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Volume 9 Issue 3

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

Reducing Drug Discovery Timelines When Using Mouse Models

Sensory Analysis of Pharmaceutical Products Using Electronic Tongue and Nose

Sizing up the Benefits of

Sterile Drug Manufacturing Techniques

What Clinical Teams Should Know About Changing Trial Logistics and How They Will Affect Development

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication


08 A Workplace Revolution – The Digital Workplace in Life Sciences The way life sciences organisations work and collaborate has changed drastically over the past decade or so. The new digital workplace is thriving and the industry is reaping the benefits that come from collaborative working. Elvis Paćelat of AMPLEXOR takes a look at the next stage of the workplace revolution, showcasing the potential of the new digital workplace for improving the way in which life sciences firms operate. 12 Regulation of Controlled Drug Substances in SAARC Countries: Unique Attention to India, Bangladesh, Bhutan and the Maldives

The global illegal drug trade represents a multi-dimensional challenge that has implications in the international community. The South Asian region is the principal trafficking route for psychotropic drugs, as it is sandwiched between the Golden Triangle and Golden Crescent, the major global producers of psychotropic drugs. Sai Pranathi Meda Venkata, Balamuralidhara V and Mahalakshmy R of JSS College of Pharmacy give a preview of the contemporary state of the regulations pertaining to controlled drugs/substances in the South Asian Association of Regional Corporation (SAARC) countries with unique attention to Bangladesh, Bhutan, Maldives and India.


24 Keeping Up with a Shifting Regulatory Landscape:

COVER IMAGE: iStockphoto ©

Patient safety is at the forefront of considerations in the pharmaceutical industry, with high expectations from patients and care providers for quality in injectable medicines. Pharmaceutical companies and their packaging and delivery system providers should be ever-diligent in ensuring that quality and compliance are top priorities, but there must also be a balance that allows for appropriate cost management. In this article, Fran DeGrazio, Vice President of Scientific Affairs & Technical Services at West Pharmaceutical Services, Inc discusses how significant to patient safety is the production of high-quality packaging components and delivery systems.

PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Winter 2017. 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. 2017 PHARMA PUBLICATIONS / Volume 9 issue 3 - Autumn - 2017

Understanding Quality by Design and its Impact on Total Cost of Ownership

30 A Pharmacy's Role in Antimicrobial Stewardship Antimicrobial stewardship strategies form a vital filtration system for our healthcare system. Here, Adrian Pittock, Marketing Director of Valley Northern, explains the vital role that pharmacists play in promoting antimicrobial stewardship (AMS) to ensure the future of treatment for infection is sustainable. All pharmacists can play their part in slowing down emergence of antimicrobial resistance and conserving precious healthcare resources. 32 Flanders: The Life Sciences Nucleus of Western Europe Flanders, a region comprising the northern half of Belgium, might be small in surface area, but it’s home to one of the most vibrant life sciences ecosystems in the world. Flanders’ strategic location, vivid network of global life sciences players, excellent supportive incentives and talented workforce make it the place to be to thrive in any life sciences subsector, explains Mr De Smit, Economic and Commercial Counsellor for Flanders at the Embassy of Belgium in London. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents DRUG DISCOVERY, DEVELOPMENT & DELIVERY 36 Sensory Analysis of Pharmaceutical Products Using Electronic Tongue and Nose Pharmaceutical companies must now count taste and smell as new priorities during formulation development, especially for paediatric and geriatric medicines. Commonly, pharmaceutical laboratories have recourse to trained sensory panels in order to assess the sensory features of formulations. Fatma Ayouni, Technical and Application Specialist at Alpha MOS, explains why the electronic tongue, a taste analyser, and the electronic nose, a smell analyser, are considered as alternative solutions that meet the formulation department’s needs for safety, rapidity and cost-effectiveness. 42 Reducing Drug Discovery Timelines When Using Mouse Models With the drug discovery timeline exceptionally long and late-stage failure rates very high, there is tremendous pressure to reduce the discovery timeframe and bring effective therapies to market sooner. How investigators approach studies that use lab animal models can directly impact those goals. Kenneth Albrecht, Ph.D., Scientific Program Manager at Taconic Biosciences, looks into the creative approaches to rodent model generation and breeding, and how they can significantly reduce the associated timeline while ensuring the timely availability of the high-quality models upon which drug discovery depends. 46 Using Intelligent Design to Deliver Safe Preservative-free Multi-dose Eye-drops A significant patient population requires the long-term use of eye-drops multiple times a day. Maintaining the sterility of eye-drops is important for patient health. Single-use doses are expensive and preservatives can cause allergies and irritation, but the intelligent design of multi-dose bottles provides a viable means of delivering safe, preservativefree eye-drops, say Lilia Petit Ben Saidane and Benjamin Quaglia of Nemera. CLINICAL RESEARCH 52 Redefining the Art of Patient and Stakeholder Engagement in Rare Disease Clinical Research

60 Developing Global Solutions for Product Safety Recent Changes in EU Requirements and New Directions in PV Globalisation Over the past 20 years, the level of globalisation in the pharmaceutical industry increased significantly for both innovative and generic drugs. Magdalena Matusiak, Associate Director, Quality Assurance & Compliance at KCR, analyses how international cooperation between regulatory bodies and the harmonisation of regulatory requirements are key elements supporting the effective development of medicines. 66 Globalising Clinical Trials Pharmaceutical companies are increasingly embracing the need for running trials across multiple sites globally. The rise of personalised medicine, and its promise of improving the drug development process and focused, faster approval of new therapies, places the industry firmly at the centre of the global genomics initiative. Rodrigo Barnes, Chief Technology Officer and Pamela Brankin, Head of Marketing and Communications at Aridhia Informatics Ltd, observe how capitalising on it requires a combination of technologies supported and enabled by increased collaboration among the industry, academia and healthcare providers. LABS AND LOGISTICS 70 What Clinical Teams Should Know about Changing Trial Logistics and How They Will Affect Development – Part 1 When it comes to clinical supplies, the journey is every bit as important as the destination. And these days, the journey of clinical supplies to investigator sites is becoming costlier and more complex, much like the global trials for which the materials are bound. In addition to discussing how supply logistics are changing, this paper by Jennifer Worsfold, Senior Director Supply Chain Solutions at Fisher Clinical Services, shows how clinical services are deploying flexible solutions to ensure secure, efficient and cost-effective passage of clinical supplies. 80 Serious About Tarmac Time – Comparison of Different Approaches for Increased Thermal Protection and New Solutions for Low-mass Pallets of Pharmaceutical Goods

Because of the rarity, heterogeneity and complex patient management associated with rare conditions, creating a pharmaceutical development programme for the treatment of one of these diseases is challenging. With this feature, Leslie Wetherell, Executive Director of Project Management and Rare Disease Franchise Lead at Worldwide Clinical Trials, explores the importance of patient and stakeholder engagement in rare disease clinical research.

Temperature excursions during loading and unloading procedures of air-freight shipments (so called ‘tarmac times’) of pharmaceutical products represent a major challenge for a fully controlled cool chain. The standard solution in the industry for this problem is thermal blankets. In this piece, Dr Florian Siedenburg, General Manager of ECOCOOL GmbH, looks into the challenge of providing increased thermal protection for low-mass pallets of pharmaceutical goods.

56 The Future of Clinical Trials


The International Council on Harmonisation has adapted its guidelines to include radical changes to the design, implementation and monitoring of clinical trials. The principles are in place; the goals are clear. Essentially, industry and ICH appear to be working collaboratively to improve the patient experience, the quality of the data, access to metadata and overall transparency of results. Doug Stewart, Director of Hosted Employment and The Training Academy, shows that collaboration, cooperation, transparency and the patient are providing the direction of travel for clinical researchers.

86 Coding Ensures Safe Food Produce


In the pharmaceuticals industry, the coding of medicinal products is governed by directives in many countries. However, Track & Trace is also gaining ground in the food industry. Indeed, products are labelled in such a way that they can be traced on their way through the entire supply chain. The necessary coding solutions form part of the packaging process and therefore need to be integrated into existing packaging guidelines, says Axel Jung, Product Manager for Laetus Track & Trace Systems. Autumn 2017 Volume 9 Issue 3

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Contents 88 How to Combine Serialisation and Late-stage Customisation

112 Sizing up the Benefits of Sterile Drug Manufacturing Techniques

Serialisation of prescription medicines will become mandatory in the EU on February 9, 2019, resulting in new labelling requirements as a prerequisite for market access. Pharmaceutical manufacturers must therefore invest in suitable solutions now. Simultaneously, late-stage customisation is getting increasingly important due to continuously decreasing batch sizes. Helmut Schneider, Product Manager in Atlantic Zeiser‘s Pharma & Packaging Solutions division, analyses the different steps to consider where in the production process to most sensibly perform serialisation. The solution chosen by the pharmaceutical company will depend on the existing infrastructure as well as several other factors.

Sterile manufacturing environments are open to many sources of potential contamination if not managed correctly. The need to ensure the safe and sterile transfer of active pharmaceutical ingredients and formulation ingredients during aseptic processing has driven the development of multiple techniques that can be employed in cleanroom environments to minimise the risks from contaminants. Christian Dunne, Global Product Manager at ChargePoint Technology, explores approaches to sterile processing and compares several techniques.

94 Steps to Properly Inspect and Purchase a Tablet Press in the US and Abroad Mark Middlemist, Pharmaceutical Equipment Expert at Equipnet, focusses on tablet presses – sharing tips from equipment specialists who have seen more than their fair share. Here’s what engineers, technicians, and procurement professionals should thoroughly inspect before committing to purchasing a used tablet press. All of the essential information has been gathered from leading engineers, technicians, and procurement professionals to provide prospective buyers with quality tips for inspecting tablet presses. 98 Innovation Drives Productivity and Efficiency in Tablet Production

116 So, You Think You Have an Invention? The success of an invention can depend not just on the advantages that the invention provides, but also on the strength of the patent that protects it. Since a patent allows a proprietor to stop other people’s activities for a long period of time, these rights are granted judiciously to ensure that both sides of the agreement are upheld and that inventors do not obtain protection for more than they are due. Dr Emma Longland, Senior Patent Attorney and Dr Ben Tolley, European Patent Attorney at HGF, discuss in seven points all the information needed to get strong protection. PACKAGING 120 DSCSA Enforcement Delay – What Now?

Innovation drives growth, and ultimately improves productivity and efficiency. This is very much apparent in the pharmaceutical and nutraceutical industries, where increasing demand from the developing world is pushing tablet tooling manufacturers to be cutting-edge. This attitude to forward-thinking development has been particularly prevalent in the last decade, with shorter lead times now essential to remain competitive, says Alex Bunting, Marketing Manager at I Holland.

With the recent FDA announcement regarding a one-year delay in enforcement of the Compliance Policy for ‘Product Identified Requirements Under the Drug Supply Chain Security Act' (DSCSA), many are left asking what this actually means for the wider pharmaceutical industry or for their own company’s initiatives. While the FDA communication specifically indicates a delay in enforcement, it is clear there is no delay of the law itself; a telling signal to the industry that this serialisation challenge is real, affirms Justin Schroeder, Senior Executive Director, Global Marketing & Design at PCI Pharma Services.

104 Continuous API Manufacturing – It’s Time to Go With the Flow

126 Tungsten in the Production of Prefillable Syringes – Also Possible Without Tungsten

There has been a recent surge in interest in the use of more continuous processes in the pharma industry, as the benefits have become more widely known. This is due to the availability of more expertise in the area of flow chemistry over the last decade, in combination with the need for the industry to develop safer, faster and more sustainable processes, with higher quality and less expensive products. Sam Tadayon, Executive Director at STA Pharmaceutical, specifically looks at the improvements flow chemistry can bring to process development and manufacturing for APIs.

Drugs based on technologically manufactured active ingredients filled into syringes currently have a share of approximately 15% of the total market value for pre-filled syringes. These high-growth biotech drugs are sensitive with regard to possible interactions with individual syringe components. Syringe system manufacturers therefore strive for a reduction or avoidance of syringe components like silicone oil or tungsten pin. This article by Bernd Zeiss, Manager Technical Support Medical Systems at Gerresheimer Bünde GmbH, tackles the issue of reduction and avoidance of tungsten in prefillable glass syringes.

TECHNOLOGY 108 Do Sterility Test Isolators Need to be So Complicated? In this feature, Gary Partington, Extract Technology Sales/ Marketing Manager, looks into a simpler system of sterility test isolators. Isolators are used to create an airtight barrier or enclosure around a piece of equipment or process, to provide absolute separation between the operator and product. According to the author, an effective sterility test isolator for low-volume testing can be a four-glove isolator with a main chamber with a safety glass hatchback window. For high-volume testing, a similarly operated isolator with six gloves or even half-suits can be used. These simpler systems achieve the goal of eliminating false positives during testing and a lower cost. 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2017 Volume 9 Issue 3



Editor's Letter The days are getting shorter, the mushrooms are out – which must mean that it’s Autumn. I have just returned from the NLS Days in Malmö, Sweden where this year’s event was attended by 1300 delegates and 800 companies, with 16,000 partnering meetings being booked. The event looked at a number of topics including – to mention just a few – “game changers in diabetes treatments” and “responses to outbreaks of emerging infectious diseases”. In this edition of the magazine you can read about how there is a revolution going on in the workplace of one life science organisation, with digitalisation plus collaborative working, and AMPLEXOR’S Elvis Paćelat looks at what the next stage is going to be. Flanders: The Life Sciences Nucleus of Western Europe Flanders, a region comprising the northern half of Belgium, might be small in surface area, but it’s home to one of the most vibrant life sciences ecosystems in the world. Flanders’ strategic location, vivid network of global life sciences players, excellent supportive incentives and talented workforce make it the place to be to thrive in any life sciences subsector, explains Mr De Smit, Economic and Commercial Counsellor for Flanders at the Embassy of Belgium in London. Reducing Drug Discovery Timelines When Using Mouse Models With the drug discovery timeline exceptionally long and late-stage failure rates very high, there is tremendous pressure to reduce the discovery timeframe and bring

effective therapies to market sooner. How investigators approach studies that use lab animal models can directly impact those goals. Kenneth Albrecht, Ph.D., Scientific Program Manager at Taconic Biosciences, looks into the creative approaches to rodent model generation and breeding, and how they can significantly reduce the associated timeline while ensuring the timely availability of the high-quality models upon which drug discovery depends. Recent Changes in EU Requirements and New Directions in PV globalisation Over the past 20 years, the level of globalisation in the pharmaceutical industry increased significantly for both innovative and generic drugs. Magdalena Matusiak, Associate Director, Quality Assurance & Compliance at KCR, analyses how international cooperation between regulatory bodies and the harmonisation of regulatory requirements are key elements supporting the effective development of medicines, wide access to advanced therapies and ensuring sufficient safety oversight. Globalising Clinical Trials Pharmaceutical companies are increasingly embracing the need for running trials across multiple sites globally. The rise of personalised medicine, and its promise of improving the drug development process and focused, faster approval of new therapies, places the industry firmly at the centre of the global genomics initiative. Rodrigo Barnes, Chief Technology Officer and Pamela Brankin, Head of Marketing and Communications at Aridhia Informatics Ltd, observe how capitalising on it requires a combination of technologies

supported and enabled by increased collaboration among the industry, academia and healthcare providers. Keeping Up with a Shifting Regulatory Landscape: Understanding Quality by Design and its Impact on Total Cost of Ownership Patient safety is at the forefront of considerations in the pharmaceutical industry, with high expectations from patients and care providers for quality in injectable medicines. In this article, Fran DeGrazio, Vice President of Scientific Affairs & Technical Services at West Pharmaceutical Services, Inc, discusses how significant to patient safety is the production of high-quality packaging components and delivery systems. What Clinical Teams Should Know about Changing Trial Logistics and How They Will Affect Development When it comes to clinical supplies, the journey is every bit as important as the destination. And these days, the journey of clinical supplies to investigator sites is becoming costlier and more complex, much like the global trials for which the materials are bound. In addition to discussing how supply logistics are changing, this paper by Jennifer Worsfold, Senior Director Supply Chain Solutions, Fisher Clinical Services, contains examples of how clinical services are deploying flexible solutions to ensure secure, efficient and cost-effective passage of clinical supplies. We hope you enjoy this edition of the magazine and I hope to see meet you at the Genesis Conference on 14 December in Westminster, London. Lucy Robertshaw Directer, Lucy J.Robertshow Consulting

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

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

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 and


Autumn 2017 Volume 9 Issue 3

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Regulatory & Marketplace

A Workplace Revolution – The Digital Workplace in Life Sciences The way life sciences organisations work and collaborate has changed drastically over the past decade or so. The new digital workplace is thriving and the industry is reaping the benefits that come from collaborative working. But what technology is underpinning this and what further potential does it have? AMPLEXOR’S Elvis Paćelat takes a look at the next stage of the workplace revolution.

For the last 19 years, AMPLEXOR has attracted some of the biggest names in life sciences to its annual conference. BE THE EXPERT 2017 was no different. A stellar line-up of speakers gathered in Budapest in May, to talk life sciences and outline their vision for the future and how technology can play a role. Included in the presentations, and one of the key topics of conversation between delegates, was the concept of the new digital workplace. Such changing ways of working was the focus of the keynote speaker, Michael Woodbridge of global analyst firm Gartner. Michael‘s presentation focused on how the new digital workplace can help transform life sciences. Like a number of other regulated industries, life sciences has been slow to adapt to these new ways of working, but Michael discussed the potential of the new digital workplace for improving the way in which life sciences firms operate. But the question to ponder is what exactly is meant by the term ‘digital workplace’? The New Digital Workplace – What Is It and What does it Entail? Definitions vary as to the exact nature of the new digital workplace, but Gartner’s is perhaps the most accepted take.1 It defines the digital workplace as a ‘business strategy to boost employee engagement and agility through a more consumerised 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

work environment’. There are three underlying strands to this strategy: Engaging Employees: The strategy must ensure employees are engaged in the creation of a new workplace environment. This includes a blend of IT and business staff that act as co-owners of technology strategy and execution. Additionally, programmes must prioritise user experience; employees are more demanding of technology due to their personal technology experiences which are more streamlined than their work equivalents. In order to engage employees with their workplace environment, organisations must provide or support similar consumerised experiences.

Reimagining the Workplace and its Technology: Creating a vision, strategy and implementation plan that exploits emerging technology to make employees more effective. Ideally a digital workplace would include technology that is cohesive (in that it provides an integrated experience) and adaptive (in that it can adapt to change and support personalised ways of working). There isn’t one single piece of software that can be described as digital workplace, but typical catalysts for such a programme include intranet refresh programmes, cloud office migrations, and modernisation of content services capabilities. Changing Nature of Work: The strategy must be cognisant of the fact that work patterns are changing, influenced by many factors including globalisation, workforce retirement, increased outsourcing, crowdsourcing, and the establishment of the millennial generation in the workforce. A digital workplace programme should look for ways to reimagine not just the tools and environment they work with, but how the work is actually executed. Such a strategy can help digitally transform an organisation.

