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Volume 8 Issue 3

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

A Practical Guide to Serialisation Four Areas in which Gene Editing Is Already Advancing the Treatment of Disease Optimising Formulation Performance Through Spray-drying Improving Patient Adherence Through Packaging

Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh EDITORIAL ASSISTANT Veronica Tomasiello BOOK MANAGER: Anthony Stewart BUSINESS DEVELOPMENT: John Donalds DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks FINANCE DEPARTMENT: Martin Wright RESEARCH & CIRCULATION: Heather Bayran 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: 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 November 2016. 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. 2016 PHARMA PUBLICATIONS Volume 8 issue 3 - Autumn - 2016

08 Regulatory Transformation: The Time is Now The emerging pharma agenda, including digital health and other bold ambitions, demands more from regulatory teams than risk containment. So the new grace period for IDMP preparations is well-timed, says Siniša Belina, senior life sciences consultant at AMPLEXOR Life Sciences, in this article. It gives the industry muchneeded breathing space – to rethink their regulatory information management strategies and deliver something greater that supports the new business strategy. 12 Food for Thought: Regulators now Hunger for Greater Control of Nutrition and Nutraceuticals As Western nations’ obsession with diet and wellbeing grows, and the lines between pharma and food begin to blur, regulators’ appetite for transparency and standards adherence is increasing. In this piece, Peter Muller of Schlafender Hase observes that their aims are to prevent manufacturers from misleading consumers, and to remove any risk of people overdosing on active ingredients. But the evolving requirements could catch some companies off guard, especially if they currently lack regulatory discipline. So it will be up to life sciences to show the way. 16 Drug Filling in Nepal: An Overview This paper, brought to us by Kaushik Devaraju, Balamuralidhara V. and T. M. Pramod Kumar at JSS College of Pharmacy, and Dr Jayasheel B Gangaiah at Alcon Laboratories, provides an overview of the pharmaceutical market and regulation involved for import and drug registration in Nepal. The Nepal pharmaceutical market is worth around Rs. 600 crores, with Nepali companies dominating at 30%, and the remainder being dominated by Indian/MNC companies and 10-15% being institutional business. With over 26.4 million people, it is a prescription-based market often influenced by retailers. 20 Barcelona and the BioRegion of Catalonia: A Life Sciences Hub in Europe With Barcelona hosting two of the most relevant events in the upcoming life sciences calendar – CPHI (4-6 October, 2016) and BIO Europe Spring (20-22 March, 2017) – the organisation Biocat offers a most timely analysis of its possibilities. The city is the capital of the BioRegion of Catalonia, the most dynamic bioregion in Spain and one of the most active in Europe. With a population of more than 7.5 million and territory comparable to Belgium or Israel, Catalonia is among the top four European countries in terms of the number of life sciences companies per capita. 24 The Effect on Companies as Medical Device and Pharma Grow Closer and Closer Angela Spang, founder, owner and managing director of JUNE MEDICAL, started her days as a sales rep in medical device with JNJ and the now discontinued Gynecare franchise, and in those days there was a very distinct line between medical device and pharma. So clear, in fact, that despite the fact that the two JNJ companies (Johnson & Johnson Medical and Janssen-Cilag) were in the same building in Stockholm, they had never had any employee crossover at all. A couple of years later, Angela was the first person ever to go from one side to the other and shares her experience. 28 A Practical Guide to Serialisation Requirements for serialisation are already active in some parts of the world and will soon be obligatory in most major markets. David Sheedy, serialisation IT deployment manager at Zenith Technologies, sets out a practical roadmap for the successful implementation of a serialisation programme and describes 14 steps to success. As we look ahead to the pending requirement for drug serialisation in the US and Europe, pharmaceutical manufacturers need to act soon or risk fines, loss of market share and damage to both reputation and stakeholder confidence. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1



30 Endothelial Receptors as Drug Targets In June, Cecilia Stroe, staff editor of IPI, attended the Faron Pharmaceuticals R&D day in London to find out all about their work in life-saving drug development. In this review, she tells you that when it comes to overcoming acute respiratory distress syndrome (ARDS), all roads lead to the mighty immune system. There are special molecules of fundamental importance for it, since they direct the cells to sites of inflammation to create an immune response. However, they are also responsible for harmful cell trafficking taking place in acute and chronic inflammations, as well as in tumour progression and metastatic spread of cancer. Therefore, these molecules are potential targets for developing drugs.

54 Securing Stability in the Airfreight Pharma Supply Chain With an increasing demand for pharmaceuticals to be shipped to patients across the globe, the role of the airfreight industry in the supply chain process has become even more pivotal. Ira Smith, Director of Strategic Development Global Transport and Logistics at Pelican BioThermal, writes an article outlining the reasons for this change. In addition to this, there is the need for high-value, highlysensitive pharmaceuticals to be shipped to more remote regions than ever before, via more complex routes, while facing more extreme temperature excursion risks. This also presents packaging manufacturers and logistics providers with greater stability supply chain challenges and risks.

34 Four Areas in which Gene Editing is Already Advancing the Treatment of Disease Chris Thorn from Horizon presents an overview of the areas benefiting from gene editing in the treatment of disease. The last three years have seen an explosion of interest in gene editing, in no small part due to the discovery of CRISPR-Cas9, a primitive adaptive immune response in bacteria that has been co-opted for genetic engineering with the ability to target almost any gene in a huge variety of organisms. The field is progressing fast, with robust debates occurring across the globe about how this technology should be ethically applied, and huge investments being made to make these therapeutic aspirations a reality. However, it may yet be a few years before we see CRISPR in the clinic.

58 Questions of Choice The technology we need for on-board temperature and other quality monitoring of cargo has been around for a while and continues to get more and more sophisticated and accurate. Having said that, a bewildering array of different monitoring and capturing technologies makes for a big headache when it comes to selecting the best equipment for a particular need. In this Q&A, Alan Kennedy talks to CSafe Global’s Director of Certification & Regulatory Compliance, Jonathan Neeld, about the choice of ambient monitoring equipment for active cold-chain containers.

CLINICAL RESEARCH 40 Electronic Data Delivering Pharmaceutical Analysis for Eye Conditions Degenerative eye conditions, particularly age-related macular degeneration, already affect millions of people and this will increase dramatically in the future as the population ages. Christian Martin, managing director of Medisoft Limited, explains how advanced electronic medical records (EMR) are meeting the need for efficient systematic data recording to understand current realworld clinical outcomes and to support research and development alongside patient care. 44 Developments in Imaging Technology Advance the Fight Against Fungal Infections The frequency of invasive fungal infections has increased significantly over the past two decades and continues to do so. In this article, Sharon Janssens, Application Scientist at Bruker, will determine the challenges associated with infection persistence and antifungal therapeutics. Additionally, she will explore how increased sensitivity in the latest pre-clinical imaging instruments is giving researchers new insight into fungal infections, in order to shape the future development of more effective treatments. LABS 50 Guideline Update: Bacterial Endotoxin Testing To ensure patient safety, it is vitally important that bacterial endotoxin testing (BET) is carried out on representative batches of manufactured medical devices prior to release, and that manufacturers align with current thinking on BET practices. Several revisions to USP Chapter <161>, Transfusion and Infusion Assemblies and Similar Medical Devices, came into effect August 2015, particularly regarding product unit descriptions, sampling and suitability testing. In this paper, Allen L. Burgenson, US Manager Regulatory Affairs at Lonza, highlights some of the key revisions, outlining amendments on the methodology, guidelines and practices.


62 Serialising for the Future In his last article, Glen Hodgson, Head of Healthcare at GS1 UK, looked at the benefits of standardisation and how vital it is for the future of the NHS in England. And, where pharmacy is concerned, standardisation is having its moment through the introduction of pack serialisation for companies producing, supplying and buying pharmaceutical products through regional initiatives across the globe. Ultimately, serialisation is part of the bigger drive for patient safety through greater traceability in all areas of healthcare. And GS1 standards are the glue that can hold all this together. TECHNOLOGY 64 Social Media-sourced Real-world Evidence – A Novel, Cheap, Effective Method Dr Martin Goldman, consulting pharmaceutical physician, and Peter Brady, Chief Executive Officer at Orbital Media, analyse the advantages of using social media to gather real-world evidence (RWE) in clinical trials. The use of social media as foundation to collect real-world evidence via internet portal platforms has proven itself in studies to be a rapid, inexpensive way of assembling vast amounts of data reporting patients’ real experiences of treatment, including efficacy, safety and societal impact. MANUFACTURING 70 Optimising Formulation Performance through Spray-drying Techniques to Overcome Solubility and Bioavailability Challenges The challenges in the formulation development of new chemical entities (NCEs) have never been greater. Ian Barker, Ph.D. MRSC, Principal Scientist at Juniper Pharma Services, explores these difficulties and offers some solutions. New NCEs, being designed to be more selective in their interaction with biological targets, are faulted with poor aqueous solubility. These compounds are unlikely to progress to commercialised products if approached with conventional formulation development strategies; most will require some form of enabling technology to overcome bioavailability barriers. 74 How Formulation Can Affect Tablet Tooling Developing a formulation for solid oral dosage that can be compressed in a modern tablet press, and at high speed, can cause a number of technical challenges, and many of these are down to the physical content of the formulation being used, from moisture content to abrasiveness. Rob Blanchard, I Holland R & D Manager,

Autumn 2016 Volume 8 Issue 3


Contents maintains in this article that the tooling used needs to reflect the formulations being compressed to ensure a quality fault-free end product. He then takes a look at the most common problems with formulation composition and how they affect production. 78 Protection for Valuable Ingredients In this article, Frank Hellerung, Head of Business Development at SternMaid GmbH & Co.KG, illustrates that microencapsulation and coating can protect substances against adverse external effects and optimise their properties. The two processing methods are among the options offered by fluid bed technology, by which the physical attributes of products and their applications can be influenced specifically. 82 Multiple Granulation Techniques Delivering Flexibility in Drug Development and Manufacturing In his piece, David O’Connell, Director of Pharmaceutical Development at PCI Pharma Services, shares his knowledge of pharmaceutical granulation, a common technique for solid oral drug production, whether as tablets, capsules or granules for use in bottles or sachets. Granulation is of benefit in overcoming challenges such as active content uniformity; densification of formulation; powder flow properties; compression properties; controlled API release profiles and API bioavailability. 86 R&D Should Mimic Future Up-scaling to Meet Production Expectations Dr Charles N. Kettler, Director at Natoli Scientific, explains that, when a new drug formulation progresses from the development side of R&D to the realm of manufacturing, there is often a reality check with respect to process scale-up and the performance of the formulation at production scale. Problems with capping/lamination and sticking/picking are often first realised at this grand scale of compression that is required to supply market demand. Compression tools, as a potential root cause of the current problem, have many additional variables that are not often considered, and certainly not tested before scale-up is studied.

and packaging service providers are obliged to give consideration to this landscape when selecting an appropriate software and database solution for serialisation and track & trace applications. 98 Improving Patient Adherence through Packaging In this piece, Rupert Taylor, Global Category Manager Healthcare & Personal Care at Essentra, shares his views on how to make patient adherence better while meeting the new regulatory demands implemented in an effort to increase citizens’ protection from counterfeit medications. Patient adherence describes the extent to which a person’s behaviour – for example, taking medication, following a diet or executing lifestyle changes – corresponds with agreed recommendations from a healthcare provider. 102 Serialisation Ensures Security Against Counterfeiting Tanja Feldmüller, Head of Business Intelligence & Marketing at August Faller Group, points out product piracy as a serious problem in the pharmaceutical industry. If the customer is sold a counterfeit drug, he or she will not only lose confidence in the product, but in the brand as well. There is also a risk of harm to health. But this can all be prevented. There are now numerous ways to protect both the consumer and the company’s own brand, while standing up to counterfeiters. 106 Manufacturing Change This is an interview with Gregor Deutschle, Business Development Manager for SCHOTT’s RTU platform adaptiQ®. He talks about the key challenges facing biomanufacturing and how ready-to-use (RTU) systems are involved in these problems. He also describes how the relationship between customers and suppliers is changing, and provides a case study and an overview of SCHOTT’s new product.

PACKAGING 90 The Future of Serialisation Software is Modular and Scalable Michael Urso, Product Manager in the Pharma & Packaging Solutions division at Atlantic Zeiser GmbH, outlines the criteria to select a serialisation product, taking into account that the regulations governing the serialisation of medicines are becoming more complex and extensive worldwide. Pharmaceutical companies


Autumn 2016 Volume 8 Issue 3





Editor's Letter Contract manufacturing organisations (CMOs) of small- and large-molecule drug substances and formulated drug products have had profitable businesses in recent years. Growth rates for contract manufacturing have been much higher than those of the market for the pharmaceutical/biopharmaceutical industry due to several factors: •

Increasing consumption of medicines around the world, both in emerging markets as incomes rise, and mature markets due to aging of the population; A more robust pipeline of drug candidates and an increasing rate of FDA NDA/BLA approvals; The growing number of biologic drugs in development, many by traditional pharma companies that lack biotech expertise; The entrance of numerous small, virtual startups into the market that have no manufacturing capacity; The rise in patent expiries and increasing generics competition, which is driving a greater need for cost-efficiencies and access to novel, proprietary technologies for achieving product differentiation; And the increasing complexity of both small- and large-molecule drugs, such as antibody-drug conjugates (ADCs) and highly potent compounds that require specialized skills and capabilities.

There are questions, however, as to how long such strong growth can continue. Merger and

acquisition activity has been rampant among both sponsor companies and contract service providers, leading to real consolidation within both sectors. Several pharma firms have also acquired contract service providers to achieve vertical integration. Others have elected to invest in their own in-house capabilities — often smaller, flexible, multiproduct facilities designed to meet the dynamic needs of today’s marketplace. Well, we will meet a large amount of companies at the upcoming CPHI/ICSE Exhibition in Barcelona this year. We are happy to announce that International Pharmaceutical Industry is available again at CPHI/ICSE, the world’s leading pharmaceutical platform. This time, one of the most colourful cities of the world opens its doors to the pharmaceutical industry, offering products and services that cover the entire supply chain. In this edition, IPI focuses on serialisation, gene editing, formulation performance and patient adherence. As Western nations’ obsession with diet and wellbeing grows, and the lines between pharma and food begin to blur, regulators’ appetite for transparency and standards adherence is increasing. In the Regulatory Section, Peter Muller of Schlafender Hase observes that their aims are to prevent manufacturers from misleading consumers, and to remove any risk of people overdosing on active ingredients. But the evolving requirements could catch some companies off guard, especially if they currently lack regulatory discipline. So it will be up to life sciences to show the way.

One of the hot topics in this issue is serialisation. Requirements for serialisation are already active in some parts of the world and will soon be obligatory in most major markets. David Sheedy, at Zenith Technologies, sets out a practical roadmap for the successful implementation of a serialisation programme and describes 14 steps to success. As we look ahead to the pending requirement for drug serialisation in the US and Europe, pharmaceutical manufacturers need to act soon or risk fines, loss of market share and damage to both reputation and stakeholder confidence. In the Drug Discovery Section, Chris Thorn from Horizon presents an overview of the areas benefiting from gene editing in the treatment of disease. The last three years have seen an explosion of interest in gene editing, in no small part due to the discovery of CRISPR-Cas9, a primitive adaptive immune response in bacteria that has been co-opted for genetic engineering with the ability to target almost any gene in a huge variety of organisms. The field is progressing fast, with robust debates occurring across the globe about how this technology should be ethically applied, and huge investments being made to make these therapeutic aspirations a reality. However, it may yet be a few years before we see CRISPR in the clinic. I hope you like the features presented in this issue. If you are at CPHI/ICSE in Barcelona, please visit us at 3B95. I look forward to meeting you there. Orsolya Balogh Managing Editor

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

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

Autumn 2016 Volume 8 Issue 3

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Regulatory & Marketplace

Regulatory Transformation: The Time is Now

The emerging pharma agenda, including digital health and other bold ambitions, demands more from regulatory teams than risk containment. So the new grace period for IDMP preparations is well timed. It gives the industry muchneeded breathing space – to rethink their regulatory information management strategies and deliver something greater that supports the new business strategy, says Siniša Belina, senior life sciences consultant at AMPLEXOR Life Sciences

(IDMP) information management standard is very good news. Originally, organisations were facing a deadline of this July to get their processes and systems in order. As that date got nearer, many companies were doing what they usually do when faced with a big change and a looming cut-off date: focusing solely on what they needed to do to keep the right side of the authorities. Any thought of additional business benefits had been put on the backburner.

Regulatory compliance has always been a double-edged sword for life sciences. It is an essential and central focus for investment because public safety, consumer confidence and sales depend on it. Yet this preoccupation with rules and risk can also be a barrier to innovation, because any deviation from the status quo increases the chance of non-compliance.

The extra breathing-space means companies have a chance to get back on track, and to resume conversations with the broader business about what a more structured approach to information management, across the various operational boundaries, could achieve and what this might look like.

This is a problem for the pharma industry, because maintaining a clean record and keeping patients safe are not the only challenges it faces. Companies are also under growing pressure to be more responsive, more open and transparent, more adventurous and experimental, and more aligned to broader developments in the market (such as digital health initiatives). A conservative, risk-averse environment is not an ideal to promote and cultivate these traits. The call for greater agility, openness and boldness means that regulatory decision-makers need to look up from their immediate remits and play a more proactive and facilitating role in organisation-wide information delivery. Instead of focusing solely on becoming more efficient at responding to medical authority requests, regulatory affairs functions need to be looking for opportunities to share and recoup some of their investment – by extending the benefits of better information management to the rest of the business. In this context, the recent announcement that pharma companies now have until 2018 to comply with the new global identification of medicinal products 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

While there is much buzz around ‘digital transformation’ in life sciences at the moment, it was regulatory transformation that dominated the agenda at Amplexor’s recent industry conference in Salzburg, and this is no coincidence. If entire pharma organisations are going to deliver the sweeping changes needed to enable collaboration, customer-centricity and fresh business models, they first need to transform the agility and scope of their regulatory information management. Get this right, and companies can start to move more swiftly and confidently towards their newer, more ambitious goals – without fear of compromising regulatory vigilance. In short, unless RA operations are progressive, what chance does the wider business have? Think Big The step change needed is considerable, so it is a boon that companies now have a much longer run-up to IDMP. IDMP is not just about different and better ways of supplying required information to the regulators. It is about a more robust and comprehensive way of managing the associated data, with ramifications - as well as numerous benefits - for many other business functions, from manufacturing to sales and marketing.

It also supports greater collaboration and data exchange, not just internally between different departments and geographical locations, but also with supply chain partners, the broader medical profession, and with customers. As long as companies rely on Excel spreadsheets to capture, store and distribute data, their opportunities to do more than tick boxes for regulators is extremely limited. Without validation and proper controls, there is no certainty that the information as it exists in the local system is consistent with that which has been submitted to the authorities. And when information is being collated across multiple countries, with or without involvement from affiliates, there are further dimensions that affect consistency – even if the company has put in place procedures to try to maintain a level of control. Standardisation helps overcome these inconsistencies, allowing regulatory departments to move towards a single version of the truth – an authoritative master data source which, irrespective of where this is located, is where all updates happen and is the sole feed into all other systems and outputs. Once everyone is using the same parameters and original data set, confidence in that data increases and it becomes easier to achieve cross-border transparency. Although its primary concern is boosting patient safety, IDMP encourages this kind of discipline. In imposing a data-based standard, it isn’t concerned only with finished documents and submissions, but the content and context of those assets – so that all of it becomes searchable data, stored in a standard format that a range of systems can understand and use. Once companies have that, they can call up information quickly, automate content redaction and perform numerous other actions on the data – efficiently, reliably, comprehensively and in a way that is highly traceable and auditable. Retrieving accurate, current data and collating reports then takes a fraction of the time it had taken traditionally, and Autumn 2016 Volume 8 Issue 3

Corporate Chapter Profile Title How does it work? For the pharmaceutical, medical device and basic ingredients industry both human and veterinary branches

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Users; presently we have more than 1000 members using our site and have 20 new users joining each week. Site visits; 100 to 400 visitors daily, where depending upon the activity required we perform from our office performs functions such as direct mailing, search engine activities (Google ads) and activities on social media like LinkedIn. Each visitor visits 3 pages and the average visit duration is about 3 minutes/visit. We have exhibited at CPHI/Madrid and Medica Düsseldorf, and got very positive reactions from our members getting matched 365 days/7 days a week! We are the official match making service for CPHI/ICSE Barcelona 2016. GoMed2Med, the provider of the online matchmaking business service for the pharmaceutical and medical device industry and UBM, one of the world’s leading business-tobusiness event organizers launched Live Pharma Connect, a business match and meet service for CPhI Worldwide 2016. Live Pharma Connect is a free online tool open to visitors and exhibitors allowing both parties to make pre-arranged pharma specific, mutually beneficial meetings during the event. This is how to develop business in the future!


Regulatory & Marketplace painstaking manual processes of reentering and triple-checking information are eliminated. Intelligence for All Regulatory departments haven’t been used to – nor have they especially needed – this kind of responsiveness until now. But as compliance criteria expand and become more complex, and as pharma organisations become more ambitious in their future commercial plans, that need is growing. Where once it was just pockets of the organisation – sales teams or manufacturing operations – that benefited from advanced information systems and had the latest data at their fingertips (via a mobile or tablet), that imperative is now fanning out across the enterprise. Being able to deliver good-quality regulatory information quickly to support perpetually evolving and tightening compliance requirements is one thing (and something the revised IDMP deadline helps to make possible). The next consideration – and the bigger opportunity – is to make systems more interactive and capable of supporting more dynamic information management in other areas. Another reason to take a broad, all-encompassing view of regulatory information management is that the specific requirements for IDMP implementation are still being agreed. Being able to comply with the detail still depends on the regulators issuing final guidelines, and of course each region – the FDA versus the EMA, for example – is likely to have its own particular roll-out plan. In the interim, leading companies are using the time to assess their existing data assets to establish where these currently reside and what may be missing. Unstructured data, tucked away within documents, needs to be extracted and tagged so that it can be called up in searches and exploited for other uses. The scenario companies need to work towards is one where everything – the detailed content of submissions, translations, and information about surrounding activities (correspondence with partners and affiliates, for example) – can be captured, managed and shared readily and in a user-friendly way. That means supporting data access (without any need to re-enter the information)

within other operational and business systems – including ERP systems, labelling management systems, sales systems, and manufacturing systems. By devising such a big and comprehensive data model in IDMP, the industry globally is promoting that wider perspective and wider use case. This is a data model that spans all of the departments of pharma organisations in one way or another, and all functions will need to feed it in an IDMP-compliant way, so the benefits should flow both ways. Establishing a Plan Calculating the return on investment isn’t immediately straightforward as there are so many variables: the scale of the transformation will depend a lot on how systems look now. Just from leveraging RIM system content rather than using spreadsheets and manual processes to look up information should deliver administrative time savings of at least 30 per cent. And that’s before any of the broader business benefits. Commonplace transactions such as selling on dossiers to other manufacturers or resellers are vastly simplified, too. In place of scanning boxes worth of paperwork, dossiers can be transferred electronically. In a digital age, where old models are being challenged and disrupted, old ways of working are no longer applicable. Anything that supports a quicker response is important, so managing information in a format that’s easy to analyse and share – versus having to search reams of paper in a basement – has got to be a step in the right direction. Next Steps Whatever technology companies may promise, regulatory transformation is not a shrink-wrapped solution that pharma organisations can buy off the shelf. This is a journey, and one that must start sooner rather than later. The starting point must be to take stock – of existing system investments, existing data sources, and the scale of change users can be realistically expected to cope with. Getting buy-in to change takes time and should not be underestimated as a challenge, however much directors may be pressing for transformation. Next, decide on and be clear about

Chapter Title the goal. If this stops with compliance, that’s okay – but don’t sell the business short if you don’t have to. There is a great deal more to gain by looking for the bigger picture, not least an even stronger business case and ROI story. Once you have decided on your end point, it’s time to plan the route. There is no universal approach that will suit all companies, so this will need careful consideration. The change programme is likely to involve a combination of consultancy, systems integration, and a degree of upgrading to existing infrastructure to add new functionality. If approached properly, this is a journey that will take at least 18 months, so the re-drawing of IDMP goalposts should not be taken as a chance to press the ‘pause’ button, deferring decisions until the fourth quarter of 2017! Far better that organisations use this time to develop a robust and well-thought-out setup that they can have confidence in. IDMP and transformational RIM is something new and unprecedented; there aren’t existing processes for this. So use the extra time to re-evaluate where you are now, where you are going, and what it will take to create a way of doing this that will see you through the next 10 years.

Siniša Belina is senior life sciences consultant at AMPLEXOR Life Sciences. He started his professional career at Pliva (now a member of the TEVA Group), where in addition to his responsibilities in manufacturing, he also engaged in successful EDMS implementation projects. Belina later joined KRKA’s Regulatory Affairs Department, and finally moved to AMPLEXOR. He applies his detailed knowledge of pharmaceutical documentation and processes to areas of business process analysis and EDMS optimisation. Web: Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 10










Regulatory & Marketplace Food for Thought: Regulators now Hunger for Greater Control of Nutrition and Nutraceuticals As Western nations’ obsession with diet and wellbeing grows, and the lines between pharma and food begin to blur, regulators’ appetite for transparency and standards adherence is increasing. Their aims are to prevent manufacturers from misleading consumers, and to remove any risk of people overdosing on active ingredients. But the evolving requirements could catch some companies off guard, especially if they currently lack regulatory discipline. So it will be up to life sciences to show the way, says Peter Muller of Schlafender Hase As the shelves of any supermarket soon reveal, public demand for healthier diet choices and enriched functional foods is at an all-time high. Governments and health service providers are encouraging the trend, promoting illness prevention through better lifestyles and eating habits, as a means of reducing the strain on healthcare and of bringing chronic diseases under control. The life sciences industry, keen to reduce its reliance on expensive blockbuster drugs, has recognised the opportunity and wants its share of the action. Many firms are now embracing health foods and nutraceuticals through acquisition or partnership, or the expansion of existing businesses to include new divisions. Yet, where operations and staff have come from outside the pharma industry, it is likely that there will be gaps in those businesses’ understanding of the strict regulatory landscape they will be subject to. Growing Diet Consciousness Accurate product labelling will be a big area. In May this year, the FDA issued new guidance on food labelling1, to drive greater standardisation in the way health and nutrition information is presented to US consumers, bringing national requirements more in line with Europe. Its new Nutrition Facts label guidance, which applies to packaged foods, aims to ensure that labelling reflects the latest scientific information, including the link between diet and chronic diseases. New requirements also include updated 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

serving sizes, and a refreshed design which highlights information such as calorie content, portion size, and added sugar content. New nutrients must be declared too, including Vitamin D and potassium, to combat associated deficiencies. Most manufacturers will have until July 26, 2018 to comply with the final requirements; smaller players will have an additional year to make the changes. In Europe, food labelling changes are further ahead. New requirements issued in 2014 will need to be met from December this year2. Key changes include improved legibility of information (minimum font size for mandatory information); clearer and harmonised presentation of allergens (e.g. soy, nuts, gluten, lactose) for pre-packed foods (emphasis by font, style or background colour) in the list of ingredients; requirements around certain nutrition information; specific detail on the vegetable origin of refined oils and fats, and of substitute ingredient for 'imitation' foods; and clear indication of "formed meat" or "formed fish", as well as products that have been frozen and defrosted. Health Canada has issued its own proposed guidance which is now with the industry for comment3, so we can expect to see more requirements filtering through in due course. No one wants to get caught out by the new requirements. Food recalls are an almost everyday occurrence. Just recently, The Nut House in the UK was forced to recall cakes containing whey powder, because this wasn’t mentioned on the label. Another labelling error saw Lidl UK recall an Italian chicken product, while rival Aldi had to withdraw a range of yoghurts because the labels failed to mention hazelnut among the ingredients. Let Food be Thy Medicine In the soaring nutraceuticals market, rules are becoming stricter too. In addition to meeting emerging standards on what is presented, and how, companies will need to watch that they aren’t making claims they can’t substantiate about a product’s secondary benefits. Authorities in Scandinavia have been quite clear

that if nutrition companies are going to start making medicinal claims about their products, they must categorise themselves as pharmaceutical businesses and be bound by similar requirements. The concept of ‘functional foods’ originated in Japan in the 1980s4, according to the European Food Information Council (EUFIC). Local health authorities had homed in on the need to control soaring healthcare costs and improve people’s quality of life, as the nation’s population aged and grew. This resulted in the development of foods specifically to promote health, or reduce the risk of disease. It is no surprise, then, that Japan (the third-largest health food market in the world) now has the most evolved approach to associated labelling5. In April 2015, the country’s Consumer Affairs Agency (CAA), the government body with oversight of food labelling and health claims, set out new provisions for labelling of ‘Food with Functional Claims’ (FFC). For the time being, these are voluntary, but the expectation is that they will lead to more formal requirements in the not-too-distant future – and the rest of the world would do well to take heed, as similar measures are likely to fan out to other regions and countries eventually. For now, the measures are more enabling and empowering than restrictive, designed to accelerate product approvals and stimulate growth in the market. For example, Japan’s guidance permits companies to display a product’s specific health benefit and an associated area of the human body on retail food packaging. The associated registration process is more streamlined than that used for the existing Food for Specialised Health Uses (FOSHU) category. This eliminates the need for a protracted approvals process before a company can add a specific functional claim to the label of qualifying products. Under the new FFC guidelines in Japan, FFC labelling must include cross-category quality labelling items as well as 16 specific items, including ingredients and recommended daily intake, instructions and precautions, and various safety notices. CAA has Autumn 2016 Volume 8 Issue 3

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Regulatory & Marketplace also revised its regulations for Food with Nutrient Functional Claims (FNFC) to increase product eligibility, expand the list of eligible nutrients, and to include fresh foods. In other markets, requirements around nutraceuticals vary considerably; it is early days in regulatory terms in most regions. In the EU, products that claim to be a ‘nutraceutical’ must be certified by the European Food Standards Authority. In the US, by contrast, products don’t (yet) have to pass stringent government tests as long as they are not claiming to treat or prevent a specific disease6. But the likelihood is that the authorities will have to clamp down. The public will expect it, and there may be risks to consumers if they aren’t given adequate and consistent guidelines on when and how to use a nutraceutical product, or about the possible contraindications if they are already taking other dietary supplements. Health Canada has been considering the regulatory imperative and challenges too7: how nutraceuticals/ functional foods should be defined; whether such products ought to remain as either foods or drugs under the Food and Drugs Act; what kinds of health claims (if any) should be allowed on food labels; and what standards of evidence would be necessary and sufficient to prove a health benefit. India has also been consulting and drafting regulations8. As well as serving its own market, India will have seen the opportunity to provide nutraceuticals to the world market, because of its low costs of production. International nutraceuticals firms are likely to look to this economy to bolster profits in an area of business with greater pressure on pricing (compared to drugs). The signs are that India may take a tough line, too, to engender trust in its products. Earlier this year, the Food Safety and Standards Authority of India ordered companies to follow strict norms in manufacturing and testing of health supplements launched after 20119. Prevention is Better than Cure: Staying Ahead of the Regulators All in all, the above is a good indication of what is coming. If food and nutraceuticals manufacturers are found to fall short of regulatory labelling requirements, they will have to take prescribed corrective action and preventative action (CAPA). This will include showing that they have or plan to develop a system for 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

addressing non-compliance issues and product recalls. So it is far better that they put such measures in place up front. That means defining processes and systems which ensure that costly mistakes are not made on product labels and packaging – something companies can show to auditors, which spans the whole production chain. It is the absence of rigour that will lead to omissions and errors. It isn’t just health claims that regulators need to control, either. Growing public consciousness means customers are becoming more demanding in their expectations to know every aspect of a product’s origins and its social, ethical and environmental credentials. In January, Brazil’s Ministry of Justice issued fines totalling $3 million to big names including Nestlé and PepsiCo for failing to disclose that their goods contained genetically modified organisms (GMOs). Managing changes to labelling is a full-time job that should not be underestimated. In heavily regulated industries such as life sciences, regulatory affairs teams work flat out to check and double-check every detail, aware that the slightest misprint or mistranslation could have serious ramifications. It is no coincidence that the food and nutraceuticals industries are now beginning to look to pharma for guidance on best practices. The market has 2-3 decades’ experience of managing complex control processes of the kind other manufacturers now need, so provides a valuable reference point. One of the techniques many companies here have adopted is an automated approach to initial rounds of label checks, using sophisticated text verification. This process can make very light work of substantial proofing burdens, quickly picking up even the tiniest discrepancies between regulatory text, artwork briefs and packaging artwork. Emerging labelling requirements exceed the scope that an artwork team, supplier quality function, print supplier or marketing department can realistically handle, and threaten to take time away from other important tasks. While human beings should never be distanced entirely from critical checks, reliable automation provides a valuable shortcut through several layers of laborious proofreading, accelerating time to market and freeing up skilled resources for more specialist

work. It is these kinds of labour-saving techniques that adjacent markets will need to consider now, as they prepare for what is coming down the line. References 1. Changes to the Nutrition Facts Label, FDA: GuidanceRegulation/ 2. Food information to consumers – legislation, European Commission: food/safety/labelling_nutrition/labelling_ legislation/index_en.htm 3. Consulting Canadians to Modernize and Improve Food Labels: What We Heard, Health Canada: label-etiquet/modernize-report-moderniserrapport-eng.php 4. Functional foods: The basics, EUFIC, June 2006: expid/basics-functional-foods/ 5. Japan’s New Health Claims Labeling System Creates Opportunities, USDA FAS GAIN report, August 2015: http:// Publications/Japan%E2%80%99s%20 New%20Health%20Claims%20Labeling%20 System%20Creates%20Opportunities_Tokyo_ Japan_8-3-2015.pdf 6. Nutraceuticals and the future of intelligent food, KPMG/, September 2015: nutraceuticals_and_the_future_of_intelligent_ food_827879 7. Archived policy paper: Nutraceuticals/ Functional Foods and Health Claims On Foods, Health Canada, June 2013: nutra-funct_foods-nutra-fonct_aliment-eng.php 8. Draft Food Safety and Standards (Food or Health Supplements, Nutraceuticals, Foods for Special Dietary Uses, Foods for Special Medical purpose, Functional Foods, and Novel Food) Regulations, Government of India, Ministry of Health and Family Welfare, Food Safety and Standards Authority of India 2015: Pdf/Draft_Regulation_on_Nutraceuticals_ WTO_23_07_2015.pdf 9. New FSSAI rules on nutraceuticals may leave companies like Sun Pharma, GSK ailing, The Economic Times, April 2016: http://articles. news/71977410_1_supplements-food-safetynotification

Peter Muller, Managing Director, Schlafender Hase, Americas For the last 20 years, Peter Muller has worked on software and process improvement projects with Fortune 500 companies from various industries: pharmaceutical, consumer goods, food, aerospace and defence. He has a wealth of experience working with international clients to define their organisation's goals and help them leverage new technologies to achieve productivity gains, process improvements and cost savings. Contact: Email: Autumn 2016 Volume 8 Issue 3

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Regulatory & Marketplace

Drug Filling in Nepal: An Overview Abstract The Nepal pharmaceutical market is worth around Rs. 600 crores, with Nepali companies dominating at 30%, and others being dominated by Indian/ MNC companies. 10-15% is institution business. With over 26.4 million people, it is a prescription-based market often influenced by retailers. The regulatory system is governed by Department of Drug Administration (DDA), which is one of the three departments under the Ministry of Health (MoH). Nepal doesn’t follow the CTD format. The regulatory process in Nepal is carried out by a local importer who submits the documents, samples, labels, etc. The aim of this article is to provide an overview of the pharmaceutical market and regulation involved for import and drug registration in Nepal. Key Words: Nepal, drug registration, registration   Introduction Nepal, officially the Federal Democratic Republic of Nepal, is a landlocked country located in South Asia. It is located in the Himalayas and is bordered to the north by China and to the south, east, and west by India. Nepal is separated from Bangladesh by the narrow Indian Siliguri Corridor, and from Bhutan by the Indian state of Sikkim. The mountainous north of Nepal has eight of the world's ten tallest mountains, including the highest point on Earth, Mount Everest.1

2. Pharmaceutical Market Nepal became a WTO member on 23rd April 2004, and the accession of Nepal to WTO has brought both opportunities and challenges to the Nepalese pharmaceutical industry. The world market for pharmaceuticals is now open to the Nepalese industry and simultaneously the Nepalese market is open to industries worldwide. The market is around Rs. 600 crores, with Nepali companies dominating with 30% and others are dominated by Indian/ MNC companies. 10-15% is institution business. It is a prescription-based market often influenced by retailers. 2.1 Major Companies in Market The Nepalese pharmaceutical market has one of the highest brands per capita and is highly import-driven. The market is highly dependent on imports from domestic and multinational companies of India, Bangladesh, and others. The top 10 companies hold 33% of the total retail pharmacy market by sales value and the next top 30 companies hold 62% of the market. The top 10 pharmaceutical companies in the retail market are given in Table 1.

