements, lower the fixed costs associated with manufacturing, and ultimately strive to make targeted medicine a reality.”
References Secondary Sources: • h t t p : / / w w w . b i o i n f o . c o m / SingleUse_BioProcessIntl_2.2012. pdf • http://www.genengnews.com/ gen-articles/single-use-bioreactorroundup/4840/?page=2 • h t t p : / / w w w . americanpharmaceuticalreview. com/Featured-Articles/39300Adoption-of-Single-use-DisposableTe c h n o l o g y - i n - B i o p h a r m a Industries-Manufacturing-Economicand-Regulatory-Issues-to-Consider/ • h t t p : / / w w w . americanpharmaceuticalreview. com/Featured-Articles/37041Single-use-DisposablesTechnologies-in-BiopharmaceuticalContract-Manufacturing/ • http://www.outsourcing-pharma. com/Contract-Manufacturing/ Catalent-plans-single-use-overhaulof-bioreactors
Sarabjeet Singh Sharad is Lead Analyst with Beroe Inc., a global provider of customized procurement services specializing in sourcing, supply chain visibility, financial risk analysis and environmental impact to Fortune 500 organisations. Sarabjeet specializes in tracking various areas of drug development. He has worked on multiple projects for many Fortune 500 pharma clients in different categories such as Clinical, Preclinical and Product Development services. Sarabjeet earned his undergraduate degree in Bachelor of Pharmacy from Hemwati Nandan Bahuguna Garhwal University, Uttarakhand and postgraduated in MBA (Marketing) from ICFAI, Gurgaon. Email: email@example.com
Spring 2014 Volume 6 Issue 1
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Beyond Asthma and COPD interpretation, with the result that most pMDI users rarely breathe at the ideal flow rate. Although DPIs, with necessarily higher airflow resistance, are inherently easier to use correctly, performance still remains unimpressive with many marketleading products achieving operational efficiencies of only 25%.
In this article we look at the key drivers – commercial, technological and regulatory – fuelling current innovation, and consider the challenges that need to be addressed now. The launch of the first pMDI in the 1950s marked a significant stage in the fight against asthma and COPD. Sufferers were provided with a robust, portable and discreet device, relatively easy to use, sufficiently effective, cheap to produce, and which became readily accessible across the world. And the pMDI is still a significant market player. The widespread use of the DPI, launched in the late 1960s, has further strengthened a dominant market position which remains unchallenged to this day, demonstrated in recent findings by BCC Research, which claims that the global pulmonary drug delivery market will be worth $44bn by 2016. Most of this growth is coming from BRIC countries where cases of asthma and COPD unfortunately continue to climb rapidly, and where the next generation of inhaler devices for asthma and COPD will find a ready market. But these significant new markets are emerging just as many established products are coming off-patent, and as a result pharmaceutical companies looking 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY
to actively pursue these opportunities face an important decision: to replicate or innovate in order to gain market share? The dilemma is whether to create a fully substitutable device, eligible for shorter and significantly less costly clinical trials and therefore a faster route to market, or to invest in new, innovative solutions which could reshape the market in the longer term. The global market is now so large that many players can profitably coexist for some time – but as regulation evolves in order to push improvements and establish a baseline in inhaler performance, I believe that the optimal strategy is to innovate. Innovation allows the creation of new and better inhalers which can specifically address problems inherent in inhaler design. For example, coordination (especially among users of pMDIs) and technique have long been underlying concerns for regulators. A slow, deep inhalation is often required, but defining ‘slow’ and ‘deep’ is not only difficult but is also open to personal
Recent advances in the scientific understanding of the complex physics involved means that many new inhalers currently in development offer significant improvements in efficiency, so we can look forward to a step change in expectations as they reach and populate the mass market. These next-generation devices will also highlight the gulf between old technology and new approaches, putting further pressure on regulators and pharmaceutical companies to drive up standards. So far I’ve talked about trends in asthma and COPD, but many companies are now actively developing inhalers capable of delivering a much wider range of therapies. These include pain relievers or vaccines, and drugs required
to manage conditions such as cystic fibrosis and diabetes - applications where inhalers could offer significant benefits. For example, inhalers could deliver pain relief in seconds rather than minutes by exploiting the lungs’ incredible drug absorption speed - a regular headache or migraine could be addressed virtually immediately, but so could breakthrough cancer pain, radically improving quality of life. And benefits extend beyond the therapeutic. An inhaled vaccination, for example, would eliminate the need for clean, sterile needles; a dry powder Spring 2014 Volume 6 Issue 1
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
overdose. These (and many other) issues have to be thoroughly understood before pMDIs and DPIs can migrate fully into other applications, but the potential benefits and commercial opportunities are so significant that the effort will be worthwhile.
vaccine would not need to be chilled until used, greatly simplifying transport and storage; and clinicians could provide groups of users with single-dose inhalers, thereby speeding up a vaccination programme. The inhaler therefore offers a realistic alternative to tablets, which take time to metabolise, and injections, which users don’t like doing themselves. The technology is coming on in leaps and bounds, as is device design, and there is real desire in the sector to modify existing drugs, extend patents, and therefore create new market segments. But if such applications are to be realised then increased efficiency becomes even
more important, especially if the drug being inhaled – say an insulin dose or analgesic – could be life-saving, and even more so if the ‘wrong’ dose could be life-threatening. Dose composition, uniformity and delivery will come under much closer regulatory scrutiny, and as a result inhaler design will have to undergo considerable adaptation.
Typical asthma DPI formulations comprise mainly an inert carrier fraction, used simply to ‘dilute’ the few tens of micrograms of drug that is required for each dose, and to improve handling characteristics during production, due to the carrier’s larger particle size. But drugs such as insulin or pain relief therapies do not need to be diluted with a carrier fraction, due to the higher quantities of active drug required. As well as reducing cost and simplifying the filling process, this has marked implications on the technical requirements of the inhaler, as different mechanisms are needed to create a reproducible, respirable aerosol. The therapeutic indices of these drugs are also often significantly narrower than the usually wide therapeutic indices of drugs for asthma and COPD. As a result, even tighter controls will be needed to ensure the consistency of the delivered dose, and this is likely to be achieved by a combination of improved inhaler design, excellent human factors engineering, and clever particle engineering. Inhaler design will also have to accommodate different dosing regimes. Current DPI products deliver 60 doses (a typical month’s supply if delivered twicedaily), but new designs may have to deliver doses more frequently, in larger quantities or as single doses, or be ‘ready when / if needed’. As a result, different and improved feedback mechanisms are required so that users know when a dose has been delivered correctly, when the device needs to be replaced, and – crucially – to prevent unknowing
Alongside new application areas, an additional future driver is the need to adapt device design to individual user needs. Inhalers could be used across the whole population, from those with limited physical ability (as a result of their condition or their age) to those who are not even ‘ill’ – such as someone about to be vaccinated. As a result, devices will need to cope with user lung power that could range from just a few Watts to over 50 Watts. In response to these different, but equally valid, user needs, one strategy could be to use a central inhalation engine across a range of devices, from a disposable device for vaccinations to a capsule-based inhaler for pain management. This presents a very real opportunity to make best use of R&D budgets through technology reuse while also generating patents and other IP. With so many drivers converging, it is not surprising that inhaler technology is now at such an exciting stage. Decades of research, development, and user experience have created a body of knowledge which is leading to innovation in new and unexpected directions, guided by evolving regulations, and supported by constant technological improvements. Device design is changing in response to the current and future drivers influencing the market, and the most successful could have just as much – if not more – impact on global health as those launched over 50 years ago.
David Harris, Head of Respiratory Drug Delivery, Team Consulting. David heads up Team’s commercial activities and projects in respiratory drug delivery, utilising his scientific and engineering background. Email: firstname.lastname@example.org INTERNATIONAL PHARMACEUTICAL INDUSTRY 49
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Modifying MDI Canister Surfaces to Improve Drug Stability and Drug Delivery Hydrofluoroalkane (HFA)-based propellants are widely used in modern metered-dose inhalers (MDIs), due to their lack of hazardous and environmentallydamaging effects. However, an HFA’s active pharmaceutical ingredient can interact with the canister substrate, causing deposition of the drug to the canister walls, or interact with the solution, causing degradation and resulting in increased impurity levels. Over the past few years, a number of surface coatings have been developed that can be applied to MDI canisters and valve components, to protect the contents from deposition and degradation. More recently, plasma processes have been developed to modify and improve the surface energy performance of an MDI canister. This approach has a number of advantages to alternative coatings but requires careful optimisation to ensure the highest quality finish and MDI performance. Richard Turner, Business Development Director, Presspart Manufacturing Ltd, explains.
from those of the CFCs traditionally used in MDIs.
Metered dose inhalers are commonly used to deliver drugs for treating respiratory and nasal disorders. The drugs are administered by aerosol, in suspension or solution, with a liquefied gas propellant. For over 50 years, chlorofluorocarbons (CFCs) were the propellants of choice, but these have now largely been phased out, in line with the Montreal Protocol.1
Range of Coatings Applying a suitable surface coating to the MDI components improves the stability of the formulation as well as the product performance, and helps to extend the product’s shelf-life. A range of coatings have been developed that can be applied to both the canister and valve components to protect the contents from deposition and degradation.
Replacement propellants have been developed over the past two decades based on hydrofluoroalkanes (HFA), specifically HFA 227 and HFA 134a. These substances are not ozonedepleting, and are also non-flammable and chemically inert, making them ideal candidates for use in medical products. However, some properties of these compounds are substantially different 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The surface properties of a device can have an important effect on the device’s interactions with its most immediate environment and substances with which it comes into contact. As a result, the device’s surface chemistry has a vital role on the surface functionality and, therefore, overall performance of the device and drug. When HFA-MDI drug formulations are in suspension, interactions with the canister substrate can cause deposition of the drug on the canister walls or on exposed surfaces of the valve components. Interactions with solutions more commonly cause degradation, resulting in increased impurity levels. In both cases the interaction leads to a reduction in the drug content in the formulation, resulting in the patient receiving less than the prescribed dose.
Commonly used coatings include barrier coatings, such as anodisation of the canister, to change the surface characteristics and ultimately act as a protective barrier for sensitive formulations. Various low-surface energy coatings are available for suspension formulations. For example, a surface treatment has been specially developed for deep-drawn 5052 aluminium canisters and is suitable for budesonide HFA; new coating compounds have been developed that prevent certain HFA-containing drug formulations (for example, salbutamol) from interacting with the MDI and adhering to canister walls. Fluorocarbon polymers are commonly used to coat the interior canister surfaces to eliminate adhesion or deposition of
albuterol on canister walls; albuterol is widely used with MDI drugs, particularly beclomethasone diproprionate. Fluorocarbon polymers used in coatings are commonly made from multiples of one or more of a variety of monomers; particularly preferred coatings tend to be pure perfluoroalkoxyalkylene (PFA), and blends of polytetrafluoroethylene (PTFE) and polyethersulphone (PES), due to their relatively high ratios of fluorine to carbon. In addition, coatings that combine fluorocarbon polymers with non-fluorcarbon polymers (such as polyamides) are used for certain formulations to improve adhesion of the coating to the canister walls; other coating types include epoxy-phenol resins. Coating Techniques Standard metal-coating techniques can be used to pre-coat the metal substrate and cure it, prior to shaping the metal into the components (for example, through deepdrawing or extrusion). This pre-coating method has the advantage of being well suited to high-volume production. Other coating techniques include: spraying the insides of preformed cans; dipping; or electrostatic drypowder coating, followed by curing. Many of these processes require high temperatures (up to 400 °C when curing), which can create additional costs and complications. Furthermore, only the most robust canisters (that is, those produced through deep-drawing) should be subjected to such high temperatures, as less robust canisters can become unrolled or suffer other morphological changes under these conditions. Plasma Processing Technologies More recently, gas plasma-based processes have been developed to modify and improve the surface energy performance of an MDI canister. Gas plasma processing is an industrial technique that is carried out in a vacuum to coat a wide range of substrate materials. The process involves constant or pulsed excitation of gas by either radio frequency (RF) or microwave field to produce an energetic plasma. The process creates an ultra-thin layer that protects against degradation, Spring 2014 Volume 6 Issue 1
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More recently, an improved process has been developed that eliminates the issues associated with typical plasma system designs. Using proprietary gas/ monomer delivery configurations and electric field control (designed specifically for can coating geometry), uniform coatings can be deposited (Figure 1b).
Figure 1:- a) Traditional plasma processing does not ensure a uniform coating to internal wall of the canister. b) The new plasma process gives a uniform coating to canisters
deposition and corrosion. It is a lowtemperature process (<75°C for metallic substrates and <45°C for polymeric substrates), and is ideal for uniform treatments of components with complex shapes, including small components in large volumes. The coating adheres well to the component substrate, because the plasma process cleans the component surface while in the vacuum, resulting in an ultra-clean substrate-coating interface. Using gas plasma to tailor the surface chemistry has the advantage of providing uniform surface treatment without changing the properties of the bulk material. The process can be used to change the outermost layers of the material only, without polymerising a coating, resulting in modifications to the functional chemistry. These modifications can be used “stand-alone” or with the addition of a subsequent surface coating through a single process cycle, depending on the application and desired properties. Optimising the Plasma Process Plasma processing of MDI canisters can bring multiple benefits to the MDI performance, helping to reduce drug deposition and also to improve the stability of formulations where interactions with the aluminium substrate would lead to product degradation and reduced shelflife. However, plasma processing for MDI canisters needs to be highly controlled to ensure complete consistency of treatment and uniformity of coating to the internal walls of the canisters. Plasma chemistry is critical to the performance of the coated canisters – the right choice of precursor chemistry enables a robust process with excellent performance. A variety of plasma
54 INTERNATIONAL PHARMACEUTICAL INDUSTRY
treatments have been tried in the past, including single- and dual-layer technologies with a range of monomers, but these have failed to penetrate the market due to poor scalability and cost viability. However, alternative developments have become available that make plasma a real choice for MDI cans. A cost-effective process has been established using an optimised plasma chemistry consisting of an intrinsically robust monomer, highly ionised to form a high crosslink density. The ultra-pure gases and monomers do not contain any solvents, so do not produce any waste by-products. The result is a coating technology without the extractable issues potentially encountered with some polymer systems. It is critical that plasma processing achieves complete and consistent coating across the entire surface of the inside of the canister. Traditional plasma processes, RF or microwave, are particularly difficult to control when internal surfaces are to be treated. Poor penetration of plasma ions with low energy results in nonuniform, thin or porous coatings with poor performance. Increased ion energy to aid depth of can penetration gives rise to ion etching at the can neck and a more “line-of-sight” process. This partial “line-of-sight” process leads to non-uniformity/thickness variation in such geometries (see Figure 1a). For thin nanometre coatings on MDI cans this is observed as striations in colour or colour bands down the can. With the best compromise the coating builds up around the canister lip, throat and base, with depletion at the rim, shoulders and can corners.
Dedicated system design configurations mean constant, high deposition rates with extreme reproducibility in terms of coverage, chemical speciation and product performance. The unique combination of process equipment design and precursor monomer means the technology is now scalable to handle the throughput and commercial demands of the MDI world market. This process has been used to develop several different plasma coating options that successfully prevent drug deposition on the can walls, and prevent drug degradation in solution or suspension. Examples include surface treatments for budesonide, formeterol, fluticasone proprionate and beclomethane dipropionate, amongst others. Conclusions Gas plasma processing offers considerable advantages in the coating and treating of MDI canisters for improving the stability of the formulation and extending product shelf-life. In addition, the ability to plasma process high volumes of the canisters fulfils the high volume demand from the MDI market. References 1. Montreal Protocol on Substances that Depletethe Ozone Layer (http://ozone. unep.org) Richard Turner has spent the past 13 years with Presspart Manufacturing, currently as the Business Development D i r e c t o r Pharmaceutical. Presspart are part of the Heitkamp & Thumann Group, who currently manufacture more than 70% of the annual global requirement of pMDI cans and a host of other components for drug delivery devices. Email: firstname.lastname@example.org Spring 2014 Volume 6 Issue 1
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CNS – Still Sending Out the SOS? In 2006 I wrote that despite the billions of dollars of sales and billions of dollars of research spent on CNS research, there remained huge areas of unmet medical need.1 Currently, CNS drug sales are dominated by antipsychotics and antidepressants, and despite some leading drugs recently going offpatent, sales of branded drugs are still growing. Despite a growing trend for pharmaceutical companies to leave the CNS field, antipsychotic sales continue to grow, with $18.2 billion in sales in 2011, up $2.1 billion from 2010. In 2011, 57 million prescriptions were filled for antipsychotic drugs, up 2.4%, and, importantly, 60% were filled with branded drugs.2 Three drugs, Abilify, 1 ($5.2 billion in 2011 sales), Seroquel, 2 ($4.6 billion in 2011 sales), and Zyprexa, 3 ($3.0 billion in 2011 sales) account for more than 65% of the total $18.2 billion spent on antipsychotics. These statistics are intriguing as Zyprexa lost patent protection in October 2011 and Seroquel followed in 2012; Abilify falls to generic competition outside the United States in 2014 and within the United States in 2015.2 However, despite the large sales there still remains unmet need for patients. Table 1 shows the disease burden measured in disability-adjusted life years (DALYs). A DALY is a measure of overall disease burden expressed as the number of years lost due to ill-health, disability or early death. Not only do the CNS disorders have a large individual burden of disease; the numbers of patients affected by these conditions is very large indeed. For example, for the US it is reported that there are as many as 5 million Americans age 65 and older that have AD, and that number is expected to double for every 5-year interval beyond age 65.4 Bipolar disorder affects approximately 5.7 million American adults, or about 2.6 per cent of the US population aged 18 and older in a given year.5 Approximately 2.4 million American adults, or about 1.1 per cent of the population aged 18 and older in a given year, have schizophrenia.5 In addition, as many as one million Americans live with Parkinson’s 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Table 1: Global burden of mental, neurological and substance-use (MNS) disorder3
disease, with approximately 60,000 Americans diagnosed with Parkinson’s disease each year.6 Back in 2006 I discussed the challenges being faced by drug companies working in CNS.1 Here’s a summary of the main ones: •
Lack of knowledge of the basic biology of many common disorders, so that diagnosis is made by reviewing the symptoms and then ruling out other disorders if possible, so you are left with a “probable” diagnosis. This was typically the method of diagnosis for Alzheimer’s disease, schizophrenia, depression, bipolar disorder and Parkinson’s disease. This lack of knowledge on the biology then means that there are poor animal models or cell lines, as naturally you are making a model based on imperfect knowledge. The lack of knowledge on the biology has also meant that there are almost no biomarkers for disease progression, meaning all drug trials ended up having, by default, to be
designed around symptomatic changes. Whilst that is no bad thing per se, it does present challenges when these disorders present with many symptoms that fluctuate. The measurement of these symptoms is done by the use of rating scales; however, these scales, either questionnaires or subjective scoring of symptoms – often by the doctor or occasionally by the patient – were, in the main, not designed with the aim of being used in a clinical trial and subjected to complex statistical analysis. To reduce a complex multivariate disorder down to a single large number, made up of scoring multiple symptoms, and then to try and explain to regulatory bodies what a change of one or two points over six months actually means in terms of clinical benefit, is an almost impossible challenge faced by drug companies working in CNS. This is not a challenge faced in oncology, heart disease or diabetes, where shrinkage or disappearance of a tumour, or changing cholesterol or insulin to a normal range, is clearly related to a clinical benefit. Spring 2014 Volume 6 Issue 1
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Clinical trial design also presented enormous challenges, from selecting an end point from the many rating scales and sub-scales on offer, to decisions on the power of the study, the selected scales lacking sensitivity and inter-rater variability with subjective scales, so that designing a trial to demonstrate disease modification was almost impossible in most indications.