The Digital Workplace in Life Sciences So if the new digital workplace involves using new tools and technologies to foster a more open and collaborative culture, how embedded are these ways of working within life sciences? As a heavily regulated industry, there has certainly been a reluctance to adopt some of the underlying technologies that support the digital workplace, and for a number of organisations they are forced to remain in the technological dark ages because of legacy technologies in situ, and the perceived cost of changing the technological infrastructure. System validation is, in fact, a hugely important factor. The validation process typically leads to reluctance to implement any system changes regularly. Such principles can take deep root across an organisation which can in turn restrict other areas of the business that might be able to move at a more agile pace. Life science companies also work with incredibly long life cycles. It can sometimes take years and years to bring a drug to market, working through research, trials and beyond. With long life cycles and somewhat restrictive regulatory and compliance challenges, making big change is difficult. Even implementing relatively straightforward technologies, such as a cloud-based office suite, can be a challenge. The digital workplace is not about one particular technology or another, but cloud-based office is a highly typical starting point and Gartner research has estimated that by 2020, more than 60% of enterprises will have provisioned, in whole or in part, a cloud office platform.2 So for life sciences firms, the digital workplace is starting to become a real and tangible proposition. It is also prudent to look beyond the technologies involved and focus Autumn 2017 Volume 9 Issue 3


Regulatory & Marketplace on employee engagement aspects of the new digital workplace. By gathering the right blend of people to work on a digital workplace vision and strategy, initiatives and new ways of working will soon become apparent. A typical catalyst project within life sciences is an organisation embarking on the modernisation of its electronic content management (ECM) capability. With enterprise content now coming in such a wide variety of file types, ECM is an ongoing challenge for life sciences firms. Although this is a different challenge to the new digital workplace, it is also an effective place to start. What can be Achieved with the Digital Workplace? The life sciences industry has always been incredibly innovative with how it uses technology to support standard work practices. eCTD, for example, was an early adopter of structured information exchange. And there have always been pockets of excellence when it comes to innovation and delivering something transformative. The innovation model has changed from external innovation to a more collaborative and ‘distributed' model, where many connections beyond the firewall are creating intellectual property, coming up with new ideas for drugs, therapies and more. There are almost 4000 entities performing molecular R&D today, many of which are involved with large pharma partners. 

workplace is digital R&D. R&D has, of course, always been a significant element within life sciences, but a recent Accenture report – Industry at a Crossroads: The Rise of Digital in the Outcome-Driven R&D Organisation – highlighted the fact that slow take-up of new digital technologies is hindering the progress of pharma in research and development (R&D) and improving patient outcomes.3 The report focused on an ongoing shift from a product-orientated outlook to a patient and health system outcome focus, and reported that digital solutions are contributing process improvement and additional value across the enterprise, including R&D. Accenture’s analysis revealed that those companies that have embraced digital technologies report stronger performance in R&D capabilities, improving trial design, collaboration with external organisations to better understand a patient’s medical journey and providing improved data to medical liaison professionals during drug studies. Yet the survey of senior life sciences executives also showed that 42% of respondents are still ‘exploring’ or ‘waiting and seeing’ how digital innovations might improve their organisation. Is this an example of the culture within some

life sciences firms not matching up to the technology? The Lab of the Future Another exciting possibility within life sciences is how the lab of the future will develop. The lab is at the heart of much innovation within the sector and how it will look in 10, 20 and 50 years’ time is a topic much loved in the industry. In 2016, real estate services firm CBRE addressed this with its Lab of the Future report, which placed collaboration firmly at the heart of future laboratories.4 Major advances in disciplines such as computer modelling, and data sharing and analysis, have meant that traditional lab work has taken more of a back seat and led to an increased focus on using big data to optimise and speed up the research process. This can allow researchers to more accurately predict which projects or lines of inquiry are most likely to lead to success, which in turn can help with a more efficient use of resources, enabling more substantial outputs. When this is factored in, alongside developments such as the increasing complexity of research projects, it is obvious that more collaboration is taking place, both inside and outside the lab. And this means that the lab of the future must reflect this increased collaboration, reflecting again how the new digital

However, as an industry, life sciences has also become somewhat mired in restrictive practices, often applied across the organisation. A digital workplace strategy will help organisations challenge long-standing principles and implement an agile, innovative workplace where people want to go, whilst still maintaining the levels of governance and compliance required. This is becoming more essential as organisations and partner ecosystems become more diverse (particularly in research and new product development) and move beyond organisational boundaries. Digital R&D One of the specific advances supported by the new digital 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace

workplace can shape events in life sciences. Such initiatives all need an effective, digitally dexterous, workforce and this is not possible without the execution of a strong and cohesive digital workplace strategy. And measurement is important too – organisations need some measure of how successful the new digital workplace investment can be, and capturing, interpreting and learning from metrics is a key component of a digital workplace programme. Only from measuring the effects of a holistic programme can the measures introduced be understood and refined. The actual metrics here can vary widely, but common examples at a general level include workforce effectiveness, employee agility, employee satisfaction, retention and other organization-specific goals. Within life science, several major firms have digital workplace initiatives that are intimately tied to R&D success. Connecting people, content and complex information across very difficult and dynamic functional domains (e.g. scientific, clinical, and regulatory) is the name of the game. Many of the incredible advances and innovation within life sciences

have come about despite, not because of, the working environment and culture in such organisations. Yet the adoption of digital workplace strategies can improve innovation, encourage collaboration and properly equip and prepare a workforce for modern working practices. Developing a more engaged and effective workforce, and equipping them with the tools that support and augment their decision-making whilst unburdening them from the routine, are far more likely to drive change and innovation that can be truly transformative. REFERENCES 1.  Gartner IT Glossary – the digital workplace http://www.gartner. com/it-glossary/digital-workplace/ 2.  Gartner Forecast Analysis: Enterprise Application Software, Worldwide, 2Q15 Update, August 2015: newsroom/id/3119717 3.  Industry at a Crossroads: The Rise of Digital in the OutcomeDriven R&D Organisation, May 2016: us-en/insight-injecting-digital-rdjourney-patient-outcomes 4.  CBRE Lab of the Future, June 2016: real-estate-services/occupier/

facilities-management/labof-the-future occupier/ facilities-management/ lab-of-the-future

Elvis Paćelat Executive Vice President, Life Sciences, AMPLEXOR. Elvis is a business and technology executive with more than two decades of international experience in the life sciences market. With detailed technical understanding and expertise in compliance and regulatory content management solutions for life sciences, Elvis is a specialist in business impact analysis. At AMPLEXOR, he is responsible for driving the corporate strategy and market success of the AMPLEXOR Life Sciences business. Elvis is committed to delivering benefit for clients, partners and shareholders, whilst supporting client-centric strategies and spearheading groundbreaking innovations. Article inspired by Michael Woodbridge presentation at AMPLEXOR BE THE EXPERT 2017 event. Email:


Regulatory & Marketplace

Regulation of Controlled Drug Substances in SAARC Countries: With Unique Attention to India, Bangladesh, Bhutan and Maldives

The global illegal drug trade represents a multi-dimensional challenge that has implications in the international community. Common illegal drugs trafficked internationally include cocaine, heroin, and methamphetamine; collectively known as controlled substances. The basis for the regulation is to control the danger of addiction, abuse, physical and mental harm, trafficking by illegal means, and dangers from the actions of those who have used these substances. The South Asian region is the principal trafficking route for psychotropic drugs, as it is sandwiched between the Golden Triangle and Golden Crescent, the major global producers of psychotropic drugs. This review article gives a preview of the contemporary state of the regulations pertaining to controlled drugs/substances in South Asian Association of Regional Corporation (SAARC) countries with unique attention to Bangladesh, Bhutan, Maldives and India. Key Words: Controlled substances, Narcotic Control Act, NDPSSAA

Introduction The south Asian region is the principal trafficking route for psychotropic drugs, as it is sandwiched between the Golden Triangle and Golden Crescent, the major global producers of psychotropic drugs. Locallyproduced drugs like cannabis and opium are the major drugs of abuse in the countries of the region. The strong nexus between the terrorist organisations, drug traffickers and money launderers in South Asia has entrenched this menace. Most of the nations in the region are party to one or other of the UN conventions on drug trafficking, but their provisions are not incorporated into the domestic legal framework. Consequently, the legal provisions applicable in these countries are not sufficient to deal with the complexities of this trade.1 The South Asian Regional Convention on Narcotic Drugs and Psychotropic Substances was signed on November 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

23, 1990 and entered into force on November 15, 1993.2 Moreover, there are separate acts and regulatory authorities available in each of the representing countries for the control of misuse of controlled substances. INDIA Regulation of Controlled Drug Substances in India Country Profile •  Capital – New Delhi3,4 •  Currency – Indian rupee5 (INR) •  Official language – Hindi •  Drug regulatory authority – Central Drug Standard Control Organization •  Narcotics regulatory authority – Narcotics Control Bureau India is the only country authorised by the United Nations Single Convention on Narcotic Drugs (1961) to produce gum opium. Eleven (11) other countries, i.e. Australia, Austria, France, China, Hungary, the Netherlands, Poland, Slovenia, Spain Turkey and the Czech Republic, cultivate the opium poppy, but they do not extract gum. The regulation of narcotic drugs and psychotropic substances is governed by the NDPS Act. Regulatory Bodies for Narcotics in India: •  The Narcotics Control Bureau (NCB) is India’s primary national drug control agency, established to prevent and combat the abuse of narcotic drugs and psychotropic substances. •  Th e D i r e c t o r at e o f R e v e n u e Intelligence (DRI) and the Indian Customs Service are also authorised to pursue narcotics investigations. •  The Central Bureau of Narcotics (CBN) is India’s supervising agency over the licit cultivation of opium poppy in India. CBN is responsible for abuse prevention and enforcement functions, including investigations of violations of the NDPS Act, the issuance of licenses for the manufacture of synthetic

narcotic drugs, and export/import authorisations for narcotic drugs and psychotropic substances.

The most significant drug-related challenges facing India are the rise in methamphetamine manufacturing and trafficking, the diversion of licit controlled substances, the smuggling of pharmaceutical preparations containing narcotic drugs and psychotropic substances from India to neighbouring countries, and constraints on enforcement capacity and interagency coordination. Narcotic Drugs Controlled under Indian NDPS Act6 "Narcotic Drug" means coca leaf, cannabis (hemp), opium poppy straw and including all manufactured drugs; "Manufactured Drugs" means (a) all coca derivatives, medicinal cannabis, opium derivatives and poppy straw concentrate (b) any other narcotic substance or preparation which the Central Government may, having regard to the available information as to its nature, or to a decision, if any, under any International Convention, by notification in the Official Gazette declare to be manufactured drug; Govt. of India's Notification S.O. 826(E) dated 14/11/1985 and S.O. 40(E) dated 29/01/1993 & S.O. 1431(E) dated 21/06/2011 wherein the Central Government has declared certain narcotic drugs and preparations to be manufactured drugs. According to these notifications preparations, admixtures, extracts or other substances containing any of these drugs also come under the definition of manufactured narcotic drugs. "Psychotropic Substances" means any substance, natural or synthetic, or any natural material or any salt or preparation of such substance or materials included in the List of Psychotropic Substances specified in the Schedule  to the NDPS Act, 1985. "Poppy Straw" means all parts (except the seeds of the Opium poppy after Autumn 2017 Volume 9 Issue 3

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Regulatory & Marketplace harvesting whether in their original form or cut, crushed or powdered and whether or not juice has been extracted therefrom; "Controlled Substance" means any substance which the Central Government may, having regard to the available information as to its possible use in the production or manufacture of narcotic drugs or psychotropic substance or to the provisions of any International Convention, by notification in the official gazette, declare to be a controlled substance. Import and Export of Narcotic Drugs and Psychotropic Substances: The Government of India has recently amended the NDPS Rules 1985 vide Gazette Notification No. GSR 224(E) dated 25th March, 2015, that may be called the Narcotic Drugs and Psychotropic Substances (Second Amendment) Rules, 2015, which has become effective from the date of publication in the official Gazette, i.e. 26 th March 2015. After these amendments, the provisions relating to the import and export of narcotic drugs and psychotropic substances are as follows: •  Narcotic drugs or psychotropic substances [defined under section 2 (xiv) and section 2(xxiii) of the NDPS Act, 1985] can be imported into / exported out of India subject to Rule 53 of NDPS Rules 1985, provided that import into India or export out of India of narcotic drugs and psychotropic substances specified in Schedule I of these rules shall be for the purpose mentioned in Chapter VIIA. •  The import of (i) opium, concentrate of poppy straw, and (ii) morphine, codeine, thebaine, and their salts is prohibited, save by the Government Opium Factory. •  The import of morphine, codeine, thebaine and their salts by manufacturers notified by the government for manufacture of products to be exported or the import of small quantities of morphine, codeine and thebaine and their salts, not exceeding a total of 1 kg in a calendar year for analytical purposes, is permitted after following the procedure under rule 55 and subject to the 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

conditions as may be specified by the Narcotics Commissioner. •  Rule 55(3) and rule 58(3) of the NDPS rules, 1985 specifies that every application for an import certificate / export authorisation shall be in such a form and manner as prescribed by the Narcotics Commissioner. A fee of 1000 Rupees shall be paid (in the form of a demand draft drawn in favour of Drawing & Disbursing Officer, Central Bureau of Narcotics payable at Gwalior) to the Central Government along with the application for issue of each import certificate / export authorisation.

For import and export of the narcotic drugs and psychotropic substances, the following procedure is hereby prescribed: 1. Applicant for issuance of import certificate should be as per “IMP1” along with the background information specified as “IMP-2”. 2. For export the applicant will apply in the application form specified as “EXP-1” along with the background information specified as “EXP-2”. 3. Correspondence which relates to matters concerned with “Narcotics Drugs and Psycotropic Substances” may be addressed to the Narcotics Commissioner in an envelope superscribed “FOR NARCOTIC DRUGS”.7 Manufacture of Psychotropic Substances: 1. No person shall manufacture any of the psychotropic substances defined under section 2(xxiii) of the NDPS Act, 1985, except in accordance with the conditions of a licence granted under the Drugs and Cosmetics rules, 1945 framed under the Drugs and Cosmetics Act, 1940 (23 of 1940) by an authority in charge of drugs control in a state appointed by the State Government. 2. Besides, every manufacturer of psychotropic substances is also required to register with the Narcotics Commissioner in terms of Rule 65 of the NDPS Rules. Export / Import Any narcotic drugs or psychotropic substances can be imported into / exported out of India subject to Rule 53 and Rule 53-A of the NDPS Rules, 1985.

The import of (I) opium, concentrate of poppy straw, and (II) morphine, codeine, thebaine, and their salts is prohibited save by the Government Opium Factory under the provision of Rule 54 of the NDPS Rules, 1985. The import into and export out of India of any narcotic drugs or psychotropic substances specified in Schedule I  is prohibited under the provision of Rule 53 of the NDPS Rules, 1985. The export of any narcotic drugs or psychotropic substances or preparations containing any of such narcotic drugs or psychotropic substances specified in  Schedule II  shall be prohibited to the countries or to the region of such country specified therein, under the provision of Rule 53-A of the NDPS Rules, 1985. The manufacture of  psychotropic substances specified in  Schedule III  can be allowed for export purpose only, under the provision of Rule 65(1) of the NDPS Rules, 1985. The import of psychotropic substances specified in Schedule III may be allowed for test / analysis purpose as well as for re-export purpose. Procedure Followed for Processing of Applications / Requests from Companies for Above Functions (I) Manufacturing Licence / Renewal of Manufacturing Licence Any company / applicant desirous of manufacturing any synthetic narcotic drugs shall apply to the Narcotics Commissioner in  a prescribed manner  along with the necessary documents. The manufacture of narcotic drugs is governed by an estimate system. While allowing the manufacturing licence, it is ensured that the total quantity of drug allowed to be manufactured during any year does not exceed the annual estimated requirements of India as furnished and subsequently published by to the International Narcotics Control Board, Vienna, Austria. As regards the renewal of m a n u fa c t u r i n g l i c e n c e s , t h e manufacturers  are  required to apply to the Narcotics Commissioner at least 30 days before the expiry of Autumn 2017 Volume 9 Issue 3

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Regulatory & Marketplace their licence along with the relevant documents. On the basis of the demands made by the manufacturers and being mindful of their performance, i.e. internal consumption and export of the drug, the manufacturing licences are renewed for the suitable quantities within the estimates of that drug for the year. (II) Export Authorisations for Export of Narcotic Drugs and Psychotropic Substances Any company / applicant desirous of obtaining export authorisation shall apply to the Narcotics Commissioner in a prescribed manner along with the necessary documents. The export of narcotic drugs and psychotropic substances is governed by an estimate system. While allowing export authorisation, it is ensured that the annual estimated requirement in respect of particular narcotic drugs and psychotropic substances (as published by INCB, Vienna, Austria) does not exceed the estimated requirement in respect of the importing country. Such export authorisations are allowed by the Central Bureau of Narcotics subject to the following conditions: a.  Any kind of amendment as well as extension in validity of export authorisation would not be allowed. b. The shipment should be made in one consignment within the validity of the export authorisation. c. The exporter is required to submit export details immediately after effecting export.

