Volume 10 Issue 1
An update on Pulmonary Drug Delivery of Dry Powders Sharper Images, Faster Measurement, Chemical Identification Morphological Imaging is Evolving Demand for Unique Identification of Products Call for Investments Life Sciences in Flux Global Opportunities for a Global Industry
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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 The Importance of Building Regulatory Competencies to Address a Broadening Skills Gap DIRECTORS: Martin Wright Mark A. Barker BOOK MANAGER: Anthony Stewart email@example.com BUSINESS DEVELOPMENT: Alessia Giangreco firstname.lastname@example.org EDITORIAL: Orla Brennan email@example.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright firstname.lastname@example.org RESEARCH & CIRCULATION: Virginia Toteva email@example.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit B202.2, 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: firstname.lastname@example.org www.ipimediaworld.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Summer 2018. 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. 2018 PHARMA PUBLICATIONS / Volume 10 issue 1 – Spring – 2018
The regulatory profession is a relatively new profession, having been established just a few decades ago, and people still tend to enter the field from other related disciplines. The regulatory workforce broadly includes either those who possess plenty of experience, having performed roles in other areas of the pharma sector, or graduates and younger recruits who simply enter the industry from other career fields. In order to address the skills gap, Matthew Clark of the Regulatory Affairs Professionals Society (RAPS) explains that there is a real need for formal training and certification to become standard practice for regulatory professionals. 12 European Commission Review of SPC Legislation and Bolar Exemption The SPC regulation was introduced 25 years ago and has resulted in a complex landscape of national case law and numerous decisions from the Court of Justice of the European Union (CJEU) regarding its interpretation. This article by Marie-Louise Jardle and Mike Nelson of HGF highlights the complexity of exclusivity for medicinal products in Europe and illustrates challenges faced by the EC in seeking a fair balance which stimulates innovation and the development of new medicines with the growing costs of healthcare in Europe. 18 Dealing with Medical Device Regulations In 2008, the European Commission initiated a public consultation on existing requirements covering medical devices, which produced more than 200 comments and proposals for change from a wide variety of stakeholders. As a result, the European Commission released, in 2012, its plan to restructure the EU’s medical device regulatory framework, along with a regulation that would replace existing directives for medical devices and active implantable medical devices. In this article, Richard Poate from TUV SUD explains the need to comply with the latest regulatory requirements, or risk products being withdrawn from the market. 22 Drug Regulatory Requirements in Bhutan: A Glance With the participation of officials from the Ministry of Health in international conferences on pharmaceutical safety and the International Conference of Drug Regulatory Authorities (ICDRA), Bhutan recognised the need to introduce a National Drug Policy and Medicines Legislation. Regulatory procedures have been developed to ensure promotional activities of medicines are fair, balanced, and aimed at rational drug use. Bhutan is a fast-emerging market. This article by Mr Balamuralidhara, Kaushik Devaraju, Prof. Pramod Kumar and Dr Gaurav Mathur of JSS College gives you an outline of drug regulatory requirements for registration of new drugs and other classifications of medicine of Bhutan. 30 Ireland’s Medtech Success Story Ireland’s medtech sector is internationally recognised as a leading global cluster characterised by a deeply evolved ecosystem, encompassing leading multinationals, specialised research and clinical capabilities and a dynamic start-up and indigenous base. In this article, Sheila O’Loughlin from Enterprise Ireland explains how it is that an island of just over 4.7 million people emerged as one of the world's top five medical technology hubs over the INTERNATIONAL PHARMACEUTICAL INDUSTRY 1
Contents last 20 years, rivalling key clusters such as Minnesota and Massachusetts. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 36 Emerging Treatment, Peptide Receptor Radionuclide Therapy, Provides New Treatment Option for Gastroenteropancreatic Neuroendocrine Tumours With nuclear medicine therapeutics expected to represent 60% of the projected $26 billion global molecular nuclear medicine market by 2030, new alternative treatments are now beginning to emerge for conditions including gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Of these nuclear medicine innovations, peptide receptor radionuclide therapy (PRRT) is an option that combines the advantages of two of the most successful approaches to cancer treatment: external beam radiation and tumour targeted therapy. This article by Stefano Buono and Rachel Levine of Advanced Accelerator Applications explores this treatment. 40 An update on Pulmonary Drug Delivery of Dry Powders Inhalation of air is a vital process for all human life. Inhalation for drug delivery has been established as an effective delivery method of active pharmaceutical ingredients to a human body, mostly in the field of anesthesia and respiratory diseases. In this article, the status and new trends in the field of drug delivery to the lungs will be reviewed by Rachel van Rijn and Harry Peters of DFE Pharma, with focus on the delivery of active pharmaceutical ingredients (APIs) in the form of dry powders. 46 MALDI Imaging at High Speed Over the last decades, MALDI-TOF mass spectrometry (Matrix-Assisted Laser Desorption/Ionisation Time of Flight) has proven its usefulness and robustness in many applications, helping life scientists to meet their toughest challenges. This article by Rohan Thakur of Bruker Daltonics will focus on how new laser technology can improve sample throughput for MALDI imaging. It will demonstrate how MALDI technology is being utilised in drug development as an established tool for compound distribution analysis and an emerging tool to boost efficiency in the drug finding process, specifically for ultra high-throughput drug discovery screening. 50 Key Challenges of Bringing New Drug Delivery Devices to Market There are many challenges in bringing a good new product to market, from correctly identifying the right commercial opportunity and establishing appropriate input requirements, to developing and industrialising a product which is appealing, usable and robust. There are myriad development tools, techniques, processes and best practices that multi-disciplinary teams can employ to tackle these challenges. Chris Hurlstone, Team Consulting’s Director of Engineering, gives an account of what these challenges are, and how they can be overcome. CLINICAL RESEARCH 54 Successful Adoption of eConsent – Best Practices for Integrating eConsent Technology Research sponsors and investigative sites are continuing to explore the use of electronic informed consent (eConsent) in today’s clinical trials. eConsent utilises electronic 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY
systems and processes, such as audio and video features, to communicate study information to study participants to securely obtain and document informed consent. In a time when the clinical trials industry is seeing an influx of technology across the clinical trials lifecycle, Mika Lindroos of CRF Health explains why there is a need to move towards consolidating these technologies and bringing complementary platforms together wherever possible. 58 The Future of Patient Recruitment for Clinical Studies Clinical studies are important; they are the gold-standard method of evidence generation. Ultimately, the decisions we make about our own healthcare are based on their results. To date, almost 1 million trials have been conducted according to the most complete register, and an estimated 27,000 trials are added to that list each year. The problem of poor recruitment is widespread; 80% of trials miss recruitment deadlines, and a staggering 11% of all trials fail to recruit a single patient. Dan Hydes of Ignite Data Solutions explains why we should all be demanding much better results. MANUFACTURING 62 Sharper Images, Faster Measurement, Chemical Identification: Morphological Imaging is Evolving Examples of how rapid advances in visual equipment and computing power have combined to deliver smart, sleek and easy-to-use technology are ubiquitous in modern life, and exemplified in the laboratory by the capabilities of cuttingedge imaging systems. In this article, Debbie Huck-Jones from Malvern Panalytical looks at how morphological imaging works, the analytical workflows associated with its application, and the data that can be generated, highlighting technological advances that enhance data quality and system applicability. 68 Tailored Fill Release Performance – GELITA® Pharmaceutical Gelatines Cover the Complete Spectrum of Capsule Fill Release Profiles for Highest Efficacy and Consumer Compliance Gelatine offers manufacturers of drugs as well as dietary supplements a versatile excipient that has been used in the pharmaceutical industry for decades. Among its key applications is capsule production: Approximately 90 per cent of all pharmaceutical-grade gelatine is processed into this sleek and widely-used drug dosage form. However, the type of active ingredient, climate conditions and storage times make different demands on a capsule’s properties. By adjusting the production process for soft capsule gelatin, Dr Becker of Gelita explains how we can modify the specific effect, timing and duration of the fill release to tie in with consumer needs. PACKAGING 70 Automating Packaging Lines to Benefit Clinical Trial Supply The growing demand for complex oncology drugs and medicines to treat a wide range of therapeutic areas has driven heightened levels of clinical development activity and changed the clinical trials landscape drastically. Ongoing technological development in the clinical trials space is also driving change in the way clinical trials are managed, and how the drug supply is developed, manufactured and packaged. Dave Wilson, head of operations at Sharp Clinical Services, explains why companies are increasingly Spring 2018 Volume 10 Issue 1
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Contents seeking to automate processes in response to a demand for improved productivity while maintaining high-quality results. 72 Why the Need for Centralised Content Management is on the Rise Despite the advances in electronic content management over the past decade, many of the biggest global life sciences companies still manage their local translations in a highly fragmented way. Not only does this lead to a rise in costs, but it also comes with risks to safety and slows down product speed to market. AMPLEXOR’s Jason Arnsparger explains how agile organisations can keep pace with markets because they can adapt and respond quickly to the environment around them, and that in life sciences, centralised, systematic control of global product information is the best way of achieving this. 76 Serialisation for Late Starters In an industry as vast as the pharmaceutical market, every company is at a different stage of implementing serialisation to ensure complete compliance when new EU and US regulations come into force. Due to the challenge of introducing a robust serialisation solution, many companies are now experiencing unforeseen issues as the industry starts to recognise the magnitude of the task at hand. Zenith Technologies’ Carlos Machado and Sea Vision’s Marco Baietti provide a comprehensive guide to serialisation success. 80 Demand for Unique Identification of Products Call for Investments Serialisation, FMD (European Union Falsified Medicine Directive), DSCSA (United States Drug Supply Chain Security Act) and UDI (Unique Device Identification) are all regulations that have been in the making for a long time, and will be implemented in the very near future. A part of most of the regulations is the demand for unique identification of each product or device, making it possible to track and trace the medicine from the pharmaceutical manufacturer and all the way to the patient who picks up the medicine from a pharmacy or hospital. Jens Heidemann Sørensen and Ulla Laursen of LSS Labelling Systems visualise the possibilities for marking and labelling solutions that meet the legal requirements. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 84 Risk Migration within Global Pharma Supply Chain Logistics The need to mitigate risks within global pharma supply chain logistics is driving innovation within the temperaturecontrolled packaging sector. Innovation and new technologies are proving paramount to the emergence and evolution of smart temperature-controlled packaging protecting pharmaceutical payloads worldwide. To help eliminate excursions in temperature in cold chain, Adam Tetz from Pelican Biothermal discusses the growing demand for reliable, high-performing packaging products to safeguard sensitive shipments.
new entrants are well positioned to compete because their models are oriented to specifically support digital technology and software development – more so than existing, analogue-native medical technology companies, which are organised to comply with regulations. Based on their experience, Mitch Beaumont, Prashanth Prasad, Ulrica Sehlstedt and Mandeep Dhillon of Arthur D Little have identified two sets of primary “levers” that executives can use to impact the changes to their companies’ business and operational models that are necessary to support a digital business. 94 Life Sciences in Flux: Global Opportunities for a Global Industry During the 20th century, humanity achieved something almost unbelievable: it actually pushed back death. In 1900, average global life expectancy was 31, a figure largely unchanged since biblical times. Yet by 2000, that had risen to 66.4 years and it now stands at 71.4. The factors shaping this change are complex and numerous, but the life sciences – the sector that includes drug development and healthcare providers as well as research into cuttingedge procedures and technologies – is central to the story. This article by Fiona Ashdown from Insource explains how to maximise the potential of these phenomenal industries. 98 Why Laboratories are Choosing Gas Generators over Gas Cylinders Pharmaceutical laboratories use a variety of analytical techniques as part of research and development and quality control of products. Many of these processes require high-purity gases, many of which can be produced by gas generators. Dr Ed Connor of Peak Scientific explains that, for a number of reasons, including safety, cost and convenience, more and more laboratories are abandoning gas cylinders in favour of gas generators to supply the gases they require for their analyses. 102 How to Avoid Becoming a Casualty of the Impending Battle for Data Control The General Data Protection Regulation (GDPR) is the outcome of many years of negotiation aimed at harmonising the EU countries’ approach to data protection issues. Currently in a transitional phase, the GDPR came into force in May 2016, but is scheduled to take effect in all member states on 25 May 2018. Whatever the nature of an organisation, it is very unlikely that it won’t be affected in some way by GDPR. Mark Lumley at Schulmans and Mark Stevens at Formpipe explain the importance of understanding the potentially all-encompassing scope of the legislation and the consequences of non-compliance.
TECHNOLOGY 90 How Established Medical Technology Companies can Go Digital with Operational Model Changes There is significant value to be captured with digital products and services in the healthcare industry. Many 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
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Editor's Letter It’s spring in the northern hemisphere and the daffodils are out, which means for the life science sector lots of annual conferences. Bio Europe Spring was held in Amsterdam this year. I moderated, for the fourth year, The Future of Swedish and Danish Life Science at Medicon Village in Lund, and this year’s topic was precision medicine and big data. It was great to see so many people from the international community, and that we all care about the future of our sector. When I attend events, I always come away wondering whether we are really doing the most with what we have, and in this edition of the magazine I hope that you will get an update on where the industry is. The article by Fiona Ashdown from Insource explains how to maximise the potential of these phenomenal industries. She talks about how in 1990 the average global life expectancy was 31 and this had never changed from biblical times, yet by 2000, after we put a man on the moon we are now seeing an average of 71.4. But are we doing enough and what has made us so successful at keeping people alive?
4.7 million people emerged as one of the world's top five medical technology hubs over the last 20 years, rivalling key clusters such as Minnesota and Massachusetts.
does this fall to us as patients not being offered alternatives? Dan Hydes of Ignite Data Solutions explains why we should all be demanding much better results.
There will always be challenges and hurdles to overcome in such a complex industry to get a good new product to market, especially convincing investors to wait potentially 10 years for a drug to make money. However, Chris Hurlstone, Team Consulting’s Director of Engineering, gives an account of what these challenges are, and how they can be overcome.
Today’s world is all about data protection, and the General Data Protection Regulation (GDPR) is the outcome of many years of negotiation aimed at making the EU countries come together to make the protection of our personal data safe. That is why Mark Lumley at Schulmans and Mark Stevens at Formpipe explain the importance of understanding the potentially all-encompassing scope of the legislation, and the consequences of noncompliance.
With the past five years of big pharma shrinking and virtual companies starting, one area of the sector that has become very important is regulatory support, which has previously been internal with an organisation. Matthew Clark of the Regulatory Affairs Professionals Society (RAPS) explains that there is a real need for formal training and certification to become standard practice for regulatory professionals.
Zenith Technologies’ Carlos Machado and Sea Vision’s Marco Baietti provide a comprehensive guide to serialisation success and how a whole industry has come together to ensure that patients are no longer going to be potentially getting counterfeit drugs that could kill them. Looking further ahead into the year, the annual Anglo Nordic Conference is being held for the 15th year on 24th May at The Country Hall in London on the bank of the Thames. I hope to see you there.
Sheila O’Loughlin from Enterprise Ireland explains how it is that an island of just over
When we take our medication daily, do we ever think about the clinical trials that we have done on this drug, or the preclinical studies? Unfortunately, we do have a problem with patient recruitment and with getting enough patients to be able to start a trial on time. Staggeringly, 11% of all trials fail to recruit a single patient, but
In this our 1st edition of the year, leading industry experts take a look in to some of the hot topics in the pharmaceutical s e c t o r. W i t h t h e European Commission’s latest regulatory requirements (the MDR) seeing manufacturers of medical devices who sell within the European Union face major changes, the race is on for companies to comply, lest they risk products being withdrawn from the market. In the realm of drug
discovery and delivery, at the cutting edge of treatments for conditions including gastroenteropancreatic neuroendocrine tumours, Stefano Buono and Rachel Levine of Advanced Accelerator Applications shed light on the complex landscape of peptide receptor nuclear therapy. In the age of technological development, experts from Data solutions and CRF health advocate for a simpler and more efficient way to manage clinical trials, with “companies no longer having to spend time rectifying issues arising from paper-based consent forms further down the line.” – Mika Lindroos CRF
Health. In packaging, AMPLEXOR’s Jason Arnsparger emphasises the necessity for centralisation in the life science sector in an effort to resolve the “highly fragmented way” in which companies manage their local transactions. As ever, this issue promises to be jam packed with carefully formulated information and advice relevant to the industry, from medical device regulation to clinical trials, which I hope very much that you will enjoy. Orla Brennan Editorial Assistant, IPI
and Executive Vice President, Vienna School of Clinical Research
Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy
Lucy Robertshaw Director, Lucy J.Robertshow Consulting
Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research, Center of MCH, Astana, Kazakhstan Catherine Lund, Vice Chairman, OnQ Consulting
Jagdish Unni, Vice President - Beroe Risk and Industry Delivery Lead - Healthcare, Beroe Inc.
Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters
Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT
Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group
Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma
Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting
Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group
Jim James DeSantihas, Chief Executive Officer, PharmaVigilant
Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)
Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics
Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation
Stefan Astrom, Founder and CEO of Astrom Research International HB
Maha Al-Farhan, Chair of the GCC Chapter of the ACRP
Steve Heath, Head of EMEA - Medidata Solutions, Inc
Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories
T S Jaishankar, Managing Director, QUEST Life Sciences
Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace
The Importance of Building Regulatory Competencies to Address a Broadening Skills Gap The global life sciences industry is expected to reach >£1.4 trillion in gross value by 2023 (approximately $1.6 trillion today) 1. In 2014, the European pharma sector generated 19.8% of global pharma sales2 and the EU-5 is set to grow by 25% between 2017–2022, accounting for 69% of the European pharma market in 20223. In the coming decades, healthcare spending is expected to outgrow the economy in Organisation for Economic Co-operation and Development (OECD) member countries by 3.3% versus 2% compound annual growth rate (CAGR), creating a sustainability challenge for healthcare systems and new opportunities for life sciences industry growth 4. This has huge potential for the pharmaceutical industry and, with significant industry changes taking place over the coming years, it is critical to support the regulatory workforce that will be charged with navigating through this period of rapid development and regulatory uncertainty.
The regulatory profession is a relatively new profession, having been established just a few decades ago, and people still tend to enter the field from other related disciplines. The most recent Scope of Practice and Compensation Survey of the Regulatory Profession conducted by the Regulatory Affairs Professionals Society (RAPS) found that more than 88% of respondents began working in other specialities before moving into regulatory and generally originated from the bench sciences or engineering fields. The regulatory workforce broadly includes either those who possess plenty of experience having performed roles in other areas of the pharma sector, or graduates and younger recruits who simply enter the industry from other career fields. These recruits are entering the profession with excellent academic qualifications (around 99% of those who took part in the 2016 survey hold a university degree 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY
and more than 42% have achieved a master’s degree) but possess little to none of the practical competencies required in the role. With a growing proportion of many experienced professionals reaching retirement age, this poses a skills gap issue. As a result, this skills gap is becoming more noticeable just as the role of regulatory professionals is becoming increasingly important within a broader strategic business model. In addition, in response to the increasing evolution of global industry regulations, more dynamic product and technological development and changing business models, the role of regulatory professionals in the pharmaceutical sector has had to adapt. Today, there is a greater reliance on the strategic support of regulatory professionals on more complex issues. Regulatory has also become a much more formalised career path, helped by the increase in dedicated training and educational support. Closing the Skills Gap The relationship between the regulatory professionals in the pharmaceutical industry and healthcare professionals (HCPs) and healthcare organisations (HCOs) plays a vital role in ensuring life-enhancing pharmaceutical products are safe and effective and reach the market efficiently. So what can companies do to support the regulatory workforce and lessen this skills gap? Professional development organisations are ideally positioned to work with the pharma industry to help to bridge the gap and ensure a highly skilled and competent regulatory workforce. Continuous development is vital in an industry where change is so frequent. This is also true as the path to globalisation broadens and product portfolios grow in variety. Regulatory professionals have had to expand their range of skills to deal with
multi-geographical workloads across numerous product types on a global scale. Demand for professional development support has surged over the last decade. Individuals are also recognising the importance of keeping up with industry- and sector-specific information, which has led to the development of the industry-recognised Regulatory Competency Framework (RCF) and the growing uptake of the Regulatory Affairs Certification (RAC), the only postgraduate certification in regulatory affairs. Professionals with RAC have proven that they possess the core competencies required to successfully operate in a progressively changing industry. The Changing Role of Regulatory So influential is the globalisation of the industry and product diversity that just 7.2% of participants in the RAPS survey reported that their role focused on a single country and nearly 75% were involved with multiple sites and variations of products. As detailed above, the everincreasing expectations for regulatory professionals to help guide and support a company’s strategic focus has shifted the perception of the profession. Whereas previously, regulatory professionals were solely expected to submit and gain product approvals, they now play a part in shaping the wider strategic vision for the whole company. As their role diversifies, they are required to take an active role in discussions across a multitude of departments, including research and development, manufacturing and quality, all the way through to marketing, sales, legal, finance and management, and sometimes even working in areas directly involving clinicians and consumers. Furthermore, regulatory knowledge must extend beyond simply knowing Spring 2018 Volume 10 Issue 1
R.G.C.C. International GmbH. R.G.C.C. International GmbH is a leading company in analysis of Circulating Tumor Cells as well as Cancer Stem Cells. Through their analysis, is able to oﬀer services in clinical ﬁelds as well as in R & D in pharmaceutical industry. By using the most advanced and innovative technologies of molecular and cellular biology, R.G.C.C. International manages to overpass several restrictions and diﬃculties that the analysis of CTCs and CSCs involves. Hence, through such an approach a massive amount of information and data has been generated in order to be used for identifying new “drugable” targets as well as oﬀering methods in clinical practise like new and precise assays, risk scale and classiﬁcation of cancer patient.
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Representatives all over the world contact R.G.C.C. International for further information or visit our website at www.rgcc-group.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 9
Regulatory & Marketplace
the regulations, to understanding their practical application and potential wider business implications. These professional networks for sharing information and best practices are more important now than ever. By tapping into a global network, a regulatory professional can benefit from the knowledge and expertise of the entire network in many different areas, including vital details about different regional and national regulatory systems. A shared body of knowledge benefits all stakeholders from recent graduates to experienced regulatory professionals, manufacturers, marketers and regulators. The rise of technologies that allow nearly unlimited communication with anyone around the world has made it possible for professional societies and associations with a global reach to connect professionals to specialised and regional know-how with increasing ease. While it’s not that easy to address experience as this comes with time, professional development programmes underpinned by clear competency frameworks are one way to assist the regulatory workforce. Training providers must continuously develop their programmes to meet the changing educational requirements of a workforce whose role is rapidly evolving. This also means that even those professionals with vast experience in 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY
regulatory issues are recommended to commit to a professional development programme. Final Thought In order to address the skills gap, there is a real need for formal training and certification to become standard practice for regulatory professionals. Only then can they be best equipped to advance public health in the most efficient and compliant manner. A dedicated approach to professional development for this workforce, coupled with the industry ’s willingness and encouragement of knowledge-sharing, will no doubt ensure that regulatory professionals continue to strive to build their competencies. As the remit of a regulatory professional has diversified so much, this workforce can have a real impact on both their employers’ businesses and the patients who ultimately benefit from the healthcare products. REFERENCES 1.
https://www.gov.uk/government/ uploads/system/uploads/ attachment_data/file/650447/
LifeSciencesIndustrialStrategy_ acc2.pdf 2. https://www2.deloitte.com/ content/dam/Deloitte/ global/Documents/ Life-Sciences-Health-Care/gx-lshc-
2015-life-sciences-report.pdf 3. http://info.evaluategroup. com/rs/607-YGS-364/images/ Evaluate-European-DrugForecasts-Infographic-IG.pdf 4. https://www.gov.uk/government/ uploads/system/uploads/ attachment_data/file/650447/Life SciencesIndustrialStrategy_acc2.pdf
Matthew Clark Matthew Clark has been an executive with the Regulatory Affairs Professionals Society since 2006, having served as vice president of marketing and communications and vice president of brand management. He currently is vice president of publishing and content strategy. In his 20 years of experience, he has focused on uncovering customer insights and delivering innovative brand strategy supported by effective marketing and content strategy for non-profit and for-profit organisations. He holds a Master of Mass Communications in media management from the University of South Carolina and Bachelor of Arts in psychology and journalism from Syracuse University. Email: email@example.com
Spring 2018 Volume 10 Issue 1
INTERNATIONAL PHARMACEUTICAL INDUSTRY 11
Regulatory & Marketplace
European Commission Review of SPC Legislation and Bolar Exemption The SPC regulation was introduced 25 years ago, and has resulted in a complex landscape of national case law and numerous decisions from the Court of Justice of the European Union (CJEU) regarding its interpretation. This article highlights the complexity of exclusivity for medicinal products in Europe and illustrates challenges faced by the EC in seeking a fair balance, which stimulates innovation and the development of new medicines with the growing costs of healthcare in Europe.
In October 2015, the Single Market Strategy was adopted by the European Commission (EC) to stimulate growth within EU1. Among other things, it was announced that the EC will ‘consult, consider and propose further measures, as appropriate, to improve the patent system in Europe, notably for pharmaceutical and other industries whose products are subject to regulated market authorisations’. The EC has raised concerns that the present SPC legislation impairs the competitiveness of EU-based generic drug manufacturers compared to non-EU manufacturers and deters innovating drug companies from performing research and clinical studies in the EU2. Expected growth of societal spending on generic medicines has intensified worries regarding reliance on import from foreign suppliers of drugs essential to public health. To address this, the EC has initiated both targeted consultations and public consultations inviting citizens and stakeholders in the pharmaceutical industry, the plant protection industry and the medical devices industry to provide their views 3. The focus of the public consultation, which ended on January 4, 2018, was: (a) the creation of a European supplementary protection certificate title (i.e. a Unitary SPC, instead of a bundle of national SPCs, based on a European patent with unitary effect in accordance with the proposed Unitary Patent Regulation); 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY
(b) an update of the scope of EU patent research exemptions; and (c) the introduction of an SPC manufacturing waiver for export purposes in sectors requiring regulatory market authorisations. Although this consultation exercise was focused on research exemptions and SPCs, the extent of the EC incentives review is still unknown and may lead to further review or revisions of other European exclusivity provisions such as orphan and paediatric exclusivity. Patent and SPC Rights The patent system was established to encourage and to stimulate innovation. In return for disclosing the details of an invention to the public, the applicant may be rewarded with a 20-year national right to exclude others from making, using and selling the patented invention provided the invention meets the requirements for patentability. After expiry of the patent, anyone is free to practise the disclosed invention. The monopoly right granted in exchange for the disclosure of an invention is intended to provide a competitive advantage for the patent proprietor and act to incentivise innovator companies to invest in new research and development. Pharmaceutical products generally take a very long time to develop, often 10–15 years; the success rate is low, around 10% from the first clinical trial phase; and costly clinical studies are required to obtain market authorisation4. Furthermore, pharmaceutical products are highvalue assets, which are often easy to copy, making them an attractive target for competitors. For innovating pharmaceutical companies, patent protection is therefore crucial to ensure return on the investment required to bring new medicines to the market and address unmet medical needs for patients. However, as a result of the long development time and regulatory requirements for a medicinal product, in many cases by the time a product is approved and the product finally
enters the market, significant patent term is already lost. To compensate for the loss of patent term resulting from the regulatory approval process in Europe, the SPC regulation for medicinal products was introduced in 1993. This provides up to five years of additional exclusivity for the approved product (Regulation (EC) No 469/2009 and Regulation (EC) No 1610/96). Regulatory Exclusivities In addition to exclusivity provided by patent and SPC rights, medicinal products also enjoy protection of the regulatory data used to support the approval of a product in Europe. This can provide additional exclusivity for a product. A company seeking marketing authorisation for a generic/biosimilar version of a previously approved product can use the so-called abridged procedure and cross-refer to pre-clinical test data and clinical trial data submitted by the original innovator company. To balance the competing interests in the industry, the innovator company is rewarded with data and market exclusivities which prevent generic companies, during a certain time after market authorisation, from referring to the innovator’s data in a regulatory filing for the same drug substance. In November 2005, the regulatory exclusivities in Europe were harmonised in all member states to provide eight years of data exclusivity from the date of first authorisation in the European Community and an additional period of two years of market exclusivity are provided in all member states, with the possibility of one additional year of data exclusivity under certain circumstances. During the market exclusivity period, another company cannot place a generic/ biosimilar product on the market, even if the medicinal product has already received a marketing authorisation. To encourage development of medicines for rare diseases, Regulation EC 141/2000 for orphan drugs came into force in 2000. Drugs developed for conditions that occur in the European Union in less than five out of every Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace 10,000 inhabitants will get 10 years of orphan drug exclusivity after market approval. The orphan drug exclusivity blocks acceptance of an application for market authorisation and approval of the same drug, and close structural analogues acting through the same mechanism, for the same indication during the term of the exclusivity period. The regulation for orphan drugs seems to have had the intended purpose of encouraging development of medicines for rare disease5. Critics of the orphan drug regulation have suggested it has led to highly-priced orphan drugs and that the incentive to obtain orphan drug status may deprive society from medicaments for broader, less profitable indications. Incentives for the development of paediatric medicines were introduced in 2006 through Regulation EC 1901/2006. This regulation provides for six-month extension of the SPC term or a two-year extension of orphan drug exclusivity as reward for performing paediatric studies. The recent 10-year report by European Commission concluded that the regulation has boosted paediatric research and development of paediatric medicines in the EU at least in areas where the needs of adult and paediatric patients overlap6. However, the report identifies a weakness in the regulations for stimulating development of medicines for paediatric diseases that qualify as orphan conditions and states that further combined evaluation of the Orphan and Paediatric Regulations is needed. The results of this evaluation are expected in 2019.
the experimental use exemption in the different national jurisdictions. In 2004, the EU introduced through amendments of Directive 2001/82/ EC (veterinary medicinal products) and Directive 2001/83/EC (medicinal products for human use), respectively, an exemption from infringement of patent rights or SPC rights for conducting the necessary studies needed to demonstrate bioequivalence when using the abridged procedure. The aim of the so-called Bolar exemption was to harmonise among the member states and to speed up market entry of generic medicines. However, the Bolar exemption was implemented under national law, which resulted in significant variations across the EU member states. Some countries, like Sweden and the Netherlands, implemented the Directive narrowly, covering only studies and trials required for generic drugs, while other countries, like Germany, France, and Denmark, have applied the Bolar exemption more broadly, covering both clinical trials conducted on a patented drug to test its effect on a new indication and on an innovative drug falling within the scope of a patent. In October 2014, when the UK Legislative Reform (Patents) Order 2014 came into effect, the UK broadened the experimental use exemption, setting out that ‘anything done in or
Bolar Exemption A generic company needs to demonstrate to regulatory authorities bioequivalence with the generic product and the approved innovator product, and often clinical trials are required to do this. Such trials are generally performed before expiry of the patent(s) covering the innovator’s product and could be at risk for patent infringement. Also, an innovating company may run the risk of infringing a competitor’s patent when conducting clinical trials on a new drug substance. Most member states have an experimental use exemption which allows for certain experimental activities on patented inventions. At present, there are significant variations in the interpretation of
There is still uncertainty in several member states as to whether the Bolar exemption applies to tests performed in the EU for the purpose of obtaining marketing authorisations on the medicinal product in non-EU countries. In principle, this could force companies to repeat clinical trials in a non-EU country or to carry out clinical trials outside Europe, leading to additional delays and costs. Also, certain member states do not exempt trials using a patented reference product to meet national requirements on pricing and reimbursement and/or do not allow the supply of patented active pharmaceutical ingredients (APIs) to a third-party manufacturer. These uncertainties, and the fact that the Agreement on the Unified Patent
14 INTERNATIONAL PHARMACEUTICAL INDUSTRY
for the purposes of a medicinal product assessment which would otherwise constitute an infringement of a patent for an invention is to be regarded as done for experimental purposes relating to the subject-matter of the invention’.
Court merely refers to the European Directives mentioned above, warrant for EC’s review and a more uniform and predictable application of Bolar exemption throughout Europe. Views from the Generic Industry The manufacturing of a patented drug in the EU for commercial purposes, including exporting the drug to non-EU countries, whilst the patent or an SPC covering the drug is in force without the consent of the patent proprietor is, at present, prohibited. The generics/biosimilar industry, for instance, represented by the lobby group Medicines for Europe, stress that EU-based manufacturers are at a disadvantage compared to manufacturers based in countries where there is no SPC or similar protection, such as Brazil, Russia, India and China. As long as the SPC is in force, the EU-based manufacturers are prevented from exporting to markets where there is no protection. Also, the EU-based manufacturers argue that they would have a lead time disadvantage compared to non-EU manufacturers when entering the EU market upon expiry of the SPC. The concern is that these issues may force the EU-based companies to move production outside of the EU via delocalisation or outsourcing. The study commissioned by the EC, completed in 2016 and published in October 2017 7, on the economic impact of the SPC export waiver and a broadening of the Bolar research exemption to, for instance, cover API manufacturing for stockpiling purposes, concluded that such manufacturing waiver would boost sales, investment and jobs in the European pharmaceutical industry. Views from the Innovator Industry Representatives for the innovator industry, such as European Federation of Pharmaceutical Industries and Associations (EFPIA), argue that the introduction of a manufacturing waiver would weaken their intellectual property rights and undermine the European innovating pharmaceutical industry instead, leading to loss of jobs, decreased R&D investment and higher prices on branded drugs in the EU market to compensate for the shorter period of exclusivity and the risk of lower revenues. Arguments are raised Spring 2018 Volume 10 Issue 1
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Regulatory & Marketplace that SPCs often expire only slightly later than corresponding product protection on non-EU markets and that the economic value in exporting to non-EU markets prior to an SPC expiry therefore has been exaggerated by said study. Also, it is argued that many generic manufacturers already produce in low-cost non-EU countries and are unlikely to relocate the production to the EU. Arguments have also been raised that imports from areas such as Europe anyhow are restricted in many emerging markets by local measures such as import bans and increased taxation on foreign products in favour of locally-produced generic drugs. Moreover, there is a concern on how to differentiate between manufacturing for export purposes or for sale in EU countries where there still is SPC protection. It is argued that this would result in difficulties in providing proof of infringement leading to lengthy, expensive litigations. Comprehensive Economic and Trade Agreement National SPC manufacturing waivers have been considered by some member states, but amendments in national patent law would not apply to SPCs granted for unitary patents which thus require EU legislation. A further factor to consider is that any changes to the SPC system would also need to comply with the Comprehensive Economic and Trade Agreement (CETA) signed in October 2016 by Canada and the European Union. The agreement entered into force provisionally on September 21 2017 but must be ratified by all EU member states before it is fully enacted. For example, in CETA the EU has agreed to continue to provide 2-5 years SPC protection. To meet the CETA obligations, Canada introduced a Certificate of Supplementary Protection (CSP) which came into force in September 2017. The CSP may provide up to two years of extra protection for patents relating to human and veterinary drugs containing a new medicinal ingredient, or a new combination of medicinal ingredients, protected by an eligible patent. The new Canadian CSP framework provides for an export waiver allowing generic products to be made or sold for the purpose of export. Maybe the Canadian export waiver will influence the EC to implement a similar provision in the EU? 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Compulsory Licences All EU states face challenges dealing with the cost of healthcare provision, a problem which is compounded by aging populations. In 2016, the Dutch government asked for advice on alternative approaches for tackling the problem of high pricing of patentprotected drugs. In November 2017, The Dutch Council for Public Health and Society (RVS) recommended in an advice8 that authorities should consider, for instance, the option of granting compulsory patent licences in accordance with the Convention on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) to create competition and make medicines more affordable and broadly available to patients. The Dutch advice came just a few months after the German Federal Court of Justice (FCJ) for the first time affirmed a compulsory licence granted by the German Federal Patent Court (FPC)9. The first compulsory licence granted by FPC was set aside by FCJ10. Compulsory licensing under the proposed unitary patent is left to national courts, but the EC might be forced to consider also unified regulation on compulsory licences. Conclusion To conclude, it will indeed be a delicate exercise for the EC to balance the interests of the concerned parties when considering whether to keep the existing EU legislation or try improving it through non-legislative instruments and/or legislative changes.