The list went on and on. So now we are in 2014, eight years later, and has the world in CNS changed? What have been the breakthroughs and the changes for patients, and is the need any closer to being met? What has changed is that there is much more collaboration and combined effort in approaching these diseases. Let’s look at a few examples. Alzheimer’s Disease There is certainly much more talk about Alzheimer’s disease (AD), in the general press as well as in the scientific field. Having a neurodegenerative disease such as AD means it is difficult for the patients to speak up for themselves due to their deteriorating condition and the cognitive changes this brings about. This is unlike the situation for sufferers of cancer or heart disease. Now families affected by AD and newly-diagnosed patients are more likely to speak out, and this has raised the profile enormously for AD. This has led to a spotlight being put on the relatively paltry amount of research funding that has gone into this field. For example, Alzheimer’s Research UK is the largest charitable funder of dementia research in the UK. In 2010-11 it invested £5.1 million. This is its highest investment to date, but if we compare it to the £332 million invested by Cancer Research UK, or the £120.7 million by the British Heart Foundation, the scale of disparity becomes clear.7 It is to be hoped that this increased profile can become a model for other indications such as schizophrenia, where there are millions of affected people but little awareness among the general public of how much of a burden this disorder is. While there is increased public awareness of AD, it is a sobering fact that no drug has been approved as a treatment for AD, or its symptoms, for over a decade. Not only that, but the 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Main patient population
Cognition at five years
Target engagement at two years;
Primary aim and duration
E280A carriers within 15 years of expected age of onset DIAN
mutation carriers, 15
years before and up to
a subsequent trial will assess cognition three years on
10 years after expected age of onset A4
Cognition at three years
patients with PETamyloid positivity Prevent*
A prospective cohort
Participants are children of
study to identify mid-
individuals with or without a
life biomarkers of late-
diagnosed AD allocated to high,
medium and low-risk groups
according to parental clinical status and ApoE genotype. The biomarkers examined over two years are plasma and CSF Aβ42 amyloid, Tau and pTau, proinflammatory cytokines, acute-phase proteins, medial temporal-lobe atrophy, white matter lesion volume, cognitive performance related to transentorhinal and hippocampal functioning and hypothalamicpituitary-adrenal and sympathetic axes regulation
Table 2: Summary of non-industry sponsored upcoming and current prevention trials in Alzheimer’s disease *Detected pathologies are communicated to the participant’s general practitioner with their permission. Risk status by genotype would not be revealed.API - the Alzheimer’s Prevention Initiative.11
last 10 years have been characterised by one negative AD study after another, such as Janssen/Pfizer/Elan’s widelytipped Bapinizumab8 and Baxter’s Gammagard,9 so you could be wondering if there is any hope on the horizon for AD patients? In response to these failures and the recognition of the scale of the challenge facing drug developers in AD, there is now a greater willingness for pharmaceutical companies to come together to share information and collaborate. Initiatives such as the Global CEO Initiative on AD have been created, including companies such as Pfizer, Lilly, Janssen and Sanofi as members. The mission of the CEO initiative is for “… the private sector to forge robust publicprivate partnerships to stop Alzheimer’s disease and dementia. Our vision is that the CEO Initiative becomes the leading business voice on this seminal public health issue of our time, which will
have profound impact in fiscal, social and political matters as we “change the game” on Alzheimer’s. By working together and in partnership with leading non-governmental organizations and governments, the CEO Initiative will identify and pursue research, therapy development, financing, and public awareness projects of the highest priority that, when achieved, can transform the global fight to stop Alzheimer’s disease.”10 Biology Playing Catch-up Another change is that the last decade has seen greater involvement of patient advocacy groups actually funding the clinical trials, as well as greater research money for trials from governments. There are three US studies currently being set up, either looking at altering the progression of the disease or preventing it. In addition, there is also a publiclySpring 2014 Volume 6 Issue 1
CLINICAL & MEDICAL RESEARCH
funded clinical trial in the UK looking at altering the mid-life risk factors of developing AD, called the PREVENT study. These studies are summarised in table 2. These trials are aiming either to alter the progression of, or prevent the development of symptoms of, AD, and so are either enrolling patients very early in the course of the disease or are seeking pre-symptomatic patients with a positive biomarker such as a gene that is considered to put them at risk, or amyloid plaques, detectable by imaging techniques. There is much still to be learned of the role of these biomarkers on the diagnosis of AD.15 But these clinical trials are being set up as seeking to find an effective disease-modifying treatment and also validate those biomarkers that have been proposed as being of relevance. This is a brave move. Patient Advocacy Groups Leading the Way It is not just in AD that patient advocacy groups are leading the clinical-based research. In Parkinson’s disease, patient advocacy involvement through charities such as the Michael J Fox Foundation, Cure Parkinson’s Trust and Parkinson’s UK are funding not just basic research, but are now funding ground-breaking clinical trials. In the UK, a trial in 36 patients with Parkinson’s disease will test an infusion of GDNF (Glial Derived Neurotrophic Factor) delivered directly into the brain by a pump and catheter that has been implanted into the brain, allowing delivery directly to the relevant sites in the brain. The study is being funded by Cure Parkinson’s Trust and Parkinson’s UK. Meanwhile, the Michael J Fox Foundation is funding a follow-on study of Exenatide in Parkinson’s disease. Commenting on the trial, the Foundation said “Currently there are no treatments confirmed to have beneficial effects on slowing or reversing the progression of PD. Identifying agents that can modify the progression of Parkinson’s represents the major priority for research in this field.” Learning from Rare Disorders Patient advocacy groups’ funding of clinical trials is already common practice in some rare diseases. It would seem that the large but neglected CNS indications are now following the path established by the rare or orphan diseases in order to get the result that patients want: a cure or a treatment that makes a difference www.ipimedia.com
to the condition. The advocacy groups drive the research agenda, and then with any luck drug companies will follow. As an illustration of how this is working in the rare disease field, the Parent Project Muscular Dystrophy (PPMD) was set up by Pat Furlough, a mother of two boys with Duchenne Muscular Dystrophy. Duchenne is the most common fatal, genetic childhood disorder, which affects approximately 1 out of every 3,500 boys each year worldwide. In 1994, Pat, together with other parents of young men with Duchenne, founded PPMD to change the course of Duchenne and, ultimately, to find a cure. When PPMD began their work, the level of investment in the Duchenne research field was nearly nonexistent. Over the years, PPMD has acted as a catalyst — funding research that is both promising and cutting edge. They were the first organisation to create a drug development initiative on validated targets (Project Catalyst) to invest in the generation of boys currently affected by Duchenne. As a result of their investment, the field is now ripe with promise and there are more than 30 drugs being followed in their therapeutic pipeline, with seven in Phases II and III.16 All these drug candidates have had research funding by PPMD. Conclusion In conclusion, it appears that we are now in a position where there is a greater recognition of the need for advances in major CNS disorders, as well as less stigma associated with having these disorders. The challenges that existed in 2006 largely remain; however, progress is being made to address these. There is a new willingness for pharmaceutical companies to share information and collaborate, and patient groups are now taking a lead in driving the research agenda so that the aim is a cure, or at least something that provides a clinically meaningful benefit to the patients. This is no bad thing, and it is to be hoped that this leads to faster progress. References 1. McGoldrick S. SOS from CNS. International Clinical Trials. 2006; Summer / Autumn: 44-7. 2. Lindsley CW. The Top Prescription Drugs of 2011 in the United States: Antipsychotics and Antidepressants Once Again Lead CNS Therapeutics. ACS Chemical Neuroscience. 2012; 3: 630-1. 3. Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, et al. Grand challenges in global mental health. Nature. 2011; 475: 27-30. 4. National Institute of Neurological Disorders and Stroke. Dementia: Hope Through Research. Accessed: 15 January 2014 http://www.ninds.
nih.gov/disorders/dementias/detail_dementia. htm National Institute of Mental Health. The Numbers Count: Mental Disorders in America. Accessed: 15 January 2014 http://www.nimh.nih.gov/ health/publications/the-numbers-count-mentaldisorders-in-america/index.shtml. Parkinson’s Disease Foundation. Statistics on Parkinson’s. http://wwwpdforg/en/parkinson_ statistics Accessed 15 January 2014. Alzheimer’s Research UK. Report: Defeating Dementia: Building capacity to capitalise research strengths on the UK’s research strengths 2012. Anon. Clinical Trials of Intravenous Bapineuzumab Halted (08 Aug 2012). Accessed: 16 January 2014 http://www.alzforum.org/news/researchnews/clinical-trials-intravenous-bapineuzumabhalted Carrol J. UPDATED: Baxter adds Gammagard to growing roster of PhIII Alzheimer’s failures (7 May, 2013). Accessed: 16 January 2014 http:// www.fiercebiotech.com/stor y/baxter-addsgammagard-growing-roster-phiii-alzheimersfailures/2013-05-07#ixzz2qZbMU0Ht Gobal CEO Initiative on Alzheimer’s Disease. Mission and Vision. http:// wwwceoalzheimersinitiativeorg/mission-andvision#sthashortX248a Accessed 15 January 2014. Reiman EM, Langbaum JB, Fleisher AS, Caselli RJ, Chen K, Ayutyanont N, et al. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis. 2011; 26 Suppl 3: 321-9. Moulder KL, Snider BJ, Mills SL, Buckles VD, Santacruz AM, Bateman RJ, et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res Ther. 2013; 5: 48. Alzheimer’s Disease Cooperative Study. Antiamyloid Treatment in Asymptomatic AD - The A4 Trial. Accessed: 16 January 2014 http://www. adcs.org/Studies/A4.aspx Ritchie CW, Ritchie K. The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer’s disease. BMJ Open. 2012; 2. Noel-Storr AH, Flicker L, Ritchie CW, Nguyen GH, Gupta T, Wood P, et al. Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia. Alzheimer’s & dementia: the journal of the Alzheimer’s Association. 2013; 9: e96-e105. EndDuchenne.org. Therapeutic Pipeline. Accessed: 16 January 2014 http://www.parentprojectmd. org/site/PageSer ver?pagename=Advance_ pipeline
Susan McGoldrick is a co-founder and Managing Director of QCTR Ltd. Susan is an experienced pharmaceutical executive having worked in various roles within the pharma industry. In 2006, QCTR was founded to fulfil the need of providing high-quality clinical research in the areas of neurology, psychiatry and orphan diseases. Email: email@example.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 59
CLINICAL & MEDICAL RESEARCH
The Anticipated Clinical Effect of the new Alzheimer Drug ANAVEX PLUS in a Predictive Humanised
Disease Background Today there is significant unmet medical need and heavy economic burden across multiple diseases characterised by cognitive impairment and dementia. In Alzheimer’s disease (AD), which is the most common form of dementia, currently available drugs provide limited and transient effects on cognition. Healthcare costs associated with the epidemic of Alzheimer’s, including nursing home care, will continue to grow dramatically from today’s $200 billion, more than cancer and heart disease combined, to $1.1 trillion in 2050, and new therapies with better and more durable efficacy are urgently needed. Dementia affects 820,000 people in the UK and 5.3 million Americans. Cognition-enhancing symptomatic programmes are hence very important to Alzheimer’s disease (AD). In addition, an estimated 80% of schizophrenia patients suffer from cognitive impairment and 1.3 million patients in the US suffer from Lewy body dementia. Currently there are no approved therapies for treating cognitive impairment in schizophrenia or for treating Lewy body dementia. ANAVEX PLUS, the proprietary combination of ANAVEX 2-73 (AV2-73) with donepezil, the most prescribed Alzheimer’s drug, combines cholinergic pharmacology with muscarinic and sigma-1 receptor activity, and can potentially combine symptomatic, neuroprotective and potentially diseasemodifying properties (Villard 2011; Lahmy 2013). The objective is to provide guidance for a Phase II dose-response of ANAVEX PLUS by utilising a predictive humanised calibrated cortical cognitive model for Alzheimer’s Disease, named the quantitative systems pharmacology (QSP) model in mild-to-moderate AD patients. Table 1 shows the Affinity values of ANAVEX 2-73 versus different human receptor subtypes. Note the relatively modest affinities of the compound for muscarinic receptors. This will lead to a limited effect on circuit properties, except for the M2 mAChR (muscarinic acetylcholine receptor) autoreceptor. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Table 1: ANAVEX 2-73 Pharmacology and Affinity Receptor Values Blocking this receptor increases presynaptically released Ach (acetylcholine), which has a symptomatic memory improvement effect.
Figure B shows that the network consists of 80 pyramidal cells (green) and 40 inhibitory cells (yellow) with about 10,000 synapses.
The Quantitative Systems Pharm acology (QSP) model of AD outlines the following: Figure A: QSP is a representation of the cortical cognitive model for Alzheimer’s disease. The membrane potential that is modulated by the effect of GPCR (G protein-coupled receptor) on the conductance of voltage gated ion-channels is calculated at a time resolution of 0.050 msec. AD pathology is introduced as a lower cholinergic tone and a gradual loss of synapses and neurons over time.
Figure C shows that we used a metaanalysis (Ito 2010) of the clinical effect of 28 different drug-dose-time points on ADAS-Cog changes and simulated those historical studies in the QSP model. The correlation between model outcome (positive is worse) and the clinical results suggest that the model captures a substantial amount of variance (Roberts 2012). Note that the cortical network model is calibrated starting from primate electrophysiology data that addresses some of the translational disconnect between rodents and humans on the GABA inhibitory tone (Povysheva 2006). Spring 2014 Volume 6 Issue 1
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substantially from a target engagement level of already 40% and beyond. Placebo values for 12 and 26 weeks (broken lines) are derived from Ito 2010. A maximal effect of 4 points at 12 weeks and 3 points at 26 weeks on top of 5 mg donepezil is very likely to be detected clinically, which corresponds to 7 points and 5.5 points respectively for ANAVEX PLUS.
Anticipated ADAS-Cog Changes with ANAVEX 2-73 as Stand-alone Therapy
Experimental (blue diamonds) and fitted (line) dose-response of ANAVEX 2-73 effect on Na-channel inhibition as a function of concentration (left) or target engagement with 18F-TZTP (right). The data suggest that at target engagement of 40% (where the clinical benefit starts), the compound also starts to potentially affect the Na-channel. We tested different combinations of the effect of ANAVEX 2-73 on the Na-channel in the cortical network. For instance, COMB1 is calculated suggesting a 25% weighting factor on the fast Na-channel, a 75% weighting factor on the persistent Na-channel and a 100% weighting factor on the Nachannels located on inhibitory neurons. The area under the curve (AUC) impact is shown for a stand-alone therapy. The data suggest that inhibition of the fast Na-channel can substantially reduce the outcome. This can be partially rescued by an inhibition of the Na-channel on inhibitory interneurons.
Anticipated ADAS-Cog Changes of ANAVEX PLUS (Combination of ANAVEX 2-73 with Low-dose Donepezil) Anticipated stand-alone ADASCog response of the cholinergic pharmacology of ANAVEX 2-73 as a function of M2 tracer 18F-TZTP for mild-to-moderate Alzheimer patients at 12 and 26 weeks. We omitted the Nachannel pharmacology (see further). It is clear that the beneficial effect increases substantially from a target engagement level of 60% and beyond. A maximal
effect of 4 points at 12 weeks is likely to be detected clinically. Anticipated ADAS-Cog response of the cholinergic pharmacology of ANAVEX PLUS, the combination of ANAVEX 2-73 with 5 mg donepezil as a function of M2 tracer 18F-TZTP for mild-tomoderate Alzheimer patients at 12 and 26 weeks. The beneficial effect increases
Off-target Na-channel Pharmacology of ANAVEX 2-73 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Graphical representation of the effect of different Na-channel weighting factors on the ANAVEX 2-73 and ANAVEX PLUS dose-response. Both the complete cholinergic pharmacology and the Nachannel pharmacology are used to predict the outcome in a 12-week trial. COMB0 is the situation without Nachannel pharmacology. The data suggest that adding 5 mg donepezil partially rescues the potential negative impact of Na-channel inhibition. Anticipated effect of ANAVEX 2-73 and ANAVEX PLUS on ADAS-Cog in the Alzheimer cognitive model, assuming the compound is a full antagonist at the M1 mAChR postsynaptic receptor and has a Na-channel pharmacology with weighting factors Na-f 0.35, Na-p 0.65 and Na-i 0.75. In this case, the augmentation therapy with 5 mg donepezil at 12 and 26 weeks shows a clinical benefit, that starts at target engagement levels above 40%. Spring 2014 Volume 6 Issue 1
Fast-tracking Essential Drug Glycosylation Expertise - from Outsourcing to Insourcing Imagine the following:
You are a successful senior biopharma executive leading the programme for a potentially highly profitable biologic drug. However, there are serious competitors and the race is on to be first to the market. There is a complication though. Your drug’s glycosylation is known to influence its safety and efficacy profiles sufficiently enough that you have to thoroughly characterise its glycosylation patterns, then optimise and strictly control it. This is both to satisfy the regulators and to produce a therapeutic with excellent clinical performance. You know that problems with drug glycosylation – even those with simple glycan profiles such as mAbs – can seriously impact regulatory approval and, if not resolved, cause significant financial loss. In the last five years biologics companies in the US have lost millions of dollars through glycosylation problems, and every day’s delay in product development costs your company many thousands of dollars. Dealing properly with drug glycosylation requires specialist expertise but, unfortunately, your company’s glycoguru has long since gone – so you want to rebuild the glyco-expertise in your group. However, this drug needs to be fast-tracked and your development resources (scientists, time, and money) are completely stretched. What can you do? This is an increasingly common scenario. Glycosylation is not the only thing to consider for a biopharmaceutical – but it is high up on your priority list. One approach is for you to keep cell line engineering in-house or with a CMO, and outsource the early-stage glycoprofiling to a specialist glycoanalytical services lab. The problem with this is that you could have long-term dependency on the contract lab as they are unlikely to share their proprietary secrets. So, you have an expensive long-term outlay and delay building up your in-house expertise. This leaves you vulnerable for a critical part of your drug development. There is an alternative approach which we have developed over the last three years at Ludger to support our collaborators and clients. We call it the “Out-To-In” (OTI) model. OTI involves us working as an extension of our partner’s organisation, first providing method www.ipimedia.com
Determine Glycosylation Critical Quality Attributes (GCQAs) for the drug. Develop study plan.
Ludger performs glycoprofiling pilot study on the drug, then develops and validates a glycoprofiling scheme tailored for the drug and, where appropriate, for the analytical platforms used by the sponsor. Ludger performs glycosylation analysis on drug as per partner requirements.
Method Transfer. Ludger scientists train partner scientists and help with developing and interpreting validation studies.
Partner performs glycoprofiling in-house. Ludger provides key glycoprofiling technologies (including kits and reagents), technical support, ongoing training and consultancy.
development and analytical services, then transferring validated methods into our partner’s R&D and QC labs. In the long term, we provide all the specialist glycoprofiling kits and reagents we use in our glycoprofiling labs, plus full technical support and consultancy. Table 1 shows the main stages of OTI as currently implemented at Ludger for our biopharma clients. In this way, OTI allows our partners to fast-track their studies and development programmes, gain experience in specialist areas of glycosylation analysis and, when they are ready, have optimised, validated glycomics methods developed for their glycoprotein transferred into their own labs. During stage 2 (“Out” stage) we typically perform three levels of glycosylation analysis, each with increasing detail: Level 1 (determine overall shape of glycosylation, tentative identities and relative quantitation via percentage molar abundances of major glycans) Level 2 (more detailed glycoprofiling - topology and glycosidic linkages of individual glycan structures, more accurate quantitation of major and minor glycan structures) Level 3 Glycosylation site analysis: Level 2 analysis on each glycosylation site At all analysis levels, we focus on the Glycosylation Critical Quality Attributes of that particular drug (i.e. those glycosylation parameters that most
impact the safety and efficacy profiles of the therapeutic). To this end, the analytics are driven by what’s known, and what we think we don’t know, about the mode of action and in vivo behaviour of the drug. OTI is now the main model we use at Ludger. The most extensive deployment is with our partners in research collaboration programmes for the discovery of glycosylation biomarkers of chronic diseases. The collaborations include EU-funded FP7 multi-lab projects such as HighGlycan and IBDBIOM, both of which involve large-scale glycomics studies of glycosylation pattern changes correlating with progression of inflammatory diseases. There the challenges include how to perform reliable glycoprofiling of thousands of biological samples (including blood and gut tissue) in a timely and affordable way. So far, our experience of OTI with clients is mostly focussed on US-based R&D labs of multi-national biopharma companies. Now, we are expanding to use OTI with drug companies in Europe and rapidly developing biopharma companies in the Far East.
www.ludger.com Tel: +44 1865 408 554 INTERNATIONAL PHARMACEUTICAL INDUSTRY 63
CLINICAL & MEDICAL RESEARCH
Because the functional effect of ANAVEX 2-73 at the human M1 mAchR is unclear, we tested different scenarios from a full agonism to a full antagonism. Due to the relatively weak interaction of the drug on this receptor, the effect is small and accounts for less than 1 point on the ADAS-Cog scale for a full antagonist for a 12-week trial in mild-to-moderate AD patients.