(III) Import Certificate for Import of Narcotic Drugs and Psychotropic Substances Any company / applicant desirous of obtaining an import certificate shall apply in a prescribed manner  submitting the necessary documents. The import of narcotic drugs and psychotropic substances is governed by an estimate system. While  allowing an import certificate, it is ensured that the estimated requirement of a particular narcotic drug and psychotropic substance (as reported to the INCB and subsequently published by INCB) 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

does not exceed the requirement in respect of India. Such import certificates are granted subject to condition that the importer will submit the import details immediately after effecting import, and any kind of amendment or extension in validity of export authorisation would not be allowed. MALDIVES Controlled Drug Substance Regulations in Maldives Country Profile •  Capital - Male •  Currency - Maldivian rufiyaa (MRF) •  Official language - Dhivehi •  Drug regulatory authority - Maldives Food and Drug Authority •  Narcotic Drugs Regulatory Authority Maldives Narcotics Control Board The Republic of Maldives is a nation of islands, situated about 400 miles south west of Sri Lanka in the Indian Ocean. It consists of 1190 coral islands spread well over 90,000 square miles. The islands are grouped into 26 natural atolls that together form a chain 820 km in length and 130 km at its widest point. Administratively, the islands are grouped into 20 atolls. The Maldives is very well connected with the outside world through its international airport and sea ports. It is potentially vulnerable as a point for the illegal shipment of precursor chemicals or large quantities of drugs destined for other countries.8 Drug Situation in Maldives: In the Maldives, drug trafficking and drug abuse appear to be by-products of the country’s recent increased exposure to the outside world. Drug abuse was reportedly not a problem before the mid-1970s. The appearance of drug abuse in its present form seems to have coincided with the development of tourism in early 1970s. This period also witnessed increased overseas travel by Maldivians. With the introduction of heroin, drug abuse among the young age group escalated dramatically. Despite stringent drug laws, intensive efforts to prevent drug entry by several agencies there has been growing concern about the problem of drug abuse. In order to

prepare a National Master Plan for Drug Abuse Control in the country, the government approached UNODC to support a detailed assessment of the drug scenario in the country. A preparatory mission visited Maldives in 1999 with financial support provided by UNODC to prepare guidelines for a Rapid Situation Assessment Survey.9 Preventive Measures - Law on Drugs: A number of measures have already been taken to control the situation. The demand reduction aspect is under the narcotics control board (NCB). In terms of primary prevention, the government has taken the initiative to amend the law and to deal with the few cases of drug abuse detected in the principal Legislative Act of the Maldives, many awareness programmes have been instituted. The Law on Drugs, which was enacted in the 1970s, dealing with narcotic drugs and psychotropic substances is Law No. 17/77. The law on drugs then was thus very simple and reflective of the prevailing situation at that time. However, due to many changes that have taken place in the country since the adoption of the first Law, the government revised the Law to effectively deal with the drug menace and to take measures to combat drug trafficking and to prevent the abuse of drugs in the changed circumstances. Consequently, the government in 1995 introduced substantial amendments to Law No. 17/77 by providing for severe penalties for the manufacture, importation and sale of narcotic drugs in the Maldives. The Law at present prescribes life imprisonment for such offences. Further, for the first time, provisions were made for treatment and rehabilitation of drug users. The amendment of 1995 provides a comprehensive mechanism for the treatment and rehabilitation of drug users and a system of parole for first-time users. The amended law also has two tables, one containing a list of prohibited drugs and the other containing a list of controlled substances. The Government of the Republic of Maldives is determined to bring about a reduction in the demand for and the supply of illicit drugs.10 This determination was reinforced Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace with the establishment on the 16th November 1997 of the Narcotics Control Board, which is responsible for coordinating demand reduction efforts, management of rehabilitation programmes, and maintaining communication with national and international drug control and law enforcement agencies. Awareness Programmes: •  A n u m b e r o f c o n t i n u i n g d r u g awareness programmes which are aimed at various sectors within the community are being conducted or organised by the Narcotics Control Board. •  An awareness programme for all the parents of school children of Grade 7 in schools in Malé is conducted annually. The Atoll Awareness Programme aims to cover the entire Maldives within the next three years, with programmes conducted in every inhabited island in the country. These awareness programmes target atoll and island chiefs, healthcare workers, teachers and island committee chairpersons. Seven atolls have so far been covered under this programme. •  A prevention programme is being planned to run for all Atoll chiefs and island chiefs in Malé, outlining a comprehensive plan of action. The development of youth counsellors for the atolls is also a major concern. Television and radio advertisements about the dangers of drugs are routinely shown and information is available to the public. •  It had started the medical detoxification services at its rehabilitation centre at Himmafushi Island. In the area of tertiary prevention, we are rehabilitating the affected individuals. There is a plan to upgrade the facilities at its halfway house. •  Re c e n t ly t h e g o v e r n m e n t h a s formed a national task force in the area of substance use to coordinate and plan various activities.

by the 1972 Protocol), the United Nations Convention on Psychotropic Substances, 1971 and the United Nations Convention against Illicit Traffic in Narcotics Drugs and Psychotropic Substances, 1988.

through a Presidential Decree on the 16th November 1997, which strengthened the efforts aimed at addressing the issues of drug control. The National Narcotics Control Board is primarily responsible for the co-ordination of demand reduction and awareness building programmes, maintaining communication with international drug control agencies and management of rehabilitation programmes. Further amendments to the law in 1995 brought the management of the Drug Rehabilitation Centre (DRC), previously under the Ministry of Health, directly under the NNCB.11

Legislation: Official recognition of the drug problem came in 1977 when a person was arrested with 350 grams of hashish. As a result, the first principal legislative act of the Maldives dealing with narcotic drugs and psychotropic substances (Law No 17/77 - The Law on Drugs) was passed the same year in order to help the legal system deal with it, and to act as a deterrent. Since the adoption of the Law on Narcotics Drugs, the many social and economic changes brought in the country have resulted in an increase in the magnitude and nature of the problem. Hence, the government in 1995 introduced substantial amendments to Law No. 17/77.

The primary functions of the NNCB are drug demand reduction, awareness building, management of rehabilitation programmes and maintaining communication with international drug control agencies.

Institutions: The National Narcotics Control Bureau (NNCB) was established

The Drug Control Bureau of the Police Headquarters and Maldives Customs Service together are

Narcotic Drug Control Framework Convention Adherence The Government of the Republic of Maldives has ratified all three UN conventions related to narcotic drugs; namely, the Single Convention on Narcotics Drugs, 1961 (as amended


Regulatory & Marketplace responsible for illicit drug seizures in the country. The Ministry of Health plays an important role in demand reduction issues. The main policy-making body for the AIDS control programme is the National AIDS Council, a multi-sectoral body of government institutions and NGOs. National Policy: The government has stated its determination to bring about a reduction in the demand for and supply of illicit drugs. This was reinforced with the establishment on 16th November 1997 of the NNCB, which is responsible for coordinating demand reduction efforts, management of rehabilitation programmes, and maintaining communication with national and international drug control and law enforcement agencies. International Cooperation: Many workshops and training programmes have been carried out recently with the cooperation of various international agencies to increase awareness among government officials. Customs officials and operational staff from regional airports / seaports met in May 1999 to exchange information on trends of drug smuggling within the region. In September 2000, the Government of Maldives and UNDP (Maldives) signed a three-year project funded by the Government of Italy to strengthen the drug control programmes in the Maldives. The broad development objective is to protect the youth from drug abuse through drug prevention measures and to provide them skills for productive employment. The Government of the Maldives contributes fully to international initiatives in drug control regarding both control of supply and drug demand reduction. The government is a signatory to the 1990 SAARC Convention on Narcotic Drugs and Psychotropic Substances. BANGLADESH Regulation of Controlled Drugs in Bangladesh •  Country Profile •  Capital - Dhaka •  Currency - Bangladeshi taka (BDT) •  Official language - Bengali 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•  Drug regulatory authority - Directorate general of drug administration •  Narcotics Control Board - Department of Narcotic Control, Bangladesh

There were only some colonial laws (the Opium Act 1878, the Excise Act 1909, the Dangerous Drugs Act 1930, the Opium Smoking Act 1932 and the Prohibition Rules 1950) inherited from the British and Pakistani period. These laws were intended and designed for earning government revenues through excise-levying activities. The government of the People’s Republic of Bangladesh enacted the Narcotic Control Act in 1990, repealing all the colonial laws with a view to dealing with drug problems true to the aspiration of the country’s society.




The Narcotics Control Act 1990: The Narcotics Control Act 199012 was passed in 1990 by repealing all previous laws for control of narcotics, treatment and rehabilitation of drug addicts. The government has enacted the Narcotics Control Act, 1990 as amended in 2000, 2002 and 2004, in order to update the law. Features of Narcotics Control Act 1990: The Narcotics Control Act 1990 (as amended in 2000, 2002 and 2004) has the following salient features, reflecting the growing needs for effective action against drug smuggling on the one hand, and corroborating on the other the international efforts to contain this problem. 1. The Narcotics Control Act 1990 came into force on 2nd January, 1990. 2. Interception of illicit drug trafficking through law enforcement, control of narcotic drugs and psychotropic substances used in medical, industrial and scientific purposes coupled with treatment and rehabilitation of the drug addicts underlie the propriety of this law. 3. It provides legal coverage for establishment of the Department of Narcotics Control (DNC) as the nodal agency of the government to fulfill the objectives of the law in question. It also provides the



legal basis for the formation of the National Narcotics Control Board (NNCB) as the highest policymaking body of the government for formulating necessary policies and strategies to combat the drug problem in the country. The Narcotics Control Act 1990 empowers not only the Department of Narcotics Control but also the other agencies of the government, like the police, the BDR (the border security force), the customs and the coastguard for drug enforcement activities. Further, the law provides for mutual cooperation among the different law enforcement agencies as and when required, for conduct of search, seizure and arrests. The law introduces an effective licensing system for controlling import, export, manufacturing, processing, distribution, sale, transport, possession and use of licit narcotic drugs, psychotropic s u b s t a n c e s a n d p re c u rs o r chemicals. The Narcotics Control Rules 1999 is the legal instrument for carrying out the licensing provisions enshrined in the law. This law prescribes deterrent punishment for various categories of drug offences, as well as for breach of the conditions of the licenses issued under the law. The law prescribes the highest penalty of death sentence for the offenders accused of possessing either heroin, cocaine or cocaine derivatives exceeding the quantity of 25 grams. Similarly, the illegal possession of pethidine or morphine or possession of tetrahydro-cannabinol exceeding the quantity of 10 grams renders the offender or offenders concerned liable to death sentence or life-long imprisonment. The death sentence has also been prescribed for certain other drug offences of a serious nature (Section 19 of the law). The law takes the wisdom of the three major UN Conventions and the SAARC Convention on narcotic drugs and psychotropic substances, particularly in regard to forfeiture of sale proceeds from illegal drug business, freezing of bank accounts and property, sending of juvenile offenders to the correction centre in lieu of imprisonment, inclusion of Autumn 2017 Volume 9 Issue 3



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Regulatory & Marketplace the controlled delivery technique, compulsory maintenance of accounts of licit drugs by the license holders, incorporation of the 22 precursor chemicals, and so on. 9. The law provides the legal basis for the Chemical Laboratory of the Department of Narcotics Control and its proper functioning in respect of forensic analysis of all seized drugs and suspicious substances. This lab, established in Dhaka, caters to the needs of all the agencies charged with the responsibilities of drug enforcement and thereby it plays an important role in quick disposal of drug cases under trial. 10. The amendment of 2000 to the law brings about the government’s first foray into the control of precursor chemicals from a drug control point of view. 11.An amendment of 2002 has introduced the minimum time limit of 15 days for completion of investigation of drug cases filed under this law. 12.Another amendment in 2004 redefines alcohol by reducing the lowest limit of alcoholic strength from 5% to only 0.5%. Any liquid preparation containing more than 0.5% alcohol shall fall within the purview of the law. This amendment is intended to safeguard our young generations from the clutches of the so-called energy (alcoholic) drinks and their bad impacts. 13.The law has 61 Sections in all. It has two Schedules, of which the first lists the narcotic drugs and psychotropic substances, including the 22 precursor chemicals. The second schedule on the other hand lays down the rates of excise duties to be imposed on domestically produced liquor and alcoholic spirit.

Relevant Provisions of the Narcotics Control Act (NCA) 1990 Section 9: Restriction on import, export, sale, purchase, manufacture, processing, transport, possession, use or any other kinds of operations except for medicinal, scientific, or legitimate industrial purposes under licence, permit or pass. Section 11: Provision of issuing licence / permit / pass Section 12: Restriction on issuing 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

licence to persons with criminal records. Section 19: Penal provision of imprisonment for two to 15 years for precursor-related offences. Section 20: Imprisonment for two to 15 years and fine for keeping utensils and apparatus of precursors. Section 21: Imprisonment for five years and fine for knowingly letting out places, transport, establishment or apparatus for the commission of an offence. Section 22: Imprisonment for two to 10 years for illegal handling of precursor chemicals without licence, permit or pass. Section 23: Imprisonment for five years and fine for breach of the condition of a licence, permit or pass for a precursor chemical. Section 25: Imprisonment for up to 15 years for abatement or conspiracy. Sections 27 & 28: Cancellation and suspension of licence / permits of drugs and precursor chemicals. Section 32: Inspection of licence for drugs and precursors. Section 33: Seizure and confiscation of illicit drugs and precursors. Section 46: Financial investigation and freezing of assets. Section 50: Specialised Chemical Examination Laboratory for quick examination of drugs and precursors. National Narcotics Control Board (NNCB):13 The Narcotics Control Act 1990 was passed in 1990 by repealing all previous laws for control of narcotics, and treatment and rehabilitation of drug addicts. For achieving the objectives of this law, a high-powered committee styled 'National Narcotics Control Board' was formed in the same year. The committee is headed by the Home Minister with the Director General of the Department of Narcotics Control acting as the Member-Secretary. Functions and Responsibilities of the Board: 1. To frame policies for prevention of possible injurious effects of narcotics and to take measures for their implementation. 2. To undertake any research or survey for the collection of data and information relating to various aspects of narcotics.

3. To f ra m e p o l i c i e s re l at e d t o manufacture, supply, use, and control of narcotics. 4. To frame policies relating to treatment and rehabilitation of narcotics addicts and to take measures for their implementation. 5. To undertake educational and publicity measures for creating necessary public awareness about the evil effects of narcotics. 6. To maintain liaison with all the concerned ministries and agencies relating to anti-narcotics matters and to coordinate all such activities. 7. To take any measure necessary for the performance of the aforesaid  functions and responsibilities.

Meeting:14 a. Subject to the other provisions of this section, the Board shall determine the procedure of its meetings. b. All meetings of the Board shall be held at the place and time as determined by the Chairman. c. The Chairman shall preside over all meetings of the Board and in his absence any other member of the Board nominated by him shall preside. d. The quorum of a meeting of the Board shall be constituted by onefourth of the total members. e. No action or proceeding of the Board shall be illegal on the ground that any defect or vacancy exists in the constitution of the Board nor shall such an action or proceeding be questioned only on that ground. BHUTAN Controlled Drug Substances Regulation in Bhutan Country Profile •  Capital – Thimphu •  Currency – Bhutanese ngultrum (BTN) •  Official language – Dzongkha •  Drug regulatory authority – Drug Regulatory of Bhutan(DRAB) •  Narcotics Regulatory Authority – Bhutan Narcotics Control Board, Bhutan Narcotics Control Agency

The Bhutan Narcotic Control Agency (BNCA)15 was established in 2006 following the enactment of the Narcotic Drugs Psychotropic Substances and Substance Abuse Act in 2005. It functions as the secretariat to the Narcotic Control Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace Board and is the nodal agency of the government for all matters related to narcotics drugs, psychotropic substances and substance abuse. The Key Objectives of BNCA are: 1. To carry out advocacy and public awareness programmes on the ill effects of drugs and alcohol abuse. 2. To carry out awareness and advocacy programmes on the ill effects of drugs and alcohol abuse and provide services to drug users through drop-in centres (DICs). 3. To rehabilitate drug- and alcoholdependent persons by providing detoxification, treatment, counselling, and community support programme and after care services. 4. To develop IEC materials to carry out mass campaigns amongst all sections of the youth on the ill effects of drugs and alcohol abuse. 5. To curb the rising drug trafficking. 6. To enhance capacity development within the agency and amongst all stakeholders in drug and tobacco law enforcement, prevention, and treatment and rehabilitation services. 7. Enhance the coverage of tobacco and drug control, prevention, treatment and rehabilitation services in the country. 8. Strengthen coordination and communication processes with relevant agencies and enhance/ establish cooperation in regional and international organisations for technical and financial assistance on research, surveillance and exchange of information. The above-mentioned objectives are implemented through the three divisions namely the Demand Reduction Division, the Supply Reduction Division and Tobacco Control Programme. The Demand Reduction Division is responsible for prevention, early detection, treatment, rehabilitation and after-care services of drug dependent persons and drug users. Acts, Rules and Regulations: 1.Narcotic Drugs, Psychotropic Substances and Substance Abuse Act 2005 (NDPSSAA)16 It consists of the following chapters:

Chapter 1 Preliminary-The Title, Commencement and Scope of the Act Chapter 2 Classification of Drugs, Precursors and Controlled Substances Chapter 3 Control of Licit Activities Chapter 4 Special Provisions Chapter 5 Educational Measures Chapter 6 Treatment & Rehabilitation Chapter 7 Narcotics Control Board Chapter 8 Bhutan Narcotics Control Agency Chapter 9 Enforcement Measures Chapter 10Special Investigating Techniques Chapter 11 Drug Related Money Laundering and Regulated Measures Chapter 12 Regulatory and Criminal Offences Chapter 13 International Cooperation Chapter 14 Amendments, Authoritative Text and Definitions National Drug Control and Framework: Convention Adherence Bhutan is a party to the United Nations Convention against Illicit Traffic in Narcotics Drugs and Psychotropic Substances, 1988. It became party Country


to the 1961 and 1971 Conventions on 24 and 18 August 2005, respectively. Licit Control The Health Ministry authorises the issues of the import licences by Ministry of Trade and Industry for controlling the import of precursor chemicals. The Health Ministry authorises the issuance of import licences and authorisations for licit drugs and, to some extent, precursors. Bhutan has no pharmaceutical industry; most of the precursor chemicals are imported from India. At present, Bhutanese authorities tend to rely on Indian authorities to control imports of precursor chemicals from India, however this will change under the proposed new Bhutan legislation. International Cooperation Bhutan is an active participant in regional initiatives to address the drug issue. The government is a signatory to the 1990 SAARC Convention on Narcotic Drugs and Psychotropic Substances. Bilateral and multilateral conventions are self-executing under Bhutan’s law, but need domestic Status

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Revenue, Narcotics

1985 (NDPS)

Control Board (NCB), Central Bureau of Narcotics (CBN)



Law No.17/77,

Narcotics Control



Board (NCB), Drug

Transit country

Control Board (DCB) of Police Headquarters


Regulatory & Marketplace 14. National Narcotics Control Board holds meeting after two and a half years. Published: 2005-0531 Bd ST  Updated:  2005-05-31. Available at: bangladesh/2005/05/31/nationalnarcotics-control-board-holdsmeeting-after-two-and-half-years 15. Bhutan: Poverty Reduction Strategy Paper, International Monetary Fund, IMF Country Report 10/180, June 2010. Washington, D.C. 16. Narcotic Drugs, Psychotropic Substances and Substance Abuse Act 2005, Kingdom of Bhutan. Available at: http:// acts/2014/Narcotic_Drugs_act_of_ Bhutan,_2005Eng.pdf.

Sai Pranathi Meda Venkata is pursuing a Masters in Regulatory Affairs, Department of Pharmaceutics, Jagadguru Sri Shivratreeshwara University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India.

implementing legislation to be fully effective. The following table gives the summary of the drugs, acts and regulatory authority and trade status in each country. REFERENCES 1. Manoharan N. Drug Trafficking in South Asia: A Profile, Sri Lanka Articles, #1113, 30 August 2003. Available at: http:// html. 2. S o u t h A s i a n Re g i o n a l C o nv e n t i o n (SAARC) on Narcotic Drugs and Psychotropic Substances, November 23, 1990. Electronically published 19th April 2012. Available at: http://www. southasian-regional-conventionsaarc-convention-narcoticdrugs-psychotropic-substances/ p28007. 3. New Delhi, wiki/New_Delhi#cite_note-3. 4. Wells John C. (2008). Longman Pronunciation Dictionary, 3rd edition, Longman,  ISBN 9781405881180. 5. Indian rupee. Available at: https:// 6. Malik S. et al. Supreme Court on 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Narcotics and Drugs with the NDPS Act, Drugs and Cosmetics Act, and NDPS Rules, Edition: 2nd Edition, 2016. 7. Narcotic Drugs and Psychotropic Substances Act, 1985. Available at: http:// narcotics india. /upload/ download/ document_ id08b2dbd c9ca941d2 37893bd 425a f8 b fa.pdf 8. Maldives, UNGASS Goals on Control of Precursors, South Asia, Annexure IV, Page 63. Available at: https:// www. unodc. org/ pdf/ india/ publications/ ungass _ Goals/19_annexureiv-countryreportmaldives.pdf. 9. Maldives - Country Health Profile, 2000. Available at: india/publications/south_Asia_Regional_ Profile_Sept_2005/11_maldives.pdf. 10. Drug Laws in Maldives. Available at: http://www.Addictionsupport.aarogya. com/law/drugs-a-law/drugs-a-law-inmaldives.html. 11. Minh P. Rapid Situation Assessment of Drug Abuse in Maldives 2003, Narcotics Control Board Republic of Maldives 2003. Available at: http://www.shareefweb. com/documents/Maldives%20Reports/ Drugs%20Abuse/UNDP%20drug%20 report%202003.pdf. 12. The Narcotics Control Act 1990, Department of Narcotics Control, Ministry of Home Affairs. Available at: 13. National Narcotic Control Board, Official website of Department of Narcotics Control, Available at: http://www.dnc.