European Parliament and Council on the state of paediatric medicines in EU, 10 years of the EU Paediatric Regulation (October 2017). 7. Charles River Associates (CRA), Assessing the Economic Impacts of Changing Exemption Provisions During Patent and SPC Protection in Europe (February 2016, published October 2017). 8. Council for Public Health and Society (Raad voor Volksgezondheid en Samenleving, RVS), Development of new medicines – better, faster, cheaper (November 2017). 9. FPC, GRUR 2017, 373 – Isentress (August 2016), and FCJ, GRUR 2017, 1017 – Raltegravir (July 2017). 10. FPC, GRUR 1994, 98 – Compulsory Licence (June 1991), and FCJ, GRUR 1996, 190 – Polyferon (December 1995).
Marie-Louise Jardle Marie-Louise Jardle is Patent Director and European Patent Attorney with HGF GmbH in Basel. Her practice covers all aspects of patent work, including drafting and prosecution of patent applications, defending and attacking patents in EPO opposition and appeal proceedings, providing freedom to operate analysis, and IP risk assessment and advice in due diligences. Marie-Louise has particular experience from patents on new chemical entities, drug delivery, medical devices, implants, polymer compositions, nicotine products, and hygiene consumer products. Email: firstname.lastname@example.org
REFERENCES 1. 2.
European Commission, Upgrading the Single Market: More Opportunities for People and Business (October 2015). European Commission, Roadmap: Optimising the Internal Market’s industrial property legal framework relating to supplementary protection certificates (SPC) and patent research exemptions for sectors whose products are subject to regulated market authorisations (February 2017). European Commission, Public Consultation on Supplementary Protection Certificates (SPCs) and Patent Research Exemptions (October 2017). Ingrid Torjesen, The Pharmaceutical Journal, Drug development: the journey of a medicine from lab to shelf (2015). European Commission, Inventory of Union and Member States incentives to support research into, and the development and availability of, orphan medicinal products (February 2016). European Commission, Report to the
Mike Nelson Mike Nelson is a Partner and European Patent Attorney with HGF GmbH in Basel. Mike specialises in pharmaceutical patents and advises clients on a broad range of technologies including new chemical entities, drug delivery and formulations, methods of treatment and drug repurposing. Mike also has extensive experience on patent term extensions, regulatory data exclusivity, IP due diligence, licence negotiations, oppositions and appeals. Email: email@example.com
Spring 2018 Volume 10 Issue 1
INTERNATIONAL PHARMACEUTICAL INDUSTRY 17
Regulatory & Marketplace
Dealing with Medical Device Regulations
In 2008, the European Commission initiated a public consultation on existing requirements covering medical devices, which produced more than 200 comments and proposals for change from a wide variety of stakeholders. As a result, the European Commission released in 2012 its plan to restructure the EU’s medical device regulatory framework, along with a regulation that would replace existing directives for medical devices and active implantable medical devices.
This means that manufacturers of medical devices who sell within the European Union (EU) will soon face major changes in the EU’s decades-old regulatory framework, as the Medical Device Regulation (MDR) was officially published on 5 May 2017 and came into force on 25 May 2017. The MDR will replace the EU’s current Medical Device Directive (93/42/EEC) and the EU’s Directive on active implantable medical devices (90/385/EEC). Manufacturers of currently approved medical devices will have a transition time of three years until 26 May 2020 to meet the requirements of the MDR. For certain devices this transition period can be extended until 26 May 2024. However, special requirements must be met to be grant the extension. MDR Overview The MDR differs in several important ways from the EU’s current directives for medical devices and active implantable medical devices. Changes in the regulation include expansion of the scope of products covered, more rigorous requirements for clinical evaluation including changes to clinical investigations, mandatory unique device identification (UDI) mechanisms, and increased post-market oversight by EU notified bodies. Specific changes include: Product scope expansion – the definition of medical devices and active 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY
implantable medical devices covered under the MDR is expected to be significantly expanded to include devices that may not have a medical intended purpose, such as coloured contact lenses and cosmetic implant devices and materials. Also for inclusion within the scope of the regulation are devices designed for the purpose of “prediction” of a disease or other health condition. Reclassification of devices according to risk, contact duration and invasiveness – the MDR will require device manufacturers to review the updated classification rules and update their technical documentation accordingly by considering the fact that class III and implantable devices will have higher clinical requirements and a regular scrutiny process. It is expected that device manufacturers will also be required to collect and retain post-market clinical data as part of the ongoing assessment of potential safety risks. These changes will result in a dramatic increase in the time and resources needed by manufacturers to conduct the required studies and to maintain post-market documentation. More rigorous clinical evidence for class III and implantable medical devices – manufacturers will need to conduct clinical investigations in case they do not have sufficient clinical evidence to support the claims done on both safety and performance of a dedicated device. Systematic clinical evaluation of Class IIa and Class IIb medical devices – manufacturers will need to re-prepare their clinical evaluations by considering the new wording of the regulation on equivalence approach and under which circumstances it is possible to justify not conducting a clinical investigation. Identification of “qualified person” – device manufacturers will be required to identify at least one person within their organisation who is ultimately
responsible for all aspects of compliance with the requirements of the new MDR. The organisation must document the specific qualifications of this individual relative to the required tasks. Further, qualifications of responsible persons will be subject to review by notified bodies to ensure requisite knowledge and skill. Implementation of unique device identification – the MDR mandates the use of unique device identification (UDI) mechanisms. This requirement is expected to increase the ability of manufacturers and authorities to trace specific devices through the supply chain, and to facilitate the prompt and efficient recall of medical devices that have been found to present a safety risk. To support this effort, the European Databank on Medical Devices (Eudamed) is expected to be expanded to provide more efficient access to information on approved medical devices. Rigorous post-market oversight – the MDR will grant notified bodies increased post-market surveillance authority. Unannounced audits, along with product sample checks and product testing will strengthen the EU’s enforcement regime and help to reduce risks from unsafe devices. Annual safety and performance reporting by device manufacturers will also be required in many cases. Specifications – the MDR will give the EU Commission or expert panels the authority to publish common specifications. These common specifications would exist in parallel to the harmonised standards and will be seen as state-of-the-art, and would be considered as part of the evaluation process by notified bodies. No “grandfathering” provisions – under the MDR, all currently approved devices must be recertified in accordance with the new requirements. Manufacturers with currently approved devices will have three years to demonstrate compliance with the MDR’s new Spring 2018 Volume 10 Issue 1
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 19
Regulatory & Marketplace requirements. Exemptions are under negotiation right now. Addressing Complexities It is important to note that, as an EU regulation, the MDR will have the force of law throughout the EU after the date of application. This approach will eliminate country-by-country interpretations of the requirements permitted under current directives, and is also likely to speed up the actual effective date of the MDR’s requirements across the EU. The complex development process for medical devices, combined with the changes, are likely to make the transition period a complicated and time-consuming process for most device manufacturers. Because of these complexities, medical device manufacturers are well-advised to stay current on the progress of the MDR through the regulatory approval process, as well as additional changes that may impact them. In addition, since a large number of medical devices are expected to require notified body review and approval, delays in the review and approval process by notified bodies should be expected. Manufacturers of currently approved devices are therefore advised to evaluate potential compliance issues and to develop a plan to address them promptly, if they want their products to remain on the EU market. Advanced preparation and early action will be key to ensuring a smooth transition to the new requirements. The Medical Devices Quality Management System ISO 13485 ISO 13485 addresses the development, implementation and maintenance of a quality management system intended for use by medical device manufacturers and suppliers. ISO 13485 – Medical devices – Quality management systems – Requirements for regulatory purposes, would offer manufacturers process-focused support to help them address their approach to tackling the introduction of the MDR, as it addresses the development, implementation and maintenance of a quality management system for medical device manufacturers and suppliers. 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The standard details how customer specifications and relevant regulatory requirements should be incorporated within an organisation’s quality management system. Although ISO 13485 is similar in scope and intent to ISO 9001, it also includes additional quality management system requirements specifically appropriate to an organisation involved in one or more stages of the medical device life-cycle. As a result, ISO 9001 certification is generally not an acceptable substitute for certification to the requirements of ISO 13485. In the European Union (EU), the requirements of EN ISO 13485 have been harmonised with the Conformity Assessment Procedures of the EU’s Medical Device Directive (93/42/EEC); the Directive for In Vitro Diagnostic Medical Devices (98/79/EC); and the Directive for Active Implantable Medical Devices (90/385/EEC). Conformity Assessment Procedures in conjunction with a certification to EN ISO 13485 by a notified body provides a presumption of compliance with relevant EU legislation. Health Canada also mandates that medical device manufacturers marketing their products have their quality management system certified to ISO 13485. The ISO 13485 Revision Work to revise ISO 13485 began in April 2012. As this was the first revision of ISO 13485 since 2003, the ISO working group responsible faced the significant task of addressing nearly a decade of changes in technology and regulatory requirements. The revised standard ISO 13485:2016 was finally published on 1 March 2016, and has a three-year transition period for device manufacturers and other organisations certified to ISO 13485:2003. All ISO 13485:2003 certificates will expire on 28 February 2019, and the transition period is now over half completed. There are significant changes in a number of important areas: Quality Management System (Clause 4) All processes that are part of a manufacturer’s quality management system will now need to be developed using a risk-based approach. This represents a significant expansion of the risk management approach in
ISO 13485:2003, in which only product design controls and product realisation processes were subject to risk management requirements. In addition to this important change, processes that are outsourced must also apply a risk-based thinking approach. This section of the standard also states that any software used as part of the quality system must be validated and documented. In addition, the revised standard requires the maintenance of a comprehensive technical file for each manufactured device, that includes a description of the device along with all relevant specifications and records. Management Responsibility (Clause 5) Changes to this section of ISO 13485 primarily involve clarifications of existing requirements regarding q u a l i t y m a n a g e m e n t sys t e m planning, responsibility and authority, management representation and management review. Resource Management (Clause 6) The standard will now oblige device manufacturers to define the specific skills and experience required for personnel involved in the maintenance of the quality management system. Further, ISO 13485 certified organisations will have to maintain systems for ensuring that personnel maintain the requisite knowledge through ongoing training, as well as a mechanism for assessing the effectiveness of such training. A new clause in this section also addresses contamination control issues for sterile medical devices, and includes requirements related to the validation of processes intended to ensure the integrity and effectiveness of sterile device manufacturing. Product Realisation (Clause 7) Clause 7 addresses specific requirements within each of the areas defined within this enlarged scope of product realisation. Further, as previously noted, medical device manufacturers will be expected to incorporate risk management principles in determining the application of these requirements. New sub-clauses have been added in design and development for transfer of design and development outputs to manufacturing and maintaining a design and development file. Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace Measurement, Analysis and Improvement (Clause 8) Under this section of the revised standard, device manufacturers will be expected to formalise their processes for obtaining feedback from both production and post-production activities, and to develop sound methods for incorporating that feedback into its risk management programme. The revised standard also strengthens requirements regarding the investigation and control of non-conforming products, as well as those related to corrective and preventative actions. New sub-clauses have been created in monitoring and measurement for complaint handling and reporting to regulatory authorities. Transitioning to the New Requirements There are important structural differences between ISO 13485:2016 and ISO 9001: 2015. These are likely to complicate the compliance and auditing process for medical device manufacturers which are currently certified to both ISO 13485 and ISO 9001. Given the extent of the changes, as well as the structural differences
between the revised ISO 13485:2016 and ISO 9001:2015, transitioning to the new requirements is likely to take a considerable investment of time and resources. Therefore, medical device manufacturers and other ISO 13485 certified organisations are advised to promptly begin the process of evaluating the application of the standard’s updates against their existing quality management system, in order to determine the scope of required changes and the time that will be needed to implement them. Likewise, while getting to grips with these significant changes associated with the MDR may take some effort now, it will prove to be a good return on investment. For those who leave it too close to the deadline to have their products assessed against this new regulation, they will find that notified bodies will be booked solid as the deadline approaches. If your product isn’t approved in time, it will have to be withdrawn from the market. Invest in appropriate re-designs now and have them assessed against the new requirements to reap rewards further down the line.
Richard Poate Richard Poate is Senior Manager at TÜV SÜD Product Service, a global product testing and certification organisation, and at its sister company, TÜV SÜD BABT, the world’s leading radio and telecommunications certification body. Richard Poate is currently responsible for the medical business in the UK. Previously having worked for the UK Ministry of Defence, then in medical physics with the National Health Service and then in industry, he is a qualified engineer with a background in electronics and active medical devices and has over 24 years’ experience working in product compliance and approvals. Email: firstname.lastname@example.org
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Regulatory & Marketplace
Drug Regulatory Requirements in Bhutan: A Glance With the participation and exposure of officials from the Ministry of Health to international conferences on pharmaceuticals safety and the International Conference of Drug Regulatory Authorities (ICDRA), Bhutan recognised the need to introduce a national drug policy and medicines legislation. Regulatory procedures have been developed to ensure promotional activities of medicines are fair, balanced, and aimed at rational drug use. DRA is also obliged to share the local ADR data to the global database for the purpose of signal detection globally, after Bhutan became a member of the WHO international drug monitoring system. Bhutan is a fast-emerging market. This article gives an outline of drug regulatory requirements for the registration of new drugs and other classifications of medicine in Bhutan.
Introduction Bhutan, officially the Kingdom of Bhutan, is a landlocked country in South Asia at the eastern end of the Himalayas. Thimphu is its capital, and it is bordered to the north by China and to the south, east and west by India. To the west, it is separated from Nepal by the Indian state of Sikkim, while farther south it is separated from Bangladesh by the Indian states of Assam and West Bengal. Bhutan distributes free medicine to its people. Bhutan is also notable for pioneering the concept of gross national happiness1. Legal Framework and Regulations DRA Guidelines and Regulations • Bhutan Medicines Rules and Regulation 2012 • Guideline for Registration of Biotechnology Products for Human use • Guideline for Application for Registration of Medical Product 2013 • Guideline for Disposal of Pharmaceutical Waste • Guideline for Health Supplements • Guideline for Registration of Biotechnology Products for 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Veterinary Use Medicines Act 2003 Blood and Blood Products Regulation of Bhutan 20162
formulations of the same medicinal product. d) The applicant must ensure that the name of the manufacturer(s), address and contact details are consistent throughout the application, e.g. in the
Regulatory System (Organisational Structure)
Regulatory Requirements for Registration Procedure for Application for Registration: The route of product registration is broadly classified under 1. Abridged evaluation 2. Full evaluation In general, the product registration will follow the full evaluation route, while the abridged evaluation is granted for those products wherein the safety, efficacy and quality parameters of the specific medicine are evaluated by other recognised agencies. I. Application for Registration a) The application for registration of each product under abridged and full evaluation should be made on form V-PAR and form VI-PFR, respectively. b) Products which are packed together in combination for a therapeutic regimen (example for the treatment of Helicobacter pylori) will be classified as a combination pack product and shall be registered as a single product. c) Separate applications should be made in respect of different
manufacturing licence, GMP certificate, COPP, authorisation letter, etc. e) The application for registration must be accompanied by the token fees, which may be revised from time to time, along with the documents detailed under each category of medicines. f) After filing the application for registration along with the required documents, the dossier at DRA undergoes a two-stage evaluation, viz., general document evaluation and technical document evaluation. II. General Requirements of the Dossiers The dossier should be: • In English or Dzongkha or both • Properly bonded • In A4 size paper • Contain price structure of the medicinal products • Be complete as per the specifications detailed in this guideline • Contain certificates or testimonies obtained from other agencies or authorities in original form, or in case of duplicate or electronic submission, attested by the public notary or a court of justice. Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace III. Classification of Medicine For convenience of registration, medicines are classified into nine categories based on indications and target species, viz. 1. Human allopathic medicines: Modern conventional medicines which have therapeutic indications based on clinical research and are used in humans. 2. GSo-ba-rig-pa medicines: Traditional medicines recognised by the Bhutan Medical and Health Council, which are manufactured using the ingredients and methods as per the gSo-ba-rig-pa text. 3. Veterinary allopathic medicines: Modern conventional medicines which have therapeutic indications based on clinical research and are used in veterinary medicine. 4. Biologics and biotechnology products: Includes the use of the new genetic tools of recombinant DNA to make new genetically modified organisms or genetic engineering, bioinformatics, transformation, diagnostics and vaccine technology. Biological products include, but are not limited to, bacterial and viral vaccines, therapeutic serums, antitoxins, human blood components and their derivatives, and certain products produced by means of biotechnology.
7. Active pharmaceutical ingredients for extemporaneous preparation: Any substance or mixture of substances used in the compounding of extemporaneous preparations for intended therapeutic effect. This, when used in the formulation, forms an active component to which the therapeutic effect of a product is attributed. This excludes the API used by the pharmaceutical manufacturers. 8. Antiseptics/skin disinfectants: Includes any medicated chemical used as an antiseptic or for the purpose of disinfection of skins of human and animal. This excludes the medicated chemicals used on inanimate objects. 9. General sale list: The list as defined by the Drug Technical Advisory Committee and Bhutan Medicines Board. The list of such medicines will be made available on www.dra.gov.bt.3
1. Abridged Registration Abridged evaluation shall be applicable to: a. A product that has been evaluated and approved by at least one of the following referenced drug regulatory agencies at the time of submission of application for registration; • • • • •
• • • •
Australia Therapeutic Goods Administration (TGA) Health Canada (HC) US Food and Drug Administration (FDA) European Medicines Agency (EMA) UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) Japan DRA Health Science Authority of Singapore (HSA) Drug Control Authority of Malaysia (BPFK) Thai Food and Drug Administration (FDA)
5. Complementary medicines: Products with therapeutic claims as determined by DRA and are intended to supplement the diet taken by mouth in forms such as pills, capsules, tablets, liquids or powders and not represented as a conventional food/sole item of a meal or diet. Products with therapeutic claims which do not fall under human allopathic, veterinary allopathic, gSo-ba-rig-pa, biologics and biotechnology products will be considered as complementary medicine. 6. Medical gas: Gas which is of pharmacoepial standard and is used in health institutions for its therapeutic purpose. www.ipimediaworld.com
Flowchart of Drug Registration INTERNATIONAL PHARMACEUTICAL INDUSTRY 23
Regulatory & Marketplace b. Medicinal product, including vaccines which are pre-qualified by WHO, UN, OIE or other UN-recognised international organisations. Data Requirements for Abridged Registration • • • • • • •
Documentary evidence to support abridged evaluation Declaration letter Letter of authorisation from the manufacturer Price structure Product sample Specimen of package, label and insert Therapeutic indications – product information summary
2. Full Registration 1. Full evaluation route shall be applicable to all the category of medicines which does not fulfil abridged evaluation criteria. 2. The medicines which are evaluated via full evaluation are required to fulfil data requirements as given below:
• • •
III. Quality Profile
1. This part of the document will apply to all categories of medicines evaluated via the full evaluation route, unless specified otherwise. 2. The product profile should provide the following information on the finished product:
• • • • • • •
Company profile Current Good Manufacturing Practices (cGMP) certificate Manufacturing licence Certificate of the pharmaceutical product (CoPP) Letter of authorisation from the manufacturer Evidence of free sale Price structure
24 INTERNATIONAL PHARMACEUTICAL INDUSTRY
• • • •
• • • • •
• I. General Documents
4. For g.so-rig-pa medicine, g.so-rigpa name and copy of reference formulary (g.so-rig-pa text) must be furnished.
II. Product Profile
Part I – General documents Part II – Product profile Part III – Quality profile Part IV – Pharmacological documents. 3. While Parts I and II are applicable to all the categories of medicine, Part IV is, however, applicable only to allopathic medicines for humans and animals; and biologic & biotechnology products. 4. The quality document and pharmacological document required is detailed under each category of medicine, while general documents and product profile are common, unless specified.
Letter of evidence Product sample Specimen of package, label and insert
Generic or international non-proprietary name (INN) Brand name or trade name (if applicable) Dosage form Strength of the finished product Reference of the official standards of the finished product (e.g. compendial pharmacopoeias or manufacturer’s in-house specification) List of all the ingredients in the dosage form and their amount on a per unit basis, as per the label claim and batch quantities Description of the organoleptic characteristics of the product, including shape, size, superficial markings for identification purposes, colour, odour, taste, consistency, type of tablet coating, type of capsule, superficial markings for identification purposes, etc. Physico-chemical properties such as colour, shape, particle size, pH, solubility in water and other solvents, existence/absence of polymorphs and pseudopolymorphs, hygroscopic nature, etc. When describing a liquid, state clearly whether it is in the form of a solution (clear), suspension, emulsion, etc. Commercial presentation of packaging and pack size in terms of quantity/weight/volume, etc.
3. In addition, the following information is required for biologics and biotechnology products: a. Qualitative statement describing the physical state of the product (eg. lyophilised solid, powder, liquid etc.) b. Statement describing the type of finished product (e.g. live/attenuated, killed/inactivated, etc. for vaccines)
• • • •
Technical documents for raw materials Certificate of analysis (CoA) of raw materials Manufacturing process Analytical method for finished product Certificate of analysis (CoA) of finished product Disintegration and dissolution profile Stability test report Package information Certificate of analysis (CoA) of package and label
IV. Pharmacological Documents a. Product information summary b. Bioequivalence (BE) study c. Pre-clinical & clinical studies data a. Pre-clinical data b. Clinical data4 V. Priority Review for Registration 1. The priority review will be given in terms of the time, viz., if such applications are received, the dossier evaluation will be given priority. However, the data requirements should be fulfilled. 2. The priority review may be given for treatment of disease conditions that are of local public health concern. This may include the medicines for cancer, HIV, dengue, tuberculosis, hepatitis and malaria. 3. The request for priority review should be made at the time of submitting the dossiers along with justification, which warrants a priority review. DRA, however, reserves the right to deny a request for priority review if it is deemed appropriate. This will be communicated to the applicant. VI. Responsibility of Marketing Authorisation Holder, MAH 1. The applicant shall be responsible for the product and all information supplied in support of his application Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace for registration of the product. 2. He shall be responsible for updating any information relevant to the product/application. The DRA should be informed in a timely manner of any change in product information during the course of evaluation, and after product registration, if the information pertains to rejection/ withdrawal, additional data on product efficacy and safety or current Good Manufacturing Practice (cGMP) compliance of the manufacturers. 3. He shall notify the authority of any changes related to product quality, efficacy or safety throughout the product’s life cycle in the country. 4. The MAH must assume responsibility for the quality, safety and efficacy of his/her products. 5. The MAH is responsible for ensuring that the product imported for local sale and supply is identical, in all aspects, to that supplied at the time of registration. Any change in the product particulars must be notified to DRA and approval obtained before import. VII. Processing of Applications 1. Initiation of Review Review of applications will follow a queue system. 2. Stop Clock a. The clock starts once payment has been confirmed for a submitted application and will stop whenever the DRA needs to seek further information from the applicant. The clock restarts when the DRA receives complete responses from the applicant. b. A period of 6 (six) months will be given within which the applicant should submit the additional information/clarification required for each correspondence from the DRA. c. The clock stops when the DRA informs the applicant of its regulatory decision. 3. Rejection of the application a. An application for registration will be rejected in the following instances: •
I f the applicant fails to respond to the enquiries or submit the required additional documents within six (6) months from the last correspondence date. OR
he applicant fails to submit all the T required documents and complete the registration formalities within one (1) year.
b. Once the application is rejected, the applicant will be informed and the dossiers will be handed over to the applicant. c. If the applicant wishes to re-process the same, the application must be re-submitted along with a complete set of documents and token fee. The dossier will then be considered new.5 VIII. Renewal of Product Registration 1. Application for renewal shall be submitted in form VIII-PRR of the regulation at least 30 days before the expiry date of the registration along with the processing fee. 2. A grace period of three months may be given if the current MAH provides a written justification with evidence of having carried out the renewal process with the manufacturers prior to the date of expiry. 3. Upon completion of the grace period or failure to provide the evidence, the product shall be deemed de-registered from the actual registration expiry date. Once de-registered, the application will be considered new and full documents must be submitted. 4. The renewal with conditions and documents prescribed below is
applicable only to the medicines which are evaluated via full registration route. 5. The medicines which were evaluated via the abridged evaluation route shall be renewed upon submission of a complete set of documents as initial registration. 6. The procedure for the renewal of the registration is the same as the initial registration. However, one-time renewal of registration shall be granted with the fulfilment of the following conditions and documents. IX. Change in the Particulars of the Registered Product – Post-registration Changes 1. The MAH may apply for any post-registration changes during the valid period of registration under the following procedure and conditions: •
Apply to the authority on form VIIa-PRC with proposed changes for allopathic medicines and form VIIb-PRC for gSo-ba-Rig-pa medicines. Import the product only upon the confirmed incorporation of the post-registration changes by the authority.
2. Only following post-registration, change is accepted. The change must be submitted with supporting documents as indicated against each proposed change7:
Type of post-registration change: Change in product name Conditions to be fulfilled
There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process, etc.) except for the product name change.
Documents to be submitted
1. Official letter from principal manufacturer requesting the change of product name. 2. A declaration letter from the manufacturer and MAH that there is no other change to the product/label, except for the finished product name change. 3. Revised draft package insert and label incorporating the proposed variation. 4. Updated certificate of pharmaceutical product (CoPP) (where applicable). 5. Product sample with proposed name.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 25
Regulatory & Marketplace Type of post-registration change: Change in the specimen of package insert, patient information leaflet, unit carton label, inner label and/or blister strips. Includes: 1. Change of the layout/artwork 2. Addition/deletion/replacement of pictures, diagrams, barcode, logos and/or texts on the package and label 3. Change in information in the insert Conditions to be fulfilled
There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process etc.) except for the above specified change.
Documents to be submitted
1. Official letter from principal manufacturer requesting the change of product name. 2. Current approved product labelling. 3. Proposed product labelling, a clean and annotated version highlighting the changes made. 4. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change. 5. Relevant document/reference to support the changes (where applicable). 6. Product sample with proposed change.
Type of post-registration change: Change of pack size/fill volume and/ or change of shape or dimension of container or closure for non-sterile product Conditions to be fulfilled
1. Shelf-life specifications of the finished product remain unchanged. 2. The new size is consistent with the dosage regimen and duration of use as approved in the package insert. 3. The change only concerns the same packaging type and material.
Documents to be submitted
1. Justification for the proposed pack size. 2. Revised drafts of the package insert and labelling incorporating the proposed changes (where applicable). 3. Stability data at zone IV for at least three different batches. Both real-time and accelerated stability test report must be submitted. 4. Price structure for the new pack. 5. Information and data on package and label. 6. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change. 7. Certificate of analysis for the finished product. 8. Product sample with proposed change.
Type of post-registration change: Change of outer carton pack sizes for a finished product Conditions to be fulfilled
1. Primary packaging materials remain unchanged. 2. No other changes except for the change of outer carton pack sizes for a finished product.
Documents to be submitted
1. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 2. Letter of declaration from the manufacturer and MAH stating that there are no other changes except for the change of outer carton pack sizes for a finished product.
Type of post-registration change: Change in any part of the (primary) packaging material not in contact with the finished product formulation, such as colour of flip-off caps, or colour code rings on ampoules Conditions to be fulfilled
Documents to be submitted
The change does not concern a part of the packaging material which affects the delivery, use, safety or stability of the finished product. 1. Information and data on package and label. 2. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 3. Letter of declaration from the manufacturer and MAH stating that there are no other changes except for the intended change. 4. Price structure, if applicable. 5. Product sample.
26 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Type of post-registration change: Reduction of shelf-life of the finished product a) As a package for sale and/or b) After first opening and/or c) After dilution/reconstitution Conditions to be fulfilled
1. For (a) & (b) â€“ The studies must show conformance to the currently approved shelf-life specification. 2. For (c) â€“ The studies must show conformance to the currently approved shelf-life specification for the reconstituted product.
Documents to be submitted
1. Results of appropriate real-time stability studies covering the duration of proposed shelf-life of at least two pilot/production-scale batches of the product in the authorised packaging material. 2. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 3. Justification letter for the change of shelf-life of the finished product (where applicable). 4. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change.
Type of post-registration change: Change of the name or address (for example: postal code, street name) of the manufacturer of finished product Conditions to be fulfilled
1. The manufacturing site remains the same. 2. Not applicable to the case in which it involves change in ownership of the manufacturer. 3. No other changes except for the change of the name and/or address of a manufacturer of the finished product.
Documents to be submitted
1. Official letter from the manufacturer requesting for the change in name/address of the plant. 2. A valid GMP certificate, CoPP which covers the GMP certification or official document from the relevant authority confirming the new name and/or address. 3. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 4. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change. 5. Product sample. 6. Price structure, if applicable.
Type of post-registration change: Change in storage conditions Conditions to be fulfilled
There is no change to the product except for the intended change.
Documents to be submitted
1. Stability test report. 2. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change. 3. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 4. Product Sample
Type of post-registration change: Price structure Conditions to be fulfilled
There is no change to the product except for the intended change.
Documents to be submitted
Price structure of the product.
Type of post-registration change: Additional indication Conditions to be fulfilled Documents to be submitted
1. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change. 2. Revised drafts of the package insert and labelling incorporating the proposed variation (where applicable). 3. Product sample. 4. Price structure, if applicable.
Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace Type of post-registration change: Change of product labelling due to safety updates Conditions to be fulfilled
The change relates to tightening of the productâ€™s target-patient population â€“ The change is an addition of warnings, precautions, contraindications or adverse events/ effects to the approved product labels.
Documents to be submitted
1. Official letter stating: (a) the reasons for the notification, AND, (b) the status of the proposed changes in other countries; 2. Letter of declaration from the manufacturer and MAH stating that there are no other changes on the label except for the intended change and that the changes are supported by data.
Type of post-registration change: Change of pharmacoepial standard of the finished product Conditions to be fulfilled
There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process, etc.) except for the intended change.
Documents to be submitted
1. Official letter from manufacturer authorising the change of pharmacoepial standard. 2. A declaration letter from the manufacturer and MAH that there are no other changes to the product/label except for the change in the pharmacoepial standard. 3. Revised draft package, insert and labelling incorporating the proposed change. 4. Updated certificate of pharmaceutical product (CoPP) (where applicable). 5. Price structure, if applicable. 6. Product sample.
Type of post-registration change: Substitution of the raw materials in case of pSo-ba-rig-pa medicines Conditions to be fulfilled
There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process) except for the substitution of the raw materials.
Documents to be submitted
1. Justification for change. 2. Official letter from manufacturer authorising the substitution. 3. A declaration letter from the manufacturer and MAH that there are no other changes to the product/label except for the intended change. 4. Revised draft package, insert and labelling incorporating the proposed change. 5. Photocopies of gso-ba-rig-pa text references which have such similar therapeutic indications. 6. Price structure, if applicable. 7. Product sample.
Type of post-registration change: Substitution of the specifications for the pre-processed raw materials in case of pSo-ba-rig-pa medicines Conditions to be fulfilled
There is no change to the product (formulation, release and shelf-life specifications, manufacturing source and process) except for the specifications of the pre-processed raw materials.
Documents to be submitted
1. Justification for change. 2. A declaration letter from the manufacturer and MAH that there are no other changes to the product/label except for the intended change. 3. Test report on pre-processed raw materials. 4. A copy of preprocessing method from g.so-rig-pa text if available or a copy of method used. 5. Price structure, if applicable. 6. Product sample.6
Timelines The registration certificate shall be issued within 30 working days from the date of receipt of complete required documents, unless otherwise a longer period is required, in which case, the party will be informed.7 Validity of Registration The registration of a product shall be valid for a period of three (3) years and shall be specified on the certificate.8 Fees: Fees for Registration The fees for registration of the medicinal product may be revised from time to time by the DRA. In such cases, the public shall be notified. 1. Processing fee: Every application for registration shall be accompanied with a processing fee of Nu. 150.00 (one hundred and fifty only). 2. Registration fee: The registration fee of Nu. 1500.00 (one thousand five hundred only) per product shall be paid at the time of issuance of registration certificate. 3. Other charges: a. The authority may charge any applicant such costs as it may incur for the purpose of carrying out laboratory investigations if and when necessary, prior to registration of the product. b. Any payment made is not refundable once an application has been submitted and payment confirmed. Applications without the correct fees will not be processed.8 Conclusion Bhutan is a fast-emerging market. On the brighter side, DRA has been successful in regulating all manufacturing premises, pharmacies and persons handling the pharmacy business, and there is increased compliance to Good Storage Practices, distribution practices and management of defective medicines, and the Blood and Blood Product Regulation 2015 has been approved for implementation. DRA has increased our routine sampling and testing and reporting of adverse drug reactions, thereby ensuring that medicines are of the required quality, safety and efficacy.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 27
Regulatory & Marketplace DRA is working towards instituting a quality system by bringing out a quality manual. It is expected to comply with ISO 9001:2015 standards.