1. Country Profile

Table 1. Top 10 companies in Nepal

• • • •

Capital – Kathmandu Currency – Nepalese Rupee (NRs) Official language – Nepali Drug regulatory authority – Department of Drug Administration (DDA)



2.2 Sales and Distribution System All pharmaceutical industries market their products solely within the country. Their pharmaceutical products reach the end users through a four-tier distribution system consisting of distributors, stockist, sub-stockist and retailers. According to the recent statistics of the DDA, there are 2350 medical wholesalers and 18,255 pharmacies operating in the country.2

3. Regulatory System DDA is one of the three departments under the Ministry of Health (MoH). The Drug Consultative Council (DCC) headed by the Minister/MoH advises the government on basic principles and administrative matters pertaining to drugs, whereas the Drug Advisory Committee (DAC) headed by the Secretary/MoH advises DDA on technical matters like R&D and other regulatory aspects. Besides various administrative as well as functional sections at its central office, it has three regional sections at Biratnagar in the Eastern region, Birgunj in the Central region, and Nepalgunj in the Mid- and far Western Region. The national medicines laboratory, which is a principal medicines testing laboratory of the government, operates under DDA's organisational umbrella. The functional arrangements within the DDA central office comprise three divisions, i.e. Registration & Licensing Division, Inspection Division, and Management Division.3 4. Registration of Manufacturer: The following documents should be submitted through the authorised Nepalese importer for the company (manufacturer) registration: a. An application by the company for company registration b. Letter of authority to the importer issued by the responsible person of the company c. Site master file (as per PIC/S guidelines or guidelines provided by Department of Drug Administration, Nepal) d. Up-to-date manufacturing licence issued by drug control authority e. List of products and dosage forms intended to be registered f. Letter of warranty (in format provided by Department of Drug Administration, Nepal) g. Latest GMP internal audit report h. Photocopy of wholesale registration of Nepalese importer i. A complete set of documents for at least one product needed for product registration Autumn 2016 Volume 8 Issue 3


Regulatory & Marketplace •

If the submitted documents are satisfactory, the company will be registered on the payment of NRs 50,000.00 (for the SAARC country) or NRs. 80,000.00 (for countries other than SAARC). The company will be audited on the payment of USD 1500.00 for SAARC country or USD 2500.00 for other than SAARC countries. Audit will not be done for the industries situated in the USA, Canada, European Union, Australia and New Zealand or for re-audit of products to be exported to those countries. After the company registration, the department can process the product registration.4

5. Registration of Product The following documents should be submitted through the Nepalese importer for the product registration: a. Schedule 4 'Ga' Application form for product registration as per Registration Regulation of Drug Act 1978. (Available at the department and to be filled by Nepalese importer) b. Schedule 6 Application form for product recommendation letter as per Registration Regulation of Drug Act 1978. (Available at the department and to be filled by Nepalese importer) c. Attested copy of Valid Certificate of Pharmaceutical Products (CPP) as recommended by WHO (Attested by Drug Regulatory Authority or Notary Public) d. Detailed formulation including recipients, colour, flavour etc. e. Product specification f. Methods of analysis g. Samples of the product (two-unit pack), labels and carton analytical report from own lab and from any of the laboratories for the same batch: government laboratory of the exporting country or Nepal, Nepalese laboratories – FDC Laboratory Pvt. Ltd., Zest Laboratories Pvt. Ltd., Multi Pharmaceuticals Laboratories Pvt. Ltd h. Real-time stability study report for at least two years or for shelf-life period if less than two years. •

If the product has to be registered as per article 2 of the “Requirements for Registration of Foreign Pharmaceutical Manufacturer to


Export their Products to Nepal”, product registration certificate of the importing country has to be submitted. The above documents are to be indexed and submitted in an index file. The product registration document for each product should be submitted in a separate individual file.

An approval letter schedule 7 (letter of recommendation for import of drugs) will be issued by Department of Drug Administration. 6. Timelines • Time taken for receiving the approval (i.e. fresh registration) is 3-6 months • Re-registration must be submitted thirty-five days before the expiry of the existing registration • If the renewal is not made within the specified time limit pursuant to Sub-section (1), and an application is made, setting out the reasons for the failure to renew, within three months after the date of expiry of the time limit, the Department shall make renewal by charging an additional fee of twenty-five per cent of the renewal fee. A licence, recommendation letter or certificate not renewed even within that time limit shall be invalid.

Nepal doesn’t follow the CTD format. The regulatory process in Nepal is carried out by a local importer from submitting the documents, samples, labels etc. One of the limitations is that the validity of product registration is one year. The Drug Consultative Council (DCC) headed by the Minister/MoH advises the government on basic principles and administrative matters pertaining to drugs, whereas the Drug Advisory Committee (DAC) headed by the Secretary/MoH advises DDA on the technical matters like R&D and other regulatory aspects. References 1. Nepal 2. h t t p : / / w w w. s l i d e s h a r e . n e t / abhishekmsra/os-report 3. 4. attachment1.pdf

Kaushik Devaraju – Ph.D. Research Scholar, Regulatory Affairs, Department of Pharmaceutics JSS College of Pharmacy, Mysuru kaushik. Balamuralidhara V. – Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysuru.

7. Validity of Registration • Product registration is valid for one year 8. Fees • Company registration - NRs. 50,000 • Company audit - USD 1500.00 for SAARC country or USD 2500.00 for other than SAARC countries • Product registration - NRs. 2400 • Letter of recommendation for import of drugs - NRs.3003 Conclusion Nepal is a fast-emerging market. Total market size today stands around 5 billion. There are around 350 companies. The market has around 4000 brands, which are either local brands, Indian brands or brands which are imported and sold. This market is growing fast. With a more professional approach, it can give rich dividends to Indian companies. The Department of Drug Administration (DDA) is one of the three departments under the Ministry of Health (MoH).

Dr Jayasheel B Gangaiah – Head of Pharmacovigilance and regulatory affairs, Alcon Laboratories (India) Pvt Ltd., Whitefield, Bangalore 560048

T. M. Pramod Kumar – Professor & Head of Department of Pharmaceutics, Regulatory Affairs Group, JSS College of Pharmacy, JSS University, Mysuru.

Autumn 2016 Volume 8 Issue 3


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Regulatory & Marketplace

Barcelona and the BioRegion of Catalonia: A Life Sciences Hub in Europe Barcelona is hosting two of the most relevant events in the upcoming life sciences calendar: CPHI (4th-6th October, 2016) and BIO Europe Spring (20th-22nd March, 2017). The city is the capital of the BioRegion of Catalonia, the most dynamic bioregion in Spain and one of the most active in Europe. With a population of more than 7.5 million and territory comparable to Belgium or Israel, Catalonia is among the top four European countries in terms of the number of life sciences companies per capita. The BioRegion of Catalonia brings together 734 companies according to the Biocat Report1: 221 biotechnology, 46 pharmaceutical, 94 innovative medical technology, 208 suppliers and engineering firms, 130 consulting and professional services and 26 active investment organisations. With these figures, despite being one of the smallest countries in Europe by population, Catalonia is among the top four European countries in terms of number of companies in the healthcare sector per inhabitant2. Specifically, it has more pharmaceutical companies per capita than any country in Europe except Belgium. The Spanish pharmaceutical industry is mainly concentrated in Catalonia, where 40% of the sector’s laboratories are located. The largest in the sector – all Catalonian – are Almirall, Bioiberica, Esteve, Ferrer, Grifols, Lacer, Reig Jofré and Uriach. Barcelona is also home to the world’s top biopharmaceutical companies, such as Amgen, Novartis, Roche, Sanofi, Bayer, B. Braun, Boehringer Ingelheim, Chiesi, Hartmann, Lundbeck and Menarini. Catalonia is also ranked fourth among European countries in terms of biotechnology companies per inhabitant (behind Sweden, Switzerland and Israel) and fourth in medical technology companies (behind Israel, Sweden and Switzerland). Only between 2013 and September 2015, 75 new life sciences companies were created in the BioRegion. On other words: one new venture born every 10 days. The companies in the life science 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sector post yearly turnover of €14.36 billion in Catalonia, 48% of which come from pharmaceutical companies, 20% from biotechnology companies, 22% from medical technology companies and the rest from other kinds of life sciences companies. In total, companies in the BioRegion account for 7% of the GDP of Catalonia and employ 42,133 workers. 88% of the companies in the BioRegion are SMEs. Nearly half of these are microenterprises with fewer than 10 workers and annual operating income under €2 million. Over the past two years, the number of medium-sized companies (between 50 and 250 workers and annual revenue of between €10 million and €50 million) has doubled and accounts for 22% of all companies, which is a sign of progressive consolidation in the sector. The main therapeutic areas in which Catalan biotech and pharma companies work are cancer (often focusing on rare diseases) and neoplasms, dermatology, infectious diseases, and diseases of the nervous system and the respiratory system. In fact, oncology is one of the great strengths of the BioRegion of Catalonia, which has significant assets throughout the value chain, from basic research through highly specialised companies, with hospitals playing an important role in translational and clinical research. In terms of companies, research and production of gene-based diagnostic kits and research of new drug-delivery systems is particularly significant. More than €100 Million in Investment Between 2013 and 2015, companies in the BioRegion attracted more than €100 million in investment, more than half over the past year. The Catalan biotech company Oryzon Genomics signed in 2014 the largest deal ever reached by a Spanish biotechnology firm, selling the rights to exploit its experimental drug ORY-1001 for acute myeloid leukemia — with orphan drug status — to pharmaceutical corporation Roche for a total of $500 million. That agreement confirmed the great potential of research

being conducted in Catalonia and has drawn the attention of international investors to companies in the BioRegion, which has helped attract funds for other important operations. The other large operation in 2015 in the BioRegion was carried out by Minoryx Therapeutics, a company doing research into rare neurodegenerative diseases that closed a €19.4-million round to fund clinical validation of MIN-102. This drug is a candidate to treat X-linked adrenoleukodystrophy (X-ALD), a rare disease that causes motor dysfunction and can lead to death, for which there is currently no treatment available. This round, led by Ysios Capital, was in addition to two smaller operations closed by Minoryx in early 2015. Additionally, a Catalan investment manager, Ysios Capital, led in 2015 the most important round even seen in a Spanish biotechnology company. Specifically, it involved Sanifit, a company based in Mallorca, which obtained €36.6 million to fund development of SNF472, a drug to treat cardiovascular disease linked to calcification in kidney dialysis patients. Scientific Research The Catalan research model, based on autonomous centres, results-based contracts, independent assessment of national and international experts and a firm commitment to attracting talent (through ICREA programmes), has been proven effective and put a whole slough of institutes with just under 10 years of history among the top bodies in the world in their respective disciplines. The BioRegion of Catalonia has 89 research bodies: 41 research centres working in the health and life sciences or related subjects, such as nanotechnology, photonics, chemistry, etc; 15 university hospitals (of a total of 101 public and private hospitals), 11 universities with degrees in the life sciences, seven technology centres, 13 science and technology parks with activity in the life sciences and two large research facilities, the Barcelona Supercomputing Center (BSC) and the Alba-CELLS Synchrotron, Autumn 2016 Volume 8 Issue 3

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Regulatory & Marketplace which in addition to serving the national and international scientific community, also have research groups carrying out their own lines of research. There is also the National Center for Genomic Analysis (CNAG), which was integrated into the Center for Genomic Regulation in July 2015, and is now known as CNAG-CRG. Some of these bodies are among the most prestigious in the world, including CRG (ranked ninth in the top 100 biomedical centres in the world), ICIQ (ranked first world institution in chemistry) and ICFO (ranked first world institution in physics). The number of publications in the healthcare and life sciences sector increased 168% between 2000 and 2015. Although Catalonia represents only 1.5% of the EU’s population, researchers in Catalonia produce 3.15% of all scientific production in Europe and 0.99% in the world, and 29% of publications in Spain. Catalonia is ranked second in the EU in number of grants per inhabitant received from the European Research Council (ERC). In 2014, a process began to group together separate entities under a shared banner in order to gain critical

mass and boost competitiveness by taking advantage of the synergies at different research institutes. As a result, in mid-2015 the Barcelona Center of Science and Technology (BIST) was created, bringing together six large Catalan research centres: the Center for Genomic Regulation (CRG), Institute of Chemical Research of Catalonia (ICIQ), Catalan Institute of Nanoscience and Nanotechnology (ICN2), Institute of Photonic Sciences (ICFO), Institute for High Energy Physics (IFAE) and Biomedical Research Institute of Barcelona (IRB Barcelona). BIST aims to create the conditions necessary to promote top-notch research and boost the international visibility of member centres, as well as fostering collaboration in areas like postgraduate training, knowledge transfer, developing and managing science and technology platforms and attracting talent. The six BIST centres, all with Severo Ochoa recognition, have a joint total of 1700 researchers in 150 research groups, more than 500 students and an average of 75 PhD dissertations each year. BIST members generate around 1000 scientific publications per year – more specifically, researchers at these centres published 144 articles in journals like Nature and Science between

2008 and 2012 — and have received a total of 49 grants from the European Research Council (ERC). In academia, Catalonia has three universities among the top 200 in the world (UB, UAB, UPF) and two of the 10 best business schools in Europe (IESE, Esade). The 11 Catalan universities that offer degrees in the biosciences graduate roughly 6500 students each year in the health and life sciences. According to calculations from the ACUP (Catalan Association of Public Universities), Catalan public universities were responsible for 51% of all Catalan scientific production from 2007 to 2011, with nearly 58,000 publications and an average impact of 1.38. In the life sciences arena, 92 spin-offs were created in Catalan universities between 1992 and 2015, 85 of which were still active in late 2015. The Catalan hospital system is made up of 195 establishments: 65 publicly owned (13 of which are university hospitals), 36 private (two of which are university hospitals), 62 social health centres (government subsidised), 17 psychiatric and/or social health centres (with or without government subsidies) and 15 psychiatric centres (subsidised). These centres employ more than 89,000 workers, approximately one-third of whom work at the 15 university hospitals. In total, these hospitals and the nine associated research institutes have 5000 researchers. Six of these hospitals are Spain’s top science research producers in the field of clinical research and human health research, such as Hospital Clinic of Barcelona or Vall d'Hebron University Hospital. The 15 Catalan university hospitals and their research institutes account for 32% of all scientific publications (2007-2011) and are home to 24% of the accredited research groups in the life sciences. Clinical Trials Catalonia performs more clinical trials than any other region in Spain, mainly in oncology, and in Phase II (17%) and III (44%). The recently launched Barcelona Clinical Trials Platform maximises the potential of the region, providing a single point of access to some of the main university hospitals and to the national primary care network. With the aim of positioning Catalonia among the leading European regions in


Autumn 2016 Volume 8 Issue 3

Regulatory Manufacturing & Marketplace conducting clinical trials, the Barcelona institutes and hospitals in Catalonia. References Test method: Method A – Membrane Filtration Clinical Platform (BCTP) brings and negative controls. For aqueous solutions: 1. Biocat report 2015. Catalonia Life The methodTrials calls for the routine use of positive Aseptically transfer a small quantity of fluid to the membrane and together the most important institutes Barcelona: The Epicentre of the Bioregion Sciences andA on Healthcare Outlook filter it. Transfer aseptically the combined quantities of the preparation Apparatus: in Catalonia by volume of clinical of Catalonia (Internet). http://informe.biocat. under examination in the two media onto one membrane. Cellulose nitrate filters are used fortoaqueous, trials into a single platform, improveoily and The weakly city alcoholic of Barcelona and itsprescribedcat/en/ solutions, and cellulose acetate filters are recommended for strongly the coordination, integration, quality, metropolitan area are home to 90% of 2. Site Selection for Life Sciences If the solution under examination has antimicrobial properties, wash the alcoholic solutions. inclusivity and speed of clinical research. the Catalan life sciences sector. Strategic Companies in Europe 2015. KPMG membrane(s) by filtering through it (them) not less than three successive geographical location, an extensive Venture quantities, each of 100 ml, of&sterile fluidValuation A. Diluting Fluids: (IP, BP): was created by peptic the Department transport quality of life FluidBCTP A: Dissolve 1 g of digest of animal tissue infrastructure, (such as of Health andpeptone) Biocat inorthe quarter of and human capital the most Doamong not exceed a washing cycle of five times or 200 ml, even if it bacteriological its final equivalent in water to make 1 litre, filter are The strategic of tothe valued into aspects foreign has beenby demonstrated during validation that such a cycle does not or2014. centrifuge to clarify, line adjust pHCatalonia 7.1 ± 0.2, dispense flasksofin Barcelona the In antimicrobial activity. The quantities of fluid used Healthquantities Plan 2016-2020, with companies already setfully up eliminate in the city. 100ml and sterilize atdealing 121° C for 20 minutes. should be sufficient research and innovation, promotes the 2014, Barcelona was awarded withto allow growth of a small inoculum of organisms (approximately 50 CFU) sensitive to the antimicrobial substance in the Fluid B: If the test sample contains lecithin or oil, use fluid A to each litre consolidation of the BCTP with the aim the European Capital of Innovation presence of the residual inhibitory material on the membrane. ofofwhich has been 1 ml of polysorbate adjust to pH 7.1±by the increasing theadded number, quality and 80, ("iCapital") prize EU and ranked After aseptically remove the membrane(s) from the holder, 0.2, dispense into flasks and sterilise at 121°inC for 20 minutes. importance of clinical trials conducted Sixth best urban area forfiltration, business in transfer the whole membrane or cut it aseptically into two equal parts. Catalonia. By having different centres join Europe, and it is repeatedly included Biocat is the organisation that Transfer one half to each of two suitable media. Incubate the media for Quantities of sample to be used: forces and take advantage of synergies in most of the international rankings. and promotes the not less than 14 days. coordinates For parenteral preparations: in clinical research, it will be possible to Barcelona attracts nearly 40% of foreign healthcare and life sciences sector in Whenever possible, use the whole contents of the container, but in any attract innovative therapiesprescribed in the early investments in Spainthe and is Catalonia. containers of media periodically the 14 days of case not less than the quantities in Tableannual 3(E), diluting where Observe Set up asduring a public/private stages oftodevelopment Catalonia. more international incubation. If the test specimen is positiveBiocat before 14 dayscreated of incubation, necessary about 100 mltowith a suitable diluent home such astofluid A. than 3400 foundation, was in For products sterilised by companies, most of further them incubation related istonot necessary. 2006 at the behest ofterminally the Government a validated moist heat process, incubate the test specimen for not less For ophthalmic and other preparations: As of January 2015,non-parenteral the centres that innovation and high-end technology of Catalonia and the Barcelona City than national seven days.and Take an amount the range prescribed column (A) Over of Table2000 belong to the within platform totalled 2740 in services. Council to provide a joint strategy for 3(E), if necessary, in using the contents more thaninternational one container, and participations trials, with of 13,498 conferences, such as Mobile the Catalan biosciences sector as the mix thoroughly. For each medium use the amount specified in column For liquids immiscible with aqueous vehicles, and suspensions: patients recruited. BCTP kicked off as a pilot World Capital and some editions of BIO- foundation of a new economy based on Carry out the test described under for aqueous solutions but add a (B) of Table 3(E), taken from the mixed sample. programme but it is expected to expand in Europe Spring, take place every year in knowledge and innovation. sufficient quantity of fluid A to the pooled sample to achieve rapid the middle term to include other research Barcelona. filtration. Sterile enzyme preparations such as penicillinase or cellulose

High purity systems require high quality products. That´s what Adca Pure is all about.




Regulatory & Marketplace

The Effect on Companies as Medical Device and Pharma Grow Closer and Closer I started my days as a sales rep in medical device with JNJ and the now discontinued Gynecare franchise, and in those days there was a very distinct line between medical device and pharma. So clear, in fact, that despite the fact that the two JNJ companies (Johnson & Johnson Medical and Janssen-Cilag) in the same building in Stockholm had never had any employee crossover at all. A couple of years later, I was the first person ever to go from one side to the other. In those days, reps were frequently invited to help out in theatre and to even scrub up in some cases. I was hugely intimidated after attending a six-week training course in JNJ headquarters in New Jersey when I went back to Sweden and in one of my first weeks was asked by the operating surgeon: “Do I cut deeper?” while using the Versapoint bipolar resection device we were just launching. I didn’t know it at the time, but that was a defining moment in my career. On the spot, I decided that I was never, ever going to answer any questions about how to treat a patient. How could I? I wasn’t a doctor, or a nurse; I wasn’t even medically or scientifically trained. Don’t get me wrong – the six-week sales training with JNJ is one of the best industry training courses there is to prepare a sales team to add value to high-demand customers in a scientific field. It was relentless: days, evenings, weekends. Tests every third day. Not for the fainthearted. But obviously this is far from giving sales people the knowledge and authority to tell a doctor how much deeper he should cut into tissue. I can tell you the cutting mechanism of the instrument, the power of bipolar technique, the physics and even the technical spec of the advanced technology in front of you. But telling you how to treat your patient? Not a chance. When I moved over to Janssen-Cilag, the first thing that struck me was how different the internal training was. The focus on what to say and how to say it was much higher than in the medical device world (where doing was the key word: what does the surgeon do? What do you do? What to do with the patient before and after?). The two companies 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

consequently hired very different people, with different mentalities and different profiles. So how does it work now, when the amount of medical devices which also have a drug component has vastly increased just over the last 10 years? What changes do companies have to go through to fit into the new world, and how is the sale of devices/drugs different? Here are a couple of key points that have changed dramatically: • Source of information: • The internet now means that anyone can access information at any time, which brings into question the role of the sales representative. • Personal interactions: • In a fast-moving industry when time is limited, there is less time to get to know sales representatives, particularly since reps tend to move job roles fairly quickly. • Clinical data availability: • The rep used to be the source, but has now been replaced with online journals or even search engines swiftly delivering replies in nanoseconds. • Ubiquitous feedback: • Social media means that patient opinions – good or bad - can be shared with an audience of millions at the click of a button. My first meeting with a product that could fit in both camps was Intergel, a medical device which had the objective to reduce intra-abdominal adhesions following surgery. It was an orange, slippery substance made of hyaluronic acid delivered in a squeezy bottle. It is no longer on the market. At the same time, drug-coated sutures, stents (I remember Vicryl + and Cypher) and many other innovations hit the market, and the change was immediate and it kept changing. The change in the last 10-15 years on how many products now have both pharma and med device is enormous.

According to one industry analysis, the global implantable drug delivery device market was valued at USD 11.6 billion in 2011 and is expected to reach an estimated value of USD 21.1 billion in 2018. The research reveals that the Asian implantable drug delivery devices market held a market share of over 15% in 2011, and was forecast to have the fastest CAGR during 2012 to 2018 – due to rapid growth in countries like India and China1. This is no doubt a new world for seasoned medical device reps who now have a different set of data to learn, and a very different sell: • The medical device sell is direct to the user, but in the traditional pharma sell, the consultant is only the prescriber - the patient is the actual user. • Introductions of buyers: • Buying groups have changed the world for both pharma and medical device companies and their sales forces. • Drugs have been subject to generic replacement for quite some time, and the impact this can have on combination products medical device is relatively unknown. • End user contact: • There are many areas where end user education is crucial to get an optimal outcome. Does information transfer correctly through layers of messengers as we have more complex products of combination types? • Patient influence and knowledge levels: • Never before have patients been so well informed and educated about their potential issues and available solutions. The requirement on doctors and caregivers has changed. • Modern requirements on the sales force: • It is no longer enough to find a company representative who can talk about technical specs, electrical bleeds, maintenance contracts and PAT testing. They now also need to be knowledgeable about issues such Autumn 2016 Volume 8 Issue 3

Regulatory Manufacturing & Marketplace Preparation of test solutions: at the specified wavelength in accordance with the instructions of the as half-life, drug interactions and A sale is impersonal and fleeting. It 100% accurate. Solution A: Solution of the product under examination at the initial lysate manufacture. serum levels. doesn’t on its own create a consumer. A The customer has the responsibility dilution (test solution) loyal customer believes in you, notofonly Solution B: Test solution spiked with CSE at a concentration at or near Interpretation results:for what product they buy, but also for However, perhaps that iscurve less (PPC) relevant all your product. The days didonly a ifhow that product is being used and what the middle of the standard Thewhen assay we is valid together... sale and moved on are and outcome is for theofpatient. Don’t aim Solution C: Standard solutions of CSE in water BET covering the linear 1. long The gone, standard curvethe is linear for the range CSE concentrations part of the standard curve we need to let go and takeused; a new shape. for “making a sale”, and never, EVER Solution D: Waterthe BET (NC)Rep 2. The coefficient of correlation r istreat not less than 0.980; Why I Sacked Sales attempt to a patient. Aim to inform 3. The mean % recovery of the added endotoxin the positive Nobody Likes Being “Sold To” and educate. Once you shiftin your focus, product control is between 50% and 150%.will transition into Method: Well, I didn’t really. But I did change the entire process Add solution D, followed by solutions C, A, B. Add lysate and carry the concept of the old-fashioned sales I have never met anyone who likes thinking for the future, not just for today. out the assay solution in accordance with the instructions of the lysate The concept of total quality control test refers to the process of reps and introduce a team of service phone sales people that hang up as soon Changing the mind-set and approach manufacture. striving to produce a perfect product by a series of measures

people. Changing a name doesn’t always

as they realise you’re not buying. Ever ultimately drives ROI because cultivating requiring an organised effort in order to eliminate errors at

accomplish the goal, but in this case it been in the position when you’ve bought repeat customers is less time-consuming Calculation: every need stageorinwant the production. In-processthan product testing has accomplished a change in attitude, something and less expensive creating newis Calculate the endotoxin concentration of solutions A and B you fromdidn’t the really required in order to check the conformance of the product with regression equation obtained with solutions of series C. Calculate the approach and atmosphere. Not bad for and walked away with a bad taste in ones. Focusing on your customer standards as specified in the pharmacopoeias. mean percentage recovery of the added endotoxin by mouth? subtracting the in the a couple of months’ work. your Well, the compendial medical device experience in every interaction increases The pharmacopoeiasthehave laid down specified limits mean endotoxin concentration in solution A fromworld the mean it is endotoxin coupled with morals. likelihood that the people will come concentration in solution B. within which the value should fall in order to be compliant as The medical device world is filled with back. If you want a good ROI, spend as Interpretation of results: per the standards. As the final samples taken for the finished them. Two categories, with the same goal: How on earth can someone with a much time and money on improving the product testing a representative largewould batch,ona sell stuff. Either the seasoned professional marketing or economics diploma tell isa only customer experienceofasa you The assay is valid only if significant difference still remains because of minor variation whoThe hasstandard been around “thethegood how to use a medical device? It conversion. 1. curve is since linear for range ofdoctor CSE concentrations in the specified limits in different pharmacopoeias. Since the old days used; when we could all go drinking makes absolutely no sense. Don’t chase a markets have facts. openedWhat up due to globalisation, is necessary together” or the new, slick, shiny-looking make sure you know your Keeps a Consumer itComing Back 2. The coefficient of correlation r is not greater sale than and 0.980; for a product the standards of the place where 3. mean % recovery the added in endotoxin positive device rep The determined to proveofthemselves In inthethemedical world, to it comply is forwith More? it is we to beremember marketed. For medical device and pharma the focus control is between 50% on andtheir 150%. absolutely crucial that theirproduct first job. Measured to 90% sales results, they are quick in, eager to where the responsibility lies for each role. is on patient outcomes — this translates End point chromogenicwill method As the official pharmacopoeias are different in different make a deal…and move on within Pharma and medical device companies to managing customer expectations so Add solution D, followed by solutions C, A, B. The chromogenic parts of the globe, there is a need for the harmonised limit 18 months. should communicate the facts of a they know what to expect. The medical substrate and lysate are added to the solution and incubated for the within which a product should fall to meet the pharmacopoeial product and ensure that their facts are device is only as good as the customer recommended time. Stop the reaction and measure the absorbance

Companies all around the world challenge us every day to create new products tailored to their needs. We embrace these challenges. We are engaged with




Regulatory & Marketplace

is, so education and information play an enormous role in the end result. And then, whether it’s convenience (making it easy and reliable) or company culture (donating products to charity), customers need a compelling reason to choose you time after time. Be clear, honest and objective. Never push a sale, but focus on observing needs and match it with your offering. And that is exactly why I made the decision to completely eradicate our sales team. I don’t hire sales people anymore. The Death of International Congresses I touched upon this earlier: how and from where do customers in medical device and pharma get their influences? Twenty years ago, international scientific meetings used to be a source of great learning for doctors and nurses, but also a lot of fun and a bit of a break from the daily routine. The change in regulations made sponsoring less available (a good thing, for many reasons) so fewer people could afford to go. And of course, a trip half way around the world (in some cases), being gone for most of a week, with hotel fees and registration costs, made it a big investment. But…it was all worth it, and even necessary. This is where the greatest research was presented with the 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

latest updates from the most experienced thought leaders. Today the world doesn’t function like that anymore. Social media and online news makes innovation and clinical data instantly available to anyone across the globe. So why would doctors still fly around to meetings if there really isn’t anything new? There is always a big win from meeting and discussing, but most international congresses are not designed that way. They are dinosaurs from the old times, when professors sit at podiums and a presenter stands at a podium and reads off data from a PowerPoint presentation. Healthcare professional attendee numbers are declining and so are sponsors. No manufacturer can spend a fortune paying for stand space, shipping expensive exhibition materials and paying company representatives to attend a five-day meeting if they don’t have anything new to launch, especially not when so few customers are attending. They are just showing the same things that they can show customers at home. I believe we need to rethink the whole concept. Accept that the old days are gone, and so are the old ways.