Balamuralidhara V He is an Assistant Professor in the Department of Pharmaceutics in JSS College of Pharmacy, Jagadguru Sri Shivratreeshwara University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email:

Mahalakshmy R. She is a PhD Research Scholar in the Department of Pharmaceutics in JSS College of Pharmacy, Jagadguru Sri Shivratreeshwara University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email:

Autumn 2017 Volume 9 Issue 3


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Regulatory & Marketplace

Keeping Up with a Shifting Regulatory Landscape: Understanding Quality by Design and its Impact on Total Cost of Ownership

Patient safety is at the forefront of considerations in the pharmaceutical industry, with high expectations from patients and care providers for quality in injectable medicines. But it is about more than just manufacturing quality drugs. Also contributing significantly to patient safety is the production of high-quality packaging components and delivery systems.

As a result, the US Food and Drug Administration (FDA) and other regulatory agencies around the world are requiring drug makers to develop and institute quality processes in the manufacturing of drug products and their container closure and delivery systems. It goes without saying that pharmaceutical companies and their packaging and delivery system providers should be ever-diligent in ensuring that quality and compliance are top priorities, but there must also be a balance that allows for appropriate cost management to maintain affordability for the patient and profitability for the drug maker, which will ensure continued investment in bringing needed therapies to market. Biologics and Increased Regulatory Focus on Quality There continues to be a steady rise in new biologic and biosimilar drugs coming onto the market to treat chronic conditions such as multiple sclerosis and certain autoimmune diseases. Additionally, biologic therapies show promise for helping acute conditions, such as certain types of cancer, become manageable chronic conditions by targeting specific components of a disease in ways never thought possible before. This trend isn’t going away. In fact, the QuintilesIMS Institute predicts that spending on biologic treatments for autoimmune diseases and a range of related disorders will reach $75–90 billion by 2021. In addition, biosimilars will be available for several of the 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

leading autoimmune products in the same timeframe, potentially allowing wider use of these medicines.1 Quality is particularly at the forefront with the influx of new biologic and biosimilar drugs, which often have very specialised needs around containment and delivery. For example, biologics can have sensitive compositions that pose the potential for interaction with materials traditionally used for packaging and delivery systems. In particular, the fact that many sensitive biologics are coming on the market as combination products is spurring regulatory agencies to more closely scrutinise the compatibility of packaging c o m p o n e nt s w i t h i n j e c t a b l e drugs and their delivery systems. Regulatory guidances such as ICH 8, 9 and 10 are also contributing to the increased focus on quality within the biopharmaceutical industry. These factors are ushering in new considerations for biopharmaceutical companies and their packaging and delivery system partners around drug delivery and risk mitigation. In this new era, the adoption of quality by design (QbD) principles in the design and manufacturing of packaging and delivery system components for injectable drugs products helps to ensure that how the therapy is contained and delivered is engineered with these stringent and specialised needs in mind. The adoption of QbD principles delivers an improved, data-driven output, providing manufacturers with superior product and process understanding that minimises risk, emphasises patient-critical quality requirements and supports drug product effectiveness in an industry where patient-centricity is paramount and quality must be top of mind from the very beginning. QbD principles were designed to promote an understanding of the

drug product and manufacturing process, starting with product development. During the design and development process, a QbD-driven approach requires manufacturers to define desired product performance goals and identify critical quality attributes (CQAs). The product and process can then be designed to meet those attributes, potentially improving understanding of how material attributes and process parameters impact CQAs and enabling manufacturers to mitigate variability. QbD has helped facilitate more expedient and efficient introduction of high-quality biologics to market because stakeholders are now armed with critical data that allows them to control potential risk factors. It also allows drug, packaging and delivery manufacturers to continually monitor and adjust their manufacturing processes to ensure consistent quality throughout a drug product’s lifecycle. The scientific, risk-mitigationbased QbD approach is fast becoming an essential strategy for bringing high-quality biologics to market quickly and efficiently, while identifying and controlling potential quality concerns. High-quality components designed using QbD principles and processes can help optimise the performance of drug delivery systems and protect sensitive drug products with exceptional cleanliness and barrier properties, while helping to ensure patient safety. While pharmaceutical companies are working to ensure that new quality and compliance paradigms for a drug and its packaging are met, a balance must be achieved between the realities of managing costs in an effort to provide a product that meets the requirements of payers along with facilitating profitability to support adequate business Autumn 2017 Volume 9 Issue 3

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Regulatory & Marketplace reinvestment. The adoption of QbD concepts over recent years has helped pharmaceutical companies and their packaging and delivery partners balance these priorities effectively. However, some manufacturers have been slow to integrate QbD for one very clear reason: cost. Instituting QbD processes in manufacturing requires a significant up-front investment, which can understandably lead some in the industry to initially shy away. That said, the benefits of incorporating QbD principles into manufacturing can go a long way in reducing the total cost of ownership (TCO) for a given product. QbD’s Impact on Total Cost of Ownership To ensure that the QbD return on investment is maximised, it is important to understand the total cost of ownership – i.e., the analysis of price, risk, quality, service and delivery performance – in evaluating the overall cost of a product versus its benefit. Reducing end-of-line rejections is an example of how the pharmaceutical manufacturer can clearly recognise benefits from TCO. QbD can often drastically lower end-of-line rejections to very minimal rates and generate significant cost savings by enabling more products to go to market for patient use. This, in turn, reduces the probability of product shortage and helps to manage capital expenditures more effectively. The end result? More revenue is generated for the pharmaceutical or biotech company.

component that has been through optimised washing, sterilisation and automated vision verification processes can combat issues from particulate and extractables. Instituting a QbD Approach for Components As industry demands for high-quality components have evolved, there is growing need for packaging components developed using QbD processes. A QbD approach promotes a holistic understanding of the drug product, its integrated delivery system and the manufacturing process. Employing a QbD strategy for packaging components starts with product development. When designing and developing a product using QbD principles, manufacturers must first define desired product performance goals and identify CQAs. The product and process can then be designed to meet those attributes, potentially improving understanding of how material attributes and process parameters impact CQAs

and enabling manufacturers to mitigate variability. As a result of this knowledge, a company can continually monitor and update its manufacturing process to ensure consistent product quality. The design and manufacturing of high-quality components should follow a development lifecycle programme that uses a quality target product profile (QTPP) to establish CQAs for control of breakloose and glide forces. The QTPP can serve as a guideline throughout the development process – which should include risk-based design inputs, finite element analysis modelling, data generation on multiple concepts and final product performance verification with barrels from multiple suppliers – to ensure that targeted specification values for breakloose and glide force are met. By applying a holistic, QbD approach to the design and development of

Container closure systems represent another area where a TCO model can support QbD initiatives. While drug packaging is often the final consideration in the drug development process, the selection of appropriate, high-quality primary packaging components is critical to drug stability and the effectiveness and compliance of a commercial manufacturing process. For example, selecting a vial made from a cyclic olefin polymer, such as the Daikyo Crystal Zenith® polymer, and a high-quality, ready-to-use 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2017 Volume 9 Issue 3

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Regulatory & Marketplace prefillable syringe components, packaging manufacturers can gain a thorough understanding of both the product and the process. This, in turn, enables multiple benefits for manufacturers and end users: •  Improved Functionality – Highquality components, such as plungers, can enhance the functionality of prefillable syringes and self-injection systems. Using QbD principles can help to optimise breakloose and glide forces – aspects that are very important when syringes are used in combination with an injection system. By optimising a delivery system’s functional and dimensional performance, it is possible to improve the consistency of injections and the rate of injection times. •  P a t i e n t C o n f i d e n c e – A s e l finjection system needs to function consistently and reliably in order for patients to have confidence that it will work. QbD-designed components allow for larger-size delivery systems and greater dosing volumes which may enable home administration, and encourage device use and more accurate dosing – all of which can help boost a patient’s confidence in their use of a self-injection system. •  Efficient Manufacturing – Employing a QbD approach in the manufacturing process can significantly reduce variation from part to part. This can help facilitate more efficient manufacturing processes and support a reliable supply of drug products.

Use of QbD principles ensures that components are developed using science-based and data-driven decisions, and that they meet critical specification for defects, visible and sub-visible particulate and extractables consistently. The knowledge gained throughout the QbD process can be used on an ongoing basis to maintain continuous improvement by the manufacturer. Partnering to Enhance Quality Efficiency in manufacturing and the ability to meet critical compliance 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

standards are a must to compete in today’s market. Effective packaging selection early in the development process can be key for pharmaceutical manufacturers. Early partnerships between pharmaceutical companies and drug delivery device companies help pharmaceutical manufacturers select consistent components that can be used throughout the drug product’s lifecycle and potentially mitigate risk associated with issues such as particles. Additionally, as delivery systems are utilised to a greater extent with many speciality pharmaceuticals, the ability to ensure the packaging and delivery system work together effectively minimises risk and total cost. The best way to maximise a drug product’s safety and efficacy is for pharmaceutical companies and their drug packaging and delivery partners to collaborate at the onset of the entire manufacturing process, from design and development to commercialisation and administration. This will ensure that they build new quality principles into the product from the very beginning. Choosing a packaging partner that employs a QbD philosophy, pharmaceutical manufacturers can employ high-quality packaging components that can help lower their total cost of ownership through reduced compliance risk, filling rejection rate and process costs. Full return on investment can be realised once a drug product is commercialised and has gained patient loyalty through ease of use and therapeutic benefit. The collaboration and use of QbD principles to design high-quality components ensures the highest levels of reliability, which ultimately helps the pharmaceutical industry achieve its most critical goal: providing safe and effective drug products for their patients. REFERENCES

Fran DeGrazio Vice President of Scientific Affairs & Technical Services at West Pharmaceutical Services, Inc. Fran DeGrazio has been in the pharmaceutical packaging industry for over 30 years with extensive expertise in the area of delivery of injectable drug products, such as vial/closure combinations, prefillable syringe systems and injectable combination products. Throughout her tenure at West, Fran has served in various functions within the analytical laboratory and research and development areas. Thirteen years were spent in the Technical Customer Service and Contract Laboratories areas with responsibility for strategic planning and implementation for both organizations. Fran was promoted to Vice President, Quality Assurance, Americas, in 2002 with responsibility for quality assurance and quality control for nine manufacturing facilities, the corporate analytical laboratories and the regulatory organization. In May 2006 she transitioned into the role of Vice President of Marketing and Strategic Business Development leading initiatives such as the concept of applying Quality by Design to closure development. As of 2012, Fran assumed a role as Global Vice President, Research and Development, Strategic Program Management and Technical Customer Support leading all packaging new product activities. As of February 2016, Fran was asked to develop a new organization for West. In this role, she leads the Scientific Affairs and Technical Services organization for the enterprise. This role is focused on assuring West’s scientific industry leadership as we innovate new products and services for the et. Fran holds a degree in Chemistry from Cabrini College in Radnor, Pennsylvania, USA.

1. QuintilesIMS Institute. Outlook for Global Medicines through 2021: Balancing Cost and Value. December 2016.

Autumn 2017 Volume 9 Issue 3


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Regulatory & Marketplace

A Pharmacy's Role in Antimicrobial Stewardship

Antimicrobial stewardship strategies form a vital filtration system for our healthcare system. Here, Adrian Pittock, marketing director of Valley Northern, a UK leading pharmacy and healthcare supplier, explains the vital role that pharmacists play in promoting antimicrobial stewardship (AMS) to ensure the future of treatment for infection is sustainable.

Only certain objects can fit through a filter, such as a sieve or fine mesh. Liquid and small particles will pass through, while other particles are stopped in their tracks. The same idea should be applied to prescribing antimicrobials. Certain people need them, and therefore should pass through the filter and receive this treatment, whereas others should be held back by the filter, to try other treatment options before resorting to antimicrobials. Inappropriate use of antimicrobials, such as antibiotics, is the key driver in the spread of antimicrobial resistance, meaning that infectious microbes are no longer killed by the treatment. Additionally, with the discovery and production of new antimicrobials slowing down, there is greater concern for the sustainability of our current supply of treatment. Ultimately, steps need to be taken to preserve the antimicrobials we already have, which relies on a reinforced filtration system across the entire healthcare sector. National Backing The National Institute for Health and Care Excellence (NICE) defines antimicrobial stewardship as "an organisational or healthcaresystem-wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness." It encompasses everyone in healthcare. Professor Dame Sally Davies, Chief Medical Officer, said in the 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2013 Chief Medical Officer's report, "Antimicrobial resistance poses a catastrophic threat. If we don't act now, any one of us could go into hospital in 20Â years for minor surgery and die because of an ordinary infection that can't be treated by antibiotics". This alarming notion shows the importance of reinforcing the antimicrobial filter. NHS England released Commissioning for Quality and Innovation (CQUIN) in 2016, which was a financial incentive for pharmacies to reduce the indiscriminate or inappropriate use of antibiotics, and review antibiotic treatment within 72 hours of administration. The CQUIN framework is intended to reward excellence, encouraging a culture of continuous improvement. Rebecca Carter, a neurosciences specialist pharmacist based in Oxfordshire, believes a key strategy to achieving CQUIN targets is education. "I would advise focussed training in areas where over consumption of antimicrobials is high, to help them to identify areas in their practice where they may be able to use alternative agents, or increase their knowledge of antimicrobial stewardship." Responsibility Community pharmacists have some of the most significant opportunities to intervene and prevent unnecessary antimicrobial use, as patients often go to their community pharmacist first to seek expert advice. This is an opportunity to quash any misconceptions surrounding antimicrobials, as well as to educate the community on infection prevention strategies, including good hygiene, hand washing and vaccinations. Pharmacy labels, like the ones provided by Valley Northern, are available to affix to pharmacy bags to enhance existing communication strategies. Often, conversations in

a pharmacy may be forgotten by the time the customer gets home, but pharmacy labels continue to get the message across for much longer. Labels such as 'complete entire course' will continue to speak volumes for as long as the label is visible. These labels resonate with customers as they take their prescription home, away from the busy pharmacy environment. Additionally, influenza vaccinations should be proactively marketed to vulnerable groups, saving on antimicrobial resources in the long term. By simply sticking a label on pharmacy bags stating 'flu jabs are available here', this message is clear. Small changes such as using pharmacy labels can complement AMS efforts greatly. Alternatives If prescribers aren't sure if antimicrobials are required, delayed (back-up) prescriptions are an alternative to immediate antimicrobial prescribing. It encourages other treatment as a first step, but allows a person to access antimicrobials without another appointment if their condition gets worse. However, a survey in the British Medical Journal found that 72 per cent of the general public were unaware of this delayed system. With this delayed way of prescribing likely to increase further to complement AMS strategies, patients may require reassurance and advice from their pharmacists as they may have expected to receive antibiotics. With changes like this ongoing, community pharmacists not only need to keep up to date with the most recent guidelines, but create a pharmacy environment indicative to AMS. Pharmacies are an ideal place to display antimicrobial resistance and infection prevention leaflets. When patients bring their antibiotic prescription to a pharmacy, Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace conserve precious healthcare resources. Without pharmacists’ supportive efforts, a gaping hole would be present in a vital filtration system.

Adrian Pittock marketing director of Valley Northern.

this is an important opportunity for pharmacists to have discussions about what has caused the infection, alternative treatment and the risks of taking antibiotics. Additionally, pharmacists can act as reinforcement within the antimicrobial filtration system, asking questions that

GPs may have already asked but are worth asking again. Questions could surround current medicines, hygiene and allergies. All pharmacists can play their part in slowing down emergence of antimicrobial resistance and

Adrian began his career in the warehousing team at Valley Northern. His role advanced into marketing and product development and he was instrumental in designing the ProBox® range, which improves patient safety. In 2015 he was appointed marketing director and continues to develop innovative products and promotional campaigns. Email:


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Regulatory & Marketplace

Flanders: The Life Sciences Nucleus of Western Europe Flanders, a region comprising the northern half of Belgium, might be small in surface area, but it’s home to one of the most vibrant life sciences ecosystems in the world. And for good reason; Flanders’ strategic location, vivid network of global life sciences players, excellent supportive incentives and talented workforce make it the place to be to thrive in any life sciences subsector.

A Location with Maximum Impact At the Epicentre of the Action With Brussels as its capital, Flanders is one of the three independentlygoverned regions of Belgium – the third most globalised country in the world, according to the 2017 KOF Index of Globalisation. Its location in the north of Belgium puts Flanders right in the midst of a European network for life sciences that includes the UK (London-OxfordCambridge), France, Germany and Switzerland – four nations known for their life sciences strengths. Flanders at-a-glance - Fourth most productive workforce in the world - Top five European knowledge region - Top 15 in R&D spending - Cutting-edge road, rail, waterway and air infrastructure

Located at the intersection of several cultures and the largest markets of the continent, Flanders is strategically placed for maximum connection and interaction. West of Germany, north of France, south of the Netherlands and just a quick jaunt from the UK, its spot at the hub of Europe’s economic power gives it some unique attributes found nowhere else in the world. Exceeding Specialised Transport Needs With 60% of Europe’s purchasing power found within 500 kilometres 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of Flanders, it’s no wonder that 800 European distribution centres, many of them focused on pharma logistics, have been established in the region. Its low costs, well-developed infrastructure and favourable tax incentives make Flanders the second most attractive investment region among neighbouring areas.1 Unbroken cold chain transport in Flanders is among the best in the world, adding to the region’s advantages for pharma development and logistics.

electronics for pharma and healthcare, focusing on technologies that steer easier diagnosis and more comprehensive treatment like labs-on-chips, neuroprobes, health wearables and more. As a pioneer in digital technologies, the centre possesses unparalleled expertise in applications revolving around health and care, including robotics, medical device optimisation, prostheses and care services planning.

Even more, Brussels Airport is the first IATA CEIV pharmacertified airport company in the world after being recognised for its technologically advanced, transparent and rapid handling processes for pharmaceutical and biotech products. The airport is already seeing higher volumes of pharma products from around the globe being transported through its facilities.