Overview of Different Na-channel Pharmacology on Outcome
Discussion The significant ADAS-Cog response of ANAVEX PLUS (ANAVEX 2-73 “plus” donepezil) is due to a potential strong synergistic action between presynaptic autoreceptor block by ANAVEX 2-73 and prolongation of residence time of Ach (acetylcholine) by donepezil-mediated Acetylcholinesterase block. This more than additive effect is likely driven by the enhanced desensitisation of the a4b2 nAChR that relieves GABA tone in the cortical network. The model assumes that the beneficial clinical effect declines over time as disease progresses. Interestingly, the study focused only on the symptomatic effects, as no potential beneficial sigma-1 receptor effects, which are neuroprotective and potentially disease-modifying were yet implemented or considered in this study.
Impact of Na-channel Pharmacology 12 Weeks Donepezil (DON) 5mg Augmentation
General Conclusion Stand-alone therapy ANAVEX 2-73 provides symptomatic benefit in mild-to-moderate AD patients at around 3.5 points on the ADAS-Cog scale at target engagement levels of 60% and greater. This is slightly higher than donepezil alone, which is prescribed in three doses; 5mg, 10mg and 23mg, respectively. However, ANAVEX PLUS, the combination of ANAVEX 2-73 with already the lowest dose donepezil (5mg) results in additional effect of 3-4 points on top of stand-alone therapy in mild-tomoderate AD patients already at target engagement levels of 40% and greater. Including placebo values, this corresponds to a maximal effect of anticipated ADAS-Cog response of 7 points at 12 weeks and 5.5 points at 26 weeks for the combination ANAVEX PLUS (donepezil / ANAVEX 2-73) in mild-tomoderate AD patients. These findings support the advancement of ANAVEX PLUS into a Phase II human efficacy study.
Effect of Na-channel Pharmacology on ADAS-Cog Outcome
Effect of Lower Partial Agonism at the M1 mAChR
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References 1. Ito 2010, Alzheimer’s & Dementia 6, 39 2. Lahmy, Neuropsychopharmacology (2013), pp. 17061723 3. Povysheva 2006, Cereb Cortex 16(4):541-52 4. Roberts 2012, Alzheimer’s Res Ther. ;4(6):50 5. Villard, J. Psychopharmacol. (Oxford) (2011), pp. 11011117 Dr Christopher Missling is President and Chief Executive Officer (CEO) of Anavex Life Sciences Corp (www.anavex.com). Dr Missling has 20+ years of healthcare industry experience within large pharmaceutical companies, the biotech industry and investment banking. He has been an investment banker in the healthcare practice at Deutsche Bank and most recently was head of healthcare investment banking at Brimberg & Co. in New York. Dr Missling has an MS and PhD from the University of Munich in Chemistry and an MBA from Northwestern University Kellogg School of Management. E-mail email@example.com Co-authors: Tangui Maurice, Athan Spiros, Patrick Roberts, Hugo Geerts Spring 2014 Volume 6 Issue 1
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LOGISTICS & SUPPLY CHAIN
The New GDP Guidelines: A Year On
World Courier welcomed the publication of the EU GDP guidelines, which created a yardstick by which logistics providers could be measured and compared. A year on from the first publication, they are now fully in force, and there has already been an update from the EU. World Courier’s Sue Lee looks at the regulations’ impact on the pharmaceutical supply chain in Europe and beyond. The EU GDP guidelines were published on March 7th, 2013, allowing companies six months to complete implementation, and this seems a perfect opportunity to reflect upon the effects on the specialist courier industry and the shipping of pharmaceuticals. The updated guidelines were universally agreed to be long overdue. The old guidelines 94/C 63/03, published almost 20 years earlier, were much shorter and open to interpretation, and did not address a lot of the changes in the supply chain which had taken place in the intervening time.
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Compliance became mandatory within the EU on the September 7th, 2013. There has been one update since then. GDP 2013/C 68/01 has already been superseded by 2013/C 343/01. Published and enacted in November, this corrected a couple of factual errors and expanded on the rationale. Prior to publication, GDP was somewhat of a poor relation when compared to GMP, and the existing four pages published by the EU merely advised on the wholesale distribution of medicinal products for human use. By their own admission they did not “cover commercial relationships between parties involved in distribution of medicinal products nor questions of safety at work.” The new guidelines have an extra 10 pages, divided into 10 chapters, and covering all the activities related to distribution, including ‘all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal
products to the public. Such activities are carried out with manufacturers or their deposi¬tories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned.’ So what has this meant for supply chain providers over the last year? It might appear, looking at the list of chapters, that they are only required to concern themselves with Chapter 9: Transport, but there is so much more to it than that. In almost every section there are items which have to be performed either alone or in conjunction with the manufacturer, even though the ultimate responsibility for compliance remains with the manufacturer. The guidelines begin with requiring an adequate Quality Management System, through outsourcing, training, temperature control, qualification, documentation, and plenty more. There’s little in there that doesn’t need consideration, actioning
Spring 2014 Volume 6 Issue 1
Do you think you are equipped to play at the top? GxP compliant services globally World Courier acknowledges the critical role that Good Practice plays in servicing its biopharmaceutical customers. We remain dedicated to ensuring GxP compliance at a worldwide organizational level as it relates to the transport and storage of investigational drugs, biological samples and ancillary supplies used in global clinical trials. World Courierâ€™s GxP Policy uses established principles of Good Distribution Practice (GDP), Good Storage Practice (GSP), Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) as they relate to each business individually (transport and storage) and follows all relevant guidance documents supporting these practices.
More information: www.worldcourier.com
LOGISTICS & SUPPLY CHAIN
control, and absolute transparency. Qualification must be available including seasonal variation, and that has presented problems for many companies who have at best done stress testing, and at worst have had no data available to show their fleetâ€™s capacity to cope with all weathers.
and documenting by both shipper and logistics provider. For our company, the process started a few years earlier when we conducted a review of all the relevant regulations, guidelines, and recommendations, whether nationally, regionally, or globally. We concluded that we had to put in place responses and actions to sections (relevant to transport) across all the regulations, including WHO Annex 5 on good distribution practices for pharmaceutical products, the IATA perishable cargo regulations, the existing EU guidelines and USP 1079. We took it step by step, creating structures, SOPs, training, and additions to our premises and equipment, internal auditing, and all the associated materials required to get into line with the requirements. When the new EU guidance was published we were already in compliance. What we have seen over the last year or so has been a huge increase in the number of quality and technical agreements which have been worked on, negotiated over and signed off. Some companies on both sides have taken their allocated tasks seriously and embraced these agreements which define the responsibilities undertaken by each party. Other companies need careful negotiation to make sure that each section is allocated and that neither party assumes that the other is taking something on. Once everyone agrees who is doing what, then things actually get completed. There is a clear onus on the manufacturer to ensure that actions 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY
undertaken by third parties have been performed properly and in compliance with the guidelines, and this has led to a rise in the number of audits taking place, with a much clearer set of criteria to audit to. Now everyone knows the expectations and the acceptable response to each item in the guidelines, and companies can be compared fairly. The expanded requirements to be able to prove transport conditions have increased the necessity to supply temperature monitors, although their use was already very widespread in clinical trial drug supply. Data has to be available very quickly so that supplies can go on sale and be dispensed. All the time that they are waiting for release is dead money in the supply chain, or has the potential to impact on supply to patients waiting for their prescriptions to be filled. Many shipments are sent with USB-enabled monitors so the data can be downloaded directly by the consignee and returned to the origination point. New protocols have been instigated by many companies to allow temperature data to be directly linked into supply chain management systems, so that release can take place for prescribing without additional delays and potential quarantining. We have seen a tremendous rise in the number of shipments being sent by road using temperature-controlled vehicles. Shippers can track their consignment in the dedicated vehicle, seeing exactly where it is anywhere across Europe and beyond, and exactly what the temperature of the contents is. Whilst not required in the guidelines, this allows the shipper
What is most heartening about the last year is that a really full dialogue has started between manufacturers and logistics providers. It seems that the guidelines have made it clear to everyone that arranging transport and fulfilling the requirements of the GDP guidelines is something that we have to work on together. This is no longer something which the manufacturing company imposes on their supplier, but something that we both need to comply with, understanding that collaboration is the way to succeed. Sue Lee has worked for World Courier for 25 years. During this time she has experienced a variety of customer service and operational functions, including the setting up of numerous, multi national, clinical sites for the transportation of biological samples in her capacity as Head of the Major Clinical Trial Unit. Sue has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. More recently in her role as Regional Quality Manager, Sue has been auditing and developing procedures and systems for regulatory compliance, package and vehicle testing, as well as temperature control and mapping. Currently, Sueâ€™s role includes delivering pertinent technical information and updates on latest industry developments via technical presentations, articles and white papers, workshops, association and discussion group involvement and direct links with other industry professionals. This also includes direct involvement delivering and maintaining World Courierâ€™s online presence. Email:firstname.lastname@example.org
Spring 2014 Volume 6 Issue 1
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LOGISTICS & SUPPLY CHAIN
Where does Controlled Room Temperature Fit in the Cold Chain? There have been many attempts over the years to produce a one-size-fitsall temperature profile against which to qualify temperature-controlled packaging (TCP), and many users argue a more lane-specific approach based on empirical data is required. While users and suppliers continue to demonstrate why one profile is more realistic than another, one question has gone under the radar for too long: to what temperature profile should a 15-25°C (or controlled room temperature as it’s often referred to) shipper be qualified?
your 96-hour qualified CRT solution goes out of specification after just two days? Historically, water-based CRT solutions have been qualified in a different manner than 2-8°C solutions. They are not designed to control the temperature between 15-25°C degrees, in fact there is no temperature control going on inside a water-based 15-25°C solution. The
qualification process has been adapted to reflect this. If you take the time to compare the qualification temperature profiles of 2-8°C and 15-25°C solutions that utilise water-based coolant for the same payload and duration, say 96 hours, you will find that a different temperature
Across the board, controlled room temperature (CRT) solutions have been qualified against a completely different set of profiles than 2-8°C counterparts. Look at any temperature-controlled packaging supplier portfolio, or within a TCP user, and you will find similar variations and stresses within the qualification profile for cold chain shipping. However, for CRT shipments sent from the same location, to the same destinations, via the same logistics network, a completely different qualification profile is used to quantify the performance. Since the introduction of the new GDP guidelines last September, this inconsistency is becoming more evident as the attention begins to focus on CRT shipments and the requirement to ship within label conditions. CRT shipments that were shipped unmonitored and in uncontrolled packaging are now creating tension as the need to demonstrate temperature compliance uncovers a hidden world of issues. As is stated in the guidelines: “CHAPTER 9 — TRANSPORTATION 9.1. Principle Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity. A risk-based approach should be utilised when planning transportation.” Now that you are using CRT qualified packaging have you ever wondered why 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2014 Volume 6 Issue 1
H I L A N D ER S | P H OTO: M O RG A N EK N ER
Diabetics do it better envirotainer.com
What if we only hired diabetics to work in the active cold chain? Would they take more care handling healthcare products? We think they would. They know what happens if they donâ€™t get insulin. Of course we donâ€™t just employ diabetics. But we do share their understanding of the value of what we ship in our containers. We educate the members of the active cold-chain on the difference they make to the lives of diabetics and others who rely on healthcare products. Because people do a better job when they understand the importance of why they are doing it. Anna Klettner is one of those people. She is a diabetic and she works for us.
LOGISTICS & SUPPLY CHAIN
profile was used in the qualification process. Shown here the CRT profile example and ISTA 7D profile both have a duration of 96 hours and temperature extremes of +35°C, and -5°C and -10°C respectively, it is clear to see that one profile offers a much greater thermal challenge. Yet, any CRT packaging solution qualified to the above CRT profile can claim to be qualified for 96 hours for temperatures ranging from -5°C to +35°C. It is quite evident that a 2-8°C qualified shipper has been designed to provide protection against a specific temperature profile for a specific duration, while the reverse can be said for the CRT solution. It is the profile that has been designed around the capabilities of the shipper in
environment, the internal temperature will begin to change. This is because there is no change of phase to absorb the energy differential. If you analyse the temperature profile you may find there is a lot of time spent at 20°C with short spikes above and below the 15-25°C boundaries. On closer inspection you will see this time is used to recover the internal temperature to prolong the qualified duration while allowing the manufacturer to make bold claims about shipper performance against extreme highs and lows of temperature. Comparing the average temperatures of the CRT and ISTA 7D profiles shown above really demonstrates the narrow band a water-based CRT solution is qualified to work within.
on lane selection and at key touch points. The reality is, if you’re using a waterbased solution and your product cannot experience any temperature deviations, you should be using a dedicated healthcare courier to provide the conditions to which the shipper has been qualified. This is reaffirmed again in the new GDP regulations: “CHAPTER 9 — TRANSPORTATION 9.3. Containers, packaging and labelling Selection of a container and packaging should be based on the storage and transportation requirements of the medicinal products; the space required for the amount of medicines; the anticipated external temperature extremes; the estimated maximum time for transportation including transit storage at customs; the qualification status of the packaging and the validation status of the shipping containers.” So the selection of a CRT shipper should be based on the anticipated external temperatures experienced during transit and the qualification status of the packaging. This will ensure the CRT water-based shipper remains within an environment it is designed to be in – controlled room temperature. Suddenly the cost of making a CRT shipment is growing – as well as purchasing TCP packaging, a higher level logistical service is also required.
order to produce a solution that performs for the desired length of time. If you have two shipments, one 2-8°C and one 15-25°C, going to Singapore from London for example, on the same day with the same carrier, you can be pretty confident that both shipments are going to experience the same ambient temperatures during their journeys to Singapore. So why have they been qualified to different temperature profiles? If you dig a little deeper, you will find water-based CRT solutions provide no temperature control, only thermal ballast and insulation. As soon as the shipper is placed in a different temperature 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The new regulations remind us that “it is the responsibility of the wholesale distributor to ensure that vehicles and equipment used to distribute, store or handle medicinal products are suitable for their use and appropriately equipped to prevent exposure of the products to conditions that could affect their quality.” (9.2)1 In order to get your 96-hour waterbased solution to work and last 96 hours, the logistics environment it is exposed to during transit must be controlled within its qualified parameters. This requires working with your logistics vendor to ensure special handling instructions are received and understood, and care is taken
The cost of shipping CRT in a compliant manner is growing fast. While we are constantly reminded that cold chain products are growing and will make up $250b of global sales in the next few years, that leaves close to $700b that isn’t cold chain with a large portion of that with CRT storage instructions on the label. With regulators putting more pressure on everyone to ship within listed storage temperatures, you can bet that the number of products with CRT controls will grow also instantaneously. In fact, according to the FDA Centre for Drug Evaluation & Research (CDER) in 2012, 24 of the 31 new drug applications for new molecular entities are listed as CRT products. In the past few years, CRT has been pushed to the back of the shelf, and logistics partners have been scrambling Spring 2014 Volume 6 Issue 1
LOGISTICS & SUPPLY CHAIN
to put global facilities in place to handle cold chain products. Now looking at the above statistics from the FDA CDER, and with a change in the regulations, we are staring at a new problem. What is the way forward? The alternative is to use a CRT solution that has been qualified to the same temperature profile as the 2-8°C shipments and is designed to handle the external temperatures seen under normal shipping conditions. Traditional TCP technologies will perform to some degree for local and regional next day deliveries but for longer, more challenging routes, something else is required. TCP that utilise phase change materials offer true temperature control and provide a real solution that is available today. Whether encapsulated within a low-cost insulation material or a high-tech space age material, PCM that change phase within the CRT range is required and provides true temperature control. Using materials that change phase
within the required temperature range is so important to providing real temperature control. The latent heat of a 20°C PCM is approximately 200Jg-1 compared with the specific heat capacity of water at 20°C, which is 4.2 Jg-1. The PCM is able to absorb a lot more energy while remaining at a constant temperature. This increase in thermal performance means the CRT solution can be designed, tested and qualified to the same temperature profile as 2-8°C shippers. So whatever temperature profile is representative of the transit route, whether it is an industry standard such as ISTA 7D or one based on empirical data, you can qualify both 2-8°C and 15-25°C shippers. This puts your company in a position of strength with regulators and customers, as you can assign specific temperature profiles to specific routes. Then all temperature control packaging to be used on that route – regardless of whether it’s 2-8°C, 15-25°C or even dry ice – can be qualified to that temperature profile.The first step is to compare the temperature profile of your 2-8°C and CRT solutions and the method and mode
of transport used to ship, and question whether your qualified CRT solution and freight method match up. So where does CRT fit in the cold chain? Well, it was on the back burner but you can now call it breaking news. About Intelsius: Incorporated in 1998, Intelsius is a subsidiary of DGP Life Science Ltd, which is headquartered in York, United Kingdom. With a strong focus on developing environmentally sustainable products and procedures, the company offers solutions to ensure the integrity of customers’ products and samples. Intelsius has a growing global presence with manufacturing facilities, distribution hubs and local offices situated throughout the world, including North America, Europe and Asia. For more information, visit www.intelsius. com. References 1. h t t p : / / e u r - l e x . e u r o p a . e u / LexUriServ/LexUriServ
David Johnson joined Intelsius as a Business Development Manager in January 2013. While relatively new to Intelsius, David is not new to the industry, having held high-level sales and management positions at another company in the temperature-controlled packaging industry. David is recommended and recognised for his skills, expertise and knowledge of the pharmaceutical industry, clinical trials and cold chain logistics. He has represented the industry at dozens of trade shows and has given presentations at conferences around the world. David holds a degree in mechanical engineering and began his career in pharmaceutical process engineering before finding his passion for business development. He is a member of the International Society of Pharmaceutical Engineering (ISPE). His last article, “How Packaging Solutions are Easing Multi-site Challenges”, appeared in the June 2012 issue of the Journal for Clinical Studies. Email: firstname.lastname@example.org www.ipimedia.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 73
LOGISTICS & SUPPLY CHAIN
Cost of Quality (CoQ) - An Analysis of the Cost of Maintaining a State of Compliance “You can easily spend 15% - 30% of your sales dollars on non-conformance.” (Philip Crosby) A Little History Since the 1930s, famous quality gurus (including: Deming, Juran, Crosby, Ishikawa, Taguchi) have promoted the use of quality tools and techniques to improve product quality and reduce operating costs. Their contributions have made a significant impact on the world, improving not only manufacturing operations and businesses, but all organisations including state and national governments, military, educational institutions and many others. One of the tools and techniques, Cost of Quality, allows organisations to analyse and address the cost of poor quality.
Reworking a service, such as the replacement of an erroneous order.
In short, any cost that would not have been expended if quality were perfect contributes to thecost of quality. Example: Documentation and the associated errors are familiar aspects of all parts of the pharmaceutical industry. To illustrate the points made in the text, we will look at cost of quality examples relating to managing documentation so as to reduce the CoQ.
Dr Joseph Juran first discussed cost of quality analysis in 1951 in the first edition of Quality Control Handbook.
CoQ Categories Dr Armand Feigenbaum identified the four cost categories in 1956 in “Total Quality Control” in the Harvard Business Review, Vol. 34, No 6:
Dr Armand Feigenbaum identified the four cost categories in 1956 in “Total Quality Control” in the Harvard Business Review, Vol. 34, No 6.