In Summary: The medical device and pharma industry are in for some dramatic changes in the next few years, for several reasons. We aren’t ready for it, we aren’t leading the way into it, and most of us can’t imagine what our new normal will even look like. If you do, I’d like to hear from you.

Angela Spang has a broad and long background in international business with both medical device and pharma, having held internationally focused senior positions with Johnson & Johnson (JNJ), Allergan (AGN) and American Medical Systems (END). She is Swedish but lives in the UK with her two daughters, their Canadian father and a cat who thinks she is a dog. She is a bit upset about being voted off the Island but recognises Brexit wasn’t necessarily personal. Email: Website: Twitter: @angelaspang. Autumn 2016 Volume 8 Issue 3

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Regulatory & Marketplace A Practical Guide to Serialisation

Requirements for serialisation are already active in some parts of the world and will soon be obligatory in most major markets. As we look ahead to the pending requirement for drug serialisation in the US and Europe, pharmaceutical manufacturers need to act soon or risk fines, loss of market share and damage to both reputation and stakeholder confidence. While challenging, serialisation is achievable and can even bring wider business benefits, providing the process is well planned and executed. David Sheedy, serialisation IT deployment manager at Zenith Technologies, sets out a practical roadmap for the successful implementation of a serialisation programme and describes 14 steps to success. The Road Ahead The EU Falsified Medicines Directive (EUFMD) Safety Features Delegated Regulation states that the serialisation of licensed drug products will be a legal requirement for companies in the EU from early 2019. Similarly, serialisation will be required in the US from November 2017 in line with the US Drug Supply Chain Security Act (DSCSA). Issues such as drug counterfeiting, adulteration, misbranding and diversion have all led to the trend towards serialisation. In fact, the World Health Organisation (WHO) estimates that the problem of falsified medicines accounts for between seven and 15 per cent of all medicines circulated in developed countries. Pharmaceutical serialisation, which requires drug manufacturers to add a unique code to the packaging of medicines and maintain a database of serial numbers, aims to establish the authenticity of each product and ultimately improve patient safety. As track and trace requirements and regulations vary widely across various countries and geographies, their implementation can prove challenging. For the average pharmaceutical firm, trying to focus on core business, while also keeping track of the new regulations and their timelines, is an almost impossible 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

task even within the major markets. The scale of the task can also be daunting. For example, a pharmaceutical manufacturer may have multiple manufacturing lines, in multiple locations, with more than 75 per cent of the business needing to comply with the new regulations. Despite the challenges, when implemented well, track and trace approaches such as serialisation can bring many benefits to the industry. Maintaining confidence in the drug supply chain benefits all legitimate manufacturers, as does combatting counterfeiting. Serialisation will no doubt enhance the reputation of the industry and safeguard patients. Enhanced product authentication and integrity also protect the companyâ&#x20AC;&#x2122;s brand and, therefore, shareholder value. In addition, the process of introducing unique serial numbers will greatly improve the visibility of the supply chain and control of inventory and logistics across an increasingly global marketplace. A Roadmap to Serialisation Success There are four core stages in the implementation of a serialisation programme, which require input from the highest levels of the business, professional project management and the assistance of third-party specialist partners.

in specific markets, but the project can also deliver return on investment through greater supply chain visibility, reduction of grey market losses, fewer recalls and improved product quality. Step 3. Carry out independent vendor selection Identifying the third-party software and hardware providers to make serialisation processes a reality takes both time and careful consideration. Most serialisation solutions come from small, specialist providers that may not have the project management and integration experience needed to deliver the end-to-end solution across multiple layers of systems. In this case, you may require a system integrator with specialist knowledge of serialisation challenges and processes to ensure the seamless implementation of the technology. You may also need to upgrade and possibly replace your packaging and printing equipment. Step 4. Manage key stakeholders Plan for and manage departmental involvement, making sure everyone knows their responsibilities and the impact the

Access & Design Step 1. Translate market regulations and impact Itâ&#x20AC;&#x2122;s essential that you clarify and understand the various different requirements of all the markets you serve. Start with those countries that are introducing new rules early â&#x20AC;&#x201C; such as South Korea, Turkey and Brazil. A full impact assessment of how the new rules for each territory, including the EU and US, will affect your operations is recommended. Step 2. Justify the project with KPIs and ROI The project will no doubt incur significant costs and these need to be justified, measured and managed to create a solid business case for the changes. The key driver may be the need to comply with regulations in order to do business Autumn 2016 Volume 8 Issue 3

Regulatory &Chapter Marketplace Title project could have on their processes and workflows, time, budgets and people. As well as having a dedicated taskforce to drive the project forward, it is vital that the leaders in the organisation are fully aware of the scale and complexity of the task ahead. Step 5. Programme design During this stage you should set out what the project will look like and how it will operate. This includes defining project governance processes, planning around quality, validation and testing and incident management. It’s important to identify key stakeholders from each site and business area that will be impacted by the project and to formalise management reporting. Step 6. Best practice architectures Map out the current state of your complete supply chain process and how this will need to change to incorporate serialisation. At this point it becomes possible to define the scope of the work at hand. The supply chain team needs to be heavily engaged at this stage and your vendors may also provide input. Build Step 7. Line impact assessments At this stage, you should gather information on the engineering solutions installed on your packaging floors. This will help you to plan your replacement or upgrade paths if required.

with minimal impact to product supply and production. Step 10. Education and training Who will provide training for the people impacted by the new processes, technologies and ways of working? Decisions should be made as early as possible about how training will be delivered, who needs it and to what extent. Third-party suppliers can help you to implement serialisation solutions, as well as delivering training and ongoing local level support. Consider which of the potential vendors have training capabilities during step 3. Deployment Step 11. Standardisation deployment If your serialisation solution needs to be deployed in more than two sites, then a standard approach to installation, configuration and testing will bring many benefits. These will include more consistent approaches, reduced testing cycles and a reduction in line or even site downtime. Step 12. Release management Any solutions you purchase as part of your serialisation project are likely to continue to change for at least the next five years. This means you will need to make the process of receiving, testing and releasing changes to your manufacturing sites and enterprise systems as efficient as possible.

Step 8. Serialisation schema Different markets will require your products to be serialised in different ways. As a result, coming up with a standard approach to how you will hold the data within your company is not an easy challenge. It is best to be guided by industry standards in order to insulate your company against changing market regulations. This approach should provide the most flexibility to adapt to new regulations that will inevitably emerge in the future.

There will be several release cycles in the early stages of implementing your project, as your vendors get to know your specific requirements. Each pharmaceutical manufacturer will have a slightly different setup, so there will be no “off-the-shelf” solution that can answer all your requirements. As part of step 3, you should have selected a partner who is willing to listen to and act on your requests.

Step 9. Change management Change will come from many sources and directions, including external regulatory changes, internal changes to scheduling and resources, vendor-driven changes to their offerings and product portfolio changes within a manufacturing site. All of these changes need to be prepared for and communicated to all who may be affected. Only then can they be managed

Step 13. Managing the line impact Making changes to your packaging lines, to equipment or to standard operating procedures (SOPs), will impact the line efficiency rate. Introducing standard ways of working and creating effective, well-delivered training packs will help reduce the amount of time your line performance is reduced. You may also find that by introducing standardisation,


reviewing line operations and replacing outdated machines, line efficiency may actually increase. Step 14. Post-development support It’s important to have an effective support system in place to manage any issues post-integration. First-line support should be your packaging line personnel, who will need training to fix any day-to-day issues that arise. Creating a support structure that captures learnings from incidents and delivers feedback to other sites and parts of the business will bring real benefits. An experienced, knowledgeable second-line support team will also be able to help capture and share learnings across sites. Agreeing a support contract with your vendors is critical to ensure long-term issues get resolved. Summary Serialisation will impact all aspects of a pharmaceutical manufacturer’s business, and the process of preparing for the new regulations needs to be given the necessary attention and focus. As well as improving patient safety and protecting the reputation of the pharmaceutical industry, serialisation creates an opportunity to make your organisation leaner, more efficient, more agile and more profitable. Choosing the right partners to help guide the process and manage complexities is key.

David Sheedy is a product manager at Zenith Technologies and is responsible for defining and developing product strategies. David joined the company in 2001 and has worked in many roles including serialisation IT deployment. Having worked within the life science industry for 15 years, David is an expert in pharmaceutical processes, in particular serialisation. He also has a wealth of knowledge in systems integration, automation and distributed control systems (DCS). David has a BEng in electronic engineering and an MSc in software development, meaning that he has sound technical expertise, as well as being well experienced in practical project management. INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

Drug Discovery, Development & Delivery Endothial Receptors As Drug Targets

In June, Cecilia Stroe, Editor of IPI, attended the Faron Pharmaceuticals R&D day in London to find out all about their work in life-saving drug development. She tells you that when it comes to overcoming acute respiratory distress syndrome (ARDS), all roads lead to the mighty immune system.

on the surface of vascular endothelial cells. These `homing` molecules form an essential cellular trafficking guidance system, which we all need to maintain our normal physiology. Unfortunately, many diseases use this system as well and the most harmful are extended inflammation and cancer spread.

Endothelial Receptors as Drug Targets Faron Pharmaceuticals Ltd is a drug discovery and development company focused on creating novel treatments for medical conditions with significant unmet needs. The company, based in Turku, Finland, has identified several molecular mechanisms involved in the control of endothelial functions as a source of innovations and currently has a pipeline of products in two critical areas: ischaemic conditions such as acute respiratory distress syndrome (ARDS) and cancer immunotherapy.

In addition to our blood vasculature, our bodies also include a drainage system called the lymphatic system. The same `GPS` guidance system also operates there but the recognition molecules are unique. In both of these capillary networks, the endothelial cells control the entry of migrating cells and maintain a barrier between circulation and tissues. “We identified several, new endothelial molecules involved in this guidance system and the maintenance of the endothelial barrier. We believe that the control of these molecules provides a unique way to treat many life-threatening conditions, with high unmet medical need. Our two lead indications – acute respiratory lung injury and control of tumour immunity – are both based on the malfunction of the endothelial barrier, both of which we learned to control,” explains Sirpa Jalkanen.

There are special molecules of fundamental importance for the proper functioning of our immune system, the ones that direct the cells to sites of inflammation to create an immune response. However, the same ones are also responsible for harmful cell trafficking, which takes place in acute and chronic inflammations as well as in tumour progression and metastatic spread of cancer. Therefore, these molecules are potential targets for developing drugs.

Faron`s lead drug, Traumakine, is currently in Phase III development for acute respiratory distress syndrome (ARDS), a severe, life-threatening medical condition characterised by widespread inflammation in the lungs and sudden failure of the respiratory system. ARDS causes inflammation of the alveoli in the lungs which are unable to perform the normal oxygenation of blood. It is characterised by rapid breathing, difficulty getting enough air into the lungs and low blood oxygen levels. Common causes of ARDS are sepsis, pneumonia, aspiration of fumes, food or stomach contents going into the lung, or significant trauma. The condition was first described in 1967 and gained wide attention during the Vietnam war, when it was nicknamed “white lung” as X-rays presented the lungs of the patients as white. According to the experts, ARDS is the leading cause of respiratory failure in intensive care unit patients requiring mechanical ventilation and oxygen therapy. Currently, there are no approved pharmacological treatments for ARDS, and although its mortality has decreased

“Imagine cars speeding in a dark tunnel, 100,000 kilometres long, without lights, at a speed of 800km/h, navigating their way to their destinations. This applies to cells, which migrate in our vascular system and need to move around. This movement is part of the normal surveillance system to detect any harmful event that would put our life at risk. It is our innate defence system and it also provides the initial immunological reaction against any foreign material entering the body,” says academician Sirpa Jalkanen, Professor and Chair of Immunology, University of Turku, Finland. The `GPS` for these moving cells is a molecular recognition system consisting of special molecules on the surface of migrating cells and their counterparts 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2016 Volume 8 Issue 3

Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing Phone: +33 (0)4 74 94 06 54


Drug Discovery, Development & Delivery mortality remains high. An effective pharmacotherapy is desperately needed," points out Dr Bellingan. At the moment there is no effective drug treatment for the syndrome; patients tend to be treated with mechanical ventilation and optimisation and support of vital functions. "Traumakine has been shown to reduce capillary leakage and we were very happy to see this translate into a benefit in ARDS patients as predicted. The drug promotes the formation of a local anti-inflammatory molecule and improves the amount of oxygen entering the bloodstream from the air," adds Dr Bellingan.

in the last decade due to improvements in supportive care and in the treatment of the underlying conditions, it still remains high, associated with a mortality rate of 35% to 45% depending on the severity of the condition. “Traumakine has been granted Orphan Drug designation in Europe, which allows a period of 10 years market exclusivity following market approval by EMEA,” says Dr Markku Jalkanen, CEO of Faron. “Our key aim in 2016 is the completion of the Phase III INTEREST trial recruitment. Subject to the completion of successful Phase III trials and achievement of regulatory approvals, Traumakine could be the first effective, mechanically targeted, disease-specific pharmacotherapy for ARDS patients,” he adds. Faron’s presently ongoing, clinical trial is a Phase III double-blind, randomised, parallel-group comparison of efficacy and safety of interferon-beta and placebo in the treatment of patients with moderate to severe ARDS. The study, named INTEREST, is to be conducted in 55 hospitals in Belgium, Finland, France, Germany, Italy, Spain and the UK, and 300 ARDS patients in total will be recruited. Treating ARDS – Beyond Supportive Care The Phase III INTEREST trial is being led by Professor Geoff Bellingan from University College London Hospitals and Professor Marco Ranieri from the University of 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Rome. In respect to Traumakine, Dr Bellingan has chaired the steering committee for the Phase I/II trial and now for the pan-European Phase III INTEREST study, and has published articles in various publications. The scientific rationale for Traumakine treatment is based on the use of interferon-beta for the restoration of the endothelial barrier function in ARDS patients. Supply of oxygen and nutrients to individual cells of various organs are maintained by vasculature and especially by the long and thin blood vessels called capillaries. Their integrity is sustained by endothelial cells covering the inner surfaces of these vessels, forming a barrier between circulation and tissues. The breakdown of this barrier results in leakage of blood content to tissues. If this happens in lungs, the lung air space is filled with protein-rich fluid and blood cells, preventing normal gas exchange. A key molecule to maintaining endothelial barrier and lung function is CD73, an endothelial ectoenzyme, which can produce local adenosine. According to Dr Bellingan, Traumakine’s active pharmaceutical ingredient, interferonbeta-1a, increases CD73 expression, resulting in increased local adenosine. Subsequently high local adenosine levels reduce capillary leakage and increase lung function by allowing normal gas exchange to return.

The first clinical trial in the Traumakine programme was a Phase I/II open-label study to assess the safety, tolerability and preliminary efficacy of interferon-beta in the treatment of patients with ARDS. This study consisted of dose escalation (Phase I) and dose expansion (Phase II) phases. In the dose escalation phase, four interferon-beta levels were tested. The dose expansion phase was conducted to determine the optimal tolerated dose. A total of 37 ARDS patients were treated at nine hospitals in the UK with highly encouraging results. Interferonbeta was found to be safe and welltolerated in ARDS patients, and the optimal tolerated dose was established. The selected pharmacodynamic marker for interferon-beta bioactivity showed clear dose response and the treatment target molecule (CD73) levels were induced during the dosing period. Most importantly, interferon-beta treatment significantly reduced the all-cause mortality at day 28, the primary end point of the study, compared to the control cohort (Bellingan et al. 2014, Lancet Respiratory Medicine 2: 97). Traumakine was associated with an 81% reduction in odds of 28-day mortality. The results of the trial were published together with the molecular studies of Professor Sirpa Jalkanen. By Cecilia Stroe, Staff Writer - IPI

"Pulmonary vascular leakage occurs early in acute lung injury/ARDS, and Autumn 2016 Volume 8 Issue 3

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Drug Discovery, Development & Delivery

Four Areas in which Gene Editing is Already Advancing the Treatment of Disease The last three years have seen an explosion of interest in gene editing, in no small part due to the discovery of CRISPR-Cas9, a primitive adaptive immune response in bacteria that has been co-opted for genetic engineering with the ability to target almost any gene in a huge variety of organisms.

mutations that drive many cancers, and with this knowledge comes the ability to identify novel drug targets or prognostic markers.

Most press attention has focused on the potential applications of gene editing in a therapeutic context – using the technology to directly edit an individual’s DNA. For example: to correct diseasecausing mutations, to introduce resistance to infections, or to create immune cells capable of fighting off cancer.

RNAi technologies initially looked as if they might provide a new avenue for more effective drug discovery, but offtarget effects and incomplete knockdown make this a fraught approach unless stringently controlled.

The field is progressing fast, with robust debates occurring across the globe about how this technology should be ethically applied, and huge investments being made to make these therapeutic aspirations a reality. However, it may yet be a few years before we see CRISPR in the clinic. Nevertheless, gene editing is already having a tremendous impact on drug discovery and development. Through the application of gene editing, scientists can hone in on better drug targets quickly and then create better disease models in which to test and refine the next generation of targeted therapies. Gene editing technologies are also being used to improve the development of nextgeneration diagnostics, as well as the manufacture of biological drugs such as monoclonal antibodies or peptide-based therapies. Better Drug Target Identification Thanks to next-generation sequencing, we are starting to understand the genetic


However, taking these initial findings all the way through to the clinic is an enduring challenge.

Better Disease Models If ways can be found to drug these novel targets, then the key to progressing these drugs to the clinic is demonstrating their potency, specificity and “drug-like” properties such as solubility. Initial studies are performed in cell-based assays (for example, the concentration of a drug required to induce cell death), and then in animal models, where both phenotypic and pharmacokinetic properties can be monitored.

Gene editing offers a more robust approach to interrogating gene function, and with the advent of CRISPR-Cas9 can now be applied much like RNAi on a genome-wide level. The contribution of this technology to drug discovery looks like it will be substantial, primarily because the off-target effects appear to be fewer in CRISPR-Cas9 target identification screens.

The challenge in the past, however, is that what occurs in these cell and animal models often does not reflect well what might occur in humans. We have cured cancers in mice many times over, but many of these breakthroughs have yet to translate to advances in human treatment. This is in part due to the differences in physiology and biology observed in cells or animals relative to humans. But in some cases this is also because the genetics of the models used do not reflect those of the diseases observed in the clinic.

Not only have CRISPR screens recapitulated the results generated with RNAi, but in many cases have been found to add an extra level of depth – identifying further novel hits. Additionally the specificity of the system means that these putative targets are less likely to be red herrings and more likely to be very real, very valuable drug targets.

Using gene editing, scientists can recapitulate the mutational drivers of disease in the lab. For cells, this offers two distinct advantages - not only is the model now more clinically relevant, but the process of generating an engineered cell line produces a pair of genetically identical cell lines, one now mutated and the original “normal” non-mutant.

Devoid of the caveats associated with siRNA and shRNA reagents, these novel targets can be uncovered and rigorously validated using CRISPR-Cas9, producing a pipeline of innovative and validated targets for entry into drug discovery programmes.

This normal cell line serves as the perfect control for studying the effect of the mutation – for example, is a drug now able to kill the mutant cell while leaving alive the normal control (evidence that a drug will be less toxic)? These cell pairs can be used in vitro in a

Autumn 2016 Volume 8 Issue 3

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Drug Discovery, Development & Delivery

variety of drug-testing assays such as cell proliferation or migration. Additionally, through the use of 3D culture, co-culture environments or xenografting, (where growth will more closely reflect that of a tumour in the clinic), more accurate assessment of the response of the edited cancer cells to targeted agents can be made. Gene editing also facilitates the creation of more faithful animal models. As with cell lines, genes of interest can be manipulated to reflect clinical observations. But further to this, gene editing tools have opened up the possibility of using organisms with physiology and behaviours closer to that of humans, something which has previously been extremely challenging. For example, the study of Parkinson’s disease (PD) has been impaired by the lack of PD models that completely recapitulate key clinical and neuropathological features of the disease. The mouse, historically a widely-used animal model that is relatively easy to genetically engineer even without gene editing tools, does not develop PD-like symptoms. To address this problem, Horizon Discovery, in collaboration with the Michael J Fox Foundation, has used gene editing to create a collection of 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

rat models of PD that exhibit many of the associated phenotypes such as impaired movement and loss of sense of smell, and these models are proving invaluable in assessing the efficacy of novel therapeutics. Development of these PD models would simply not have been possible without gene editing. Better Diagnostics Even with the big breakthroughs in disease treatment that have been made in the last decade, the best strategy for increasing patient survival, particularly when it comes to cancer, is early diagnosis. The five-year survival rate for women with stage 0 or 1 breast cancer is close to 100%. The survival rate for women with stage IV or metastatic breast cancer is 22%. Similarly, the survival rate for patients with stage I lung cancer is 42%, while patients with stage IV lung cancer have a 1% chance of survival. Detecting cancer earlier requires diagnostic tests with improved sensitivity and reliability. These, in turn, will allow clinicians to make informed decisions about treatment regimens. Identifying and treating only those patients that will respond to specific drugs has a number of benefits – not only saving lives, but improving quality of life for those patients

who would otherwise have to suffer the side-effects of a treatment without benefiting from it, and also reducing the overall costs for the healthcare providers and insurance companies that pay for these treatments. Unfortunately, the results these tests provide are not always accurate. A key step in improving the performance of these diagnostic tests is their validation and ongoing quality control – the unequivocal demonstration of their sensitivity and reproducibility. For many assay developers, this has meant benchmarking against existing “gold standards”, but as technologies have advanced and capabilities have leapt forward, this has become increasingly challenging. There is a requirement, therefore, for an objective standard against which assays can be measured and their consistency routinely monitored. In the past, such objective reference materials have been difficult to source. Individual patient tissue samples are finite, inconsistent between patients, and can even vary significantly within a single sample in the case of cancer. Cell lines are a more sustainable source of material, but can themselves exhibit a great deal of heterogeneity and, for rare biomarkers, cannot always be sourced. Synthetic materials such as pieces of Autumn 2016 Volume 8 Issue 3



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Autumn 2016 Volume 8 Issue 3

Drug Discovery, Development & Delivery

synthesised DNA or peptides can serve, but do not mimic the genomic or cellular context of a patient biopsy and so cannot act as a complete control for entire diagnostic workflows. Gene editing provides a means to manufacture sustainable, genetically defined reference materials. Cell-based disease models provide a reliable and source of positive and negative controls that can support testing for any genotype, including those rare and difficult to source as patient samples, are consistent regardless of when they are used, and can be mixed (mutant and normal) homogenously throughout and embedded in FFPE so that they present exactly as patient samples do. Additionally, mutant/non-mutant dilutions can be created to truly test the limits of sensitivity of an assay. This allows assay developers to push the bounds of their assays and achieve detection limits consistent with those required for noninvasive “liquid biopsies”. Better Bioproduction An increasing proportion of new drugs today are biopharmaceuticals or “biologics”. These are drugs that are manufactured from a biological source rather than chemically synthesised. Between 2006 and 2011, the FDA approved an average of 15 new biologics every year. Critical to taking biologics to market (alongside determining their efficacy as discussed above) is the ability to scalably 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and cost-effectively manufacture these drugs. Although many systems have been developed to do this over the past 25 years, the predominant expression system used is Chinese hamster ovary (CHO) cells.

Better Treatment of Disease Above, we highlight how gene editing is already having a significant impact on many facets of the drug development process. At every step the consequence will be better outcomes for patients.

Yields achieved with CHO cells have increased about 100-fold since they started being used, but advances in cell line technology are still limited by the biology of these cells, and fundamental improvements to CHO cell lines are therefore needed to increase the potential of this host system still further. Additionally, as the pharmaceutical industry moves toward an ever more fragmented market (driven by the movement toward personalised medicine), smaller manufacturing batches must become economically viable. Finally, as therapeutics based on novel protein architecture are developed, modifications of such systems are needed to maximise benefits derived from exciting new therapies.

Through the identification of novel drug targets, the more rapid and effective validation (or disqualification) of drugs, the identification of the individuals that will benefit from treatment, and the ability to cost-effectively manufacture a wider array of targeted therapies, gene editing is underpinning many of the seismic shifts in translational research required to make the era of personalised medicine a reality.

To these ends, gene editing is being applied to the optimisation of the CHO cell system to improve bio-manufacturing. The modification of CHO cells is still in its infancy, but one can reasonably anticipate that through the manipulation of gene transcription, protein translation and trafficking, or even through the introduction of entirely new molecular pathways, we might see a multiplicative effect on specific productivity through better yields, purer product, and better control over the process.

Chris Thorne has been working at Horizon for five years, during which he has been responsible for the genetic validation of all cell lines in Horizon’s catalogue, has been part of the launch of Horizon’s diagnostic reference materials and has supported hundreds of academic labs as they implement CRISPR genome editing with Horizon’s tools. Prior to Horizon Chris completed his PhD at the University of Liverpool. Email: chris.thorne@horizondiscovery. com

Autumn 2016 Volume 8 Issue 3

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Clinical Research

Electronic Data Delivering Pharmaceutical Analysis for Eye Conditions Degenerative eye conditions, particularly age-related macular degeneration, already affects millions of people and this will increase dramatically in the future as the population ages. The last decade has seen the development of the first wave of drugs to treat this condition but new pharmaceuticals need to be developed to improve patients’ health. Consequently there is a need for efficient systematic data recording to understand current real-world clinical outcomes and to support research and development alongside patient care. Christian Martin, managing director of Medisoft Limited, tells International Pharmaceutical Industry how advanced electronic medical records (EMR) are meeting the challenge.

new drugs to treat the growing number of people with chronic diseases.

By 2020, it is estimated 196 million people around the world will be suffering from age-related macular degeneration (AMD) and that figure will rise to 288 million by 2040, according to a study in the Lancet Global Health – and many more will suffer from conditions such as glaucoma and diabetic retinopathy.

Benefits of Pharmaceutical Companies Working with EMR Companies and Clinicians Pharmaceutical companies are increasingly supporting the implementation of EMR systems into hospital eye departments, as they recognise this both helps the efficiency of service delivery in very busy clinics, and that the data collected will be valuable in assessing the real-world benefits of current treatments and in developing new treatments. As the number of patients treated for common ease conditions increases, so does the volume of data available for analysis. It is now possible to look at outcomes for a whole population rather than just a sample of patients, that may introduce bias. Increasingly, pharmaceutical professionals are recognising the benefits of such standardised data and are supporting an increasing range of clinician-led studies to collate and analyse this data.

The huge increase in clinical workload across ophthalmology is staggering. In 2011-12 there were over six million outpatient attendances in England, a figure that has been increasing by one million per year due to a combination of an ageing population, availability of new pharmaceutical treatments for previously untreatable diseases such as wet AMD, retinal vein occlusion and diabetic macular oedema, and the fact that these patients currently require frequent, often monthly, follow-up appointments for several years. Such an increase in retinal appointments presents significant challenges for clinicians, but thanks to advanced EMR systems, also provides an opportunity for pharmaceutical companies who can make use of the surge in patient records to identify how effective the new drug has been. The rapid increase, due in part to longer lifespans, is fuelling investment in the treatment of degenerative eye conditions, and driving the opportunity for pharmaceutical companies to develop 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

But developing and improving ophthalmic medications brings challenges. Advanced EMR systems are now able to play a significant role in the pharmaceutical research and development cycle. Many thousands of patients have been accurately phenotyped allowing rapid identification of patients that meet inclusion and exclusion criteria for clinical trials; the EMR potentially offers a platform to run the clinical trials and it is possible to compare how “realworld” clinical outcomes compare with the results from randomised controlled clinical trials.

Now, with increased competition in the pharmaceutical industry, manufacturers who are launching new products need to work smarter and faster to market drugs to a wider audience. There is a compelling case to move away from the old methods of focus groups, one-to-one interviews, and mountains of paperwork, to the major benefits from EMR systems. Never before has it been possible to obtain such a wealth of data which can be drilled down to uncover not only how effective drugs have been, but also

how effective they have been on certain groups of patients – such as patients of a particular age range, gender, race, being treated for a particular condition. This is because EMR can bring key patient data together in a simple, easyto-use system, that allows physicians to see patterns in a patient’s disease, as well as the patient’s response to treatment. This provides speedy results for assessing the effectiveness of pharmaceuticals, especially newly-developed treatments. Pharmaceutical R&D teams have always operated in a challenging environment to produce data that is consistent, reliable and well-linked. EMR have the potential to automatically collect such data at all stages of the value chain, from trials to real-world use after regulatory approval. This is a fundamental requirement to allow companies to derive maximum benefit from the latest technology trends. For pharmaceutical companies to benefit from the new opportunities now open to them, their leaders have to be open to a different approach to solving fundamental problems. The companies that are prospering are, almost without exception, led by visionaries not tied to older ways of operating, but willing to embrace the implications of the latest technology. Pharmaceutical research and development has traditionally been a secretive activity conducted within the confines of the department, with little internal and external collaboration. But, by breaking away from such constraints, which can limit progress, and enhancing collaboration with external partners, pharmaceutical companies are able to extend their knowledge and data networks. End-to-end integration aims to improve the linking of data elements at all stages of the process with collaboration between all stakeholders in drug research, development, commercialisation and clinicians delivering services. A New Era of Big Data Embracing links with EMR collaborating with clinicians

and and

Autumn 2016 Volume 8 Issue 3

Clinical Research including the drugs/pharmaceuticals used to treat them and the effectiveness of such treatments. Previously, it was almost impossible to gain basic insights from hospital eye departments, such as the proportion of cataract operations that resulted in significantly improved visual acuity, but now for sites using Medisoftâ&#x20AC;&#x2122;s EMR, this data and many other outcomes are available at the click of a mouse. If trials are conducted on the EMR platform, it will be possible to monitor safety and operational signals requiring action in real time. Instead of rigid data silos, data captured electronically can flow easily between functions, and this easy flow is essential for powering the real-time and predictive analytics that generate business value. hospitals that hold this data will help pharmaceutical companies be more effective in understanding many aspects of their market and product development. It will, for example, help companies identify areas of unmet clinical need and the market size, and will speed recruitment into trials, shortening the duration of trials, which has the potential to give more years of patent protection after regulatory approval. Using an advanced EMR system like Medisoftâ&#x20AC;&#x2122;s has the potential to help save time and money across the whole research and development cycle. There is the potential to intelligently pool the huge amount of data held on patients and their treatments if pharmaceutical companies work in partnership with clinicians, hospitals and EMR suppliers. The aim is more effective, targeted and personalised therapies, marketing opportunities from knowing more about patients, and allround efficiencies. IT-enabled portfolio management through EMR systems allows for datadriven decisions to be made quickly and seamlessly. Smart visual dashboards should be used whenever possible to allow rapid and effective decision-making, covering the analysis of current projects, business development opportunities, forecasting and competitive information. An example of the need for the best data collection system possible can be found within AMD. In 2008, the National Institute for Health & Care Excellence approved the use of a new class of drug to treat wet age-related

AMD, which is the commonest cause of blindness, and its treatment requires monthly monitoring over several years. As a result of the decision, the demand for retinal appointments has increased by more than 300% in seven years.

The expansion of data beyond clinical trials will also become more commonplace. Already, some leading pharmaceutical companies are building proprietary data networks to gather, analyse, share, and respond to realworld outcomes and claims data.

Real-world Clinical Trials The Medisoft EMR system is already collecting highly-structured clinical data on the whole population being treated in many geographical locations in the UK for many eye diseases. This allows robust analysis as biases due to case selection are eliminated. Real-world clinical trials can be conducted quickly and at vastly lower cost than in the past. For example, to answer a question, such as: within the constraints of real-world service delivery, which anti-VEGF drug is more effective at maintaining or improving visual acuity over five years would require a large number of eyes in each group.

An EMR system can report at every stage of a patientâ&#x20AC;&#x2122;s journey. This covers the initial consultation, pre-operative assessment, biometry, anaesthesia, surgery, telephone calls, follow-up clinic visits and assessments in the community. Letters are generated automatically and can be electronically transmitted to their recipients. Interactive clinical summaries, showing disease progression and treatment over several years, can be collated on a single page and audits of activity and clinical outcomes from thousands of patients can be produced in seconds.