Digital Domination: imec Strengthens its Pole Position A new five-year agreement brings an extra EUR 29 million to imec in 2017 with the goal of keeping Flanders at the head of the medical biotech pack. Operating one of Europe’s most productive start-up incubators and giving rise to 78 spin-offs in the last handful of years, imec also applies for approximately 120 science and tech patents per year. With 80% of its budget generated via partnerships with industry leaders, imec is a critical driving force behind the translation of biotech research into products that serve the medical community. Every euro invested in imec results in eleven euros of revenue for collaborators and six euros in business investments.

An Ecosystem that Brings Life Sciences to Life The European knowledge economy is driven in a large part by Flanders, which combines a range of governmentsupported and private R&D platforms, scientific institutes and strategic research centres active in a range of science and technology domains. A high level of academic-industrial collaboration in Flanders results in a dense network of human health industry players, resources and driving forces that rely on each other and build upon shared innovations. Even more, due to its knowledge economy and atmosphere of open innovation, small-scale start-ups in Flanders are able to work alongside – and compete with – global industry players. Key Strategic Research Centres As a strategic research centre for nanotechnology, imec is a renowned synonym for ‘cutting-edge’. It plays a crucial role in the design of

©Flanders Investment & Trade

Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace With a dual-pronged approach that combines basic research and translational initiatives, VIB, Flanders’ institute for biotechnology, is a vast source of knowledge, expertise and infrastructure relevant to pharmaceutical, agricultural and industrial applications. Its scientists are globally recognised frontrunners in their fields. VIB’s 10 core facilities support research and innovation by providing highly-advanced ‘omics’ technologies and research capacities to external organisations and private companies. The World’s Most Fertile Soil for Bio Innovation Founded in 1996, VIB has taken the world by storm, attracting the brightest minds in biosciences to conduct basic research with the ultimate goal of using their insights to benefit society. VIB employs approximately 1470 scientists from more than 60 countries, who have been responsible for major breakthroughs that have rocked the fields of cancer research, immunology and inflammation, neurobiology and molecular neurology, microbiology, medical biotechnology, structural biology and plant systems biology. Pioneering spin-offs, including ADX Neuroscience, Actobiotics, ThromboGenics and Formac Pharmaceuticals, have been launched by this international powerhouse of biotechnology knowledge.

University Hospitals and Research Clusters Five top-notch universities are found in Flanders, each featuring its own blend of strengths in various domains of human medicine, technology, management, life sciences and more. When it comes to health-driven universities, Leuven University and Leuven University Hospital excel in life sciences. The institution boasts a fully-fledged life sciences campus that employs 1300 researchers and offers 2000 beds. In other words, interaction between research and patient care flourishes here. The Leuven Medical Technology Centre coordinates research groups in the areas of robotics and automation, drug administration, tissue regeneration and bionic systems, among others. Its Centre for Drug Design & Discovery

technology platform accelerates small molecule drug discovery, and has been responsible for supporting the development of drugs to treat AIDS, cancer, epilepsy, Alzheimer’s disease, and others. VUB and Brussels University Hospital operate their own strategic research centres in neurosciences, reproductive medicine, diabetes, oncology and cardiovascular studies. In addition, their Laboratory for Molecular and Cellular Therapy, Structural Biology Lab and Cellular and Molecular Imaging Labs offer ultramodern in vivo imaging and protein observation technologies. Ghent University Hospital is one of the largest and most specialised hospitals in Flanders, and Ghent University is home to key centres of medical expertise and research groups. Its Department of Basic Medical Sciences is involved in translational medicine in the fields of anatomy and embryology, stem cell biology, medical physics, physiology, radiobiology and tissue engineering. The Ghent University Inflammation Research Centre investigates the molecular mechanisms of inflammation, while the Bimetra Clinical Research Centre aims to strengthen translational biomedical research. The University of Hasselt BIOMED research institute employs 140+ researchers to investigate novel areas of neuroscience, autoimmunity, cell physiology and biophysics, and morphology and histology. Antwerp University and Antwerp University Hospital are known for their excellent care and international research initiatives in the domains of cardiology, clinical biology, haematology, immunology, metabolic disorders, molecular imaging, neurosurgery and more. They also operate focused institutes and consortiums responsible for vaccine evaluation, fundamental science and emerging ‘omics’ research. Enablers, Accelerators and Sector Organisations There are also various bio-incubators, pharma innovation accelerators and

science parks targeting life sciences start-ups located in or near several of Flanders’ key cities: Ghent, Leuven, Antwerp and Hasselt. These include BioVille, the BlueHealth Innovation Centre and StartupVillage. Cluster and sector organisations such as FlandersBio, beMedtech, Healthcare Belgium, and Agoria’s Healthcare Technology Club provide support, guidance and collaboration opportunities to industry players to promote information exchange, business growth and innovation. Global Success Stories Begin in Flanders Did you know that researchers from Flanders… ...were the first to unravel the DNA sequence of a gene? …developed pioneering pharmaceuticals for pain management, anaesthesia and schizophrenia treatment? …developed tPA thrombolytic therapy for myocardial infarction? …were the first to use stem cells in bone marrow transplants? …created a lab-on-a-chip for early breast cancer discovery?

When it comes to pharmaceuticals, the top 10 biggest players in the world operate key facilities in Flanders. Janssen Pharmaceutica, Pfizer, Sanofi and Novartis are among the big names to benefit from Flanders’ advantages. Janssen Pharmaceutica Takes Cutting-edge to the Next Level A subsidiary of American pharma giant Johnson & Johnson, Janssen Pharmaceutica has been a pioneer among successful global firms with key locations in Flanders. It was recently given the green light by its parent company to move forward with an investment of EUR 42 million in a state-of-the-art campus that will house its Small Molecule Analytical Development and Pharmaceutical Sciences departments. With construction kicked off in 2016, this brand-new facility will be operational by 2020 and enable Janssen to test new drugs and develop novel ways of administering medications.


Regulatory & Marketplace Other life sciences domains that build on, contribute to and intersect with pharma, are well-represented in Flanders. Agricultural biotech is huge in the area, thanks in large part to the molecular research of award-winning scientists at Ghent University. Syngenta and Bayer operate R&D centres in Flanders, which is one of the world’s key agricultural biotech clusters. Nanotech-focused strategic research centre imec establishes corporate partnerships on a constant basis with the goal of innovating marketable solutions to real business challenges. Working with industry players active in biotechnology, biopharma and red biotech not only expands the knowledge base; it enables the success of SMEs, start-ups and other stakeholders affected by new developments in these domains. Pharma-medical Collaborations in the Spotlight World-changing ideas can’t take flight in a vacuum. Interaction is always a key ingredient. As many as 77 pharma companies with locations in Flanders and Belgium as a whole channelled EUR 2.89 billion into R&D in 2016,2 mainly through collaborations with healthcare organisations and professionals. Pharma is a Star in Flanders’ Investment Firmament Pharma in Flanders - #2 in Europe for number of clinical trials per capita - EUR 2.9 billion in R&D investments per year - Fastest clinical approval in EU (15 days) - Exports 1/6 of all medications originating from the EU - 5% of global pharma output is developed here

pharmaceutical industry takes centre stage when it comes to foreign investment – and Flanders has taken notice. Sanofi Brings Home the 2017 Investment of the Year Trophy Winning out in a public vote over worthy contenders from Japan, France and the United States, French biopharma company Sanofi won the 2017 Investment of the Year Trophy at the 5th annual Foreign Investment Trophy. A EUR 300 million investment was funnelled into the 8000m2 expansion of its production space in Flanders, where it creates monoclonal antibodies destined for next-gen biological medicines.

A Long History in Flanders Brings Big Wins to Johnson & Johnson Five decades and hundreds of millions of euros invested later, Johnson & Johnson was recognised for its pharma ambassadorship in Flanders through the Lifetime Achievement Trophy 2013. “The company’s continued investments in pharmaceuticals and biotech, key sectors of our economy, are testament to Johnson & Johnson’s long-term vision, and it continues to inspire new companies,” said former Minister-President Kris Peeters upon presenting the award.

Home to Every Incentive for Success Achieving sustainable growth for your pharma, biotech or biomed business is smooth sailing in Flanders thanks to the region’s worldwide reputation for bright ideas – the fourth highestscoring nation in the world for innovation3 and the first in Europe for cooperation between scientific institutions and SMEs.4

Leading the way in innovation linkages5 (i.e. innovative SME collaborations, public-private co-publications, etc.)

•  •  •  •  •  •  •  •  •  • 

Belgium (Flanders) – 160.4 Netherlands – 156.6 Switzerland – 154.8 Iceland – 146.6 Austria – 129.8 Germany – 129.7 United Kingdom – 124 Finland – 123.9 Norway – 118.6 Sweden – 116.4

Significant Tax Savings on Novel Ideas Developing the next disruptive biotechnology or ground-breaking medicine? The region offers incentives that target research-heavy sectors such as pharma and biotech. The innovation income deduction renders up to 85% of a firm’s net earnings from innovation tax exempt, allowing companies to reinvest the funds to fuel ongoing development. Other Generous Incentives for R&D Initiatives The investment deduction for R&D is worth 13.5% of the acquisition value or qualifying asset, or 20.5% of the depreciated amount of the investment. R&D companies are also exempt from paying 80% of the personal income withholding tax of researchers in specific scientific fields. Got Innovation? Get in Touch with VLAIO Flanders Innovation & Entrepreneurship (VLAIO), a governmental

As one of the most important sectors of Flanders’ economy, the

©Flanders Investment & Trade


Autumn 2017 Volume 9 Issue 3

Regulatory & Marketplace organisation responsible for stimulating growth, innovation and entrepreneurship, is the ideal funding partner for companies in any domain developing new products and services. Depending on the type of R&D activity and company, VLAIO offers a number of support programmes and grants that can fund up to 80% of your innovation project. Even further, VLAIO offers expert advice and guidance to businesses seeking to sharpen their competitive edges. Connecting Talent, Value and Culture Not only does the quality of its educational system receive top marks in global rankings, Flanders’ workforce is one of the most productive in the world. Skilled people, a rich cultural heritage and plenty of attractive incentives designed just for expats make Flanders the perfect intersection of skill, utility and taste. Topping the Charts in Science Education Flanders comes in fourth worldwide in higher education, and third in maths and sciences6 – surpassing neighbours Germany, the Netherlands, UK and France in the tested quality of its education.

The five universities in Flanders top the charts in pioneering research and industry-relevant innovation. In fact, three of them hold places on the 2017 Reuters list of most innovative universities, and the University of Leuven was ranked #1 in Europe when it comes to submitting patents, valorising research, generating spin-offs and facilitating university collaboration with companies. Ghent University and Vrije Universiteit Brussel also hold competitive rankings.

In addition to its universities, other sources of highly-trained scientists, technicians and administrators include entrepreneurial coursework offered by MBI Life Sciences & Health Academy and the Flanders Training Network Life Sciences (FTNLS). Providing targeted training in corporate life sciences settings, OPINNO, a network of biotech SMEs, offers internships in a wide range of domains. Even more, VIB provides a diverse array of training programmes aimed at life sciences researchers interested in exploring emerging domains and technologies.

Connect with Flanders Investment & Trade Flanders Investment & Trade (FIT) is your source of expertise regarding every aspect of doing business in Flanders. This governmental organisation provides comprehensive support for companies seeking to invest in and source from Flanders via its 90 offices worldwide. In addition to its broad network of stakeholders, working with FIT brings companies the benefits of tailored data, business-relevant insights and expert advice tailored to their unique situation.

The strong numbers above indicate the robustness and multimodality of the region’s talent pool, and its focus on transforming life sciences and tech research insights into products that benefit society. Companies of all sizes interested in boosting their innovation strength and expanding into new markets can easily reach their growth goals by hiring bright minds in Flanders.

In partnership with VIB, VLAIO and FlandersBio, Flanders Investment & Trade offers the services of a skilled life sciences welcome team dedicated to providing support and guidance to foreign life sciences and biotechnology investors in Flanders. Visit to get in touch.

Where International Life Sciences Professionals Thrive A broad range of fiscal advantages are offered by the Government of Flanders to expatriate employers, managers and executive personnel working in the region on a temporary basis. These include tax-free expat allowances covering living and housing costs, and unlimited tax reimbursement of moving expenses, schooling costs and more.

1. Financial Times 2. 3. ZEW Center for European Economic Research, Innovation Indicator 2014 4. Innovations Indikator 2015; Bloomberg Innovation Index 2017 5. E u r o p e a n C o m m i s s i o n , E u r o p e a n Innovation Scoreboard, 2017 6. WEF Global Competitiveness Report 2016-2017

As previously mentioned, targeted R&D staff employment advantages can exempt companies from paying up to 80% of the payroll withholding tax of scientists and skilled technicians such as PhDs, engineers and personnel with master ’s degrees. In addition to the financial and tax incentives, Flanders is a great place to live. It has an enterprising, lively atmosphere that places emphasis on art, culture and history as well as new technologies and modern pursuits. Its advanced healthcare system is comprehensive and easy to use, and its high standard of living and relatively low costs are significant draws.


Ben De Smit Economic and Commercial Counsellor for Flanders at the Embassy of Belgium in London. Before his posting in London, Mr. De Smit was Director Business Development of the Belgium-Flanders Foreign Investment Office in Asia Pacific. In 1989, he was appointed by the Belgium-Flanders Government to attract direct investments from Asia Pacific into Belgium-Flanders. Within his role at Flanders Investment and Trade he facilitates investment projects in Flanders and gives support to Flemish export companies. Email: flandersinvestmentandtrade@


Drug Discovery, Development & Delivery

Sensory Analysis of Pharmaceutical Products Using Electronic Tongue and Nose Taste and Smell: Key Parameters During Formulation If the taste and smell of medicines have long been considered as a minor concern, nowadays patients are no longer willing to swallow bad-tasting remedies or medicines with a bad odour. Therefore, pharmaceutical companies must now count taste and smell as new priorities during formulation development, especially for paediatric and geriatric medicines.

Moreover, the increasing interest for oral forms such as disintegrating tablets, dissolvable films, chewable tablets, syrups, etc. has led to the development of numerous tasteor odour-masking strategies using sweeteners, flavourings, vehicles, and coatings. To monitor taste and smell features during formulation, it is important to dispose of a solid base of excipients, fully screened taste-masking agents and reliable testing methods to control the process. Commonly, pharmaceutical laboratories have recourse to trained sensory panels in order to assess the sensory features of formulations. In addition to being time- and money-consuming, these human tests yet require a strict supervision of health risks. These drawbacks can explain why the electronic tongue, a taste analyser, and the electronic nose, a smell analyser, are considered as alternative solutions that meet the formulation department’s needs for safety, rapidity and cost-effectiveness. The Electronic Tongue: An Instrument that Measures and Compares Tastes The specificity of the electronic tongue analyser is that its working principle is similar to human taste perception. Instead of measuring a n d i d e nt i f y i n g t h e va r i o u s compounds responsible for taste in a liquid solution, as many analytical techniques can do, the e-tongue captures the global profile of a taste. 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In the mechanism of human taste perception, chemical compounds responsible for taste are perceived by taste receptors. With the electronic tongue, sensors detect the same dissolved organic and inorganic compounds. Like human receptors, each sensor has a spectrum of reactions different from the other. The information given by each sensor is complementary and the combination of all sensors’ data generates a unique fingerprint. In the biological mechanism, taste signals are transmitted by nerves up to the brain as electric signals. In the same way, e-tongue sensors generate electric signals (potentiometric variations) in the presence of dissolved compounds. In the human sense of taste, the brain compares the patterns of activated sensory nerves to its library of known tastes and consequently identifies or builds a taste perception. With the e-tongue, this step is achieved by a statistical software which interprets sensor data as taste patterns. Running an analysis is fast and easy. Liquids are directly analysed without any preparation. Solids require a preliminary dissolution before measurement. A reference electrode and sensors are dipped in a beaker containing a test solution for 120 seconds. A potentiometric difference between each sensor and the Ag/AgCl reference electrode is measured and recorded by the e-tongue software. The set of sensors and reference electrode are rinsed with distilled water between two analyses. Results are displayed within minutes as decision tools. The Electronic Nose: An Instrument that Assesses Aromas and Odours An electronic nose is an instrument that can evaluate the smell of products in a way similar to the human nose, i.e. the overall smell

fingerprint. The first electronic noses used a technology of gas sensors to detect the volatile compounds responsible for smell. Later on, some instruments featured a detection system based on mass spectrometry, and finally the most recent ones use gas chromatography to assess the volatile and odorous compounds. For example, HERACLES Electronic Nose (Alpha MOS, France) uses a technology of dual fast gas chromatography (two columns of different polarities in parallel coupled to two flame ionisation detectors) to detect the chemical compounds responsible for the aroma characteristics of products. The chromatograms are obtained in a few minutes and can be processed as a fingerprint of the product using multivariate statistics and chemometrics. This data processing thus allows the comparison of overall sensory profiles, to evaluate the sensory conformity or for scoring sensory attributes. At the same time, chromatography analysis makes it possible to investigate the molecules involved upon searching by Kovats index matching through a specific library of chemical molecules with their Kovats index, chemical data and related sensory attributes. How E-tongue and E-nose can Help Formulation Development? By providing a fast and objective measurement of the sensory characteristics, the e-tongue and e-nose significantly reduce development time and costs, subjectivity, bias, and safety concerns. The various applications in the pharmaceutical industry include: •  measuring and comparing the tastemasking efficiency of formulations produced with different masking techniques •  investigating the origin of an offodour and evaluating the efficiency of odour-masking techniques Autumn 2017 Volume 9 Issue 3


Visit us at CPhI 2017 in Frankfurt, stand 8.0H51 A recent study proves that more than half of the population has problems swallowing tablets and capsules. From breaking and dissolving to not taking them at all, people invent their own strategies to cope with tablets – which may reduce efficacy and treatment success. At HERMES PHARMA, we have over 40 years of experience in making medicines easier to take – from product design through to manufacturing and packaging. If you need support with developing new products that are specifically designed to meet the needs of modern patients, contact us:

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Drug Discovery, Development & Delivery •  supporting the development of placebos for blinded clinical testing by assessing the taste-matching between active formulation and placebo •  comparing the taste of test medicines or generic products with competitive products (benchmarking) •  evaluating the taste and flavour stability of formulations over time.

Some examples of these main applications will be presented. Taste-masking Optimisation of an Active Principle Many pharmaceutical active principles are known to have a strong, bitter taste that can negatively impact palatability and acceptance by the patients. That is why various excipients are used in oral formulations to mask this bitterness. The objective of this study was to investigate the optimal formulation of excipients, allowing the achievement of the best masking of an active principle bitterness.

In terms of taste, the active formulations containing excipient B are farther from their corresponding placebo than active formulations containing excipient A. Bitterness-masking efficiency was evaluated by calculating the taste distance between each formulation and the corresponding placebo consisting of the same composition of ingredients but without the active principle. The shorter the distance, the better the masking. The e-tongue measurement showed that the formulations containing excipient B with either of the two flavours had a low masking power (Figure 2: Distance between each formulation and its corresponding placebo). On the contrary, the formulations containing excipient A proved to be much more efficient in masking the active principle taste. It appeared that pear flavour was slightly more efficient than strawberry for the taste-masking.