• • • •
The Cost of Quality “The cost of quality” is a term that is widely used – and widely misunderstood! The “cost of quality” isn’t the price of creating a quality product or service. It’s the cost of NOT creating a quality product or service. Every time work is redone, the cost is really the cost of poor quality.
Prevention Costs Costs incurred in planning, implementing and maintaining a quality management system that is intended to ensure conformance to quality requirements. This is the cost of preventing failure. This represents the application of a quality assurance approach to quality and focuses on developing robust, reliable systems.
The Cost of Poor Quality (CoPQ) “COPQ is the sum of all costs that would disappear if there were no quality problems.” (Dr Joseph Juran) Obvious examples of the cost of poor quality include: • • • •
Reworking a manufactured item; Retesting a product; Rebuilding or repairing a machine; The correction of mistakes in documents and records;
74 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Prevention costs Appraisal costs Internal failure costs External failure costs
Prevention Costs Prevention of errors in documentation can be achieved by good document design. The aim is to create documents that are: • easy to understand; • unambiguous in terms of the information required; • simple and quick to complete; • easy to verify for completeness by the users.
Appraisal Costs Costs incurred in measuring and auditing design, products, components and materials in order to establish the degree of conformance with quality requirements. This is the cost of checking to try to prevent failure. This represents the application of a quality control approach to quality and includes checking and testing, measurement of performance, auditing, etc. Appraisal Costs: includes the costs of measuring, evaluating, auditing, etc. Quality Assurance and Quality Control If an activity is carried out to PREVENT the possibility of occurrence of defects it is usually QUALITY ASSURANCE. If an activity is carried out to appraise an outcome or DETECT defects it is usually QUALITY CONTROL. “Quality cannot be tested into products; it should be built in or should be by design.” (FDA, Guidance for Industry: Process Analytical Technology) QC testing based on sampling will miss errors, so cannot be relied upon. Similarly, manual inspection relies on the human animal, which is prone to make mistakes, so also cannot be relied upon. Automated inspection of 100% of all components, activities, etc. has a higher level of reliability, but can be expensive and cannot be applied to many activities. QA focuses on developing systems that are configured so as not to be able to fail – quality right first time, right every time. QA systems are designed to be mistakeproof. Practical everyday examples of mistake-proof systems and devices include: the UK 3-pin plug, which can only ever be inserted in the socket of the
Spring 2014 Volume 6 Issue 1
LOGISTICS & SUPPLY CHAIN
a systematic approach for identifying, understanding and remedying the financial impact of poor quality; more than the cost of the quality organisation; more about providing an activity-based costing model to drive decision-making.
“It’s not an accounting exercise. . . . It’s meant to empower employees to make better quality decisions.” “Defects cost us money . . . and the closer the defect gets to the customer, the more expensive it is. The earlier we address defects, the more cost-efficient and effective we can be as an organization.” (Matt Pearson, Associate Director, Operational Excellence)
right type with the connections properly connected; a car with an automatic gearbox, which can only be started in “park” and is impossible to stall by driver error; a photocopier or computer printer which will prevent operation if the correct reassembly procedure is not followed following a paper jam; computer software that won’t progress if critical fields have not been completed properly, etc. The Japanese manufacturing industry uses the term “Poka-yoke” for systems that are mistake-proof. Many industries have moved away from using QC testing to manage quality and adopted a QA approach. Examples include: automotive, aerospace, electronics, consumer durables (white goods). Consider the reliability of these compared with, say, 30 years ago. However, the pharmaceutical industry has been slow to adopt a QA approach and is reluctant to move away from QC. Internal Failure Costs Internal failure costs arise where products, components and materials fail to conform to quality requirements prior to transfer of ownership to the customer. This is the cost of dealing with internal failure. This category will include scrap, rework, etc. Internal Failure Costs These are the costs incurred as a result of document errors – either mistakes in
the information recorded, or missing information. Included will be the costs associated with correcting omissions and errors, delays in releasing product, etc. External Failure Costs External failure costs are incurred when products fail to conform to quality requirements after transfer of ownership to the customer. This is the cost of dealing with external failure. This is the most damaging as it results in significant customer dissatisfaction as well as cost. External Failure Costs These are also the costs incurred as a result of document errors, but where the error is found by the customer - i.e. too late! Included will be the cost of replacement product, customer complaints, company reputation, loss of future sales, etc. Genentech Genentech introduced a CoQ initiative in 2008/9 at their US facility. They noted that CoQ is: • •
the process of determining costs associated with quality and poor quality work; a measure used to align quality and production goals to drive right first time and engrain quality in operations;
CoQ Application Although used widely in many industries – automotive, consumer goods, electronics, aerospace, etc. – the take-up in the pharmaceutical industry is low. This is symptomatic of an industry that is generally very slow to adopt tools, techniques and methodologies from other industry sectors. Calculating CoQ Using a simple but detailed questionnaire, data is collected under the four categories: • Prevention costs: quality planning; audits; reviewing and verifying designs; process and equipment qualifications and validations; training; quality improvement programmes; etc. • Appraisal costs: in-process inspection; inspection and test equipment; finished product inspection and test; product and material identification and traceability; standard documents and records – use, control and storage; etc. • Internal failure costs: nonconforming product; replacements, rework; re-inspection; downtime, breakdown; scrap, write-offs, low yields and wastage; quality records investigations – errors & corrections; surplus inventory; etc. • External failure costs: loss of reputation; customer complaints, investigations and reports; market withdrawals; product rejected and returned; customer defections/sales loss due to poor service; total cost of recalls and product liability, etc. INTERNATIONAL PHARMACEUTICAL INDUSTRY 75
LOGISTICS & SUPPLY CHAIN
How Much Quality Costs Generally, pharmaceutical companies enjoy a very high overall profit ratio, with a net profit margin of around 30% (Various sources). However, individual operating units and factories are often a cost centre, not a profit centre, such that a tight control over operating costs is a key driver. Other parts of the pharmaceutical supply chain, such as distribution, will have much lower profit ratios – <4% is quoted for the logistics industry (Source: Global Transport & Logistics Financial Ratio Analysis 2012. Transport Intelligence Ltd.) Total Cost of Quality is, on average, 25% of the value of sales. (Source: Cost of Quality as a Driver for Continuous Improvement, Roger E Olson, Systems Quality Consulting.)
“Inspection with the aim of finding the bad ones and throwing them out is too late, ineffective and costly. Quality comes not from inspection but improvement of the process.” (Dr W. Edwards Deming) Activities should focus on developing robust processes that require minimal inspection.
“You can easily spend 15% - 30% of your sales dollars on non-conformance.” (Philip Crosby)
The most effective way of achieving the highest quality at the lowest cost is by developing robust, reliable processes that produce quality product on a consistent basis – right first time, right every time.
“In most companies, the cost of poor quality runs at 20% - 30% of sales.” (Dr Joseph Juran)
This is a QA approach to quality. Aim for aerospace levels of reliability – 6-sigma and beyond!
Therefore the cost of poor quality is often equivalent to the value of net profit! At 25% CoQ: • the first two hours of the eight-hour working day are spent covering the cost of poor quality!
Maintaining Performance “You can’t manage what you don’t measure.” (Quality mantra, incorrectly attributed to Dr W. Edwards Deming.)
you haven’t cleared the cost of poor quality until sometime Tuesday!
Managing CoQ The most expensive cost is that of external failure. Not only does it have a financial impact, it is severely damaging to the company’s reputation. Activities should focus on eliminating external failures. The focus should then be on reducing internal failure costs to zero. If a goal greater than zero is selected, it’s like saying defects and failure are OK in this organisation! Internal failures create scrap. Appraisal costs result from checking and testing – QC. 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY
“If you don’t keep score, you’re only practising.” (Jan Leschly, CEO, SmithKline Beecham, 1994-2000) Maintaining Performance The key to running any operation is timely measurement of the drivers of the desired output. The output from any process is determined by the way in which the process modifies and changes the various inputs. Knowing which parameters of both input and process have an influence on the output is key to managing the process; otherwise, it’s simply luck that the process delivers the desired output. Measuring the output without an understanding of how it is derived will lead to frustration and inappropriate, and possibly damaging, tampering with the process. Conclusion A full and
understanding of the sources of the cost of poor quality allows the identified costs to be eliminated or reduced. With cost of (poor) quality representing a very significant proportion of the overall cost of running an operation, the opportunities in terms of measureable operational improvements and financial savings are very significant. There are a number of widely-used and well-proven tools and techniques to help with the analysis of cost of (poor) quality and to address the identified improvement opportunities.
Robert J Hayes has worked in the Pharmaceutical Industry for over thirty years. His experience includes Production and Engineering Management, New Product Development, Factory Design, Supply Chain Management, Validation and a variety of support functions. He has a special interest in the use of risk management and modern quality methodologies. Bob is Vice-Chair of the Pharmaceuticals Technical Activities Committee of the Institution of Mechanical Engineers (London). He is a Fellow of the IMechE. As well as his experience in the Pharmaceutical industry, Bob has also worked in a range of other industries, including: aerospace, precision engineering, FMCG, insurance and e-commerce. This breadth of experience presents the opportunity for Bob to introduce new ideas and best practices when working with his current clients. Email: email@example.com
and Spring 2014 Volume 6 Issue 1
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LOGISTICS & SUPPLY CHAIN
GDP and the Challenge of Protecting Controlled Ambient Pharmaceutical Freight The new GDP regulations are well documented elsewhere, but what’s the operational reality? There’s no getting away from the fact that protecting controlled ambient (CRT – controlled room temperature) freight where there has been little or no previous budget is a challenge. With 2-8°C goods, there is budget to use proven and robust temperaturecontrolled packaging (TCP) or active containers. Where budget allows, it would obviously be sensible to use TCP or active containers to protect CRT product, but what if the cost is too high? Supply chain managers often consider a passive thermal protection in the form of thermal blankets or reflective pallet covers. The challenge is that these forms of protection do not offer ‘control’ of temperature change, but simply slow it down. This means that there is little guarantee how long the freight will be protected for when exposed to high or low ambient temperatures and direct sunlight. Not something that sits well with QA and supply chain managers! The reality of many supply chain routes is that they are fairly well protected for the majority of the journey. The warehouse, truck and aircraft all offer shade and some form of knowledge about the ambient temperatures inside. So for a high percentage of the journey, there is little or no threat of excursion. The main threats come between protected environments, usually when the freight is outdoors between warehouses or on the airport ramp. The duration is often relatively short (30 minutes in small airports, 4-6 hours in large airports) but the threat can be extreme. Middle East airports can see tarmac temperatures of 70-80°C in a 40-50°C air temperature. Canada can see -40°C windchill in -20°C ambient. Supply chain managers require protective equipment that is costefficient but also capable of giving the right level of protection for those short durations. Thermal covers are often an
78 INTERNATIONAL PHARMACEUTICAL INDUSTRY
ideal solution in being lower cost and thermally effective, as long as they are sourced appropriately. Various materials will perform quite differently, so a company offering a range of solutions may suit shippers with various types of routes and forms of transport. This will enable a manager to use lowercost solutions on lower-risk lanes and high-performance solutions on high-risk lanes. Many elements can affect the performance of a thermal cover. Product mass can be the one with the most impact, e.g. a pallet of cough mixture bottles will keep temperature far better than a pallet of single pack vials that has little mass. A higher performance cover may have to be used on lower mass pallets than
Graph 1: Direct Sunlight Test, comparing two pallets covered by SilverSkin PB550. Monitor F-016 shows temperature in pallet with no mass (empty boxes), E-020 shows pallet with full mass (500ml water bottles in boxes).
higher mass pallets Packaging will help insulation so it’s important to insert temperature monitors inside any packaging to get a real appreciation of the temperature that the product is exposed to. If temperature monitors are placed outside the packaging but under the thermal covers, the temperatures will be quite different and cause undue concern. In the example ‘Graph 2’ below, it can be seen that the temperature inside the box doesn’t reach 30°C over
Graph 2: Direct Sunlight Test of Pallet Covered with SilverSkin PB550 Thermal Cover. Monitor CLI-016 shows temperature inside a cardboard box, CLI-015 shows monitor in same position as CLI-016 but outside the cardboard box, under the thermal cover.
the test period, although the temperature under the cover reaches 30°C within 40 minutes. Single-use Covers and Multi-use Blankets Single-use covers are usually lower cost and made from single-skin or thin laminate materials, with the primary effect of preventing air flow between ambient and product, as well as acting as a direct sunlight reflector. These are ideal where reuse or collection is not viable. Wraps and caps are other terms used for covers. Multi-use blankets tend to be higher cost with thicker insulation protected by some form of abrasiveresistant material either side to give added durability, enabling reusability. These are ideal for ‘closed loop’ situations or where it’s economically viable to retrieve them. Quilts are similar to blankets apart from having a cross stitch to retain the insulation. Peter Lockett, Co-Founder & Technical Director of TP3 Global, manufacturer of SilverSkin thermal covers for pharmaceutical shipments. Mr Lockett is an active member of the PDA and is involved in the PCCIG Task Force contributing to the forthcoming report, Guidance for the Qualification and Use of Passive Thermal Protection Systems for Global Distribution. Email: email@example.com
Spring 2014 Volume 6 Issue 1
T h e r m a l
c o v e r s
Protecting Pharmaceutical and Perishable product against hot and cold temperature spikes in the supply chain
30 Top Front Right 013 Bottom Front Left 016
Top Rear Left 017 Ambient
1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 134 141 148 155 162 169 176 183 190 197 204 211 218 225
Specification Sizes up to full Air Cargo ULD Single / Multi Use Solutions Innovative & Propriety Materials Qualified Performance Global Availability Quick and Easy Fit Manufacturing in UK (for EMEA), India (for Asia), Australia and USA VALIDATION – Chamber Testing and Direct Sunlight Testing Carried Out
Elemental Impurity Analysis in Pharmaceuticals A method to identify the presence of heavy metals in pharmaceuticals was introduced in the United States Pharmacopoeia more than 100 years ago. Today pharmaceutical companies are still using essentially the same method, the USP <231> Heavy Metals Limit Test. This paper will give an overview of the current method limitations, considerations for the new methodology, and the riskbased assessments being carried out by manufacturers. The current colorimetric methodology was intended to control metals which form a sulfide precipitate, such as lead and copper, which are potential contaminants from water pipes, manufacturing equipment and processes. However, the risk factors for metal contamination have changed dramatically, for example with the use of metal catalysts, yet the standards for their control have changed little in more than 50 years. The method is no longer fit for purpose, and most heavy metal limits currently in place have little basis in toxicology. To that end, whilst IPEC (International Pharmaceutical Excipients Council) Americas state that they are unaware of any known metal impurity issues impacting patient safety, they, along with pharmaceutical manufacturers and regulators, agree on the need to enhance and harmonise future testing. However, harmonisation of pharmacopoeia methods has a history of making slow progress and it is not surprising that this task has taken as long as it has in coming to what appears to be a conclusion, when the Q3D Expert Working Group expects to reach Step 4 later this year following the publication at Step 2 of the ICH Q3D document in June 2013. So Why the Need to Change the Method? As previously mentioned, the principle of the current method is the formation of coloured sulfide precipitates, to visually demonstrate the presence of metallic impurities. There are five key issues with the current procedures: •
Specificity: There is no comprehensive list of the elements common to the
80 INTERNATIONAL PHARMACEUTICAL INDUSTRY
pharmacopoeia heavy metals limit tests. Whilst the method identifies that there is a heavy metal present, it does not identify which impurity or combination of impurities has been identified. As a simple limit test, it cannot identify trace elemental impurities in the presence of organometallic compounds where the metal component produces an insoluble metal sulfide. •
Sensitivity: The current method lacks the sensitivity to determine some of the listed elements to the required detection limits, even though it typically involves using up to 2g of substance for testing purposes. This sample requirement can make testing
Class 1 Class 2A Class 2B Class 3 Class 4
In addition to these limitations, with the published ICHQ3D Guidelines on Elemental Impurities comes the establishment of permitted daily exposure (PDE) limits for each element of toxicological concern, determined using publicly available data. The elemental impurities have also been placed into categories that are intended to facilitate risk assessment as part of quality risk management. This risk assessment process follows the principles employed in ICH Q3C: Residual Solvents, and means that a suitable and specific method can now be chosen and validated for the ongoing assessment of elements of concern in raw materials and/or finished products. Alternative Methods
Included Elemental Impurities As, Pb, Cd, Hg V, Mo, Se, and Co Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, and Ru Sb, Ba, Li, Cr, Cu, Sn, Ni B, Fe, Zn, K, Ca, Na, Mn, Mg, W, Al
very costly for small-scale production of early-stage development batches. • Accuracy: All results are based on a lead standard, while the colour and intensity of the different precipitates formed can vary considerably from that of lead sulfide. The test is also subjective, in that it relies on an analyst’s opinion on whether the precipitate in the sample is lighter or darker than the prepared standard, which can be further complicated if the background is not a colourless solution. • Some key elements form soluble sulfide salts, meaning they are not detected using this wet chemistry approach. • The current method of ashing (@600°C) and acid dissolution is prone to sample loss, particularly the volatile elements such as mercury and selenium, and is also matrix dependent. The current limit test often appears to be applied with little thought to validation for the matrix concerned.