With traditional paper-based processes, this question could not be answered, but pooling of data on a regional or national basis from EMR systems can answer such questions very rapidly. With the right data, pharmaceutical companies have the tools to immediately identify the best applicants for clinical trials, measure the effectiveness of new drugs on large numbers of patients, and obtain extensive knowledge about entire disease states and patients. Improved data collection gives a clear view of the patient care pathway,

Improving Pharmaceutical Treatments with EMR Modern eye care requires a wide range of sophisticated diagnostic and monitoring equipment and collating the data from the equipment proved challenging until the development of suitable EMR systems, which interface with the diagnostic systems to ensure results are readily accessible as a part of the care pathway. Data collection in ophthalmology has finally reached the required levels and it now seems surprising that despite all the modern equipment and facilities in hospitals, many eye departments lack a central repository for all recorded patient information, increasing the risk of human error and lost records. Clinical teams INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Clinical Research

had to compare information stored in several locations. Repeat visits were often required, as access to data across different sites was not available. Clinic letters would be delayed and evaluating a service was almost impossible. That has now changed with the capability of EMR systems giving an uncluttered “data rich” interface, allowing clinicians immediate access to the information they need at their fingertips. EMR solutions fit well with government plans to reform the NHS into a clinicallyled, patient-centred service focused on outcomes. As part of the reform, local professional networks (LPNs) for eye health, dentistry and pharmacy are being established. Their objectives are to improve outcomes, deliver high-quality care, reduce inappropriate variation and decrease health inequalities. Adopting 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

EMR gives the capability to collect nationally-agreed standardised datasets for all common eye conditions, and the benefits are best exemplified in the most common eye diseases: glaucoma, cataract, wet AMD and diabetic retinopathy. For each disease, decision support functions and graphic displays of relevant data over time can greatly improve the accuracy, quality and consistency of clinical decisions. In glaucoma, care decisions made at clinic are often dependent on data recorded months or years earlier, and a timeline graphical presentation of all relevant data improves the consistency and speed of clinical decisions and avoids re-prescription of unsatisfactory or harmful medications. For cataract surgery, software can

automatically calculate a precise tailored risk score for the most common operative complication – posterior capsular rupture. With AMD, by making more use of non-medical staff and displaying all relevant data to make decisions quickly, doctors can see many more patients during clinics. For diabetic retinopathy, clinicians can take advantage of an automatic link between hospital eye care and diabetic photographic screening services, eliminating a major paper chase and improving failsafe measures. At a provider level, the data empowers sites to compare results between clinicians, across patient cohorts, and to assess the impact of changes in treatment approach, tasks that could not have otherwise been completed effectively. An Effective Solution Medisoft has gained a dominant market Autumn 2016 Volume 8 Issue 3

Clinical Clinical Research Research position in the UK with its Medisoft Ophthalmology product now deployed in over 150 hospitals, and the company, a winner in the 2016 Queen’s Awards for Enterprise and Innovation, has recently expanded its system to allow shared care between hospital eye departments and community optometrists and, with The Royal College of Ophthalmologists, is establishing an online National Ophthalmology Database to increase visibility of standards of ophthalmic care across the UK.

“drill through” to identify patients most at risk, allowing them to prioritise care, so patients who are being reviewed unnecessarily can be distinguished from those who would benefit from more regular assessments.

The ever-increasing number of patients, particularly for those with suspected glaucoma and retinal diseases, means solutions are needed to manage the demand and increase efficiency within eye departments. Using specialised EMR software, such The National Database, representing as Medisoft Ophthalmology, transforms the culmination of several years of the delivery of services by allowing innovation, will offer a unique tool for maximum use of non-medical staff, and national audit, research, revalidation speeding decision-making by doctors of doctors and for commissioning by the presentation of data in easy-toophthalmology care in the UK. interpret graphical timeline displays, and is much more cost-effective than outdated AFigure key example of this patient in practice is thecardrecording systems currently used by some 1 – Universal contact software’s ability to present thousands of pharmaceutical companies. The system outlined previously are addressed. An implementation team will also ensure visual field assessments in a single novel was developed using industry-recognised This implementation team works in that patient contact cards are available graph, allowing the immediate visibility non-proprietary tools and has brought collaboration with the client (sponsor/ and provide patients and participating of all the patients with glaucoma, the substantial cost savings for the NHS, CRO – clinical research organisation) clinical personnel with all the information severity of their disease and how rapidly and as more hospital eye departments to fully understand the complete study they need about the support services in they are progressing. It is such data that abandon paper records, those savings support requirements – including all a neat, compact and readily-available gives the medical experts the ability to will increase further. aspects of patient support, whether package. The patient contact card should clinical, medical, logistical or technical. have a universal design to ensure that the

Christian Martin, Managing Director of Medisoft. With a strong technical background, Christian has overall responsibility for Medisoft’s operations and business development. Prior to joining the company in 2011, he was Chief Technology Officer for the NHS National Screening Programmes and helped to design and launch the NHS Diabetic Screening Programme. Christian has managed the company through a period of rapid growth and is overseeing the redevelopment of Medisoft’s product suite to ensure that it takes advantage of the best available technologies and meets the needs of a global market.

contact centre can easily direct the patient, or in the case of the patient presenting themselves at a hospital or clinic other than the study centre, the treating healthcare professional, to the necessary information to assist with queries about the patient’s participation in the study.

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Clinical Research Developments in Imaging Technology Advance the Fight Against Fungal Infections Across the world, millions of people contract invasive infections that are difficult to diagnose and treat, and can be life-threatening. The frequency of invasive fungal infections has increased significantly over the past two decades and continues to do so. Fungal infections have a major impact on human health (Pfaller et al., 2006), causing high levels of morbidity and mortality, and resulting in increased healthcare costs (Spellberg et al., 2008). Around 1.5 million people die each year as a result of invasive pathogenic fungal infections, and more than 90% of these deaths result from species belonging to one of four genera: Cryptococcus, Candida, Aspergillus and Pneumocystis (Brown et al., 2012). In this article, we determine the challenges associated with infection persistence and antifungal therapeutics. Additionally, we will explore how increased sensitivity in the latest preclinical imaging instruments is giving researchers new insight into fungal infections in order to shape the future development of more effective treatments. Although anybody can contract an invasive fungal infection, patients most at risk are those that are hospitalised or with compromised immune systems, as these patient groups struggle to fight infection. In the US, from 1980 to 1997, the annual number of deaths in which invasive mycosis was listed on the death certificate increased by 320% (Low and Rostein, 2011). This was due in part to the increasing number of organ transplants and the use of new and more potent chemotherapeutics and regimens, which increased the pool of immunocompromised patients dramatically (Low and Rotstein, 2011). Challenges Associated with Antifungal Therapeutics Despite medical advances, the impact of invasive fungal infections on the global healthcare system continues to grow. The Candida fungus is the most common cause of healthcare-associated bloodstream infections in the US. Each case is estimated to result in an additional 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

three to 13 days of hospitalisation and increased healthcare costs of $6000 to $29,000 per patient (Magill et al., 2014; Morgan et al., 2005). Although there is a significant market for antifungal therapeutics, treating invasive fungal infections remains challenging due to their increased resistance to first- and second-line antifungal drugs, such as fluconazole and echinocandins, including anidulafungin, caspofungin, and micafungin (CDC, 2015). Statistics show that approximately 7% of all Candida bloodstream isolates tested at CDC are resistant to fluconazole, whilst approximately 1% of all Candida tested at CDC showed echinocandin resistance (Clevelant et al., 2012; Lockhart et al., 2012; Hajjeh et al., 2004; Kao et al., 1999). The causes of antifungal resistance are numerous. Some species of fungi are naturally resistant to specific types of antifungal medication, whereas others may develop resistance over time due to improper antifungal use. Studies indicate that antibacterial medications can also contribute to antifungal resistance, for example by creating favourable conditions for Candida growth (BenAmi et al., 2012). Common measures to prevent and reduce the incidence of antifungal infections include the growing role of infection control staff, education and co-operation of healthcare professionals and patients, and also improving diagnostic techniques on offer. Disease Dynamics and Persistence Overcoming the persistence of fungal infections is a key driver for the development of effective antifungal treatments. Even when a therapy is considered to have been successful, infection may still be present in the tissue at levels too low for detection by common imaging and analytical techniques; consequently, if a treatment is withdrawn, relapse of the infection can occur (Delarze and Sanglard, 2015). Therefore, gaining a deeper understanding of the dynamics of infection

as well as developing new, more effective treatment options remains a major goal for researchers around the globe. Preclinical-imaging is the visualisation of living animals for research purposes. The technique involves using multiple imaging modalities and bioluminescence, which detect the luciferase light emission from engineered cells to monitor tumour cells, infections, gene expression and monitoring response to therapy in realtime. Pre-clinical in vivo imaging is widely regarded as a key tool within the drug discovery and development pipeline, giving researchers clear visibility of cellular changes at a molecular level and the ability to visualise where fungal cells congregate and persist in the body. The result is a deeper understanding of disease progression, and the mode of action and pharmacokinetics of potential antifungal therapeutics. Technological advances are increasingly aiding researchers to optimise in vivo testing in the pre-clinical setting and translate their work from in vivo models into the clinical situation. The development of multi-modal preclinical imaging systems is transforming research practice, facilitating use of complementary imaging techniques to improve understanding of disease progression and drug efficacy. One such multi-modal imaging system* enables five imaging modalities to be conducted consecutively, with simple, fast and automatic transfer between different imaging techniques and accurate coregistration of the images produced. Technological developments have also emerged to tackle the issues of detection limits often faced by researchers. Enhanced camera functionality now brings a new level of sensitivity, speed and versatility to non-invasive procedures, providing unprecedented performance levels during extremely lowlight applications and thereby enabling researchers to discover important biological mechanisms in disease to inform treatment and monitoring.

Autumn 2016 Volume 8 Issue 3

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

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

Accelerating Enrollment

Digital Marketing

Locating Lost Patients


Clinical Research

Figure 1. Fungal load in relationship with luminescence CASE STUDY - New insight into the progression of fungal infections Dr Dominique Sanglard of the Institute of Microbiology, University of Lausanne, Switzerland, has recently employed an advanced multi-modal pre-clinical optical imaging system* with superior sensitivity and five imaging modalities in one instrument, allowing the detection of extremely low levels of infected cells within tissues. The Candida species, in particular C.albicans, have specific virulence traits and can easily develop resistance to antifungal therapeutics. Dr Sanglard and his research team are currently working to gain an improved understanding of the dynamics and progression of C.albicans infection, and to identify novel antifungal agents and establish their activities directly in vivo using animal models of infection. Sanglard’s researchers are using preclinical imaging to study how infection moves around the body and ascertain where infected cells might collect. The multi-modal system has allowed them to detect fungal infections at extremely low levels in vivo in the kidney tissue, which is notoriously difficult to detect. It is typical to see signs of disease at 105 – 106 cells per kidney; however, fungal infection can persist at 102 – 105 cells per kidney. The enhanced camera sensitivity has enabled the researchers to detect infection at unprecedented low levels of 102 – 103 cells per kidney (Figure 1). Dr Sanglard said: ‘The sensitivity of the Xtreme II is unparalleled, enabling us to detect very low levels of C. albicans infected cells within the kidney and other 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tissues. In fact, in our hands we see the Xtreme II being twice as sensitive as other instruments we have used, allowing us to observe disease progression earlier, and to explore where any infection persists after therapy.’ BOX OUT: Achieve new levels of sensitivity, speed and versatility in pre-clinical research Advances in pre-clinical imaging technology are providing researchers with enhanced capabilities to characterise and measure biological processes in vivo, thereby paving the way for a better understanding of physiological and disease mechanisms in the pre-clinical setting. The Bruker Xtreme II combines five imaging modalities as standard, with access to Bioluminescence, Multispectral VIS-NIR Fluorescence, Direct Radioisotopic Imaging and Cherenkov radiation. A high-speed digital X-ray scanner adds to the functional images with morphological features. The latest software allows simple, fast and automatic transfer between different imaging techniques and accurate coregistration of the images produced. Enhanced camera capabilities now bring a new level of sensitivity, speed and versatility to non-invasive procedures, enabling researchers to discover important biological mechanisms in disease to inform treatment and monitoring. By cooling the camera to less than -90° C and using exceptionally low-read noise electronics, unprecedented performance levels during extremely low-light applications – such as bioluminescence and Cerenkov imaging – are achieved.

The use of multi-modal animal beds, which are compatible with a number of instruments, removes any requirement to disturb the animal during a cross-platform study and ensures accurate positioning to facilitate the layering of images to improve insight during subsequent study. Conclusion As the global demand for antifungal therapeutics continues to rise – driven largely by the high mortality rates and increased healthcare costs associated with severe fungal infections – researchers are focusing their studies on the disease dynamics and the effects of treatment in greater detail. Imaging is at the forefront of the revolution in pre-clinical information, providing increasingly valuable insights into disease mechanisms and progression. A range of imaging modalities are already being used to inform therapeutics in a number of clinical areas, most significantly in infectious disease research fields, such as antifungal studies. Technological advances are aiding the translation of pre-clinical research work from in vivo models into the clinical situation. The development of highly sensitive, multi-modal systems is bringing new cross-platform capabilities, facilitating enhanced insight, more accurate analyses and improved access to useful data and enabling higher test throughput. Looking forward, these innovations will surely put more powerful data into the hands of researchers, further accelerating the development of antifungal drugs and informing clinical practice. *Bruker Xtreme II

Autumn 2016 Volume 8 Issue 3

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Clinical Research

References 1. Ben-Ami, R., Olshtain-Pops, K., Krieger, M. (2012). Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrobial Agents and Chemotherapy 56:2518-23. 2. Brown, G.D., Denning, D.W., Gow, N.A.R., Levitz, S.M., Netea, M.G., White, T.C. (2012). Hidden killers: human fungal infections. Science Translational Medicine 4 (165): 1-9. 3. CDC. (2016). Antifungal resistance. h t t p : / / w w w. c d c . g o v / f u n g a l / antifungal-resistance.html. Last accessed 30th Jun 2016. 4. Cleveland, A.A., Farley, M.M., Harrison, L.H. (2012). Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clinical Infectious Diseases 55:1352-61. 5. Delarze, E., Sanglard, D. (2015). Defining the frontiers between antifungal resistance, tolerance and the concept of persistence. Drug Resistance Updates 23: 12-19. 6. Hajjeh, R.A., Sofair, A.N., Harrison, L.H. (2004). Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

from 1998 to 2000 in a populationbased active surveillance program. Journal of Clinical Microbiology 42:1519-27. 7. Lockhart, S.R., Iqbal, N., Cleveland, A.A. (2012). Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011. Journal of Clinical Microbiology 50:3435-42. 8. Low, C.Y., Rotstein, C. (2011). Emerging fungal infections in immunocompromised patients. F1000 Reports Medicine 3 (14): 1-8. 9. Magill, S.S., Edwards, J.R., Bamberg, W. (2014). Multistate point-prevalence survey of health care-associated infections. The New England Journal of Medicine 370: 1198-208. 10. Morgan, J., Meltzer, M.I., Plikaytis, B.D. (2005). Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infection control and hospital epidemiology 26:540-7. 11. Pfaller, M.A., Pappas, P.G., Wingard, J.R. (2006). Invasive fungal pathogens: current epidemiological trends. Epidemiology of Invasive Mycoses 43 (1): S3-S14.

12. Spellberg, B., Guidos, R., Gilbert, D., Bradley, J., Boucher, H.W., Scheld, W.M., Bartlett, J.G., Edwards, J. (2008). The epidemic of antibioticresistant infections: a call to action for the medical community from the Infectious Diseases Society of America. The Epidemic of AntibioticResistant Infections 46: 155-164.

Sharon Janssens is an Application Scientist at Bruker. Sharon studied Master of Applied Science Biochemistry at Hogeschool Gent after which she obtained a Master of science in Biomedical Engineering at Ghent University in Belgium. Sharon obtained her PhD in biomedical engineering from the Technical University of Eindhoven in The Netherlands before joining Bruker in Kontich, Belgium as an application scientist for both microCT and optical imaging. Email: Autumn 2016 Volume 8 Issue 3

Chapter Title



cause an array of serious conditions including septic shock. Even endotoxin from dead bacterial cells introduced to medical devices during manufacture can later compromise patient safety when used clinically. There are currently three approved techniques for endotoxin testing, one of which is the kinetic chromogenic technique, such as the Kinetic-QCL™ Kinetic Chromogenic LAL Assay manufactured by Lonza. In the presence of endotoxin, the lysate begins to cleave the chromogenic substrate, causing the solution to become yellow. The time required for the change is inversely proportional to the amount of endotoxin present. The concentration of unknown samples can then be calculated from a standard curve. Details on how to extract for BET testing will be outlined in this article.

Devices to be Tested With medical devices ranging from simple fluid catheters to complex knee replacements, there are various guidelines that aim to properly define devices and provide guidance on conducting BET. Manufacturers must be clear on how to appropriately sample and test their device.

Guideline Update: Bacterial Endotoxin Testing

The medical sciences harness a vast assortment of equipment and tools that are implemented for the effective diagnosis and treatment of disease. Guidelines provided by the Association for the Advancement of Medical Instrumentation (AAMI) entitled ‘ANSI/AAMI ST72/Ed.2, Bacterial Endotoxin – Test methods, routine monitoring, and alternatives to batch testing’ define medical devices as “products that have direct and indirect intravascular, intra-lymphatic, or intrathecal contact” and advise that all such products shall be evaluated for the presence of endotoxin. In addition to this, the revised guidelines provided by the USP give a brief list of examples of devices to be tested, which are outlined in Figure 1.

Introduction To ensure patient safety, it is vitally important that bacterial endotoxin testing (BET) is carried out on representative batches of manufactured medical devices prior to release, and that manufacturers align with current thinking on BET practices. Several revisions to USP Chapter <161>, Transfusion and Infusion Assemblies and Similar Medical Devices, came into effect August 2015, particularly regarding product unit descriptions, sampling and suitability testing. These changes have been made to help safeguard against the shipping of medical devices that may be unsafe for clinical use due to the presence of endotoxin. So what are the implications for those conducting BET? This article highlights some of the key revisions made to USP Chapter <161>, outlining amendments on the methodology, guidelines and practices. Bacterial Endotoxin Testing – A Critical Step Bacterial endotoxins are components of Gram-negative cell walls that are pyrogenic in nature. The LAL-based BET test is FDA-approved, and following revisions to the USP Chapter <161>, has undergone minor changes that need addressing if manufacturers’ practices are to remain up-to-date. For more than three decades, the FDA has approved the use of a limulus amoebocyte lysate (LAL)-based test for the quantification of endotoxin present in medical devices prior to release. The updated guidelines drawn up in USP Chapter <161> provide manufacturers with standardised instructions for the proper implementation and documentation of the BET. It is essential that practices and guidelines outlined by the USP Chapter <161> are adhered to when undertaking BET on devices being distributed for use in the medical field, as this ultimately helps to ensure patient safety. Endotoxins are the lipopolysaccharidecontaining component of Gram-negative bacterial cell walls which, on accidental introduction to a patient’s cardiovascular and/or lymphatic systems, are pyrogenic 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Fluid catheters and administration sets and are known to cause an array of Extension and transfer sets serious conditions including septic shock. Implantable medical devices Even endotoxin from dead bacterial cells Dialysers and dialysis tubing and introduced to medical devices during accessories manufacture can later compromise Heart valves patient safety when used clinically. There Vascular grafts are currently three approved techniques Intramuscular drug delivery catheters and for endotoxin testing, one of which is the gels with non-pyrogenic claim (including demineralised bone matrices and drug kinetic chromogenic technique, such as delivery systems) the Kinetic-QCL™ Kinetic Chromogenic Fig 1. Examples of medical devices as outlined by USP Chapter <161> LAL Assay manufactured by Lonza. In the Fig 1. Examples of medical devices as It is worth noting that complex devices with multiple parts require very careful consideration when planning and presence of endotoxin, the lysate begins outlined USP Chapter <161> executing BET. All components that act by as fluid paths or come into contact with systemic fluid must be included the initial extraction process. It is highly recommended that manufacturers developing a protocol for special to cleave the chromogenic inproducts, substrate, such as artificial skin, have it reviewed by their local regulatory agency before implementation. causing the solution to become yellow. It is worth noting that complex devices The time required for the change is with multiple parts require very careful inversely proportional to the amount of consideration when planning and Speaking the languages of science and business, from bench to boardroom endotoxin present. The concentration BioStrata of Ltd,executing BET. All components that Milton Hall, Ely Road, Milton, Cambridge, Cambridgeshire CB24 6WZ UK act T: +44 (0)1223 828200 E: W: unknown samples can then be calculated as fluid paths or come into contact with from a standard curve. Details on how to systemic fluid must be included in the extract for BET testing will be outlined in initial extraction process. It is highly this article. recommended that manufacturers developing a protocol for special Devices to be Tested products, such as artificial skin, have it With medical devices ranging from reviewed by their local regulatory agency simple fluid catheters to complex before implementation. knee replacements, there are various guidelines that aim to properly define Establishing a Sampling Plan devices and provide guidance on USP Chapter <161> guidelines demand conducting BET. Manufacturers must be a proper sampling plan. Strategies clear on how to appropriately sample are dependent both on batch size and and test their device. frequency. Considerations must be made with regard to the nature of the device The medical sciences harness a vast itself: whether it is part of a kit, or is used assortment of equipment and tools individually in medicine. that are implemented for the effective diagnosis and treatment of disease. It is recommended that a proper Guidelines provided by the Association sampling plan is ascertained prior to the for the Advancement of Medical start of BET, as the number of devices to Instrumentation (AAMI) entitled ‘ANSI/ be tested can vary depending on batch AAMI ST72/Ed.2, Bacterial Endotoxin size. In the US, USP Chapter <161> – Test methods, routine monitoring, dictates that a sample for end-product and alternatives to batch testing’ define testing should be in its final configuration medical devices as “products that have and packaging, including all component direct and indirect intravascular, intra- parts necessary for the function of the lymphatic, or intrathecal contact” and device. Representative sampling is advise that all such products shall be required, and the sample plan is created evaluated for the presence of endotoxin. and justified based on the assumption In addition to this, the revised guidelines that the manufacturing process is provided by the USP give a brief list of validated and in a state of control. The examples of devices to be tested, which number of devices chosen for routine are outlined in Figure 1. testing is dependent on the size of the lot, level of control in the manufacturing process, and historical performance of the manufacturer.

The USP previously made it a requirement that if the manufacturing Autumn 2016 Volume 8 Issue 3


Labs batch size contains fewer than 100 items, majority of manufacturers adhere to the a minimum of three random devices from procedures outlined in USP 161. the batch should undergo extraction and Copy BET testing. If, however, the batch size is The Endotoxin Release Limit (ERL) larger than 100 items, then 3% (rounded The endotoxin release limit for extracting up to the nearest whole number) of the solutions is calculated from the number Establishing a Sampling Plan batch should undergo testing. The new of devices tested and the volume of LAL USP Chapter <161> guidelines demand a proper sampling plan. Strategies are dependent both on batch amendedsizeguidelines add that no reagent water for extraction. and frequency. Considerations must more be made with regard to the natureused of the device itself: whether Both of a kit, or is used individually than 10it is part representative samplesin medicine. are are accounted for in the formula. requiredIt isfrom each that batch, that allascertained prior to the start of BET, as the number of devices recommended a properand sampling plan is to be tested can vary depending on batch size. In the US, USP Chapter that a are samplefixed for end-values batches manufactured must have samples The ERL<161> for dictates devices product testing should be in its final configuration and packaging, including all component parts necessary for taken from themofin to ensuresampling the is required, (constant K),sample andplan vary depending the function the order device. Representative and the is created and justifiedon the on the assumption thatof the the manufacturing is validated and in a state ofpurpose. control. The number of sample based is representative lot. Inprocessdevice's intended For medical devices chosen for routine testing is dependent on the size of the lot, level of control in the manufacturing addition,process, changes made to USPof Chapter and historical performance the manufacturer.devices that will not come into contact <161> include the definitions used in the with cerebrospinal fluid, the ERL is set The USP previously made it a requirement that if the manufacturing batch size contains fewer than 100 items, a selectionminimum of devices testing, inshouldatundergo 20 EU/device. however, there is a of threefor random devices outlined from the batch extraction and BETIf, testing. If, however, the size is larger than 100 items, then 3% (rounded up to the nearestthat wholethe number) of the batch Figure 2batch below. possibility device will should come into undergo testing. The new amended guidelines add that no more than 10 representative samples are required with the ERL from each batch, and that all batches manufactured mustcontact have samples takencerebrospinal from them in order to fluid, ensure the sample is representative of the lot. In addition, changesismade USPlower Chapter at <161> include the definitions set tofar 2.15 EU/device. used in the selection of devices for testing, outlined in Figure 2 below. Product Unit Individual medical device in primary packaging. The device is used independently of other like devices in medical practice Individual medical device. Used individually in medical practice but packaged in one primary package alongside a number of identical medical devices Set of components within primary packaging. Components are assembled as a product and used together clinically Kit of procedure-related devices. Each used independently in clinical practice and where each may have a different endotoxin limit

Item for Testing The individual device

The individual device taken from the primary packaging

Combination of the components

Each device with non-pyrogenic claim / all devices together

Fig 2. Definition of product unit types as outlined in USP Chapter <161>, and how testing should be carried out on each device/set of devices.

Fig 2. Definition of product product typesisas in USP Chapter <161>, and how By contrast, if the beingunit manufactured a kitoutlined of procedure-related medical devices where each device is used independently in clinical then each device that has testing should be carried outpractice on each device/set ofa non-pyrogenic devices. claim must be tested either individually, or together with all other kit components. Similarly, when a BET assay is being performed on devices that are to undergo sterilisation, tests must be taken for both the pre- and post-sterilisation samples. Equivalency in the results either side of the sterilisation stage must be achieved in order to ensure that the sterilisation process itself does not have any adverse effect on the accuracy of the test result. If each medical device within a kit has a different endotoxin limit, they must all be tested individually.

By contrast, if the product being manufactured is a kit of procedurerelated medical devices where each device is used independently in clinical thedevice languages science and business, from bench to boardroom practiceSpeaking then each thatofhas a nonBioStrata Ltd, Milton Hall, Ely Road, Milton, Cambridge, Cambridgeshire CB24 6WZ UK pyrogenic claimT: +44 must be tested either (0)1223 828200 E: W: individually, or together with all other kit components. Similarly, when a BET assay is being performed on devices that are to undergo sterilisation, tests must be taken for both the pre- and post-sterilisation samples. Equivalency in the results either side of the sterilisation stage must be achieved in order to ensure that the sterilisation process itself does not have any adverse effect on the accuracy of the test result. If each medical device within a kit has a different endotoxin limit, they must all be tested individually.

There is potential for considerable variability in the endotoxin content of the extract due to the volume of water required to wash devices of differing sizes and the variable number of devices that need to be tested. The ERL for extracting solutions is calculated from a formula that compensates for both (for example 40 mL of water may be used to wash a small device such as a syringe, but 500 mL may be used for washing a larger item such as a pacemaker). The formula used is (K x N)/V, (where K is equal to the endotoxin limit for each device, N the number of devices tested, and V is the volume of solution used to extract the endotoxin from the device). The BET Extraction Procedure In order to test a medical device for the presence of endotoxin, the endotoxin has to be washed off (extracted/rinsed) from the surface of the device. Guidance for this process has also been addressed in the new updates. The principle behind the testing of devices for the presence of endotoxins, outlined in Chapter <161> of the USP guidelines, has also been updated. The test itself works on a pass-or-fail basis depending on whether the test result exceeds the pre-calculated ERL for the devices being tested. Sampling of medical devices involves â&#x20AC;&#x2DC;washingâ&#x20AC;&#x2122; the device and

The European regulations are more ambiguous as both the number of devices that should be tested and the frequency of testing are determined by the manufacturer, based on a series of risk assessments. For this reason, and Fig 3. A complex medical device. A single extraction would be needed for the femoral as a result of the frequency of export of component, the plastic spacer and the metal plate, as these form the completed device devices for commercial sale to the US, the 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2016 Volume 8 Issue 3

Labs testing the rinse for the presence of the endotoxin. The updated guidelines state that devices are to be soaked or immersed, or fluid pathways flushed, with extracting fluid (normally LAL reagent water obtained commercially, such as that manufactured by Lonza). The device is immersed for an hour in LAL reagent that has been heated to 37± 1°C. All methodologies require the testing to be carried out in duplicate with a positive product control (PPC) to ensure no interfering factors are present. The PPC recovery specification is 50 - 200%. It is worth noting that devices that are larger in size, or which have a cumbersome design that makes the extracting phase difficult, may be cut into sections (although these sections may need to be tested separately). Any of the FDA-approved BET methods can be used to test the extract. Clearly, extraction vessels, containers and other equipment used in the process must also be free of endotoxin and are tested to eliminate any interfering factors that may give a positive or false negative result.

Figure 3 shows the components that encompass a total knee replacement. A single extraction would be needed for the femoral component, the plastic spacer, and the metal plate, as these form the completed device. There is no limit to the volume of water that can be used for the extraction, as this is accounted for by the ERL equation - (K x N)/V. The ERL may however may be a low value due to the high volume of water needed. Conclusion The significance of comprehensive endotoxin testing on appropriate medical devices cannot be overstated, owing to the serious implications for patient safety if infection arises as a result of contact with cardiovascular and lymphatic systems, and/or cerebrospinal fluid. Patient safety is at the absolute heart of medical care, and responsibility for this begins at the manufacturing stage. It is vital that manufacturers, both in the US and Europe, remain up-to-date with the latest guidelines and regulations that apply to their region, and that careful considerations are made with regard

to the devices being tested; particularly whether they are in fact comprised of multiple components. Failure to do so can not only lead to serious penalty, but would also represent a serious case of negligence, and failure to account for the lives of individuals relying on the manufactured devices.

Allen L. Burgenson, US Manager Regulatory Affairs at Lonza. Allen has over 30 years’ experience in FDA-regulated industries, including Foods, Drugs, Biologics, Medical Devices, and Cosmetics. He has worked in R&D, QC, QA and Regulatory Affairs. Allen is involved in several scientific organizations, including the Horseshoe Crab Advisory Panel for the Atlantic States Marine Fisheries Commission (ASMFC) and serves as President of the Capital Area Chapter of the Parenteral Drug Association (PDA).

Product News Sartorius Stedim Biotech presents the first fully integrated upstream platform Unique product and service portfolio extensively covers all steps from cell line development to commercial manufacturing processes Sartorius Stedim Biotech (SSB), an international leading supplier for the biopharmaceutical industry, has developed an innovative and fully integrated technology platform to meet the requirements of today’s upstream bioprocessing. It combines a top-performing expression system with outstanding equipment and process control for the rapid development and scale-up of robust, high-titer commercial manufacturing processes. The biopharmaceutical industry is facing a series of challenges that it must address

in order for it to deliver safe and efficacious products to a market made increasingly competitive by the emerge of biosimilar products. Companies must rapidly assess and then focus their investments on those drug candidates that have the greatest chance of being successful. To do this they must cut drastically early-stage development timelines and increase the speed with which they can reach the clinic. The upstream technology platform, which combines a range of products and services that Sartorius Stedim Biotech has developed, addresses this challenge without compromising on product quality, process productivity or robustness. Biopharmaceutical manufacturers will be able to reach the clinic in 14 months by leveraging this new platform. The royalty-free CHO expression platform of SSB’s subsidiary Cellca delivers the titers required to meet companies’ cost of goods objectives. Cellca can establish a research cell bank for their clients within just 4 months. The automated ambr15 micro bioreactor system is capable of controlling 24 or 48 micro bioreactor experiments. The system accelerates clone selection and scales up readily to BIOSTAT® STR single-use bioreactors, which biomanufacturers have successfully implemented at pilot and GMP production scales. To reduce early stage development timelines still further, Sartorius

Stedim Biotech has integrated more than one hundred off-the-shelf and pre-qualified assays from BioOutsource into its platform allowing the rapid testing and analysis of biosimilar products. “Our upstream platform is currently unique on the market and addresses customers’ needs and challenges of the biopharma industry in an exceptional way. It connects outstanding process technologies and brings biology to single-use bioprocessing. We are therefore introducing a whole new level of efficiency in upstream processing,” stated Stefan Schlack, Senior Vice President Marketing and Product Management Bioprocess Solutions at Sartorius Stedim Biotech. For more information visit;

Contact Sartorius Stedim Biotech Phone: 0049.551.308.0 INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Logistics Securing Stability in the Airfreight Pharma Supply Chain

With an increasing demand for pharmaceuticals to be shipped to patients across the globe, the role of the airfreight industry in the supply chain process has become even more pivotal. This, coupled with the need for highvalue, highly-sensitive pharmaceuticals to be shipped to more remote regions than ever before, via more complex routes while facing more extreme temperature excursion risks, also presents packaging manufacturers and logistics providers with greater stability supply chain challenges and risks. With increasing industry regulations and guidelines to adhere to, there is a need for robust, reliable, temperaturecontrolled packaging (TCP) shipper systems to meet the growing global demand. Another key issue is adhering to good distribution practices (GDP), which are currently EU-driven yet making their way around the world including ‘to ship as labelled’. If the label says this product is to be stored at 2-8 degrees it must be transported at that level. It’s about getting logistics providers and suppliers working together to meet current GDP guidelines and regulatory requirements. One of the biggest changes the industry is seeing revolves around these guidelines, which varied from region to region. The world is becoming a more cooperative place with regard to pharmaceuticals and their transportation. What is emerging is a greater consensus of quality standards throughout the world. There is a shift towards consistent, constant improvement on packaging and advantages to gain by those willing to cooperate together as a team within the supply chain industry to get the job done. The increasing need for more stable shipper solutions had resulted in the emergence of more advanced, newgeneration passive bulk shippers, which has changed the TCP and logistics supply 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Industry trends include new TCP technologies, innovative designs, the advent of reusable, pioneering, passive bulk shippers, and the use of more advanced materials.