REFERENCES 1. 2.
https://en.wikipedia.org/wiki/Gross_ National_Happiness http://dra.gov.bt/wp-content/
3. 4. 5. 6. 7.
uploads/2016/05/DRA-NewsLetter-31.03.2016.pdf https://en.wikipedia.org/wiki/Bhutan http://dra.gov.bt/profile/ http://dra.gov.bt/wp-content/ uploads/2017/04/draprofile.png www.dra.gov.bt http://dra.gov.bt/wp-content/ uploads/2015/07/Guideline-forApplication-for-Registration-ofmedical-product-2013.pdf http://dra.gov.bt/applicationregistration-fees-and-renewal-fees/
Kaushik Devaraju M.Pharm, PhD Research Scholar, Regulatory Affairs, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru Email: firstname.lastname@example.org
Balamuralidhara V. Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru. Email: email@example.com
T.M. Pramod Kumar Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru. Email: firstname.lastname@example.org
Dr Gaurav Mathur Director, Global Regulatory Affairs & Head – AsiaPac Data Sciences, Safety & Regulatory Operations, Quintiles Research (India) Pvt Ltd., Bengaluru. Email: email@example.com
28 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
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#10701 0318 29 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Regulatory & Marketplace
Ireland’s Medtech Success Story
Ireland’s medtech sector is internationally recognised as a leading global cluster characterised by a deeply evolved ecosystem, encompassing leading multinationals, specialised research and clinical capabilities and a dynamic start-up and indigenous base.
Exports of Irish medical devices and diagnostic products stand at €12.6bn and represent 8% of the country’s total figure, making Ireland the secondlargest exporter of medtech in Europe. This number has grown four-fold in the past 10 years, particularly impressive in the context of the economic turbulence seen in this period. This is a country which truly punches above its weight in medtech – responsible for the manufacture of 33% of the world’s contact lenses, 75% of replacement knees and 50% of ventilators in acute hospitals worldwide. So how has an island of just over 4.7 million people emerged as one of the world's top five medical technology hubs over the last 20 years, rivalling key clusters such as Minnesota and Massachusetts? And how can it maintain this exceptional performance? International Attraction As a small open economy, Ireland has always understood the importance of an outward-looking approach and the benefits to be gained from embracing close international relationships.
30 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The country’s success in attracting large medtech players to its shores, spearheaded by the country’s inward investment agency IDA Ireland, is well documented and has created a strong foundation for the vibrant ecosystem that exists. Ireland is today regarded as a destination of choice for medtech investment in Europe, accounting for one-third of new projects in 2015. Nine of the world’s top ten medical technology companies have a base in Ireland and it is the second-largest employer of medtech professionals in Europe, per capita. Many of these have multiple sites, such as Boston Scientific, the largest medical device employer in Ireland, which employs over 5300 across three sites. The breadth and depth of investment has become increasingly sophisticated in recent years, moving from a largely manufacturing base to functions such as shared services and research, with 60% of companies engaged in their own R&D.
Examples include Stryker, whose global technology development centre and centralised additive technology manufacturing hub in Cork undertakes leading-edge work in 3D medi-printing, and Cook Medical’s Limerick operations which are home to global R&D projects at their innovation centre and also hosts their Europe shared service centre. DePuy Synthes has brought extensive operations to Ireland with a state-of-the-art manufacturing facility, global supply chain and innovation centre in Cork. Native Talent While such overseas investment is critical, fostering homegrown innovation is also high on the agenda, with 60% of Ireland’s 450 medtech companies indigenous. Ranked by PitchBook as the third-largest seed investor in Europe, Enterprise Ireland, the government’s trade and technology organisation, invested €31 million in Irish start-ups
Spring 2018 Volume 10 Issue 1
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Regulatory & Marketplace The success and potential of Irish-owned medtech businesses has not gone unnoticed either, with a number of acquisitions in recent times, such as the sale of Galwaybased stroke care company,Neuravi, to J&J last year, and Avery Dennison Corporation’s acquisition of Longford wound care company Finesse Medical.
in 2017, supporting a total of 181 companies, and plays a critical role in supporting ambitious Irish companies to achieve greater scale in global markets through fostering and developing entrepreneurship. EI invested in 25 life sciences start-ups in 2017, with spin-outs from academic research accounting for 25% of these. With spin-outs from academia delivering the strongest growth in sales, it makes sense to prioritise them as future growth prospects. A key source of these high potential stars is BioInnovate, a 10-month course funded by EI and industry that embeds participants in the clinical environment and is modelled on Stanford University’s Biodesign programme in California. The initial focus is on clinical need and fellows are tasked with identifying problems, then finding innovative solutions. Time is spent in a clinical environment in Dublin, Cork, Limerick, Galway and internationally. This is unique in Europe, and the only international programme recognised by Stanford through its affiliate programme.
detection of kidney reflux in children and Signum Surgical’s novel minimallyinvasive technologies to treat colorectal diseases. Companies are then funneled through Enterprise Ireland’s commercialsation and innovation funding supports and given access to the 33-strong overseas office network to help them sell and scale their products in global markets. Building these companies to become Irish multinationals is the end goal. One such company which has achieved this is Aerogen. Established in 1997, it is today the global leader in aerosol drug delivery systems. Described by CEO, John Power, as ‘the Intel chip of aerosol drug delivery – the brand people look for’, Medtronic is one of a number of major players which have integrated Aerogen’s technology into their own platforms. With around five million patients in intensive care units treated in 75 countries worldwide, the company is certainly making its mark on a global scale. Ireland’s goal is to replicate and accelerate this success.
The Innovation Agenda Innovation has been a core component of Ireland’s medtech growth to date and a critical part of its future. Backed by substantial investment in science and technology, Irish SMEs were ranked number one for innovation by the European Commission’s 2017 Innovation Scorecard and over 50% of medtech companies have a dedicated R&D function. The Irish Government is continuing to put innovation first through its Innovation 2020 strategy. One of its main aims is to ensure that companies based in Ireland outperform their competitors in international markets. A key target is to grow the number of research personnel in industry by 60% to 40,000 by the end of the decade. Science Foundation Ireland is a key piece of the jigsaw. It was founded in 2000, with the objective of making Ireland a global leader in globally relevant scientific and engineering research, discovery and innovation. Funding oriented basic and applied research across science, technology, engineering and mathematics, it has elevated Ireland to a prominent position on the world stage, currently placed 11th in global scientific rankings. The view of SFI is that Ireland’s investment in science needs to
The ambition? To disseminate innovation back in to industry and the clinical community but also, to generate a strong pipeline of highlyinnovative start-ups focused on a clear clinical need. To date, five spin-outs have emerged with a further 20 technologies in development. These include Kite Medical’s noninvasive diagnostic solution for 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
Regulatory & Marketplace prototyping, precision engineering and manufacture. Partnering with leading multinationals on their doorstep has allowed companies to develop best-in-class services and to move up the value chain from being component suppliers to design and manufacturing partners, chosen for their ability to offer innovative solutions to global customers. Anecto boasts the widest range of testing services in Europe for medical devices and a state-of-the-art test facility serving 85% of the world’s top 20 medtech companies, while Acorn Regulatory, one of the largest pharma and medtech regulatory firms in Europe, is active in over 76 markets. almost double in the coming years in order to continue to innovate at the rate the scale required for economic success. Collaboration is regarded by many as the cornerstone of Ireland’s success in the sector. The close ties within the ecosystem, between academia, industry, clinicians and government, is unrivalled. A cohesive strategy and the investment in an agreed approach has enabled the industry to flourish. Examples of this joined-up approach include the Health Innovation Hub Ireland which partners clinicians, academics, and entrepreneurs to evaluate products in a clinical setting and HRB-CRI, a national clinical research network providing centralised support in the conduct of multicentre trials across Ireland. Engagement with industry is key. AMBER, the SFI funded materials science centre at Trinity College Dublin, recently announced a collaboration with Irish company, Kastus, through the Industry Fellowship Programme, which supports industry-academia research partnerships. Joint reach will focus on the area of antimicrobial coatings, which have already been commercialised by Kastus to fight superbugs. Galway, where a third of Ireland’s medtech employees are based, is undoubtedly the epicentre of activity. The recently launched BioExel Medtech www.ipimediaworld.com
Accelerator, is the first of its kind in Ireland to focus solely on the medical technology sector. CÚRAM, the Science Foundation Ireland Centre for Research in Medical Devices, was formed in 2016 and is based at NUI Galway. It brings together over 200 research partners and 24 industry partners, both SMEs and multinationals, such as Boston Scientific and Stryker, to develop innovative and transformative devicebased solutions to treat global chronic diseases. The Regenerative Medicine Institute (REMEDI), is a world-class biomedical research centre and home to Ireland’s only stem cell manufacturing facility. Irish companies are working closely with third-level researchers with Knowledge Transfer Ireland, allowing SMEs to match needs to available skills. Ones to Watch Ireland excels across a number of areas, with particular strengths in cardiovascular (80% of global stent production is carried out in Ireland), orthopaedics, ophthalmics and diagnostics. Supply Chain Partnerships In addition to this strength in device development, Ireland is renowned for its thriving medtech supply base, offering end-to-end solutions across all areas of the supply chain, including design,
The biennial Med in Ireland event in Dublin showcases the breadth of the offer – with 70 Irish companies along with the research, clinical and VC community meeting over 300 medtech customers and senior execs from 42 countries. Digital Health Perhaps the most exciting area for growth comes from the convergence of two worlds where Ireland really excels – software and health. As well as the stellar growth seen in medical devices and pharma, the country has also emerged as a global force in data and IoT – now regarded as Europe’s leading data centre and home to 10 of the world’s top 10 ICT companies, including Google, Facebook and IBM. Digitalisation of healthcare and collaboration beyond traditional boundaries will undoubtedly transform the sector and Ireland is uniquely positioned to play a pivotal role. Indeed, half of Irish medtech companies have a connected health element to their business. Data capture and analysis and digital therapeutics are becoming increasingly central themes in healthcare and enablers of self-management of chronic conditions – a substantial driver of cost in healthcare. Large players in both medtech and pharma are gravitating towards the opportunity and are looking to invest. INTERNATIONAL PHARMACEUTICAL INDUSTRY 33
Regulatory & Marketplace Again, collaboration drives innovation. Technology centre ARCH (Applied Research for Connected Health), supported by IDA Ireland and Enterprise Ireland, brings together world-class clinicians, academics and patient groups to explore and evaluate potential connected health solutions. Members include Intel, HP, Novartis and Philips Healthcare alongside Irish companies such as swiftQueue, RelateCare and BlueBridge. Some of the trailblazers in the space include SilverCloud Health, a leading provider of evidence-based online mental health and behavioural healthcare solutions. Having raised more than £6m in funding in 2017, its clinician-developed Digital Therapy Platform has gained strong traction in both the UK and US markets, allowing healthcare providers to increase reach, lower costs and provide effective care.
S3 Connected Health Solutions has seen a phenomenal increase in revenues in recent years driven by its digitally enhanced patient support services for pharma, medtech, and healthcare providers. The company predicts 28% growth in 2018, stemming largely from pharma companies seeking solutions to improve patient self-management and to improve patient engagement and support, and from its connected
services around devices. 100 new hires in the past two years, doubling the employee count, shows the potential for growth in this space. The Future The strategy continues to evolve, to ensure that Ireland remains at the forefront of the global medtech stage. Ireland is perfectly positioned with access to a European market of 550 million people, a world-class research system, a highly-evolved tech transfer and clinical infrastructure, and an internationally-renowned regulatory environment. Challenges remain – growing and attracting relevant talent, especially around STEM, ensuring continued investment in a competitive landscape, and creating high-quality, scalable start-ups. One thing is certain, collaboration and innovation will continue to drive the agenda. Ireland’s medtech future is looking bright.
Sheila O’Loughlin Sheila O’Loughlin is a Senior Market Advisor and global life sciences lead for Enterprise Ireland, supporting Irish companies in the pharma, medical device and digital health sectors. She has 20 years’ experience connecting Irish innovation to the UK healthcare, biopharma and medtech industries. Email: firstname.lastname@example.org
34 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 35
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Drug Discovery, Development & Delivery Emerging Treatment, Peptide Receptor Radionuclide Therapy, Provides New Treatment Option for Gastroenteropancreatic Neuroendocrine Tumours With nuclear medicine therapeutics expected to represent 60% of the projected $26 billion global nuclear medicine market by 2030,1 new alternative treatments are now beginning to emerge for conditions including gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Of these nuclear medicine innovations, Peptide Receptor Radionuclide Therapy (PRRT) is an option that combines the advantages of two of the most successful approaches to cancer treatment: external beam radiation and tumour targeted therapy. By using targeting molecules to selectively deliver radioactive payloads inside tumour cells, PRRT has the potential to provide efficacy and safety in the treatment of GEP-NETs. But why have GEP-NETs previously been so difficult to treat and what benefit does PRRT bring to patients?
What are GEP-NETs and How Challenging are they to Diagnose? Neuroendocrine tumours are a group of tumours originating in the neuroendocrine cells of numerous organs. The term neuroendocrine refers to the dual features of these cells, which are a cross between nerve cells and hormone-producing endocrine cells. GEP-NETs are subdivided into two primary categories: tumours of the gastrointestinal tract and those in the pancreas. GEP-NETs are also a rare disease. According to the European Society for Medical Oncology (ESMO), the incidence of GEP-NETs is estimated to be 5.25 per 100,000 per year.2 In the UK specifically, the estimated incidence of gastrointestinal NETs is approximately 2.65 per 100,000 per year, while the estimated incidence of pancreatic NETs in the UK is less than 0.2 per 100,000 per year.3 Nevertheless, the prevalence of NETs is relatively high, as they are often slow-growing malignancies and generally associated with prolonged survival, if properly managed.4 NETs are generally slow-growing, and in many cases do not secrete 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY
hormones. As a result, they can remain clinically silent in the early years of the disease process, often delaying diagnosis in many patients.5 Other patients do experience symptoms, which may include abdominal pain, diarrhoea, fatigue and flushing, among others; however, these symptoms can vary widely between individual patients and are often mistaken for other conditions.6 Misdiagnoses can include irritable bowel syndrome, rosacea, ulcer, allergies, Crohnâ€™s disease, anxiety and menopause.7 GEP-NET Treatment Options Treatment options for patients with GEP-NETs vary from person to person, depending on the origin of their tumour, as well as the stage, grade, tumour burden, patient health history, and other factors. Following diagnosis of GEP-NETs, surgery is often the first-line therapy for treating early-stage NETs. However, many patients with NETs are diagnosed once metastases have already occurred, limiting the curative ability of surgical approaches. Other treatments currently available for GEP-NETs include somatostatin analogues (SSAs) such as octreotide LAR and lanreotide autogel, which are recommended as first-line systemic therapy in midgut NETs to control tumour growth.8 There are further targeted treatments available for these patients, such as everolimus and sunitinib, which are approved for pancreatic NETs based on the results of two placebo-controlled trials in progressive pancreatic NETs. These are considered first-line therapies, when SSAs are not a viable option.8 Everolimus is also considered an option for patients with progressive gastrointestinal NETs.8 Systemic chemotherapy is another option indicated in progressive pancreatic NETs and can be used in both Grade 1 and Grade 2 tumours.
However, this treatment is only recommended in patients with higher tumour burden or in patients with significant tumour progression within 6â€“12 months.8 External beam radiation, which is commonly used in other cancers, is not typically considered for patients with advanced GEP-NETs, due to the diffuse nature of the disease. What does Peptide Receptor Radionuclide Therapy Provide as a Treatment for GEP-NETs? Peptide Receptor Radionuclide Therapy (PRRT) is a form of targeted treatment using a small molecule which carries a radioactive component. Administered intravenously, the targeting molecule binds to a specific receptor expressed by the tumour cells, and is then internalised into the target cell. The radioactive component of PRRT (called the radionuclide) emits energy radiation that can destroy tumour cells. Because this radionuclide is attached to the molecule which binds to receptors on tumour lesions, the radiation can be specifically targeted to tumour cells in order to destroy them. PRRT is administered concomitantly with an amino acid solution to protect against renal uptake of the radionuclide as it is cleared from the body. Lutetium 177 (Lu 177) is a commonlyused radionuclide for PRRT, selected fo r i t s m e d i u m - e n e rg y b et a emissions and relatively short tissue penetration of 2 mm, which results in direct impact to tumours with minimal ancillary damage to surrounding normal tissues. Lu 177 also has a relatively long half-life of approximately 6.73 days compared to some other radionuclides used in targeted therapy.9 PRRT was originally developed in the early 1990s by clinicians at Erasmus Medical Center in Rotterdam, Netherlands, to treat advanced neuroendocrine tumours (NETs). A Spring 2018 Volume 10 Issue 1
ExpreS2ion Biotechnologies is world leading within recombinant protein expression in Drosophila Schneider-2 insect cells using ExpreS2 ExpreS2 is a virus-free S2 cell expression platform for R&D in diagnostics, vaccines, and therapeutics, basically Challenging Proteins Made Easy
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• Protein expression screening
• Secreted or secretable protein
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HEK293 or baculovirus (BEVS) • Issues with protein cleavage during
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production using e.g. BEVS
• Transfer of cGMP compatible
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manufacturing processes to customer or CMO partners • Clinical use regulatory approved
variable glycosylation • Heterodimers Select scientific publications: 1. Jin et al. 2017 “Accelerating the clinical development of proteinbased vaccines for malaria by efficient purification using a four amino acid C-terminal ‘C-tag’ ”, Int J Parasitol 2. Hjerrild et al. 2016 “Production of full-length soluble Plasmodium falciparum RH5 protein vaccine using a Drosophila melanogaster Schneider 2 stable cell line system”, Sci. Rep. 6 3. Wright et al. 2014 “Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies”, Nature
ExpreS2ion Biotechnologies ApS · Agern Allé 1 · DK-2970 Horsholm · Denmark www.ipimediaworld.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 37 Tel (+45) 42 56 68 69 · info@expreS2ionbio.com · www.expreS2ionbio.com
Drug Discovery, Development & Delivery small number of hospitals in Europe started using PRRT in the late 1990s and early 2000s (University Hospital in Basel, Switzerland; the European Institute of Oncology in Milan, Italy; Zentralklinik Bad Berka in Bad Berka, Germany; Uppsala University in Uppsala, Sweden; and Medical University of Innsbruck in Innsbruck, Austria) and there are many additional centres using it today. In the late 1990s and early 2000s, “early adopters” of PRRT were successfully using another isotope called yttrium 90 (Y 90) coupled to various somatostatin analogs used to treat patients with NETs. In 1998, Y 90-labeled dotatoc was used in the treatment of 10 patients with different somatostatin receptor–positive tumours. In 2001, the results of a Phase II study of Y 90-labeled dotatoc in 41 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and bronchial neuroendocrine tumours demonstrated an overall response rate of 24% and a significant reduction in carcinoid syndrome in 83% of the patients.10 In 1998, a group called Specific Peptides for Imaging and Radio Isotope Therapy (S.P.I.R.I.T.) was established to develop marketable radiopharmaceuticals using targeting peptides and peptide-like molecules to deliver diagnostic or therapeutic medical doses to specific sites within the body. One of the peptides originating from this network was lutetium (177Lu) oxodotreotide. The first clinical studies with lutetium (177Lu) oxodotreotide started in 2000.10 In 2003, a study of lutetium (177Lu) oxodotreotide therapy in 35 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) demonstrated complete remission in one patient (3%), partial remission in 12 patients (35%), stable disease in 14 patients (41%), and progressive disease in seven patients (21%), including three patients who died during the treatment period.10 In 2010, Advanced Accelerator Applications, S.A. stepped in and developed Good Manufacturing Process-compliant manufacturing of lutetium (177Lu) oxodotreotide, negotiated a regulatory pathway with 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY
the US Food and Drug Administration and the European Medicines Agency, and started a pivotal multinational Phase III study (NETTER-1) at 41 global sites in 2012.10
* As of January 2018, Advanced Accelerator Applications, S.A. is a Novartis company.
By 2015, the NETTER-1 study had met its primary endpoint of assessing progression-free survival, demonstrating that treatment with lutetium (177Lu) oxodotreotide and standard of care (octreotide LAR injection) significantly improved progression-free survival compared with a high dose of octreotide acetate injection in patients with advanced midgut NETs. In January 2017, the results of this Phase III trial of lutetium (177Lu) oxodotreotide in patients with midgut NETs were published in the New England Journal of Medicine.10
Subsequent NETTER-1 Quality of Life (QoL) analysis also provided evidence of benefit in key domains that are pertinent to midgut NETs, including global health and diarrhoea.11,12 Lutetium (177Lu) oxodotreotide PRRT was approved by the European Commission in September 2017, based on data from the NETTER-1 study and data from an open-label trial conducted by Erasmus Medical Center in Rotterdam, Netherlands in patients with somatostatin receptor positive tumours. This is the very first registered peptide receptor radionuclide therapy to be brought to the European NET patient community. What is Next for PRRT? As clinical experience with PRRT for NETs has grown over the past decades, researchers have studied similar approaches for other malignancies. One such example is the development of radio-labelled l i g a n d s fo r p ro s t at e - s p e c i f i c membrane antigen (PSMA), a protein known to be over-expressed in prostate cancer. Since some of these newer compounds are not necessarily using a peptide base, such as in PRRT, this approach is increasingly being referred to as radioligand therapy, or RLT.10 Regardless of the nomenclature used, PRRT has established a new treatment paradigm in oncology.
REFERENCES Goethals P-E, Zimmermann R. Nuclear Medicine Market Essentials 2017. Louvain-la-Neuve: MEDraysintell, 2017. 2. Öberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastroentero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Annals of Oncology. 2012;23 (Supplement 7):vii124–vii130. 3. Ramage J, Ahmed A, Ardill J, Bax N, Breen JD, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012;61: 6-32. 4. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:306372. 5. O’Connor JM, Marmissolle F, Bestani C, et al. Observational study of patients with gastroenteropancreatic and bronchial neuroendocrine tumors in Argentina: Results from the large database of a multidisciplinary group clinical multicenter study. Molecular and Clinical Oncology. 2014;2(5):673-684. 6. Kaupp-Roberts S, Srirajaskanthan R, Ramage JK. Symptoms and quality of life in gastroenteropancreatic neuroendocrine tumours. EMJ Oncol. 2015;3:34-40. 7. Carcinoid.org. Could you have a neurendocrine tumor? Accessed at: https://www.carcinoid.org/ wp-content/uploads/2015/07/ NET-Cancer-inforgraphic-Nov-2016. pdf. Last accessed: February 2018. 8. Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape U-F, Öberg K. ENETS Consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016;103:172– 185. 9. Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J. Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017 Mar; 64(1): 52–60. Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery 10. Levine R, Krenning E. Clinical history of the theranostic radionuclide approach to neuroendocrine tumors and other types of cancer: Historical review based on an interview of Eric P. Krenning by Rachel Levine. 2017. J Nucl Med. 2017;58:3S-9S. 11. Strosberg J, Wolin EM, Chasen B, Kulke MH, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Öberg K, Lopera Sierra M, Ruszniewski P, Krenning E. Improved time to quality of life deterioration in patients with progressive midgut neuroendocrine tumors treated with 177Lu-DOTATATE: the NETTER-1 Phase III trial. 2017 Meeting of the European Society for Medical Oncology, Madrid, Spain. Annals of Oncology (2017) 28 (suppl_5): v142-v157. 12. Strosberg J, Wolin EM, Chasen B, Kulke MH, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Öberg K, Lopera Sierra M, Ruszniewski P, Krenning E. QOL improvements in NETTER-1 Phase III trial in patients with progressive midgut neuroendocrine tumors. 2017 North American Neuroendocrine Tumor Society, Philadelphia, Pennsylvania.
Stefano Buono is the founder of Advanced Accelerator Applications, S.A. (AAA), a radiopharmaceutical company specialising in nuclear medicine theragnostics. Following the 2018 acquisition of AAA by Novartis, Mr Buono serves as an advisor to the company. Prior to founding AAA, Mr Buono worked at the Centre for Advanced Studies, Research and Development, or CRS4, in Italy. During his six-year tenure with CRS4, he headed a team of engineers working on different international research projects in the field of energy production and nuclear waste transmutation. Before this, and alongside his appointment at CSR4, Mr Buono worked with Physics Nobel Laureate, Carlo Rubbia at CERN. He actively participated in the development of CERN’s Adiabatic Resonance Crossing (ARC) method.
Rachel Levine is the Director of Communications for Advanced Accelerator Applications, S.A., a radiopharmaceutical company specialising in nuclear medicine theragnostics. She has specialised in strategic communications for the healthcare sector (including biotech, speciality pharmaceuticals, managed care, healthcare services, and medical device and delivery) since 2000, with a primary focus on oncology. Prior to joining AAA, Rachel advised a diverse group of international companies in healthcare and other sectors as managing director of a global investor and public relations agency, and then as vice president and head of investor relations and communications for a publicly traded biotechnology company.
Product News Sartorius Stedim Biotech launches new ambr® 250 high throughput bioreactor system for perfusion culture •
Unique, single-use perfusion system offers a fast-track to intensified cell culture process development
Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry announced the launch of the ambr® 250 high throughput (ht) perfusion, a new automated parallel bioreactor system. It has been specially designed for rapid cell culture perfusion process development to optimize production of therapeutic antibodies. The ambr 250ht perfusion system has been developed in collaboration with major biopharma companies. It combines 12 or 24 single-use perfusion mini bioreactors (100-250
mL working volume) with associated singleuse perfusion components, all controlled by one automated workstation. The combination of this multi-parallel processing capacity and fully single-use perfusion vessel enables scientists to perform more perfusion culture experiments in a fraction of the time and cost of using traditional perfusion-enabled bench top bioreactors. This new innovation supports a range of hollow fiber perfusion applications, enabling Design of Experiments (DoE) studies for high cell density process development in a Quality by Design (QbD) approach. Central to the system is the novel perfusion bioreactor assembly, which is based on the established and award-winning ambr® 250 bioreactor design. Intensified cell culture processing is enabled via new components such as high efficiency spargers, perfusion pump chambers and an industry standard hollow fibre for cell retention filter. The geometrical similarity of the mini perfusion bioreactor design to BIOSTAT STR® pilot and manufacturing scale bioreactors, enables rapid scale-up of optimized perfusion processes, and shorter development timelines.
The ambr 250ht perfusion system has been specially designed for rapid cell culture perfusion process development to optimize production of therapeutic antibodies.
The ambr 250ht perfusion system is simple to set up and use, due to the fully assembled a n d i r r a d i at e d p e r f u s i o n bioreactors which include all the essential components. This includes single-use sensors to continuously monitor pressure at the culture fluid inlet and permeate outlet, enabling online
monitoring of transmembrane pressure, as well as standard parameters such as pH and DO. Dr Barney Zoro, ambr Product Manager at Sartorius Stedim Biotech, explains: “By introducing our new ambr 250ht perfusion system, we are offering our customers an important enabling technology for early-stage development of intensified cell culture processes. Transitioning from fed-batch to perfusion culture offers the potential to reduce capital intensive risk by using 1-2000L single-use bioreactors instead of 10,000L production volumes in stainless steel. ambr 250ht perfusion is a predictive process development tool that could lower the cost of goods of antibody production, as well as significantly shortening development timelines.” ambr® systems are designed and manufactured by Sartorius Stedim Biotech/TAP (Royston UK), specialized for automated cell culture and fermentation systems for life science research, development and production. The ambr® systems are widely used for cell line development and process optimization at pharmaceutical, biotechnology and academic laboratories. They are proven to provide a reliable model and consistent scalability to a range of upstream processes.
Contact: Sartorius Stedim Biotech Phone: 0049(0)551.308.0 firstname.lastname@example.org, www.sartorius.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 39
Drug Discovery, Development & Delivery
An Update on Pulmonary Drug Delivery of Dry Powders Inhalation as a Powerful Tool for Drug Delivery Inhalation of air is a vital process for all human life. Inhalation for drug delivery has been established as an effective delivery method of active pharmaceutical ingredients to a human body, mostly in the field of anaesthesia and respiratory diseases. In this article, the status and new trends in the field of drug delivery to the lungs will be reviewed, with focus on the delivery of active pharmaceutical ingredients (APIs) in the form of dry powders.
The respiratory system and especially the lung form is an underestimated organ for the delivery of drugs, where so far most non-volatile inhaled drugs target local conditions, like asthma and chronic obstructive pulmonary diseases (COPD). The large surface area of the lung, in combination with the opportunity to circumvent the first pass metabolism and the enzymatic degradation in the gut, offer however a unique opportunity to deliver APIs for both local and systemic diseases. Inhalation is now gaining more recognition, as inhaled drugs that treat systemic diseases are being developed and approved by the regulatory authorities. Historically, inhaled drugs were specifically administered to treat respiratory diseases like asthma and COPD. The first examples of inhalation to treat asthma appeared in the 19th century, like the improved Nelson Inhaler and the asthma cigarette. At this moment, three different kinds of inhalation devices can be recognised based on their technology: •
Nebuliser: these devices use oxygen, compressed air or ultrasonic power to break up solutions and suspensions of APIs into small aerosol droplets that can be directly inhaled from the mouthpiece of the device. The nebulisers are frequently used in hospitals.
40 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Pressured metered dose inhaler (pMDIs): these devices deliver a specific amount of medication into the respiratory system, in the form of a short burst of aerosolised medicine. The formulation consists of the drug, a liquefied gas propellant and, in many cases, stabilising excipients. First pMDIs were developed and launched by Riker Laboratories (now a subsidiary of 3M) in 1956, as a technology competing against the nebuliser. The MDI became rapidly popular because this type of device is small (portable), inexpensive, theoretically easy to use, fast, and silent compared to nebuliser equipment. In spite of the advantages over nebulisers, many patients had difficulties in operating an MDI correctly. The first propellant gasses, chlorofluorocarbons, were replaced by hydrofluoroalkanes (HFAs) in the 1990s. Dry powder inhalers (DPIs): these devices assist the delivery of an API in a dry powder state, often in combination with one or more excipients, to the lungs. The aerodynamic particle size in these formulations has proven to be crucial, since only particles small in size and appropriate in shape will be able to penetrate the alveolar system of the lungs. The excipient, although not always applied, can act as a carrier by facilitating and influencing the deposition of the AP in the lungs. The most commonly used devices are the reservoir device, the capsule device and the blister-based device.1 The advantage of DPI is that the system is simple, economical and more environmentally friendly than the pMDI devices. However, dry powder inhalation does rely on the inhalation force and the ability of the patient to extract the powder from the device and subsequently draw in the dry powder particles to reach the lungs.
While the first MDI device was launched in 1956, dry powder inhaler devices were not commonly available in the market until the 1980s. While in the past, metered dose inhalers dominated the global inhalation market, dry powder inhalation is currently seen as the inhalation technology with the greatest potential, with vast possibilities for new and improved therapies. In the last few years, new excipients, technologies and applications for DPIs have begun to emerge. The remainder of this article will focus on the understanding and new trends of dry powder inhalation for drug delivery. The Principles of Dry Powder Inhalation: Since the first launch of a DPI drug, the Aerohalor of Abbott, in 1948, the technology evolved in the following 40 years from single-dose capsulebased devices with a carrier-based formulation to multi-dose devices and finally the first multipl e unit-dose blister inhalers in the 1990s, the Diskhaler® and Diskus®.2 The key pharmaceutical players in the field – GSK, Boehringer Ingelheim, Teva, Astra Zeneca and Novartis – have an influential role in this field. For delivery into the lungs, the aerodynamic particles in a DPI formulation need to be small (1–5 um) and highly controlled. Commonly the drugs were micronised to achieve the most optimal aerodynamic particle size for entry into the pulmonary system, thus leading to poor flow properties and making them difficult to handle during manufacturing. In addition, most common medications against asthma and chronic obstructive pulmonary disease are active in the microgram range, providing a challenge for the filling process. In most cases, lactose was therefore added to provide bulk to the formulation, in order to facilitate manufacturing of the formulation and subsequent filling of the devices. Since the launch of the first dry powder inhalation drug, the Spring 2018 Volume 10 Issue 1
Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing
www.nemera.net email@example.com Phone: +33 (0)4 74 94 06 54
INTERNATIONAL PHARMACEUTICAL INDUSTRY 41
Drug Discovery, Development & Delivery understanding of the role of the excipients has grown further, indicating that the properties of lactose are not only important to improve powder flow and dispensing, but also to contribute to the final delivery of formulation into the lungs. After inhalation, the coarse carrier particles, carrying the drug, will be deposited in the mouth and throat regions, while detaching and propelling the API particles further into the respiratory systems. To control this process and the final deposition of the drug particles, a deep understanding of the cohesive and adhesive behaviour of the particles in a formulation is imperative. Lactose remains at this moment the most commonly accepted carrier by regulatory authorities globally in the area of the dry powder inhalation. The strict control of the physical properties of the lactose, including the particle size distribution, is required to ensure that the performance of the dry powder inhalation formulation is robust and consistent. In particular, the control of fine lactose particles in the final formulation can provide a strong tool to optimise the delivered dose into the lungs.3 Over the years, it has come to be understood that the deposition of the API into the alveolar system depends on a range of parameters (see Figure 1): •
The active pharmaceutical ingredients and its physical-
chemical properties [like particle size, surface properties and morphology]. Blending and filling: studies have shown that process parameters of the preparation and filling of a DPI final formulation can influence the deposition of the inhaled drug.4
On the one hand, the market entry of generic dry powder inhaler medications is hampered in • countries like USA and Brazil by the tight regulatory requirements. For example, in the largest market for respiratory medicine, the USA, the generic registration procedures of the fluticasone/salmeterol combination by companies like Mylan, Hikma • The physical-chemical properties and Novartis have so far not led to of the lactose. a registration: all three companies • Design parameters of the device, are currently working on their including the mouthpiece response towards the objections configuration, grid structure and and questions raised by the FDA. mouthpiece length, impaction This setback has proven to be highly angle of the powder with devices beneficial for GSK, which has thus and air inlet size.1 been able to hold on to its largest market for Advair. On the other hand, Because some of the parameters approval for the different doses of the influencing the lung deposition of fluticasone/salmeterol combination the DPI formulation cannot easily was awarded by the FDA to Teva in be adapted, manipulation of the January 2017 following a new drug lactose carrier provides a tool for application under section 505(b). the R&D teams developing new DPI Looking at the market developments, medications, to achieve the most the question remains open if this optimal performance for their new AirduoTM RespiclickTM product will be drug. able to conquer a significant market share. New Developments in the Field of DPI The high commercial value of In addition, the combined effect respiratory drugs, in combination of the parameters affecting the with patent expiry of the inhaled, performance of a DPI provide a blockbuster drugs have spurred challenge to the R&D teams of a wide range of activities from generic pharmaceutical companies companies who strive to develop to achieve both in vivo and in vitro and launch generic equivalents of equivalence of an original drug. In the DPI products. Because many other words, even though the physical of these companies have limited properties of the API, the carrier and experience in the field of dry powder the device might be available for inhalation and its challenges, duplication, detailed information on they have encountered some production conditions is not easily setbacks during the development accessible. Here, the carrier can be process. applied as a tool for fine-tuning the performance of the DPI drug with meticulous manipulation of physicalchemical properties of the lactose. In some cases, a carrier with physical properties, customised to meet the specific requirements, can provide a solution. Close collaboration with an expert in the area of inhalation-grade lactose will, in these cases, speed up the development process.