To overcome the inherent deficiencies of the current wet chemistry-based procedure, all parties have been looking to employ modern instrumental techniques that identify and quantify individual elements. The three major pharmacopoeias, United States, European and Japanese, describe procedures based on analysis by ICP-OES (or ICP-AES) and ICP-MS. Whilst they do not rule out alternative techniques such as AAS, XRF, UV and IC, the standard method of reference will be ICP. The USP proposed the ICP route in 2005, when it introduced the introduction of USP Chapters <232> Elemental Impurities Limits and <233> Elemental Impurities Procedures. The key benefits of ICP instruments, whether ICP-OES or ICP-MS, are: • • •
Can perform multi-element analysis simultaneously Achieves the detection limits required Can be run unattended Spring 2014 Volume 6 Issue 1
Physical matrix effects can be overcome using internal standards Large linear ranges
This means the issues of specificity, sensitivity and accuracy of the current procedure are addressed. However, as with any instrumental technique, the analysis is only as good as the sample preparation technique involved. With this in mind, it is critical to have an understanding of the material to be analysed and the elemental impurities of interest in order to select the most appropriate sample preparation technique. The proposed USP procedures, whilst stating that preparation techniques involving either neat, direct aqueous solution or direct organic solution are acceptable, also outlines a procedure using closed vessel digestion. This latter procedure can have a number of benefits: • • • •
Enhanced digestion temperatures, reducing digestion duration whilst achieving higher digestion quality Reduced acid consumption resulting in reduced blank values and better matrix matching with standards No loss of volatile elements Reduced contamination risks
Considerations on Transitioning to ICP Whilst there are obvious benefits from the use of modern instrumentation in replacing the well-established wet chemistry limit test, there are a number of considerations. Firstly, there is the capital expenditure; an ICP-OES costs in the region of £50k and an ICP-MS
£100k, with a closed vessel microwave digestion system £20k. Secondly, the cost of installation of the equipment, services and ongoing running costs. Thirdly, there is the training of staff in the new technique or, in some instances, the employment of another analyst with the relevant experience to operate the equipment and interpret the data. Finally, there are validation considerations. The USP and other pharmacopoeias have produced some general outline procedures for elemental impurities testing by ICP; the USP states: By means of verification studies, analysts will confirm that the analytical procedures ....... are suitable for use on specified material If alternative procedures are used then the USP requires that these are fully validated to USP <1225>. However, there is the proviso in USP <232> that says: If, by validated processes and supply-chain control, manufacturers can demonstrate the absence of impurities, then further testing is not needed. Developing and validating an ICP method for a new material, in theory, begins with identifying whether the procedure needs to be a limit test to show the absence of elemental impurities, or a quantitative procedure for one or more elements known to be present. From a practical point of view, given the large linear range of ICP instruments, it is often more efficient in terms of time and costs to move straight to the development of
a method capable of quantifying any elemental impurities known to be present. With such emphasis on validation requirements, for each material requiring elemental impurity testing, pharmaceutical manufacturers are looking carefully at the cost benefits or otherwise of investing in these techniques, especially with the added costs of any ongoing routine testing required. Risk Assessment/Control Strategy As previously mentioned, pharmaceutical manufacturers are applying the principles of quality risk management, with the risk assessment being based on scientific knowledge and principles as set out in the ICH Q9 guidance document. This process can be described in four steps: • Identify: Identify known and potential sources of elemental impurities that may be present in drug product • Analyse: Determine the probability of observance of a particular elemental impurity in the product • Evaluate: Compare the observed or predicted levels of elemental impurities with the established PDE • Control: Document and implement a control strategy to limit elemental impurities in the product The data on elemental impurity content for the components of a drug product can be derived from a number of sources. These include: published literature, data provided by reagent and/or excipient manufacturers, and data previously generated on the product. However, manufacturers have been finding that there is little or no substantive information on the levels of elemental impurities available for making this risk assessment. There are also materials where it will be difficult to obtain consistent data. For example: plant-derived materials or natural products and inorganic minerals which may be grown or mined in differing parts of the world, where it may not be possible to set a reliable baseline of typical elemental impurities content. Whilst pharmaceutical manufacturers may push excipient suppliers to provide the data, rather than produce it for themselves, are there sufficient incentives for these suppliers to warrant investment in the equipment to obtain the required data? With this lack of reliable data, some manufacturers have decided to generate the data themselves for their current product ranges, to assess if any particular INTERNATIONAL PHARMACEUTICAL INDUSTRY 81
Element Lithium Vanadium Chromium Cobalt Nickel Copper Arsenic Selenium Molybdenum Ruthenium Rhodium Palladium Silver Cadmium Tin Antimony Barium Osmium* Iridium* Platinum Gold Mercury Thallium Lead
Class 3 2A 3 2A 3 3 1 2A 2A 2B 2B 2B 2B 1 3 3 3 2B 2B 2B 2B 1 2B 1
product or dosage form gives rise to significant levels of elemental impurities, using a generic quantitative screening method for 30 common elements. In other cases, where manufacturers use a limited range of excipients, the approach has been to assess multiple batches of raw materials. This data can then be used for risk assessment and shared across product ranges. ICH Q3D requires the manufacturer to measure the significance of the level of an observed elemental impurity relative to the PDE. A control threshold of 30% of PDE in the drug product has been established and is to be used to determine if additional controls may or may not be required. Case Study The results above are part of an investigation recently carried out at Butterworth Laboratories Ltd into three formulations of the same product, with multiple batches for each formulation being prepared using closed vessel microwave digestion and analysed by ICP-MS. The results obtained show that there may be concern over the levels of lithium, cadmium and lead. The manufacturer now needs to evaluate these figures with respect to the PDE as they all exceed the 30% threshold. It should be borne in mind that the PDE figures are based on a 10g daily dosage of the formulation. 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Recommended PDE µg/g, Based on 10g/day dosage Oral 78 12 1100 5 60 130 1.5 17 18 100 100 10 17 0.5 640 120 1300 100 100 100 13 4 0.8 0.5
Mean Result µg/g Chewable Tablet Extended Tablet 2mg 25mg 200mg 25mg 58.9 61.6 0 0 1.7 1.7 0.1 0.6 2.6 1.1 0.1 0.1 0.1 0.1 0 0.1 0.5 0.8 0 0.4 0.6 0.4 0 0.1 0.2 0.3 0 0 0.2 0.1 0.2 0.1 0.1 0.1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.4 0.2 0 0 0.3 0.2 0.3 0.1 0 0 0 0 9.2 4.3 0.8 0.9 0 0 0 0 0 0 0.1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 1.1 0 0
The majority of drug products are not formulated for this dosage level and as such it may be that the levels determined are perfectly acceptable. If not, ongoing analytical strategies can be implemented to regularly monitor the levels in raw materials and/or the finished product.
house expertise. Unless they identify that there is a significant need for ongoing monitoring, it is likely that they will continue to use sub-contractors to perform this work if they cannot persuade the raw materials suppliers to provide the necessary data at source.
Many manufacturers are outsourcing such testing to contract testing laboratories, who already have the equipment, trained staff and expertise in elemental impurities analysis by ICP for this risk assessment stage. Given the level of metals testing required by the pharmaceutical industry, many have never invested in ICP technology up to this point and so do not have any in-
References ICH Q3d Draft Document: July 2013 ICH Q9 Finalised Guideline: November 2005 USP 36 – NF 31 Second Supplement <232> Elemental Impurities – Limits USP 36 – NF 31 Second Supplement <233> Elemental Impurities - Procedures
David Riches started his career at Messers Sandberg Testing Laboratories which specialises in testing samples for the construction industry. He moved to Butterworth in 1986 as an Analytical Chemist specialising in Elemental Microanalysis. David is currently Head of Analytical Operations having previously held the posts of Analytical Operations Manager and Senior Manager of Inorganic & General Chemistry.
John Welch started his career with Kodak Ltd at their Research Facilities in Wealdstone, Harrow, before moving into the pharmaceutical industry with Upjohn Ltd. He moved to Butterworth in 1987 as an Analytical Chemist and has occupied roles including Laboratory Manager, QA Manager and is currently Head of Business Operations. An active member of the RSC, John has spoken at RSC and MHRA Seminars on subjects relating to contract analytical chemistry.
Spring 2014 Volume 6 Issue 1
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(volumetric dosage, 100 per cent weightcheck). – Blistering with the most recent technologies enabling individual on line cell identification. – Filling of capsules, tablets and soft gel capsules into plastic pots. Well-Established Liquid and Semi-Solid Forms – Manufacture of solutions and suspensions of high sugar and/or alcohol content. – Filling and packaging of solutions, suspensions and emulsions on flexible lines (barcode scanners, on-line weighing and optical control). – A wide range of equipment to manufacture and package gels, ointment creams, suppositories, pastes and enemas. All under highest controlled conditions. Vifor Pharma is the pharmaceutical division of the Galenica group, based in Switzerland.
Antimicrobial Copper: An Engineering Approach to Reducing Cross-contamination Copper, as well as being man’s oldest engineering metal, is now recognised as a proven, broad-spectrum antimicrobial material. Well over 60 published papers support its efficacy against pathogens that cause healthcare-associated infections (HCAIs), both in the laboratory and the busy clinical environment. This article will explore the latest research – including ongoing study of the mechanism by which copper exerts its antimicrobial effect and the implications for its use as an infection control measure – and investigate how and where it is being used in the healthcare field and beyond. Well before microorganisms were discovered, the Egyptians, Greeks, Romans and Aztecs used copper-based preparations to treat burns, sore throats and skin rashes, as well as for day-today hygiene. Copper was also used to ward off infection in battlefield wounds. In the 19th century – with the discovery of the cause-and-effect relationship between germs and the development of disease – scientific evidence started to be gathered. Most recently, in the last few decades, extensive research has been carried out on the antimicrobial properties of copper and its alloys against a range of microorganisms threatening public health in food processing, healthcare and air conditioning applications. The latest exploration of copper as an additional infection control measure was a large-scale, US Department of Defensefunded intention-to-treat, randomised control trial.
ICU at Memorial Sloan-Kettering Cancer Center
84 INTERNATIONAL PHARMACEUTICAL INDUSTRY
ICU at Memorial Sloan-Kettering Cancer Center Conducted at the Medical University of South Carolina (MUSC), Ralph H Johnson Veterans Administration Medical Center and Memorial Sloan-Kettering Cancer Center between 2007 and 2011, the study aimed to assess copper’s antimicrobial efficacy in intensive care units (ICUs). The institutions replaced stainless steel, aluminium and plastic touch surfaces with antimicrobial copper (hereafter referred to as ‘copper’ in this section) on the following frequentlytouched objects within selected rooms in each of the ICUs: • • • • • •
Bed rails Nurses’ call devices IV drip poles Monitor bezels and data input devices (computer mice, laptop keyboard bases) Over-bed tables Chairs.
During the trial, the level of bacterial contamination on matched copper and non-copper surfaces was determined weekly. No changes were made to clinical practices or cleaning regimes in the study rooms. The trial – conducted by infectious disease clinicians led by Dr Michael Schmidt, Professor and Vice Chair of the Microbiology and Immunology Department at MUSC – had three distinct stages. The first stage established the baseline microbial burden on the frequentlytouched objects in ICU rooms before installation of the copper products. The average microbial burden of the rooms was found to be 16,885 colony forming units (cfu) per 100 cm2. The key surfaces shown to be most contaminated and, not surprisingly, in closest proximity to patients and visitors, were replaced with copper components. The second stage was the replacement of the most contaminated touch surfaces with copper, and subsequent comparison of the microbial burden on these and
non-copper equivalent surfaces over a period of 135 weeks. Eight rooms were upgraded with copper and matched with control rooms across the three sites. The first paper published reported the average bioburden observed on copper surfaces was 83% less than on the noncopper surfaces (465 vs. 2,674 cfu/100 cm2; P = <0.0001, see Figure 1)1. Another paper showed the importance of the hospital bed rails as reservoirs of contamination, and that standard rails
Figure 1: Sustained reduction of microbial burden on common hospital surfaces through introduction of copper. Proposed hygiene standard level is indicated in orange. Schmidt M G et al., JCM. 2012.
became recontaminated significantly more rapidly than copper after disinfection (at 6.5 hours 434 vs. 5,198 cfu/100 cm2; P = 0.002). In the third and final stage, the incidence of healthcare-associated infections in ICU rooms with and without copper products was assessed. During the patient phase, 650 randomly assigned admissions were studied throughout 104 weeks. The number of copper components in the individual rooms was recorded throughout each patient’s stay, e.g. whether or not the patient was in a bed with copper rails (bariatric patients needed special beds, which were not available with copper rails). Patients were allocated to rooms randomly and their medical condition was assessed according to APACHE II scores. A retrospective assessment of records by clinicians, blinded to patient status, assessed whether individuals contracted an HCAI. The key paper from this phase was Spring 2014 Volume 6 Issue 1
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published in an ICHE Special Topic Issue: The Role of the Environment in Infection Prevention in May 2013: Copper Surfaces Reduce the Rate of HealthcareAcquired Infections in the Intensive Care Unit. It reports a greater than 50% reduction in HCAIs associated with copper rooms. Statistically this reflects a reduction in HCAIs in patients cared for in copper rooms versus standard rooms 10 (3.40%) vs. 26 (8.12%); P = 0.013). The paper also reports a significant association between level of contamination and HCAI risk, with 89% of HCAI occurring among patients cared for in a room with a bioburden >500 cfu/100cm2; P =0.038 (regardless of the presence/ absence of copper).2 See Figure 2.
Figure 2: Quartile distribution of HCAIs stratified by microbial burden measured in the intensive care unit room during the patient’s stay. There was a significant burden association between burden and HCAI risk with 89% of HCAIs occurring among patients in rooms with a burden of more than 500 cfu/100 cm2. Salgado et al., ICHE, 2013.
Other papers from this study are in preparation and those already published have already instigated a number of discussions about larger trials in Europe and elsewhere. In summary: • In the test ICUs, touch surfaces were shown to serve as significant microbial reservoirs that could transfer microbes between patients, healthcare workers and visitors, despite regular cleaning. • Objects upgraded with copper or copper alloys consistently had bacterial burdens >80% less than equivalent objects – and below the proposed safe value of 2.5 cfu/cm2. • During the course of the twoyear study, the minimal observed oxidation did not reduce the efficacy of the copper. • Limited placement of copper surfaces significantly reduced the rates of 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY
HCAI (by greater than 50%). The copper surfaces were shown to work in tandem with standard infection prevention practices to significantly reduce burden and HCAIs. • Preliminary analysis indicates that rate of infection reduction was linked to exposure frequency. • Use of copper surfaces represents the first instance where an intervention Professor Bill Keevil designed to reduce burden has had a clinical impact among ICU Professor Keevil explains: ‘Whilst studies patients. have focused on HGT in vivo, this work investigates whether the ability of Alongside clinical trials, research into pathogens to persist in the environment, the mechanism by which copper exerts particularly on touch surfaces, may its antimicrobial effect is ongoing. Some also play an important role. We have of these indicate a wider role for copper shown prolonged survival of multidrugin preventing the spread of infection not resistant Escherichia coli and Klebsiella just in hospitals, but also in public spaces pneumoniae on stainless steel surfaces such as airports and train stations. for several weeks. However, rapid death of both antibiotic-resistant strains and There are several probably-interacting destruction of plasmid and genomic DNA mechanisms proposed by which copper was observed on copper and copper kills bacteria, including: alloy surfaces, which could be useful in the prevention of infection spread and • Causing leakage of potassium gene transfer.’ or glutamate through the outer membrane of bacteria On the significance of these findings • Disturbing osmotic balance beyond the healthcare environment, • Binding to proteins that do not he observes: ‘Copper touch surfaces require copper have promise for preventing antibiotic • Causing oxidative stress by resistance transfer in public buildings generating hydrogen peroxide and mass transportation systems, which • Degradation of bacterial DNA. lead to local and – in the case of jet travel – rapid worldwide dissemination The last of these points has been of multidrug-resistant superbugs as soon extensively explored at the University of as they appear. Southampton, where researcher Professor Bill Keevil, Chair in Environmental ‘People with inadequate hand hygiene Healthcare, has been studying the from different countries could exchange antimicrobial efficacy of copper and their bugs and different antibiotic copper alloys for over two decades. resistance genes just by touching a stair rail or door handle, ready to be picked Horizontal gene transfer (HGT) up by someone else and passed on. is largely responsible for increasing Copper substantially reduces and restricts the incidence of antibiotic-resistant the spread of these infections, making infections worldwide, which has led to an important contribution to improved an increasing number of difficult-to-treat hygiene and, consequently, health.’ HCAIs. Professor Keevil published a paper in mBio showing that while HGT Based on the weight of published can take place in the environment – on evidence – and with the expanding frequently-touched surfaces such as door availability and variety of products – handles, trolleys and tables – made healthcare facilities around the world are from stainless steel, copper prevents this installing antimicrobial copper surfaces process from occurring and rapidly kills as an adjunct to existing infection control 3 bacteria on contact. procedures, and it’s not just hospitals and clinics: public spaces such as those discussed by Professor Keevil are benefitting from copper. •
Spring 2014 Volume 6 Issue 1
Brazil’s Congonhas Airport and Chile’s Santiago Bueras Metro Station are among the first public spaces to harness copper’s hygienic properties to help protect the health of travellers using their facilities. Furthermore, in October 2013, a train on the Valparaiso Metro in Chile was the first of its kind to be equipped with antimicrobial copper hand rails and poles.
environments. They were so impressed by the results they opted to outfit their own facility with antimicrobial copper.
A copper-equipped corridor at IRM
Santiago Metro, Courtesy Cristian Barahona ‘Improving the travel experience for passengers is in our DNA,’ July Friedmann, Vice President of Alstom South Cone – who constructed the train – said of the project. ‘We’re taking the first step, presenting the world’s first copper train, and hope that other networks will be interested in the health benefits it can offer.’
‘We helped to test a particular copper alloy, which showed good antimicrobial efficacy,’ Philippe Strohl, Scientific Director for IRM, explains. ‘As our laboratory is compelled to separate its different activities in order to reduce the risks of cross-contamination via hand contact, we decided to equip it with door handles made from antimicrobial copper. Our technical staff will therefore carry less microbial burden between different laboratory areas.’
Laboratories across Europe have also begun installing antimicrobial copper surfaces to help improve hygiene. The Nestle Research Centre in Switzerland and Fraunhofer In House Centre in Germany are among the first to explore its potential.
Antimicrobial copper surfaces are solid – antimicrobial through and through, so dents and scratches will not impair efficacy and there is no surface coating to wear away. Available in a range of colours, antimicrobial copper products can be cleaned according to standard hospital protocols, in accordance with manufacturers’ instructions. Acting as an adjunct to existing infection control procedures, antimicrobial copper offers a cost-effective way to reduce surface contamination, 24/7 and in between cleans, and continuously reduce the risk of infections spreading.
Also using antimicrobial copper touch surfaces is the Institute of Microbiological Research in Mitry-Mory, France. The private laboratory assists companies with the development of disinfectant products and the management of the environmental impact of these, and recently carried out testing of antimicrobial copper alloys designed to be deployed in healthcare
References 1. Schmidt MG, Attaway HH, Sharpe PA, John Jr J, Sepkowitz KA, Morgan A, Fairey SE, Singh S, Steed LL, Cantey JR, Freeman KD, Michels HT and Salgado CD. Sustained Reduction of Microbial Burden on Common Hospital Surfaces through
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Introduction of Copper. J Clin. Microbiol. 2012, 50(7):2217. DOI: 10.1128/JCM.01032-12. 2. Cassandra D Salgado, MD; Kent A Sepkowitz, MD; Joseph F John, MD; J Robert Cantey, MD; Hubert H Attaway, MS; Katherine D Freeman, DrPH; Peter A Sharpe, MBA; Harold T Michels, PhD; Michael G Schmidt, PhD. Copper Surfaces Reduce the Rate of Healthcare-Acquired Infections in the Intensive Care Unit. Infection Control and Hospital Epidemiology, Vol. 34, No. 5, Special Topic Issue: The Role of the Environment in Infection Prevention (May 2013), pp. 479-486. 3. Sarah L. Warnes, Callum J. Highmore, and C. William Keevil. Horizontal Transfer of Antibiotic Resistance Genes on Abiotic Touch Surfaces: Implications for Public Health. doi:10.1128/mBio.0048912. 3(6): mBio.
Angela Vessey, Director of Copper Development Association in the UK, studied Physiology (BSc) at Bedford College, University of London, and Applied Immunology (MSc) at Brunel University. Her early career was in medical research in the Immunology Division of the National Institute for Medical Research. She joined Copper Development Association, a non-profit trade association in 1996 and became Director in 2001. In 2005, she initiated the Antimicrobial Copper programme in the UK to exploit the benefits of copper for preventing the spread of infection. In 2007, she commenced a partnership with University Hospitals Birmingham to deliver a clinical trial to investigate copper’s efficacy in a clinical environment. In 2010, she was appointed European Manager for a geographically-expanded Antimicrobial Copper programme to disseminate information and to work with industry to make efficacious products available for healthcare facilities. Email: angela.vessey@copperalliance. org.uk Spring 2014 Volume 6 Issue 1
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Developing a Lyophilised Portfolio The increasing popularity of biotechnologically manufactured drugs has created a challenge for the pharmaceutical companies that produce them. Such drugs are more often far more ‘delicate’ than more conventional compounds. When delivered as standard, liquid formulations in aqueous solution, they tend to be unstable, which has a negative impact on their shelf-life. One solution is freeze-drying, a process that involves extracting the water from the substance in a vacuum and at a low temperature. Before administering the drug, the freeze-dried, or lyophilised, substance must be reconstituted, which means it has to be mixed with a solvent or water. Because reconstitution is an essential part of the administration of lyophilised drugs, both developers and manufacturers must have this part of the process in mind early on, particularly when predicting the success of their drug. What makes lyophilisation and reconstitution viable, however, is the wide range of available systems that can be used as primary packaging for the lyophilised substance, from simple vials to sWFI syringes for reconstitution and special dual-chamber cartridges for pen injector systems for the homecare segment.