Airfreight Investment for Pharma Takes Off To secure stability in the airfreight pharma supply chain, TCP manufacturers have seen the air cargo industry stepping up their game when handling pharmaceuticals, including a rise in the pharma sector standard operating procedures (SOPs).

These trends mean pharmaceutical payloads shipped at a variety of different temperature range requirements can be safely and securely delivered globally by air and arrive intact, having been maintained at the correct temperature during transportation.

The International Air Transport Association (IATA), the trade association for the world’s airlines, representing some 260 airlines which equates to 83% of total air traffic, has led the way in increasing air cargo’s share of the global pharma product transport sector.

This is in part due to a more recent collaborative approach to secure and sustained stability within the airfreight pharma supply chain by all key stakeholders involved in transporting high-value medical materials.

To combat a previous lack of compliance and standardisation in the air transport supply chain, IATA established a Centre of Excellence for Independent Validators in Pharmaceutical Logistics (CEIV Pharma) to help organisations and the air cargo supply chain aim for and achieve pharmaceutical handling excellence.

chain industry landscape, previously dominated by active containers in the air cargo transportation of pharma products.

A collective approach, involving all key stakeholders within the supply chain process, is proving positive when it comes to mitigating cold chain risks in the pharma air cargo market. However, there is no room for complacency and the air cargo industry is responding by investing millions in stateof-the-art holding centres at airports for TCP, which are being utilised by pharma companies. Taking a more collaborative approach is proving positive when it comes to mitigating cold chain risks in the pharma air cargo market. This is something that will be even more paramount as it is predicted the global pharmaceutical industry will spend more than $10 billion on cold chain logistics by 2018. New trends, including home healthcare with vital medications being transported direct to patients, clinical trials in more remote regions, bespoke biologics and advanced therapies, are drivers in the vital role airfreight is increasingly playing in the supply chain process.

The airfreight logistics industry is stepping up its game by coming up with special programmers to handle pharmaceuticals and standard operating procedures to ensure staff are careful when handling pharmaceuticals, and that holds true for major carriers. Most major freight-carrying airlines have recognised the needs of the pharmaceutical industry and that’s why they are investing in these acceptance centres that include temperaturecontrolled rooms capable of holding several containers’ worth of material at various temperature ranges. Passive Versus Active Shipper Systems In a bid to ensure stability in the airfreight logistics chain for pharma, another trend is the emergence of other viable, reliable options to the active containers currently used in the supply chain. Historically, the active container market has been served by a relatively small group of suppliers who spent years building the market place for active container systems. Autumn 2016 Volume 8 Issue 3

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Reßect & Protect

Logistics With a limited choice of suppliers dominating the active container market place previously, pharmaceutical companies didn’t have many options regarding the bulk transportation of pharmaceuticals via airfreight, but pharma logistics decision-makers are now looking at alternatives within the airfreight sector. Hence the advent of increasing numbers of TCP manufacturers developing and investing heavily in more bulk passive systems that compete with active shippers on a quality level, and also on temperature and price, making the sector more competitive. To secure stability of pharma payloads, the most recent industry innovations include vacuum insulation panels (VIPs) and phase change materials (PCM). These newer materials, which are a move away from traditional waterbased components, ensure bulk passive TCP can perform reliably throughout the pharma airfreight supply chain without the need for batteries, electricity or human intervention required by active containers. As less human interaction is required with the advent of passive bulk systems, there’s less likelihood of human error, which accounts for most temperature excursions along the supply chain. In essence, fewer hands equal greater safety. The benefits of these new-generation bulk passive shippers, that don’t require power components, mean lighter containers – making them more costeffective when utilising air cargo hold space. As well as offering stability at different temperature ranges and at multiple sizes/volumes, the emerging passive bulk shippers require less training for handling operatives within the supply chain system. They eradicate the need to train people how to change batteries, how to dial in settings – it’s a case of close the door of a passive system and it’s on its journey. With shippers facing more complex, global routes, the more advanced passive bulk shippers in the marketplace are able 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to maintain pharmaceutical payload temperature in excess of five days. If there is ever a customs delay, some of the industry’s innovative passive shippers incorporate a hibernation feature, whereby if they were placed in a fridge awaiting customs clearance it would either slow the clock down or stop it completely, halting the aging process of that packaging. As companies become aware of advancements in VIPs and PCMs, more TCP manufacturers are able to compete for longevity, quality and temperature maintenance without using batteries or similar power sources. Shipper systems are continually improving. Large passive reusable containers and improved engineering and manufacturing techniques mean an emergence of these bulk, reusable solutions that are pallet accepting. They demonstrate an innovative improvement in weight, performance, ergonomics, and ease of use, essentially improving on what is already out there, and the latest shipper solutions are easier to handle, better performing and more cost-effective because of their performance capabilities. Advantage of Airfreight Pharma Transportation The advantage with shipping pharma by air is significantly reduced lead times from a manufacturing and planning standpoint. However it is critical the airfreight logistics chain can ensure temperature stability for pharma customers. Time and temperature have long been the enemy and challenge for the pharmaceutical industry, so the fewer time and temperature deviations, the better the result. This is where utilising airfreight comes to the fore and means a pharma payload can be anywhere in the world within 48 hours. Using airfreight, the critical advantage is these medicines can be delivered quickly to patients who need them. If administered proficiently, with proper planning, this can be achieved in a way that reduces overall costs when a more collaborative approach is adopted. TCP




working very closely with the third-party logistics suppliers (3PLs), and the airlines on instructions on how to maintain packaging within the supply chain, should there be a case of a customs holdup, which could delay an aircraft. The pharmaceutical companies constantly revisit their total spend in airfreight, which calls for a cooperative approach in the community, including airfreight shippers, TCP manufacturers and service providers, who have to stay one step ahead and ever vigilant of trends within the pharmaceutical industry itself. It’s up to the airfreight industry to collaborate on more innovative ways of driving down logistics costs and making it more efficient, by using more efficient packaging and gaining greater efficiencies of space on aircrafts. Cooperation is the Way Forward Increasingly, the industry is seeing the emergence of a more collaborative approach between the TCP manufacturers, pharmaceutical companies, freight forwarders and airline companies in a bid to secure stability in the pharma supply chain. Traditionally, there hasn’t been a cohesive approach between the supply chain companies and sitting down in a tripartite arrangement was unheard of. It’s evident there was a need in the market to help bridge this communication gap. What’s essential is ensuring all the industry key players are involved and sitting around the same table. It’s no longer a question of purchasing a TCP box separately, it’s asking how can a passive bulk transporter be utilised in a more effective and intelligent way within the air supply chain logistics network? To achieve greater pharma supply chain stability, it’s essential to know what the 3PLs, the freight forwarders and the airlines need to do regarding temperature-controlled transport. Increasingly, TCP manufacturers are more intimately involved in the pharmaceutical manufacturers’ processes from the outset. There is a need to bring all these parties to the table and acknowledge the fact it is no longer ‘just a box’ – rather, how can this highlyAutumn 2016 Volume 8 Issue 3

Chapter Logistics Title coming to realise the value of reuse. Clearly a more collaborative approach is a move in the right direction to ensure stability, and the supply chain working well together will see the future rise of reusable shipper systems. The school of thought is to gain a picture of what the collective industriesâ&#x20AC;&#x2122; goals are, i.e. the ultimate goal is patient safety and quality, alongside how to deliver pharma products in a costeffective manner while adhering to all the regulatory issues involved. Quality pharmaceuticals should be a standard right to all people on this planet, an inherent right.

advanced passive system be utilised to its maximum within the current supply chain network? Therefore packaging companies need to have their own personnel who know what it is the airlines are bringing to the table in terms of their responsibility, alongside the 3PLs and forwarders who have enormous responsibility in tendering this cargo around the world. Within big pharma, the logistics managers are looking at bottom line costs, their supply chain costs. These large pharma companies know they have to adhere to regulatory, stringent standards and have to balance that with driving supply chain costs down. In the past TCP companies were always viewed as somewhat of a specialised commodity. TCP vendors know what challenges exist on all sides and quite often bring people together who normally wouldnâ&#x20AC;&#x2122;t have direct contact with one another, and help in driving costs down. Crucially, the supply chain overall has to be in sync with one another, adopting a more collaborative approach, but the motivation for this change is driven by budget. Some of the challenges in approaching industry issues collaboratively lie in actually breaking with tradition, essentially asking for a paragon shift within pharma and within the

forwarding community. Collectively, TCP suppliers can help influence the 3PLs on this paradigm shift and suggest TCP companies are included at the beginning of their pitch to pharmaceutical companies about the services they are offering, bringing more solutions to the forefront and focusing on the need to maintain stability in the pharma supply chain. Stepping Up the Game and Future Trends A key industry trend is the rise of reusable passive packaging, which is another game changer. Previously, passive packaging always represented single-use and then it was thrown away. Some packaging companies have genuinely considered being good stewards of the planet, recognising they can build more robust systems, where essentially the packaging has a longer life as all the components can be swapped out, much like you would replace the parts of a car. The challenge is getting companies to understand that the reverse logistics system makes sense from a reuse point of view. So, although reusable passive packaging costs might initially be slightly higher than throwaway packaging, by increasing the turns companies use the reusable packing, their cost per use goes down, lessening their carbon footprint and achieving a very high level of quality each time they ship. Companies are

Pioneering passive temperaturecontrolled transport is constantly improving, along with a standardisation and acceptance of guidelines throughout the globe, working towards the goal of providing safe pharmaceuticals to the people who most need them.

Ira Smith, Director of Strategic Development Global Transport and Logistics at Pelican BioThermal, has over 25 years of experience in the field of global supply chain logistics. Ira has had executive roles with both the airline and the freightforwarding industries. His initiatives have included implementing one of the first dedicated healthcare vertical market departments for KLM Royal Dutch Airlines. He was Senior Vice President of Sales and Marketing (Pharma and Healthcare) for Kuehne+Nagel international AG, overseeing a global staff of professionals dedicated to providing a complete suite of international logistics services. Before joining Pelican BioThermal as Director - Strategic Development Global Transport and Logistics, Ira was President of PharmaSafe USA; a leading edge consulting group to the pharmaceutical and biotech industries. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 57


Questions of Choice Alan Kennedy talks to CSafe Global's Jonathan Neeld about the choice of ambient monitoring equipment for active cold-chain containers. Q. Jonathan, the pharma and biotech industries are continuously seeking reliable ways of ascertaining the location, condition and ambient environment of sensitive products during transit. It's a regulatory, safety and commercial necessity; we are surrounded by data collection, data storage and data relaying technologies. Bluetooth, wi-fi, RFID, GPRS, satellite, cloud, datasticks, smartphones and so on. In your opinion, where is the industry going with all this? A. As you suggest, the technology we need for on-board temperature and other quality monitoring of cargo has been around for a while and continues to get more and more sophisticated and accurate. However, logging the data is the easy part. Getting timely access to the logged data is the next hardest bit. And the hardest bit of all, of course, is using the data to avoid risk and loss. Having said that, a bewildering array of different monitoring and capturing technologies makes for a big headache when it comes to selecting the best equipment for a particular need. This is because things are still very much up in the air when it comes to the most effective and sustainable data sensing, recording, storage and transfer technologies. And, of course, there are related problems concerning the political and regulatory barriers that surround cross-border data transmission, the maintenance of data security and the perennial safety debate around the potential for interference with on-board aeronautical systems. Q. Have CSafe considered including an integral data logging system in their active containers? A. Yes, of course. At CSafe we have been carefully considering whether integrating a particular system or technology into our active containers is a sensible way forward. A 'built-in' approach does offer some benefits in that you can focus on ironing out the weaknesses of the selected system and make it as user-friendly as 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

possible. But, when you factor in the pace of change in this field and the fact that there are no 'one size fits all' solutions, the adoption of a specific monitoring technology isn't an approach that makes sense for us or our customers at this time.

is concerned, individual carriers must review the manfacturer's data and submit it to the FAA as part of their operational procedures and put in place the necessary training and infrastructure to ensure correct usage.

Q. Why is this? A. There are many reasons. First of all, shippers need to be looking at systems that are, as far as possible, future-proof. Data monitoring technology is advancing very fast and as we edge closer and closer to real-time in-flight monitoring, users need to be sure they are not painting themselves into a corner when it comes to future options.

In Europe, on the other hand, the airlines have more responsibility for both types of device and it is the responsibility of a carrier's engineering and quality groups to assess, select and implement any T-PED (transmitting portable electronic devices) systems that are adopted or approved. And even under those circumstances where T-PEDs are permitted, a flight captain can enforce any additional restrictions he/she deems necessary in the interests of safety. It's a complicated situation overall and we are unlikely to see a harmonisation of the different national and regional approaches any time soon.

Secondly, while they may be bound by common regulatory parameters, every shipper has its own ideas about the best way of monitoring its particular products for quality. And rightly so, because all products are different, sometimes very subtly different, and they all have different stability parameters. This need for flexibility and choice is further accentuated by the sheer number of different shipping environments, distribution conditions and modal permutations that are out there. The increasing trend towards large-molecule drugs and biosimilars is adding to this need for flexibility since many of these bio-engineered medications do not lend themselves to a 'one size fits all' approach when it comes to in-transit safety monitoring. Thirdly, we are faced with the problem of conflicting regulatory requirements in Europe and the USA. In the US, the use of transmitting devices largely falls under the auspices of the Federal Communications Commission (FCC) who govern commercial radio frequency spectrum and who limit the use of aero-based GPRS equipment due to its interference with terrestrial cellular networks. On the other hand, the Federal Aviation Authority (FAA) is responsible for flight safety matters and they have rules in place designed to minimise the potential for random electromagnetic interference with flight control systems. As far as the use of short-range devices

Q. Are there any issues surrounding the compatibility between different monitoring and tracking systems? A. This is another reason why CSafe has not incorporated a particular monitoring or tracking system in its container fleet. If all cold-chain packaging manufacturers started embedding their own monitoring hardware and software into shipping containers, then shippers would quickly find themselves having to deal with numerous different data sources, data formats, data devices and data locations. Far better for individual shippers to define their own monitoring and tracking needs and apply the resulting solution(s) with their supply partners. Shippers also need to be considering the impact that mandatory track-andtrace security systems are going to have on the whole product monitoring process. For example, how sensible will it be in future to be running track-andtrace and environmental monitoring systems in parallel? Continuous supply chain visibility and prognostic product monitoring have several things, such as geo-positioning, in common, and combined systems are likely to be cheaper, quicker and less power-hungry than autonomous units. Autumn 2016 Volume 8 Issue 3

Logistics And another factor to consider when relying on built-in equipment is that there could potentially be data-ownership implications, especially if the container units concerned are leased rather than owned by the shipper. Who then legally owns the data being collected? Although this might be an issue that can be managed up-front through contractual terms, it's another consideration that needs to be resolved to avoid difficult or costly disputes further down the line. Q. So what are shippers looking for? A. In practice, they often want different things. Some shippers want deviceindependent data recording, some want to use bespoke hardware or software and others just want ongoing flexibility. The need for flexibility in data capture can be readily appreciated by taking into account the 'human factor.' A large proportion of temperature excursions and other unnecessary impacts during transportation are caused by simple human error. In some locations, the appropriate operative training has not been available; in other cases, it might just be that a dedicated IR reader is not to hand at the right time. Far better in these particular cases for a shipper to have the option of using a logging system that it has deemed foolproof, or one that does not rely on particular receiving-end infrastructure or training. At the end of the day, when we are talking about the safety of drugs for human consumption, it is vital that the quality controls put in place during physical transportation are driven by need and necessity rather than being subject to the limitations imposed by a manufacturer's stock solution. Q. Are there any other downsides to a reliance on vendor-fitted tracking and monitoring solutions? A. Yes. Ready-fitted monitoring equipment not only presents the buyer with a "Hobson's choice", but also creates the not-insignificant burden of ensuring that all interline distribution partners carry the necessary approvals for its use. Interlink relationships can be changeable, so there can be considerable managerial and documentational implications of using different vendor-integrated systems. And there is the issue of what might happen if an airline has not approved the device? If realised early, a shipment could be delayed or, perhaps, re-routed. But if intercepted by a regulatory authority

following unauthorised use, the result could be a hefty fine for the airline. Q. But surely it is cheaper and easier for a shipper to simply buy an off-the-shelf packaging solution that is already fitted with compatible monitoring equipment? A. It could seem that way but, as I have already indicated, the cheapest product monitoring solutions today are not necessarily going to be the cheapest solutions tomorrow. The cost of electronic apparatus has fallen geometrically over the past few years and this trend is likely to continue for the foreseeable future. This rapidly reducing cost of monitoring is a good reason why it makes sense to be careful about getting locked in to a proprietary system too early. For example, there is currently significant development in low-cost 'Bluetooth Smart' devices that piggyback off smartphones or wifi networks. These devices will be capable of utilising communication and location functions for real-time data-streaming to the cloud. Q. So what do you suggest? A. Over the past 10-15 years the cost of temperature and other dataloggers has dropped dramatically. Accuracy has improved greatly and data storage, transmission and handling capabilities have progressed immeasurably and the old chemical-based indicators have largely been consigned to the history books. It's been an exponential shift and this pace of change is only going to accelerate in the foreseeable future. The right thing to do right now is to design with flexibility in mind and keep your options open. Shippers should draw up their own system specifications, conduct the appropriate validation exercises and be careful not to prematurely commit or overcommit to a particular system or technology. Q. What exactly do in-built temperature loggers monitor? A. Some in-built systems are reactive or historical in nature rather than preventative or predictive. In other words they effectively tell you that a product's safety envelope has been violated, rather than tell you that it is in danger of being violated. The way things are at present, there can be lengthy gaps, not in the recording of information, but in its timely receipt. Knowing that something has been corrupted or contaminated is of great benefit in preventing that product entering the chain of consumption, but

it has no preventative value other than the learnings that might emerge from a post-event inquest. The best systems for the in-transit monitoring of sensitive drug products are those systems which have resulted from a close partnership between the shipper and its suppliers; one where the result is an optimum combination of protection, performance and cost for the risks concerned. Q. Are there any other considerations that need to be taken into account when looking at data monitoring and tracking systems? A. Yes, there is the whole question of carrier approvals for in-flight recording devices. Carriers in Europe, at least, have the ultimate responsibility for approving which technologies they are prepared to carry. Again, it's all about safety and the last thing a shipper wants is to be tied in to a platform which uses a technology that is unacceptable to the major carriers or which involves prolonged approval processes. Users must be aware that the majority of these systems utilise lithium batteries which, following a number of over-heating incidents, are currently the focus of restrictions and technical investigation by the regulatory authorities. At best they have to be declared as part of the shipmentâ&#x20AC;&#x2122;s manifest. Q. Which monitoring technologies does CSafe Global currently favour? A. This is a bit like asking how long is a piece of string. All the technologies currently being used have their adherents and all have their pros and cons. As things stand, GPRS cellular technology, in conjunction with GPS satellite tracking, seems to be the most viable when the need for positioning is taken into account. And of course there is wi-fi. The increasingly widespread availability of in-flight wi-fi is allowing passengers ready access to the web for streaming music and videos and for conducting business. These on-board wi-fi systems are linked to a combination of satellite systems and ground-based cell masts, and it's reasonable to assume that this infrastructure will be available soon for cargo monitoring in the near future. Bluetooth technology will also become very popular when continuous location monitoring is not required. Bluetooth UHF frequency has the advantage of allowing product temperature and other physical parameters to be viewed from a smart device without opening the shipping packaging or container.


Logistics Q. Finally, what do think the future holds for in-flight pharma monitoring/ tracking? A. The future will probably be hybrid systems which use a combination of technologies to provide real-time connectivity, global geographical coverage, additional monitoring features, dynamic control of container environments, a high degree of reliability and all with minimal power draw. Technologically, what we see now is just the tip of a big iceberg, with hybrid systems using Bluetooth and wi-fi looking to be the next phase. The emphasis will continue to shift from monitoring to control and the costs of the equipment, but probably not the associated support systems, will continue to fall. Cargo safety and security will remain a huge issue and one that will continue to be impacted by unpredictable events such as terrorist activity.

Q. How soon? A. Well, it probably won't be widely [available] very soon, because in addition to the technical and regulatory dimensions there is also the small issue of cost. The cost of retro-wiring a fleet of aeroplane for wi-fi is prohibitive. However, since future passenger planes, at least, are being pre-wired for wifi, it will eventually be nothing more than a marginal cost increase to extend this to the lower cargo deck for lower deck-freight monitoring on commercial airlines. Q. As with mobile phones, smartwatches and the like, remote temperature recording and transmitting devices are only as good as their power source. How much of a problem do battery limitations present? A. Well of course, data logger manufacturers want their products to be seen in the best light and as a result you might see some unlikely operating timespans quoted by some providers. "Typical" and "estimated" battery durations are of very little value since in practice the dependable operating span will depend on settings and usage conditions which, of course, are unpredictable and can change very quickly. This unpredictability means that in practice a reasonable power safety margin must be allowed, further reducing the available power 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

reserve. This means that some batteryhungry systems may not be there when you most need them. And it makes it very difficult for shippers to compare this critical property since different suppliers use different measurement parameters. For example, the stated battery-life of most monitoring units can be prolonged by simply extending the sampling rate interval. The latest generation of data loggers also tend to offer an ever-widening range of measurements. But buyers and specifiers need to be sure that they actually need all of these metrics and, if so, they must be aware of the fact that every sensor requires power. As with a smartphone, the utility of even the best, most highly-featured, data collection device tends to disappear when its battery goes flat. And although it may have a non-volatile memory crammed with data, this information is of limited value if it only relates to a partial journey. Of course, these power limitations are gradually being addressed. For example, the latest generation of Bluetooth technology, designated 'Low Energy', provides considerably reduced power consumption whilst maintaining a similar communication range to standard Bluetooth. This version promises typical operating times of up to one year.

There will also be further global harmonisation of technical standards and regulation, but this will be much slower than technical developments. The biggest challenge of all will be whether organisations, regulators and other stakeholders will be able to cope with the volume and complexity of data generated and be astute enough to take advantage of the insights it brings. All of these are reasons why it is sensible not to be jumping in at the deep-end during this period of rapid change.

Jonathan Neeld is the Director of Certification & Regulatory Compliance at CSafe Global. With more than 25 years of expertise in the Design and Certification of Aviation and regulatory products, Jonathan specializes on the development, certification and Regulatory Compliance of active temperature control products. He is actively involved with several industry working groups including IATA ULD Technical Panel, ULD CARE, SAE aviation committee and PDA Pharmaceutical Cold Chain Interest Group. Participation in these working groups by industry experts is paramount to enable the publication of standard operational procedures and safety guidelines for the Aviation and Pharmaceutical industries. Email: Autumn 2016 Volume 8 Issue 3

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Logistics Serialising for the Future In our last article, we looked at the benefits of standardisation and how vital it is for the future of the NHS in England. And, where pharmacy is concerned, standardisation is having its moment through the introduction of pack serialisation for companies producing, supplying and buying pharmaceutical products through regional initiatives across the globe. Serialisation is gaining prominence as a topic because it addresses a number of issues in the increasingly global, and equally increasingly complicated, healthcare supply chain. It means the introduction of a system in place to track and trace the journey of prescription drugs from manufacture all the way to the patient. It also means that manufacturers, suppliers and pharmacies will have to work together to create a system that works. Ultimately, it is part of the bigger drive for patient safety through greater traceability in all areas of healthcare. And GS1 standards are the glue that can hold all this together.

How Will Serialisation Bring About Greater Patient Safety? What do unique numbers on packaged medicines have to do with safer care? Well, according to Interpol, more than one million people die each year from counterfeit drugs. In some areas of Asia, Africa and Latin America, counterfeit medical goods can form up to 30% of the market and the World Health Organisation (WHO) estimates that 1% of all medicines in the developed world are counterfeit. Illegal drugs enter the supply chain and without serialisation, it’s very difficult to track them. Even in the UK, just two years ago the Medicines and Healthcare products Regulatory Agency (MHRA) seized £8.6m worth of illegal drugs, and we’ve also seen the number of defective medicines reported by the MHRA rise from five in 2001 to 50 in 2011. It’s because of these numbers that we’re seeing an increasing amount of legislation globally to tackle falsified medicines. Front of mind is the EU’s Falsified Medicines Directive (FMD) which

requires two mandatory safety features that will allow medicines to be verified and authenticated, and should appear on the packaging of all relevant medicines by February 2019. The Directive aims to prevent falsified prescription medicines entering the supply chain and reaching patients by strengthening all aspects of the manufacture and supply chain across Europe. It means that manufacturers of pharmaceuticals must put a 2-dimensional barcode on the packaging of all products to identify the product, expiry date, batch number and serial number – these must also be on the packaging in a ‘humanreadable format’. They also need a tamper-proof security seal. It’s not just Europe that’s taking action – legislation is being rolled out in the US and Canada, and many countries such as Argentina, India and China already have serialisation systems in place. Many manufacturers produce goods for multiple markets and, although legislation seems to be unifying towards serialisation, there are nuances and variations in every market – as well different timescales and stages that these laws are coming into effect. From a pharma point of view, this has the potential to be a real nightmare, especially if changes are left to the last minute. Companies must consider and invest in technology that can cope with significantly different requirements and feed into different regulatory databases, which may have varying requirements of data to be updated at varying points in the supply chain – that’s on top of meeting the demands of their customers, as they do today. This integration is a must for any company selling or buying drugs – failure to comply will mean that pharmaceutical companies cannot sell their products. What Needs to Happen? As mentioned earlier, serialisation requires the product, expiry date, batch number and serial number on all packaging, as a 2D barcode and in human-readable format. But it isn’t just about printing some numbers on a box – it’s about greater collaboration and


Autumn 2016 Volume 8 Issue 3

Logistics communication between manufacturers, suppliers and pharmacies. If the benefits are traceability and certainty of origin, this can only be achieved if the information and the technology in the background is there and ready to be called upon when needed. It’s true that pharmaceutical companies have been barcoding products for years, but serialisation adds new complexities to nearly every aspect of their operations and onward supply chain – these aren’t going to go away on their own. While some companies have clear strategies and programmes well underway and have done so for years, with vast amounts of resource focused on delivering serialisation efforts in markets around the world, there are many that have not. The time is now for those that haven’t started yet and don’t want to get left behind. As far as the EU regulations are concerned, they don’t require product aggregation – think a case/palletlevel barcode, plus everything within that container associated to that single barcode – but they don’t preclude it either. Products may need to be validated against, or decommissioned from, the national/European database at any point in the supply chain. This would lead to a significant demand for a manufacturer to aggregate products as it would be time-consuming to break containers to individually scan products. In other markets, such as the US, legislation is moving towards a complete ‘track and trace’ model, meaning there is complete visibility of the movement of goods along the entire supply chain – and this is where aggregation is a prerequisite of meeting legislation. Currently, the EU FMD is seen as a ‘bookend’ model, meaning that products are entered into the database by a manufacturer and then decommissioned as they leave the supply chain (for example by the customer). It’s also worth noting that, in relation to the recent EU referendum on 23 June – when the UK voted to leave the European Union – the UK will still press ahead with EU FMD in some form. By not legislating against falsified medicines, the UK could otherwise become an easy target for fake medicines to enter our legal supply chain, having adverse implications on patient safety. 63 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Where Does GS1 Come In? GS1 UK have been working for 40 years to help the retail sector ensure supply chain traceability using barcoding standards. Over the years, we’ve helped thousands of grocery retailers and their suppliers to capture and share accurate information about their products – from source to customer. And, it’s this experience that has helped position us as the go-to standard in the fight against counterfeiting. For this reason, amongst others, the European Federation of Pharmaceutical Industries and Associations (EFPIA) chose the GS1 2D DataMatrix as its data carrier of choice for the identification of products, encoded with a product code, serial number, batch number and expiry date. The support for GS1 standards given by the EFPIA, and the improvements they make to the healthcare supply chain, are driven by a number of factors. First and foremost, patient safety – GS1 standards mean globally unique codes and certainty of product identification to ensure the safest possible treatment of patients. It’s one of the many reasons that the Department of Health has mandated the use of our standards in all Acute Trusts in England, and is another incentive to tackle this now. Suppliers to trusts in England will need to become GS1 compliant if they want to keep supplying to those trusts. This compliance brings an interoperability that means manufacturers, suppliers, pharmacies and hospitals are all speaking the same language, using the same standards, and ensuring that they can work across markets, stakeholders and sectors. GS1 standards also keep things simple for those looking at serialisation as an added complication. They’re one solution that can be used for all levels of packaging, which allows the user to choose what’s appropriate for them. Also, our standards are ongoing so they’re futureproof and won’t be superseded, and they’re proven as a robust data carrier. GS1 standards are already being used worldwide by the retail sector and this next drive will see them adopted across healthcare globally. The Opportunity on Offer There’s no doubt that serialisation, and the legislation surrounding it, requires a lot of work and investment from everyone

working in pharmaceuticals. Where significant upgrades in IT capabilities are needed – with every medicine receiving a different serial number – this will bring together information from a vast network of manufacturers. Whilst doing this, investment in aggregation solutions at the same time would allow for a full ‘track and trace’ model, now or in the future, to cover for its potential to become a requirement in Europe as it is currently in the US. While this all seems like a big undertaking, the efficiencies it will bring to the supply chain, and to inventory and dispensary processes for pharmacists, will be more than worth it. In meeting these requirements, companies will be meeting the needs of the EU’s Falsified Medicines Directive, other serialisation legislation across the globe, and in England, you’ll be meeting the requirements of the Department of Health. Starting now on serialisation isn’t just what legislation across the globe is asking businesses to do, it makes sense for the future of the industry.

Glen Hodgson, Head of Healthcare at GS1 UK, is charged with supporting the NHS and the healthcare industry to deliver a more robust approach to patient safety and greater efficiency. He is a highly accomplished senior executive, with over 15 years of national and international experience, and has served at board level in many operational and commercial roles in the pharmaceutical/healthcare arena. Email:

Autumn 2016 Volume 8 Issue 3


Social Media-sourced Real-world Evidence – A Novel, Cheap, Effective Method Synopsis The promotion and use of medicines should be based on the evidence. Whilst prospective controlled clinical trials are the gold standard, they represent a snapshot of limited use of a healthcare intervention, even if patient-reported outcomes are included. Real-world evidence (RWE) seeks to portray outcomes when real patients in the marketplace use a medicine. The use of social media as foundation to collect real-world evidence via internet portal platforms has proven itself in studies to be a rapid, inexpensive way of assembling vast amounts of data reporting patients’ real experiences of treatment, including efficacy, safety and societal impact. Is there a perfect storm approaching the healthcare industry? Is there a confluence of the increasing costs of research and development, the difficulty of providing convincing evidence of the benefit/risk of a treatment, the political needs of regulation, the downwards pressure on pricing? The counterflow is the demand to pay for a growing and aging global population with greater expectations, the requirements of providing a greater spectrum of healthcare, and risks of patent expiry, generic substitution and biosimilars. A back-of-the-envelope calculation (if things are still done that way) might show that when the return on investment for providing the data for new medicines approaches zero, it no longer makes economic sense to conduct research. According to a US-centric report in March 2016 of a recent analysis by the Tufts Center for the Study of Drug Development, the average cost to develop and gain marketing approval for a new drug is pegged at $2.558 billion. The analysis, included in the May issue of the Journal of Health Economics, indicated that the $2.558 billion figure per approved compound is based on estimated average out-of-pocket costs of $1.395 billion and time costs (expected returns that investors forego while a drug is in development) of $1.163 billion. 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

When post-approval R&D costs of $312 million are included, the full, product lifecycle cost per approved drug, on average, rises to $2.870 billion, according to Tufts CSDD1. It is hardly surprising that the prices of innovative prescription medicines are so high. A recent report in 2014 by the US Department of Health and Human Services2 showed that a substantial part of this cost relates to clinical studies, which typically can make or break a new product. The prospective controlled clinical trial is the gold standard by which medicines are judged in terms of efficacy and safety. They are the basis for the evidence which is used to support a doctor’s prescribing of a product, and have been the basis for promotional claims to both the healthcare professional and the patient/consumer. Inevitably, clinical trials are a snapshot in time of highly selected populations treated for typically unrepresentative short periods of their lives. They demand inclusion and exclusion criteria to sharpen the precision of the questions they ask, are typically age-restricted, and only rarely include the full supermarket trolley of treatments that a real patient might be using. Whilst drug regulators have used evidence from clinical trials as their gold standard for decisions about authorising medicines, there have been critics of this standard. One of the more vociferous critics is Ben Goldacre, and in his 2012 book, Bad Pharma3, in a section headed “Test your treatment in freakishly perfect ‘ideal’ patients”, he proposes that the patients in trials are often nothing like real patients seen by doctors in everyday clinical practice. He considers that because of stringent inclusion and exclusion criteria, it is possible to recruit the patients most likely to respond to a treatment, which may suggest that an intervention is more effective than might be experienced in real life. This is particularly important in comparative studies where a study may be trying to show that X is more effective than Y. Clearly the real situation is the one that should count.