Using the electronic tongue testing method, a number of candidate formulations could be investigated rapidly. It could be determined that the best masking is achieved with excipient A and pear flavour. In that case, this instrumental technique helps significantly improve the taste of oral forms without any safety concerns linked to human testing. Selection of the Best Flavour Candidate for a Stable Masking of Active Principle Bitterness Over Time In order to mask the bitterness of an active principle in a liquid oral form, four flavours (strawberry, pineapple, fruit mix 1, fruit mix 2) are tested. The objective is to determine which of the four candidates offers the best combination of masking efficiency and sensory stability over time. The method consists of taste and aroma assessment. To quantify the taste-masking power, several active formulations and corresponding

Four formulations of an analgesic syrup containing two different excipients (A and B) combined with two flavouring agents (strawberry and pear) were tested. Taste evaluation was done using the ASTREE Electronic Tongue (Alpha MOS, France). Upon mapping the e-tongue measurements computed by principal components analysis (Figure 1: Taste map of the different active formulations and corresponding placebos), a clear difference of taste is observed between active and placebo formulations.

Figure 2: Distance between each formulation and its corresponding placebo

placebo were analysed. Taste analysis was performed with ASTREE Electronic Tongue.

Figure 1: Taste map of the different active formulations and corresponding placebos 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To evaluate flavours’ stability over time, the different formulations were analysed right after preparation and after one month of storage under stressed conditions. Both taste and aroma stability were quantified using, respectively, the electronic tongue and HERACLES electronic nose based on fast gas chromatography, that gave additional information on the chemical composition. Autumn 2017 Volume 9 Issue 3

Drug Discovery, Development & Delivery In terms of taste masking, the three flavoured formulations proved to significantly improve the masking of the active principle bitterness, compared with the unflavoured formulation (Figure 3: Distance between each formulation and its corresponding placebo – Quantification of the taste masking improvement). The two fruit mix formulations showed a similar masking power, better than the one of strawberry formulation.

e-nose showed that, in strawberry, new chemical components appeared over time, whereas the change of aroma of the other flavours mainly corresponded to a loss of intensity. Using the e-tongue and e-nose, it was possible to rapidly screen various formulations and reliably select the flavour (fruit mix 2) that efficiently and durably masked the medicine bitterness. The objective of this study was to investigate the optimal formulation of placebo in order to best match the taste of the real medicine.

Figure 3: Distance between each formulation and its corresponding placebo – Quantification of the taste masking improvement

To quantify the change in taste and aroma over time, the distances between each fresh and aged formulation were calculated with e-nose and e-tongue data (Figure 4: Distance between each fresh formulation and the corresponding aged formulation, based on odour measurement (left) and taste measurement (right)).

Taste-matching Optimisation of a Placebo for Clinical Trials In double blind clinical trials, patients receive either an active formulation or a placebo without knowing what they get. To guarantee the reliability of the tests, it is important that active and placebo formulations have a similar taste so that this parameter will not influence the patients’ evaluation.

Figure 4: Distance between each fresh formulation and the corresponding aged formulation, based on odour measurement (left) and taste measurement (right)

Six placebo formulations were prepared by adding two different bitter compounds (sodium benzoate and caffeine) at three distinct concentrations for each substance. For taste comparison purposes, a placebo without bitter compound and two active formulations (corresponding to two dosages: 500 mg and 1 g of active principle) were also prepared. Taste evaluation was performed using the ASTREE Electronic Tongue. In s t r u m e nt a l re s u lt s we re plotted on a principal components analysis (Figure 5: Taste map of all formulations) in order to visualise the taste map of all placebo and active formulations. This map shows the relative distribution and proximity of samples in terms of taste. The various formulations are clearly differentiated. Placebos containing sodium benzoate seem to be closer and to better match the active references, especially the active formulation with 1 mg of API.

It appeared that the strawberry formulation showed the most important change in taste and the lowest in aroma. Conversely, fruit mix 1 contributes to the highest change in aroma, but the lowest in taste. Finally, fruit mix 2, with relatively low distances for aroma and taste, is the most stable over time. The analysis of the chemical composition with the GC-based

Figure 5: Taste map of all formulations INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Drug Discovery, Development & Delivery To quantify the taste differences and similarities between bitter placebo formulations and the medicine, the Euclidian distance between each bitter placebo and the active medicine was calculated (Figure 6: Distance between active medicine and each placebo formulation). The shorter the distance, the higher the taste-matching. Similarly, the lower the discrimination index, the lower the taste difference.

Odour and taste evaluation were conducted respectively with the HERACLES electronic nose (headspace mode) and the ASTREE electronic tongue (liquid analysis). Instrumental measurements were processed using principal components analysis (PCA, Figure 7: Odour map of all medicines obtained with HERACLES Electronic Nose & Figure 8: Taste map of all medicines

Figure 6: Distance between active medicine and each placebo formulation

Based on the ASTREE Electronic Tongue measurements, it appears that for the two active dosages (500 mg and 1g), the lowest distance and discrimination index are obtained with the placebo containing 0.05 mg/mL of caffeine. The placebo formulation containing 0.05 mg/mL of caffeine is the best match to both active medicines.

obtained with ASTREE Electronic Tongue). These graphics allow one to compare the overall odour and taste of the different medicines.

Both e-nose and e-tongue analyses showed first that the brand drug and the generic have different odour and taste. And within the group of generic samples, both the ones having received a patient complaint and the aged ones prove to have significantly different odour and taste, compared with the fresh good generic. Using the Kovats index method on HERACLES e-nose measurements, it was possible to investigate the nature of the main volatile compounds detected in the headspace of active formulations. It could be observed that the complaints on the bad tablets could be due to an important presence of acetic acid and maltol, compared with other tablets. The combined use of the two sensory analysis instruments allowed rapid comparison of the odour and taste profile of various tablets and to identify the cause of defect in some products, without incurring health risks linked with human testing.

The taste of pharmaceutical formulations containing different bitter compounds at various concentrations could be rapidly tested using the ASTREE E-Tongue instrument. The study proves that it is possible to safely develop a taste-matching placebo for consistent and reliable clinical trials.

Figure 7: Odour map of all medicines obtained with HERACLES Electronic Nose

Identification of the Causes of Off-flavour in Generic Tablets In this study, the aim is to investigate the possible causes of off-odours and off-taste in generic tablets for which the producer received complaints from patients. The sensory stability of these tablets was also followed up over time. The set of samples included: the brand medicine (B), a generic (G) considered as good and non-aged, four samples of the generic, having received claims (GC1 to GC4) and three aged batches of the generic tablets (GA1 to GA3).

Figure 8: Taste map of all medicines obtained with ASTREE Electronic Tongue


Autumn 2017 Volume 9 Issue 3

Drug Discovery, Development & Delivery Conclusion Organoleptic properties deeply influence the drugs’ success. Unfortunately, hazardous, long and expensive tests can sometimes limit taste evaluation in the early stages of product development. As an alternative, the e-tongue can provide a technically suitable and cost-effective method for screening a large number of formulations and directing early formulation activities, while eliminating both safety concerns and subjective bias.

Fatma Ayouni Fatma AYOUNI joined Alpha MOS 11 years ago. She starts at Alpha MOS laboratory as an application specialist, developing analytical projects for customers, and moved to technical and application support for 3 years. She integrates the sales department end of 2016. She has an engineering background in analytics, specialized in quality and food safety, and good skills on chromatography and sensory analysis. Specialized in electronic sensing systems with more than 20 years of experience Alpha MOS company positions as the world leader in the design and development of instruments dedicated to odour, taste and visual aspect (color and shape) analysis.

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Drug Discovery, Development & Delivery

Reducing Drug Discovery Timelines When Using Mouse Models With the drug discovery timeline exceptionally long and late-stage failure rates very high, there is tremendous pressure to reduce the discovery timeframe and bring effective therapies to market sooner. How investigators approach studies that use lab animal models can directly impact those goals. Creative approaches to rodent model generation and breeding can significantly reduce the associated timeline, while ensuring the timely availability of the high-quality models upon which drug discovery depends.

In Search of Speed Lab animals, particularly mouse models, are critical tools at multiple stages of the drug discovery process. During target validation, investigators might use a mouse model in which the gene of interest is deleted or over-expressed to assess the effects and to explore whether modulation of the gene can impact the disease state. During pre-clinical development, animal models are the tool of choice for testing drug safety and efficacy. Often, these models are customised to suit the study objective. For instance, a mouse gene may be replaced with its human counterpart to more closely mimic the disease state. But while customised models can provide greater precision and translatability, the model generation and breeding process can be lengthy. With pressure to reduce timelines and costs, investigators have a strong interest in shortening this process where possible. A variety of approaches may be considered when attempting to reduce the model generation timeline, some of which have limitations or undesired consequences. Waiting until after a target has been validated before generating the model may seem prudent because it increases the odds the model will be relevant; yet, the downside is a significant time lag – upwards of a year in some cases. There may be pressure to generate multiple models prior 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to target validation and hope one proves a suitable match; yet, that may or may not save time, certainly will not save money, and is not in keeping with the 3Rs philosophy of reducing animal use. Some labs may attempt to speed the genetic modification process itself, but that often involves reducing the level of quality control applied. As a result, the time gained typically comes at the price of increased risk of introducing unwanted genetic modifications, which can yield confusing data and erroneous conclusions. It can also lead to the need to remake the model, greatly extending the timeline. For the drug discovery timeline to be accelerated effectively, it also must be done prudently to avoid unwanted or undesirable consequences. When using mice for drug discovery, the model and cohort generation processes can be accelerated in ways that do not sacrifice quality or waste resources. In fact, it is possible to cut as much as four months from the total timeline for model and cohort development in certain cases. The key lies in leveraging well-established and widely available techniques while retaining stringent controls. A look at the traditional approach to model generation and breeding, and a feasible alternative, illustrates the advantages to be gained. The Traditional Approach At its most basic level, genetically engineered mouse model development involves first introducing the desired modification into the mouse genome, then producing founder animals and expanding the colony to a size that is useful for scientific studies. Genome modification can be accomplished via traditional techniques such as homologous recombination in embryonic stem (ES) cells, or newer gene editing techniques such as CRISPR/Cas9. Once the genome is modified, chimeras or founder mice are bred to wild-type mice to generate a few animals that carry the

desired genetic mutation. These mice are then bred to expand the colony and generate an appropriately sized cohort for study use. The associated timeline depends on the genome modification technique utilised, as well as the number of animals generated in the first phase, size of the cohort, and required genotype. On average, a model generation and breeding project using ES cells may take 40–42 weeks to produce germlinetransmitted heterozygous mice, while a project using CRISPR in embryos may require only 24 weeks. While this reduction in time alone might suggest that CRISPR in embryos should be used to speed all custom model generation projects, the size and complexity of the modification impacts whether CRISPR is the most effective technique. For simple genome modifications, such as knockouts, small knock-ins, or point mutations, CRISPR in embryos is often a very effective way to speed model generation. However, as the modification desired increases in length and/or complexity, the cost and effort increase greatly and any time savings may be eroded. For those reasons, more complex genome modifications tend to require the use of ES cell-based targeting. As Figure 1 illustrates, the timeline for ES cell-based genome modification, generation of chimeras, and production of a few heterozygous mice averages 42 weeks. To reach an appropriately sized experimental cohort of homozygous mice may take an additional 28 weeks of breeding, bringing the total timeline to 70 weeks. In some cases, that timeline may not match the desired schedule for the study, nor the overarching desire to accelerate drug discovery and obtain important data – and answers – sooner. When complex genome modifications are required, and a more Autumn 2017 Volume 9 Issue 3

Drug Discovery, Development & Delivery coat colour typically are selected to move forward as breeders. Though this approach is commonly used, it has limitations that impact its effectiveness. In some instances, mice with the desired coat colour actually have a low percentage of the modified allele, and vice versa. When this occurs, it may not be discovered until after multiple rounds of breeding. As a result, time and budget dollars are lost to rounds of breeding that have not achieved the desired results quickly.

rapid timeline to experimental cohort is desired, it is possible to accelerate the process without sacrificing quality control by using two well-established techniques: molecular analysis of sperm and in vitro fertilisation (IVF). As Figure 2 illustrates, use of these methods makes it possible to arrive at a study-sized cohort of mice with the required genetic modifications while reducing the timeline by 12-16 weeks on average. In turn, investigators can get research studies underway sooner, obtain faster answers to inform key strategic decisions about future resource use, and reduce the drug discovery timeline and associated costs.

The Value of Molecular Analysis of Sperm Molecular analysis can help speed delivery of an experimental cohort by identifying the male mice best suited to move forward as breeders. Using ES cell-based targeting for the genome modification step, the ES cells are first manipulated in culture to achieve the desired mutation,

then injected into blastocyst-stage embryos (at approximately 3½ days post-fertilisation). The objective is for these ES cells to become integrated into the developing embryo and become germ cells so that the genetic modification is transmitted to the next generation. The injected embryos become mice that are known as chimeras – organisms with multiple, genetically distinct cell lineages. Typically, if the embryos used for injection are derived from mice with a certain coat colour (e.g., white), then the ES cells will be derived from mice with a different coat colour (e.g., black). The chimera’s resulting coat

colour – a mix of black and white – is traditionally viewed as a good visual indication of the percentage of germ cells derived from the ES cells. With the ES cells taken from a black mouse, widespread patches of black coat are seen as indicative of a high uptake of the ES cells in the chimeras. In turn, the chimeras with the greatest percentage of the black

Molecular analysis of sperm can help avoid this potential delay by providing a more accurate and rational method for selecting male chimeras for breeding. Sperm from the male chimeras can be analysed (e.g., by quantitative PCR) to determine the percentage of cells that carry the altered allele. Rather than rely on coat colour as a surrogate indicator, this analytical approach gives a direct measure of a chimera’s appropriateness for breeding to most quickly attain the desired genotype in the study cohort. In addition, the harvested sperm can be analysed to assess the donor’s fertility potential, another important factor when selecting the most appropriate breeders. By obtaining this information before breeding begins, the investigator can move forward with greater confidence that the resulting cohort will meet the study’s needs. Arriving at Study-sized Cohorts Rapidly Once the most useful chimeras for breeding have been selected via molecular analysis, the use of IVF enables the production of study-sized cohorts to occur at an accelerated pace. The selected male’s sperm can be used to simultaneously fertilise hundreds of oocytes, generating a large number of offspring faster than is possible through natural mating. This approach makes it possible to greatly scale up the offspring output to a cohort size required for the study, on a shorter timeline. In addition to accelerating the time to cohort, IVF can yield several other advantages that reduce INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Drug Discovery, Development & Delivery timelines and afford flexibility. Since IVF progresses on a more predictable timeline than natural mating, it allows investigators to plan for their studies more effectively. Because multiple rounds of chimera breeding can be skipped, the total time to arrive at a suitable cohort size can be reduced by three to four months. IVF also offers the flexibility to breed animals at whichever health status the investigator deems preferable for a given study; in some instances, a highly restrictive health status, even a germ-free status, may be required. Another important component of this strategy is the production of chimeric males that lack a selectable marker cassette, thus obviating the need to mate the genetically modified mice to a recombinase-expressing mouse line and the addition of an extra breeding generation. This can be accomplished in a number of different ways, including: in vitro deletion of a standard selection cassette in ES cells by recombinase transfection, in vivo deletion in the male germ line using self-excising selection cassettes, or by performing CRISPR in ES cells. The use of CRISPR in ES cells simplifies vector construction, and because of the relatively high efficiency of genome modification and ability to screen multiple clones, the vector does not need to contain a selectable marker. Real-world Results By combining molecular analysis for chimera selection and IVF for rapid cohort expansion, it is possible to obtain a cohort of the necessary size much faster than with traditional techniques. Data from two real-world custom model generation projects, both employing CRISPR in ES cells, demonstrated the ability of this approach to ensure selection of the breeders with the highest percentage of modified allele, thereby avoiding the time and expense of potentially unproductive rounds of breeding. Both projects illustrated that while coat colour is traditionally used in the selection of the most appropriate breeders, it is not always an accurate indicator of germline transmission. In the first project (Figure 3), chimera #1 had nearly 80 per cent 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

desired coat colour, yet only about 15 per cent of the sperm had the modified allele as determined by molecular analysis. While visual inspection alone would have identified chimera #1 as a good choice for breeding, after several rounds of breeding it would have been determined that, in fact, this male was a poor choice. Similarly, chimera #3 did not have a strong correlation between coat colour and percentage of sperm carrying the modified allele. Cryopreserved sperm from chimera # 2 was used in an IVF with oocytes derived from wild-type females. All 76 of the pups born in project 1 were black, indicating 100% germ line transmission of the ES cells. Genotyping revealed that all 76 pups were heterozygotes, which was expected because the original ES cell clone was homozygous for the genetic modification. A second project, also illustrated in Figure 3, yielded similar results. Based on coat colour alone, chimeras #1 and/or #4 would have been selected for breeding; however, molecular analysis revealed that chimera #4 would be the better choice. Moreover, chimeras #3 and #6 would likely not have been considered for breeding, but molecular analysis showed that both chimeras would be reasonable choices. Cryopreserved sperm from chimera #2 was used in an IVF with oocytes derived from wild-type females. Sperm from chimera #2 was chosen over chimera #4 because it was determined that the sperm from chimera #2 had a significantly higher fertility rate (71%

vs. 53%). All 79 pups born as a result of this IVF were black, indicating 100% germ line transmission of the ES cells. Because the original ES cell clone was heterozygous for the genetic modification, it was expected that 39 of the 79 offspring would be heterozygotes. Of the 72 mice genotyped, 34 (or 47%) were heterozygous, which was consistent with expectations. The use of molecular analysis for selection of the most appropriate breeders, combined with IVF for rapid expansion to the necessary cohort size, has proven a highly rational and accurate strategy for approaching mouse model generation and breeding when genome modifications are accomplished using ES cells. By leveraging these well-established techniques, investigators can move forward with pre-clinical studies sooner, obtain the information needed for strategic decisionmaking faster, and reduce both the timeline and associated costs of drug discovery.Ac ortuis cre pra viderte in tus Cat, pere faciam ima, ia ad

Kenneth Albrecht, PhD, is scientific programme manager, Taconic Biosciences and an adjunct assistant professor at Boston University School of Medicine. He has authored or co-authored over 25 scientific publications and has been engaged in mouse model generation and characterisation for almost 25 years. Email:

Autumn 2017 Volume 9 Issue 3

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Drug Discovery, Development & Delivery

Using Intelligent Design to Deliver Safe Preservative-free Multidose Eye-drops A significant patient population requires the long-term use of eye-drops multiple times a day. Maintaining the sterility of eye-drops is important for patient health. Single-use doses are expensive and preservatives can cause allergies and irritation, but the intelligent design of multidose bottles provides a viable means of delivering safe, preservative-free eye-drops.