Figure 1: Formulation of a dry powder inhaler: Performance depends on various parameters 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY
These challenges to launching generic versions of DPI drugs can be overcome, as is exemplified by the successful launches of generic products of the fluticasone/ salmeterol combination in Europe: Elpenhaler of Elpen, Salmex of Celonpharma, Airflusal of Sandoz and Aerivio Spiromax of Teva (see Figure 2). Spring 2018 Volume 10 Issue 1
Are You Thinking of Moving Towards Perfusion? Today’s bioprocess professionals need to stay on top of many things: Scale-up parameters and equipment capabilities, control strategies and automation, validation requirements and documentation to name a few. New ﬁelds of applications like stem cell technology are evolving into powerful tools of the future. Become an expert in bioprocessing. Join us at www.eppendorf.com/bioprocess-experts
Eppendorf ® and the Eppendorf Brand Design are registered trademarks of Eppendorf AG, Germany. All rights reserved, including graphics and images. Copyright © 2017 by Eppendorf AG.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 43
Drug Discovery, Development & Delivery
Figure 2: Example of successful launches of the generic fluticasone/salmeterol combinations
While the European and North American respiratory market has developed to a mature and stable market, growth opportunities in emerging countries remain vast, due to the large number of undiagnosed and/ or untreated patients suffering from asthma and COPD, in combination with increased air pollution and smoking, related to fast-growing economic activities. This potential has provoked extensive development activities for inhalation drugs in countries like India, Brazil, Bangladesh, North Africa and China. The success of these development projects highly depends on the hurdles for regulatory approval in the specific countries. For example, the unclear strategy of ANVISA and the recent changes in the Chinese regulatory system might suspend the launch of affordable drugs for patients suffering from respiratory diseases in these specific countries. Efficacy of pulmonary delivery highly depends on how the patient actually uses their device, especially since most DPI devices are breathactuated. Patient compliance and adherence to their inhalation therapy is therefore essential, to ensure a positive outcome of the treatment. The question remains as to what the influence of the patient adherence to the different devices launched by the generics for the same active ingredient is, even though the incentive to switch is cost-driven. To 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY
enhance patient compliance, features including sensors for airflow and dose monitoring have been developed over the past few years.1 Sharing of this information on mobile phones and other portable devices of patients and their doctors will help to improve the delivery efficiency of DPIs. Examples of these features are included in the SmartTurbo, SmartDisk, SmartMat and Propeller.1 In the last 10 years, a few new devices have been developed. The API in the Taper device5 is contained in small micro-depressions (â€œdimplesâ€?) in micro-structured carrier tape, so that the dose for each inhalation can be varied with the specifications of each dimple. Another innovation is the Respira AOS,6 where the API is coated on a ball in the chamber of the device. The ball oscillates upon inhalation between the mesh and the device wall, releasing the drug towards the lung. The life cycle management programmes of the key pharmaceutical players in the market, in anticipation of the patent expiry for the inhaled blockbusters, have focused on the development of different combination therapies. A recent example is the approval of the triple combination therapy of GSK, Trelegy Ellipta, by both FDA and EMEA at the end of 2017. In addition, innovative treatments to treat respiratory diseases include
the search for new biological targets and biological medicines, as is exemplified by the 2014 launch of Nucala, a once-a-month-injection of GSK. Even though delivery of the biologicals to treat asthma have not utilised pulmonary drug delivery so far, examples of pulmonary delivery of proteins have been appearing. The following examples showcase how inhalation is now applied to treat systemic diseases, like diabetes and pulmonary hypertension. Two DPI products have been approved by the FDA to deliver insulin to diabetic patients. Even though the first inhaled insulin (Exubera) has been withdrawn from the market within one year, Afrezza, launched in 2014, remains an example of an elegant delivery of proteins by inhalation. In the formulation of Afrezza, Mannkind applied its Technosphere7 platform of self-assembling (fumaryl diketopiperazine) carrier particles to the absorption of large active molecules. The same platform has now been applied to the pulmonary delivery of the new drug Tresprostinil for the treatment of pulmonary arterial hypertension (PAH).8 In some cases, delivery of high doses of API to the pulmonary system posed challenges which could be solved by similar powder processing and particle engineering techniques as for the low-dose DPIs. Improvement Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery
Figure 3: Examples of innovation in Dry Powder inhalation
of the deposition can be achieved by preparing low-density (high-porosity) particles. Examples to decrease particle density are the creation of hollow particles (void space on the inside), of particles with corrugated or wrinkled surfaces (void space on the outside), or of solid foam particles. The conditions to obtain such particles by spray drying and the excipients needed have been extensively reviewed.9 A successful example is the PulmoSphere™ technology, applied by Novartis to deliver high doses of antibiotics [TOBI Podhaler]. Pulmonary vaccination is currently still in its infancy: development has so far proved to be most challenging, because of the one-time dosing in combination with the lack of a direct measurable biological effect. At this moment, DPI seems to be favoured above inhalation of solutions, because the dry state favours the stability of the vaccine. More research will be needed
to prove the value of vaccination via the pulmonary delivery. This article has summarised some of the new developments in the area of pulmonary delivery: these demonstrate how powerful inhalation can be, offering a viable and noninvasive drug delivery route for a wide variety of drugs, including small molecules, biologicals and vaccines. REFERENCE 1.
http://www.americanpharmaceutical review.com/Featured-Articles/185892Review-of-Dry-Powder-Inhaler-Devices/ Sumby BS, Churcher KM, Smith IJ, et al. Dose reliability of the serevent diskhaler system. PharmTech Int. 1993;5:20–27. Shur J, Harris H, Jones MD, Kaerger JS, Price R. The role of fines in the modification of the fluidization and dispersion mechanism within dry powder inhaler formulations. Pharm Res. 2008;25:1631–40 Kinnunen H, Hebbink G, Peters H, Shur J, Price R; AAPS PharmSciTech, Vol. 15, No. 4, August 2014. DOI: 10.1208/s12249014-0119-6 Hodson PD, Stein SW, Chiou HC, Wang Z, Robison TS, Domroese MK, Walburg, BD; US8985102, Dry powder inhalers, Priority date 2009-05-18. Donovan MJ, Pappo J, Smyth H; US8651104, Bead-containing dry powder inhaler, Priority date 2010-12-07. Richardson PC, Boss AH. Technosphere insulin technology. Diabetes Technol Ther. 2007;9:S65–S72. http://investors.mannkindcorp.com/ news-releases/news-release-details/ mannkind-opens-enrollment-phase-
1-trial-treprostinil Vehring R. Pharmaceutical particle engineering by spray drying. Pharm Res. 2008;25:999–1022
Rachel van Rijn Rachel Van Rijn is Category Manager Inhalation at DFE Pharma. Rachel Van Rijn is a result-driven senior leader with strong interpersonal skills, high sense of urgency and business sense. Motivated by interdisciplinary and international communication, complex projectstrategy, customer contact, business strategy and team work. Solutiondriven, strong analytical capacity and helicopter view. Long experience in drug development in both generic and ethical pharmaceutical companies. Inspired by the complexity of Dry Powder Inhalation. Education, PhD at University of Pennsylvania. Email: Rachel.vanRijn@dfepharma.com
Harry Peters Senior Application Specialist Inhalation
INTERNATIONAL PHARMACEUTICAL INDUSTRY 45
Drug Discovery, Development & Delivery
MALDI Imaging at High Speed Improving Sample Analysis Times in Pharmaceutical Research
Over the last decades, MALDI-TOF mass spectrometry (Matrix-Assisted Laser Desorption/Ionisation Time of Flight) has proven its usefulness and robustness in many applications, helping life scientists to meet their toughest challenges. Companies and academic institutions rely on instruments such as MALDI-TOF and MALDI-TOF/TOF mass spectrometry sys t e m s t o a c c e l e rat e t h e i r research. Scientists in areas such as pathology, biomarker research, and studies in drug characterisation, for instance, who wish to map tumour heterogeneity and link this information to disease outcome. Tissue imaging of protein distribution continues to be one of the most powerful analytical techniques to meet this challenge.
This article will focus on how new laser technology can improve sample throughput for MALDI imaging. It will demonstrate how MALDI technology is being utilised in drug development as an established tool for compound distribution analysis and an emerging tool to boost efficiency in the drug finding process, specifically for ultra high-throughput drug discovery screening. Current Challenges MALDI imaging is a spatially resolved, label-free analytical technique for direct analysis of biological samples. Acquisition speed and sample throughput are limiting factors in mass spectrometry imaging (MSI) experiments, in particular in clinical research where large cohorts of patients have to be analysed to encompass the biological variance of human samples. Translational clinically-oriented research with imaging mass spectrometry is critically dependent on speed and robust operation. Current instrumentation can limit its full adaptation. There is a need for instrumentation to overcome this limitation, enabling scientists to engage in high-throughput clinical studies. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Acquisition speed also limits MSI experiments at high spatial resolution, especially for larger tissue sections. New MALDI imaging solutions represent a paradigm shift in terms of productivity, cost of ownership and ease of use, establishing mass spectrometry imaging as a powerful and reliable information source for personalised medicine research. Innovative MALDI Analysis Technologies In the pharmaceutical environment, MALDI has widespread applicability. Today this ionisation technique is used in lead discovery in ultra highthroughput screenings, absorption, distribution, metabolism, and excretion (ADME) applications and quality control of biopharmaceuticals, or for biological/clinical diagnostics for, e.g., microorganism identification in clinics. Common requirements of these applications are: speed, time to analysis results, throughput, ease of use, definition and robustness. The instrumentation market is responding to and addressing the need for scientists to increase sample throughput and improve data quality, helping them to make the best decisions in the shortest amount of time. New mass spectrometry imaging solutions re-define the key performance measures for MALDI imaging, offering 10 times faster imaging measurements than traditional MALDI-TOF systems, without losing sensitivity. Compound Distribution Analysis While MALDI imaging analysis applications cover a broad range, a commonality is to evaluate spatial distribution of compounds in various tissue types. MALDI imaging is an analytical method for the detection of potential biomarkers directly from tissue sections that has gained popularity over the past decade. The development protocols for spatially resolved digests are of particular interest. Most importantly, on-tissue digestion allows the analysis of
peptides from formalin-fixed paraffin-embedded (FFPE) tissue, the most common type of sample in clinical pathology. In addition, it allows detection of larger proteins using peptides as proxies and facilitates biomarker ID by means of MS/MS. A recurring challenge is bottlenecks on instrument time due to the demand on imaging analyses, with traditional instruments being able to run at 2 pixel/s. Routine studies with more than one example quickly reach the limit of feasibility. In addition, the demand for higher spatial resolution increases the pixels per area with the reciprocal square of the pixel diameter. Thus, faster acquisition is not only mandatory for bringing scientific examples into routine applications, but also copes with the demand of reduced focus sizes at higher spatial resolution. In addition, higher specificity for MALDI imaging experiments is often very beneficial. High mass resolution, exploiting MS/MS modes of acquisition for targeted images is an establishing technique. There is a need for instrumentation to be faster and allow for MS/MS mode at the same speed. As an example of a MALDI MS/MS imaging acquisition, an image is shown in Figure 1. After an on-tissue digest using trypsin, a fragment of peptide ARTKQTAR is displayed. Notably, the entire acquisition of 32,000 pixels at a raster width of 30 um only took 33 min. Acquisition time is reduced by a factor of 5â€“10, allowing an entire experiment to be completed in a single workday. It presents a powerful tool to evaluate and optimise on-tissue digestion protocols. Mass Spectrometric Imaging Solution â€“ Data Example The following example illustrates initial data from a production prototype of a next generation MALDI-TOF instrument that enables acquisition Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery •
Intact protein analysis (~2,00020,000 m/z). Due to the low charge states of MALDI ions and the mass cut-off of other analyser types, this is usually reserved to MALDI/TOF instruments such as the rapifleX MALDI Tissuetyper (Fig. 3).
(Tryptic) peptide analysis (~500-4,500 m/z) is the main way to access FFPE tissues. The digest step typically limits spatial resolution (Fig. 4).
Performance of the platform was based on the following criteria: •
Generation of consistent, spatially informative images at high spatial resolution with fast acquisition speed.
Preservation of tissue integrity after laser irradiation to enable subsequent conventional histology.
Capability to process, analyse and visualise large MSI data sets both during and after the acquisition in reasonable time.
Figure 1: MS/MS image of peptide ARTKQTAR from H33_Mouse (precursor: 931.54Da -> fragment: [b+18]7 775.4Da)
speeds of up to 50 pixel (spectra) per second at pixel sizes of 10 μm and smaller. Data is shown from the most common application areas of MSI, including lipid, peptide and intact protein analysis. Methods Sample preparation and matrix application were done according to previously published standard procedures. For lipid and intact protein analysis, fresh-frozen tissue sections (10 μm) were mounted on conductive glass slides and coated with DHB matrix using a custom-built sublimation chamber. For proteins, an additional rehydration step using acetic acid (5%) in a humid chamber was conducted after matrix deposition. For peptide analysis, thin sections (4 μm) of FFPE tissue were mounted on conductive glass slides. After paraffin removal and antigen retrieval (Tris buffer, pH 9), samples were digested and coated with HCCA matrix using an ImagePrepTM device (Bruker Daltonik GmbH, Bremen, Germany) according to standard protocols. All MS imaging data was acquired on a production prototype of Bruker’s next generation MALDI-TOF instrument, rapifleX MALDI TissuetyperTM. The instrument is a linear / reflectron geometry MALDITOF instrument on the basis of the novel 10kHz smartbeamTM 3D laser. This laser uses process-optimised laser beam focusing optics to generate a narrowly-focused (<5 μm diameter) Gaussian laser spot. Combined with a www.ipimediaworld.com
set of rotating mirrors, the laser spot can be positioned fast and precisely on the sample, allowing truly square pixels. Results Initial data for three major application areas of MALDI-TOF-based tissue imaging are shown. These differ mainly in sample preparation and the m/z-range analysed. •
Lipid analysis (~500-1,500 m/z) is typically performed at small pixel sizes to achieve highest spatial resolution (Fig. 2).
The analysis of tumour heterogeneity is one of the most important biomedical research challenges in oncology and personalised medicine. MALDI imaging is perfectly suited to get an unbiased molecular view on
Figure 2: Rat testis analysed at different pixel sizes (a-c, shown to scale). At 25 μm (a), tissue structure is not clearly visualised, demonstrating the need for higher resolution. At 10 μm, detailed morphology is visible (b). Tissue integrity is fully preserved even at smallest pixel sizes (5 μm, c-e). A large measurement (0.4 cm2, 394,629 pixel) acquired at 10 μm pixel size in just 137 min (48 pixel/sec) shows highly consistent data quality (f). Five mouse brain sections (594,434 pixel total) measured in ~4h (43 pixels/sec) were imported, analysed and visualised in SCiLS Lab 2015b on a regular desktop PC in ~2h. We show a segmentation map (g) and a component analysis of all spectra, showing separation of cortical, hippocampal and cerebellar tissue (h). INTERNATIONAL PHARMACEUTICAL INDUSTRY 47
Drug Discovery, Development & Delivery
Figure 3: Sagittal rat brain section (1.36 cm2) analysed at 30 μm pixel size (151,164 pixel) (a). Total acquisition time ~4h (~11 pixel/s). Four highly localised ion distributions show delicate structures such as the hippocampal pyramid cell layer (b) and the ependyma (c) clearly. Sample courtesy of Julian Langer (MPI of Biophysics, Frankfurt) rapifleX MALDI Tissuetyper allows analysis of large, diffuse tumour samples in an enabling timeframe. Human prostate carcinoma (2.24 cm2) analysed at 30 μm pixel size (248,825 pixel) (d-g). Total acquisition time ~8h (~8.5 pixel/s). Ion distributions show fibromuscular tissue (blue), tumour cells (green), intraglandular mucous material (red) and periglandular regions (yellow). Sample courtesy of Axel Walch (Helmholtz Zentrum München) Figure 4: Human liver infected with Echinococus spec.(1.62 cm2) analysed at 30 μm pixel size (180,002 pixel) (a). Total acquisition time ~2h (~24 pixel/s). The hydatid cyst is clearly separated from the host tissue (grey). At higher magnification (b,c) the host (red) and parasite layers (blue) of the cyst are clearly distinguished. Human lung cancer TMA (d). 99 individual cores analysed at 50 μm pixel size (51,932 pixel). Distributions of 5 peptide m/z-values are shown. TMAs represent a unique possibility to analyse samples from many patients at high throughput. Here, we generated data from ~1 patient/ minute. Samples courtesy of Jörg Kriegsmann, Proteopath GmbH, Trier
tumour heterogeneity. An instrument that offers enhanced speed and performance gives scientists the possibility to analyse even large tumour specimens over huge patient cohorts with sufficient spatial resolution to get a comprehensive understanding of tumour heterogeneity. Boosting Efficiency in the Drug-finding Process New laser technology in MALDI
instrumentation not only gains speed for MALDI imaging but can also be used at the very beginning of the drug discovery pipeline. The process of drug discovery includes the testing of millions of pure compounds against enzymes relevant within the context of a certain disease. This screening is a time-consuming and, therefore, costly necessity for finding new leads for further drug development.
Mass spectrometry instrumentation has applications for ultra high-throughput drug discovery screening. Recent technical improvements in mass spectrometry instrumentation allow for much higher acquisition speed and robustness compared to previously available MALDI-TOF instruments. This reduces the time for a 2,000,000 screening campaign to around a week (depending on, e.g., the number of laser shots per spot, or the target geometry (384 vs 1536 vs 6144)). In one example, after such a two million screening campaign utilising 6144 target geometries, there was no need to clean the lens stack1, achieving the highest level of throughput continuity. Reaching New Heights in Imaging Performance Mass spectrometry imaging solutions such as the rapifleX MALDI-TOF mass spectrometry system offers high acquisition speed (up to 50 true pixels / seconds for faster and better images), pixel sizes of ≤10 μm for highest spatial resolution to retrieve biological information, non-overlapping, quasi-square pixels
48 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery and delivers consistent image quality at high throughput and high spatial resolution. 3D lasers offer enhanced pixel-to-pixel reproducibility and a novel ion source design provides increased robustness. Current advanced TOF/TOF systems have been re-designed from the ground up to meet today ’s highest demands for in-depth intact and top-down protein characterisation, and high-performance, high-throughput mass spectrometry imaging (MSI). Next-generation systems offer higher speed, enhanced mass resolution and mass accuracy, and a significantly enhanced MS/MS mass range to enable new research and routine applications. Researchers require speed and ion source robustness, wide dynamic range, higher specificity and resolution, which all contribute to the detailed characterisation of biologically and clinically relevant lipids, peptides and proteins.
Scientists have set the expectations for a system that offers in-depth protein characterisation and imaging of tissues, cell cultures, or other applications. MALDI imaging is a game-changer for research and large-scale validation where enhanced ease-of-use, robustness and stability are vital. MALDI can be utilised at the very beginning of the drug discovery process and high-throughput screening (HTS), as well as in drug imaging: from identifying potential drug candidates to verifying their distribution and toxicity in tissue. REFERENCES 1.
P. Marshall, M. Leveridge, C. Haslam, G. Clarke, J. Chandler, A. Dunn, N. Hardy, M. Pemberton, S. Dikler, J. Fuchser, Ultra High Throughput Drug Discovery Screening by MALDI-TOF Mass Spectrometry – Exceeding One Million Samples per Week, Poster W-T-223 , 21st International Mass Spectrometry Conference, Toronto, Canada, August 20th – 26th 2016.
Rohan Thakur Rohan Thakur is the Executive Vice President at Bruker Daltonics has over 20 years of experience in mass spectrometry, including 14 years in MS development, and has several patents in the field of ion optics. During his career he held positions as Director Global Marketing for mass spectrometry solutions at Thermo and was Director of Drug Discovery at a Pharma CRO for two years before joining Bruker. Dr Thakur received his PhD in Chemistry from Kansas State University and did post-doctoral studies at Rutgers University, where his work involved using high-resolution MS analysis to prove the formation of ring-opened benzene metabolite-DNA and protein adducts. Email: firstname.lastname@example.org
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Drug Discovery, Development & Delivery Key Challenges of Bringing New Drug Delivery Devices to Market
There are many challenges in bringing a good new product to market, from correctly identifying the right commercial opportunity and establishing appropriate input requirements, to developing and industrialising a product which is appealing, usable and robust. And there are myriad development tools, techniques, processes and best practices that multi-disciplinary teams can employ to tackle these challenges.
Where the product being developed is a medical device, these challenges frequently become greater and more difficult to overcome. Safety and effectiveness of use, which is always important, becomes paramount and potentially more difficult to achieve. Device reliability and robustness is also critical and poses its own challenges, either because of higher levels of complexity of the technologies involved or due to the need to manufacture the device in high production volumes, potentially in excess of 100 million per annum. The highly regulated nature of the medical devices industry also adds new demands and challenges for the development team to overcome. Drug delivery devices (in some cases also described as combination products) are one category of medical device where many of these challenges come to bear, and bring a particular set of demands. These relate to: • • • • •
Regulatory landscape Repurposing established primary pack technologies Co-ordinating parallel development paths Confirming overall system performance Overcoming barriers to entry
Some of these challenges and demands are more difficult to resolve than others. Regulatory Landscape Medical device development is heavily 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY
regulated, as is drug development; hence the drug delivery device sector is about as heavily regulated as it gets. Regulations and guidance abound, covering everything from quality management systems (e.g. 21 CFR 820/210/211, ISO 9001 and 13495, ICH Q8/Q10), requirements for system performance and test methods (e.g. ISO 20072 and the ISO 11608 series), risk management (ISO 14971; ICH Q9), human factors engineering (HE 74/75, IEC 62366), electrical and software systems (IEC 60601 series, IEC 62304), clinical trials (ICH E6, ISO 14155), just to name a few.
The result of ongoing regulatory change plus long development timescales, as illustrated in Figure 1, is that all drug delivery device developments take place in a regulatory environment where there will be some uncertainty. Wherever you position a development programme onto the timeline, some aspect of the development will need to be compliant with some regulation or guidance that is either newly introduced or subject to change. Strategies for coping with this can help, though only go so far.
Figure 1 – Changing regulatory landscape for medical device
What makes the situation especially challenging is a combination of two things: rate of change, and development timescales. The lifecycle of many of these regulations is such that they are either very new, or have been recently introduced. Some start life as guidance which is then developed into formal regulations; others are introduced and then relatively swiftly updated as industry thinking progresses. Regulators are still developing views and positions in key areas, such as human factors engineering and device testing. Within this landscape, the development of new drug delivery devices takes a long time – frequently five to 10 years or more, depending on the starting point and the level of innovation.
Dedicating sufficient time and resources to monitoring and keeping fully up to speed on the regulatory developments, and understanding their implications, is crucial. Implementing changes as soon as is practicable, so as to be compliant quickly with current guidance and regulatory requirements, will give the best chance of staying up to date when further changes are made. Working out the regulatory pathway from the start is also important, including which regulations you intend to comply with. With novel systems in particular, i nt e r p ret at i o n of re g u l at o r y requirements and views on how they Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery should be applied is not always clear and consistent, including across governing bodies. For example, will your device be considered a medical device or a combination product? What will the best approval strategy be for a platform technology, as opposed to a specific presentation? What are the requirements for unique combinations of drug and device that are already approved in existing, adjacent combinations, or for changes in route of administration for the same drug product? Engaging in dialogue and obtaining multiple views is strongly recommended. Repurposing Well Established Primary Packaging Technologies Another rule of thumb in device development that has relevance to drug delivery devices is the need to ensure that core technologies are sufficiently well proven before embarking on projects that have them at their heart. In some cases, the presence of unproven technologies may be obvious – a new drug formulation method, for example, or a novel injection system drive/energy source. In other cases, the situation may be less clear. One of the key aspects of demonstrating a technology’s level of readiness is to prove it in the appropriate use environment. In both respiratory and parenteral drug delivery, there are well established primary packaging technologies – the pMDI canister and the pre-filled syringe – which, in their basic device presentations, are very well proven. However, challenges can arise when incorporating these core technologies into more complex drug delivery system designs, such as a breathactuated inhaler or an auto-injector.
Fundamental design parameters, including manufacturing tolerances and valve operating characteristics for the pMDI canister, and glass robustness or glide forces for the pre-filled syringe, become much more critical to mechanism interaction and device performance than for manually operated devices. It may be necessary to work with suppliers on the specification for these items, in order to fully characterise and control design specifications that were previously not important, and this may not be without difficulty. Having supplied the same product for many years in its current form the manufacturer may (understandably) be reluctant to introduce new or tighter controls, and it should be recognised that the design of the new delivery system will probably need to change to accommodate the primary pack, rather than vice versa. Co-ordinating Parallel Development Paths The development of a new drug delivery device often entails the parallel development of a drug formulation and a delivery system, and the co-ordination of these activities can bring with it numerous challenges. The pharmaceutical world and the medical device world are quite different, with people from different backgrounds working in different organisations to different processes and regulations. Tools, techniques and terminologies vary across the two industry sectors, as does the nature of many of the technical challenges faced. If the interactions between drug product and delivery device were straightforward or unimportant then there would be less of an issue, but in fact they tend to be complex and
Figure 2 - Established primary pack technologies www.ipimediaworld.com
critical. Performance of one element of the overall system is frequently dependent on the other. For example, the materials, geometries and method of construction of the device can easily influence the stability, dose accuracy and effective delivery of the drug, while the volume, viscosity or transport properties of the drug can significantly alter size, operating characteristics (e.g. forces, pressures, flow-rates) and efficiency of the delivery device. In addition, because of the need to test drug efficacy in a progressive series of clinical studies, the device technologies need to be developed and verified to ensure they meet ever more stringent performance and safety requirements. B e c a u s e of t h e s e c r i t i c a l interactions, the development programme needs to be co-ordinated and Figure 3 illustrates how the two strands – for a new drug and device combination – can progress in parallel, with various touch points along the way. While the very early discovery and research phases of drug development are likely to have started independently of the device, with initial performance tested through use of established delivery technology platforms such as a nebuliser or a syringe, the full device development needs to start in good time. As soon as treatment regimes, risk profiles and formulation properties are established to some level of confidence, key device design decisions can be made. INTERNATIONAL PHARMACEUTICAL INDUSTRY 51
Drug Discovery, Development & Delivery
Figure 3 – Parallel drug and device development paths
In addition to the overall requirement for effective co-ordination of – and collaboration between – the two halves of the development programme, some specific challenges include: •
Needing to select a preferred device technology concept early in the development of the drug formulation, even though they may be inter-dependent Ensuring availability of active drug formulation – or an effective placebo – to support device development early in the detailed design phase Freezing and verifying the device design to allow use of devices in Phase IIb studies, while mitigating the risk of needing to change the design due to late modifications in dosing/formulations (volumes, viscosities, excipients) Deciding when to commit to high cost, highly intensive scale-up activities, if there are any uncertainties relating to manufacturing reliability and robustness, design validation or clinical efficacy
Confirming Overall System Performance The progression to design validation activities and, in particular, Phase III clinical trials is a major commitment in the development programme. Establishing the necessary high levels of confidence that the overall product will be safe and effective to 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
use can be challenging, especially as the drug delivery system in fact comprises three – not two – constituent elements: the drug, the device and the user. Each element has its own specific level and nature of complexity, and each can be assessed as a combined pair during the development process:
the best chance of success during Phase III trials and design validation. These final steps will be the first time that all three elements of the system are tested together in truly representative environments, and uncovering new issues now will cause major difficulties to any programme.
Overcoming Barriers to Entry Following successful design validation of the drug delivery device and regulatory submission, transfer of the design to commercial manufacture can be carried out. There will be further challenges to overcome during this phase, which frequently involves: major scaling up of device and drug manufacturing processes, including filling systems; transfer of technical know-how; setting up of supply chain logistics and post-market support and surveillance.
Drug and user combination, through preparatory clinical studies Device and user combination, through human factors engineering Device and drug combination, through design verification
Figure 4 – Proving complex elements of a complex system
Ensuring that rigorous, effective design verification and human factors engineering programmes are planned and executed, including all risk management activities, alongside an equally well managed and implemented set of Phase I and Phase II clinical studies, will give
However, even when you are ready to go to market, a final challenge – overcoming any barriers to entry – can remain. Some of these apply generally to new product development, and some are more specific to drug delivery devices: Freedom to Operate The intellectual property landscape in the field of drug delivery devices is densely populated and very active. Steps can be taken during development to help ensure freedom to operate for a new device design, Spring 2018 Volume 10 Issue 1
Drug Discovery, Development & Delivery could be at least ten years earlier. New, alternative drug and device solutions may have appeared which render your product offering less attractive, or competitors may just have done the same thing better, faster or cheaper. Even if these commercial threats appear well before your launch your product, the nature of these developments and the tight constraints can make it very difficult to respond to such competition.
but success is hard to guarantee. For example, the delay between filing and publishing of new patents means there is a ‘black hole’ which landscaping exercises cannot see into, and potential infringements are not always clear cut. Different strategies can be employed, such as filing your own IP or gaining access to existing IP through licensing, but resolution of issues can be challenging, especially if they arise late in the development when change is extremely difficult.
not be any surprises at this stage. However, any issues arising during design transfer and manufacturing scale-up which mean the drug and device cannot be manufactured as efficiently as expected, will result in an increase in final costs that influence commercial viability of the product. Examples could include limits on production tool cavitation, the need for more tightly controlled processes, lower than anticipated yields or – in the worst case – rejection of some production batches.
Partnering Agreements Quite often the drug product and delivery device are owned by different organisations. In principle, the commercial agreements covering how the final product will be brought to market will have been covered in advance, but in some cases agreements are only covered late in the day, which can be a challenge. Where new devices are developed as platforms and then pharmaceutical partners sought to create specific combinations, the process can be more problematic as it is not just commercial and logistical elements which need to be aligned, but also technical, e.g. is the device well suited to the drug formulation, therapy area and user profile? And if the answer to this is not known, what are the costs, timescales and risks in finding out?
Market Acceptance In some cases, drug products successfully reach the market, but fail to establish themselves. The inhaled insulin drug ‘Exubera’ is one high-profile example, but there are many others. This can happen for different reasons, including lack of take-up from users or healthcare providers, or insufficient funding from payers. This can happen because of reduced efficacy or increased side-effects compared with what was seen in the clinic, or purely because appetite for the new product was misjudged, for some reason. The latter can, in theory, be mitigated by ensuring that the ‘correct’ user and product requirements are specified from the start when the direction of the development is set.
Production Costs Increasingly accurate estimates of production costs will have been made during the development and pilot tooling process, so there should www.ipimediaworld.com
Competition Another implication of long development timescales for drug delivery products is that the market will have moved on from when you started your development, which
In Summary Bringing new drug delivery systems to the market can be a difficult undertaking. The specific nature and demands of the pharmaceutical and medical device sectors present challenges that go far beyond those experienced in the development of many other products, and these challenges are not always under the full control of the development team. However, with the right approaches, systems, tools and people involved, and with effective collaboration across multiple functions, organisations and cultures, these challenges can certainly be overcome. The many highly successful drug delivery devices on the market today, bringing benefits to patients around the world, demonstrate this.
Chris Hurlstone Director of Engineering at Team Consulting, ensures Team delivers consistently world-class consultancy services and robust, reliable, user-focused and commercially successful device solutions. Chris has more than 20 years’ experience with Team, developing technologies and devices for healthcare markets. He has successfully brought products to market in technical lead and project management roles, including inhalers, injectors and an award-winning ophthalmoscope, and in the process has worked extensively with global suppliers of manufacturing and technical expertise. Email: firstname.lastname@example.org
INTERNATIONAL PHARMACEUTICAL INDUSTRY 53
Successful Adoption of eConsent Best Practices for Integrating eConsent Technology Research sponsors and investigative sites are continuing to explore the use of electronic informed consent (eConsent) in today’s clinical trials. eConsent utilises electronic systems and processes, such as audio and video features, to communicate study information to study participants to securely obtain and document informed consent. Driven by the promise of improved support for participant comprehension and prevention of common consent regulatory deficiencies, switching to an electronic approach can reduce regulatory risk through the capturing of better quality data and a documented informed consent process.