A clinical trial typically sets out to examine outcomes, and the most important one is designated the primary outcome measure. Depending on the therapeutic indication of the product, it may be something that the patient personally experiences such as pain or shortness of breath. Many studies focus on more nebulous factors such as measuring blood pressure or serum cholesterol, which are asymptomatic. Death is a favoured outcome, but the patient only comes to benefit from it if they do not die. Current thinking is advising the addition of patient-reported outcomes where patients respond to a structured instrument, which asked them about symptoms and how they feel. If these correlate well with pharmacological activity, they have proven to be a useful surrogate endpoint. However, collection of patient-reported outcomes in trials suffers from the same shortcoming that the conclusions can only apply to the selected group of individuals who were recruited into the study and under the study limitations. What is really needed as an adjunct to the clinical trial data is information about what happens when a medicine is being used in the real world. In the real world, patients (and also some prescribers) do not always read the instructions before throwing them away. They may not take the medicine as it was intended, and there may be any number of confounding factors that were not envisioned in the clinical trials, such as bizarre diets, use of additional alternative therapies, taking the medicines continuously for a long time, being outside the age range that was tested in clinical trials, and doctors prescribing additional medicines which were not part of the original studies. This is the basis of real-world evidence, or possibly, more appropriately, the realworld experience of using a healthcare intervention. Real-world data includes data on: • Outcomes (both clinical and patientreported), • Resource use (NHS, patient and Autumn 2016 Volume 8 Issue 3

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societal), Treatment pathways, Service models, Patient preference, experience, and compliance.

Some of this information already exists, in that there are health records for real patients kept by their doctors, which may be part of the general practice research database. For some chronic diseases there are registries, where the ongoing fate of patients is recorded, health providers have substantial data, and a variety of other bodies are on the receiving end of information, e.g. the MHRA yellow card is real-world data. If the data sets contain the primary information that is sought after, e.g. safety or efficacy, then these are valuable assets, but if the patients never generate data that is collected, or the dataset is limited, then the scope of the evidence may be limited. The common factor between all of these sources is that the data are retrospective, and in order to collect the information, there has not been a structured attempt to modify any healthcare intervention: what is recorded is what happened and was experienced. As the everyday management or selfmanagement of a condition is real rather than being part of a prospective protocol (it is accepted that treatment guidelines are essentially protocols, but by and large do not place conditions on what else patients do) it means that nonclinical aspects of the use of healthcare can be evaluated, e.g. real costs to the provider and patient, societal impact of the condition and its treatment, and overall experience considerations by the user of the products. In this way, it may be possible to provide value information to help justify pricing. All of the formal collection of health information, either from prospective studies or retrospective real-world data, makes three big assumptions: that the patient interacts with a healthcare professional who collected information, that the conditions are not self-treated, and that no one else is influencing the treatment apart from a healthcare professional. These are pretty massive assumptions, that view the patient inside a care cocoon. What would be useful to know is what happens when the patients are not being observed? The obvious solution is to involve the patients in the information supply chain, and find a way 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of allowing them to tell what it is really like to be treated. One of the mixed blessings of the internet has been health information. On the one hand, there is widespread access to high-quality contemporary information from reliable sources, e.g. NHS, university and hospital websites, official patient group websites, but these are outweighed by potential disinformation either from commercial enterprises or groups and individuals with an axe to grind4. Social media has added to this, and people with health problems seem more willing to air their issues and problems in virtual public rather than have a proper consultation. In the developed world, ease of access to social media is almost infinitely easier than access to professional healthcare. Patients will share their good and bad news, and competent authorities have recognised this by mandating that licence-holders should be aware of adverse events recorded in social media. Facebook has been a key player in linking social media and illness, but its seemingly unedited constructs might not seem like a logical place to put one’s trust. The converse side of the interaction between social media and patients is that it is a potential starting point to find patients who are real. According to Pew Research Center, a US-based non-partisan fact tank that informs the public about the issues, attitudes and trends shaping America and the world (sourced from the internet), just under ¾ of internet users access Facebook, and lesser numbers use other high-visibility social media sites5.

have a strong 2.5million of 13-17 year olds using Facebook, along with 26% of users still in the 25-34 age demographic.6 Given that many Facebook users say that one of the main reasons for using their account is competitions and offers, it is clear that they are prepared to engage online. A recent development in thinking has been the novel use of social media to recruit respondents to participate in real-world evidence studies of healthcare interventions. Whilst Facebook seems a first stop, there are other ways to access the users of healthcare, and it is the expectation of anyone who engages with contemporary marketing of any kind to provide an email address and possibly a (mobile) telephone number. Potential advantages of recruiting social media users for RWE studies: • • • •

• •

Cheap – process is very cheap and does not need substantial incentivisation to succeed; Rapid – if targeted correctly can result in big data sets very quickly; Big numbers – cohort sizes can be massive: potentially data on 1000s of patients; Flexible – can adjust the selection demographics to suit the study, e.g. those who are currently using a product; Very convenient for patients who do not even need to leave their chair, let alone their house; Non-clinical data e.g. quality of life experience, societal impact on working/home life can be accumulated easily; Typically in an RWE study, there are no exclusion criteria.

Potential disadvantages of using social media to recruit for a RWE study: According to Warren Knight, an “international social media speaker, author and award-winning entrepreneur and coach”, in 2016 Facebook is the leading social network, with over 1.44 billion monthly active users worldwide and over 31 million in the UK alone. Facebook’s demographic in the UK is fairly even with 49% male users, and 51% female. He indicates that 60% of the UK population has a Facebook account. Whilst Facebook’s younger demographic seem to be looking elsewhere, they still

• • •

No control over numbers: the expected cohort may never materialise; Ownership of data: if a study is contemplated, this should be clearly defined at the outset; Responder bias – because you are using a target list with a known interest in a disease/treatment, the potential for cohort bias must be considered and made transparent in any report or data use; Security – need to consider data Autumn 2016 Volume 8 Issue 3


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protection for input and data output, possibility of malevolent attack on project site, and prevention of multiple entries from the same responder. Consideration should also be given to a declaration of age of the respondents and consent for their data to be collected anonymously, stored and used; Possible spike of adverse reaction reports for a medicine; The most accessible model is based on open non-comparative data, and the statistical requirements for a comparative study between treatments would make the method complicated and cumbersome; Depends on access to social media, and the method instantly disenfranchises those who do not have computer access, the computer illiterate, the very elderly and those too disabled to use social media.

In practice, recently a successful method for collecting real-world data using social media and similar for evaluating over-the-counter medicines has been successfully developed by Iatros Consulting with Orbital Media, and their clients, and put into practice to produce retrospective open data. The method of real-world data collection using social media is ideally suited for consumer brands where the legacy evidence for efficacy may be old, and possibly based on formal studies carried out a long time ago. It may also be suitable for non-medicinal products where there is general acceptance by consumers but little evidence to support efficacy and safety. The key ingredient to success is planning and a structured protocol. The required endpoints and how they will be evaluated should be clearly defined, and for a medicine, ideally should be consistent with the SmPC. It is worthwhile thinking about what magnitude of response will be credible. The method is ideally suited to investigate retrospectively if the common usage of a product is inconsistent with the PIL. The questions to be answered are best phrased in a non-comparative way, e.g. not asking if a worked better than b. The endpoint should be one that can be easily understood by patients and records their experience of a product, e.g. recording blood pressure is not feasible but asking about pain relief is a realistic endpoint. Responses can be factual, e.g. age,

binary, e.g. yes/no answers, response on a visual analogue scale or a Likert scale. A patient response platform is created to collect the required data, and this is piloted to check the appropriateness of language, endpoints and sensitivity of the response measurements. The Output Data Define the Value of the Study Collecting data from a social media platformed RWE study can happen very quickly, and rather than prevaricating over under-recruitment to a clinical trial, the opposite problem may be the case. However, a poorly conceived plan may still fail to recruit. If the studies are open, retrospective and involve no mandated intervention, it is feasible to have an interim review of outcomes to confirm that the platform model and syntax of questions and answers are functioning correctly. This may give an early idea about the key responses and if the study is not functioning correctly, the opportunity exists to prematurely stop. Every study will have a demographic output. In contrast to clinical trials, this output gives a truer picture of who is using a medicine and how it is being used. It may also produce surprises discovering who the biggest target market is, who is recommending a product (e.g. doctor or nurse) and how long it is being used for. When the studies are complete, a formal final report is created. This may point to the need to look at subsets of the patients. There is no stratification prospectively and thus the validity of a subset may depend on the number of patients in that subset. Typically, the cohort sizes in studies involving consumers have been in thousands, and this means that not only are any findings based on numerically representative samples, but subsets may also be sizeable. The final stages of considering the data include writing papers for publication (we have published our first study in a peerreviewed journal7) and discussion of what promotional claims may be made on the basis of findings. The outputs of social media-based RWE studies have proved to be acceptable by responsible bodies as evidence for supporting claims. If the study shows something to be so, then providing the claim is accurate within the context of the study, then it should be acceptable, especially if published. RWE studies using social media have

proven to be a rapid, cheap way of conducting research, and provide data that may add to the value of promotional claims, reinforce licensed indications and patterns of use, and may also assist with price justification. If you feel the storm approaching, RWE may offer good protection for the rainy day. References 1. Dimasi, J.A., Grabowski, H.G. and Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, Volume 47, May 2016, pp.20-33 2. pdf/77166/rpt_erg.pdf accessed 19 July 2016 3. Goldacre, B. Bad Pharma: How drug companies mislead doctors and harm patients, Fourth Estate, 2012 (UK). ISBN 978-0-00-735074-2 4. Benigeri, M. and Pluye, P. Shortcomings of health information on the Internet: Health Promot. Int. (2003) 18(4): 381-386. 5. Mobile messaging and social media http:// accessed 17 July, 2016 6. the-demographics-of-social-media-usersin-2016/ accessed 19 July 2016 7. Goldman, M. and Lodhi, I. A real-world evidence study evaluating a treatment for nappy rash. Br J Nurs. 2016 Apr 28;25(8):432-9. doi: 10.12968/bjon.2016.25.8.432.

Dr Martin Goldman trained as a gastroenterologist and is now a consulting pharmaceutical physician. After many years advising on the development and marketing of medicines, with the support of some very bright colleagues, he pioneered the concept of a novel methodology for conducting real-world evidence studies of healthcare using social media. Email: Peter Brady is Chief Executive Officer at Orbital Media, specialist social and digital agency. Having co-founded the company 13 years ago, he has specialised in working with consumer healthcare brands on digital and social innovation. Working in partnership with Dr Martin Goldman and other industry figures, Peter has spear-headed the development and implementation of a unique realworld evidence solution using social media. Email:

Product Report

The Future of Product Formulation Innovation in Pharmaceutical Technology By: Roberto Castangia, Global Sales Manger, Biopharma Group Drug Development in Numbers Increasing demand for new medications makes the pharmaceutical industry one of the most complex sectors (Figure 1) for technological innovation in response to market demands.

Figure 2 | R&D investments in the Pharmaceutical sector over 35 years. Adapted from: US Food and Drug Administration. Novel drugs 2015

concept though development, into commercialisation until withdrawal from market. The product life cycle management (PLM) has become of critical Fig. 1 Distribution of the R&D investments over the importance to ensure sustainability and total sales in different iindustrial sectors. Adapted cost-efficiency. from PhARMA, 2015.

According to EvaluatePharma, worldwide prescription drug sales counted from 2014 to 2020, are expected to reach almost one trillion dollars with a compound annual growth rate (CAGR) of 4.8%.

As shown in Figure 3, the capitalised cost for a drug throughout its development has been estimated at around $2.5 billion (USD), 90% of which is cost sustained for R&D in the pre-approval stage. When compared to development 10 years ago, the cost is now 2.5 times higher (DiMasi et al., 2016)

Economic success is attributed to the ability to offer the most reliable benefits to society and to improve overall public health in terms of life expectancy, quality of life and more affordable medical assistance. With its impact on human health, drug development (DD) has directly contributed to extending life expectation by almost 15 years when compared to the mid-20th century. This success, however, has come with a price. Resources for research and development (R&D) require strict control to sustain the long-term investments and tackle problems such as patent expiration. In addition, new drugs require a high level of originality, efficacy and safety when compared to existing over-the-counter (OTC) or generic equivalents (Figure 2). From a different perspective, a new product requires a high level of accuracy in the prediction of the response to the market throughout its life cycle, from 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3 | Estimated capital cost in NME development. Adapted from: DiMasi et al., 2016.

Trends account for investments that have to be sustained over a span of more than 20 years, assuming the new molecular entity (NME) is approved by regulatory agencies and reaches the market. In order to mitigate development costs, many companies have cut the number of R&D personnel or have outsourced projects to highly specialised

independent service companies and R&D consultancies. This has supplied a demand for new emerging markets of CRO and CMO, which have been growing exponentially for the last 10 years (Schuhmacher et al., 2016). Biopharma Technology represents the ideal outsourced R&D/ service assistance concept in offering unbiased formulation, analysis and optimisation throughout your development process. In 2015 the FDA approved 45 new drugs over a precedent average of 28. It is worth noting that 16 out of the 45 new drugs were approved as First-inClass, meaning that they have a different mechanism of action from those of the same kind (Figure 4). The significance of these originate from new technologies and advances in computational chemistry, genomics, and molecular and cellular biology, which have provided great opportunities and presented new challenges. For example, progress in molecular biology has given access to therapeutic targets on wellcharacterised structures and functions, unveiling details not previously fully understood. Old Drugs, New Therapies: Formulation to Reformulation In a scenario of pharmaceutical and biotech companies rushing for NMEs, a parallel approach has been embraced to consider development from a completely new perspective. This is the case in modified dosage forms and generic formulations development. In the last decade, it has been attracting primary attention as it relies on a reformulation of approved active pharmaceutical ingredients (APIs) and the optimisation of safety, efficacy and release time. The principle appears simple but the implications in development cost and time are enormous. In this instance, discovery and screening; the most expensive and timedemanding phases in a de-novo process, are bypassed, ensuring a quicker route to market. In addition, the regulatory Autumn 2016 Volume 8 Issue 3

Product Report playing a crucial role in the development of personalised medicine, supporting biological data analysis in a highthroughput fashion with speed previously inconceivable.

Figure 4 | NME biannually approved by FDA. Adapted from: US FDA. Novel drugs 2015.

approval for commercialisation is less cumbersome and can often be obtained avoiding expensive, long clinical trials. In practical terms, the development time of a reformulated API can be shorted to 4-10 years, versus 12-20 years typically required in a de-novo approach. The idea of using clinically approved APIs goes along with the scope of discovering new actions/applications, and applies their activity in treatments that are diverse from their original intent. This specific approach is otherwise known as drug repositioning (Ashburn and Thor, 2004). Nowadays, there are many examples of repositioned drugs that have found successful applications in new therapies. An example is aspirin, which is a wellknown case. The German company Bayer developed it in 1897 as an antiinflammatory and painkiller but now, it is also used as an antiplatelet drug for treating and preventing heart attacks and strokes. Viagra, ibuprofen and Rogaine are also well-known examples of repositioned drugs. The paradigm shift of new applications for old drugs has unveiled the complexity and amplified the need for greater understanding of delivery and targeting strategies. Innovation is Multi-modal When discussing innovations in the pharmaceutical field, the crucial contribution of complementary disciplines should not be neglected in chemistry and biology. The synergetic approach of informatics, physics and engineering has allowed the integration of the generation, collection and analysis of millions of datasets in a successful manner. In addition, interdisciplinary models are accounting for the remarkable progress in diagnostics and medical devices. For example, the field of bioinformatics is

Data analysis, with new and more affordable DNA sequencing techniques, is supporting pharmacogenetics and pharmacogenomics in understanding implications of genes in drug interactions and metabolism. In cancer therapy, for example, tailored dosages can rely on higher efficacy and reduced side-effects, increasing overall tolerability and cost efficiencies (Berm et al., 2016). New therapies have also taken advantage from the use of immunology, identifying in the immune system an alternative to chemotherapy in the treatment of diseases and ailments. Although known for over 100 years, immunogenic approaches have recently become valid alternatives to surgery, radiotherapy and targeted therapy. Looking to the Future… The capital cost for advanced technologies holds pharmaceutical and biotech companies to financial constraints. Where some act as innovators and knowledge creators, experts suggest that a model that accounts for internal core competencies, outsourced service providers and cost sustainability, should be adopted. For the majority, cuttingedge innovation is unaffordable, therefore success can still be guaranteed following models such as generics business, drug repositioning or targeting emerging markets (Schuhmacher et al., ‎2016; Banerjee and Thakurta, 2015). From a social perspective, it should not matter in which way pharmaceutical innovation occurs as long as progress of human health is the core objective within regulation guidelines. Whilst this is a commonly accepted concept, the recent exposure to health threats has provided examples for which human necessity is not fitting the innovation model.

If you would like to find out how Biopharma Technology can help with your outsourcing requirements, whether it be for formulation development, analysis, optimisation or even a process review, please contact us: or +44 (0)1962 841092. References 1. D.G. Arnold, J.L. Troyer, Journal of Health Politics, Policy and Law, Vol. 41, No. 2, April 2016 2. T.T. Ashburn and K.B. Thor, Nature Reviews, Drug Discovery, volume 3, August 2004, 673 3. K. Banerjee and R. Thakurta, Journal of Generic Medicines 2015, Vol. 12(2), 50–59 4. T.U. Berendonk, et. al., Nature Reviews Microbiology 310, April 2015, volume 13 5. E.J.J. Berm et al., PLOS ONE, DOI:10.1371/journal.pone.0146262 January 11, 2016J. 6. M.A. Blair et al., Nature Reviews, 42, January 2015, volume 13 7. J.A. DiMasi et al., Journal of Health Economics, Vol.47, 2016, 20–33 8. H.R. Meredith, Nature Chemical Biology, March 2015, volume 11 9. P.K. Owens et al., Nature Reviews, Drug Discovery, January 2015, volume 14 10. US Food and Drug Administration. Novel Drugs 2015. Published January 2016. Accessed May 2016.http:// DevelopmentApprovalProcess/ DrugInnovation/UCM485053.pdf . 11. EvaluatePharma World Preview 2015, Outlook to 2020, Accessed May 2016 http://www.evaluategroup. com/public/reports/EvaluatePharmaWorld-Preview-2015.aspx 12. PhARMA, Annual 2016 Pharmaceutical Industry Profile, Accessed May 2016 http://www. 13. V. Sathyanarayanan, S.S. Neelapu, Molecular Oncology 9, 2015, 2043 2053 14. A. Schuhmacher et al., J Transl Med, 2016, 14:105

This has, along with the recent upsurge in drug-resistant bacteria and the ongoing debate as to the cause, shaken the global community, revealing the weakness of current technologies and the incapacity to proactively address the reason; and so the debate continues.


Chapter Title Manufacturing Optimising Formulation Performance through Spray-drying Techniques to Overcome Solubility and Bioavailability Challenges Introduction The challenges in the formulation development of new chemical entities (NCEs) have never been greater. New NCEs are being designed to be more selective in their interaction with biological targets, but this relates to a general trend in increasing lipophilicity for new drug candidates and correspondingly poor aqueous solubility. Indeed, it is estimated that 40-70% of all NCEs identified in drug discovery programmes are insufficiently soluble in aqueous media, resulting in inadequate or variable absorption from the GI tract following oral administration.1,2 These compounds are unlikely to progress to commercialised products if approached with conventional formulation development strategies; most will require some form of enabling technology to overcome bioavailability barriers. To date, enabling technologies typically aim to overcome bioavailability issues by dramatically increasing the surface area to volume ratio of the drug compound, when compared to its natural form. Two prominent examples of this are 1) amorphous molecular dispersions, whereby drug is dissolved into a polymer matrix which dissolves away during transit through the GI tract to present individual molecules of the active pharmaceutical ingredient (API) to the body for absorption and; 2) nano-crystalline presentations of the API in either a suspension or a dissolvable matrix designed to prevent aggregation of the nanoparticles. Marketed products such as Ememd®, Ritalin LA®, Tricor®, Zortress®, Kaletra®, Onmel® and many more are based on either nanocrystals or molecularly dispersed drug in polymer presentations. With most development programmes on critical timelines to establish the development fate of the NCE in question, a paradigm shift in the approach to formulation development is required where the focus is on quickly establishing whether an enabling formulation has the potential to overcome bioavailability challenges or not.


Juniper Pharma Services’ proprietary enabling technologies rapid screen platform, which assesses compounds against a range of enabling technologies, including amorphous molecular dispersions and nano-milled crystalline options, focuses on screening NCEs to provide pharmacokinetic- (PK-) ready formulations within eight weeks, allowing critical decisions to be made at an early stage in the drug development process. Case Study – Fenofibrate Fenofibrate (used to reduce cholesterol levels in patients at risk of cardiovascular disease) is a poorly-water-soluble compound with estimated solubility being approximately 0.09 mg mL-1.3 Work was undertaken to assess this compound for dissolution enhancements in both a nanomilled and an amorphous molecular dispersion presentation. Nano-Milling Input material was first assessed for susceptibility to brittle fracture/size reduction by mechanical attrition by hand grinding in a pestle and mortar. Corse assessment of particle size and morphology by scanning electron

microscopy (SEM) of the resulting hand ground materials demonstrated that particles were much reduced in size with no evidence of plastic deformation (Figure 1).

Figure 1. SEM of fenofibrate starting material.

Figure 1: SEM of hand ground (pestle and mortar)





Figure 2. SEM images of nano-milled fenofibrate in different excipient conditions. Note: scale bars are for 1 µm for top left and right, and 0.3 µm for bottom left and right. Autumn 2016 Volume 8 Issue 3

Bringing together the best of

When it’s


compound, every step matters. API

DRUG PRODUCT PC1-16-0005-210x297mm-Apr., 2016 © 2016 Pfizer Inc. All rights reserved. Pfizer CentreOne is a Trademark of Pfizer Inc.

Chapter Title Manufacturing Of the four formulations screened, those containing hydroxypropyl methylcellulose (HPMC, 2273_003 and 2273_004) clearly resulted in the smallest particle sizes. SEM data demonstrated that PCS data for 2273_004 was potentially misleading, with particle sizes in 2273_003 being clearly smaller than those in 2273_004.

Figure 3. XRPD spectra of nano-milled fenofibrate in four different excipient conditions. From top to bottom, black: virgin fenofibrate, red: 2273_001, blue: 2273_002, green: 2273_003 and pink: 2273_004. XRPD spectra demonstrate no change in the form of fenofibrate or introduction of amorphicity, with additional peaks at ca. 4 2θ in 2273_002 and 2273_004 attributed to excipients used in the respective formulations.

As a result of these data, formulation 2273_003, which is a combination of HPMC and a common pharmaceutical surfactant (vitamin E TPGS), was scaled up 150x (15 g API) using a WAB DynoMill. Additionally, to generate a solid oral dose, the anti-solvent (water in this instance) used in the nano-milling process was removed by spray-drying using a Buchi B-290, along with a co-dissolved matrix excipient (mannitol) designed to include the nano-crystals and prevent aggregation. This process yielded a solid powder (72% yield), which is capable of either being used directly as a capsule fill or as an intermediate in tablet formulations. The resulting materials were analysed by PCS, XRPD and SEM, the results of which are included below as Table 2, Figure 4 and Figure 5.

Figure 4. XRPD spectra of fenofibrate input material (black) and nano-milled batch 1691_013 after spray-drying and removal from the mannitol matrix. Starting materials were subsequently subjected to wet media ball milling using a Fritsch Pulverisette 7 Planetary Micro mill in four different excipient combinations on a small scale, with resulting nanosuspensions being assessed by photon correlation spectroscopy (PCS), SEM and X-ray powder diffraction (XRPD) studies, to rapidly assess for suitable stabilising conditions. The results of this study are collated in Table 1, Figure 2 and Figure 3. Table 1. ZAVG particle sizes of nanomilled fenofibrate in different excipient conditions. Formulation ID ZAVG (nm) 2273_001 840 2273_002 >2500 2273_003 250 2273_004 250 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 2. ZAVG particle sizes of nanomilled fenofibrate batch 1691_013 (fenofibrate/HPMC/Vitamin E TPGS) and the same material post-spray-drying in a mannitol matrix. Formulation ID ZAVG (nm) 1691_013 (as manufactured) 300 1691_013 (after spray-drying and redispersion) 460 Amorphous Solid Dispersions Additionally, fenofibrate was screened in a film casting study to assess polymer/ excipient combinations as candidates to form amorphous molecular drug dispersions. Mixtures of polymers and excipients, along with 20 wt% fenofibrate were dissolved into solvents and evaporated onto microscopy slides for assessment by polarised light optical microscopy. The resulting films were subsequently subjected to a short stability study (one week, 40°C/75% relative humidity, open conditions) and re-evaluated for phase separation/ recrystallisation. The results of this stability study are shown below in Figure 6. Clear birefringence was seen across multiple formulations, which is indicative of recrystallisation of fenofibrate from the polymer matrix, and amorphous phase separation was observed in others, eliminating them as potential excipient combinations for the production of drug in polymer amorphous molecular solid dispersions. A number of clear candidates were identified from the screen, one of which was using Soluplus®, a tri-block co-polymer designed for use in the production of amorphous molecular solid dispersions through hot melt extrusion. Based on this screen, a fenofibrate/ Soluplus® (1:4 wt/wt%) formulation was produced by hot melt extrusion using a Thermo Scientific Pharma 11 Twin Screw hot melt extruder. The resulting extrudate was pelletised and ground to a fine powder in a hand-held mill and subsequently shown to be amorphous by XRPD (Figure 7).

Figure 5. Left: SEM of spray-dried nanomilled fenofibrate, batch 1691_013, in a mannitol matrix. Right: SEM of the spraydried material after redispersion in water and centrifugation.

Dosage Forms Two different dosage forms were subsequently employed to deliver the enabled formulations for dissolutions studies. Spray-dried nano-milled material was formulated into a ca. 48 mg instant release tablet formulation using PROSOLV® Easytab SP (blend Autumn 2016 Volume 8 Issue 3

Additionally, fenofibrate was screened in a film casting study to assess polymer/excipient combinations as candidates to form amorphous molecular drug dispersions. Mixtures of polymers and excipients, along with 20 wt% fenofibrate were dissolved into solvents and evaporated onto microscopy slides for assessment by polarised light optical microscopy. The resulting films were subsequently subjected to a short stability study (one week, 40°C/75% relative humidity, open conditions) and re-evaluated for phase separation/recrystallisation. The results of this stability study are shown below in Figure 6.

Chapter Title

Manufacturing It should be mentioned that although in vitro dissolution testing in aqueous media is an effective means of comparing the drug dissolution behaviour of formulation candidates, it does not fully predict oral bioavailability. A recent extension to the enabling technologies rapid screen programme has therefore been the inclusion of the pharmacokinetic assessment of candidate formulations in an animal model (rat or dog).

Figure 6. Cross polarised light optical microscopy of film casts of various polymer/excipient combinations with 20 wt% fenofibrate incorporated after 1 week stability at 40 °C/75% relative humidity.

Clear birefringence was seen across multiple formulations, which is indicative of recrystallisation of fenofibrate from the polymer matrix, and amorphous phase separation was observed in others, eliminating them as potential excipient combinations for the production of drug in polymer [1] Lindenberg et al. European Journal of Pharmaceutics and Biopharmaceutics 2004;58(2):265–278. [2] Hauss et al. Drugs and Pharmaceutical Sciences. Vol. 170. NC, USA: Informa healthcare; 2007. Oral lipid based Formulations-Enhancing the Bioavailablity of Poorly water soluble drugs; pp. 1–339. [3] Yadav et al. International Journal of PharmTech Research, 2009, 1(2), 256-263.

References 1. Lindenberg et al. European Journal of Pharmaceutics and Biopharmaceutics 2004;58(2):265– 278. 2. Hauss et al. Drugs and Pharmaceutical Sciences. Vol. 170. NC, USA: Informa healthcare; 2007. Oral lipid based Formulations-Enhancing the Bioavailablity of Poorly water soluble drugs; pp. 1–339. 3. Yadav et al. International Journal of PharmTech Research, 2009, 1(2), 256-263.

Figure 7. XRPD spectra of fenofibrate input material (black) and powdered fenofibrate/Soluplus® (1:4) solid amorphous dispersion (blue) after production. of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate), whilst the hot melt amorphous molecular dispersion was used in a direct capsule fill in size zero gelatin capsules at ca. 48 mg strengths (Table 3). Each of these dosage forms was subjected to dissolution in pH 6.8 phosphate buffer solution against a control of unmicronised fenofibrate, the results of which are demonstrated in Figure 8. Dissolution rates for the enabled formulations were dramatically higher than unmicronised fenofibrate alone with between 90 and 100% of the dosed material released within the first 20 minutes of dissolution. This is in contrast to only ca. 30% of unmicronised fenofibrate only. A slight lag time is seen for the dissolution profile of the ASD (amorphous solid dispersion) formulation which was attributed to the time taken for disintegration of the gelatin capsule shell.


Figure 8. Dissolution of unmicronised fenofibrate, tablets containing nanomilled fenofibrate and capsules containing amorphous molecular dispersions of fenofibrate in pH 6.8 phosphate buffer solution at 37 °C. USP dissolution apparatus II was employed. Conclusions Fenofibrate, a poorly water soluble drug compound, was successfully processed using both nano-milling/spray-drying and hot melt extrusion to produce either milled nano-crystalline powders or solid amorphous molecular dispersions (ASD), respectively. These materials were characterised using a range of techniques, including X-ray powder diffraction, scanning electron microscopy, polarised light optical microscopy, photon correlation spectroscopy and dissolution/ HPLC assay/related substances. The resulting materials were formulated into 48 mg dosage strength capsules (ASD) or tablets (nano-milled powder) and subjected to dissolution testing. Enabled formulations demonstrated significantly higher release rates (ca. 90-100% released in 20 minutes) compared to the dissolutions rates of the unmicronised fenofibrate (ca. 30% released in 20 minutes), demonstrating the potential for enhanced bioavailability in the enabled formulations.

Dr. Ian Barker has worked at Juniper Pharma Services since 2014. Currently working as a Principal Scientist, Dr. Barker leads the enabling technologies/ drug delivery team at Juniper Pharma Services – a team dedicated to developing formulations that enhance bioavailability in poorly soluble compounds. Dr. Barker holds a Ph. D. in materials and synthetic organic polymer chemistry from the University of Nottingham.

Autumn 2016 Volume 8 Issue 3


How Formulation Can Affect Tablet Tooling Developing a formulation for solid oral dosage that can be compressed in a modern tablet press, at high speed, can cause a number of technical challenges, and many of these are down to the physical content of the formulation being used. From moisture content to abrasiveness, The tooling used needs to reflect the formulations being compressed to ensure a quality fault-free end product. Tooling and its related equipment must be chosen according to the formula being compressed, and proper tooling maintenance and standard operating procedures should be adhered to, in order to reduce the many variables affecting tablet manufacture. Here we take a look at the most common problems with formulation composition and how they can affect production.

bore ringing and tip abrasion, this can cause flashing around the circumference of the tablet.

Fines One of the first considerations is if the formulation being compressed contains very small particles. If it does, then the clearance between the tip of the punch and the bore of the die is critical. If the clearance is too large, then the smallest fines of the formulation can pass between the punch tip and die wall. This can cause several problems, including binding and tightness of the punch tip in the die bore. This in turn generates friction and heat, which can cause abrasion of both the die bore and the punch tip, resulting in die

Moisture Moisture within a tablet is often needed to help the binding effect, but this can also be a root cause of sticking. When the adhesive forces of the formulation to the punch tips overcome the cohesive forces within the tablet, then sticking can occur.


Fine particles can also pass through to the lower punch guide seals. If these are not sufficiently fitted or worn, further tightness and wear can be generated between the punch barrel and lower guides. Fines can also cause a general contamination issue as they are more easily airborne and can penetrate upper guides with similar results if seals and bellows are not used and maintained correctly. Excessive fines will result in poor tablet quality, as well as tool binding and tablet press overheating, which increases sticking and picking issues.

Water within the tablet can be one of the causes of a rise in adhesive forces. This happens by the increase in capillary action between the tooling surface and the granule. Capillary bridges form,

causing high adhesion areas, thus creating sticking. Moisture can enter into the process either in wet granulation or due to excess humidity in the compression chamber in a non-environmentally controlled area; the latter can even affect direct compression formulations. One solution would be the use of anti-stick coatings applied to the tooling, which repel rather than attract moisture, but the selection of the right coating for the job is a specialist one which not all tooling manufacturers are equipped to undertake. I Hollandâ&#x20AC;&#x2122;s TSAR Predict Service helps overcome this issue by predicting the particle adhesion of any ingredient in any formulation to all the PharmaCote tablet tooling coatings. With over 800 predictions since its release this service is proving to be very popular. When coatings are developed correctly, and their beneficial characteristics are matched to those of the formulation, they can help to increase corrosion resistance, wear resistance, and prevent sticky formulations adhering to the punch tip faces. Traditionally, the most popular coating used within the global tablet tooling industry is hard chromium, due to its low cost and general purpose characteristics in terms of average anti-stick, anti-corrosion and anti-wear properties. There are, however,

Autumn 2016 Volume 8 Issue 3


The New Era of Quality Processing starts now! The transition from statistical quality control to 100 % realtime inspection of each individual tube over its entire length enables our customers to tailor dimensional and cosmetic quality of glass tubing to specific packaging requirements. Whatâ&#x20AC;&#x2DC;s your next milestone?