Patients Need Sterile Eye-drops The topical administration of drops is an efficient and common delivery method for medicines to the eye. Patients who have undergone eye surgery need to self-administer eye-drops to prevent or treat infections and inflammation in the weeks after surgery. A significant patient population has conditions that require the long-term daily use of eye-drops. For example, dry eye syndrome is associated with aging, contact lens use and environmental factors such as windy or sunny weather. It affects an estimated 5% of over 50s in the USA1 and is usually managed using an artificial tear solution which needs to be applied up to four to six times a day, often for the rest of the patient’s life. Conditions such as hay fever and glaucoma also require the long-term use of self-administered eye-drops. It is important that all eye-drops are kept free from bacteria. The microbial contamination of eye-drops is a significant risk factor in the development of bacterial keratitis2. Post-operative patients are at particular risk of infection, as are patients who have used topical steroids, since they lower the ocular defences3. Preservative-free Formulations are Better for Patient Health One way of keeping multidose eye-droppers safe for patients is to add preservatives to the formulation. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

However, the use of preservatives can cause allergies or ocular irritation, and some can even cause a toxic response, damaging patients’ eyes 4. Any such reactions are particular issues for patients who rely on the long-term use of eye-drops for chronic conditions. In 2009 the European Medical Agency stated that the ‘inclusion of antimicrobial preservatives or antioxidants in a finished product needs special justification.’ Even when preservatives are tolerated in an adult population, there are still questions over tolerance for the paediatric population. The EMA have stopped short of a general recommendation not to use preservatives in eye-drops, but they recommend that, ‘preservative f re e fo r m u l at i o n s w h e n ev e r possible should be considered’ and that ‘ophthalmic preparations without preservatives are strongly recommended for use in paediatric patients, especially neonates’. They also noted that ‘it is nearly always technically possible to re-think the product development to remove [preservatives] or minimise their use’ 5. Preservative-free Unidoses are Effective but Expensive Unidose eye-droppers are a commonly used delivery method for preservative-free eye-drops. By virtue of being single-use, there is no opportunity for bacterial contamination at the point of use. Unidoses are ideal for clinical settings, especially during surgery. However, they are too costly and inconveniently bulky to make them suitable for home use for chronic conditions. Single-unit preservativefree drops have been calculated to be 1169% more expensive to produce than the equivalent preserved eye-drops in a multidose bottle6.

Intelligent Design for Preservativefree Multidoses The alternative way to keep eyedroppers clean is by the intelligent use of technology. Rather than relying on the anti-microbial properties of preservatives to kill any bacteria that enter the bottle, the ideal approach is to prevent any entry of bacteria into the bottle in the first place. Multidose bottles dispense drops using either a non-return valve or a filtering system. Most commercially available bottles designed for multidose preservativefree eye-drops rely on a filtering system to stop the entry of bacteria. When a drop is dispensed, the volume of the dose is compensated by air. Eye-drops can become contaminated in two main ways: by contaminated air entering the device or by contaminated liquid re-entering through the filter. Filtering Out the Bacteria? Anti-microbial filters are typically made of a nylon fibre membrane that consists of tightly-packed layers of strands of nylon fibres (Figure 1). Filters work on the mechanical principle that bacteria are large molecules that do not fit through the very small holes, while air and non-viscous solutions are able to pass through without hindrance.

Figure 1: A scanning electron micrograph of a nylon membrane filter (pore size 0.22 μm). Autumn 2017 Volume 9 Issue 3

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Drug Discovery, Development & Delivery 0.22 μm sterile filters are industry standards, but their effectiveness as bacterial filters has been challenged in the literature. Unfortunately, it has been found that bacteria are capable of routinely penetrating 0.22 μm filters, even when the molecules seem to be too big to fit through the holes. In the 2002 paper ‘Big bacteria pass through very small holes’7, Wainwright et al. found that ‘common, potentially pathogenic, bacteria (which are nominally larger than 0.2 μm) can cross a 0.2 μm nylon membrane. All of the bacteria crossed from the upper membrane surface to the solid medium below the membrane; this ability was highly repeatable and did not depend on the make of membrane used. Bacteria growing below the membrane exhibited normal size and morphology.’ In 2010, Onyango et al. 8 noted that, ‘the assumption that filters with pore sizes ≤ 0.45 μm can retain bacterial populations has repeatedly been disproved with the observation of regular passage of cells through 0.45 μm, 0.22 μm and even 0.1 μm sterile filters.’ Their findings showed that ‘staphylococcal bacteria were capable of passing through sterile filters in a viable state.’ Even where filters are shown to be effective, the filtered bacteria clearly remain on the filter. A 2006 study on the efficacy of single-use bacterial filters showed ‘a significantly greater bacterial growth on the proximal side of the filter compared with the distal side’9. Eye-drop filters act in two directions: pressure on the sides of the plastic bottle dispenses a dose through the filter to the patient’s eye; when the pressure is released, air and a small amount of liquid passes back through the filter and into the bottle. Therefore, bacterial growth on the filter represents a contamination risk for the delivered dose. What Makes Filters Unreliable? The evidence that bacteria can pass through 0.2 μm filters is clear, but the reasons are not obvious. One possibility for the observed passage of bacteria through filters 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

could be due to the nature of the material of the filters. The sponge-like structure includes holes of varying sizes (Figure 2), some of which are statistically likely to be larger than 0.2 μm. In fact, one study found that 0.2 μm filters have a distribution of pore sizes that includes some as big as 0.5 μm10.

Figure 2: A scanning electron micrograph of a Millipore membrane filter (pore size 0.22 μm) showing a distribution of pore sizes12. The bar in the bottom right hand corner of the image is 1 μm long.

Individual testing would eliminate doubt over the viability of each filter, but the process used to test filters is destructive11. The testing method introduces bacteria and liquid onto the surface of the filter. This starts bacterial growth on the filter and therefore decreases the subsequent shelf-life of the dispenser. Therefore, in-line testing of multidose dispensers that rely on filter technology is not possible. Instead, testing is carried out statistically on only a proportion of the dispensers. However, it is likely that larger holes in the filters is not the sole mechanism of bacterial penetration. Hasegawa et al.12 found that the bacteria, ‘P. aeruginosa passed through a 0.22 μm pore size filter. The membranes which allowed passing-through of bacteria showed normal bubble point values in the integrity test.’ This demonstrates that bacteria are still capable of passing through a reliable 0.22 μm pore size filter. Onyango et al.’s study8 refers to the finding of 0.5 μm holes in a 0.2 μm filter10, but notes that this, ‘is highly unlikely the reason for the observed result in our study.’ Instead, they point to bacterial motility as a major factor in filter penetration. Bacterial Motility is a Cause of Filter Penetration Bacteria come in a variety of shapes

and sizes, but many of them share the ability to self-propel by twitching, rotating or gliding. Twitching is the most common form of motility and is achieved through movement of the flagella in a way that makes the bacteria appear to swim. Studies have shown that this motility enables bacteria to move through very small channels relative to their size. Hasegawa et al.12 demonstrated that P. aeruginosa were able to pass through a reliable 0.22 μm pore size filter. They then experimented with a strain of the bacteria P. aeruginosa that was defective in twitching motility, and found that it was unable to pass through the 0.22 μm filter. They concluded that it is the flagellum-dependent motility of P. aeruginosa that enabled it to penetrate fine filters. In their 2009 paper, Männik et al.13 set out to establish how the relatively large Escherichia coli and Bacillus subtilis bacteria can move in very narrow channels. They found that ‘both E. coli and B. subtilis are motile in channels which only marginally exceed their diameters (by ~30%).’ Bacteria Also Penetrate by Growth and Division Männik et al.13 went on to find that E. coli bacteria lose their ability to swim in channels narrower than their diameter. Surprisingly, they found that, despite this, they are still able to penetrate narrow channels. They observed that over time, through the mechanism of growth and division, E. coli bacteria were able to penetrate filter channels ‘with a width that is smaller than their diameter by a factor of approximately 2. Within these channels, bacteria are considerably squeezed but they still grow and divide.’ This has clear implications for the effectiveness of filters for multidose preservative-free eye-droppers. Filtering liquid several times a day means that the filter remains wet throughout the usable lifetime of the device, presenting ideal conditions for bacterial growth. Autumn 2017 Volume 9 Issue 3

Drug Discovery, Development & Delivery An Alternative to Filters Based on Silicone A viable alternative to the use of sterile filters for multidose preservativefree eye-droppers is a non-return valve system used in conjunction with a silicone membrane to prevent contamination ingress into the system (Figure 3). The one-way valve ensures that no contaminated liquid can be re-introduced to the bottle after the drop has been dispensed, completely removing the need to filter the liquid. The intake of air into the dispenser takes place via a separate venting system with a silicone membrane, called PureFlow® technology.

provides an even greater assurance of safety for the patients. Different specific tests have also been designed to challenge the non-return valve and the silicone membrane, which are the key components that ensure the content’s sterility: Non-return valve integrity test (Figure 4) •  Goal: Demonstrate the ability of the one-way valve to prevent microorganisms from entering the bulk solution even after severe misuse. •  Method: 50 drops dispensed into air and then the tip of the TSB

Venting hole integrity test •  Goal: Demonstrate the ability of the silicone membrane to protect contents against microbial ingress, even after severe misuse. •  Method: 50 drops dispensed into air from TSB filled bottle and then a contaminated solution is placed in the venting hole to sit in contact with the silicone membrane for two hours. •  Result: No cloudiness/contamination observed in the content. > PureFlow technology protects the finished product against micro-organisms.

Figure 5: Venting hole integrity test

Figure 3: The system uses a non-return valve that removes the need to filter the liquid. This makes it possible to use a silicone membrane to filter the air.

The principle of PureFlow technology is that air diffuses through the membrane in order to enter into the bottle and compensate the negative pressure inside. The diffusion of gas molecules through the silicone membrane is a slow process in which the gas molecules migrate from free volume to free volume (permeability). Therefore, PureFlow technology isolates the solution from the external environment and maintains its sterility. The separation of the dose delivery from the venting system means that the membrane is kept dry. This minimises the risk of bacterial growth on the surface of the membrane, and also means that the testing process is non-destructive. In fact, devices that use this technology can be tested individually in-line as a consistent part of the manufacturing process to ensure robust quality standards. This

(tryptic soy broth, a very nutritive solution) filled bottle is dipped into a contaminated solution and left immersed for several days. •  Result: No cloudiness/contamination observed in the content.

> The non-return valve avoids any contamination of the content by preventing liquid back-flow.

Figure 4: Non-return valve integrity test

A non-return valve combined with a silicone membrane venting system demonstrates how intelligent design can be used to prevent the entry of bacteria into a bottle, making it possible to deliver safe, multidose, preservative-free eye-drops. As such, PureFlow® technology provides a safer alternative to filters as all the critical components linked to the sterility of the device are 100% controlled online by air testing, ensuring that each single device released is safe for use by patients. REFERENCES 1. In the US an estimated 3.2 million women age 50 and over and 1.68 million men age 50 and over are affected by dry eye syndrome: a. Schaumberg D A, Sullivan D A, Buring J E, Dana M R, Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003; 136:318-26. b. Schaumberg D A, Dana R, Buring J E, Sullivan D A, Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Arch Ophthalmol. 2009; 127:763-8. 2. a. Templeton W C, 3rd, Eiferman R A, Snyder J W. et al Erratia INTERNATIONAL PHARMACEUTICAL INDUSTRY 49

Drug Discovery, Development & Delivery keratitis transmitted by contaminated eyedroppers. Am J Ophthalmol 1982 93723–726.726 [PubMed] b. McCulloch J C, Origin and pathogenicity of Pyocyanea in conjunctival sac. Arch Ophthalmol 1943; 29:924-36. c. Hogan M J, The preparation and sterilization of ophthalmic solutions. Calif Med 1949; 71:414-6. d. Theodore F H, Contamination of eye solutions. Am J Ophthalmol 1951; 34: 1764. e. Theodore F H, Practical suggestions for the preparation and maintenance of sterile ophthalmic solutions. Am J Ophthalmol 1952;35:656-9. f. Vaugh D G, Jr, The contamination of fluorescein solutions with special reference to Pseudomonas aeruginosa (Bacillus pyocyaneus). Am J Ophthalmol 1955;39:55-61. 3. Rahman M Q, Tejwani D, Wilson J A, Butcher I, and Ramaesh K, Microbial contamination of preservative free eye drops in multiple application containers,

Br J Ophthalmol. 2006 Feb; 90(2): 139–141. 4. Report of the International Dry Eye Workshop. Ocul Surf 2007; 5[2]; 65-204. 5. EMEA Public Statement on Antimicrobial Preservatives in Ophthalmic Preparations for Human Use (Doc. Ref.: EMEA/622721/2009). http:// en_GB/document_library/ Presentation/2010/09/ WC500096784.pdf 6. Hertel F, Pfeiffer N, Einzeldosisapplikationen in der Glaukomtherapie. Vergleich der Kosten mit Mehrdosis. Ophthalmologe 1994; 91:602-5. 7. Wainwright M, Al Talhi A, Gilmour D J, Anderson R W, Killham K, Big bacteria pass through very small holes, June 2002 Volume 58, Issue 6, Pages 558–560. 8. Onyango L A, Dunstan R H, Roberts T K, Filterability of staphylococcal species through membrane filters following application of stressors, BMC Research Notes 2010, 3:152. 9. Unstead M, Stearn M D, Cramer

Lilia Petit Ben Saidane Program Manager, Lilia Petit Ben Saidane is Program Manager at Nemera in charge of various product development projects including the development of Nemera’s proprietary preservative free multi-dose ophthalmic platform. Lilia joined the company in 2013. In her previous career Lilia worked as a Program Manager in various companies and organizations including Schneider Electrics, Eurocopter, Renault and the French Red Cross. Lilia holds a Master in Industrial Engineering from Grenoble Industrial Engineering & Management School as well as a Masters in Humanitarian Project Management from Bioforce Development Institute Lyon. Lilia is also a trainer in project management.

D Chadwick M V, Wilson R, An audit into the efficiency of single use bacterial/viral filters for the prevention of equipment contamination during lung function assessment. Respir Med 2006; 100: 946–950. 10.Osumi M, Yamada N, Toya M, Bacterial retention mechanisms of membrane filters. PDA J Pharm Sci Technol 1996, 50:30-34. 11.Benezech T, A method for assessing the bacterial retention ability of hydrophobic membrane filters, Trends in Food Science & Technology 12 (2001) 36–38. 12.Hasegawa H, Naganuma K, Nakagawa Y, Matsuyama T, Membrane filter (pore size, 0.22-0.45 μm; thickness, 150 μm) passing-through activity of Pseudomonas aeruginosa and other bacterial species with indigenous infiltration ability, FEMS Microbiology Letters 223 (2003) 41-46. 13.Männik J, Driessen R, Galajda P, Keymer J E, Dekker C, Bacterial growth and motility in submicron constrictions, PNAS, 2009, 106: 35 14861–14866.

Benjamin Quaglia Senior Design Engineer. Benjamin Quaglia graduated as a Material Engineer from INSA in Lyon, France. In 2011, he joined Rexam. More recently the 4 drug delivery devices plants of Rexam, including the Innovation Centre became Nemera. Today, Benjamin is a Medical Device developer engineer focused in the development of ophthalmic and inhaler drug delivery devices. He developed for Nemera own IP products including Novelia® as well as working on customer inhaler product developments. Email: benjamin.quaglia@

Email: lilia.petit-bensaidane@


Autumn 2017 Volume 9 Issue 3



dermal/ transdermal



nasal/ buccal/ auricular

Nemera always puts patients first, providing the most comprehensive range of devices in the industry, including off-the-shelf innovative systems, customized design development and contract manufacturing. 06 54 • • Phone: +33 (0)4 74 94INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Clinical Research

Redefining the Art of Patient and Stakeholder Engagement in Rare Disease Clinical Research According to the US Orphan Drug Act, a rare disease is one that affects fewer than 200,000 people1. In EU countries, any disease affecting fewer than five people in 10,000 is considered rare2. Currently, there are an estimated 5000 to 8000 diseases affecting 400 million people worldwide with conditions including cystic fibrosis, Duchenne muscular dystrophy, sickle cell disease and haemophilia B3. An array of therapeutic interventions are being evaluated across the spectrum of these disorders.

Because of the rarity, heterogeneity and the complex patient management associated with rare conditions, creating a pharmaceutical development programme for the treatment of one of these diseases is challenging. It almost goes without saying that the industry cannot approach trials in the same manner as studies for drugs in other disease areas, which have well-established and highly-codified development pathways. From patient recruitment and retention to protocol design and regulatory approach, careful, strategic planning is critical to a study’s success. Here, Worldwide Clinical Trials Executive Director of Project Management and Rare Disease Franchise Lead, Leslie Wetherell, explores the importance of patient and stakeholder engagement in rare disease clinical research, including the crucial role patients and their care network should have in supporting protocol development as well as the part stakeholders can play in ensuring positive outcomes. Understanding Unique Patient Populations When embarking on a rare disease clinical trial, it is crucial for researchers to truly understand the patients and their unique situation before the protocol is designed. In essence, the task requires developing 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

an appreciation for the experience of the disease (the illness) from the perspective of family and patients. Patients with a rare disease are likely to have waited a considerable time for a diagnosis. In a survey collaboration with 70 European rare disease organisations (EurordisCare2), several aspects concerning diagnosis were compared for eight rare diseases in 16 European countries (5980 patients). Important findings were that 25% of patients had to wait between five and 30 years from early symptoms to confirmatory diagnosis of their disease. Moreover, before receiving a confirmatory diagnosis, 40% of patients first received an erroneous diagnosis that subsequently led to medical interventions (surgery, medicinal treatment or psychological care). Those with a confirmed diagnosis are, in the majority of cases and at the very least, facing a reduced quality of life either immediately or later in life, and in many cases a reduced life expectancy. Despite being faced with such challenges due to the rarity of these conditions, patients often confront a lack of available information or resources. This means that patients and those in their family and social network often have to act as their own researcher and to advocate for their own care. Depending on where they live and the rarity of their condition, patients can sometimes find it difficult to receive appropriate medical care. In some cases, there are no treatment options available to them, with the exception of supportive therapy. All of these challenges mean that rare disease sufferers are typically under a great deal of emotional pressure, not to mention financial burden in terms of finding and funding treatment, and therefore may be wary – or equally very passionate – about participating in interventional clinical research. Because of this,

patient recruitment into prospective studies and retention following enrolment are two of the most daunting challenges in rare disease drug development. Patient-focused Engagement Patient populations for rare drug trials are naturally much smaller than other drug trials, meaning every single patient's participation is vitally important. Once patients are recruited, sponsors must make the study experience as smooth as possible and, where practical, reduce the burden on the patient and caregiver throughout the trial, from initial design through to completion, in order to retain them for the duration of the study. As previously mentioned, sufferers of rare diseases and their caregivers are typically well-informed about their condition and know the disease and the latest research on it better than anyone else. If they do not buy in to what the team is trying to achieve with the study, or the suggested approach, then there is little hope of recruiting the patient. With that in mind, researchers should view potential patients and their caregivers as valuable assets from the initial stages of protocol development and utilise the crucial insights they have to offer. They can provide an unrivalled perspective and understanding on what it is like to actually live with a particular condition. The results of this first-person feedback can often be very different from insights gained via secondary research. Researchers can then use this primary information to design a study compatible with a patient’s lifestyle and define a robust patient engagement strategy, tailoring the programme to the patient’s needs and around their lives. In all cases, conducting research as close as possible to where the patients are based will minimise Autumn 2017 Volume 9 Issue 3

Clinical Research disruption to their everyday lives and therefore increase chances of long-term participation. If a patient will need to spend considerable time travelling to site visits, researchers should provide accommodation and transport. Once the study is underway, patients’ voices should be routinely solicited to ensure the outcomes that matter most to them are continuing to be met, and to avoid any costly dropouts. Designing and executing a trial which is effective the first time, and delivers high recruitment and retention levels, is crucial with rare disease studies. Small patient populations mean there is little opportunity to make and learn from mistakes. If patients drop out, researchers will lose their chance – there is not a back-up ‘pool’ of participants waiting and willing to take part. Researchers must also proactively plan for a long-term commitment to the patient – from the planning stage and during the study, through to post-launch – and communicate this to them. Demonstrating this commitment will ensure the patient

feels valued and that their health outcomes are at the centre of the trial, in turn supporting compliance and retention. Outreach, Support and Engagement Tactics In addition to engaging with patients, meeting the needs of many other stakeholders is also critical with rare disease studies, potentially more so than in any other clinical programme. Given the multiple organ systems frequently affected by many rare diseases, these could include patient advocacy groups, specialised doctors and physicians, nurses and rehabilitation staff, and sites and clinics. By proactively engaging all stakeholders at the earliest time possible and maintaining these relationships throughout the study process, researchers can help to ensure that everyone feels part of the study and that they are adding value to the protocol. Fostering this collaborative approach from the outset will not only facilitate recruitment but also support retention and add commercial value long term.