While there are clear benefits for making eConsent common practice within clinical trials, some in the industry still doubt the adoption of yet another new technology, due to the challenges and perceived costs of integration. However, far from adding extra costs to already tight budgets, it is estimated that the costs dedicated to implementing eConsent will be much more economical compared to the amount of money that companies spend rectifying issues arising from paper-based forms further down the line. The potential to drive significant operational efficiencies, minimise regulatory risk, ensure participant comprehension and achieve long-term cost savings, point to the kind of transformative budgetary impact that could be achieved by implementing this solution across multiple trials. The more the eConsent system is used, the smarter it gets, with more data and trust between users. In addition, by integrating eConsent technology with existing platforms, researchers can remove the need for any additional technologies to be included in a trial’s design, significantly reducing the burden and complexity for study teams. The following best practices seek to provide some guidance on ensuring successful integration of 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY
eConsent technology and can be grouped under six key themes: 1. Integrate 2. Engage 3. Plan 4. Manage 5. Trust 6. Practice 1. Consider How eConsent Integrates with Existing Technology At the outset, sponsors need to consider all the different platforms and technology that they will be using throughout the study programme, including eConsent, and how they can work alongside or integrate with each other to achieve the best possible outcomes. This evaluation should be started as early as possible. When adopting eConsent, users face the challenge not only of replacing previous paper-based consent systems with the new electronic process, but also of ensuring that the eConsent technology integrates with any existing platforms, such as eCOA or trial management solutions. eConsent solutions are now being developed which integrate with the existing technologies that many sponsors are already using within their clinical trials, such as eCOA platforms. By integrating informed consent and eCOA solutions, for example, on a single platform and on the same device, study teams can gain all the benefits associated with eConsent, while removing the additional burden that would be inherent with the use of a separate system. This also provides considerable savings to researchers by removing the need to purchase an additional system, as well as the time and cost associated with integration procedures and training. 2. Engage with the Associated Ethics Committees Involving IRBs as early as possible in the process is pivotal. IRBs are required to have standard operating procedures (SOPs), so a gap analysis should be done to ensure they can properly
support the electronic approval and review. Acceptance by the reviewing IRB/IEC is essential; they must be satisfied that the informed consent meets the regulatory requirements for content and supports their review process. If not, this will slow down the research and approval process. If involving a central IRB, sponsors should choose an IRB with SOPs that can support eConsent. In addition, being able to provide an IRB with exactly the documents they need to review and approve is key in the process. Effective data management, such as data flow, security, PHI management and roles management should be taken into consideration and good documentation design here can greatly facilitate the process. To help with this, sponsors and sites should make sure they know how the applicable IRB will review the electronic consent process. For example, will they review it in a similar way to eCOA by examining screen shots? Or will they want to experience the eConsent process on the device? 3. Plan and Agree on Roles and Responsibilities Up-front To ensure integration runs as smoothly as possible, it is important to agree, from the very beginning, to the roles and responsibilities for each study team (sponsor, sites, IRB/IEC) that is responsible for the development and implementation of eConsent. A collaborative system design approach can really support this. Study teams should think about the integration of the process with the end goal front-of-mind. Some examples are: for the IRB, “How will the consent be reviewed and approved per site?”; for the sponsor, “How will the consent process be monitored?”; for all, “How will it be audited by the regulatory authority?” and “How will it be documented, so the data is defensible to regulators?” By designing the process with the end result in mind, and working in collaboration with partners to agree to responsibilities within a study team and between study teams, we can ensure Spring 2018 Volume 10 Issue 1
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 55
Clinical Research the smooth integration of eConsent. An eConsent solution that supports this is important. Paper informed consent development involves multiple stakeholders; this remains true for eConsent as well. The paper consent document development process involves a lot of back and forth between parties which can be very uncontrolled and risky. In eConsent, the development will still involve the exchange process, but take advantage of the electronic system support for version control to better manage the back and forth between stakeholders. 4. Manage Relationships with Stakeholders As well as engaging with ethics committees, it is crucial for sponsors to ensure they consider the needs of the multiple stakeholders that will be impacted by this new technology. In a large, multi-centre, multi-site study, for example, there will be numerous stakeholders as well as potentially multiple IRB/IECs with different approval requirements. For that reason, selecting an eConsent solution that has the flexibility to add any additional content required by a stakeholder, as well as still support the efficiency of getting a consent approved quickly, is crucial. 5. Gain the Trust of Site Teams Gaining the trust of research site teams is vital to ensure the smooth transition from paper-based to electronic informed consent. Site teams are often very busy and can feel overstretched, so it is important they do not feel any additional burden because of the introduction of this new process. By engaging site teams as early as possible in the process and ensuring they understand the technology; reasons for implementation; how eConsent can improve the consent process and decrease risk of consent issues; and by offering comprehensive training and support before and during implementation, sponsors can build confidence in the solution and ensure sites do not revert to previous paper processes. To try and understand some of the barriers to adoption and encourage uptake, CRF Health has carried out demonstrations of eConsent with several different research sites. The 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY
investigation sites who took part expressed concerns at the increasing burden to them by adding an additional log-in and system to manage. Ensuring that the eConsent solution has been designed with the user in mind and integrates with other systems as much as possible is essential. By offering comprehensive training and support before and during implementation, sponsors can build confidence in the solution and ensure sites do not revert back to previous paper processes. This can be delivered through training materials within the tools, user guides, manuals and helpdesk support. As a result, site teams are engaged as early as possible in the process and understand the technology; reasons for implementation; how eConsent can improve the consent process and decrease risk of consent issues. Ease-of-use and technical support are key to acceptance of a technology system to replace one that someone is used to using (paper), even when it is not working. Look at the slow acceptance of electronic case report forms (eCRFs), and now they have become the preferred path. Proving that some “What Is In It For Me (WIIIFM)?” is helpful.
approach within a clinical trial is the ability to efficiently incorporate another technology into the clinical operations quality system. Overcoming this challenge offers researchers numerous benefits, including the capability to mitigate regulatory risk, improve study participants’ comprehension, and provide a more efficient way of collecting consent, therefore saving time and money.
6. Practice, Practice, Practice If possible, testing the technology within a small study with a healthy subject population and relatively simple study design would be ideal. It is a sensible idea to pilot eConsent before implementing it across a large multi-centre study or all studies. Additionally, choose a study that is geographically more condensed, e.g., early-phase research. The idea of piloting it is to test the effectiveness of the set-up process and training, check the functionality of various features, and identify any process gaps before introducing the solution into more complex and larger studies. This allows sponsors to involve other stakeholders in the set-up and approval, and provides the opportunity to incorporate valuable feedback into the design process. For all stakeholders, eConsent should continue to get better and better with each trial.
For further information on CRF Health, please visit www.crfhealth.com
In Review One of the major hurdles for sponsors when integrating an eConsent
In a time when the clinical trials industry is seeing an influx of technology across the clinical trials lifecycle, there is a need to move towards consolidating these technologies and bringing complementary platforms together wherever possible. The introduction of eConsent represents a major improvement in the overall participant consenting process in clinical trials for investigation sites, sponsors and IRB/ IECs. By implementing this kind of solution across multiple trials, there is also potential to drive significant operational efficiencies and create long-term cost savings due to companies no longer having to spend time rectifying issues arising from paper-based consent forms further down the line.
Mika Lindroos Mika Lindroos is a Director of Product Management at CRF Health and is most at home where technology meets humanity. With over two decades in software product management in the global environment, Mika’s breadth of experience spans from product and portfolio management, strategy and business development, and heading a product line at Nokia, to revenue and business relationship development at Digia. Mika is a specialist in developing and managing relationships both internal and external to his organisation, as evidenced by his varied roles in team motivation, change management, and customer relationship development. Email: email@example.com
Spring 2018 Volume 10 Issue 1
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The Future of Patient Recruitment for Clinical Studies Clinical studies are important; they are the gold-standard method of evidence generation. Ultimately, the decisions we make about our own healthcare are based on their results. To date, almost 1 million trials have been conducted according to the most complete register, and an estimated 27,000 trials are added to that list each year.
The Future Cost of Trials The global pharmaceutical market is currently estimated to be worth over USD$800 billion and is forecast to reach USD$1.12 trillion in 20221; clinical studies make up a significant portion of that expenditure. Trials are not cheap; today, the cost of developing a successful medicine can exceed USD$2.6 billion, compared to USD$179 million in the 1970s. The complexity of trials globally has also increased in recent years. Trials conducted between 2000 and 2003 saw an estimated 31 pieces of eligibility criteria, whereas trials conducted between 2008 and 2011 were subject to 46 – an increase of 48%2. Trials rarely run smoothly. Budgets are often stretched due to the failure to recruit enough participants to take part in the trial. It is important to note that ‘enough’ isn’t an arbitrary value; the number of people a trial requires is calculated by trained statisticians. Poor Recruitment If a trial does not recruit enough patients to meet its target, the results of the trial are unreliable. If a difference is detected between the treatment groups of an underpowered trial, we cannot be sure if the results we are seeing are untrue. The problem of poor recruitment is widespread; 80% of trials miss recruitment deadlines, and a staggering 11% of all trials fail to recruit a single patient3. On top of this, estimates suggest that patient recruitment 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY
accounts for ~30% of total study cost 4, so we should all be demanding much better results. Ultimately, solving the problem of patient recruitment equates to faster research at reduced costs. The Screening Stage There are many reasons why patients are lost along the way; from ineligibility to lack of awareness, but the main issues with recruitment come to light at the screening stage. Screening is the limiting step for many trials, and the process creates a bottleneck. Trials can screen thousands of patients who are interested in taking part, but the final number of people who fit the eligibility criteria is a small percentage of that original cohort. The so-called screening bottleneck is the source of overwhelming amounts of wasted time, and therefore money. A Data-first Approach Patient recruitment is a process that has remained stagnant over decades of clinical studies. It's time that we started using data and technology to ease the workload and embed efficiency. Think about it like this – when you are looking for a holiday, you likely use a streamlining service like Expedia to ensure you find the best deal. This means you don’t waste time and money searching through lots of disparate and untrusted sources of information5. The process of patient recruitment requires the same level of streamlining. Using a data-first approach prevents the need for expensive and unresponsive media strategies. Critically, this means you no longer need to rely on patients self-screening because data allows you to go straight to the right patients. By using electronic health records (EHR) to effectively ‘pre-screen’ patients before they have even been contacted, you are able to efficiently and ethically identify and contact protocol-aligned patients
using these health records, targeting people most likely to fit your eligibility criteria6,7. This ensures that you are not wasting time and resources contacting patients that will ultimately not be eligible for your study8. Screen fewer patients, and recruit more. If you take 100 patients that respond to advertising, using traditional methods, you would see an average drop-out rate of 72% at the call screening centre stage, and a further 90% of those would fail at the pre-screen evaluation stage, leaving you with just three evaluable patients. If you were to take 100 patients using a data-first approach, only 9% would drop out at the call screening centre stage and 90% at the pre-screen evaluation, leaving you with nine available patients. Real-world Studies A data-first model for patient recruitment is also the first stage in running more efficient and cost-effective real-world studies. Real-world studies offer pharma a new way to gain market approvals quickly by directly collecting data from patients in the ‘real world’9. Current models entail a significant lag time between approvals and real-world data collection, causing a gap in finance generation10. This is particularly important as we have seen recent cases come to light that show that ‘typical’ clinical trial participants often do not align with real-world patients from the same patient group11,12. This puts trial results at risk. Collecting real-world data in a timely fashion using a data-first approach ensures you are getting an accurate picture of the effects of the intervention you are testing. The Future of Patient Recruitment It’s clear that social media usage has risen in recent years and the use of online Spring 2018 Volume 10 Issue 1
pa t c h wo r k
Patches work: On the spot, reliable and compliant. ltslohmann.de
Clinical Research social tools by the pharma industry will continue to rise, but this method does not come without its flaws13. To make an impact in the world of social media, you need to build up a large following. This following needs to be made up of engaged and enthusiastic people, and that demands substantial time investment. If that time, and therefore money, was invested in traditional recruitment methods, it is likely that the pay-off would be comparable. Granted, social media can allow you to target content to specific types of people based on age, gender, location etc., but what happens if your posts are shared? That carefully thoughtthrough targeting is ineffective. The more people that see your posts, the more likely that you’ll get ineligible patients who fail screening. Ultimately, social media may seem cheaper to begin with, but if you’re having to increase screening capacity to account for that, it’s not a useful way to spend your time or money. Social media also raises the possibility of selection bias. Targeting patients that use social sites means you’ll enrol a certain type of patient into your study; i.e. a non-representative sample of the population. 5.
Why not make the leap and innovate further? Look to real-world data from patient electronic health records (EHRs) to recruit. That way you’re able to: • • •
Remove the screening bottleneck Recruit a representative sample Improve efficiency.
REFERENCES 1. 2.
Evaluate (2017) EvaluatePharma World Preview 2017, Outlook to 2022. London, UK. I n t e r n a t i o n a l Fe d e r a t i o n o f Pharmaceutical Manufacturers & Associations (2017) The Pharmaceutical Industry and Global Health: Facts and Figures 2017. Switzerland. Drennan KB (2002) Patient Recruitment: The Costly and Growing Bottleneck in Drug Development. Drug Discovery Today. Taylor P (2015) Harnessing Clinical Data. PMLiVE.
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Köpcke F et al. (2013) Evaluation of data completeness in the electronic health record for the purpose of patient recruitment into clinical studies: a retrospective analysis of element presence. BMC Medical Informatics and Decision Making. 6. van Staa TP et al. (2012) Pragmatic randomised trials using routine electronic health records: putting them to the test. BMJ. 7. Coorevits P et al. (2013) Electronic health records: new opportunities for clinical research. Journal of Internal Medicine. 8. Wong SE et al. (2016). Screen failure rates in contemporary phase II/III therapeutic trials in genitourinary malignancies. Journal of Clinical Oncology. 9. Davies N (2017) Real world evidence and pharma. The Pharma Letter. 10. Wileman H and Mishra A (2010) Drug lag and key regulatory barriers in the emerging markets. Perspect Clin Res. 11. Ignite Data (2017) Cardiac Patients in Trials Don’t Reflect Real-World Populations. Reading, UK 12. Maddox TM et al. (2017) Applicability of
the IMPROVE-IT trial to current patients with acute coronary syndrome. JAMA Intern Med. 13. Ignite Data (2017) Social Media to Recruit Trial Participants: Innovative or Ineffective? Reading, UK.
Dan Hydes Co-founded Ignite Data in 2014 with a vision to streamline the clinical research process with the application of data and technology. In that time the ethos has not changed and the company has grown quickly to become the leading provider of technology-driven Patient Recruitment and Real-World Evidence solutions in the UK. Email: firstname.lastname@example.org
Spring 2018 Volume 10 Issue 1
From Pack to Patient
We Deliver On Time & In Full. fisherclinicalservices.com
With unwavering dedication to serving clinical research and patients around the world, Fisher Clinical Services recognizes how important it is to deliver clinical trial supplies to the right patient On-Time and In-Full. From the packaging and labeling floor to a facility within our global network and on to patients at investigator sites, our experts respond with flexibility, determination and a high quality mindset. Powered by consultative project management teams with an exceptional commitment to delivering end-to-end, global clinical supply chain services, we ensure that patients receive their medication on time! Contact Us. email@example.com
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Sharper Images, Faster Measurement, Chemical Identification: Morphological Imaging is Evolving Examples of how rapid advances in visual equipment and computing power have combined to deliver smart, sleek and easy-to-use technology are ubiquitous in modern life, and exemplified in the laboratory by the capabilities of cutting-edge imaging systems. For example, in little over a decade, automated static particle imaging systems, also referred to as morphological imaging systems, have transitioned from niche to mainstream as cost:benefit ratios have improved, thanks to significantly upgraded performance and extended capabilities. Today’s morphological imaging systems have largely displaced microscopy for a wide range of routine particle characterisation tasks, and are particularly prized when additional levels of insight are of value; for example, when troubleshooting a manufacturing process, or during pharmaceutical development.
In this article, we look at how morphological imaging works, the analytical workflows associated with its application, and the data that can be generated, highlighting technological advances that enhance data quality and system applicability. We also examine the significant benefits of combining particle imaging with chemical identification in the form of Raman spectroscopy, again considering the associated analytical strategies and their application. Example studies illustrate the central role of modern imaging technology in supporting modern pharmaceutical production, from R&D through to manufacture. Introduction to Morphological Imaging Technological advances have made morphological imaging a feasible and accessible technique that enables the measurement of tens of thousands of particles in a matter of minutes to generate statistically significant particle size and particle shape data. Figure 1 shows a schematic of the morphological imaging workflow, highlighting the key features of this specialised hardware. 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Figure 1: Schematic of the morphological imaging workflow.
To capture images of representative particles, a sample must first be suitably dispersed prior to presentation to the camera. Modern instruments offer automated dry dispersion, tailored to the requirements of the specific sample, and deliver the consistent particle orientation required for effective sample differentiation. The next step is the image capture and analysis process, during which a 2D digital image of each particle is recorded. This process has improved dramatically in recent years as camera technology has evolved, with state-of-the-art systems, such as the Morphologi 4 from Malvern Panalytical, incorporating high-resolution cameras of up to 18 megapixels. The resulting enhanced i m a g e q u a l i t y i m p ro v e s t h e sensitivity of all measurements, with more sensitive shape quantification a particular benefit. The captured 2D images are then used to calculate the size and shape parameters. An image segmentation process is used to differentiate particles from the background – a process which is critical for achieving accurate and reliable information from image analysis. Here too, modern systems offer enhanced performance that can ease application and improve sensitivity.
For example, embedded in the software of the new Morphologi 4 is ‘Sharp Edge’ – an automated segmentation algorithm that makes it easier to detect and define particles with reduced user input. Technology such as this is particularly valuable for low-contrast samples, such as particles in suspension. It boosts the shape parameter sensitivity for all samples, enabling more subtle morphological differences between samples to be detected. The final step in the process is results generation. Morphological imaging provides morphological data by generating number-based distributions of size and shape descriptors from the measurements generated for each individual particle. The size metrics reported by morphological imaging include the circular equivalent diameter (CED), the diameter of a circle with the same area as the particle, and width and length measurements of each particle. Shape metrics routinely reported include: Circularity, which is a measurement of the ratio of the perimeter of a particle to the perimeter of a circle of the same area, with perfect spheres having a circularity of 1 and irregular objects having circularity closer to 0 (Figure 2). Spring 2018 Volume 10 Issue 1
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Manufacturing Convexity, which quantifies surface roughness. Smooth particles will have a convexity close to 1, while those with rougher, more irregular perimeters will have a convexity closer to 0 (Figure 2). Elongation, which is a measure of particle form and is defined by the formula [1 – width/length]. Needleshaped particles therefore have an elongation closer to 1 and those more regularly shaped have values closer to 0 (Figure 2).
the formulation process, so being able to monitor these parameters throughout is critical. Morphological imaging is therefore routinely used to objectively quantify particles in terms of morphological parameters to differentiate the performance of closely similar samples in formulation, for sensitive batch-to-batch comparability testing through to QC, and/or to optimise, emulate or troubleshoot a manufacturing route. More
addition of Raman spectroscopy to allow chemical identification is extremely valuable. Combining morphological imaging and R a m a n s p e c t ro s c o py i nt o a fully-automated, single instrument enables Morphologically-Directed Raman Spectroscopy (MDRS ® ), allowing chemical identification of particles identified as being of interest based on their morphology. MDRS accurately differentiates morphologically-similar substances, obtaining component-specific data for multi-component samples, to provide enhanced insight into the physical and chemical properties of a blend. Figure 2: Circularity, convexity and elongation illustrations.
In combination, these metrics can be used to group/classify the particles in a sample on the basis of their morphology, a highly useful capability that finds widespread application within the pharmaceutical industry. The Value of Morphological Data In many pharmaceutical applications, particle size in isolation does not define performance; particle shape is also a factor. For example, it affects the flowability and compressibility of a tableting blend, thereby influencing tablet manufacturing speed and efficiency and the properties of the finished product. When it comes to QC, detecting particle size and shape distribution anomalies in out-of-spec batches can enable rapid identification of the cause of the deviation. Specifically, in pharmaceutical development, the desired particle size and shape of the API need to be maintained through 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY
specifically, morphological imaging is particularly valuable for: • • •
Agglomeration studies, Foreign particle detection, Analytical method troubleshooting.
Furthermore, because morphological imaging is a number-based technique, it is particularly sensitive to the presence of fines, making it highly complementary to alternative sizing methods, such as laser diffraction, for scrutiny of what may be a vital portion of the particle size distribution. Beyond Particle Shape – The Addition of Chemical Identification For applications where particle morphology alone is insufficient to provide the necessary insight, such as during deformulation in generic pharmaceutical development, the
The first step of a typical workflow for MDRS is the application of morphological imaging, as discussed above, to enable morphological classification of the sample. Raman spectroscopy is then applied to individual particles or populations classified on the basis of size and/or shape, e.g. particles with a circularity <0.85 and a CED >20 µm. Figure 3 illustrates the process of chemical identification. Raman spectra are acquired for each targeted particle and then compared to a library of spectra for chemical identification. A particle spectrum correlation score close to 1 indicates a strong match to the reference spectrum, whereas a score close to 0 means ‘no match’. Using this approach, all selected particles in a sample can be securely identified as specific chemical compounds/species. Raman spectroscopy is suitable for analysing the vast majority of pharmaceutical ingredients. Spring 2018 Volume 10 Issue 1
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Manufacturing of the two devices. The analytical technique applied to gather the API-specific particle size data was Raman-based. Earlier in 2017, the first generic mometasone furoate from Apotex was approved, taking eight years to review to the point of approval. MDRS was used extensively, and was specifically highlighted as being valuable in proving data to support the claim of bioequivalence.2 Figure 3: Shows the raw spectra produced from individual particles.
An alternative workflow is to apply Raman to a randomly selected population of particles to pick out a specific component of interest and then use the resulting data to study the morphology of that specific ingredient. This is useful when, for example, seeking information about the physical properties of an API within a blend during early deformulation studies.
interest within a formulation, typically the API, and gather componentspecific morphological data. These capabilities are proving particularly valuable for:
Modern instruments offering MDRS deliver significantly faster spectral acquisitions, with time reductions of up to 80% compared with legacy systems. This is an important gain, regardless of analytical strategy, since the Raman element of the analysis is significantly more time-consuming than the application of morphological imaging. Furthermore, recently released systems, such as the Morphologi 4-ID, offer the ability to customise acquisition conditions to the sample along with an extended spectral range. This enables the identification and differentiation of a greater range of chemical components than ever before.
The following case study demonstrates the application of MDRS in the demonstration of BE for a nasal spray.
The net result is that MDRS is a flexible and very powerful technique that can be applied to all types of pharmaceutical products, from oral solid dosage to suspensions, gels, ointments and nasal sprays. Because it involves the application of Raman to individual particles rather than to a bulk sample, it offers heightened sensitivity relative to conventional Raman, which can be an important benefit when it comes to, for example, contaminant detection. However, the defining attraction of MDRS is the ability to pick out the component of 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY
• • •
Deformulation, Assessing the effect of processing steps on API properties, Demonstrating bioequivalence (BE).
Case Study: Exploring the Role of MDRS in the Approval of a Generic Form of Nasonex Nasonex, a nasal spray treatment, is a popular generic target, with successful applications in both Europe and the US. The active ingredient is mometasone furoate, a steroid used to reduce inflammation. One such successful application in the EU was for the use of two nasal spray devices, with one single formulation, in which only one device was subjected to in vivo studies. This application was supported by particle size data specifically for the API in the suspension, differentiated from the excipient present. The Committee for Medicinal Products for Human Use (CHMP) gave some interesting insight on the approval, commenting that it “considered particle-size distribution to be an adequate indicator of dissolubility, which is, in turn, an indicator of comparable safety and efficacy”1, concluding that the particle-size data could therefore be used to confirm the equivalence
In the Apotex submission, the API was based on an anhydrous form of mometasone in place of the monohydrate form used in the reference product, unlike most generics, which use an identical API. This heightened the complexity of the review process, requiring proof that the API remained in its anhydrous form for the shelf-life of the product. Apotex used MDRS to simultaneously analyse the size, shape and chemical identification of individual particles within their nasal spray suspensions. This data allowed the company to confirm both the form of the drug and its particle size, adding weight to the evidence presented to demonstrate BE. The FDA accepted these data and echoed the conclusions of the CHMP that particle-size data for API is sufficient to compare clinical efficacy and safety. This result set a precedent for submitting in vitro data in place of a clinical study. This opens the possibility of changing the FDA weight-of-evidence approach to the approval of locally-acting generic nasal sprays. As clinical studies are both cost- and time-expensive, a change in this approach could be significant and valuable. In Conclusion Recent advances in morphological imaging further enhance its value as a tool for the pharmaceutical sector, delivering faster measurement times and enhanced sensitivity for greater sample differentiation. The addition of Raman spectroscopy substantially augments the information flow from imaging, delivering powerful characterisation technology that directly answers key analytical requirements in deformulation and formulation development. Here Spring 2018 Volume 10 Issue 1
Manufacturing too, new technology is delivering substantial benefits in terms of the range of materials that can be measured, data quality and measurement speed. Today ’s analytical imaging systems, with or without Raman, are a cornerstone of the pharmaceutical analytical toolkit, providing data and insight for every step of the product lifecycle, from formulation through to process troubleshooting and QC. REFERENCES 1.
“ C h a r a c t e r i z i n g n a s a l s p r ay suspensions for regulatory and scientific purposes.”; webinar available for download at: https:// www.malvern.com/en/support/ events-and-training/webinars/ W160517NasalSpraySuspensions.html. [Accessed 24/08/2017]. https://www.fda.gov/downloads/ Drugs/DevelopmentApproval Process/SmallBusiness Assistance/UCM502012.pdf [Accessed 30/01/2018].
Debbie Huck-Jones Product Manager for Analytical Imaging at Malvern Panalytical. Debbie became product manager for Malvern Panalytical’s analytical imaging range at the beginning of 2014. She joined the company as product technical specialist (PTS) for imaging products in 2005 and later became PTS supervisor for imaging and laser diffraction. In these roles, Debbie worked closely with customers and existing users all around the world, providing applications development and support for the Morphologi and FPIA-3000 instruments. Previously, Debbie worked for ABB in the instrumentation business unit. She has an MChem with European Study from the University of Exeter, and a PhD in chemistry jointly awarded from the University of Exeter and Université Louis Pasteur in Strasbourg, which focused on the synthesis and characterisation of metal-based liquid crystals. Email: debbie.huck-jones@ malvernpanalytical.com
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Tailored Fill Release Performance
has been putting consumers off for as long as they’ve been swallowing fish oil and other omega 3 fatty acids: the aftertaste and the way the fishy oil repeats on them. This undesirable effect can be enough to deter even the most health-conscious consumers from sticking to their fish oil supplementation routine.
GELITA® Pharmaceutical Gelatines cover the complete spectrum of capsule fill release profiles for highest efficacy and consumer compliance
Gelatine offers manufacturers of drugs, as well as dietary supplements, a versatile excipient that has been used in the pharmaceutical industry for decades. Among its key applications is capsule production: Approximately 90 per cent of all pharmaceutical-grade gelatine is processed into this sleek and widely used drug dosage form. However, the type of active ingredient, climate conditions and storage times make different demands on a capsule’s properties. By adjusting the production process for soft capsule gelatine, GELITA can modify the specific effect, timing and duration of the fill release to tie in with consumer needs. The latest addition to its portfolio is GELITA® EC, the first and only gelatine product for true enteric performance. As of now, the company can cover the complete spectrum of desired fill release profiles and even eliminate the “fishy” side effects of omega 3 supplementation. Capsules Are King Gelatine capsules are among the most popular dosage forms for drugs, over-the-counter (OTC) products and food supplements. Consumers appreciate the smooth surface that makes them easy to swallow — an important aspect when it comes to patient compliance. Gelatine itself is extremely compatible with other ingredients, is non-allergenic and consists of proteins that are easily digestible in the gastrointestinal tract, which facilitates the release and absorption of active ingredients. One of the most widely recognised benefits of soft gelatine capsules is enhanced nutrient bioavailability. By encapsulating liquid- and paste-fill formulations, soft gel capsules provide opportunities to improve the absorption of poorly soluble drugs. Consumers not only benefit from a 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY
quicker onset of action, but the greater bioavailability also translates into the ability to reduce the required amount of active ingredients. Another plus is that gelatine capsules offer endless opportunities in terms of size, colour, shape and printing options, allowing for customised products and unique presentations. In general, soft shell capsules release their contents within five to 15 minutes. GELITA provides a variety of versatile and tailor-made standard gelatines which are perfect for a vast range of capsule applications that work well in most environments. Besides standard capsules, GELITA’s technology experts have developed various grades of pharmaceutical gelatine for the production of soft capsules that fit the specific requirements of individual manufacturers – from slow- to fast-fill release and even for certain types of reactive fillings and extreme storage conditions. This way, manufacturers can guarantee that their products will always deliver their specified functionality and performance. The Fish Oil Issue Soft capsules are the preferred dosage form for sensitive ingredients like fish oil because they protect them from oxygen, light, contamination and microbial growth. Unlike any other type of capsule, soft gelatine versions are hermetically sealed and airtight, so they also mask unpleasant tastes and odours associated with their contents. However, one nagging issue
Delayed Dissolution In order to address this problem effectively, the GELITA Pharmaceutical Competence Team has developed a new technology: GELITA® EC. This novel approach allows the production of enteric capsules that dissolve in the small intestine instead of in the stomach, as is the case with traditional gelatine capsules. When fish oil is released in the stomach, it floats to the top of its contents and is able to reflux upwards. For this reason, many producers have tried to make their capsules gastric juice-resistant to not release the fish oil fill until the capsule has passed through the stomach into the intestine. Currently, most enteric delivery systems are produced by applying an acid-insoluble coating to freshlyproduced soft gelatine capsules. However, this second step increases the time and costs involved in producing the capsules. The coating also creates an opaque shell, which is less appealing to consumers. GELITA’s new pharmaceutical gelatine, on the other hand, allows manufacturers to produce enteric capsules using existing equipment in a one step process. Additionally, without the second layer, capsules become brilliantly clear. Tests have proven that capsules with GELITA® EC adhere to US Pharmacopeia dissolution parameters. This means that these capsules do not release the fill during two hours in 37°C simulated gastric fluid, but are fully dissolved within 45 minutes in simulated intestinal fluid. Reliable Release Under Harsh Conditions Despite the overwhelming advantages of gelatine capsules, certain types Spring 2018 Volume 10 Issue 1
Manufacturing of reactive fillings and extreme storage conditions – such as high temperatures and humidity — may cause the gelatine in the capsule to react and cross-link. Over time, soft capsules become increasingly less soluble, which results in undesirable longer dissolution times in the GI tract and slower release of the fills. The solution to this problem is GELITA® RXL (Reduced Cross-Linking), which adds extra value to gelatine capsules. This special gelatine grade significantly reduces the amount of cross-linking issues, thus enhancing the dissolution properties of the capsules. Various attempts by the pharmaceutical industry to reduce cross-linking with additives have been only partially successful. GELITA, however, followed a different route: the company established a new production process which controls the molecular weight distribution and therefore minimises dissolution problems in soft capsules. The GELITA solution can be described as a sort of “self-defence mechanism” brought about by a combination of large and small molecules. These molecules react with the gelatine and block it, making it no longer available for self cross-linking reactions and/ or reactions with other substances within the fill formulation. To guarantee long-term capsule stability for very critical fills, the gelatine manufacturer has additionally developed GELITA® RXL advanced, the next generation of its reduced cross-linking technology. It provides reduced pellicle formation which, in turn, minimises the cross-linking
release in combination with long-term stability is required. A Partner for the Industry With its standard, EC, RXL, RXL advanced and RXL R2 products, GELITA offers pure pharmaceuticalgrade gelatine that fulfills almost all possible demands and complies with existing regulations. When it comes to finding the best gelatine grade for each application and designated use, GELITA’s experts help customers with in-depth knowledge and technical service. This not only accelerates product development, but also reduces the risk that a capsule formulation, once developed, will be found to fail dissolution or storage requirements or not fulfil consumer expectations.
potential and supports controlled fill release performance during the complete shelf-life. A Rapid Solution Especially when it comes to products such as pain medication or cough and cold formulas, consumers want rapid results for immediate relief. However, hot or humid storage conditions delay the promised effect because they slow down the fill release performance of soft gelatine capsules. To solve this problem, GELITA took the reduced cross-linking (RXL) concept provided by GELITA® RXL one step further and introduced rapid release (R²) performance to the market. Aiming to facilitate even faster release of active ingredients, GELITA worked with the University of Heidelberg to test the new formulation and analyse the benefits of soft gelatine capsules comprising GELITA® RXL R2. Capsules were stored for up to 12 months under different ICH storage conditions and, for comparison, GELITA’s standard limed bovine bone gelatine and RXL limed bovine bone gelatine with reduced cross-linking performance were assessed. The results clearly show that, even under demanding storage conditions, GELITA® RXL R2 gelatine offers faster fill release rates for both fresh and aged capsules. Hence, it provides significant benefits for the development of soft gelatine capsules for which rapid fill
And more than this, the company also delivers comprehensive service in a wide range of other business areas – from the development of concepts, formulations and prototypes to process optimisation, marketing support and regulatory advice. Thanks to decades of experience, the company’s technical experts are able to offer first-class guidance for new and established customers alike. At the same time, its research specialists are constantly exploring new and innovative application areas that help clients to enter new markets all over the world.
Holger Becker Dr. Becker studied chemistry at the Technical University of Darmstadt in Germany. In 1999 he started as a scientific assistant at the Ernst-Berl Institute for Technical and Macromolecular Chemistry in Darmstadt and worked on acrylic polymers in cooperation with BASF Ludwigshafen. In 2003 he started his industry carrier in the R&D department of Naturin Viscofan GmbH. His responsibilities included the development and implementation of new edible casings on the basis of the biopolymer collagen. In 2009 he was appointed to the Bioengineering department where he focused on the development of collagen based products. In 2013 he became a member of the GELITA AG.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 69
Automating Packaging Lines to Benefit Clinical Trial Supply The growing demand for complex oncology drugs and medicines to treat a wide range of therapeutic areas has driven heightened levels of clinical development activity and changed the clinical trials landscape drastically. Ongoing technological development in the clinical trials space is also driving change in the way clinical trials are managed, and how the drug supply is developed, manufactured and packaged. Companies are increasingly seeking to automate processes in response to a demand for improved productivity while maintaining high-quality results.
The cost implications of getting a new drug to market are incredible, with the average estimated to be around ÂŁ1.5 billion. If a drug fails towards the later stages of a clinical trial, the impact on the sponsor and its suppliers is often catastrophic. There are also wider cost concerns throughout the supply chain due to increased price pressures from governments. In this environment, itâ€™s easy to see why there is pressure from drug developers to introduce efficiencies wherever possible to combat the cost and risk of clinical trials. Automating elements of packaging lines is one key element in improving efficiency in the clinical supply process and creating added value along the way. Adoption of automation is increasing among pharmaceutical companies and their contract partners. This is particularly common across packaging operations, in a bid to reduce the time and resources associated with manual processes such as inspection and labelling. Packaging for clinical trials often runs at a smaller scale and frequency than a commercial packaging line, meaning businesses are sometimes less inclined to invest in automated activity. While a greater understanding of the potential benefits automation can offer towards improving operational efficiency is driving investment in the area, there are a few considerations to be made before introducing new technology. 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The Benefits of Automation First and foremost, itâ€™s imperative that companies ensure that implementing an automation process is appropriate in terms of both its financial impact and any effect on the process and products. Manufacturing and packaging for clinical trials tends to be a more manual process and sometimes very small scale, so for some projects, the investment in automation equipment will not be a viable option. In clinical trial study, there are many ways automation can benefit the packaging operation. Due to regulatory changes, labels for clinical trial supplies need to contain more detailed information, without having an impact on blinding of the product. The result is that more companies are choosing to label their products using a barcode or a 2D data matrix that can be scanned at kit level. In the same way that automation can benefit commercial packaging lines that need to incorporate serialisation data, it can also help companies develop efficient labelling processes that meet varying market regulations for clinical trials. Thirdparty suppliers with serialisation expertise are increasingly being relied upon to translate their approach to clinical packaging lines to support the verification of assembly processes and provide suitable coding for despatch. It also provides an easy way to generate the randomised labels that are essential for successfully blinding products. Specialised interactive response technology (IRT) can also automate activities including clinical supply management and distribution. In addition, it allows for the adapting of the study schedule as data becomes available, which helps to drive overall efficiency. Clinical trials require each product to be identical in appearance, as variations can influence the results, invalidating the study. Technological advancements in camera vision and verification systems over the last decade have allowed companies
to replace manual inspection with an automated equivalent to ensure uniform presentation of packaging and labelling, at a faster pace. Automation is also hugely beneficial when it comes to capacity and scalability, catering for evolving needs such as additional batches or scale-up. It can also make tech transfer simpler if the drug progresses to commercial supply. Again, companies can benefit from using contract partners that can cater for both clinical and commercial supply, allowing sponsors to utilise the commercial technology for clinical projects and simplifying scale-up. Selecting a contract packaging organisation (CPO) with experience of packaging products from clinical to commercial supply can enable the sponsor to gain access to facilities and technology that will add significant value to their clinical projects. Summary Adoption of automation has been on the increase throughout the pharma industry for many years; however, its benefits in a clinical trials environment are yet to be fully realised. As the pressure mounts to lower the risks and costs associated with clinical trials, businesses would be well-served to explore the opportunities that automation presents in their packing operations.