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Manufacturing many options out there. One of the most recent additions to the I Holland portfolio is PharmaCote® CT (textured chromium nitrate). This exclusive surface treatment, combined with its proven PharmaCote® CN anti-stick coating, generates an antistick tip face for tablet production, and also shows good corrosion-resistance in intensive salt spray tests, as well as good wear-resistance. Abrasive Some formulations contain ingredients which are particularly hard and sharp. Typically (but not exclusively) these are found in nutraceutical products which contain many minerals and hard organics. Through repeated cyclic compression, these abrasive ingredients can wear away both the surface of the punch tip and the bore of the die, resulting in low-quality tablets. Hard granules can even impregnate the surface of the punch tip under high compression forces. These actions can then lead to other tabletting problems, such as capping or de-lamination and sticking. This abrasive action can be countered by the use of advanced tooling materials and coatings selected for their wearresistant properties. Materials such as I Holland’s specialist Pharmagrade steels, used in conjunction with resilient coatings like I Holland’s PharmaCote RS or HPGTC (tungsten carbide dies), have high hardness values and specific structures which abrade at a much lower rate. In some cases, tool life has been increased by 700% over a standard steel tool. Corrosive Certain constituents of the formulation can contain corrosive elements such as chlorine, salts and acids, which will react with the tooling surfaces and result in oxidation. In addition, wash in place systems fitted to some modern tablet presses expose tooling to water and cleaning solutions, therefore they require tooling to have good corrosion-resistant properties. Indeed, post-compression cleaning procedures can also cause corrosion if not controlled sufficiently. Corrosion can appear as discolouration, etching or common red rust. To combat this issue, a corrosion-resistant material can be selected, however standard stainless steel types are not suitable due to the lack of hardness and wear-resistance. Therefore specialised Martensitic Stainless Steels


with high chromium content should be used. It is also possible to apply hard coatings with corrosion-resistant properties, such as other coatings in the PharmaCote range. Deformation Characteristics The characteristic of certain ingredients in a formulation can have plastic or elastic properties, leading to tabletting issues, such as sticking and capping. Where the behaviour of a particle under compression can either stay deformed or ‘spring back’ to its original shape, the dwell time of the machine can be critical. In cases of formulations with more timedependent consolidation behaviour, a long dwell time is important to create strong bonds between the particles. In a situation whereby a greater dwell period may be required, there are tools on the market to help, including I Holland’s new innovative extended dwell flat tooling (XDF) which will enable an increased compression dwell time for a formulation without the disadvantage of slowing the press, or changing press turrets and guides.

Some formulations can cause adverse effects on the punch tips when under compression, such as abrasion, pitting or corrosion. Although tools are manufactured from hardened and tempered tool steel, the demanding processes involved can lead to deterioration if the tool material is not optimised to suit the formulation being compressed. Some granules are extremely hard and abrasive and can scratch, wear and impregnate the steel surface. Other granules can contain corrosive elements which react with the steel. These effects can be reduced by understanding the nature of the formulation to be compressed and carefully selecting a material or tool coating to resist this. The important message here is that it is vital to talk to your tooling manufacturer if you are finding manufacturing problems, as they should be able to pin-point the exact root cause and corrective action thus solving your production issue.

Friability Friability, or the tendency to crack, chip or break during compression, is in part due to the formulation. If the formulation is not cohesive and does not bind together sufficiently, then friability will occur. There are several ways to compensate for friability, including looking at dwell time, weight control, expansion, tablet hardness and of course, tooling condition. All of these should be examined to produce a quality tablet. How to Produce a Fault-free Tablet? The development of formulations for solid-dose products can be a complex and problematic procedure; however, with certain considerations and measures in place, it can be achieved successfully. Pharmaceutical formulations normally contain multiple actives and multiple excipients. This can bring challenges related to particle size, flow, compressibility, interaction, content and uniformity. For example, some active ingredients may be available in granular form, while others may be available only in fine powder form; some may be hydrophilic and others hydrophobic. Because of this, the ingredient blend may have many different particle sizes and ingredients with a variety of characteristics.

Rob Blanchard I Holland R & D Manager. Since joining I Holland in 2004, Rob Blanchard – Research, Development and Quality Systems Manager – has been instrumental in the development of the PharmaCote® range of surface treatments and coatings for tablet compression tooling. He is part of the Eurostandard steering committee and responsible for I Holland’s registration to ISO 9001:2008. Rob also coordinates the company’s close collaboration with academic research bodies. Email:

Autumn 2016 Volume 8 Issue 3

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Manufacturing Protection for Valuable Ingredients

Microencapsulation and coating can protect substances against adverse external effects and optimise their properties. The two processing methods are among the options offered by fluid bed technology, by which the physical attributes of products and their applications can be influenced specifically. Conditions in the fluid bed processor are ideal for an intensive exchange of heat and substances. Warm, filtered air is blown through a distributor plate into the material container, where it comes into contact with the powder to be processed. The distributor plate gives the air specific flow characteristics, ensuring that the starting materials are mixed thoroughly and a fluid bed develops.

this framework, too, that any necessary adjustments to the formulation are made and the various steps in the process are determined. Production then takes place on industrial-scale plant designed for continuous or batch operation. In the continuous process, powdered and liquid components are fed in constantly and the finished product removed. The product is run through a screen tower; undersized particles and the oversized particles ground in-line are returned to the fluid bed process. After metal detection, the fraction with the desired particle size is filled and packaged. Wurster inserts, in-line sifting and grinding and various ports for adjusting the nozzles for topspray and bottom-spray applications

equip the fluid bed processor for all manner of different tasks. For the liquid phase, too, a wide range of equipment is available, such as heating and cooling chambers, melting grids, heatable containers with anchor mixers, jet mixers and a homogeniser. Encapsulation: Resistance to External Influences Fluid beds act like strongly bubbling liquids. Practically the entire surface of the solid particles is exposed to the particular medium: that applies to both the air for drying and the suspensions or emulsions sprayed in. Other liquids can be fed in through the nozzles above or below the product bed. In this way, it is

Specific Problem-solving Fluid bed drying has a number of advantages over conventional spraydrying. In this method it is not only a case of removing the moisture from the product. The aim is to achieve a dry product with precisely defined structures and specific attributes â&#x20AC;&#x201C; to mask an odour or taste, to achieve better dispersibility, to reduce dust, or as protection against external influences. As the fluid bed is in itself an ideal mixer, it is possible to mix several powdered substances on this plant and agglomerate them, for example, in the same step. This also prevents subsequent separation of the productâ&#x20AC;&#x2122;s ingredients. As a specialist in customised solutions for blending, processing and filling food ingredients in powder form, and also active pharmaceutical ingredients and excipients, SternMaid is excellently set up for processing functional ingredients. The contract manufacturerâ&#x20AC;&#x2122;s multifunctional fluid bed processor has been in operation since 2012. It combines numerous technical options and was designed specially to meet the diverse requirements of contract manufacturing. In order to develop new products, optimise existing ones and establish process parameters, the company first carries out trials in the laboratory, where it also conducts tests for feasibility and product attributes on a pilot scale in cooperation with the customer. It is in 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2016 Volume 8 Issue 3

Chapter Title


OF COMPLEX API Offering Diverse Expertise for Tomorrow’s Complex APIs • Early Phase Clinical Batches (cGMP) • Late Phase Clinical Batches through to Registration/Validation Batches (cGMP) • Potent & Cytotoxic Compounds

• • • •

Controlled Substances Steroids Hormones Sterile API


Manufacturing influences such as light or moisture. In the hot melt coating process the constituents of the coating – usually lipids – are melted in a container. The melt is then sprayed onto the particles of the substance suspended in the fluid bed through a heated nozzle. It cools down rapidly on their surface to form an even coating. In this way, besides masking any unpleasant taste, it is possible to combine several active ingredients in a single dosage form. This applies especially to ingredients that could not otherwise be combined, for instance because they would impair each other’s chemical stability.

possible to carry out various different processes, such as microencapsulation. One practical example: oral dosage forms of active pharmaceutical ingredients must reach their site of action as precisely as possible. To ensure that the substance is released exactly where it has the desired effect, it can be enclosed in microcapsules or granulates. With acid-resistant encapsulation, substances destined for the intestines even survive their passage through the stomach. Encapsulation also serves to mask unpleasant, bitter tastes and makes it much easier for children to take the medicine. Depot Effect A further important criterion for the tolerance of medicinal products is the speed at which the active constituent is released. At high dosages, some drugs can damage the lining of the stomach. Microencapsulation delays the release of the active ingredient, thus increasing its tolerance by the stomach as compared to conventional tablets which disintegrate quickly. Instead of being released immediately, the substance diffuses continuously in small amounts through the capsule walls. Delayed release is also used for probiotic products. Only if the microorganisms survive their passage through the stomach and reach the small intestine alive do they have a chance of multiplying and exercising a beneficial

effect on the intestinal flora. In order for probiotic cultures in foods to pass into the intestinal tract specifically and undamaged, they can be added in the form of microcapsules that open or dissolve according to the pH.

Outsourcing of Processes Fluid bed technology permits a great diversity of applications. But for small or medium-sized companies and manufacturers with a frequently changing range of products, it is a challenge to install expensive plant or constantly replace equipment to ensure it is always state-of-the-art. So it may be a sensible solution to outsource production to specialised service providers like SternMaid.

Gentle Processing Since the fluid bed process can be carried out in a low temperature range, the products are normally exposed to only moderate heat between 30 and 50 °C. The thermal effects are therefore much slighter than with spray-drying. For heat-sensitive ingredients such as microorganisms, enzymes or vitamins, the duration of the process and the temperature used are adjusted precisely in order to achieve the best possible balance between productivity and maintenance of activity. Coating: Functional Surfaces or Protective Films Resistance to gastric juices can also be achieved with a coating. This can be carried out by different methods. Fluid bed technology ensures that each individual particle is coated very precisely with a defined amount of material and simultaneously dried. The particles are enveloped in a liquid in the current of air. In the pharmaceutical industry, polymer coatings are frequently used. Certain polymers remain stable in the low pH range and only dissolve in a neutral environment. A fine, even coating of melted fats or sugar dissolved in water protects the solid matter against outside

Frank Hellerung was trained as a wholesale and foreign trade assistant. In 2002 he started work with Mühlenchemie, one of the companies of the Stern-Wywiol Gruppe, in the field of purchasing and production planning. He subsequently became a project manager, responsible among other things for process optimization, GMP implementation and various training courses. Since 2011, Frank Hellerung has been responsible for Business Development at SternMaid GmbH & Co. KG. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 80

Consistency. Proven

Increase viable CHO cell density by supplementation with recombinant Insulin Human AF CHO cells are one of the most widely used platforms for the production of biopharmaceuticals. Increased demand for safety and reliability has moved the standard for CHO cell culture media from Serum to Serum free and further on to chemically defined media. UAB in collaboration with Novo Nordisk Pharmatech (worldâ&#x20AC;&#x2122;s largest supplier of recombinant insulin) has shown that addition of animal origin free insulin to three leading commercially available off-the-shelf chemically defined media resulted in significant increases in viable cell density. In addition to this benefit insulin has been proven to aid in the expression of difficult to express proteins.

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Manufacturing Multiple Granulation Techniques Delivering Flexibility in Drug Development and Manufacturing Pharmaceutical granulation is a common technique for solid oral drug production, whether as tablets, capsules or granules for use in bottles or sachets. PCI Pharma Services offers multiple granulation methodologies addressing requirements of a wide range of active pharmaceutical ingredients (API), irrespective of potency. Granulation combines individual formulation components (API, diluents, binders, disintegrants) into a single uniform particle. The various techniques include wet granulation; dry granulation; fluid bed granulation; and hot melt granulation. Granulation is of benefit in overcoming challenges such as active content uniformity; densification of formulation; powder flow properties; compression properties; controlled API release profiles; and API bioavailability. PCI’s granulation is performed by aqueous-based solutions with investment in granulation equipment including high shear mixers, one pot processors, roller compactors and fluid bed processors. PCI has the additional capability to produce potent products (OEL down to 0.01 µg/m3) utilising high shear granulation and fluid bed processing. Containment performance is proven using standardised measurement of equipment particulate airborne concentration (SMEPAC) testing. PCI’s granulation suites include totally contained engineering systems with no open powder handling. The suites include small-scale (1-5 kg) (Figure 1) and largescale (20-120 kg) equipment. Traditional physical assessment of the granule from the operator is not required, as end-point of granulation is determined reliably from data obtained. Data is converted into user-friendly batch reports (Figure 2): the figure graphically indicates the power and torque of the impeller blades which, with relevant training, can determine the end-point of granulation prior to product over-massing. The figure also demonstrates the granulation fluid addition rate. The granulation bowls are geometrically similar with a similar design of impeller blades, meaning products developed at small-scale can be scaled up to large82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Small-scale granulation suite

Figure 2. Example of wet granulation report from potent HSM scale. PCI uses precise mathematical scale-up modelling to ensure successful larger batches. Modelling includes the scale-up of the speed of the impeller blade, the granulation fluid addition, mixing times and bowl volumes. The impeller blade speed can be altered by choosing the most appropriate model to obtain a similar physical granule (tip speed, Froude number or constant shear stress). Similar models can be performed for fluid bed granulation,

assessing the required air flows and spray rate calculations. This can be used to deliver a low API concentration within the formulation via the granulation fluid. Other elements of fluid bed granulation include low porosity density (particles remain more spherical) and end product bulk density that is similar to the starting material. This process is also utilised for pellet and tablet film or modified release coating.

Autumn 2016 Volume 8 Issue 3

Chapter Title

Analytical Support for R&D, Clinical Development and Licensed Manufacture GLP, GCP and GMP compliant MHRA and FDA inspected


Autumn 2016 Volume 8 Issue 3


Contained roller compaction PCI has a wide range of one pot processors; from small laboratory to large-scale equipment. Scale-up models can provide a faster path to large-scale manufacturing with the similar physical and chemical properties as the developed granules.

One pot processing is another granulation technique where product drying is performed using a jacketed bowl. The bowl’s insulated water jacket is used to raise the temperature, evaporating the aqueous media drawing moist air away using a vacuum system with a condenser. During the drying phase, the impeller blade is rotated incrementally, moving the colder material into closer proximity to the heated jacket wall. The Collette U600, PCI’s newest and largest one pot processor, also includes a heated bowl lid to aid drying, an inbowl camera and a sample chute which prevents heat loss when taking samples or visualising the product. 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Both the high shear granulators and one pot processors can be used to perform hot melt granulations. This type of granulation introduces a waxy bioavailability enhancing excipient to poorly soluble APIs. This granulation assists in the dispersion of the granules into a fine particulate suspension aiding absorption within the patient. Roller compaction is a process that provides a granulation method for materials that are heat- and moisturesensitive by compressing powder blends between two rollers under pressure with the resulting material sized by dry mill. The granule produced is densified with a larger particle size and better powder flow in relation to the starting material PCI’s investment in a Gerteis MiniPactor provides fully contained roller compaction for the processing of potent APIs with the ability to perform small development batches at 10g/hour and

scale-up to 100 kg/hour. This provides a distinct advantage in executing scaleup activities from development through clinical trial manufacture and subsequent commercial production. In line with the other state-of-the-art equipment, the PLC systems perform feedback loops for optimal control of ribbon thickness produced from the rollers. PCI will continue to invest in granulation methods offering clients maximum flexibility in drug development and manufacturing.

David O'Connell BSc (Hons), Director of Pharmaceutical Development, PCI Pharma Services, aids clients with formulation development, technical transfer and scale-up of solid oral, oral liquid and semisolid products for clinical trials and/ or commercialisation. David was part of the design team for PCI’s high potent contained manufacturing facility (CMF), which won the ISPE Facility of the Year award for Facility Integration (2014).

Autumn 2016 Volume 8 Issue 3

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Manufacturing R&D Should Mimic Future Up-scaling to Meet Production Expectations When a new drug formulation progresses from the development side of R&D to the realm of manufacturing, there is often a reality check with respect to process scale-up and the performance of the formulation at production scale. Problems with capping/lamination and sticking/picking are often first realised at this grand scale of compression that is required to supply market demand. Manufacturers of compression tools are often asked to proffer a reason why the tooling that has been provided is causing the formulation to generate tablets with obvious and unacceptable defects. Despite having approved the tablet design, the manufacturing manager is faced with a fix that will not involve discussions with regulatory authorities â&#x20AC;&#x201C; internal or external. Often the technicians in the compression suites will have taken the liberty to manipulate the compression conditions, in every possible combination, to attempt to solve the problem and maintain their good relationship with the floor manager. Having tried every possible mixture of precompression, final compression, feeder speed and turret speed, the obvious failure in the process has to be the tooling. Compression tools, as a potential root cause of the current problem, have many additional variables that are not often considered and certainly not tested before scale-up is studied. These tooling variables typically come under scrutiny only when there is a problem like sticking. The unfortunate reality is that the drug product formulation would have best been evaluated through a series of simple experiments to determine whether some of the potential problems should be addressed before regulatory registration of the drug product recipe. Rushing a product to market can yield some expensive and painful lessons learned when the formulation fails to meet manufacturing expectations of capacity and yield. To screen the potential formulation for scale-up problems, the following simple experiments should be considered to fully characterise formulation performance: compaction profile and strain rate sensitivity. A compaction profile offers insight into the performance of the powder under compression. The simplest 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

test is compression of the powder at different forces and testing the tablet breaking strength of the resulting tablets. An alternative approach is to normalise for the punch tip pressure as opposed to using just the compression force. A study of the powder using a range of pressure typical to the pharmaceutical industry of 50 MPa - 300 MPa, allows a simple comparison of tablets of all sizes using the same formulation. A typical profile is shown in Figure 1 for a pair of formulations that have been compressed on a single station tablet press. The formulations contain a high drug load. One formulation is a direct blend recipe while the other is a wet granulated powder. A robust tablet will typically have a tensile strength of 1 to 2 MPa. Neither of the two blends tested yields a tablet that would be acceptable.

Figure 1 Moving the compression process to a rotary tablet press yields a different result. As shown in Figure 2, the wet granulation formulation yields a tablet that increases in tensile strength with the addition of more compression force and at 150 MPa pressure, provides a robust tablet. The direct compression blend will not compress into a tablet of sufficient strength and in fact yields a

tablet that exhibits capping behaviour at higher pressures. While uncommon, the race to register has participants that will proceed directly to direct compression formulas. With data indicating that the single station tablets will provide a tablet with acceptable hardness, disintegration and dissolution, the jump to registration will be in motion before testing on the rotary tablet press is accomplished using material from the first step of the scale-up process. The majority of formulations do not bypass the required rigour of testing during scale-up; however, many do make assumptions regarding the capability of their formulation at the scale required to meet the demands of the patient population. Moving to a large rotary tablet press with 40 to 70 tooling stations significantly changes the dynamics of the powder compaction process as a result of changes in the overall speed of the compaction process. As larger tablet presses are utilised to meet tablet demands, the pitch circle diameter of the turret increases, the resulting punch vertical velocity increases and the compression dwell time decreases. Figure 3 illustrates the results of a simple strain rate study. To generate the proper data, the compression force is fixed and the tablet press is run at different speeds. For this illustration, the velocity of the tablet press pitch circle and the size of the compression tool head flat have been used to calculate the dwell time for compression, which is shown with the units of milliseconds on the X axis. For the purposes of this discussion, the dwell time is defined as the time during which the upper and lower punches have no vertical movement.

Figure 3

Figure 2

The wet granulation is capable of generating acceptable tablets at all of the turret speeds, while the strain rate Autumn 2016 Volume 8 Issue 3

TURRETS MAKE THE MAGIC HAPPEN: POWDER FLOWS, ROLLERS COMPRESS, PUNCHES…WELL, THEY PUNCH. ALL SPINNING IN PERFECT RHYTHM CREATING BEAUTIFUL LITTLE TABLETS. Then without warning, it comes to a screeching halt and you have to change the heart of the machine. When turrets fail, turn to Natoli Engineering. Our hardened, tool-steel die tables meet or exceed the Original Equipment Manufacturer (OEM) specifications, giving you increased longevity and durability. We make turrets for almost every tablet press on the market and our superior machining ensures better alignment between your punches and dies. So the next time the magic stops, give Natoli Engineering a call. Visit our website and discover the Natoli difference...TODAY!


Manufacturing problems before these problems appear. Sometimes these problems arise courtesy of small changes in environmental factors or variability in the supply chain for excipients. Running a performance lot can provide more process understanding and knowledge about the design space for a productâ&#x20AC;&#x2122;s formulation.

sensitive formulation requires a slower turret speed to make acceptable tablets. This is a problem as the strain rate sensitive formulation will not be able to produce as many tablets per hour as the wet granulation. While these tests may be easy to do, they are time-consuming and costly with respect to API costs. So what is a production manager to do when caught up with the need to satisfy the demands of management and an underperforming drug product formulation? Discuss your options with the company that provides your compression tools. They can offer tooling modification that may be capable of solving, or at least minimising, the problem. When strain rate sensitivity is a problem and requires a slower production rate to produce acceptable tablets, then tools with extended head flats can be considered. TSM-B and TSM-D type tools can be modified to increase the head flat size and provide a longer dwell time at the same turret speed. This can provide improvement in the tablet production rate or elimination of minor defects that are linked to a lack of powder consolidation time. Sometimes a drug product formulation performs well; however, after several 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

hours there will be problems with material sticking to the punch cup or die bore. There are various root causes to these problems. Sticking may be temperaturerelated and relief for that problem may require testing a coating for the punch cup to reduce powder adhesion. Heat generation can be caused by fine particles sifting past the punch cup into the die bore and there causing excess friction and an increase in temperature. The number of fines sifting past the lower punch can be reduced by reducing the clearance between the punch tip and die wall. In addition, a narrow tip width can help reduce the generation of friction and a deeper sharp relief for the lower tip can be more effective at scraping excess powder away from the die bore wall.

Another problem occasionally encountered is the appearance of tablet defects when a process is moved to production and the new tablet press has precompression capability, while the research and development machine did not. The proper adjustment of precompression should be studied in detail prior to writing the final tablet compression ticket. For a drug product formulation that has a high loading of API improper precompression setup can be a path to tablet quality problems. Active pharmaceutical ingredients are typically organic crystals that compact via a brittle fracture mechanism. Excess precompression force, followed by final compression, can result in the generation of a significant population of very small crystals that will not consolidate the same as when minimal or no precompression force is utilised. The function of precompression is to remove as much air as possible from the powder before final compression. This will, in conjunction with tapered dies, minimise problems with tablet capping. Proper setting of precompression requires the press mechanic to remove all pre- and main compression. Fill the press with powder and manually rotate the press while adding precompression force. Add this force until a tablet is ejected from the die. This tablet should look like a tablet, but fall apart when grasped. At this point the precompression is set and final compression added until the desired tablet hardness is realised.

Picking is a condition that refers to formulation becoming stuck in the letter or numbers of the tablet logo or identifier. Picking problems can often be addressed by modifications to the embossing letters or utilising compound cup configurations to improve compression in the deepest areas of the punch cup. Prepicking letter or numeral islands and isolated areas, as well as tapering the engraving cuts for some letters, will often alleviate picking problems. Consider running a fullscale performance lot, including tooling stations with different prepick and taper, to identify potential picking and sticking

The use of the proper fill cam is often overlooked during scale-up of the tableting process. All too often a tablet press is utilised with whatever fill cam is installed, and as long as conditions can be set to hit the desired weight and hardness targets, all is good. This works until operators start to see excess powder accumulating on the die table as a result of too much powder being pushed out by the dosing cam. Recycled powder re-enters the feeder and is blended once again with virgin material. Depending on the particle size distribution and the propensity of the API crystals to fracture, Autumn 2016 Volume 8 Issue 3

a fraction of the blend is now smaller and may adversely affect the quality of the tablets. The smaller particles can change the die fill dynamics, as well as contribute to the loss of small particles to the space between the punch tip and die bore. Very small particles (<10 µm) can start to accumulate in scratches and digs in the punch cup surface, leading to film formation in the cup, which is a first step toward sticking. Improper fill cam can also impact the variability in fill weight and tablet hardness as different press speeds are utilised. Different press speeds will require adjustments to the feeder speed in order to meet tablet physical property targets. Studies performed as part of a scaleup performance lot, and done with an improperly selected fill cam, can be compromised if the fill cam is changed at some point down the road. As well, feeder speed adjustments may not be as intuitive as expected. If modified feeder paddles were utilised during development to address problems with die filling of a formulation that is cohesive in nature, the same type of feeder paddles will be needed for full-scale production. Excess powder recycle, courtesy of an incorrect fill cam, can impact variability of tablet weight control and blend uniformity at different press and feed frame speeds. Proper fill cam selection is a simple step, often ignored, that can stave off problems in the future. For drug product developers that would prefer to minimise the steps from concept to registered dosage form, the previous suggestions likely describe undesirable diversions of time and resources. The previous recommendations may prove valuable

DEC_IPT_148x210+3_09-2016.qxp 12.09.16 11:03 Seite 1

for those that want to minimise the steps to a state of controlled manufacture with minimum deviations. For a perfect system work is independent of path, but not necessarily independent of regulatory pain.

Dr Charles Kettler received his BS degree in chemistry from the University of Arizona and his PhD in analytical chemistry from the University of Tennessee, studying laser-based detectors for open tubular liquid chromatography. He has worked in the area of process analytical technology (PAT) for more than twenty years in the chemical and pharmaceutical industries, implementing off-the-shelf and custom-designed measurement systems for process control. His current interest is the utilisation of innovative technology to better understand and control the unit operations involved in tablet manufacturing. Dr Kettler is currently Director of Natoli Scientific, a division of Natoli Engineering Company, Inc.

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Packaging The Future of Serialisation Software is Modular and Scalable The regulations governing the serialisation of medicines are becoming more complex and extensive worldwide. Pharmaceutical companies and packaging service providers are obliged to give consideration to this landscape when selecting an appropriate software and database solution for serialisation and track & trace applications. They must seek to identify a solution that complies not only with all the current international requirements, but also with future needs. The criteria to be applied when selecting a serialisation product are outlined below. Introduction When selecting a suitable serialisation software, it is crucial for pharmaceutical companies and packaging service providers to ensure that it not only satisfies the existing serialisation regulations, but is also capable of accommodating changing requirements. This applies in particular in view of the increasing complexity and scope of the serialisation projects and specifications that are currently being initiated and implemented in many nations across the globe. It is essential to understand that a supposedly quick and easy solution can have a detrimental impact on productivity, efficiency and security in the packaging and labelling process. Given the constant consolidation of requirements and processes, it can prove impossible to make changes quickly, and additional costs can be incurred. Preference is to be given to software whose system architecture can expand to accommodate growing requirements and future needs both regarding regulation and workflows. As a general rule, the serialisation software is the most crucial component of a serialisation project and is therefore not to be regarded as merely an adjunct to hardware components or an update for existing programs. But what criteria should a user apply when searching for an appropriate serialisation software solution? Which are the most important factors? The discourse that follows provides some answers and serves as an aid to decision-making.


Broad Range of Applications The serialisation of drug packaging, which will become mandatory in the USA from November 2017 and in the EU from February 2019, and is already prescribed in China and Turkey, presents a major challenge to pharmaceutical manufacturers and packaging service providers as regards suitable databases and software solutions. In the past, companies implementing a serialisation project for the first time often focused on the hardware required within a packaging line to apply, inspect and, if applicable, save locally the relevant codes with serial numbers on secondary packaging on ISA-95 Levels 1 and 2 (machines and single packaging lines). It is now considered better practice to give closer consideration at the outset to the appropriate configuration of a database solution that is capable of reliably controlling and managing the necessary processes also across multiple lines (Level 3), sites or even company-wide (Level 4) (see Fig. 1). The list of requirements is long. It

ranges from the secure generation, management and storage of serialisation and aggregation data, as well as their transfer to national authorities, wholesalers or logistics partners, to the integration of existing or new hardware components and simultaneous production management for multiple lines. At the same time, data security must be ensured and productivity maintained. Against this background, many pharmaceutical companies and packaging service providers have serious concerns relating to reliable implementation. In most cases it becomes evident that an 'off the peg' software solution is unable to offer compliance with the complex and diverse requirements of serialisation and track & trace applications. Wide-ranging Needs The problem is well illustrated by way of an example. Pharmaceutical company A produces an expensive cancer drug in relatively small quantities on a single packaging line, but distributes it worldwide and has to comply with numerous country-specific regulations. Contract packer B, in contrast, packages

Figure 1: Serialisation software on Level 4 controls and monitors all Level 3 systems as well as contract manufacturing organisations (CMOs). It can also exchange data with both the internal ERP system and customers (wholesalers). Other important aspects are the central data repository for serial numbers and aggregation hierarchies, the exchange of data with country hubs, and the generation of transaction statements. (All graphics credited to Atlantic Zeiser GmbH.) Autumn 2016 Volume 8 Issue 3

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Packaging an existing enterprise resource planning (ERP) system, the serialisation software must have appropriate interfaces, and a suitable process has to be defined. If an interface to an ERP system is not required, the software should be able to generate the orders and manage them efficiently, even in complex cases. Figure 2: Pharma companies and CMOs that serialise drug packaging must be able to comply with the vast array of different code formats and standards that exist worldwide.

medicines for a variety of customers in large quantities, but the products are destined exclusively for local distribution. Both companies must address the issue of serialisation – but their requirements concerning processes, workflow and data transfer could hardly be different. At the same time, neither company A nor company B is usually able to rule out having to offer a completely different range of services, even at very short notice, as circumstances change. It therefore follows that the software architecture of serialisation and track & trace solutions should be sufficiently modular to allow flexible configuration according to the individual user's processes and requirements. In the absence of modular architecture, the software has to undergo costly revision, which ultimately adds to the user's costs. Given the certainty of future changes to processes and regulations, the ability to expand functionality and increase the scale of processes (e.g. the number of lines or aggregation levels) are also highly important factors – as illustrated by the most recent developments in China and Brazil. If the software is unable to accommodate such changes, significant additional costs can arise each time the serialisation or packaging process is modified. Furthermore, the software has to be completely revalidated, which in many cases represents the bigger cost factor regarding the need of time. Analysing Existing Processes To identify an appropriate software and database solution, the first step should be to conduct an internal examination and analysis of the existing packaging process. Key questions in this connection concern where customer orders and production orders are initiated, and how the serialisation data are reported back to authorities. If this is to be done through 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Another important criterion for the software solution can be the visualisation of warehousing or logistics processes, as required when repackaging and making up consignments for wholesalers – especially when aggregation is required. No matter whether one or several medicines are being produced and packaged at the site, the complexity of the operation increases as soon as the product has to be exported to several countries where different regulations

by the serialisation software. In addition, some regions prescribe consecutive serial numbers, while others apply the random principle (see Fig. 2). The general rule applies that serial numbers belonging to a defined range cannot be issued more than once. The numbers can be based on a Global Trade Item Number (GTIN) – an identifier for trade items developed by the not-for-profit organisation GS1. As a consequence, the serial numbers contained in the codes must be held on file for a long, predetermined period. It may also be necessary to run comparisons in order to recognise duplication if the numbers are allocated by an external source, as was the case in China and is envisaged for the future by Russia. Depending on the region, the serialisation data may have to be stored for at least six months beyond the medicine's expiry

Figure 3: Integrating camera systems and scanners enables serialisation software to visualise the aggregation process across numerous stages. For smaller batches, manual packing tables with integrated cameras are a good alternative.