Over the past few years, the world of pharmaceuticals has acquired a new segment: biotechnologically produced drugs, i.e., substances made up of complex molecules. While such compounds are very effective, they are also very sensitive to environmental influences, and often do not remain stable in aqueous formulations. Lyophilisation, a process of ‘preservation’ that actually dates back thousands of years, is one of the more effective ways of giving these new drugs greater stability and a longer shelf-life, while still maintaining their effectiveness. For drug manufacturers, the challenge may at first appear daunting, but it is one that must be met if the compounds being developed are to be successful. According to statistics by the Food and Drug Administration (FDA), lyophilised drugs now account for nearly one-third of all FDA approvals for parenteralia. And, that figure is expected to rise to fifty per cent in coming years. Freeze-drying is a complex process that has evolved considerably over the past years and has proven its worth in the market. Today, exact dosing and substance utilisation is possible even with small filling volumes. Nevertheless, freeze-drying a product is quite complex and takes place in several steps. A
solution is first prepared which has certain thermal properties that will in turn suggest lyophilisation temperatures and pressure. As temperatures drop, the freeze-drying cycle lengthens. The drying part must then take place without collapse or ‘meltback’, which would compromise the product quality. Thus, designing an efficient and effective product requires perfect formulation right from the start, with the right excipients and auxiliary substances such as buffer salts, bulking agents, stabilisers and tensides. These substances are used to stabilise the complex molecular structure and its resilience in the face of the freezing. Among the other aspects of lyophilisation that need careful control is the primary packaging and its various components, some of which come in direct contact with the product. Every material has certain properties, such as heat conductivity. Such properties determine important considerations that must be taken into account, such as the distance between the substance and the cooling plate. Because the drug must be made ready for commercial manufacturing later on, exact calibration of formulation and packaging will be required to optimise costs. A final consideration is who will deliver the drug and who will receive it. That is to say, how will the drug be reconstituted, and in what vessel? Trained professionals, for example, will already be familiar with the use of vials, which, though a simple system, still requires skill. Dual-chamber syringes are quick and efficient, but more demanding to fill. For drugs in the trending homecare market, more complex systems like dual-chamber cartridges combined, for instance, with pens, ensure proper reconstitution and precise delivery. So, a company offering lyophilisation technology must have a number of specialities and offer a wide spectrum of packaging solutions. Vials consist only of a glass body and a stopper (secured by a crimp cap), which limits the risk of incompatibilities. They are also practical because the lyophilisation process is a standard in the industry.
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They hold from 0.1 ml to 200 ml of a substance or liquid and can be used for single or multiple doses. The large inner diameter means a fairly large product surface in relation to their filling volume. This facilitates heat transfer and rapid sublimation during drying. Vials do increase the loss of API, however, Lyophilised vial because the assurance of proper dosage often means they have to be overfilled.
Dual-chamber syringe Vetter Lyo-Ject速 (diluent & lyophilised product)
Dual-chamber syringes are more difficult to assemble than vials but are simpler to use, since the lyophilised substance and the solvent are in the same vessel. They consist of a glass tube divided into two chambers by a stopper. Another stopper is placed at one end, and a plunger
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and closure system is also attached. The syringe body and components must be siliconised in order to obtain suitable break-loose and glide forces. The time needed for drying could be longer than with vials due to the small diameter and the geometry of the frozen matrix during drying, which offers more resistance. Moreover, freeze-drying occurs on the middle stopper which is a few inches away from the cooling plate. Dualchamber syringes are well suited to single doses and filling volumes ranging from 0.1 ml to 5 ml. The substance is inside the injection system, so less overfill is needed, resulting in less API loss.
Dual-chamber cartridge V-LK速 (diluent & lyophilised product)
Dual-chamber cartridges are similar to dual-chamber syringes with a membrane for needles instead of a closure part. Special cartridge closures are used that can be sealed in the lyophiliser, creating a nitrogen atmosphere over the product that helps maintain the low
residual moisture. The specifications and tolerances for the outside measurements and break-loose and glide forces have to be taken into consideration. Dualchamber cartridges provide fill volumes of 0.1 ml to a maximum 1 ml for single and multiple doses. The system is ideal for use in pen systems and simple drug delivery. Of course, final assembly of the dual-chamber cartridge requires careful calibration with the pen system. The choice of a delivery system depends largely on two related factors. The primary issue is the end-user or beneficiary and how well versed are they in injecting drugs. Considerations include whether or not the users are professional caregivers in a clinical surrounding, or non-professionals like the patients or their family members. Another factor manufacturers must take into consideration is the competitive environment in which the drug will be marketed, i.e., do similar products exist on the market? Solid Reference The modest vial is the first choice for pharmaceutical and biotech companies wanting to put a lyophilised product on
Spring 2014 Volume 6 Issue 1
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the market. The processes required to fill them are virtually standard, and they have a well-defined regulatory pathway for submission. With vials, manufacturers can avoid risks in the clinical phases. They gain time and can, therefore, make better use of their patent protection. The drawback, however, is that the reconstitution requires several steps. Handling demands properly trained users, including nurses, doctors and other such caregivers. To extend the range of users, some companies add a special adapter with a luer lock connection. Cannulas are only needed for the injection process, not for reconstitution, which considerably reduces needlestick injuries, particularly among unpractised users. Accurate dosage when using vials is a risky proposition for non-professionals, so one way companies try to help out is by offering prefilled syringes with sterile water for injection (sWFI). These
Sterile water for injection syringe
systems contain the exact amount of solvent needed to obtain the right dose. A luer lock system can be used to connect syringe and vial, further easing the process. By combining vials and sWFI syringes, pharmaceutical companies can introduce a new drug, even in a highly competitive environment, because the system is user-friendly and stable. But few companies offer a comprehensive filling service for sWFI syringes. However, some contract development and manufacturing organisations (CDMOs) provide special sWFI programmes that allow the drug manufacturer to focus on their core competences. In fact, these service providers often have a range of solutions available that can support pharmaceutical companies in the development phase. The top players will deliver the systems together with stability data and approval documents to comply with USP, Ph.Eur., PH.J., and ICH guidelines. Renewal of stability data and a portfolio of standard services for filling volumes of up to 3 ml should be considered routine, since preliminary work has been clarified in bracketing concepts that cover the smallest to the largest volumes. Process capability of the needed formats, validation of the terminal 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY
sterilisation and filling processes, as well as documentation of the stability data are all part of the package. These services are particularly useful to manufacturers since they can avoid having to generate their own stability data which reduces development times and time-to-market. Drug manufacturers need a certain amount of flexibility to allow them to adjust dosing during the development process. A standardised sWFI programme gives drug manufacturers an efficient way to offer lyophilised drugs in a vial with an additional user-friendly aid system. To keep costs in check, they might also offer stability data for up to five years. The Lively Markets In their study, “The Global Use of Medicines: Outlook Through 2016,” IMS Health suggests that over the next three years, approximately one-third of all new molecular entities will be in the “follower therapies” category. This trend is compelling pharmaceutical and biotech companies to deal with growing competition. Meanwhile, the share of generics will gradually increase to 35 per cent of the total market. To remain competitive, pharmaceutical companies can rely on service providers to give support, especially if that provider is ready with long-term concepts covering product lifecycle management and packaging. The dual-chamber systems described above do endow a product with a unique selling proposition that is able to differentiate it from lyophilised drugs packaged in vials. The convenience of reconstituting the drug inside a system in one easy step and having doses readied makes injecting a lyophilised drug a lot easier for the user. These all-in-one solutions also mitigate the residual risk of needlestick injuries. Nonprofessionals can safely use the injections without worry thanks to the application of special safety needles. For drugs with multiple dosing, dual-chamber cartridges can be inserted into modern pen systems, which means that the drugs can be made available for children and older patients. This not only gives drug manufacturers access to different market segments, but will also please insurance companies, which stand to gain from the additional scope of patients at home. The Future Cycles The pharmaceutical market is volatile, and companies should look far ahead
in order to enable a competitive edge for their drug. The range of packaging solutions for lyophilised substances does support profitable product lifecycle management. There are several steps, however, that should be worked out ahead of time. Typically, a drug in a vial can establish a foothold in a market without competition fairly easily. When a competitive product enters the market, focus should move to the user perspective. Solutions like the adapters together with sWFI syringes or the standardised sWFI programme mentioned above generate added value. For standalone features, the drug can also be filled into a dualchamber system. The key, however, is long-term partnerships with an experienced contract development and manufacturing organisation (CDMO) that can provide efficient solutions to the set of challenges revolving around lyophilised substances. Besides the experience, the service provider should also be able to offer packaging solutions and manufacturing and lyophilisation expertise. Such a partnership will give pharmaceutical and biotech companies a product that differentiates itself from the competition on the market via simple and safe handling. These products will also be ready for the changes that might occur in the market, provided that the CDMO has done the necessary planning and design in the earliest stages of development already. Lyophilisation may often be considered too complicated and risky. But with the right partner, it can very quickly become the best solution to meet the challenges of the future pharmaceuticals market. Thomas Otto has been a Managing Director of Vetter Pharma-Fertigung GmbH & Co. KG since December 2002. He joined the company as a project engineer in 1990 after graduating from the Technical College in Stuttgart with an engineering degree in packaging technology and print processing. From 1995 to 1999, Otto managed the department of packaging materials development. From 2000 to 2002, he directed the department of research & development as Vice President. Email: email@example.com Spring 2014 Volume 6 Issue 1
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The Importance of Critical Temperatures in Freeze-drying Freeze-drying, or lyophilisation, is an important technology that is used across a wide range of high-value industries. In the pharmaceutical industry it is used to produce powders for tablets and to preserve vaccines, proteins, blood components and medicinal compounds. In order to freeze-dry products thoroughly, and to ensure consistent quality and activity in the reconstituted product, it is vital that the freeze-drying cycle is designed specifically for each material. This also applies to different formulations of products, since the choice of excipient can have a marked effect on the thermal characteristics. Specialist techniques such as freezedrying microscopy and differential thermal analysis can be used to determine the critical temperatures of samples of the material. This makes it possible to design robust and efficient freeze-drying cycles. The Benefits of Freeze-drying Lyophilised products can be stored easily, shipped cheaply and reconstituted safely. This makes it easier to manage product demand and reduces the dependence on cold-chain transport and storage. Freeze-drying can also increase product lifetime. For example, freezedrying a vaccine can extend its useful life from just a few hours to several months or years. The high surface area of freeze-dried products enables them to be reconstituted quickly and easily by the re-introduction of the solvent, which is usually water. This is particularly valuable in the case of emergency vaccines and antibodies, making it possible to transport and administer them in challenging situations such as emergency scenes, battlefields and remote or undeveloped sites. Because freeze-drying is a lowtemperature preservation method, it can be used on heat-sensitive drugs and biologics, largely avoiding the decomposition or loss of activity experienced under high temperatures. This also makes freeze-drying useful in
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Figure 1: The stages of the freeze-drying cycle. the production of dry pharmaceuticals that can be milled to a powder and formed into tablets. Solutions can be sterile filtered immediately before being transferred to vials and freeze-dried. The Freeze-drying Process The freeze-drying process consists of three main stages: freezing, primary drying and secondary drying. Freezedrying takes place in purpose-built driers that provide the required temperature and vacuum control. Freeze-driers may be small benchtop units for small-scale laboratory work, or large scaled-up facilities for manufacturing. The product is usually placed in partially-stoppered vials of between 2ml and 50ml capacity, before being placed on a shelf in the freezedrying chamber. The stages of the freeze-drying cycle are illustrated in Figure 1. Freezing: The liquid sample is cooled below its critical temperature. The rate of freezing and the final temperature are both important to ensure complete freezing and an optimal crystal structure in the frozen material. Primary drying: The pressure is reduced until the frozen ice is removed by sublimation.
Secondary drying: Much of the remaining unfrozen water is desorbed under vacuum. The freezing and secondary drying stages can typically be completed in hours. Depending on the critical temperature of the formulation, and its concentration and fill volume, primary drying will take hours to days to complete. The Importance of a Well-designed Freeze-drying Cycle In order to ensure that products are freeze-dried effectively, it is important to design the freeze-drying cycle for each formulation of each product. Each formulation has different physical characteristics and will behave differently as it moves through the lyophilisation cycle. A well-designed freeze-drying cycle will use a temperature gradient that will create and maintain an optimal and fully frozen structure. This may include techniques such as annealing, which is the process of raising the temperature during freezing in order to create the desired crystal structure. An open ice crystal structure is desirable in order to allow the subliming solvent to escape easily during primary drying. The key balancing act for a successful
Spring 2014 Volume 6 Issue 1
LYOCONTRACT GmbH - Your reliable partner for development and manufacture of liquid and freeze-dried drugs in vials
LYOCONTRACT GmbH, a new and future oriented pharmaceutical company, started manufacturing in 2012 after receiving its manufacturing license according to § 13 of the German Drug Law (AMG) and GMP certification. The core business is the development and GMP conform manufacture of parenterals according to customers orders. A filling line from Bosch and a freeze-dryer from HOF Sonderanlagenbau for the manufacture of parenterals in liquid or freeze-dried forms are the main focal point of the production facility. LYOCONTRACT possesses extensive professional knowledge and years of experience in contract manufacturing and can offer its worldwide customers the highest degree of quality in the manufacture of products. The Story: The owners of LYOCONTRACT GmbH, Dr. med. Milan Č. Pešić - physician, and Ms. Ruth Barg - MBA, both from Bad Harzburg, Germany have more than 30 years of practical experience in sterile filling and freeze-drying. They were very successful in pharmaceutical contract manufacturing with the internationally recognized company THYMOORGAN in Vienenburg, Germany until they sold it in 2006. Dr. Pešić and Ms. Barg have used their extensive knowledge and competence in the manufacture of sterile and freeze-dried drugs to build a new, highly modern manufacturing plant.
The Construction Phase: High value was placed on quality German work and GMP conformity during the construction of the new company. The most prestigious manufacturers of pharmaceutical equipment and production lines were contracted. During the conceptualization of the building, future expansion of the space and media for two additional freeze-dryers was already planned. The increasing requests for lyophilization capacity have lead to the fact that, exactly one year after the start of production, an order for another freeze-dryer with the same size and capacity as the current freeze-dryer was given to HOF Sonderanlagenbau.
up to 24,000 vials per hour (2R vials), has the latest Bosch technology. During the design of the system, the possibility of using dedicated and disposable equipment was taken into consideration. The automatic loading and unloading system from Motus Engineering is also located under the RABS system and ensures a person-independent loading of the freeze-dryer. The freeze-dryer has an ice capacity of 400 kg and a total shelf area of 29m²; it is possible to freeze-dry up to 126,000 vials (2R) in one freezedrying cycle. The vials are crimped in the high-performance closing machine by groninger. The labeling is done with the labeling machine by Bausch + Ströbel.
Building a team of qualified and motivated employees was important in order to create conditions for a highquality production site with competent and highly trained personnel. Production Process: The preparation of the formulated solution is done under a laminar flow from Ziel. Mixing containers are available in sizes up to 500 liters. The filling and freezedrying process are fully automated and under a RABS system (restricted access barrier system) in a clean room. The filling machine, with a volume of
The Future: In addition to product and process development, the research and development department offers the optimization of freeze-drying programs in their own development lyophilizer. LYOCONTRACT GmbH is an independent, family business. Dr. Milan Č. Pešić has appointed his successor early on by naming his daughter Dr. Katrin Pešić as general manager. With their high quality products, extensive knowledge and years of experience it is the goal of LYOCONTRACT to establish themselves as a leading contract manufacturer on the pharmaceutical market through flexibility and by meeting deadlines as a reliable and competent partner. LYOCONTRACT GmbH Volker Kobbert Buiness Manager/ Authorized Representative Dr. Michael Schön Head of Production Pulverwiese 1, 38871 Ilsenburg, Germany Tel: +49 (0) 39452/48 29-0 Fax: +49 (0) 39452/48 29-199 E-Mail: email@example.com Visit our website: www.lyocontract.de
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Spring 2014 Volume 6 Issue 1
The Effects of Freeze-drying at Different Temperatures Every formulation has a critical temperature, below which it must be cooled for complete solidification. The sample must be kept below this temperature during primary drying, otherwise there is a risk of sample collapse or incomplete drying. To design a freeze-drying cycle on a rational basis, the following information should be identified: •
Figure 2: The effects of freeze-drying above or below the critical temperature. lyophilisation cycle is to keep the temperature of the frozen material low enough during the drying phases to ensure that the material remains fully frozen, yet not so low that sublimation stops. This is an important factor, since the lower the temperature, the longer the primary drying phase. If the material is not kept at a low
The resulting temptation is often to opt for a conservative freeze-drying cycle, in order to be sure that the temperature is kept at a low enough level to ensure a robust cycle. However, freeze-drying at too low a temperature leads to inefficient drying, which is expensive in terms of both time and energy.
Tc – Collapse temperature. This is the temperature at which an amorphous material softens to the point of not being able to support its own structure while being lyophilised. • Teu – Eutectic temperature. This is the temperature at which a crystalline solute material melts, preventing any structure forming after the solvent has been removed. • Tg’ – Glass transition. This is the temperature at which a frozen amorphous material changes from a brittle to flexible structure. Figure 2 illustrates the importance of maintaining the product temperature below Tc, and the results of freeze-drying at different temperatures. The product that was dried with a temperature above Tc has suffered a complete collapse of structure. The product dried at Tc has a partially collapsed structure, which may not be immediately visible to the eye, but is likely to have quality implications. Finally, the product dried below Tc shows an excellent freeze-dried cake.
Figure 3: Freeze-drying microscopy is used to observe the movement of the sublimation front across the material. This makes it possible to identify the events during freezing and drying. enough temperature during drying, there is a risk that the solute structure will collapse and the product will not be fully dried. This leads to a poorly-preserved product that may not reconstitute well. In the case of pharmaceuticals this is an important quality consideration, and documented freeze-drying cycles can be required by regulatory bodies. 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Manufacturing efficiency and quality are both well served by investigating the freeze-drying behaviour to determine the critical temperatures for each unique formulation so that the best freeze-drying cycle can be implemented.
Determining the Critical Temperatures for a Given Formulation There are two main techniques for determining the critical temperatures for a given sample. These are freeze-drying microscopy and differential thermal analysis combined with impedance analysis. When used by experts, these technologies enable the determination of the critical temperatures, allowing for the development of safe and efficient freezedrying cycles for each formulation. Freeze-drying microscopy (FDM) is essentially the process of observing the freezing and sublimation behaviour of a small sample through a microscope. It can be used to identify temperatures at which visible changes occur, together with relative drying rates1. FDM can be used to visually identify Spring 2014 Volume 6 Issue 1
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softens. Impedance analysis can detect possible structural changes or molecular mobility which can contribute significant information on sample behaviour.
Figure 4: As the temperature is raised, the exact point of collapse (Tc/Teu) is observed using FDM. events that occur during freezing and drying (Figure 3). As the temperature is raised, the exact point of structural loss (Tc/Teu) can be determined (Figure 4). A complex material such as a pharmaceutical formulation can provide many challenges for freeze-drying, and often additional information on the behaviour of the frozen product is required. This can be provided by analysis of the thermal events and impedance changes within the frozen product.
The measurement of ZSinφ, which is a function of electrical impedance, has enabled mobility increases to be identified below traditional critical temperatures2.