Dave Wilson Dave Wilson is the Head of Operations for Sharp Clinical Services, based at the Crickhowell site in South Wales. Dave has over 17 years of end to end FMCG operations management experience, including project management, planning, warehousing, despatch and transport. Prior to joining Sharp, Dave worked as an Operations Director for Amcor Flexibles and has previously worked for Unilever and Reckitt Benckiser.
Spring 2018 Volume 10 Issue 1
HEALTHCARE Rychiger and Zellwag Pharmtech are dedicated to provide custom filling and closing equipment from laboratory scale to full production and packaging lines. We are your equipment partner in the diagnostic, medical and pharmaceutical packaging industry. Just go for the worldâ€™s leading filling and closing solution.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 71
Why the Need for Centralised Content Management is on the Rise Despite the advances in electronic content management over the past decade, many of the biggest global life sciences companies still manage their local translations in a highly fragmented way. Not only does this lead to a rise in costs, but it also comes with risks to safety and slows down product speed-to-market.
Competition in the life sciences sector has never been tougher, and for organisations to succeed requires a combination of business agility and control. Agility allows organisations to get their product to market more quickly, and control ensures that they never fall foul of local market requirements. However, despite being an industry which is subject to stringent, diverse and frequently changing regulation, life sciences has a tendency to manage content for international markets in an inefficient and error-prone way. For example, it’s not uncommon to manage patient information and labelling and packaging in a manual, decentralised, and case-by-case way. When content on packaging or labelling needs to change, each country must oversee its reviews. Visibility is quite limited, and the correct master content and relative status of each country’s version are not always clear. Where affiliates are involved, the line of sight is further blurred. It’s a situation that has become unsustainable. The life sciences market has been a slow adopter of advanced content management technology, preferring traditional ways of managing processes and content because of the comfort factor associated with hands-on checks, or viewing content development and translation as an afterthought. But the volumes of patient-facing content manufacturers and distributors are required to maintain for each 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY
product, in each market, is increasing exponentially. Not only are companies advancing into modern technologies, making more products, and expanding into more countries and emerging markets, safety and regulatory requirements they must adhere to are multiplying and changing all the time. The result is increased risk of incomplete or inaccurate information that leads to late-market introduction because compliant labelling or patient literature isn’t ready. Lengthy Update Cycles There are many different factors that can drive a change to labelling, including changes to product safety information, new or changed local regulatory requirements, and ongoing product updates due to an increase in the agile development methodology. To illustrate the challenges, take an extreme example. A company with 1000 distinct labelling deliverables distributed to international markets requiring translations in 50 different languages could face endless cycles of updates as changes are absorbed, approved and rolled out to each country. It’s not unusual for a major update cycle, impacting all labelling, to take up to two years, tripling the size of the team involved, if this is managed manually and in a highly dispersed, siloed or non-centralised manner. By the end of this highly protracted process, new changes are likely to be needed. The situation is becoming more, rather than less, challenging. Increased focus on improving patient safety internationally means countries that once accepted English as the language for product labelling and instructions for use, now require local translations. Similarly, organisations can no longer get away with imposing the most commonly spoken versions of a language (such
as Spanish); they’re now expected to reflect each market’s variations – so that Mexico, for instance, gets its own translation. This is increasing the workload associated with creating compliant patient information. It is becoming overwhelming, and an inhibitor to the agility companies seek to maintain their competitive position in a dynamic yet highly regulated global market. Adding to the market’s dynamics are the continued elevated levels of merger and acquisition activity, which are further intensifying the demands on content management – as brand names, copyright details, and corporate identity change. These changes must be reflected across all external content and often require re-submission and registration with different international notified bodies – a process that can take many months in some countries. Complexity, Risk of Error and Costs are All on the Rise If content is not managed in a structured, centralised way, complexity, risk of error, and inflated costs can grow exponentially. This situation is magnified if responsibility for local versions is left to in-country distributors or affiliates, and can lead to retrospective labelling, a common burden for companies marketing drugs internationally. It happens where content is developed in local languages and must be translated into English for verification, corrected, and then translated back into the local language, and sense-checked to ensure its meaning has not been distorted along the way. Failure to produce correct, compliant labelling and other patient information can delay market entry, or worse, result in costly product recalls, or pose a threat to patient safety. Mistakes can lead to reams of pre-printed content (e.g., stack Spring 2018 Volume 10 Issue 1
• Breath activated patented DPI’s;
• Flexible for different delivery proﬁles;
• Designed to deliver metered doses of drug from capsule;
• Safety guiding piercing system;
• Reusable systems: Replacement of the capsule with single doses;
• Available for generic and innovative drugs; • FDA DMF and CE.
Pharma & Cosmetics Patented Devices
firstname.lastname@example.org www.emphasys-industrial.com +55 11 3846 1362 INTERNATIONAL PHARMACEUTICAL INDUSTRY 73
Packaging have a single, unified content asset database which is hosted centrally. For the sake of simplicity and ease of access, it is advisable to host this in the cloud (by way of a software-asa-service model), to allow authorised teams ease of access anywhere in the world.
upon stack of instructions-for-use leaflets sitting in warehouses, ready to ship out with products) having to be pulped. Wanted: A Systematic, Centralised Approach to International Packaging and Labelling After decades of making do with the old ways of managing international labelling, the realisation is finally dawning that things can’t continue – a manual approach is unsustainable, risky and highly inefficient. Continuing to treat packaging, labelling, and regional translations as an afterthought at the end of a long and complex research and development process is potentially undermining all the investment that has gone before. In the meantime, everything points to the need for life sciences companies to adopt a systematic, centralised approach to international packaging and labelling to reduce labour, shorten time cycles, reduce risk and cost, and substantially improve market agility. So, what does best practice in global labelling look like? Establish Content Ownership Centralised content management begins with content ownership, which should be brought under a single team – for instance, technical communications. Appointing someone to own all content (including translated versions) brings clarity and an opportunity to drive change from a single focal point. As an extension of this single point of focus, it makes sense to 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The right system provider will have several data centres across different geographic regions, to ensure distance is no barrier to the system’s performance and that latency is minimised. This added advantage of using an externally hosted content management system is that companies don’t need to manage, administer or support the technology themselves (it’s all done for them). The right provider will be able to provide guidance on setting up good internal processes to ensure teams get the most from the centralised approach to global information and achieve international consistency. Given the very specific and complex needs of global life sciences content management, it is worth looking for a system that has been designed specifically to cater to the nuances of this highly regulated environment and provides a fit-forpurpose workflow for rigorous quality assurance and traceability that will be needed. A system that can manage content at a component level, rather than at a document level, is recommended. This allows approved components (e.g., associated with warnings, instructions or disclaimers), or other digital assets such as logos or symbols, to be simply plugged into different types of output. This ready repurposing reduces the overall scale of the task and the risk of mistakes being introduced each time changes are required. Measuring ROI on Centralisation The benefits of centralising and streamlining global information are well proven. Major international labelling updates involving thousands of different pieces of output have been shown to shrink from two years to six months. Desktop publishing costs can be halved across all
languages, thanks to automated publishing made possible through a centralised content management system. The typical international content lifecycle, meanwhile, can be reduced from 28 weeks to as short a time as nine weeks, through content modularisation and concurrent, rather than sequential, content development. Moreover, centralised, automated management of content has become the standard methodology in most industries now – from banking to the legal sector. It’s much easier to visualise, verify, trace and audit, and it’s many times more efficient and confidence-inspiring than ad-hoc, distributed processes which depend heavily on manual actions. Agile organisations can keep pace with markets because they can adapt and respond quickly to the environment around them. In life sciences, centralised, systematic control of global product information is the best way of achieving this.
Jason Arnsparger Jason Arnsparger is a Program Manager at AMPLEXOR Life Sciences and has been in the localisation industry, focusing on life sciences, for 13 years. He works with life sciences companies to define, develop and implement strategic processes and systems to streamline the product development and localisation lifecycle. Before joining AMPLEXOR, he worked at a leading medical device company, where he led the way in developing the localisation process and continuous process improvements. Jason has a B.A. in Modern Languages, is a certified Project Management Professional from the Project Management Institute, is a certified Six Sigma Green Belt and is training for his Six Sigma Black Belt certification. Email: email@example.com
Spring 2018 Volume 10 Issue 1
Our Commitment, The Industry Leading Experience
PCI Pharma Services â€“ a market leader for integrated drug development and commercialization The foundation of a successful partnership is trust. At PCI, we dedicate our unwavering commitment to provide the industry leading customer experience. This focus enables us to be a trusted partner to 19 of the top 20 pharmaceutical companies in the world. We earn trust by providing our clients flexibility and responsiveness, outstanding operational performance, and the support of uncompromising quality and regulatory standards. By this commitment we deliver our clients an end-to-end development and commercialization solution including drug development and scalable drug manufacturing, integrated clinical trial services, and commercial packaging services. We are trusted to support lifesaving medicines destined to over 100 countries around the world.
We invite you to learn more about what the PCI commitment can do for the success of your business.
Please Join Us at:
pciservices.com Feb. 7-8 | Paris, France
Booth J24 ÂŠ Copyright 2017 PCI Pharma Services. All Rights Reserved
Serialisation for Late Starters
In an industry as vast as the pharmaceutical market, every company is at a different stage of implementing serialisation to ensure complete compliance when new EU and US regulations come into force. Due to the challenge of introducing a robust serialisation solution, many companies are now experiencing unforeseen issues as the industry starts to recognise the magnitude of the task at hand.
For those that have delayed developing their serialisation strategy, adopting a ‘wait and see’ approach, time is quickly becoming a concern as the active enforcement US deadline in November 2018 fast approaches, followed closely by the EU regulations in 2019.This article is designed to give companies just starting out on their serialisation journey, as well as those that are already some way along, a guide to the various complexities associated with global track-and-trace requirements. What is Serialisation and Why Do I Need to Do It? During recent years, the pharmaceutical industry and regulatory authorities have placed increasing importance on the worldwide issue of falsified medicines entering the supply chain. According to the World Health Organisation (WHO), around 15% of all medicines are counterfeit. Counterfeit medicines not only pose a significant risk to patient health, but also cost the industry money, with the falsified medicines market worth over $75million per year. Doubt surrounding the integrity of the supply chain can also severely damage the reputation of manufacturers and distributors. By 2019, over 55 countries will have introduced serialisation and track-and-trace compliance laws in order to follow the passage of pharmaceutical products throughout the supply chain and combat the growing problems surrounding 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY
counterfeit drugs, reimbursement fraud and product theft. The implementation of serialisation and track-and-trace systems is a challenging process and with the requirements just around the corner, it is imperative that pharmaceutical companies act now if they haven’t already started implementing a strategy. Understanding the Benefits of Pharmaceutical Serialisation On the surface, serialisation may appear to be a relatively simple addition to production lines; a barcode or serial number must be added to every saleable drug unit. Simple, right? Varying regulations across numerous markets and the huge amount of data produced means there is more to implementing serialisation than first meets the eye. Who Needs To Be Involved? With so many different facets to serialisation, it’s important that as many stakeholders as possible understand your approach and the size of the task at hand. The more you involve each department within your organisation, the easier it will be to overcome any potential hurdles and the more successful your implementation process will be. How Do the Global Regulations Differ? One of the biggest hurdles for pharmaceutical companies is the global environment they operate in. One company can be responsible for the manufacture and distribution of drug products in numerous markets, and with no two countries passing the exact same compliance laws, they are faced with the challenge of implementing a solution that caters for lots of different regulations. For example, while the EU Falsified Medicines Directive (FMD) and the US Drug Supply Chain Security Act (DSCSA) require a randomised serial number to be produced and
incorporated into a GS1 barcode, the Chinese market requires a linear barcode using a number allocated by the government prior to production. The scope of medicines covered by serialisation rules also varies from country to country; for example, South Korea’s track-and-trace requirements extend to over-the-counter (OTC) medications, as well as prescription drugs. With these variations in mind, it’s important to consider all the markets you operate in, or that you might enter in the future. Aggregation requirements also differ depending on the country the pharmaceutical products will be distributed in. The EU FMD only requires serialisation at unit level, however South Korea and India have made serialisation mandatory on primary, secondary and tertiary packaging. This means companies supplying to these markets must ensure their serialisation systems are able to record parent-child relationships between each of the packaging levels. In many cases, it is sometimes better to incorporate aggregation as part of your standard solution, as it can also help to speed up a product’s journey through the supply chain by minimising the need to unpack batches. It’s here that bringing in outside expertise can be of real benefit. Previous experience and knowledge of the serialisation landscape is invaluable when developing a robust strategy and with time constraints getting tighter and tighter, expert knowledge can really simplify up the process of developing an effective solution. What are the Technical Considerations? When it comes to technical requirements, serialisation can be a minefield, so making the right decision when selecting hardware, software and cloud providers is absolutely vital. There is no one-size-fits-all solution and, given the extensive scope of serialisation, a comprehensive strategy Spring 2018 Volume 10 Issue 1
Packaging will most likely involve multiple vendors working in collaboration. So, where do you start? Packaging Your first consideration should be your packaging requirements. The addition of a barcode might mean you need to redesign your packaging, in which case you need to build in time for this process. A lot of serialisation legislation also requires packaging to include tamper-evidence and, if you’re supplying to markets which do, you will need to integrate this into the design as well. Codes As the type of codes required varies from market to market, this can have an impact on the print technique used. In all markets, the barcodes need to be machine-readable, making print quality a critical factor to avoid rejections and loss of stock. High-density codes, for example the GS1 barcodes used in multiple markets, will require the quality finish associated with thermal inkjet or laser printing. If you’re supplying to markets with different requirements, opting for a higher print quality as standard is a more time- and cost-effective approach. Codes Data Storage Once you have determined your requirements and chosen appropriate hardware and software providers to serialise your products and perform any aggregation, you need to consider how you’re going to store all this new data. The simplest solution is an external cloud storage provider, but it is essential to ensure they can support the transfer of sensitive date between third parties and store your data securely for the required length of time. Data integrity is paramount so doing your research, or seeking the advice of a third party with experience of implementing successful serialisation programmes, is recommended. How Do I Get Started Quickly? The various complexities associated with implementing serialisation are vast, so you need to build time into your strategy to do test runs on a pilot line to avoid costly mistakes, come the deadline. 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The US DSCSA comes into force in a matter of months and with so much to consider, companies that haven’t started to implement serialisation solutions should look to bring in third-party expertise to speed up the process. Failing to meet upcoming deadlines could mean disruption to product supply, costly downtime and an impact on your reputation. Five Tips for Serialisation Success 1. Be forward-thinking The likelihood is that as serialisation becomes the ‘norm’ in the pharmaceutical industry, regulatory bodies will identify ways to make anticounterfeiting measures even more robust. So, consider how your serialisation solution will stand up to changes in regulation. Ensuring you have a flexible solution from the outset will make it easier to adapt as legislation evolves over time. 2. Market Requirements Many pharmaceutical manufacturers will supply to multiple markets in a number of geographic locations, all of which have slightly different track-and-trace compliance laws. Again, the flexibility of your solution is key. Get to know the varying market requirements and consider whether your solution can adapt to them all. 3. Build in time to test your solution On paper, your serialisation strategy may appear robust, but there’s no substitute for rigorous testing. Testing your solution out on a pilot line will allow you to identify potential hurdles before they arise and avoid costly downtime, loss of business in key markets, product wastage and even supply shortages. 4. Ensure your staff are ready for the challenge Integrating serialisation into your supply chain should extend beyond the hardware and software requirements. With so many facets of serialisation to consider, it’s important that your entire team understand their role in compliance and how your solution will affect every part of your organisation. Investing time in training your staff will be invaluable when it
comes to overcoming problems and avoiding unnecessary expense. 5. It’s not too late to consider support Serialisation is a complex process and even if you’ve already started to develop a strategy, bringing in external expertise can help to speed up your journey and simplify the integration of new technologies. Don’t take a short-term view. While the end goal of achieving compliance before the US and EU deadlines is important, a robust support model should be in place for the long term.
Carlos Machado Serialisation director, Zenith Technologies. Experienced Executive with a demonstrated history of working in the information technology and Professional Services industry. Skilled in P&L Management, Operations Management, Sales and Marketing , Program and Project Management, Peer Mentoring, and delivering continuous Customer Satisfaction. Strong business development professional with a MSc of Project Management focused in Global Program Management from University of Liverpool. Email: carlos.machado@ zenithtechnologies.com
Marco Baietti Marco Baietti is commercial director at SEA Vision with responsibility for technical sales and advising pharmaceutical and biotechnology clients globally on the introduction of serialization software. With 20 years’ experience in technical sales, Marco has the ability to understand clients’ complex challenges and find a solution to meet their needs. Before joining SEA Vision, Marco worked for a number of leading global companies in packaging machinery. Marco has a BA in Electronic Engineering, Management Information Systems and Services. Email: firstname.lastname@example.org
Spring 2018 Volume 10 Issue 1
LSS – Labelling Systems Scandinavia Has Recently Developed a Standard Vial Labeller and Tamper-evident Labeller Both the machines will be demonstrated at Achema in Frankfurt, Germany from 11–15 June 2018 in hall 1.1 – booth E42.
Based on many years of individually designed and customised labelling solutions for the pharmaceutical industry, LSS has now developed a standard vial labeller and tamperevident labeller. Both the machines are designed with all our know-how, and high attention to: • • • • • • •
Simple and safe operation Precision in labelling Safe and secure product handling Easy function overview Inspection and control Easy line clearance Ergonomics
The LSS Vial Labeller can be used for labelling of a wide variety of smaller cylindrical products. The machine can operate both as an in-line machine integrated into a production line, or as an offline machine where vials are fed into the machine from trays and delivered back into trays after labelling. Choose freely between different print technologies such as thermal transfer print or laser marking.
The LSS tamper-evident solution is in compliance with the FMD (European Union Falsified Medicine Directive). The tamper-evident labeller seals the carton. As an option, a printer and vision system of any brand can be integrated, to provide each carton with a unique identification for track & trace and serialisation. About LSS With more than 45 years in the labelling industry, we have built up significant expertise which allows us to set and meet the highest standards in developing efficient and
reliable labelling solutions for the pharmaceutical industry. Through these many years of qualityminded work and innovation, we have managed to position ourselves as a leading supplier of labelling solutions for the pharmaceutical industry in Scandinavia. LSS was founded in 2001 as a continuation of the labelling machinery division of Avery Dennison. After 13 years operating as a privately-owned independent company, LSS was in 2014 acquired by the Logopak Group and is today benefitting from being a member of its worldwide sales and service organisation. For more information contact: LSS Etikettering A/S, Normansvej 8 8920 Randers NV, Denmark Phone: +45 7020 2500 www.lss-dk.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 79
Demand for Unique Identification of Products Call for Investments With new directives within serialisation and track and trace on the way in many parts of the world, pharmaceutical companies are facing strict requirements for being able to supply medicine with tamper-proof packaging and a unique code for each product. Some companies are well-prepared while others are facing investments within the next year.
Serialisation, FMD (European Union Falsified Medicine Directive), DSCSA (United States Drug Supply Chain Security Act) and UDI (Unique Device Identification) are all regulations that have been in the making for a long time and will be implemented in the very near future. A part of most of the regulations is the demand for unique identification of each product or device, making it possible to track and trace the medicine from the pharmaceutical manufacturer and all the way to the patient who is picking up the medicine from a pharmacy or hospital. False Medicine may be Life-threatening Governments are adopting the legal requirements to prevent false products from finding their way to the market and thus, patients may face life-threatening problems. The track and trace of every unique product also enables governments to avoid paying national insurance on a false basis, since the code is unique for every product and can only be scanned in and out of the software system once. The fraud problem is well-known to pharmaceutical companies and is a global issue. Although the regulations are not made to benefit the pharmaceutical companies, complying with the requirements provides them with the tools to track and trace every product to, e.g., avoid problems with authenticity and with the authorities. While some companies are wellprepared for the legal requirements 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY
just around the corner, many others are now facing investments to be able to comply with the new directives. Companies that are already supplying products with tamper-proof packaging have a clear advantage in being compliant with the new regulations, since investments have already been made. The many companies that have not yet invested are now very focused on getting the right equipment installed in their production lines and finding the right software for handling the unique codes and data that is necessary to follow each product or device. Rise in Devices Calls for New Technology The largest investments right now must be made in the appropriate software systems while labelling machines in the different stages of the packaging hierarchy offer different possibilities for meeting the demand for serialisation and tamper-proof sealing. Labelling machines from LSS can interface and communicate with most software systems and, for their part, the equipment can perform the printing of the serialised number on the product and supplies the medicine or device with tamper-evident labelling. Right now, the serialisation data are placed on the secondary packaging but in a few years, we expect to see a demand for serialisation data down to the primary product. We also expect to see a growing market in devices for use by patients at home. These devices must be tamper-proof and labelled with a unique track and trace code that can be scanned in and out of the software system. This development requires new technology and machinery that can handle the labelling of every part of these different devices that typically consist of a syringe, needle and a small unit for giving the right dose for each patient. Some companies would like to be prepared for this development and believe that it will
be a legal requirement in the future thus, the machines they are buying must be able to mark the primary pro-duct and each device in it. The Packaging Hierarchy When considering the best solution, the packaging hierarchy is a way of visualising the possibilities for marking and labelling solutions that meet the legal requirements. This enables pharmaceutical manufacturers to prepare for future directives in the different levels of the hierarchy. Primary products are the first level of the packaging hierarchy and can be the first step of serialisation data to be applied onto the product or device and collected by a vision system. Serialisation data can be applied either by applying a label onto the product or by direct marking on the product. Non-approved Labels are Rejected by Visual Inspection When using labels on the product, it is possible to check with vision before applying it to the product so that non-approved labels will be rejected. By using visual inspection of label presence/position, presence of cap etc. on the, e.g., vial after the label has been applied, it is possible to ensure that only approved products are passed on in the production line. Thus, companies can avoid rejection of the whole product later in the process, minimising costs and batch start/ stop. When marking directly onto the product, vison inspection cannot be made until after the marking of the product. If the marking is not approved by the vision inspection, the whole product must be rejected. Example of data for primary products:
Spring 2018 Volume 10 Issue 1
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Packaging Vision System Checks and Collects Data Next level in the packaging hierarchy is the secondary packaging, that is usually a cardboard carton in different sizes. In this level of serialisation, according to the legal requirements, the packaging must be tamper-proof, either by a label or as an integrated part of the carton. Usually, serialisation is closely connected to carton labelling – secondary packaging combined with tamper-evident labelling. Serialisation data can be marked directly onto the carton by laser or inkjet and a price sticker can be added if necessary for local reimbursement, according to the national health insurance provision. Also, a vision system or code reader must be used to check, collect and send data to the joint database. If a tamper-proof label is used, a sensor can check to ensure that all products leaving the labelling station are sealed correctly. A tamper-evident labeller is easy to integrate into existing systems and by adding a printer and vision system to serialisation software, pharmaceutical companies will have a complete solution that complies with the requirements for serialisation and track and trace. Example of data for secondary packaging:
boxes can vary from one to several labels, with the most common ones being customer and product labels.
complete integration with the existing ERP-system is possible. Example of data for pallet labelling:
Example of data for colli/shipper box packaging at the third level:
Manual or Automatic Labelling At the last level in the packaging hierarchy, the serialised products and aggregated shipper boxes are placed on a pallet for storage or shipment. The most commonly used labelling of pallets is done according to the GS1-128 standard, that requires two labels wrapped around the corner on the pallet. For a few pallets, a manual station with a thermal transfer printer and a scanner for applying the two labels by hand can be used. For a larger number of pallets, labelling can be done automatically on one, two or three adjacent sides of the pallet, and
Bullet Points Facts about Upcoming Legal Requirements for Pharmaceutical Serialisation and Unique Identification: •
In February 2019, pharmaceutical serialisation will become a legal requirement for companies in the European Union (European Union Falsified Medicine Directive)1. In the US, the United States Drug Supply Chain Security Act (DSCSA) was enacted by Congress
Third Level: Collect Aggregation Data At the third level of the packaging hierarchy, the secondary products containing primary products are packed into colli/shipper boxes and here the aggregation data can be collected. The unit should be able to interface and integrate with different types of data providers and could be either an integrated or stand-alone unit, depending on the company’s needs. The colli/shipper boxes must have a label applied or they can be marked directly onto the box. A thermal transfer printer/dispenser can be used for labelling the boxes while inkjet can be used for marking directly onto the boxes. The number of labels on the colli and shipper 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
in November 2013 and will be continued to be phased in until 20232. Governments all over the world are facing problems with medicine fraud that can be a potential risk to patient safety and/or cause large expenses for national health services. To stem these problems, part of the directives is the tamperevident proof of serialised cartons and the demand for unique identification of each product or device. This makes it possible to follow a product from the pharmaceutical manufacturer until it is sold from the pharmacy or given to a patient who is hospitalized, so that patient safety can be improved and fraud can be minimised.
be done manually or automatically depending on the number of pallets. Integration with existing ERP-systems is a possibility.
Bullet Points The Packaging Hierarchy - A Quick Overview of the Possibilities: •
First level - primary products and devices: Marking by applying a label to the product or directly onto the product. Vision inspection can ensure rejection of non-approved labels before they are applied to the product. Second level – marking carton in different sizes and sealing with tamper-evident labelling. Vision systems can ensure that all products leaving the production line are sealed correctly. Third level – colli/shipper boxes are supplied with a label or marked directly and aggregation data can be collected. Fourth level – pallet labelling can
REFERENCE 1. 2.
https://ec.europa.eu/health/humanuse/falsified_medicines_en https://www.fda.gov/Drugs/ DrugSafety/DrugIntegrityand SupplyChainSecurity/ DrugSupplyChainSecurityAct/ ucm427033.htm
Jens Heidemann Sørensen Jens is Project Sales Manager at LSS – Labelling Systems Scandinavia. He joined LSS in 2003, and is responsible for labelling projects to the pharmaceutical industry. Over the years, Jens has been responsible for projects for vials, syringes, pens, bottles, cartons and shipper boxes to some of the largest pharmaceutical companies. Email: firstname.lastname@example.org
Ulla Laursen Sales and Marketing Email: email@example.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 83
Logistics & Supply Chain Management
Risk Migration within Global Pharma Supply Chain Logistics The need to mitigate risks within global pharma supply chain logistics is driving innovation within the temperature-controlled packaging sector. Innovation and new technologies are proving paramount to the emergence and evolution of smart temperaturecontrolled packaging, protecting pharmaceutical payloads worldwide.
To help eliminate excursions in temperature in the cold chain, there is growing demand for reliable, high-performing packaging products to safeguard sensitive shipments. Increasingly, packaging companies are incorporating innovative design features and utilising more advanced technologies, to produce and manage pioneering products and ever more sophisticated systems, which help eliminate excursions in temperature in the cold chain. As temperature-sensitive pharmaceutical products are increasingly being shipped globally to more remote regions, there is an even greater demand for innovative solutions being placed on the temperature control packaging industry. An impetus for the latest generation of high-performing packaging products comes as the pharma industry continues to grow at a significant rate, with an estimated global worth of $400 billion by 2020 according to the World Heath Organization. A driver for a substantial proportion of this projected growth in the life sciences sector includes the rise in temperature-controlled biosimilars and biologics, which are biologicallybased pharmaceuticals as opposed to chemical-based. It is predicted more than 50 per cent of approved new drugs are going to be biologics or biosimilars in the next few years. The evolution of this latest drug development presents its own supply chain challenges when it comes to safe storage and transportation of these temperature- and time-sensitive pharma products. 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY
More global clinical trials are requiring stricter temperature regulations, which command compliant cold chain conditions and increasingly innovative packaging solutions. Temperature restrictions when transporting these pharma payloads present their own challenges, coupled with the fact more are being shipped to emerging markets where there are also extreme temperature ranges to contend with. These advancements in drug developments bring a rising requirement for the latest generation of highperforming packaging products, including the increase in more fragile and temperature-sensitive pharmaceutical products. Various pharmaceutical compounds, utilised within the sector, are developed under certain temperature control conditions or designed to be stored at specific temperatures to maintain their stability. Therefore it is vital, when shipping pharmaceutical products between locations, they remain at their storage condition temperatures to maintain their effectiveness at the point of use. Within the industry, there are standard temperature ranges such as deep-frozen (below -50°Celsius), frozen (-50°C to -20°C), refrigerated (4°C to 8°C) and room-temperature (15°C to 25°C). The most common temperature tolerance is 2–8°C. Many sensitive materials for the healthcare market are designed to be transported in this temperature range. Too cold and the payload will freeze. Too warm and it will also spoil. So, it’s critical that the temperature stays in the 2–8°C range for as long as seven days, without having any temperature excursions. When excursions do happen, they are typically due to human error. Such as not packing the shipper correctly, freezing the coolants or opening it for too long prior to removing the payload to a temperature-controlled storage area. With the pharmaceutical companies developing ever more complex and
temperature-sensitive drugs, there is a greater demand in the cold chain industry to meet the growing market demand for supply as well as improved packaging performance and efficiency. To help mitigate supply chain risks, the industry is seeing a greater demand for higher performing packaging products. Coupled with the rise in regulatory requirements, there is an even greater emphasis on supplying the global market with more advanced, smart packaging that does more than act as a container for precious, high-value payloads being transported to emerging markets via complex shipping lanes. The expertise of experienced engineers is a critical component within the packaging industry, with providers deploying increasingly highperforming packaging systems that need to mitigate supply chain risks and minimise temperature excursions. Any spikes or deviations in temperature, beyond the range specific pharmaceutical products are required to be stored and shipped at, could have a devastatingly detrimental effect on the payload, damaging the container’s contents and impacting on the efficacy of the products being transported. As well as the financial repercussions, equating to losses of hundreds of thousands of pounds, any excursions could, more importantly, have catastrophic consequences for the patient/end user reliant on the designated drugs being delivered intact, with maximum efficacy. Whether shipping finished products, transporting clinical trials materials or delivering sample drugs, temperature excursions can mean the difference between success and failure, profit and loss. It is essential, therefore, that pharmaceuticals are protected throughout the supply chain end-to-end as temperature excursions during transportation can even cause them to become toxic. Spring 2018 Volume 10 Issue 1
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 85
Logistics & Supply Chain Management There is increasing recognition within the supply chain of the vital role smart packaging plays and, in response to the stringent regulatory requirements, the packaging industry is taking a proactive approach. The market for transporting temperature-sensitive materials for the healthcare market, such as pharmaceuticals, blood, tissue, organs, etc. is a sub-segment, currently valued at approximately $2 billion and expected to grow to approximately $5 billion by 2026. There is an increase in the introduction of information-centric capabilities to assist with the safe shipping of pharmaceuticals around the globe. Packaging companies are increasingly utilising advanced asset management software systems, which are in place specifically to ensure pharmaceuticals are shipped to the right location, at the right time and critically, that they arrive in the right condition. Companies deploying pharmaceutical shipments worldwide benefit from the introduction of new technological advancements including web-based asset management software solutions, designed to track individual shipments globally. Integrating these cloud-based systems offers a range of capabilities benefiting the industry, including options to set up automatic maintenance, next shipments alerts and produce customisable reports. Some of the latest innovations in smart packaging, serving the life sciences and pharmaceutical industries, are critical developments as ultimately the quality of pharmaceutical products being transported has a direct effect on patient safety and the efficacy of patient therapies. The industry is also seeing a growing trend to deploy reusable systems coupled with asset management SaaS (software as a service) and reaping the associated benefits. These systems can automatically collect and analyse data from company data logger outputs. Currently operating in the market is a range of SaaS products providing collection and analysis of brandagnostic sensor data, as it’s linked to a variety of smart packaging options allowing packaging vendors to track a diversity of data including vibration, light, humidity, temperature and more. 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY
These software platforms capture and monitor information throughout the course of the shipment’s trip. The data retrieved and shared can help pharmaceutical companies make more informed choices on the most appropriate packaging systems to deploy, depending on the specific shipping lanes and routes their payload will navigate. These technologies and services help life science industry clients reduce payload risk, distribution costs and their environmental impact, ensuring temperature-sensitive, critical and high-value payloads reach their destination safely. Integrating the cloud-based system supports and enhances engineering expertise that is incorporated into the development and design of the increasingly sophisticated systems utilised by the life science industries. Increasingly passive and active bulk systems are incorporating data loggers to track the temperature throughout the course of the trip. Issues can arise because often a parcel shipment will need to be opened to access the temperature logger stored inside. Alternatively, data logger devices can be attached to a specialised container to ship a pallet of products, providing an isolated monitoring option to pick up data, which can be saved to the cloud via Bluetooth or radio-frequency identification (RFID). The latest development within the packaging industry transporting pharma shipments globally is the move toward GPS tracking, which would need to be managed via Bluetooth, RFID or manually-scanned barcodes whereby pharma companies can track packages, and their shipment progress, online.