Figure 4: Modular serialisation software allows individual modules to remain inactive until they are actually required.

apply. In China, the serial numbers are recently provided by the authorities, in the EU or US, they have to be generated

date or even for several years beyond the production date. This aspect is not to be underestimated, including when Autumn 2016 Volume 8 Issue 3

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Packaging and repeatedly revised. The capabilities of a prospective software solution become apparent at the latest when production orders are to be allocated to multiple packaging lines at the same time. In this context, the complexity and necessity of a production management platform soon become apparent. Capable serialisation software should be able to oversee the production of a single batch on multiple lines at the same time without any risk of serial numbers being duplicated – even in the event of technical malfunctions and line restarts. The chosen solution should likewise be able to redistribute current jobs if relocating production at short notice. Figure 5: Schematic of the serialisation software functions required to model the ISA95 Level 1, 2 and 3 processes reliably. storage capacity is being specified for the necessary servers and other hardware. It is to be assumed that the currently valid or imminent coding principles in individual countries and regions will be revised sooner or later, and that additional countries and new regulations – Russia is on the horizon – will need to be accommodated. If it is to be future-proof, the software solution must therefore be designed so that it can be adapted to suit changing circumstances. The greater the extent to which the serialisation and track & trace processes can be configured inhouse without any programming, the faster the response and the lower the costs when changes need to be made. Secure Aggregation at Every Level Many countries prescribe not only serialisation, but also aggregation of the secondary packaging into packaging hierarchies in order to allow the seamless tracking of medicines throughout the entire logistics chain – thus accomplishing an end-to-end track & trace capability. This entails comparing the previously serialised individual packs against the serialisation database during the manual or mechanised packaging process, in order to produce what are known as parent-child relationships (see Fig. 3). In the case of packaging by machine, note that defective and illegible packs can repeatedly impede successful aggregation and will need to be exchanged manually at the end of the 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

process. If necessary, the serialisation software must also be able to model these operations on Level 3. At the latest, for the purposes of repackaging and order picking in the warehouse, it should be possible partially to dissolve or redefine the originally established child-parent relationships. For users who already, or may in future, export to countries where a track & trace capability is mandatory, it is essential that the software and database solution accommodates these aspects. Such a requirement already exists in Turkey and is scheduled for implementation soon in the USA. Protocols like EPCIS from GS1 seem to be a good standard for information interchange within the logistics chain. A suitable software solution should be prepared for that. Management Platform for Production Before the process of serialisation and, if applicable, aggregation can begin, the relevant serialisation data for the individual products have to be defined as the basis for generating specific production orders with batch data and expiry dates in a further step. In the interests of maximising process security, the serialisation software should eliminate a particular source of errors – the human factor – as far as possible. When new product-related serialisation schemes are being created, for example, cross-checking and a release process involving several people are advisable. The software should allow such release processes to be configured accordingly

Integrating Existing Machinery If an enterprise already possesses an inventory of serialisation and aggregation machines, for reasons of economy the serialisation software should be capable of accommodating hardware components sourced from a wide variety of manufacturers. Bilateral communication between the machines and the software is essential because, apart from the regular transfer of codes and serial numbers, additional information also needs to be shared, such as user data or log files, to allow the central generation of audit trails. Another conceivable scenario is the addition to packaging lines of functions or modules at a future date, either in order to increase efficiency or in response to changed market requirements, e.g. to facilitate the application of tamper-proof labels. In this particular case, it would be good practice to be able to record and store the linking of a serial number to the successful dispensing of a sealing label. The software architecture of a suitable solution should therefore be structured to allow the functionality of packaging lines or individual machine modules to be both expanded simply at any time and visualised economically and quickly – again also in respect of validation. In addition, of course, all the data exchanged between the machines and centralised software should be easily exportable from the system, depending on the user's requirements – whether relating to completed products with serial numbers, aggregation hierarchies or audit trails. Here again, an interface to the ERP system, as mentioned above, can Autumn 2016 Volume 8 Issue 3


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Packaging be a useful resource if needed. Most companies with multiple production sites that initiate a pilot project are likely to focus initially on a single line and ISA Level 2. In every instance, however, the expandability of a software solution's functions to encompass ISA95 Levels 3 and 4 should be thoroughly explored and mapped out for the future from the outset. If the chosen software is unable seamlessly to grow along with your needs, significant additional project costs can arise in the medium term. The availability of diverse interfaces and data formats for transferring the serialisation data to central databases on an international basis (hubs) is a further key point to bear in mind when procuring and installing software. Although governments have yet to resolve many of the details, and hubs are still being established, there is no reason to postpone the acquisition of centralised serialisation software. In fact, these circumstances represent another argument in favour of attaching the utmost priority to ensuring that the software solution can be modified at a later date, irrespective of whether data are subsequently to be transferred directly to the hubs and, if applicable, distributors, or indirectly by way of the ERP system. Close scrutiny is likewise warranted in respect of both the data encryption methods and the general security standards applied in order to prevent unauthorised access to the database and illicit data transfers. Note that the entire IT infrastructure must be appropriately configured for this purpose as well. Managing Data with Intelligence and Legal Certainty The greater the number of lines and ISA-95 Levels that are to be operated by centralised serialisation software, the more important it becomes to implement intelligent user management. User rights are best managed by way of groups to which the individual users can be assigned. In this context, of course, compliance with general standards, such as CRF 21 Part 11 of the US Food and Drug Administration (FDA), is to be ensured. Interdisciplinary Project Team and Time Requirements It is essential that internal processes are thoroughly analysed and all current and 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

future requirements are defined before serialisation software is purchased, or even put out to tender. For this purpose it is highly advisable to establish an interdisciplinary project team assembled from various departments (IT, production, logistics, engineering, quality management, validation, packaging design). Sufficient time should also be allocated to such a complex project, but pressures are likely to increase in view of the approaching effective dates of statutory regulations and foreseeable capacity bottlenecks among software and hardware suppliers. Depending on the ISA-95 Levels that are to be implemented, a period of up to 24 months should be allowed from the start of the analysis to completion of the pilot phase, including procurement, implementation, validation and training both fore software and hardware. It must also be borne in mind that external partners, such as packaging printers, contract packers and, depending on the market, wholesalers, need to be integrated in the process as well, and that the relevant processes need to be defined and interfaces created in good time.

which are also managed by way of the software, satisfy the requirements of the relevant production job. The lines report the production outcomes or results to the database, from where they can be exported together with audit trails and, if necessary, encrypted and transmitted to the relevant authorities' databases or wholesalers. In the interests of enhancing its performance capabilities, the database can hold large quantities of data. Figure 5 alone illustrates that ISA Levels 1, 2 and 3 entail a high degree of complexity, which increases further when ISA Level 4 is implemented as well. A scalable software solution capable of easily assimilating additional functions, operation levels and aggregation levels is therefore essential.

Generally speaking, the following holds true as regards the quality of prospective centralised serialisation software: the greater the modularity of its structure and the easier it is to make adjustments at process level concerning the integration of machines, the more future-proof the solution is likely to be (see Fig. 4). Possible Workflow up to Level 3 Figure 5 is a schematic representation of the procedure to be followed for serialisation, using the example of a special software solution – it is valid for a single line or multiple lines (up to ISA95 Level 3). The tasks and functions of the software are shown against a yellow background. The production orders are generated in an ERP system and forwarded to the serialisation software. At the same time, serial numbers are either imported to the database from an external source and checked for nonduplication, or generated directly by the software. On the basis of predetermined product definitions – stored in the software after multiple cross-checking if necessary – batch-specific production jobs can then be generated and allocated to one or several packaging lines. The only available lines are those whose technical attributes,

Michael Urso holds a marketing degree in business administration and has been working for Atlantic Zeiser GmbH in Emmingen since 2014. As product manager in the Pharma & Packaging Solutions division, he is engaged in the marketing and further development of solutions for serialisation and track & trace applications. Among his specialisms are the late-stage coding and printing of pharmaceutical labels. He has prior experience as a product manager, strategic marketing manager and project leader in several medical technology companies. Michael Urso, Atlantic Zeiser GmbH, Emmingen Address for correspondence: Michael Urso, Atlantic Zeiser GmbH, Bogenstrasse 6–8, Emmingen, Germany E-mail: Autumn 2016 Volume 8 Issue 3

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Packaging Improving Patient Adherence through Packaging

For the past several years, government leaders, politicians and executives from major pharmaceutical providers have been working together to increase efforts to protect citizens from counterfeit medications through regulation. Countries including China, Turkey, South Korea, the United States and the European Union, just to name a few, have been developing and publishing legislation for implementation within their respective territories. This has led to a particular focus on topics such as serialisation and tamper verification. Implementation of such new legislation may require significant change on the part of manufacturers – from packaging to business structures, IT systems to supply chain management. However, despite the administrative or financial challenges that they may face, it is important that the transition is seamless from a consumer perspective; in particular, in meeting new regulatory demands – such as the EU Falsified Medicines Directive (FMD) – manufacturers must not affect the user experience and hinder patient adherence. After all, the objective of the legislation is to ensure that patients have access to genuine drugs, and – when taken properly – these products can improve their lives. Patient adherence describes the extent to which a person’s behaviour – for example, taking medication, following a diet or executing lifestyle changes – corresponds with agreed recommendations from a healthcare provider. Alarmingly, this is already a major challenge: the World Health Organisation (WHO) reported that there would be more worldwide benefits from improving adherence to existing treatments than from developing new ones. Indeed, approximately 50 per cent of patients with chronic diseases in developed countries do not take their medication as prescribed, and this figure is even higher in developing countries.1 In addition, a low level of patient adherence places a financial strain on the healthcare sector; for example, research shows that patients not taking their medicines properly costs the United Kingdom’s National Health Service £500 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

million a year. To put it in perspective, this is broadly equivalent to funding 30,000 kidney transplants or an additional 21,000 qualified nurses.2 The WHO highlights ‘five interacting dimensions’ that affect adherence, explaining that patients are not solely responsible for not taking their treatment. They suggest that there are other factors that affect peoples’ behaviour and their capacity to be able to stick to their treatment regimen, which are split into five categories: socioeconomic factors, factors associated with the healthcare team and system in place, diseaserelated factors, therapy-related factors and patient-related factors.1 Packaging has the opportunity to improve adherence from a user perspective, with the WHO stating that patient-related factors refer to ‘the resources, knowledge, attitudes, beliefs, perceptions and expectations of the consumer’. Therefore, one way to increase the number of people who take their medicine correctly is to provide additional information and detail, to ensure patients have fuller knowledge of their treatment and thus help to avoid misunderstanding. The way in which the information is delivered is also important to increasing understanding; for example, the use of graphics and illustrations alongside thoughtful layout and organisation of material can improve comprehension. Trends towards long form instructions also pose both an opportunity and a challenge for drug owners, as consumers not only want more information but also more variations of it (such as the same information in different languages or using graphics as well as words for easier access). Popular ways to increase space for information, without compromising the size of the packaging, include the use of extended content labels, booklet labels and leaflets. Extended content labels are an efficient way to add further detail to medicine bottles, allowing patients to peel the labels back to access more

information. These labels can be ‘peel and read’ or ‘peel and reseal’ – the difference being that the latter can be resealed multiple times throughout the lifetime of the product. Similarly, booklet labels are ideal for medicine bottles, allowing patients to scan through multiple pages of additional information about the product. From a carton perspective, the inclusion of a multi-fold leaflet is fairly standard; however, opportunities exist for innovation as well. These leaflets can deliver several pages of information in multiple colours and, as they can be set out in a booklet format, patients can open and flip through pages easily to find exactly the information they need. With this increased space, packaging can also incorporate supplementary information – such as ingredients, the efficacy of the treatment and possible adverse side-effects – all of which should encourage patients to take their required medications. For example, according to a recent poll by the ‘Let’s Take Care of It’ campaign and Omnicell, 36 per cent of British adults believe that if the costs of medications to the NHS were provided on the packaging – a current government proposal – they would be more likely to take their drugs properly.2 Overall, information should not only be educational to instruct patients on what is included and how they should consume the product, but also reassuring to ease any concerns that they may have about taking the drugs. Though the inclusion of innovative labels and booklets provides the space for inclusion of additional information, they can also provide a secondary aesthetic advantage. Peelable labels are more impactful and interactive than words simply printed one-dimensionally. Their ability to be opened, reviewed and resealed provides a more tangible and memorable experience. In the report by the ‘Let’s Take Care of It’ campaign and Omnicell, it was found that 66 per cent of those aged 55 or over said that they always read the label on their medicines, whereas amongst young adults aged 18 to 24, this figure drops Autumn 2016 Volume 8 Issue 3



In conclusion, the best way to improve patient adherence is to employ multiple intervention techniques. As a global leading supplier of pharmaceutical packaging, Essentra advocates a strategy of using several layers of solutions to maximise the intended patient outcome desired. With the EU FMD coming into place in 2019, the likelihood of patients receiving genuine medication should increase – the pharmaceutical industry must now place its efforts into ensuring that their patients take these authentic products correctly.

to 46 per cent. Plus it was noted that one in ten mentioned that they never read the instructions at all.2 This suggests that current instructions are not engaging enough to read. More aesthetically pleasing and interesting formats will encourage patients to engage, thus improving patient adherence. Secondly, in addition to a lack of knowledge, the WHO also cites ‘forgetfulness’ and ‘inadequate skills of managing treatment’ as patientrelated factors that negatively affect patient adherence. It is one thing for patients to understand the need and benefits of taking the medication at the correct intervals; it is another for them to remember to physically consume them. This conundrum presents another opportunity for packaging manufacturers to change: by introducing products that help indicate dosage unit and dates. Calendarised packaging is a popular solution to solve forgetfulness, particularly for once-daily, long-term medication. By printing dates by each pill in the blister pack, calendarised packaging acts as a visual reminder for patients. It also reduces dosing errors; as patients are instructed to take one pill per day, it reduces the chances of them overdosing or missing a dose. Furthermore, calendarised packaging is often packed into 7-, 14- or 30-pill blister-packs to correspond to dosage cycles that last a week, a fortnight or a month, respectively. By clearly providing the exact amount of medication that is required, the pack encourages patients to take the entirety of the contents and manage their

consumption throughout the dosage cycle. This positively impacts medication persistence – the act of continuing the treatment for the prescribed duration from initiation to discontinuation of therapy. The Healthcare Compliance Packaging Council (HCPC) describes calendarised packaging as an ‘active’ solution; its use leaves evidence of dispensing that provides feedback to both the patient and caregiver. On a more sophisticated level, microchips can be incorporated into these calendarised blister-packs to enhance adherence with the use of innovative technology. These can be added to detect if and when medicine has been taken, beep to notify patients to take their medicine, or even record responses to basic monitoring questions. The data that is recorded can then be downloaded onto the patient’s mobile device, allowing them to manage their own therapy and share the data with their doctors. The HCPC describe this type of packaging as an ‘interactive’ solution as it provides feedback and elicits a response from the patient. It is clear that packaging can both inform and support patients, generating a positive impact on adherence. However, it must be noted that packaging cannot tackle the problem alone. While it provides a platform to improve adherence from a ‘patient-related factors’ perspective, there are often other external, social and economic factors that affect adherence. Therefore, packaging must be included as a part of a wider solution to address this major public health challenge.


References 1. World Health Organisation, ‘Adherence to long-term therapies: evidence for action’, 2003: http:// publications/adherence_full_report. pdf 2. ‘Let’s Take Care of It’ campaign and Omnicell, ‘The True Cost of Medication Non-Adherence’, 2015: wp-content/uploads/2015/10/ The-True-Cost-of-Medication-NonAdherence-Report.pdf

Rupert Taylor joined Essentra in 2014 in the role of Global Category Manager Household, Food & Drink, he is now Global Category Manager Healthcare & Personal Care. His role there is to identify customer & consumer needs in the market place & deliver those solutions through the Essentra portfolio of packaging, components, special technologies & security & authentication. Prior to joining Essentra Rupert worked as Marketing & Innovation Director for Puratos Brazil, where he delivered growth via category management, pipeline development & consumer insights. Rupert’s experience spans from food & beverage ingredients, to flavours & fragrance & dairy companies, & he has over 20 year career of delivering results in both B2B & B2C environments on a global basis. Email: Autumn 2016 Volume 8 Issue 3

Carefully Crafted Our drug delivery devices are skillfully developed from extensive in-house knowledge, generations of experience and a passion for research and innovation. We care about our


craft, just as we care about your business and the patients who use your products.


Serialisation Ensures Security Against Counterfeiting Waldkirch, Germany. Product piracy is a serious problem in the pharmaceutical industry. If the customer is sold a counterfeit drug, he or she will not only lose confidence in the product, but in the brand as well. There is also a risk of harm to health. But this can all be prevented. There are now numerous ways to protect both the consumer and the company’s own brand, while standing up to counterfeiters. Beginning in February 2019, all prescription medicinal products in the EU must be provided with a security feature allowing wholesalers and pharmacies to verify product authenticity.

may have to be utilised depending on the cardboard material used and its finishing. Also, the code itself determines the choice of material and the printing method. The 1D code (China code), for example, does not easily allow for defects in the print image. If a line is missing or if the bar-space ratio is not correct, the meaning of the code will change. For the 2D data matrix code required for anticounterfeiting protection by the new EU directive, up to a quarter of the code can be missing, without information concerning the content being lost. The code can still be completely read out.

The security feature – in the form of a 2D data matrix code – aims to guarantee packaging traceability spanning the entire supply chain. Along with the product code to identify the medicinal product and the maximum 20-digit serial number, the code includes a national reimbursement or identification number, the batch number and expiry date. In addition to the machine-readable code version, the product code as well as the serial and reimbursement number must be in plain text and displayed on the packaging in a format that can be read by humans. A tamper-evident packaging seal completes the directive’s requirements.

The serialisation of adhesive labels is even more complex. While a manageable number of the carton board grades available on the market are used for a majority of pharmaceutical packaging for folding cartons, and inkjet or laser printing are primarily used as printing methods, the material diversity of the paper and plastic films used for labelling is significantly greater. Additionally, the printing methods are more numerous. Even the manufacturing process for labels is substantially different to that used for folding cartons. While the punched boxes are separated for the coding process, the labels run through the printer from a roll. The film must be held under tension during printing. It is therefore slightly stretched for this purpose and then returns to its original shape. This needs to be taken into consideration with regard to the legibility of the printed code. Moreover, the code on adhesive labels must remain completely machinereadable, if the label is positioned on a bottle, for example.   Two Technologies, One Single Code A recent project at August Faller GmbH & Co. KG called for great expertise and creativity in both areas. For a customer who provides veterinary products to China, the serial QR code required by the Chinese authorities had to be printed on both the folding cartons and the labels. In addition to the serial number, the code contains the product name, a registration number, the manufacturer and a telephone number for emergencies – and all this in Chinese characters. The project faced two major challenges. On the one

A Highly Complex Process Necessitates Extensive Know-how What sounds comparatively simple is in reality a highly complex process that is influenced by many variables. Along with the product to be coded – folding carton or adhesive label – their materials, the code to be printed, the printing technology as well as the operating speed of the packaging line play a crucial role during serialisation. All parameters must be perfectly aligned to guarantee pharmaceutical security through the use of legible code, without allocating duplicate serial numbers on the packaging. Only then can the required print quality of at least 1.5 in line with the ISO/IEC 15415:2011 standard and thus Grading C be achieved. But not every folding carton board can be printed with every printing method equally well. Another method


hand, the camera system verification had to be taught to read Chinese characters. And on the other, the same serial coding had to be applied using two different technologies on two different products. The coding for the folding cartons was performed using UV inkjet printing at the Pharma Service Centre in Waldkirch. The labels were coded in the Schopfheim plant using digital printing which is characterised by multi-colour capability and high image quality. As a result, it was an ideal option to apply easily legible Chinese characters. Alternatively, adhesive labels can also be serialised during the thermal transfer printing process in Schopfheim. Here, thermal transfer printing is particularly suitable for the Belgium label. Coding Folding Cartons Flexibly Faller has been printing various codes on a wide variety of folding cartons at the Pharma Service Centre in Waldkirch for several years now. The company has great expertise in this field and scores top marks with both a quick application of the code – the system operates at a speed of up to 60 m/min – and a high quality of the printed image. The coding system consists of a UV inkjet printer based on DOD technology (drop on demand) with a resolution of 360 dpi and environmentally-friendly LED drying technology. Coding, serialisation and verification, as well as the printing process, all run on this machine. The camera-based, in-line inspection reads the grading following the ANSI standard and enables codes that do not meet the required grading to be exported. Testing of print quality is carried out in the subsequent process step in accordance with the ANSI/ISO standard. The

For labels, the code must also be clearly legible if positioned on a bottle. Autumn 2016 Volume 8 Issue 3

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Packaging The variable data can be applied as a 1D barcode or as a 2D data matrix code, in plain text. The system processes grammages from 230 to 600 grams. The width of the coding QR code, plain text and Chinese characters on a folding field can be up to carton – not a problem for the coding system at the Pharma 72 mm. The special feature is the high level Service Centre in Waldkirch. of independence from material quality that arises through the use of UV print systems. All common styles for the folding cartons can be printed. The maximum width of the blanks is 450 mm. Flexibility is also self-evident in the positioning. The code Flexible code positioning: With its coding system, Faller can can be printed on apply the required code to any desired position on the folding the folding carton at carton. any desired position. And quantity does not minimum grading required for the EU’s play a role in the process: Faller prints 2D data matrix code is Grading C. both small and large volumes and can

Sensors in the serialisation system guarantee a safe, seamless coding process implement varied country requirements for serial coding. Faller has integrated inhouse software to manage the numbers internally which, in turn, guarantees the uniqueness of each code number. Consulting and Services August Faller GmbH & Co. KG is pleased to share its expertise with its customers. The leading provider of pharmaceutical secondary packaging develops the best combination of code, material and printing technology with them in order to code and package tamper-proof drugs. By outsourcing the packaging and/or coding processes to Faller, customers in the pharmaceutical industry can considerably reduce their own workload and accordingly, costs and time. © All photos: August Faller GmbH & Co. KG

Tanja Feldmüller, Head of Business Intelligence & Marketing Born in 1974, Tanja studied English and Media Consulting, has an MBA in International Marketing as well as a C-Level certification IPMA in Project Management. She entered August Faller Group as Head of Marketing & Product Management in 2009 and is responsible for the newlyestablished unit Business Intelligence & Marketing including the innovation activities of the packaging solution provider since March 2015. E-Mail: tanja.feldmueller@august-faller. com 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2016 Volume 8 Issue 3


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Packaging Manufacturing Change

Interview with Gregor Deutschle, Business Development Manager for SCHOTT’s RTU platform adaptiQ®. What are today’s key challenges facing biomanufacturing? We hear from our customers that flexibility is what matters most to them. This applies especially to the biotech industry, which is moving towards personalised drugs. The volumes involved are too small to lend themselves to traditional highvolume production methods. To be truly flexible, new concepts are needed, and all elements must work seamlessly in systems up and down the value chain.

Can you give an example? Our customers require us to have intimate knowledge of their processes. As a supplier of primary packaging, it is our aspiration to be aware of any critical issues in biotech filling. At the same time, the tighter regulatory framework requires pharma companies to become more involved with packaging-related questions. That, in turn, is where we have our focus. Working together can only help us to improve quality in every patient's best interest.

What does SCHOTT’s adaptiQ® look like?



Ever since we introduced this concept to the market it generated great interest within the industry. As of today 6R, 10R, 20R and 30R ISO formats are available. We are continuously extending our range and will complete the 2-30R portfolio by Q1 2017. Our strategic vision is to provide the best value for the customer, while helping to advance the technological state of aseptic processing.

How do ready-to-use (RTU) systems fit into this picture? Pharma companies need an option for supplying small volumes with incredibly precise requirements, and RTU can help. If they can fill several types of packaging on the same filling lines flexibly without long set-up times, this will make them more efficient and lower their costs. RTU formats are key to enable small-volume, high-changeover products. How is the relationship between customers and suppliers changing? The age of purely transactional partnerships seems to be over. Governments, pharma companies and the industry as a whole expect that suppliers and customers work together as partners.


Autumn 2016 Volume 8 Issue 3

Aptar Pharma: your global solution provider of innovative and proven aerosol, injection, spray and dispensing systems. Our products and services add value to your biotech, healthcare and pharmaceutical products. We provide a wide range of delivery technologies and analytical services backed by decades of proven expertise.

Review 2017 Arab Health Exhibition and Congress Arab Health is the second largest healthcare exhibition and congress in the world and the largest in the Middle East. 2017 marks the 42nd year taking place from 30 January – 2 February in Dubai, United Arab Emirates. It offers important opportunities to showcase progress and achievement in the life science and healthcare sectors, along with being able to explore new opportunities with stakeholders in the healthcare field from around the MENA region (Middle East and North Africa). "Arab Health is a great first step to any life science company thinking of entering the MENA region because it provides a lot of information, insights and opportunity to network," Paula Hassoon, CEO Global Pharma Consulting, says. Middle East and North Africa According to the UK Ministry of Defence’s Strategic Trends Programme Global Strategic Trends - Out to 2045 publication, MENA’s population is expected to increase by around 230 million by 2045, to approximately 670 million. North Africa accounts for about six per cent of the world’s population, with an average annual growth rate of 1.7%. This makes MENA an attractive place for life science companies who provide solutions for a growing population with a demand for healthcare facilities, pharmaceuticals and the means to combat lifestyle illnesses such as obesity and diabetes. The region is welcoming of cutting-edge technologies and innovations and focused on implementing smart and cost-effective solutions for healthcare. Worth the Trek The Arab Health Exhibition and Congress attracts a wide range of visitors across the spectrum of healthcare, including medical manufacturers, general practitioners, hospital doctors, hospital managers, hospital nursing staff, hospital technical managers, laboratory managers, physiotherapists, medical assistants and dealers and distributors. “I have been visiting Arab Health for three years and it’s the ideal destination 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to meet my customers from all over the world - very successful!”, Dilara Koksal, Export Manager, Pharmasent, Turkey reports. The exhibition is free to attend. The 2016 exhibition showcased more than 4000 companies exhibiting their latest innovations to more than 130,000 healthcare professionals attending from 163 countries. Sajith Kumar Menon, Director, Virgin Methods, LLC, USA attended last year and said, “Arab Health 2016 has been a great experience; it has all the updated information and new technologies from the industry. It is definitely the best healthcare exhibition I have ever attended.” Arab Health also provides exclusive networking opportunities and the ability to arrange one-to-one meetings with decisionmakers. “I visited Arab Health to meet up with suppliers and see what is new; I would recommend my peers to attend the event even despite the long travel,” Roger Davis, Chief Executive Officer, ATX Medical Solutions, Australia says.

international healthcare companies. Those include How to Conduct an Effective Clinical Simulation Training, One Stop Clinic, Relocatable Solutions from GE Healthcare and Clinic-in-a-Can, Effective Health Technology Management & Planning, PETCT Practise: Beyond FDG, Innovations in Interventional Hybrid Operating Rooms, Internet of Things (IoT) in Medicine: Tesodev Baby News Project Workshop, Performance Characteristics of GE Discovery PET/ CT Scanners Using NEMA Standards, Total IV Medication Administration, Dell Healthcare Showcase, Why Finland Seminar, Proton Therapy - The Future of Radiation Treatment, Treating with Protons - Sample Tumor Board (Bring Your Patients’ Cases), Build Your Own Proton Therapy Center, and Build Your Own PET Center. Submitted by LucyJRobertshaw



Conferences One reason medical professionals in the region attend the Arab Health Congress is due to its reputation for providing the highest quality of continuing medical education (CME) in MENA. 2017 conferences include 3D Medical Printing (30 January - 2 February), Big Data (31 January - 1 February), Business Forum (30 January - 2 February), Emergency Medicine (1 - 2 February), Leaders in Healthcare (2 February), Nutrition and Wellness (31 January), Oncology (30 31 January), Orthopaedics (30 January 2 February), Pediatrics (30 - 31 January), Preventive Medicine (1 - 2 February), Public Health (30 - 31 January), Quality Management (1 - 2 February), Surgery (30 January - 2 February), Total Radiology (30 January - 2 February) and Workforce Empowerment (1 February). Workshops There is also a selection of free workshops available for all healthcare professionals offering learning and training opportunities from leading Autumn 2016 Volume 8 Issue 3

Preview CPhI Worldwide: Barcelona 4-6 October 2016

Welcome to the 27th CPhI Worldwide, the global platform to mix with the world of pharma products, people and solutions. It has been another great year for pharma, with major growth across the industry returning, but also a very exciting and significant year for CPhI. This year we announce three major firsts: the introduction of two new events to the CPhI family – Finished Dosage Formulation (FDF) and CPhI North America – and the inaugural visit of our Worldwide event to the colourful city of Barcelona. The entire pharma community will gather to showcase their services and the latest research, and debate key industry issues, converging with leading decision-makers and innovators across the industry. Chris Kilbee, Group Director Pharma, UBM EMEA Event Overview Distinguished pharma executives from all over the world will gather at Fira de Barcelona Gran Via from 4-6 October, for three days of collaboration, information dissemination, and discussions that will define the future of the industry. This year’s edition welcomes 37,000 expected attendees from over 150 countries and 2500+ exhibitors. At CPhI Worldwide there will be over 20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma, machinery, and many more. Running directly alongside the pharmaceutical ingredients halls are four other co-located brands: • ICSE is an outsourcingfocussed event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs, bringing the contract community together under one roof. • InnoPack connects buyers and specifiers from the packaging and pharmaceutical industries, showcasing all the newest innovations in pharma packaging. • P-MEC Europe features exhibitors from traditional large-scale capital equipment to companies focussed on instrumental analysis, measuring and

testing technologies, materials testing, laboratory and quality control. Additionally, Finished Dose Formulation (FDF) will launch as a new, co-located event – a dedicated platform for every aspect of the finished dosage supply chain – attracting deeper collaborations and new audiences. FDF will gather exhibitors from big pharma and CMO, to out-licensing and dossier specialists, end product distributors, generic pharma companies, and home markets. Beyond the exhibition, the CPhI Pharma Insight Briefings offer participants the chance to access a diverse range of specialised content through succinct 45-minute sessions, free for anyone attending the show. There are further content options in the returning Pharma Forum – a dedicated content village that provides thought leadership from media partners and the CPhI Pharma Insight Reports. On the CPhI website you can download all our recent Pharma Insight reports and the eagerly anticipated 4th CPhI Annual Report – released each year at CPhI Worldwide. The report is a comprehensive and critically important publication that analyses key trends and innovations forecast by our panel of world-class experts. The CPhI Women in Leadership Forum (Wednesday 5 October, 8-11 a.m., Conference Centre Five, Fira de Barcelona, Gran Via, Spain) welcomes female pharma professionals from across the industry to come together for an exceptional networking opportunity. The forum serves as a space for women to share their experiences, exchange expertise, and discuss effective leadership strategies. With a primary objective of empowering women in pharma, the agenda includes a panel discussion led by a diverse group of senior female executives and a session focused on career development advice. On October 3, the day prior to CPhI Worldwide, the 8th Annual CPhI PreConnect Congress will take place. This affords senior executives and influential speakers a vital high-level conference to analyse and discuss the most recent innovations, trends and market developments – through a series


of thought-provoking presentations, interactive panel discussions and dedicated networking opportunities. The agenda will run across three separate tracks providing market-led educational modules, networking opportunities and panel discussions across ‘Contract Services’, ‘Drug Delivery and Design’ (in Theatre One); ‘Pharmaceutical Ingredients’ and ‘Biologics & Biosimilars’ (in Theatre Two); ‘Finished Dosage & Generics’ and ‘Pharmaceutical Packaging and Serialisation’ (in Theatre Three). Alongside more than 100 free industry seminars, CPhI Worldwide sees the return of the one-to-one matchmaking programme. This platform allows attendees to find and connect with exhibitors and companies specific to their business needs. The event will also feature the Innovation tour, organised by IMS Health, which offers attendees a guided tour of the show floor, including the Innovation Gallery – a snapshot of the most interesting products at CPhI. The revamped CPhI Pharma Awards returns to the show for its 13th year, with four more categories than in 2015 – bestowing an impressive 12 awards to celebrate the best pharma achievements. The expanded awards have been created to give wider recognition to all the great advances and technologies coming out of the pharma industry. In the vibrant city of Barcelona, this year’s event is an unmissable opportunity for all the latest and most innovative advancements, thought leadership, and above all else, a platform to drive forward pharma business. Register now for CPhI Worldwide 2016 at: Or book exhibition space at: http://

Autumn 2016 Volume 8 Issue 3

Mix with the world of pharma, products, people & solutions

Co-located with:

4 - 6 October 2016 Fira de Barcelona, Gran Via, Barcelona, Spain


A new co-located event in finished dosage formulation Bringing every aspect of the finished dosage supply chain together in one global location, from Big Pharma and CMO, to in/out-licensing specialists, end product distributors, and end-user agents “Companies producing finished formulations need to partner and outsource more to get the correct mix of technologies, and this is where we saw a huge opportunity for CPhI to introduce a finished dosage event. What we are attempting to do is bring Big Pharma and CMOs, to in/out-licensing and dossier specialists, end product distributors, and generic pharma companies to one location so that our clients can easily identiy new brand partners.”

“Outsourcing for delivery systems is another key trend, as is partnering with more established companies in specific segments. For instance, if you only have a single oncology product, partnering and out-licensing with someone who has a wider dossier is a very good strategy.”

Alan Sheppard Principal, Global Generics and Biosimilars at IMS Health

Cara Turner Event Manager for Finished Dosage Formulation

WHY ATTEND FDF Everyone is talking about it Industry experts are talking about it

The Press is talking about it

Brand new launch for 2016 – dedicated solely to Finished Dosage Formulation

Meet other formulators, assess the competition and seek out new innovations

Be part of a global event and connect with companies from around the world. This is your best opportunity to meet suppliers from major and emerging markets including the US, China, India, Turkey and Russia

Establish new in/out licensing opportunities to develop your portfolio

 Find new manufacturing partners and opportunities for outsourcing  Access FDF specific presentations to learn about the latest market trends and developments

Access other co-located events for free at the world’s premier Pharma meeting place: your registration will also be valid for CPhI, ICSE, P-MEC and InnoPack Organised by:



Autumn 2016 Volume 8 Issue 3

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Microscopic Picture taken by Ansbach University of Applied Sciences

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IPI - Volume 8 Issue 3  
IPI - Volume 8 Issue 3