The Benefits of a Well-designed Lyophilisation Cycle Once a formulation has been analysed and the critical thermal events have been determined, a cycle can be developed that is cost-effective, safe and robust. This scientific approach to the development of lyophilisation cycles results in confidence that the freeze-drying cycle will result in a product that has good stability, a long shelf-life and a known activity. In addition, the manufacturer can have confidence
Since these analysis techniques require a trained expert to be confident of a good analysis, many companies choose to outsource the design of their freezedrying cycles. The following real industry example illustrates how outsourcing the design of a freeze-drying cycle can lead to significant increases in efficiency. Reducing Freeze-drying Time by 25% The freeze-drying company BTL was asked to reduce the freeze-drying time for a product that was being dried using a conservative cycle with a duration of 61 hours. The formulation was analysed using the freeze-drying microscope Lyostat2. This identified a Tc range of –18.6°C to –17.4°C. Differential thermal analysis using Lyotherm2 identified a softening event in the impedance at –25.0°C (Figure 5). A freeze-drying cycle was carried out that was designed to maintain the product temperature below –30.0°C, allowing a 5.0°C safety margin below the lowest critical temperature identified. The final cycle was 45 hours long, resulting in a saving 16 hours of freeze-drying time compared to the original cycle, a greater than 25% improvement. References 1. Zhai et al., 2003 2. Martin et al., 2007
Katriona Scoffin is a freelance science writer working for the freeze-drying company BTL. BTL is a UK based company that supplies freezedrying equipment and offers a formulation analysis and freezeFigure 5: The critical temperatures identified by impedance and differential thermal drying cycle design service. They have analysis. DTA using Lyotherm2 identified a softening event in the impedance profile at analysed and developed efficient –25.0°C freeze-drying cycles for hundreds of samples from small drug molecules to Differential thermal analysis is used to that the product will have a cosmetically large complex bio-molecules for many observe the exothermic or endothermic acceptable cake, low moisture levels and companies worldwide. Email: firstname.lastname@example.org changes as a solution freezes, melts or a rapid rate of rehydration. 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2014 Volume 6 Issue 1
Interpack 2014 Fully Booked Again
Once again in 2014, interpack is emphasising its role as the world’s most important trade fair for the packaging sector and related processing industries. All the available spaces in the Düsseldorf exhibition centre with its 19 halls are booked out. As in previous editions, from 8 to 14 May 2014 about 2700 exhibitors are expected from industries ranging from food and beverages, confectionery and baked goods, to pharmaceuticals and cosmetics, non-food consumer goods, industrial goods and related services. At the last event in 2011, there were 165,000 visitors, of whom 84 per cent indicated that they were involved in decision-making processes in their companies. New Parallel Event: “components for processing and packaging” Interpack is reinforcing its leading role by offering visitors innovative special topics alongside the extensive range of offerings provided by exhibitors. “components for processing and packaging” is an event being staged for the first time in 2014 as an additional exhibition for suppliers to the packaging industry. Companies who are engaged in drive, control and sensor technology, products for industrial image processing, handling technology, industrial software and communication, and complete automation systems for packaging machinery, are invited to exhibit in the Düsseldorf “Stadthalle” in Congress Centre South (CCD Süd). Manufacturers of machine parts, components, accessories and
peripherals, as well as those who manufacture components and auxiliaries for packaging means, are also invited to grasp the opportunity to present their products directly alongside interpack during the first three days, from 8 to 10 May. interpack visitors and exhibitors have direct access to components for processing and packaging. And of course, the same applies vice versa. METAL PACKAGING PLAZA 2014 Interpack 2014 will again feature the METAL PACKAGING PLAZA in Hall 11. This special theme also premiered at interpack 2011 where its metal-inspired stand concept created a new meeting point for the international metal packaging community and its supplier industry. The proven concept of this special exhibition will be continued at interpack 2014 by the organisers VMV (the German Metal Packaging Association) and Empac (the European Metal Packaging Association). SAVE FOOD Congress and INNOVATIONPARC PACKAGING On 7 May 2014, one day before interpack opens its doors, the SAVE FOOD Congress will commence in the Congress Centre South (CCD Süd). This two-day event is directed at both nonprofit organisations and industry. It highlights the topics of global food loss and food waste, and explores the aspects involved, addressing a broad public audience. The SAVE FOOD initiative is a co-operation between the Food and Agriculture Organisation of the United
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Nations (FAO), the United Nations Environment Programme (UNEP) and Messe Düsseldorf. The congress supports the fundamental aims of the initiative, which seeks to network key actors in business, politics and research to instigate a constructive dialogue between all parties. The industries involved in the food, packaging and logistics sectors have an especially important role to play in the SAVE FOOD initiative. Hence, the special show INNOVATIONPARC PACKAGING (IPP) 2014 will also be staged under the motto of SAVE FOOD. Participating companies from all stages along the value chain are invited to showcase their solutions for avoiding food loss and food waste. Interpack will be open daily from 10 a.m. to 6 p.m. from 8 to 14 May 2014. Via online presales at www.interpack.com, a one-day admission ticket costs €49 (€60 at the gate). Schoolchildren, students and apprentices/trainees pay a reduced rate of €13 at the gate. A three-day ticket can be purchased via online presales for €99 (€120 at the gate). Visitors can print out all eTickets they purchase online from their own computer. All admission tickets and exhibitor passes to interpack 2014 entitle the bearer to free travel to the trade fair and back on the buses, trains and trams of the regional public transport network VRR (Verkehrsverbund Rhein-Ruhr) which also serves towns in a large radius around Messe Düsseldorf.
Spring 2014 Volume 6 Issue 1
To Deliver an Exceptional Customer Experience.
Successful Clinical Trials Start Here. We believe our customers deserve nothing less than exceptional service, at every stage of their productâ€™s development, from each phase of clinical development to successful commercialization. Our experienced team offers expertise in all aspects of clinical packaging, storage, and distribution services. We are with our clients every step of the way, providing scalable solutions to support the earliest Phase I studies to the largest global Phase III/IV studies. The ultimate measure of success is commercialization of your product, and PCI helps navigate the clinical phases in launching over 50 new products a year. Our expertise helps clients bring products to market efficiently and effectively, with keen insights to enable launch and commercial success. With an expert team focused on your investigational product, PCI is uniquely positioned to support your product throughout its life cycle.
Clinical Trial Services
Global Storage & Distribution
Life Cycle Support
Exceptional customer support for the success of your clinical trial.
PCI - One Partner for all your development needs.
Global Reach with 14 packaging facilities in North America and Europe
www.pciservices.com ÂŠ Copyright 2013 Packaging Coordinators, Inc. All Rights Reserved. AndersonBrecon (UK) Limited trading as Packaging Coordinators, Inc. is a company registered in England and Wales with company number 02543975 and VAT registration number GB 549 7026 19 whose registered office is at The Broadgate Tower, Third Floor, 20 Primrose Street, London, EC2A 2RS
A New Type of Pharmaceutical Vial Managing the Risk of Delamination
If we only take a look at the FDAâ€™s list of drug recalls and enforcement reports, we will see that the number of recalls due to delamination is on the rise. Pharmaceutical companies and packaging manufacturers are faced with the challenge of solving this problem. With this in mind, our company started the year by launching a new solution: pharmaceutical vials that minimise the risk of delamination, which can then be determined by applying a threshold value. This is achieved using an optimised manufacturing technique and a patented Quicktest.
can also cost companies a lot of money. If we assume that an average product is worth $10 for each filled vial that is recalled, this would mean American drug makers lost $1 billion between 2006 and 2011. Additional costs can result if these companies are actually forced to stop manufacturing their products, or investigate what is causing delamination and ultimately switch to using a different packaging product.
The problem of delamination is also of great concern to the regulatory authorities. The FDA, for instance, wrote a letter to the entire pharmaceutical industry for the first time in March 2011. In April 2012, the US Pharmacopeial Convention (USP) introduced the draft of the chapter <1660> that describes methods by which the stability of the inner glass surface can be better predicted and controlled. The FDA generally demands stricter risk management of pharmaceutical companies in order to get a grip on this problem. Therefore, companies are approaching their packaging manufacturers and demanding that the appropriate measures be taken. We take this demand extremely seriously. After years of intensive research and development work, we now come up with a completely new solution. â€ƒ Optimised Manufacturing Vials for injectable pharmaceutical formulations consist of borosilicate glass of the hydrolytic class 1 (USP <660>, EP 3.2.1, ASTM E438). The glass tubing is manufactured to start with and then shaped into vials during a second process. The process of forming glass tubing into containers, in other words the second high-temperature step in manufacturing vials made of glass tubing, has a significant impact on the tendency
The term delamination refers to the detachment of glass flakes from packaging as a result of interaction between the pharmaceutical formulation and the inner glass surface. Delamination usually occurs with drugs that have been stored for longer periods of time. Although no cases are known in which the glass particles actually caused harm to patients during injections, this still poses a potential risk. With intravenous injections, for instance, this could cause embolisms, thrombosis or venous inflammations. Furthermore, a subcutaneous injection could cause foreign body granulomas or the immune system to be activated unintentionally. Recalls on account of delamination 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2014 Volume 6 Issue 1
a comparative warehouse study. In this case, formulations that are known to have caused recalls due to delamination in the past were used. The result: the vials monitored for delamination that were filled with a 15 per cent potassium chloride or 10 per cent sodium thiosulfate solution remained stable at 60째C even after twelve weeks. No glass flakes were generated nor did a reactive zone form, while conventional vials showed clear signs of initial delamination. These tests were performed using high resolution SEM-EDX and ICP-OES.
of delamination to occur. Volatile components like boron and sodium evaporate, especially while the base is being formed. These substances then form inhomogeneous spots on the glass surface near the bottom. The respective positions are even more susceptible to delamination. The vial manufacturing process has been optimised in two different respects. On one hand we improved the forming process so that the inner glass surface near the bottom is now more homogeneous. The surface near the bottom is thus nearly as stable as the rest of the glass body. On the other hand, a newly developed Quicktest can be performed to determine very quickly how likely it is that delamination will occur. This means the risk of delamination can now be monitored for the first time ever. Our patented Delamination Quicktest is performed by removing several sample vials from production and subjecting them to a corrosive steam atmosphere
in autoclaves. Now, any inhomogeneous spots that are more likely to experience delamination can be identified in the glass surface. Next, the vials are filled with water and sodium is extracted from the glass surface inside an autoclave. The sodium content extracted is then determined with the help of atomic absorption spectroscopy. In the past, pharmaceutical companies had to subject their vials to visual inspections using a stereomicroscope after autoclaving in steam. Inhomogeneous spots on the inner glass surface can then be seen as distinct blurred rings and/ or colour interference rings in the zone located near the bottom. This is where delamination begins at some point in the future. We have succeeded in correlating the detection patterns with the sodium content with the help of stereo microscopy. This correlation makes it possible to replace stereomicroscopy with absorption spectroscopy as an indicator of how likely it is that delamination will occur at some point in the future. The latter method is much better suited for reaching immediate conclusions during everyday production operations. The Delamination Quicktest is used in order to monitor the values of the sodium content extracted during the forming process, and thus the tendency of delamination to occur with the vials it manufactures. Improved and monitored manufacturing results in higher chemical stability and reduces the likelihood of delamination occurring. Resistance to delamination has been confirmed by
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Delamination Controlled Our company introduced vials that are manufactured in accordance with an improved forming process at the beginning of 2014. These products can replace the existing vials that are being used with approved pharmaceuticals and there is no need to register them again. When it comes to receiving approval for new medications, these innovative vials can offer a packaging alternative to conventional products. The requirements of the FDA referred to above still apply, however. Before a new pharmaceutical product can be introduced to the market, warehouse studies must be performed with the new vials in order to rule out interactions between the formula/ medication and the inner glass surface of the packaging. Dr. Bernhard Hladik is Head of Product Management for Pharmaceutical containers within the Business Unit Pharmaceutical Systems of the SCHOTT AG. He gained a Diploma in Chemistry of the University of Duisburg and in 1996 a Ph.D. in Physical Chemistry from the Institute of Applied Thermodynamics at the University of Heidelberg. Since October 2000 he has been working for the SCHOTT AG and held different key-functions in product management, sales as well as in development. Since 2011 he is leading the Product Management group for ampoules, vials and cartridges which includes trend mapping, innovations and strategic projects like ready to fill containers and the prevention of delamination. Email: email@example.com Spring 2014 Volume 6 Issue 1
For Highest Demands. Visit us: Düsseldorf, Germany 08 to 14 May 2014 Hall 10, Stand D99
We develop and produce sophisticated plastic functional parts and packaging for the medical and the pharmaceutical industry. Our economical standard products are tailored to the needs of small and medium-sized businesses. They help you to reduce time to market and ensure that your product is presented appealingly. Use our tailor-made solutions if our standard program does not have a solution for your application. Quality management system certified in accordance with DIN EN ISO 9001:2008 and DIN EN ISO 13485:2010. Cleanroom production in accordance with DIN EN ISO 14644-1 – Class 7 and Class C of the EU-GMP guide.
Pöppelmann GmbH & Co. KG · Kunststoffwerk-Werkzeugbau · Pöppelmannstraße 5 · 49393 Lohne · Germany · Phone +49 4442 982-3900 Fax +49 4442 982-417 · firstname.lastname@example.org · www.poeppelmann.com
Space-saving Solutions Over the past decade, the amount of information required to support many healthcare products has dramatically increased due to legislation, and consumer and retail demand. This has had several major repercussions that have led to several innovative packaging formats which offer space-saving solutions. Patient information leaflets are now found in nearly all ethical pharmaceuticals and a growing proportion of OTC medicines. This trend has been driven by EU legislation which curtailed the practice of dispensing OTC tablets / medicines in a labelled container. This has led to a growing need for supporting leaflets as dose sizes reduce and the size of the carton (i.e. area of printed information) also decreases. At the same time, there has been a dramatic increase in the average size of patient information leaflets. The surface area of a leaflet, destined for several markets, will often reflect the most detailed legislation requirements for a particular country. Legislation has also governed the minimum font size used to ensure it is readable, thereby aiding understanding. The size of a leaflet, given these guidelines, is dictated by the number of times it can be intricately folded. This has meant that some of the leaflets accompanying healthcare products have become increasingly bulky with minimum type size and awkward multiple folds. In response, a number of innovative space-saving solutions have been developed. Leaflet formats such as outserts, tagserts and wrapserts, which can be produced using complex folds, have provided much-needed space. Multiple leaflets, covering different information requirements, can also be joined together by ‘friendly’ adhesive or banded together for ease of packing. This allows different types of information, even for different audiences, such as the doctor and patient, to be banded together. Two or three folded leaflets can be joined, back to back, in this way. It has also been possible to insert these 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY
leaflet formats into the product’s outer carton, which improves packing line efficiency whilst reducing inventory / SKUs. Leaflet-cartons also provide assurance the correct leaflet is combined with the right carton and the format requires no additional capital spend. It is also possible to add a fifth panel to the carton which can be detached using a perforated tear-strip and retained by the pharmacist. An increase in perfecting units on print presses – although still very specialised – has allowed the inner part of a carton to be printed as well as the outer surface. This again provides more space for patient information and, combined with clever constructional designs, easy access to it. Other solutions include high-quality mini-booklets. Booklets are a viable alternative to folded leaflets when detailed information is required in a small, reader-friendly format. Booklets are typically credit card size with up to 150 pages, but can be produced down to a scale of 35mm x 50mm x 2.5mm. Printed in an unlimited range of colours, they can incorporate labels for accurate date identification or perforated promotional coupons. The toiletries sector is also a large user of high quality booklets, which supplement information found on exterior packaging. Another alternative is a ‘wallet card’, which is commonly used to pack pharmaceutical samples in the United States. The wallet pack’s design demonstrates the ability to combine several packaging formats in a single pack. A blister card is an integral part of the pack whilst a leaflet or insert is securely attached to the wallet card. This provides packing-line efficiencies and avoids any potential costly re-work on lines where the leaflet is inserted manually. Furthermore, it prevents a pack being sent without the required information.
Samples distributed in wallet cards allow patients to begin their medication immediately. The wallet card provides plenty of space for patient information which helps to encourage compliance. Security features can also be combined including both overt and covert technologies. As well as inserts/leaflets, it is also possible to add business reply cards or an informational booklet. The label sector too has developed many space-saving options. Leafletlabels or extended labels, which use the same space on the product as a conventional label, are nothing new. However, there have been a number of new developments which extend the use of this format. It is possible now to obtain labels with five print surfaces. These labels cleverly combine three pieces, or plies, of material together to provide additional space for more detailed product information. Labels can be produced in a range of shapes, and special inks and varnishes can be applied if required. Booklet-labels offer even greater flexibility – up to 96 pages, which covers the information requirements of even the most demanding and complex products. The role of packaging cannot be overplayed. It is the first point of communication with the patient and it is imperative that it clearly communicates to the patient in a way that is easily understood – what the item is, what it’s used for, how to use it and so on. A well-designed pack conveys information clearly and in a format that is easily understood. Bob Houghton is Chesapeake’s Head of Marketing & Communication and has been involved in the packaging sector for over 20 years. As part of his role, Bob monitors market developments both in terms of emerging trends and changes to packaging formats and styles. Emai:email@example.com
Spring 2014 Volume 6 Issue 1
eXpertFOlD 50 pharma-suitable
the eXpertFOlD 50 folder-gluer from bObst has been specifically designed with small format pharmaceutical carton making in mind. sharing all the features of the eXpertFOlD range, but with even faster set-up and a smaller footprint, eXpertFOlD 50 delivers straight-line and crashlock cartons with the high productivity and superb
quality that todayâ€™s pharmaceutical carton makers need. and, if that wasnâ€™t enough, a range of options that include the revolutionary aCCubraille Gt embossing system and, soon, the aCCuCheCK carton quality control device, mean that eXpertFOlD 50 is by far the most suitable folder-gluer for pharma carton manufacture.
Get to Know your Patient Compliance and adherence are hot topics in the pharmaceutical industry these days. The challenges companies face in bringing products through their pipelines to commercialisation, coupled with healthcare reform, leave companies looking at patient adherence to medication regimens as a new opportunity. With increased adherence to the medication and better patient health, companies can positively demonstrate the effectiveness of their particular therapeutic indication and ensure they stay on the formulary for payers. For commercially available medicines, compliance rates in the US are consistently poor, including rates quoted as low as 30% for life-threatening disease states such as diabetes, heart disease, and – astonishingly – even organ transplant recipients. Despite having significant differences in the way healthcare is administered in Europe, studies show similar poor adherence rates across the world’s most developed countries. The increasing cost of global healthcare is forcing re-evaluation of the status quo. One of the pivotal changes in the healthcare reform initiative in the United States is the introduction of a “pay for performance” model, whereby providers need to tangibly demonstrate better health outcomes to receive full compensation for their services. Centers for Medicare and Medicaid Services (CMS) introduced its five-star rating programme, whereby providers can actually receive bonus payments for achieving quality standards and including launching successful initiatives that demonstrate remarkable impact on patient health outcomes.
these programmes can be impactful on certain populations. Often programmes are costly and poorly structured, which leads to missed opportunities. What is truly unfortunate is that at the time most adherence programmes are introduced, the drug company already has many years of patient data with lost opportunities to catalogue and capitalise on those learnings. Adherence monitoring, evaluations of patient behaviour, and the principles of successful patient adherence interventions need to happen in clinical development phases. The key to affecting better patient health outcomes is identifying the myriad of reasons why the patient is non-compliant and how they interact with the drug. Reasons for non-compliance may include the side-effects of the drug or the drug in combination with other medications, patients’ cost sensitivities, poor understanding of their disease state, poor comprehension of the guidelines in how to take the drug (with or without food, morning or evening, etc.), lack of perceived benefit, and sometimes even simple forgetfulness.
In clinical study there is a unique opportunity to engage the patient and act upon feedback at a rapid rate by virtue of the sheer pace of clinical study. Changes in package design, for example, can be affected much more quickly than can those in the commercial environment where drugs are governed by their drug filing and the associated shelf-life stability in that particular format, not to mention complexities with equipment and scale. Breakthroughs in technology have enabled clinical studies to gather realtime data from patients. This can be done through web portals for patients, smartphone technologies and apps, simple SMS texting, and even technology integrated into the investigational drug packages themselves. In the controlled world of clinical administration there is also ample opportunity for patient feedback if there is structure to capture and act upon that feedback, which is the critical element for success. The ability to affect patient adherence behaviour in a clinical study is truly invaluable. The sheer cost of the investment in recruitment and enrolment,
Specifically in the area of compliance and adherence, there is ample opportunity to re-evaluate the current method of administration. Pharmaceutical companies, as well as healthcare providers, initiate compliance and adherence programmes and interventions well after the drug has been made commercially available and has demonstrated poor adherence rates. If administered appropriately,
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changes can have significant impact, as demonstrated by the recent study showing the tremendous impact of simply calendarising medications in the WalMart $4 generic programme. Wal-Mart realised significant impact on patient adherence simply by delivering product to patients in pharmacy utilising unitdose calendarised packaging rather than the traditional amber vial. They now are capitalising on those gains by introducing counselling programmes and other intervention strategies to further boost patient adherence. This is just one example of how a well-thought-out adherence programme has a measurable impact on the patient and a demonstrated ROI for the payers.
preparation of study medication, and overall administration per patient is significant. If that patient then is nonadherent to the medication, then not only has the company not recouped its investment, but the results from that patient may be detrimental to the study in affirming the effectiveness of the therapy. Given the significant cost of drug development in each clinical phase, enough poor adherences in a study could ultimately result in failure of the study itself and potentially could contribute to the end of the moleculeâ€™s pipeline development.