GPS is the latest development in response to ensuring the protection of high-value pharma payloads. It is predicted advancements in GPS tracking options via a SaaS system will be part of the industry in the near future. There are benefits to pharma companies, including knowing where their shipment is throughout its transportation trip. If payloads are lost or get delayed en route, the pharma company take steps to intervene and recharge or replace coolants so the package or the bulk system gets delivered before expected temperature duration is exhausted, and this would help mitigate a temperature excursion caused by a delay. What’s currently not in place in the temperature-controlled space for smart packaging is the capabilities to have data logger sensors and SaaS platforms communicate directly with each other, which is on the horizon. The latest developments will be something that interests the pharmaceutical companies; the availability of information through a SaaS platform will be a market differentiator for the companies that produce this type of smart packaging option. Currently the information being captured is primarily via barcode, which requires human intervention to manually collect and then input the information into a SaaS system. It’s predicted there will be a move to a system whereby the relevant information will be captured and then stored in a centralised database. That information could be updated frequently at check-in points or instantly via Bluetooth. Or forensically these smart packaging systems would offer insight to find out at what point the systems failed and where that happened with a
Spring 2018 Volume 10 Issue 1
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Logistics & Supply Chain Management combination of GPS and temperature data. This would allow pharma companies to discover when and where a failure occurred and then diagnose if it’s a problem with the shipment, with logistics, with the local customs office or similar. On the horizon is the integration of GPS and temperature logging to a SaaS system in an effortless way that doesn’t involve human interaction to leverage the movement towards an internet of things, which allows products and systems to have an IP address, to be able to interact with the internet. Leveraging a movement to an internet of things (IoT) will help packaging manufacturers with making future packaging truly smart, alongside providing information on the shipment’s status back to its owner in a central office. It also allows for mid-transit interventions if needed, or examining efficiencies of scale identified, such as using different shipping lanes or different ways to palletise or bulk ship smaller products. Specialised software systems can also aid reverse logistics within the industry and can provide real-time tracking and trading through the entire end-to-end distribution cycle. These optimisation tools can help ensure payload efficacy and efficient life cycling of reusable packaging inventory assets, providing a high return on investment. Often easy to learn and use, these superior software systems help the global life sciences industry manage its demanding and expanding cold chain logistics supply chain operations, while critically meeting the stringent requirements of a highly-regulated industry. There are various technologies currently available offering the advantages of duration and temperature stability. Traditionally, packaging vendors relied on more basic thermal control methods, providing passive packaging products where the key forms of technologies deployed were ones incorporating insulating material for the outer box of polystyrene or foams, providing protection and insulation. To maintain the temperature within the packaging, combinations of chilled and frozen water were utilised. Because of the requirement to 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY
carry a lot of water and often bulky insulation, these systems sometimes proved heavy and their performance against highly variable external temperature challenges was not always completely reliable. Although robust to an extent, these antiquated systems are being replaced more regularly with more technologically advanced packaging systems being developed to meet the demand and regulatory requirements that pharmaceutical companies and the supply chain service providers need to adhere to. Most recently, the technological advancements introduced to the market have seen the advent of better insulation options by incorporating vacuum insulated panels (VIPs), thus reducing the thickness of the insulation required and improving performance. The traditional water-based systems are rapidly being replaced with ones using phase change materials (PCMs) where, via a combination of materials, the melting point of the coolants deployed is designed to the ideal temperature required. These latest advancements mean systems using PCMs are far more reliable, providing more stability within the packaging at the desired temperature and using less overall material. The payload efficiency of these newer systems can be more than twice that of the traditional water-based and foam-insulated shippers, proving more cost-effective when it comes to logistics services. Although these more sophisticated shippers can be more expensive, the trade-off is you are less likely to experience temperature excursions en route, which would lead to damaged products providing a costly consequence in the long run. In line with the increase in more complex shipping lanes and limited infrastructure in place in some developing destinations, the need
for smarter, more secure, robust packaging has become more prevalent. The more sophisticated a shipper, the more the unit cost can be, so increasingly there is a requirement for reusable systems to provide better return on investment and greater cost-effectiveness in the long run, alongside the environmental benefits these reusable systems represent. Provided the infrastructure is in place to recapture and reuse higherperforming systems, which contain higher-value components, reuse makes economical and environmental sense. The rise in reuse has trigged a corresponding increase in the global network of service centres being established to facilitate the reconditioning and repurposing of these smarter packaging options. It has also sparked the rise in SaaS systems within the packaging industry with cloud capabilities that better enable collaboration in the sometimes complex packaging supply chain, and the ability to centralise data focuses the management of packaging services intelligently. Ultimately the aim always is to continue to reduce the supply chain costs and improve performance and reliability.
Adam Tetz Adam Tetz is a Director of Worldwide Marketing at Peli BioThermal and has more than 20 years of marketing experience. He is responsible for worldwide branding, product launch and communications strategy. Prior to Peli BioThermal, Tetz held positions in product management, marketing communications and account management across a variety of industries, including medical software, financial software and professional services. He holds an MBA in marketing from the University of Saint Thomas and a BA in advertising from the University of Minnesota. Email: firstname.lastname@example.org
Spring 2018 Volume 10 Issue 1
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Sales@InmarkPackaging.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 89
How Established Medical Technology Companies can Go Digital with Operational Model Changes There is significant value to be captured with digital products and services in the healthcare industry. Many new entrants are well positioned to compete because their models are oriented to specifically support digital technology and software development – more so than existing, analognative medical technology companies, which are organised to comply with regulations. For these companies, going digital will require significant business- and operational-model changes. Based on our experience, we have identified two sets of primary “levers” that executives can use to impact the changes to their companies’ business and operational models that are necessary to support a digital business.
The DNA of Established Medical Technology Companies The operational and cultural DNA of established medical technology companies has been steeped in rigid company processes that were created to minimise the risk of non-compliance with regulatory requirements such as FDA guidance. This is a very different picture from that for many new entrants and start-ups, which are taking advantage of the benefits of digital to focus on lowering costs, increasing patient engagement, and improving outcomes1. These new developments are challenging established healthcare companies for shares of an industry that makes up about 10 per cent of the global economy2. In addition, regulators that have not been friendly to software products in the past have started to embrace new iterative development approaches to accommodate the growth of digital health3. However, going digital has strained the current ways of doing business for many established companies. In fact, some recent examples have shown that success with digital products and services requires established companies to rethink their business models and the underlying operational models. 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Roche Diagnostics and GE – Rethinking Models Roche Diagnostics saw insufficient outcomes from diabetes treatments, and decided a more holistic approach was needed to manage the disease. To that end, it adopted an ecosystem approach to connect and offer integrated digital solutions to all stakeholders involved in the diabetes management cycle, in order to optimise care processes and improve prevention. Before the ecosystem was created, Roche’s main value proposition was offering its diabetes management systems, such as glucose meters and insulin pumps. With the ecosystem, Roche could expand its value proposition for patients and enable “more time in range”, leading to fewer hospitalisations. Roche became a partner to patients, helping them manage their conditions, rather than just being a manufacturer of products. Operationally, Roche separated Roche Diabetes Care into a subsidiary with its own operating model to facilitate the creation of a world-leading big-data ecosystem for diabetes management. A new, global hub with the required digital and IT capabilities was created in Barcelona, and co-promotion and distribution partnerships were set up with a number of complementary companies, including Medtronic, mySugr and Senseonics. With this successful digital transformation, Roche went from only treating sick people in acute care settings to enabling treatment in chronic care and remote settings as well. In addition, it increased patient engagement to proactively assist in prevention by improving patient lifestyles. GE has been a leader in driving digital transformation across its many businesses. A new division, GE Healthymagination (GEhM), was created for its healthcare business, with its own innovation operating model and supporting processes designed to develop new, disruptive business models in healthcare.
GEhM borrowed from agile methods and employed an innovation approach of rapid, iterative sets of tasks to identify, define and validate opportunities in the digital-health space – a stark departure from GE’s traditional stage-gate or waterfall processes. This resulted in the “Healthy Cities” programme, which focused on improving population health for various US cities by engaging local governments, large providers, and universities. GE set up data ecosystems and the necessary infrastructure for collecting and managing population health data collected from a broad range of existing products provided by GE and its partners. Ultimately, GE successfully created a new value proposition for various city and municipal governments, a market that GE Healthcare had not previously served. In addition, GE was able to extract more value through the increased sales of its products, as these were required to deliver on the value proposition. For both of these leading medical technology organisations, we see a combination of business-model and operating-model change being used to deliberately alter how each company engages in the market and the way it works. To help executives be more strategic in considering digital transformation, it is possible to create a simple, yet comprehensive framework for thinking about these types of changes. Managing Changes with a Set of Levers Executives can proactively manage these changes and their impact by considering a set of “levers” that we have established from our experience and from assessing companies such as Roche and GE. The specific levers used, and the degree to which they are “pulled”, will be unique to each company’s environment and its ultimate goals for digital. Most medical technology companies, including the examples cited above, will focus more Spring 2018 Volume 10 Issue 1
Technology on two or three of these, with minor changes involving the others. Business Model Levers • Value proposition. Digital products and services can enhance or shift a medical technology company’s value proposition in the market. For example, it can extend its products to provide remote-monitoring capabilities that improve care and reduce costs. Or it can offer tools such as applications and reminders to increase patient engagement and improve adherence. Typically, a digital business will want to build upon the company’s existing core value proposition, rather than creating a new one. • Value extraction. Most medical technology companies have focused on selling devices, or generating revenue per unit. However, monetisation of value can take on alternative forms with digital, such as serviceoriented models, e.g., selling hours of operation for a home health device versus the device itself, and data-centric models, e.g., selling the data generated by the devices. These new models may require working with government payers and insurance companies to gain support for reimbursement. • Markets served. Digital can enable a company to shift or expand the markets it serves to open up new business opportunities. For example, digitally enabled products and services can be marketed to caregivers who are willing to pay for access to data on activity or medication adherence to give them peace of mind. Alternatively, companies may be able to create new business relationships with other value-chain players, such as home health companies, by providing information that improves the effectiveness and efficiency of in-home care delivery. Operating Model Levers • Process/methods. Going digital requires new ways of working. Software development cycle times are faster, and will be more effectively enabled by agile methods, which are www.ipimediaworld.com
fundamentally different from existing linear or phase-gate approaches employed by most medical technology companies. Robust technology and portfolio management methods are needed to keep up with the faster pace of technology change and ensure R&D resources are invested in the right areas. Delivery network. Becoming digital can create opportunities for medical technology companies to engage with a broader ecosystem to develop offers and reach the market. The complexity and system-like nature of many digital-centric solutions creates attractive opportunities to engage development and/or delivery partners Capabilities/footprint. Adding digital elements to a portfolio will require new capabilities in areas such as application development, data management and security. In addition, medical technology companies will require capabilities in areas such as consumer insight and behavioural economics to ensure their digital-health solutions meet patient/user needs and expectations. The organisational footprint should also be an important consideration to help gain technical talent or local market knowledge and access.
Case Study: ResMed ResMed is a producer of medical devices and cloud-based software applications that diagnose, treat and manage sleep apnea, chronic obstructive pulmonary disease (COPD) and other chronic diseases, with USD 2.1 billion in revenue. Just as importantly, ResMed is a global leader in connected care, with more than 3 million patients remotely monitored every day. Its path to this position was deliberate, and involved transforming multiple aspects of its business and operating models. For Mick Farrell, the CEO of ResMed, the decision to go digital was not an option. “Digital or die – it is an existential moment,” he recalls. “If we didn’t embrace [digital], we could go the way of others – as we’ve seen Netflix do to Blockbuster and Uber to taxis.” Thus, ResMed became committed to making the transition
to a software-driven medical-device company. After detailed modelling exercises to understand the value equation and investigate possible digital-enabled business models, Farrell and his team discovered “almost every time we could find value.” They launched their effort by including a communication capability in every device sold – it was not optional – and soon discovered they were creating increased value for all of their primary constituents. For example, ResMed found that it could drive adherence for CPAP therapy devices from 50 (device alone) to 87 per cent when patients were given a smartphone application, myAir™, which helped them track their sleep-therapy progress. Each morning the patient received a “myAir score”, essentially gamifying sleep. Increased adherence reduced hospitalisations, which lowered costs and greatly improved the patient’s quality of life. ResMed also discovered that its connected devices decreased set-up costs for home health providers by 59 per cent, a significant value proposition. By receiving nightly data on user performance (e.g., was the mask connected properly?) and compliance (e.g., was it used nightly?), the provider could focus its attention on users that were having issues, and reduce unnecessary outreach to patients doing well with their therapies. This digital capability has enabled ResMed to create a provider subscription service to access the software and data, and effectively changed the basis of competition for sleep-therapy devices. ResMed also needed to transform its existing operating model to support the business-model changes. Farrell restructured the company to create a vertical business for software and services, which is now 7 per cent of global revenue. A new, centralised health informatics function was established to cut across the entire organisation and support all businesses. ResMed also adopted agile development approaches to accelerate product-update cycles. Necessary skills were added by hiring cloud software engineers from other industries, in addition to some selective acquisitions. ResMed is now widely considered a global leader in digital health and INTERNATIONAL PHARMACEUTICAL INDUSTRY 91
Technology of certain characteristics for each potential solution concept that must be identified, even if done with a higher degree of certainty, to inform the next step. At this point it might be necessary to do a prioritisation of concepts. This step is an opportune time to start to seek out partnerships or employ a more open innovation model to help make progress and engage expertise not found internally.
Figure 1: The levers to guide digital transformation
connected care for medical devices. As evidenced above, it made this transformation deliberately and systematically by identifying, analysing and pulling many of the available business-model and operatingmodel levers. The First Steps Toward a Digital Transformation There is a clear set of initial steps an established, analog-native medical technology organisation should take to get started on a digital transformation. Even if an organisation has jumped into creating digital elements or dabbled in deploying a digital service, it will pay dividends to go through the steps to ensure there is a strategic alignment between what the market needs and what the company does. Step 1 – Get a firm understanding of stakeholder needs, especially latent needs, of patients, users, and other relevant players independent of the application of digital. What experiences do they currently have, and what aspects of those experiences can be improved? Are there areas where efficiency or cost need to be addressed? The objective is not to develop or test solutions at this point, but to understand 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY
what needs, if addressed, will create value for the relevant stakeholders. After those needs are understood and rationalised to create a unique list, each is evaluated to determine which might be addressed by digital, and whether they make sense for the company to pursue. This step culminates in generating ideas to address the prioritised needs. Step 2 – Develop ideas into solution concepts, often with multiple ideas brought together into one concept. A concept here can range from a high-level scenario of a potential new digital service offering to a more specific depiction of functionality being added to an existing medical device. In any case, there is a list
Step 3 – Evaluate the implications to the business model and underlying operating models for each prioritised solution concept. Different concepts can be compared, and the amount of change needed should be considered when determining the specific strategy to pursue. For example, if a concept will require significant changes to certain operating-model elements, such as existing IT infrastructure or long-term contractual relationships, then there may be a decision to forego that concept or to push it further out on a roadmap. Conversely, certain changes, such as a new monetisation model or market positioning message, might be very easy to effect and push some concepts forward faster. At this point, the archetype needed for the transformation will emerge. Step 4 – Only once the implications for the business model and operating model are understood can an organisation set its strategy and plan for going digital. Learnings from the implication assessment will impact the path forward and facilitate a more innovative way of thinking. For example, if the effort required to build new capabilities, technologies or processes appears high, then partnerships or acquisition might be the best strategy. On the other hand, if the level of change is significant
Figure 2: Steps to get started Spring 2018 Volume 10 Issue 1
Technology across the company, then perhaps the strategy would best be executed by setting up a new external entity. Conclusion Within the healthcare sector, both existing players and new entrants can create significant value with digital products and services. However, for established “analog-native” medical technology companies, going digital will require significant business and operational model changes, which can be daunting. Nevertheless, executives can proactively manage these changes and their impact by considering our set of levers that they can control. REFERENCES 1.
Succeeding with Digital Health – Winning offerings and digital transformation, Arthur D. Little, March 2016 In the United States, the world’s largest economy, health expenditure is over 17% of GDP. Source: World Bank Data (data.worldbank.org) As an example, see the US FDA’s Digital Health Software Precertification (PreCert) Program at www.fda.gov
Mitch Beaumont Partner in the San Francisco office of Arthur D. Little, and a member of the Technology and Innovation Management Practice.
Dr Ulrica Sehlstedt Partner in the Stockholm office of Arthur D. Little, leading the Nordic Healthcare Practice and affiliated with the Strategy & Organization Practice.
Prashanth Prasad Manager in the San Francisco office of Arthur D. Little, and a member of the Technology and Innovation Management Practice and Healthcare Practice.
Mandeep Dhillon Manager in the London office of Arthur D. Little, and a member of the Digital Strategy and Transformation Practice.
Visit us at 11 -15 June
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COUNTING THE COST OF BLUE DYE TESTING If you are still using Blue Dye Methylene to leak test your pharmaceutical packs, you are throwing away valuable product whether the pack fails or not. The Sepha VisionScan is an innovative alternative that uses imaging technology to provide a deterministic and non-destructive solution to improve the accuracy of your leak detection procedures. All tested product can be returned to the production line and significant cost savings can be achieved. The Sepha VisionScan represents the future in modern pharmaceutical packaging.
Visit us at Achema: Hall 3.1 Stand C70, www.ipimediaworld.com call us on +44(0)28 9048 4848 or visit www.sepha.com
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Life Sciences in Flux: Global Opportunities for a Global Industry During the 20th century, humanity achieved something almost unbelievable: it actually pushed back death. In 1900, average global life expectancy was 31, a figure largely unchanged since biblical times. Yet by 2000, that had risen to 66.4 years and it now stands at 71.41. Incredibly, we can now expect to live twice as long as our ancestors.
The factors shaping this change are complex and numerous, but the life sciences – the sector that includes drug development and healthcare providers as well as research into cutting-edge procedures and technologies – is central to the story. The life sciences sector must now serve a huge global population that spans multiple decades and numerous generations, with each of these generations having very specific sets of needs. It must meet a growing demand for personalised treatment from patients. It faces rigorous scrutiny of standards from government and industry watchdogs, since lives are literally at stake. Yet as a business, it must also sell products and services in a highly competitive market to healthcare systems that are increasingly conscious of budget restraints. Combined, these factors have created a healthcare landscape that is rapidly evolving, presenting risks as well as opportunities. Navigating this new landscape can be confusing since it’s not yet entirely obvious what the new ‘normal’ will be. However, data will be central to this sector and more specifically, the successful, secure and streamlined use of it across the entire life sciences sector. A digital world means that more and more challenges will arise relating to incorrect data and its poor access, storage and retrieval. Yet at the same time, organisations that invest in new ways of managing data 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY
accountably, securely and efficiently will reap the benefits of saved time and money, see the benefits of full compliance and also hope to see better patient outcomes. For example, when a Swiss company with offices in London ships drugs made in Poland to hospitals in China on a daily basis, the need for transparency across borders and accessibility to global markets is clear and obvious. Meeting those needs will be vital for the life sciences sector in the years to come. Global Regulatory Compliance Meeting regulatory compliance is an unavoidable part of any life sciences business. Compliance failures can not only be costly in terms of fines and damage to reputation, they can also physically harm patients. Yet while they can be seen as a financial burden, regulations also protect against damaging actions including device and drug counterfeiting, exposure to lawsuits, malicious data mining, systems hacking and even local corruption. The world may be split into numerous markets but they are all interconnected and have similar – yet not identical – compliance issues. Even allowing for factors such as Brexit and the vague ‘America First’ trade goals of the Trump administration2, the general direction is towards convergence in order to smooth the passage of cross-border deals. Against the backdrop of this regulatory convergence, the sector is also experiencing rapid, technologically-led change. One of the benefits of this for the sector is that moves to comply can also become an opportunity to review business models and processes, to see how they can improve efficiencies and customer satisfaction while at the same time staying flexible and agile
enough to respond to any future regulatory compliance. These moves put business data management centre stage. The Framework of Regulation It’s crucial that healthcare’s digital ecosystems are safeguarded across borders, with America’s Health Insurance Portability and Accountability Act (HIPAA)4 and the European Medicines Agency’s (EMA) Identification of Medicinal Products (IDMP)5 both regulating aspects of the collection, use and secure storage of health data. The EU’s General Data Protection Regulation (GDPR)6 also governs data protection issues across all industries, including healthcare. These regulations are designed to ensure that all organisations, regardless of the business sector, manage and protect their data while at the same time being accountable to both the regulators and the patients themselves. But, with these regulatory frameworks come clearly defined boundaries of the stringent use cases of medical data. By employing systems capable of handling and managing data in the ways required, organisations can build efficiencies into their practices and future-proof them against further regulations. The Future of Healthcare With increasing personalisation of healthcare being driven by consumer demand and powered by technical innovation, what will the future look like and how will the life sciences sector be able to provide it? After the rise of the internet and the rapid, widespread adoption of the smartphone, the next technological leap will be to the internet of things (IoT). This is the integration of physical objects – the ‘things’ – into the existing internet via the inclusion of low-cost chips into many, if not all, manufactured devices and objects. Spring 2018 Volume 10 Issue 1
Technology In the ‘always online’ world of IoT, a car will self-diagnose an impending breakdown, a washing machine will reorder detergent when stocks get low and even a dress can suggest matching accessories via your smart-phone. While some of these applications are certainly gimmicky, the implementation of IoT into life sciences will be hugely significant. Let’s take diabetes control as an example. Insulin pumps with continuous glucose monitoring are already in use, automatically monitoring levels and dispensing insulin with the patient only needing to use finger sticks to calibrate initial levels.7 An IoT-enabled version could extend this level of care by removing the need to periodically hook up the device to a desktop computer for data analysis. As an ‘always online’ device, data would be streamed via the cloud, allowing not just continuous monitoring but also real time analysis and, if needed, alerts and intervention. If you consider a similar IoT monitor applied to someone with heart problems, or a post-operative patient released home, or an elderly patient living alone, the benefits are clear. For a different example, consider Spritam8, a pill to control epilepsy that was approved by the US Food and Drug Administration (FDA) in 2016, produced by Aprecia Pharmaceuticals in Pennsylvania. Each dose is 3D-printed layer by layer using equipment similar to an inkjet printer. This construction makes the pill easier to swallow and the active component faster-acting, by allowing it to disintegrate quickly. Yet what’s significant about the FDA’s approval of Spritam is that it opens the door for a revolution in personalised medication – individually dosed 3D-printed pills. Should pharmacists adopt this printing technology, it would be possible for dosages appropriate for each patient to be built into each course of treatment, or even for multiple medications to be combined into a single, easy-to-swallow pill. www.ipimediaworld.com
This is such a disruptive model for drug distribution that we do not yet know its implications. How would pharma companies get an ROI, for example? How might the UK’s National Institute for Health and Care Excellence (NICE) weigh the ease-of use of such personalised medications against their possibly higher costs? Could 3D-printing ever trickle down to a high street level, with pharmacists creating doses within the store? In such a fast-moving field, there are many questions but currently few answers. New Business Models and New Opportunities Product-as-a-service (PaaS) is a concept that has gained traction in recent years, mainly due to the model’s reduced cost of purchase. PaaS removes the barrier of an initial purchase cost by replacing it with a service agreement over the lifetime of a product. In effect, the manufacturer retains ownership of the product and leases it to the user for a fee, with individual devices now starting to be tracked and serviced using IoT technology, an advance that is sure to accelerate the pace of PaaS uptake. The implications of PaaS could be huge, with hospitals eschewing massive periodic infrastructure spends to replace worn or outdated equipment for long-term agreements that also cover all maintenance, upgrades and eventual replacements. Yet PaaS can go even further than that, supplying all supplemental consumables (filters, needles, etc.) and providing real-time analytics of data produced by these devices under the same agreement. The combination of reduced up-front fees with a guarantee of ongoing modernisation makes PaaS financially attractive to healthcare providers, yet there is an additional potential benefit as the ‘always online’ status of IoT devices is particularly suited for medical uses, allowing the real-time collection of patient data for continual monitoring. In a digital world, user data has become a valuable, tradable
commodity. Aggregated, anonymised patient data from a global network of IoT devices could provide a data pool larger than from any conventional trial. Available for analysis through artificial intelligence (AI) systems, such large and comprehensive databases could provide additional revenue streams for device manufacturers. Outside of items that need to be individual, such as hip replacements, personalised treatment is a fastgrowing market that has only just started to be serviced. Yet personal data needs to be treated confidentially, which is why one of the things that GDPR will do is give individuals the right to access or delete personal data. While these protections limit some potential ways to commodify data, they also build in much-needed accountability. In time, these clarity of use cases may actually open the door for innovative new uses of traded, anonymised data. A Patient-facing Industry Highlighting the ‘Top five trends for 2017 in the life sciences sector’9, Deloitte made sure it gave one of these limited slots to ‘Connecting with customers and consumers’. Because although every business aspires to satisfied customers, few other sectors deal with stakes as high as life and death. Medical services and solutions that are customised tend to be more convenient, which means patients tend to regard them as premium services. The potential profitability of such an approach is leading to life sciences businesses focusing more time and effort on creating patientcentric services that, in turn, generate more real-time data for analysis at a more granular level. The ideal end state is a happy, cared-for patient who’s engaged with their own treatment. In this way, the life sciences sector can prove positive outcomes and enjoy long-term revenue from healthy, well-cared-for customers. How businesses handle data, manage patient expectations and develop new business models INTERNATIONAL PHARMACEUTICAL INDUSTRY 95
Technology will shape the healthcare industry’s response to meeting this need. Yet patients can only be actively involved in their own healthcare once IoT device data and their own medical records reside outside of silos, in an easy-to-access electronic form and inside a secure, accountable and well-documented environment. Conclusion The Value of Data As we have already discussed, the life sciences sector is a set of industries that overlap by supplying, consuming and developing products and services from each other. The thread that links them is data from research programmes, patients, devices or factories. Controlling, protecting and facilitating the flow of this data is already important but this will become vital as the sector undergoes a digital transformation, affecting every area of business. Meeting Regulatory Compliance Organisations should aspire to go above and beyond minimum standards for handling data in a secure and well-administered way because insights from trustworthy data improve processes and allow the development of new business models. Failure to comply to regulation can be costly to any organisation in terms of fines and bad publicity. Yet the improper working practices and system failures that led to the fines can be far more damaging in the long term. Regulation is the tool that enforces best practice. Controlling Costs Through Efficiencies The average cost of bringing a new pharma product to market is now in excess of $1.5bn. With government healthcare spending strictly controlled in most countries and the era of big-name pharmaceuticals giving way to greater use of generic alternatives, the life sciences sector needs to keep operating costs under control. Using a single source of verified, trackable data across an entire organisation prevents costly duplication of effort, allows for more agile decision-making in every department, and presents businesses 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY
with greater insights that are backed up by data from a single, trustworthy source. Enabling Innovation Soaring R&D costs and heightened stockholder expectations put pressure on businesses to release new products and services, yet increased regulation can slow this process while the growing global market for generic drugs can restrict profits. Utilising all available research data through AI analytics, including sets of cloud-gathered big data, could be how the next breakthroughs in medical research will occur. Driving New Business Models Product-as-a-Service is one way that manufacturers can restructure in order to convert one-off sales into product cradle-to-grave revenue streams. But PaaS is just one example of a disruptive data-driven model. A transition to long-term treatment solutions, from diagnosis and treatment through to condition stabilisation, could provide patients with joined-up treatment and businesses with predictable revenue streams. This is possible only with well-managed, secure and accountably accessible data. Connecting with the Customers Personalised treatment can only become a reality when healthcare providers know enough about individuals to treat them as such. With IoT-enabled devices and apps capable of providing more data on patients and globally enforceable regulation about the secure handling of this data coming into effect, the scene has been set for the life sciences sector to provide such tailored care. The onus is now on businesses to gain patients’ trust. By proving that data is safe in their hands, businesses will have the authority and reputation to expand into business areas fuelled by the rise of the digital economy. Customers are keen to take part in their own healthcare choices, but only if they can trust businesses to hold their data without any breaches of legislation. Therefore, innovative business models and improved, personalised care rely on secure, verifiable data.
REFERENCES 1. Life expectancy – www.who.int/ gho/ mortality_burden_disease/life_ tables/ situation_trends_text/en/ 2. America First policies – www. whitehouse.gov/trade-dealsworkingall-americans 3. PIP scandal leads to prosecution – www.theguardian.com/world/2013/ dec/10/french-breast-implantpipjean- claude-mas-jailed 4. HIPAA – www.hhs.gov/hipaa/index. html 5. ISO IDMP – www.idmp1.com/ 6. GDPR – www.eugdpr.org 7. Insulin pumps – www.endocrineweb. com/guides/insulin/insulinpumpoverview 8. Spritam – www.spritam.com 9. Trends for 2017 – www2. deloitte.com/content/dam/ Deloitte/global/Documents/ Life-Sciences-Health-Care/gx-lshc 2017-life-sciences-outlook.pdf
Fiona Ashdown Marketing Director, Insource Fiona leads the marketing strategy for Insource, the data software product platform. Fiona’s expertise lies within the life sciences sector and the NHS. With over 20 years’ experience developing close relationships with global organisations and partners, Fiona delivers and streamlines processes to effectively support key business objectives.
Spring 2018 Volume 10 Issue 1
More precision. More consistency. More control. IMA draws on its extensive expertise to provide the most advanced solutions for DPI processing and assembly. Direct weight control performed in line on each single capsule or device before and after filling. Absence of mechanical powder compression for improved airway intake. Accurate micro-dosing and automatic feedback and adjustment. Highly flexible and precise inhaler assembly. All of this is more than any other production equipment can achieve today. Much more than filling. Fulfilling your requirements. Leading supplier for the pharmaceutical industry, IMA provides solutions ranging from processing and packaging of dry powders to the design, assembly and performance enhancement of inhalers.
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Why Laboratories are Choosing Gas Generators Over Gas Cylinders Pharmaceutical laboratories use a variety of analytical techniques as part of research and development and quality control of products. Many of these processes require high-purity gases, many of which can be produced by gas generators. For a number of reasons, including safety, cost and convenience, more and more laboratories are abandoning gas cylinders in favour of gas generators to supply the gases they require for their analyses.
a proton exchange membrane (PEM). Hydrogen ions diffuse through the PEM membrane, before combining to form hydrogen molecules, whereas oxygen is retained and then vented to atmosphere. The hydrogen molecules which form, drag some moisture through the PEM cell and require further purification via a desiccant drier or pressure swing adsorption (PSA) drier before being supplied to the application.
and this can interrupt analyses, while also increasing the risk of contamination through ambient air entering the system. Cylinder changes also require laboratory staff to manually handle and move the cylinders, which comes with an inherent risk of accident or injury. Cylinder storage – when using gas cylinders, a laboratory needs to ensure that its supply provides
Two gases which are often supplied via gas generator are hydrogen and nitrogen. Hydrogen gas is typically used for applications such as GC (gas chromatography) and ICP-MS (inductively coupled plasma mass spectrometry) while nitrogen can be used for a variety of applications including LC-MS (liquid chromatography mass spectrometry), sample evaporation, NMR (nuclear magnetic resonance) and ELSD (evaporative light scattering detectors). About Hydrogen Hydrogen was discovered by Henry Cavendish in 1766 and it is the most abundant element in the universe, essential to all life as we know it. On earth, it is the third most available element, although in its gaseous state it does not naturally occur, and must be manufactured. It is combined with oxygen to create water (or H2O), a necessity of all life on this planet. Hydrogen gas has been used for numerous applications in industrial manufacturing and processing, most famously in the Haber-Bosch process for ammonia production, but also as shielding gas in arc welding as well as numerous laboratory applications, such as its use for detector and carrier gas in gas chromatography.
Why Laboratories Use Hydrogen Gas Generators: Cylinders vs Generators Many laboratories are now prohibited from placing hydrogen cylinders on their premises owing to health and safety restrictions. Hydrogen cylinders can contain up to 9000 litres of gas, more than enough to cause a significant explosion or fire. Hydrogen generators, which produce hydrogen on demand and therefore contain only a minimal amount of gas, are much safer than cylinders and have increasingly become the alternative of choice for many.
How Hydrogen Gas Generators Work Hydrogen gas generators electrolyse deionised water to its constitutive elements, oxygen and hydrogen, via
Hydrogen generators eliminate the need for: • Cylinder changes – gas cylinders require frequent replacement
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Illustration of electrolysis in a PEM cell
enough gas for their analyses. Not only is this a space issue, it is a potential safety issue since storing large quantities of an explosive gas can be extremely dangerous. Cylinder monitoring – gas cylinders need to be continually monitored to avoid the gas supply running out mid-analysis.
When compared to the costs of gas cylinders, which include the cost of gas, delivery charges, cylinder rental charge, staff downtime, administration, occupational health and safety measures and training, a hydrogen generator can typically pay for itself within nine to 15 months. Spring 2018 Volume 10 Issue 1
Technology Why Laboratories Use Hydrogen Gas Generators: Helium vs Hydrogen For GC users, where helium has traditionally been the carrier gas of choice, hydrogen can provide a more economical, safer and in many instances faster carrier gas. Helium is a finite resource and must be extracted from earth using large-scale industrial processing facilities, dispensed into cylinders and shipped to a laboratory. As a commodity, helium cost is subject to supply and demand fluctuations and, whilst global supply is dwindling, demand remains strong, meaning laboratory users of helium have had to endure ever-increasing prices to supply their labs. Supply issues have also been a major concern for laboratories and other helium-reliant applications (such as hospitals with MRI scanners). Qatar, the worldâ€™s second-largest source of helium supply, recently had its land trade routes blocked as part of a dispute with Saudi Arabia. It took over two months for supply to re-enter the market through a new, longer and more expensive route over sea. This caused disruption to the supply chain and increased overhead costs for suppliers, which trickled down to the end users; laboratories and hospitals. Producing high-purity hydrogen using only deionised water, a hydrogen generator removes the uncertainty of fluctuating helium costs and unreliable supply.
rapidly from a cylinder. Hydrogen generators are generally designed to contain a minimal amount of hydrogen. For example, with a hydrogen generator which contains <400cc of hydrogen, it would take nearly 12 days to reach the LEL in the same lab, and would require the entire volume of the highly diffused gas produced to remain within the room.