Successful adherence interventions would be ideally introduced in the developmental clinical phases through a focused initiative that captures, monitors, and continually addresses the results of adherence strategies, to affirm whether they are successful or need to be modified to optimise performance. This would better enable providers to build upon these successes in the commercial healthcare environment and create momentum in addressing the global adherence problem. Change is underway in the healthcare environment, and sometimes simple
A different approach to the current model can clearly yield results, and it begins in the clinical phases. With success, we can address the rising costs of healthcare while at the same time deliver better patient health.
Justin Schroeder is the Executive Director, Marketing, Business Development & Design at Packaging Coordinators Inc. (PCI). Mr.Schroeder is responsible for new account development, global marketing, and creative package design with a focus on the development and commercialization of unit dose and compliance prompting packaging. He holds a Bachelor of Science from the School of Packaging at Michigan State University, and a Master of Business Administration in Marketing from Northern Illinois University. Mr. Schroeder has been at PCI/Anderson since 2000, holding positions including Process Development / Packaging Engineer, Customer Project Manager, Director of Project Management and Planning, and most recently Senior Director, Marketing & Development Services. Previously, Mr. Schroeder held package engineering positions with Hershey Foods Corp and at the J.M. Smucker Co. (Smuckerâ€™s). Mr. Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email: firstname.lastname@example.org INTERNATIONAL PHARMACEUTICAL INDUSTRY 111
The Balancing Act of Pharmaceutical Packaging High-quality packaging is vital for any healthcare product. However, developing packaging can become challenging when specific factors are required, always with the end-user in mind.
the flexibility to meet as many different needs as possible. It is advantageous to standardise a product portfolio, this can drive high-volume synergies.
When developing pharmaceutical packaging, several factors need to be considered. Whether it’s child-resistance, tamper-proofing, stability, ease of use or efficiency for filling lines, packaging suppliers have to be one step ahead with meeting these requirements. But further to these considerations, there is a more important factor to look at: understanding the customers’ and end customers’ needs. The most important element is developing and maintaining long-term and consistent client relationships, becoming an extension to the product development team. With the end-user in mind though, two increasingly important areas are seniorfriendliness and child-resistance. Patients, especially those who have difficulty using their hands, are wanting more easy-toopen packaging for their medication, but yet there are more stringent regulations being enforced for child-resistance.
and child-resistance depends on the treatment area and target patient group, as well as the geographical areas. For instance, US legislation has driven the use of child-resistant closures. But legislation in Europe is expected to increase, considering both factors. Senior-friendliness and child-resistance is a balancing act for the packaging industry. There are a number of solutions on the market that satisfy each requirement, but the perfect solution that incorporates both does not yet exist. Optimising one factor will decrease the effectiveness of the other, which leaves packaging companies to prioritise on just one feature. Not only do companies have to meet the specific end-user requirements, such as child-resistance; there are other factors that need to be considered, such as costeffectiveness and stability. In particular, a package needs to provide a tight seal with high repeat usage and low failure rate. A unique shape or design is also important in some instances, to make a product stand out on the shelf, especially so in the OTC and nutraceuticals market.
When considering the packaging of a product, the focus of senior-friendliness
It is certainly challenging to be able to meet all the requirements on a client’s ‘wish list’, but the key is to have
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In general, pharma companies and regulatory agencies are not keen to change the way they do things because they see it increases work, cost and risk, especially in an industry that has such a big impact on health. Consequently, innovation is driven more by OTC and nutraceuticals companies, mainly for their marketing purposes and the need to attract end consumers. Continued pressure for change in the area of senior-friendliness and child-resistance also comes from patient groups, such as rheumatism associations – companies in the industry would do well to take this factor on board, but the ultimate key is to be flexible. Glenn Svedberg is Managing Director at Nolato Medical Pharma Packaging, specializing in developing and manufacturing primary plastic pharmaceutical packaging. Nolato Medical Pharma Packaging is part of the company group Nolato (www. nolato.com) and the business area Nolato Medical, a global partner within the development and production of polymer products for market-leading medical technology and pharmaceutical customers. Glenn Svedberg holds a M.Sc degree in Industrial Engineering & Management. He has worked in manufacturing companies for 20 years, in positions covering Purchasing, Marketing, Business development and Factory management. Before joining Nolato Medical in 2007, Glenn worked at Rexam, later on Polimoon/Promens where he was responsible for the “Food Nordic” division, with one site in Sweden and another one in Denmark. Email: email@example.com Spring 2014 Volume 6 Issue 1
CONFERENCES AND REVIEWS
Genesis 2013 Roundup – Ensuring Nothing is Lost in Translation The annual Genesis Conference saw 650 delegates participate in what has become one of the must-attend conferences in the life science calendar. The scene was expertly set by our four plenary speakers, Dr Louise Wood (Department of Health), Roel Bulthuis (MS Ventures), Sir Salvador Moncada (UCL) and Mike Ward (Informa). Delegates heard of the progress being made in changing what had been perceived as a relatively hostile environment in the UK to undertaking experimental medicine, towards the recent successes - 99% of NHS Trusts engaged in clinical research with 68% involved in commercial contract research. And growing. The £1Bn a year spend by the Government on clinical research infrastructure, human capital and projects being driven by relationships between better research in the NHS and improved healthcare outcomes for patients, a better international competitive standing of the UK to win investment in the sector, and the economic benefit arising from a healthier, more productive workforce for UK plc. ‘Translational Research’ seems to be used as a ubiquitous term to describe early-stage research as it moves from bench toward bedside. The availability of capital for biopharma companies was looking brighter at Genesis 2013 than it had for several years with an open IPO window in the US, venture funds raising capital, and some great deals happening between companies. There were a number of reasons to be cheerful, such as the FDA’s Breakthrough Medicines Programme being much more effective than anticipated, Sun Pharma showing that it doesn’t have to take as long to become a $2Bn company as it took to get to $1Bn, and the heating up of the US IPO market for biotechs. There were some challenges through the year though. The FDA took a somewhat negative view of consumer-directed genetic testing, the top 10 pharma saw a decline in revenues of $17Bn, and emerging markets demonstrated they would provide a bumpy ride for entrants.
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The lunchtime keynote session was led by Professor Chris McGuigan and Kit Malthouse, both setting out examples of how Government funding could help stimulate growth in the sector – Wales, with various activities such as the Arthurian Venture Fund and Ser Cymru, and the Greater London Authority, through MedCity and a soon-to-be-launched investment fund. It was suggested that the national UK Government could further incentivise early-stage investors through greater tax breaks to align early life science investing essentially with charitable donations. Breakout streams looked at some of the sector’s most creative deals and strategies and enabled participants to gain insight, for example, into the rationale behind the AstraZeneca/Bristol-Myers Squibb collaboration around the Amylin diabetes product. The debate went so far as to ask why one of the large pharma didn’t just buy the other one (which was then announced a week later!). Insights into the other selected deals and strategies, alongside debates around how we can truly progress the application of biomarker development, imaging and natural products, all enabled the delegates to consider where their company strategy, product and deal-making strategies were sitting in the wider sector. The day ended with one of the most innovative, if not challenging for the panellists, debate formats. John Hodgson chaired, asking the panellists to explain what their suggestions would be to enhance the success and competitiveness of UK biopharma. The ideas included greater pharma/NHS/payer collaboration on new medicine adoption, training of our bio-entrepreneurs by placements in eg Boston, creating exit routes for early investors as companies are built, and fully accessing philanthropic capital pools.
medicines. Mentioned earlier was the clinical research investment via the National Institute for Health Research System, but just as key is the recognition that breakthrough medicines only get discovered if first-class biomedical research is undertaken and the knowledge then used to develop better, more effective treatments. The revolution in biomedical research capacity and the associated data has encouraged the pharma industry to increasingly look to external sources of innovation to supplement their internal efforts. The pressures to reduce healthcare budgets and demonstrate value for money mean regulators and payers are seeking greater windows of benefit before agreeing to premium pricing. One of the predictions from Mike Ward was that we would see more deals involving medical technology players as drug companies feel the need to generate evidence for regulators and enhance lifecycle management of products. These outcomes are already informing the agenda for Genesis 2014. The focus will be on technologies that enable new medicine developers to demonstrate clear value to convince payers, the art of interrogating evidence in a world of Big Data such that we ask the correct questions, and how the dealmakers are assessing opportunities and their associated value. An eye on the market and reimbursement evolution and how that informs research, investment and partnering strategy will be the theme of Genesis 2014. Video highlights of Genesis 2013 and the emerging details for Genesis 2014 are available at www.genesisconference. com
The great news for the UK is perhaps the Government’s ongoing commitment to the sector and continued investment in the infrastructure and talent required to discover and develop innovative Spring 2014 Volume 6 Issue 1
CONFERENCES AND REVIEWS
The Success Continues in the Heart of London! The Anglo-Nordic region continues to be one of the fastest-growing biotech regions in the world. Now entering its eleventh year, the Anglonordic Biotech Conference provides the ideal one-stop opportunity to discover, collaborate and invest in this success. By invitation only, the conference is specifically designed to enable delegates to engage in faceto-face meetings with senior partnering executives from leading life sciences companies from the Anglo-Nordic regions and international healthcare and investment firms, helping them to expand their international business development opportunities. The conference continues to keep its popularity and is for the third time running in connection to the Anglonordic Medtech Conference III that takes place the day before at the same venue. All delegates are also invited to a private networking event at the Norwegian Ambassador’s Residence in the evening of the 9th of April. “Every year we receive the same positive feedback from the delegates. They are very happy with the format and
the size of the conference. It would be easy for us to increase the number of delegates substantially, however, the feedback we receive is that we should stay with the number of approximately 250 delegates and continue to work on www.ipimedia.com
the quality instead of the quantity,” says Mattias Johansson, Director, Anglonordic Life Science Conferences. The main focus is on both partnering and investment. The conference offers professional partnering software where delegates can pre-book one-to-one meetings and get in connection with other delegates before the conference even
started. Small and medium-sized R&D companies are offered the opportunity to do company presentations in the main conference room, which every year is visited by a large number of investment firms. There is also a large venue area
dedicated for exhibiting. Example of keynote speakers at the Anglonordic Life Science Conferences 2014: Rob Pinnock, Regional lead for UK, Spain, Portugal & Ireland, MSD Knut T. Smerud, President, Smerud Medical Research International Susan Hill, Director of Global Business Dev., Alexion Pharma International Sarl Thomas Ramdahl, COO, Algeta Prof. Johan Hyllner, CSO, Cell Therapy Catapult Roel Bulthuis, Senior Director, Head of MS Ventures at Merck Serono Eric Roman, VP, Research & Applied Markets, GE Healthcare Kari Krogstad, CEO, Medistim Benedicte Bakke, Senior Advisor, International Healthcare, DNB Bank Regina Hodits, General Partner, Wellington Partners The Anglonordic Biotech Conference XI (10 April 2014) is held in connection to the Anglonordic Medtech Conference III (9 April) at the same venue. For more information about the conferences visit www.anglonordicbiotech.com and www.anglonordicmedtech.com. Contact: Mattias Johansson, Director, Anglonordic Life Science Conferences, email: firstname.lastname@example.org
INTERNATIONAL PHARMACEUTICAL INDUSTRY 115
26th Annual I Vienna 2014
EUROMEETING Different Perspectives - One Vision: Better Healthcare for Patients.
“Anandunbiased neutral “
ACV, Vienna, Austria I 25-27 March 2014
• Participation of global regulatory agencies • The Role of Social Media in Healthcare • Patient perspective throughout the programme • Interoperability for Healthcare Providers Across the EU • Hot Topic Sessions • European Commission’s eHealth Action Plan 2012-2020 • 110+ sessions in 16 parallel themes, 300+ expert speakers • 13 pre-conference tutorials • 170+ Exhibiting companies
For all details and to register: diahome.org/EM2014
EUROPE’S PREMIER BIOPARTERNERING AND INVESTMENT CONFERENCE
2014 May 12-14, London UK WHERE GREAT MINDS, SMART MONEY AND KEY DEALMAKERS MEET Join 1000+ delegates from 30 countries at Europe’s Premier BioParternering and Investment Conference: BioTrinity 2014. Building on a reputation established over seven years of organising what is now the largest biopartnering conference delivered by a membership organisation, BioTrinity 2014 brings together R&D companies and big pharma with more biomedical investors than any other European partnering conference.
The BioTrinity Welcome Reception, Investor-Only Dinner, Connect for Drinks Reception, Big London Networking Party and Closing Drinks Reception
Interactive workshops on the latest industry trends and advice
High traffic exhibiton incorporating informal networking hubs
More than 100 corporate presentations from a hand-picked list of the best European Life Science Companies
PARTNERING Pre-arranged one-to-one meetings in private booths with 1000+ delegates
Global pharma and investors discuss financing, licensing and acquisition strategies
12-14 May 2014 London UK
Roche Signs Licensing Agreement with Sysmex Inostics GmbH for emPCR Patent Portfolio Roche announced a licensing agreement with Sysmex Inostics GmbH for its emPCR portfolio of patents. Under the terms of the licensing agreement, Roche grants Sysmex Inostics GmbH a worldwide, non-exclusive, royalty-bearing license. Through emulsion PCR (emPCR), each DNA molecule is individually isolated within its own bubble in a water/oil emulsion, which includes a capture bead and PCR amplification reagents. As a result, even though about a million molecules are prepared simultaneously, each molecule is individually amplified to one single bead, the equivalent of having a million separate PCR reactions. This technique allows for massive parallelization (high throughput) that results in a significant cost advantage over Sanger sequencing. Sysmex Inostics GmbH is primarily a clinical service lab providing analysis of free circulating tumor-DNA in plasma for prediction of drug response and for monitoring of cancer by quantifying the amount of tumor DNA to detect relapse and to detect resistance mutations, utilizing emPCR technology. Source: B3C newswire Nuevolution Announces License Agreement with Merck Nuevolution A/S has entered an exclusive license agreement with a subsidiary of Merck & Co., Inc., known as MSD outside the United States and Canada, for small molecule compounds targeting an undisclosed intracellular target for use as leads in Merck’s drug discovery and development. Nuevolution applies its Chemetics® platform to identify small molecule drug candidates for therapeutically important targets. Chemetics® uses proprietary innovative DNA labelling to allow small molecule screening at an unprecedented scale for lead discovery. The technology allows efficient screening of billions of molecules against biological targets. Nuevolution has patented its Chemetics® technology and holds a strong validated patent
portfolio within the technology field. In its existing collaborations and internal pipeline development, Nuevolution has successfully addressed several challenging targets including proteinprotein interactions by the identification of drug-like small molecules. Source: B3C newswire NBE-Therapeutics Announces Successful Validation of its SMAC™-Technology for the Generation of Antibody Drug Conjugates (ADCs) NBE-Therapeutics (“NBE”) has presented the successful validation of its enzymatic SMAC™-Technology for the generation of potent next-generation antibody drug conjugates (ADCs) at the international World ADC summit 2014 in Frankfurt, Germany. NBE’s patent-pending SMAC™Technology (SMAC = sortase-mediated antibody conjugation) utilizes highly selective sortase enzymes for sitespecific and efficient conjugation of toxic payloads to therapeutic antibodies. SMAC™-Technology allows the generation of homogeneous ADC drug substances, representing an improvement to current clinical-stage ADCs that are heterogeneous also comprising molecules with undesired properties.
the ADCC (Antibody-Dependent CellMediated Cytotoxicity) activity of one of its lead products, a bispecific anti-cancer antibody. The license is covering clinical development and production. Financial details have not been disclosed. The GlymaxX® technology for the production of afucosylated antibodies and proteins is based on the stable integration of a heterologous enzyme into any antibody producer cell line, leading to the interference with the cells’ intracellular fucose biosynthesis pathway. As a unique feature differentiating it from other approaches, the GlymaxX® technology can be applied to both novel and already existing antibody producer cell lines and entire antibody expression and discovery platforms without negatively affecting their productivity. Moreover, it is simple, rapid, potent and universally applicable. “The GlymaxX technology substantially improves the ADCC activity of one of our lead bispecific antibodies for the treatment of solid tumors so that it further enhances the tumor cell killing capacity of an already very potent molecule,” said Mark Throsby, Chief Scientific Officer of Merus B.V. Source: B3C newswire
NBE-Therapeutics’ novel ADC technology has the potential to improve the therapy of cancer. The company is now planning to leverage its validated SMAC™Technology for the development of a preclinical and clinical pipeline of nextgeneration ADC products, aimed at providing improved targeted therapies for difficult to treat cancers of e.g. breast, ovary, lung, colon and pancreas. Source: B3C newswire GlymaxX® Manufacturing Technology Improves Bispecific Antibody Activity for Solid Tumor Treatment ProBioGen AG and Merus B.V. have signed a non-exclusive commercial option and license agreement on ProBioGen’s GlymaxX® fucoseengineering technology. Under the terms of the agreement, ProBioGen is granting Merus the non-exclusive right to use the GlymaxX® technology to enhance
118 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Biopta Announces Launch of Industry’s First Catalogue of In Vitro Human Tissue Assays Biopta Ltd, the human tissue-based contract research organisation, announced a major development in discovery research with the launch of the first catalogue of assays based on human functional tissues. The catalogue Spring 2014 Volume 6 Issue 1
serves to provide the scientific community with ready access to assays that improve the prediction of safety, absorption and efficacy of drug candidates in humans. Ex vivo human tissue studies play a key part in drug development, providing pharmaceutical and biotechnology companies with a more predictive human model earlier in the development process. Many pharmaceutical and biotechnology companies have, up until now, depended solely on animal models; however, Biopta’s access to fresh functional human biomaterials means that early human tissue testing is increasingly becoming a routine part of preclinical drug discovery. Dr David Bunton Biopta’s CEO said “The literature on human preclinical pharmacology is unacceptably sparse and too many decisions on earlystage compounds are made without considering translation to human biology. By illustrating the wide range of tissues and functional endpoints that are possible in human functional P-106_HP148x210_1 06/02/2014 17:00 Page 1 tissues,
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we hope to raise awareness that drug discovery can be de-risked at an early stage.” Source: B3C newswire Promethera Biosciences successfully enrolls twenty patients in its multicentric Phase I/II trial Promethera Biosciences, a Belgian biotechnology company developing Promethera(R) HepaStem, a cell-based therapy for the treatment of liver-based metabolic diseases including CriglerNajjar Syndrome and Urea Cycle Disorders, announced the completion of patient enrolment for its first clinical trial. Promethera Biosciences is conducting a first-in-man trial with HepaStem in paediatric patients suffering from orphan diseases. This trial is a prospective, open label, multicenter Phase I/II clinical study involving Urea Cycle Disorders (UCD) and Crigler-Najjar (CN) syndrome paediatric patients. Most young patients affected by these very rare diseases have
limited therapeutic options and may die at an early age. The trial is a dose escalation study designed to evaluate the safety and the preliminary efficacy of Promethera(R) HepaStem. Promethera(R) HepaStem is an innovative cell therapy product based on the use of allogeneic progenitor cells derived from livers obtained from adult (non-embryonic) organ donors. Promethera Biosciences has successfully treated 20 patients with HepaStem in collaboration with 11 clinical centers. Given the scarcity of patients, Promethera Biosciences has conducted the trial in five countries: Belgium, France, United Kingdom, Italy and Israel. The study started in March 2012 with the first patient treated in Belgium. As of today, 20 patients aged from six weeks to 16 years have been treated with Promethera(R) HepaStem. The end of the trial is scheduled for October 2014
SMi presents the 8th conference and exhibition series...
Clinical Trial Logistics 21ST - 22ND MAY 2014 | MARRIOTT REGENTS PARK | LONDON, UK EUROPE'S LEADING CLINICAL TRIAL LOGISTICS EVENT
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PLUS INTERACTIVE HALF-DAY PRE-CONFERENCE WORKSHOP
Virtual logics: Managing quality and user acceptance testing Tuesday 20th May 2014, Marriott Regents Park, London, UK PHAR ATTEND MA Workshop Leader: Nimer Yusef, FOR Consultant and Founder, Trial-Brain £999 : 12.30pm - 4.30pm
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Spring 2014 Volume 6 Issue 1
Published on Mar 17, 2014