Just 25% of a 50L hydrogen cylinder could be enough to cause an explosion
About Nitrogen Nitrogen was discovered in 1772 by Daniel Rutherford. As an inert gas, it does not react readily with other elements and chemicals. It is highly abundant, accounting for around 78% of the earthâ€™s atmosphere, meaning we breathe in more nitrogen than any other element. Since its discovery, nitrogen gas has been used for a variety of important functions. Its inertness enables it to provide important protection for industries
where oxidation is undesirable, such as food packaging, reducing fire hazards, manufacturing of stainless steel, wine bottling, chemical analysis and, in particular, for LC-MS and GC. How Nitrogen Gas Generators Work Nitrogen generators use a supply of dry, oil-free air to purify nitrogen via a selectively permeable membrane or carbon molecular sieve material which removes oxygen, carbon monoxide and carbon dioxide. Purified nitrogen is then stored in a buffer tank to ensure constant flow and pressure of nitrogen is supplied to the application. Why Laboratories Use Nitrogen Gas Generators For many laboratories it is simply more cost-effective to use a nitrogen gas generator rather than nitrogen gas cylinders. A 2010 study by the European Industrial Gases Association estimated that gas supplied from a nitrogen generator used 30% less electricity per volume at 99.9% purity than a nitrogen production plant. For analysts using 98% pure nitrogen, the costs of production from a generator are up to 70% lower, creating significant savings on energy costs, and helping the environment. An LC-MS using 32 litres per minute (1.13 CFM) of nitrogen for eight hours per day will consume around 5.5 million litres (194,230 ft3) of nitrogen in one year of operation. This is equivalent to 620 cylinders. The cost of satisfying such a need for
Hydrogen Safety The most significant risk with hydrogen use is a leak into the laboratory environment raising the hydrogen content to an explosive level. The safety benefit of a generator can be seen by looking at a theoretical example. The lower explosive limit (LEL) for hydrogen is 4.1% in air. Therefore, the LEL of a hermetically-sealed laboratory of dimensions 5m x 4m x 2.5m with a volume of 50m3 can be reached by emptying 25% of a 50L cylinder of hydrogen. With a large enough leak this can be achieved in minutes. High-pressure hydrogen can also undergo auto-ignition when released www.ipimediaworld.com
When air enters a selectively permeable membrane, oxygen particles escape while nitrogen particles remain. INTERNATIONAL PHARMACEUTICAL INDUSTRY 99
Technology gas cylinders includes the time taken for ordering, cylinder installation, processing of paperwork on top of the cost of the gas itself and the rental of the gas cylinders. Comparing the example above with the costs associated with the purchase, installation and running costs of a gas generator producing 32 litres per minute (1.13 CFM) of nitrogen to supply the LC-MS, the generator would typically have paid for itself within one year, making it a cost-effective alternative for laboratories using gas cylinders. Nitrogen generators also remove the risk of sample contamination, which is present when using gas cylinders because of their diminishing purity as they empty or the occasional bad-quality cylinder. Generators, through providing a consistent, convenient, and more energy-efficient nitrogen gas supply, can be a great benefit for laboratories. Nitrogen Safety Changing over nitrogen cylinders poses a significant safety risk which labs can avoid by using gas generators to supply their instruments instead. For lab managers this is a growing concern, as lab workers carrying awkward and heavy cylinders around a lab are, quite frankly, an accident waiting to happen. Cylinder handling, as previously mentioned with helium and hydrogen cylinders, requires occupational health and safety training for lab workers in order for handling to take place. Even with training, cylinders still pose a significant health risk in the laboratory or any workplace where they are used. Should a cylinder be damaged or leak and quickly release a large amount of nitrogen into the laboratory, there is a risk of asphyxiation. This risk isnâ€™t present with nitrogen gas generators, which only store a minimal amount of nitrogen, insufficient to present a risk of asphyxiation. Furthermore, a generator will not contain gas at the same high pressure as it would be contained within a cylinder. Gas Generator Safety Technology Hydrogen and nitrogen generators 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY
on the market today contain a wide range of technologies to ensure user safety. Technologies such as forced air ventilation, internal leak checks, automatic shutdown and pressure sensors are all designed with safety in mind â€“ their main priority being to prevent a dangerous amount of hydrogen or nitrogen from building up within, or being released by, the generator. GC Applications in Pharma where Nitrogen or Hydrogen can be Used A large number of gas chromatography (GC) methods use nitrogen carrier gas and flame ionisation detection (FID) for analysis of both active ingredients, such as alpha tocopherol (Vitamin E) and atropine, and for determination of safe levels of formulants or chemicals used in the process of drug formulation, such as stearic acid and solvents. Nitrogen or helium are preferred for use as carrier gas in pharmaceutical analysis because of their inertness, which means that they will rarely interact with active ingredients. The United States Pharmacopeia (USP) chapter 467 details the analysis of residual solvents in pharmaceutical products and is used to determine the presence of solvents even without prior knowledge of their use in the manufacturing process, since the manufacturing processes of different companies may use different solvents. Residual solvents are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances, or in the preparation of drug substances. Residual solvent analysis (RSA) uses static headspace extraction GC-FID for separation and detection of solvents. The method for RSA, in accordance with the USP, requires the use of either nitrogen or helium as carrier gas and the FID will require hydrogen flame gas along with air or zero air flame support gas. The ASTM method, F 1884-04, for residual solvent analysis in pharmaceutical packaging material, does not define a carrier gas. This means that labs can choose the most optimum and efficient gas
for their analysis. There are clear advantages to be found from opting for hydrogen carrier gas for GC in this circumstance, with faster run times allowing higher sample throughput as well as the aforementioned benefits of replacing increasingly expensive helium cylinders with a hydrogen generator. With the safety, cost and workflow benefits a gas generator can supply to laboratories when compared with gas cylinders presented, it is easy to see why many laboratories are choosing to replace their laboratory gas cylinder supply with a gas generator. The pharmaceutical industry, particularly those working with packaging materials, have a decision to make: continue with the hassle of gas cylinders, or improve workflow and safety in the lab with a gas generator. REFERENCES 1. 2.
https://www.britannica.com/ biography/Henry-Cavendish visited on 9 March 2018. https://www.gasworld.com/ qatar-blockade-impacting-globalhelium-supply/2012946.article visited on 8 March 2018. https://www.britannica.com/science/ nitrogen#ref143342 visited on 9 March 2018. http://www.labmanager.com/ product-focus/2016/05/ laboratory-nitrogen-generatorswhy-not-do-it-yourself-?fw1pk=2#. Wqo2YOjFKUn visited on 8 March 2018
Dr Ed Connor Product Manager, Peak Scientific Dr Ed Connor joined Peak Scientific in February 2013 as a GC product specialist and now functions as a Product Manager. Prior to joining Peak, Ed completed his Dr.Sc. at ETH Zurich in 2007 using GC-MS to look at herbivore induced plant volatiles and their interaction with beneficial insects. Email: email@example.com
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Company Profile OC s.r.l. Via Circondario, 1533 04014 Pontinia (LT) Tel: +39 (0)773 840032-15 ext Web: www.cleanroomoc.com
micron) and are normally equipped with static nozzles (16 for the basket and 16 for the side arms). The basket is equipped with grids on which the parts to be washed must be positioned. To allow the loading and unloading operations of the basket from the washing machine, we provide a trolley equipped with mechanical safety systems for the safe handling of the equipment.
The patented false ceiling system offers the unique solution of locking the PVC or composite panels in a simple and effective way to the frames
by means of clipped bars allowing quick disassembly for inspection or total removal. OC s.r.l. many years’ manufacturing experience allows a scale production which does not compromise the artisan quality of each single piece assembled in its workshop. The same attention to details is paid during installation and maintenance operation as the highly skilled personnel employed always aims at an excellent product delivery. OC s.r.l. has made quality its guiding principle in products and services development as well as on research of more performing materials. All OC s.r.l. products are made of recyclable materials. OC Srl is an ISO 9001:2008 certified company. OC srl passion and capacity to elaborate customers’ needs has impressively contributed to the Research and Development activities with particular attention to washing systems. MAELSTROM HDS WASHING SYSTEM is now a well known and reliable solution to wash and dry machine parts and production equipment of various shapes and sizes. In standard execution the machine has a chamber of about 3 cubic meters of volume. To guarantee an effective cleaning of all the surfaces, the machine performs a washing phase through the washing basket, for the localised washing of the pieces, and a washing phase through the side arms. The washing basket and the side arms are made of ASME BPE SF1 pipes and fittings (MOC SS 316L Ra≤0.51
OC srl – Stainless Steel Modular partition walls
OC srl – HPL Modular partition walls
Oc srl – MAESTROM WASHING MACHINE
OC s.r.l. started its activities in the early 60's as an craftsmanship carpentry workshop making its skills and expertise available to the growing pharmaceutical industry district in Latina province, Italy, over the past 40 years.
Specific doors and partitioning walls designing and materials selection were developed in order to fulfill Clients’ high standards and requirements. Today OC s.r.l. is a leading company for the design, construction and installation of modular partition walls, doors, false ceiling, furniture and accessories for clean room and controlled environments. OC s.r.l. designers provide ad hoc and flexible solutions to Clients, always ensuring the products quality starting from the raw materials selection to manufacture, installation and post-sale assistance.
The exclusive patented hook-up system with the CH60 locking key allows very fast installation and removal of modular walls and doors. Simply acting on the blocking keys of the interested modules the size and extent of intervention will be held back too.
The main features of our washing system are: • • • • •
Perfectly integrated design in partitions walls with flush mounting Modular design for integration of optional accessories (on customer request) Totally customizable washing baskets Customizable nozzles arrangement Reduced water consumption
Homemade software development in compliance with FDA 21 cfr part 11
OC srl will be in ACHEMA 2018 fom 11 June to 15 June, Stand A60 Hall 6.1.
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How to Avoid Becoming a Casualty of the Impending Battle for Data Control The General Data Protection Regulation (GDPR) is the outcome of many years of negotiation aimed at harmonising the EU countries’ approach to data protection issues. Currently in a transitional phase, the GDPR came into force in May 2016, but is scheduled to take effect in all member states on 25 May 2018. In the UK, in an effort to ensure that this already negotiated area of law remains largely unaffected by Brexit, a new Data Protection Bill is currently working its way through the usual process in our Houses of Lords and Commons to ensure implementation of the GDPR into English law.
The GDPR applies to any organisation that is established in the EU, regardless of where they process data. It also applies to those organisations that process the data of people who are in the EU, even if the organisation itself isn’t actually located here, but is offering its goods and services to people in the EU or is monitoring their behaviour in any way. As a result of this wide casting of the net, the GDPR will apply to a vast number of organisations and, of course, that includes businesses operating in the life sciences sector, which will need to consider their handling of personal data in this new light just like everyone else. As with many areas of compliance, the risks of getting it wrong don’t just begin and end at the possible fines that can be imposed by the regulator, but perhaps just as significant is the reputational risk for a non-compliant organisation. As individuals and consumers, we are all increasingly aware of our privacy and therefore have a desire to understand more fully how our data is held. Many of the fundamental issues and principles tackled in the GDPR are not new, but simply a strengthening of existing concepts around protecting individuals and their personal data. 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY
However, when you consider the GDPR, there are five key differences worth focusing on to start with and these relate to: 1. The appointment of a data protection officer. Previously optional, for organisations that meet the criteria this action will become mandatory. 2. Breach notification. Perhaps surprisingly, so far there has been no express obligation to notify either the regulator or affected individuals if an organisation suffers a data security breach. The GDPR requires that if a data controller suffers such a breach, it will be required to notify the regulatory body, the Information Commissioner’s Office, without undue delay and not later than 72 hours after becoming aware of it. This is significantly more stringent than previous legislation, where notification was at the data controller’s discretion. 3. Data protection by design/by default. Essentially these buzz words describe an attitude requiring organisations to consider data protection compliance at the very outset of any new processing activity or new methods of handling data. 4. Changes to the use of consent. Consent has never been the only justification for processing data but is a commonly used condition to make processing lawful. With the GDPR in place it will be a condition which is undoubtedly harder to get right. Again, it’s an area of increased stringency leading to the need for a much more rounded approach when deciding if information can be kept and/or used if the condition being relied upon is consent. 5. Changes in sanctions. The previous limit for potential fines
of £500,000 for non-compliance has been replaced and the possible sanctions have now been re-categorised into two tiers depending on the type of breach. Whilst the ICO has indicated that it may take a gentle approach at first with those working on getting it right, that approach may not last. The first tier is for violations relating to internal record-keeping, data processor contracts, data security and breach notification, data protection officers, and data protection by design and default. These types of breach will carry a fine of up to two per cent of annual worldwide turnover or €10m, whichever is greater. The second tier will cover violations relating to breaches of the data protection principles, conditions for consent, data subjects’ rights, and international data transfers, the penalty for which will be up to four per cent of annual worldwide turnover or €20m, whichever is greater. Appropriately safeguarding the integrity of data, whilst complying – and demonstrating compliance – with an array of legislation is second nature to most pharmaceutical organisations, yet GDPR still represents somewhat of a game changer for the sector. The operational challenges it presents, along with the risks associated with non-compliance, are significant. So how should life science businesses best approach this transition? What are the unique challenges and opportunities facing the sector as a result of GDPR? And how best can they be overcome and exploited, from both a corporate culture and operations perspective, in order to achieve GDPR best practice? A Cultural Shift According to Mark Lumley, Fin Tech Magazine and Global 100 2017’s UK data protection lawyer of the year, partner at Shulmans law firm, and Spring 2018 Volume 10 Issue 1
Technology part of the IT and Commercial teams at Shulmans, the introduction of GDPR represents a wider – indeed global – cultural shift in the way we view, and expect commercial outfits to treat, our personal data. Referencing the Privacy and Electronic Communications (EC Directive) Regulations 2003 (PECR), which sit alongside the Data Protection Act 1998 (DPA) and offer specific privacy rights over electronic communications, and using the pending Network and Information Systems Directive as a further example of how regulators are closing in and taking a more holistic, 21st century approach to data management and information governance, Lumley believes there is a new onus on corporations to update the way they in turn view and manage data. As he states: “There used to be four basic pillars of commercial success: people, premises, products and money. Arguably, for the pharmaceutical sector, there was a fifth in the form of safety. That was before the digital revolution; now of equal importance is data. Data is incredibly powerful and of huge value to organisations, but the way we collect it, manage it and use it also represents a significant risk. Businesses need to start thinking of data in those terms and what I think the GDPR will help to do is give personal data, and data generally, greater prominence, helping it get the recognition it deserves as a core pillar of successful modern commerce.” The DPA was introduced in 1998 when the internet was still in its infancy and smartphones remained a futuristic concept, rendering it insufficient to appropriately deal with and regulate modern methods of personal data use. With consumers beginning to view data as something that belongs to them, the GDPR will reinforce this sense of ownership by the individual. However, Lumley argues it will also raise the risk profile of data management within organisations and act as a catalyst to spread data protection management beyond the traditional confines of the compliance department. Lumley comments: “GDPR will catapult data protection and information governance towards the top of the risk pyramid, where consequences for non-compliance are most serious. However, it will www.ipimediaworld.com
also impact, and require input from, multiple touchpoints within a business. From IT, who will need to audit and potentially cleanse or replace electronic databases and computerised systems containing personal data, through to sales and marketing and supply chain, who will each need to verify that not only do they have the appropriate permissions in place and are using data within the compliance parameters – and reporting breaches in line with new guidance – but that suppliers and other third parties that process personal data on their behalf are doing the same.” The Rise of the Super Regulator This cultural shift in the way we as individuals view our personal data has given rise to the emergence of a new super regulator in the form of the Information Commissioner’s Office (ICO). GDPR will provide the ICO with greater powers, creating parity with other super regulators like the Financial Conduct Authority and Competitions and Markets Authority. Examples of the ICO flexing its newly acquired muscles can be found in the recent cases of Honda and Flybe, who between them were recently fined a total of £83,000 for ‘breaking the rules about how people’s personal information should be treated when sending marketing emails’. The investigation established that Flybe had ‘deliberately sent more than 3.3 million emails to people who had told them they didn’t want to receive marketing emails from the firm’. Ironically, Honda sent 289,790 of what it considered to be customer service emails, with the intention of clarifying customers’ choices for receiving marketing, in a bid to comply with data protection law. The car manufacturer was apparently unaware that the emails constituted marketing and, because bosses were unable to evidence customer consent to receive these types of communications, were found guilty of breaching PECR and hit with a fine. We know that any organisation that controls or processes personal data is required to comply with GDPR or face the consequences. Whereas businesses operating in
food manufacturing or professional services, for example, may be struggling to implement new systems and processes, it’s likely that most pharmaceutical businesses will have transferable frameworks and resources in place, from compliance specialists to quality management software, that can be adapted to accommodate the management of the pending legislation. This doesn’t mean it’s not a daunting feat, however – far from it. And with the nature of the pharma beast intertwined with some of the most personal of data belonging to individuals, such as medical records and other highly confidential patientrelated information, the onus to tick all the right boxes and avoid becoming the pharmaceutical sector’s very own data protection cautionary tale, is huge, as Mark Stevens, compliance specialist and managing director of software firm, Formpipe Life Science, explains: “It is almost inevitable that someone in the sector will fall foul of the new regulations before they are fully understood. The regulators will be searching for the best way to enforce the new rules, without the benefit of insights that will evolve into a common-sense approach. The trick here, really, is to ensure it’s not you that’s caught out and made an example of before the sector has acclimatised to the new environment these more stringent regulations are creating.” Getting your House in Order The ICO advocates a 12-step programme to achieve GDPR compliance best practicei. First on the list is awareness. GDPR will impact every aspect of an organisation, so it’s important that all stakeholders understand the significance of the legislation and feel empowered to play their part in safeguarding compliance. Although all areas of a business need to come together to achieve best practice, designating ownership to an individual will help transform intentions into plans, and plans into action. Lumley advises that even pharmaceutical organisations that aren’t required to appoint a data protection officer under GDPR can benefit from designating an individual to spearhead change. INTERNATIONAL PHARMACEUTICAL INDUSTRY 103
Technology He adds: “For a GDPR compliance culture to flourish, organised thinking is essential. The vision needs to be clear and the challenges need to be approached holistically; there must be buy-in from all departments from legal to technical to operations – from top to bottom. “This ‘all in it together’ approach can also inadvertently encourage a lack of ownership, so by appointing a compliance or data protection officer, businesses stand a better chance of successfully co-ordinating projects, nurturing the compliance culture, becoming and remaining compliant.” Once a culture of awareness and accountability is in place, obtaining clear visibility over the data assets you possess, knowing where personal data came from and understanding what it’s used for are logical next steps, as Lumley confirms: “It’s crucial that a business identifies what information it holds, where it was obtained, what it is used for, and how its use can be justified. For example, business leaders should look at what the conditions for processing are. Simple solutions can be found when the challenges to overcome are fully understood, and they needn’t require significant investment. Creating an asset register in Excel, for instance, is a really effective way to take control of personal data and demonstrate to auditors that action is being taken.” Secondly, the ICO recommends that a variety of processes are evaluated with GDPR in mind, from how privacy information is communicated to how personal data is deleted. Assessing existing breach-reporting protocols, from detection through to investigation, to ensure they’re robust enough to cope with tougher scrutiny and shorter timeframe, need to be key areas of focus, alongside reviewing current privacy notices, checking processes and procedures against the new rights individuals will have under the legislation. Subject access requests need to be carefully considered too. Stevens advocates that: “Businesses should ask themselves: what do we need 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY
to change to ensure we are able to respond to requests within the new timescales and how will we make sure any additional information that could be requested is safely and compliantly stored yet quickly and easily accessible?” Stevens believes technology has a key role to play in this battle, stating: “Any new technology implemented by an organisation must act to improve its operation, and anyone that comes into contact with GDPR will quickly realise that improvement, at whatever level, is needed. That makes bringing in additional systems, or adapting existing ones, essential to staying on the right side of regulators. There will be those that try to fight the tide back, and there will be those that will start to build better boats before they get in trouble.” Another question to ask, as the ICO points out, is: does your business have a lawful basis for processing personal data in the first place? Once the answer has been established, findings need to be documented and, where necessary, privacy notices updated or created explaining the extent of personal data processing and lawful basis for it. Lumley explains: “The old adage that knowledge is power has led to many organisations stockpiling data - some, or in many cases much, of which will never be used. A mentality of ‘better to have it and never use it, than need it and not have it’ precipitates this, but GDPR means if you don’t know why you need any given piece of personal information, and you can’t demonstrate consent or other basis for lawful processing, you simply can’t process it. This means considering reducing obsolete and unjustified personal data hold becomes an important activity.” GDPR is seen very much in the terms of restoring control and ownership to the individual. Consent, therefore, plays an important part in establishing compliance. Reviewing how consent is obtained, recorded and managed, as well as making and documenting any changes, should be prioritised by pharmaceutical organisations. An additional risk to consider is the personal data of children and how easily existing systems can verify the ages of individuals and, in the case of
minors, demonstrate parental consent is in place for the child’s data to be processed. Other considerations highlighted by the ICO include the additional complications that arise for businesses that operate in more than one EU member state and therefore are required to determine the appropriate lead data protection supervisory authority. Working party guidelines are available to support these specific businesses in the form of Article 29. Working within both Article 29 and the ICO’s code of practice when completing Privacy Impact Assessments is also fundamental to appropriately assessing how and when to implement change. Translating Theory Into Practice On top of general changes that will need to be introduced by all data controllers and data processors, there are several sector-specific considerations that pharmaceutical firms will need to address. For instance, with pharmaceutical businesses typically operating in chains and with multiple touch-points involved in the creation and management of a drug portfolio – passing data up and down the ranks from brands to contract manufacturers, sub-contractors to consultants – it’s worth reiterating that you should be asking: who owns this information? Who has custody and who is responsible for ensuring GDPR compliance throughout the data’s life cycle? As you probably guessed, ultimate accountability at each stage remains with the data controller, as Stevens points out: “Again, there is no precedent here. How the regulators approach the question of ultimate accountability is a question yet to be answered in detail, however the focus is likely to be on the Data Controller and [it will] also look at fault. It will be interesting to see if an agent shares responsibility with an organisation tasked with an element of data control, or if the buck stops with the company ultimately benefiting from the use of the information. There will be arguments on both sides, but the only certainty I can see is that no one will want to pick up the bill for non-compliance.” Spring 2018 Volume 10 Issue 1
Technology Putting effective contracts in place will help define responsibility and practical activity; there is an existing requirement in the DPA for contracts to be in place between controllers and processors and this becomes more important under GDPR. One key consideration relates to clinical trials organisations that come into direct contact with individuals and those individuals’ personal data. Managing this data to ensure it is being used with maximum effect, whilst also ensuring GDPR compliance, is certainly going to add an extra dimension to existing processes. In practice, of course, these organisations will already be acting in a compliant way in order to meet DPA regulations. However, Stevens advocates that the introduction of tougher legislation represents an opportunity for life science firms to embrace the advantages that moving from a traditional approach to a more robust, electronic and efficient solution can bring. Stevens comments: “GDPR shouldn’t be approached with reluctance but with enthusiasm. It’s a real opportunity for the life science industry to get its house in order and invest allocated budgets wisely in retiring old, resource-hungry ways of working with solutions that shed light on what precious data businesses possess and where it is located, whilst facilitating automated analyse and control.” Don’t Pull the Panic Cord Whereas many organisations will already be appropriately armed to manage the new requirements, others will undoubtedly adopt a deer-inheadlights mentality, as Lumley confirms: “Since the beginning of the year we’ve noticed a pretty even split in how businesses are reacting to GDPR. Around a third seem to be apathetic and aren’t really doing much to prepare. At the other end of the spectrum, some businesses are treating GDPR as an opportunity. This is especially true in sectors like pharma, where safety and integrity are inextricably linked with data, and securing GDPR best practice can demonstrate a competitive edge through increased credibility. Then, as with everything, there’s a middle ground where some businesses are www.ipimediaworld.com
working through the GDPR process without great enthusiasm because they know they have to.” Whatever organisations are currently doing, the clock is ticking. Data controllers of all shapes and sizes should be feeling mounting pressure to start auditing existing processes and systems to check compatibility with the intricacies of the new laws and, if needs be, investing the person hours and financial resource required to rectify any shortcomings. As Stevens explains: “Big change brings uncertainty, and this has the potential to breed panic. This in turn can cause businesses to make rash, ill-informed decisions or assume that all problems can be fixed by implementing new software or designing new processes and procedures to better manage data. Although well intentioned, this will provide a short-term fix at best and prove an incredibly costly mistake should the new systems be deemed inappropriate by GDPR auditors.” So what questions should pharmaceutical firms be asking of their existing practices and the technology that currently supports them? Stevens believes pharmas can relieve some of the immediate pressure by retiring inadequate, legacy technology into cloud-based, archive – or preservation – systems; a cost-effective solution that takes data from one system and houses it safely and compliantly, while replacement systems are thoroughly investigated, data categorised, and informed purchasing decisions made. Stevens explains: “Retiring legacy software systems to make way for newer versions that are better able to accommodate GDPR requirements and minimise risk makes commercial sense. Understanding how the reams of historical data need to be preserved to support compliance best practice in relation to multiple sets of legislation is therefore crucial in order to reach sensible and controlled decisions.” Whatever the nature of an organisation, it is very unlikely that it won’t be affected in some way
by GDPR. Those that understand the potentially all-encompassing scope of the legislation and the consequences of non-compliance are preparing now to ensure they can shelter from the storm when it inevitably comes. REFERENCES 1.
Mark Stevens Mark has a successful track record in delivering complex projects to a range of different customers within the regulated life science industry. Graduating in 1994 from the University of Birmingham, his career has included design engineering, commissioning / validation, project management and a whole range of GxP Compliance consulting projects around the world. He has over 20 years of experience with managing teams and delivering projects that have utilised a risk based approach to achieving compliance within EU and US markets in a pragmatic and efficient manner. His consulting team specialises in EQMS, computer systems compliance, quality systems implementation and the management of complex and often business critical compliance improvement projects.
Mark Lumley Mark Lumley is a Partner at top 200 corporate law firm, Shulmans LLP. He was named Data Protection Lawyer of the Year at the Finance Monthly FinTech Awards 2017, is a national board member of Society for Computers and Law and has more than 20 years’ experience as an IT and commercial law specialist. Mark provides expert advice to clients in complex areas including GDPR and wider Information governance.
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Exhibitions & Conferences
NORDIC LIFE SCIENCE PARTNERING AT ITS BEST Event name: NLSDays 2018 Nordic Life Science Days 2018 Tag line: Nordic life science partnering at its best • 2.5 days for meeting the best the Nordic region has to offer • 2.5 days for new partnering opportunities • 2.5 days for entering into new deals Location: Stockholm, Sweden Date: September 10-12, 2018 Venue: Stockholm Waterfront Conference Center Venue address: Nils Ericsons Plan 4, Stockholm – Sweden Venue website: http://www.stockholmwaterfront.com Event Website: http://www.nlsdays.com
Nordic Life Science Days – What’s in it for you? Nordic Life Science Days is the largest Nordic partnering conference for the global life science industry. Bringing together the best talents in life science, offering amazing networking and partnering opportunities, providing inputs and content on the most recent trends. Nordic Life Science Days attracts leading decision-makers from the life science sector, not only from biotech, pharma and medtech, but also from finance, research, policy and regulatory authorities. Based on cutting-edge and advanced partnering and networking tools, Nordic Life Science Days showcases the best the Nordic region has to offer. 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The Nordic Way of Doing Life Science Business NLSDays offers networking and knowledge for anyone interested in Nordic life science, biotechnologies, pharmaceuticals, medical devices and e-health business. We offer plenty of opportunities to connect. Meetings on Your Terms Every meeting is an opportunity. At NLSDays, we focus on meeting quality, not quantity. We provide ample time for you to meet your fellow delegates in a stress-free environment. The Nordic region is proud to host some of the world’s most innovative biotech, medtech and pharma companies. It also has the 12th strongest economy, making it the perfect place to invest. Set in the vibrant city of Stockholm, the conference offers conference super sessions, workshops, company presentations and innovation posters, exhibition, face-to-face meetings and unique receptions, providing many opportunities to network with peers, potential partners and investors. The 2018 conference design will feature a new exhibition layout, creating more interactions with the exhibitors, an enriched programme featuring nine super sessions, four topical workshops, academic and startup contests, innovative 6mn and 12mn company presentations bringing more value to the presenters and the audience, new partnering areas allowing more comfort and privacy, and extended informal networking opportunities. NLSDays 2018 will take place in Stockholm on September 10–12. Based on attendance at previous events, NLSDays 2018 expects 1000 to 1200 international delegates. Highlights 1300+ 40 3000+
from NLSDays 2017: Participants Countries Scheduled Meetings
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conference solution for helping life science delegates meet efficiently and effectively. partneringONE® has the unique ability to manage the complex interactions among thousands of executives from many different companies. This sophisticated web-based partnering system enables delegates to screen potential partners, prearrange meetings and manage the entire conference partnering process. Delegates can log in and connect with the conference community, anytime, anywhere. NLSDays is a SwedenBIO event, produced by Bionordic Services AB. Contacts: General information, registrations, company presentations, exhibition and sponsorship: Olivier Duchamp, Director General, Nordic Life Science Days, CEO, Bionordic Services AB firstname.lastname@example.org Tel: + 33 (0) 608 804 515 Industry: Biotech, Pharma Academics, Research Medtech, E-Health, HealthTech CRO, CMO, Services IP, Law Firms Public, Non-Profit Investors Intended for: Executives from: • Established and emerging biotech, medtech and e-health companies • Mid-sized and large pharmaceutical companies • Institutional financial firms • Private investors including venture capital and private equity firms • Other industry-related services companies • Regulatory authorities, medical agencies • Academic research, tech transfer • Incubators, science parks • Regional and national development agencies, innovation agencies Please see website: http://www.nlsdays.com Spring 2018 Volume 10 Issue 1
Exhibitions & Conferences
DDL2017 – Review
The 28th Drug Delivery to the Lungs (DDL) Conference was held at the Edinburgh International Conference Centre between 6th and 8th December, 2017. The event hosted 740 delegates from all over the world and featured a five-session scientific lecture programme supported by 87 poster presentations. The industry exhibition was the largest yet, with 101 sponsors from the pharma industry exhibiting.
included sessions on ‘Emerging Therapeutics and Novel Respiratory Medicines’ and ‘Inhaled Therapy in Special Populations’, included talks from a range of speakers. Themes such as modelling techniques, development of inhaled antibiotics for diseases, and the use of acoustics for inhaler monitoring and characterisation were discussed over the three-day programme.
The event was preceded by a mini-symposium organised by the SimInhale COST Action group – www. siminhale-cost.eu. This specialist session addressed the difficult task of “Designing Inhalers for Children and Infants” by analysing physiological, technical and regulatory considerations; encouraging the audience to contemplate what changes or adjustments may be required to licensed adult inhalers to deliver therapeutic aerosols to infants and young children. Dr Sitaram Velaga and Mr Wilbur de Kruijf chaired the symposium and moderated a short discussion session following the lectures. The DDL programme, which
The inaugural DDL Emerging Scientist Award was unveiled during the event. The DDL organisers wished to encourage promising scientists to be ambitious and to promote their career progression. This award recognises talent and achievement of researchers within 15 years of their post-graduation. Francesca Buttini, University of Palma, won the award and presented her lecture on “Engineered Microparticles for DPI construction and Powder Administration Strategy.” Her research had impressed the judging panel and she was awarded the £1000 fund alongside being invited to present at the conference. DDL2018 will offer the same opportunity to another emerging scientist; see the website for more details. Professor Myrna Dolovich, McMaster University presented the annual DDL Lecture; ‘Looking Back and Looking Ahead: Developments in Aerosol Medicine over the last 50 years – Devices, Drugs and Detection of Disease’ and became the seventh doyen to be bestowed this lifetime achievement award. Six researchers presented their abstracts as a poster and a podium presentation as part of their bid to achieve the Pat Burnell New Investigator award. The winner was Ayasha Patel from King’s College London with her talk on ‘Loading, Release and Activity of Inhalable Benzothiazinone-Loaded Human Albumin Nanocarriers for Anti-tuberculosis Therapy’. This was
the second time Ayasha has been awarded at the DDL Conference, having won Best Academic Poster the year before at DDL27 in 2016. Congratulations also went to Judith Heidland, of Kiel University, for winning the Best Academic Poster entitled “Nano-in-microparticles for dry powder vaccination – possible for nasal application?” and to Kyrre Thalberg from Astrazeneca for winning the Best Industrial Poster with his abstract “Multi-Scale Modelling of the Formation of Adhesive Powder Mixtures for Inhalation.” All abstracts from the conference are available to view on the DDL Conference website www.ddl-conference.com. DDL2017 welcomed delegates from all across the world, including China, Korea, the USA, New Zealand and India. The interest in sponsoring this annual event builds in momentum each year, showing clearly that this is THE primary nasal and pulmonary inhaled medicines conference. For more information on this year’s conference – DDL2018 – please visit the website www.ddl-conference. com, follow the conference on Twitter @DDLConference and contact its organisers through LinkedIn – Sheila Coates and Nikki Evans. INTERNATIONAL PHARMACEUTICAL INDUSTRY 107
Exhibitions & Conferences
Genesis 2017 Round-up – From Bio-Innovation to Health and Wealth Delivery in Tomorrow’s World The annual Genesis conference, brought to you by One Nucleus, saw 750 delegates on 14 December 2017 gather in London to participate in what has become one of the must-attend conferences in the life sciences calendar.
The day kicked off with a particularly crowded room, with all ears ready for the popular recurring session of the ‘Winners and Losers’ of the year presented by Mike Ward, Chief Content Officer for Informa Pharma Intelligence Insights Portfolio at Informa. This presentation is a superb scene-setter highlighting a range of industry trends which, this last year were around the delivery of CAR-T therapies, the rise of biosimilars, the consolidation of the main pharma players, together with interesting merger models like insurance retailers, and finally the buzzword in pharma R&D in 2017: artificial intelligence (AI). AI is just the most obvious piece of non-life science technologies that can revolutionise drug discovery processes and the delivery of healthcare; the day taught us that a whole range of other sectors can contribute to the life sciences industry. This was illustrated by the engaging keynote presentation from the Director of Healthcare Technologies at ARM, Peter Ferguson, who showed us how a semiconductor and software world-leading company can support the delivery of healthcare, not only with technologies, but also with a fresh approach to the classic therapeutic models. The plenary session then concluded with a follow-up discussion from the year before on the role of technology transfer funds.
The day continued with the dynamic ‘Leadership Sessions’ distributed in four parallel streams, in which delegates can engage with issues in more depth than in the plenary sessions. The four streams were aligned with the overall theme of delivering better health and wealth for tomorrow, and covered: •
Understanding today’s deal with the example of iOnctura and AstraZeneca/Merck in order to build tomorrow’s medicine A digital tomorrow, and how digital health is changing the landscape of clinical developments and patients’ approach to their healthcare delivery A collaboration stream acknowledging the increasing complexity of future medicine and the need for multiple stakeholders’ involvement, especially to improve the emergence of innovative technologies and patient-centricity. The example of another 2017 big trend was taken with microbiome as an exciting but complex area A stream focusing on innovative technologies within R&D and the importance in developing tomorrow’s medicines, including toxicity study development and genomics.
of unmet medical needs still exists. But this nearly philosophical question apart, the conclusions were positive on where the sector is developing in terms of embedding new technologies and adapting to an increasing changing landscape. Of course, the conversation continued at the drinks reception, where delegates could network and share their thoughts on the day. These outcomes are already informing the agenda for 2018. The focus is on Driving Success in Life Sciences & Healthcare: Convergence of Technology, Investment and People. It will reflect on the advances in R&D technologies, the increasingly interdisciplinary approach to the diagnosis and treatment of health disorders and a continuing diversification of capital sources that is enabling the transformation of great science into great solutions at a global scale. Whilst global healthcare challenges are ever changing, advances in science and technology have never been faster. The new insights and ability such advances afford those discovering, developing and delivering better solutions for patients leaves the sector well-placed to meet the challenges ahead. Addressing patients’ unmet needs, of course, brings for researchers, clinicians, investors, payers and policy-makers the opportunity to make a real-world difference. Video highlights of Genesis 2017 and the emerging details for Genesis 2018 are available at www. genesisconference.com
Finally, the day concluded with a panel discussion comprising of seven thought-leaders from around the globe who discussed whether the life sciences industry is ambitious enough. Since the industry deals with human lives, it is difficult to raise self-satisfaction when the concept 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Spring 2018 Volume 10 Issue 1
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I hope this journal guides you progressively, through the maze of activities and changes taking place in the pharmaceutical industry
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