Physicians, sites and clinics can play a key role in patient engagement for rare disease studies. Typically, they have access to patient databases and can identify patients they may have treated in the past or are currently treating who could be suitable for the study. These stakeholders can also provide links to social and digital assets for referrals. While they cannot disclose personal information regarding patients, they can provide researchers with information about the pool of potential participants available via their clinic/site. In addition, physicians often have a strong relationship with their patient, more so than with patients of non-rare diseases, so getting their buy-in to a trial protocol can make the difference between them recommending a particular study to a patient, or not making the recommendation at all. It is also important for sponsors to reach out and engage with patient advocacy groups during the initial stages of a protocol design because having their cooperation at this point can have an impact on enrolment. In addition to listing the clinical trial on their website, sponsors can connect to potential patients and their


Clinical Research carers via the rare disease group’s social media, blogs and forums, etc. These groups usually include patient caregivers or the relatives of patients, as well as physicians and key opinion leaders (KOLs) in the specific indication. By taking the time to engage with members of any relevant groups, sponsors can also gain valuable insight on a particular condition, including what life is like for patients as well as what is important to the caregivers and others in the patient’s network. Social media can also be a useful tool in its own right when it comes to sourcing and enrolling patients. That said, it should be approached with caution. While it is a much more cost-effective way for sponsors to reach a large audience compared with individually targeting hundreds of physicians and sites to find individual patients, communication via social media introduces the potential for biased reporting of experiences from trial participants. The balance between open dialogue and confidentiality must be accommodated thorough study design and patient/family education. Maximising Site Engagement With rare disease studies it is possible – and quite likely – that there will only be one or two patients enrolled per site. Retaining these patients is crucial; so while it may not be practical and/or cost-effective for a CRA to visit each site on a regular basis, it is important that they work hard to build and maintain good relationships with them. They can do this via intermittent on-site activity combined with regular remote interaction. By scheduling interactions when a site has the potential patient to enroll, CRAs can quickly respond to questions regarding regulations or some other matter. When response is immediate, site personnel may feel more comfortable reaching out to the CRA in the future, thus avoiding any long-term issues. In order to get further buy-in from the sites, CRAs must be able to engage with them at a deeper level of understanding disease 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

pathophysiology and study rationale. So while CRAs are likely to be familiar with the approaches taken in rare disease trials, they should also be trained and well-read on the disease indication of that specific study, the biological justification for the intervention and the justification of assessments so they are able to provide added trust and reassurance to the teams on site. Specialised Study Teams Beyond the CRA’s responsibilities, it is important to discuss a study team’s role in improving patient engagement. Rare disease clinical studies are complex and not for the weak of heart. They require an experienced team who arrive at study initiation with a well-defined repertoire of experience, including a willingness to adapt quickly to the various challenges these trials can present. Sponsors must work closely with study teams to agree on processes and establish the level of rigour that needs to be applied, to ensure each member of the research team is prepared to undertake the study, and importantly, get it right first time. The team, ideally structured using a matrix for organisational management, must also be dynamic and highly engaged on recruitment, retention and quality in order for the study to be a success. Furthermore, it is crucial that the team has a clear understanding of “patient mapping,” i.e. the patient’s pathway of treatment for the given indication, from how patients are identified, diagnosed and initially treated through to how the disease and management progresses over time. Gathering a wealth of information about how patients travel unique pathways of treatment to the point where they are ready for a trial can be invaluable in aiding understanding, boosting recruitment and retention and ultimately ensuring a high quality of care is delivered. The need for observational studies to inform the natural history of a rare disease, treatment pathways and disease burden provides a strong impetus for creation of a companion research initiative in many development programmes.

Final Thoughts Over recent years, not only has there been increased investment in rare disease clinical research, but there have been record high FDA approval rates for drugs treating rare disease indications4. While this is positive news, clinical trial methodology to support this kind of research will continue to have its challenges. But by demonstrating uncompromising commitment and putting the patient and their care network at the heart of their study from its inception, and by building and maximising reciprocal relationships with the wide range of stakeholders involved, including physicians, advocacy groups and regulators, researchers can further improve drug development efforts in this field. REFERENCES 1. U.S. FDA, Developing Products for Rare Diseases & Conditions, Designating an Orphan Product: Drug and Biological Products, Orphan Drug Act – Relevant Excerpts, August 2013, Accessed 15 May 2017. 2. European Commission, DG Health and Food Safety, Public health, Rare diseases, Policy, Accessed 15 May 2017. 3. World Health Organization, Priority Medicines for Europe and the World "A Public Health Approach to Innovation," Background Paper 6.19 Rare Diseases, 12 March 2013, Accessed 15 May 2017. 4. U.S. FDA, Novel Drug Approvals for 2017, 12 May 2017, Accessed 16 May 2017

Leslie Wetherell Executive Director, Rare Disease Franchise Lead at Worldwide Clinical Trials, is located in San Diego, California. She has over 20 years in the pharmaceutical industry, working in biotech, pharmaceutical and the CRO industry. In her role, she is responsible for the portfolio management of rare disease studies within the immune mediated inflammatory disorder therapeutic area. She has extensive experience in hematology, oncology and rare disease in a variety of indications conducted in over 40 countries.

Autumn 2017 Volume 9 Issue 3

BIOCLINICA GLOBAL CLINICAL RESEARCH Engaging the Right Patients and Connecting Them to the Right Sites in an END-TO-END SOLUTION

 Established, readily-available global network of dedicated research centers  Unified by globalized SOPs  Access to select patient populations  Innovative patient recruitment & retention methods  Expertise in key therapeutic areas


Clinical Research

The Future of Clinical Trials

to improve the patient experience, the quality of the data, access to metadata and overall transparency of results. The principles are in place, the goals are clear – how will this all be implemented?

In 2015, Professor Allen Frances of Duke University published an article sharing his fears, concerns and indeed, open scorn for the current methodologies of pharmaceutical clinical trials. “It’s been many years since I have trusted anything I read in a medical or psychiatric journal. There is an enterprise wide positive bias; findings never seem to replicate; benefits are hyped; harms are hidden.”1

Allen goes on to apportion blame for this state of affairs: “Drug companies bear most of the blame — the research they sponsor is shoddy and market driven. Scientists are also to blame when they torture data so much it will confess to anything. Medical journals are to blame when they publish positive findings from lousy studies and reject negative results from well done studies. And journalists are to blame when they uncritically accept phony claims.”2 For anyone who is professionally involved in clinical research, these criticisms were deeply concerning, and were shared by many others.3 It was clear that radical changes were needed. “The only responsible courses of action are to improve designs and measures, standardise implementation, change sponsors,

achieve complete transparency, report harms as thoroughly as benefits, and eliminate hype. With all the limitations, there is simply no substitute for randomised placebo controlled studies — we must improve them because we can’t do without them.”3 The criticism of the pharmaceutical industry was accurate, but it appears that the industry was aware of these issues as well – in 2012, Transcelerate was formed as a collaboration “across the global biopharmaceutical research and development community to identify, prioritise, design and facilitate implementation of solutions designed to drive the efficient, effective and high quality delivery of new medicines.”5 Their initiatives are many and varied, but are certainly addressing the potential solutions proposed by Allen. In summary, they propose transparency of data, data sharing, far more patient involvement in trial design and agreed standard protocol templates, allowing far more clarity and reproducibility of trials. The International Council on Harmonisation appears to share many of the same aspirations. It has adapted its guidelines to include radical changes to the design, implementation and monitoring of clinical trials.6 So essentially, industry and ICH appear to be working collaboratively


Patient-centric Trials "Patients want transparency. Help us to understand what's working and what isn't. Share results. Give us hope for a cure or a better medicine. Treat patients taking part in a clinical trial as investors; they are investing their bodies in your trial so keep them informed about that investment. They also want to be thanked afterwards. These are basic things.”7 There is a strong movement towards including patient groups and representatives in the trial team, from design through to sharing of results. Patients want their study to be integrated into their care. They want the culture of the sponsor and the site to be centred around them. Many companies, both CROs and sponsors, are paying more than lip service to this, with departments being devoted to patient involvement. Given that recruitment of patients to trials is one of the biggest challenges in clinical research, this represents a welcome move. More importantly though, this enables patients to ask the questions that they want answered, not simply those of the marketing department. Leading on from this, any developments that make trials more available to patients with work commitments or those who live long distances from sites are desirable. Patient profiling, identifying the individual needs of the person taking part, can help to reduce issues with recruitment, broaden the patient demographic and improve retention on studies. Wearable Technology The internet of things and wearable technologies (such as health trackers Autumn 2017 Volume 9 Issue 3

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Clinical Research

and smartwatches) mean that data can be collected much more easily, as well as over longer periods. For example, rather than a single twelve-lead ECG being taken at the site on a specified day, ECG data can be captured over the course of the whole study with minimal inconvenience. Patient surveys and interviews can be captured via the internet, enabling scheduling of events to suit the patient. These initiatives are already happening, but in a relatively restricted fashion. The advantages are undeniable, and are already leading to further innovations, and the concept of the siteless clinical trial. Siteless Clinical Trials The concept is that the more the patient can be treated, communicated with and observed remotely, the less need for the patient to disrupt their normal routine. As well as convenience for the individual, this would also mean that anomalies caused by changes to routine, and the artificial nature of the site visit, would be minimised. As recently as last month, one company had raised over $38 million to advance these technologies, believing that as well as improving the experience of the patient, capturing more raw data and eventually lowering costs, these technologies will also enable minority groups to be far better represented.8 Risk-based Trial Design and Monitoring These technologies, along with older ones such as eCRFs for data capture, and digital upload form monitoring systems directly into the trial databases, mean that far greater amounts of data can be captured and analysed – which in turn calls for a very different approach to monitoring the studies, and indeed to their design. Risk-based trial design and monitoring is a requirement of ICH GCP from June this year in all new 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

studies. This effectively ends the routine monitoring visit, replacing it with centralised monitoring of trial data and algorithmic applications being used to present these data to the study team, all the while being conducted in real time, to give indications of the main areas for the remote monitor to concentrate on. Not without a certain amount of controversy (there are concerns that the site/CRA relationship will be affected negatively), there is little doubt that this approach will improve both patient safety and data quality.

shifting in their chairs uncomfortably, but this researcher feels a lot more comfortable than he did when he read the thoughts of Professor Frances!

All of which, in turn, leads to larger, cleaner data sets.

1. allen-frances/the-crisis-ofconfidence-_b_6432236.html 2. allen-frances/the-crisis-ofconfidence-_b_6432236.html 3. plosmedicine/article?id=10.1371/ journal.pmed.0020124 http://www. 4. allen-frances/the-crisis-ofconfidence-_b_6432236.html ibid. 5.  http://www.transcelerate 6. Public_Web_Site/ICH_Products/ Guidelines/Efficacy/E6/E6_R2__ Step_4.pdf 7. magazine/2016/may_2016/ patient-centricity_ghost_in_the_ machine 8. news/science-37-gets-fundingdevelop-site-less-clinical-trials/

Big Data The pharmaceutical industry has been relatively slow to catch up with the “big data” revolution. Much of this delay can be put down to jealously guarded intellectual property concerns of a legal and financial nature. However, calls for the publishing of all study reports have grown, and the requirements of regulatory agencies have enforced them. This is not the same as publishing individual data sets, or indeed collective ones, but it does appear to have had the effect of encouraging cooperation with the data themselves. In fact, some of the blue chip pharmaceutical companies have been actively setting standards for data sharing since 2013, but it is only now that the real efforts appear to be bearing fruit. Given that the volume of data captured in trials is going from mega- and gigabytes to terabytes, it is logical to share anonymised data captured for similar interventions. In summary, collaboration, cooperation, transparency and the patient are providing the direction of travel for clinical researchers. There will, no doubt, be surprises on the way, and IP lawyers may be

The Clinical Professionals Academy ensures it keeps up to date with all the latest developments, with continual review and updates of our modular course content for our Training Academies. Source: https://www. clinicalprofessionals.

Doug Stewart He has over twenty years of experience in clinical operations, fifteen of which are at managerial level. Qualified in biochemistry, medical law and general nursing, Doug was a research nurse in the NHS and CROs in Phase I, before becoming a CRA. He then worked in Project Management, as an Associate Director and Director in Clinical Operations in two leading CROs, before working as Senior Director with a global CRO and Head of Division for Viral Challenge Studies in a specialist CRO. He has also worked for several life science organisations in a consultative capacity.

Autumn 2017 Volume 9 Issue 3

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Clinical Research

Developing Global Solutions for Product Safety Recent Changes in EU Requirements and New Directions in PV Globalisation

Over the past 20 years, the level of globalisation in the pharmaceutical industry increased significantly for both innovative and generic drugs. International cooperation between regulatory bodies and the harmonisation of regulatory requirements are key elements supporting the effective development of medicines, wide access to advanced therapies and ensuring sufficient safety oversight. Since 2012, when European (EU) pharmacovigilance (PV) legislation came into effect, we can observe continuous dynamic improvement of safety data quality, credibility and transparency. More strategic groundbreaking changes in drug safety are planned for Q3/Q4, 2017. The European Medicines Agency (EMA) is about to finalise the process of a European pharmacovigilance legislation implementation and to introduce enhanced functionalities of a EudraVigilance database. At the same time, EMA is constantly extending and enhancing the cooperation with competent authorities outside the EU to facilitate the exchange of information, knowledge and experience between some of the world’s largest regulatory bodies.

the coordinating role of the Agency in safety monitoring and safety data analysis. Following the public consultations, EMA has already published the following GVP guidelines (Q1 and Q2, 2017): •  GVP Module II - Pharmacovigilance System Master File (Rev. 2) •  GVP Module V – Risk management systems (Rev. 2) •  GVP Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2) •  GVP Module XVI – Risk minimisation measures: selection of tools and effectiveness indicators (Rev. 2) Additionally, the following updated documents are expected to be released in Q3, 2017 by EMA: •  GVP – Annex I – Definitions (Rev. 4) •  GVP Module XV – Safety communication (Rev. 1) •  GVP Module IX – Signal management (Rev. 1) and revised guidance on statistical methods •  GVP Module VI – Management and reporting of adverse reactions to medicinal products (Rev. 2)1,2.

Centralised Vigilance for Global Safety Oversight The EudraVigilance (EV) system launched by EMA has enabled a harmonised process of safety reporting and safety data assessment across Europe. Regulatory authorities, marketing authorisation holders (MAH) and clinical trial sponsors all use the same format, timelines and terminology for the electronic submission of suspected adverse drug reactions (ADRs) that occurred in European Economic Area (EEA) and in non-EEA countries. More than 1.2 million ADRs were reported to EudraVigilance in 2016; the majority of ADR reports were non-EEA reports for centrally authorised products. EMA is going to introduce enhanced functionalities of the EudraVigilance database in November 2017. EudraVigilance changes were driven by the need to simplify the reporting process, improve the quality of data, and enhance analysis and tracking functionalities. A modified EudraVigilance system will require submission of individual case safety

Harmonisation of Pharmacovigilance Legislation The European regulatory system for medicines monitors the safety of all medicines that are available on the EU market through the entire lifecycle of the products. The European pharmacovigilance legislation that came into effect in 2012 fulfilled the growing need for harmonisation of requirements and standards across all EU countries. Since that time, Good Pharmacovigilance Practice (GVP) guidelines have been evolving dynamically under EMA experts’ regular observations and public consultations with the stakeholders. In 2017, EMA is going to finish the implementation of the pharmacovigilance legislation, enhancing 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Graph 1. Increase of ADR reporting in 2012-2016 for products authorised in EEA and non-EEA (source: European Medicines Agency, Annual Report 2016) Autumn 2017 Volume 9 Issue 3



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Autumn 2017 Volume 9 Issue 3

Clinical Research

reports (ICSRs) that occur inside or outside the EU, only to EMA, without separate reporting to other national competent authorities. The ICSRs submitted to EudraVigilance will be automatically transmitted to the competent authority of the member state where the event occurred. This will significantly decrease the regulatory burden concerning safety submission processes and limit the number of duplicated reports.

Uppsala Monitoring Centre (UMC). Member states will no longer be responsible for transferring this data. New EudraVigilance functionalities will come into effect on 22nd November 20173,4.

Additionally, EMA implemented a new requirement to report all non-serious cases of suspected adverse drug reactions that occur in the EEA into the EudraVigilance database. This modification will streamline the signal-detection and data-analysis processes.

Common Language for Global Solutions Globalisation of safety standards and systems requires the development of widely acceptable and flexible tools supporting data unification, analysis and reconciliation.

EMA continues to enhance the collaboration with the World Health Organization and has announced that safety data reported via EudraVigilance will be automatically directed in electronic format to the WHO Collaborating Centre, the 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The detailed change management plan released by EMA presents information on the technical changes of the EudraVigilance system, as well as business process changes required to work with the new system5.

The best example of a standardised international solution is the Medical Dictionary for Regulatory Activities (MedDRA), developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in the late

1990s. Since that time MedDRA has been regularly upgraded to become a highly specific tool for sharing medical information and is recognised worldwide. Currently MedDRA is commonly used through all phases of the medicinal product development cycle in regulatory communication, safety monitoring and reporting (E2B Individual Case Safety Report), as well as product registration (within the ICH’s Electronic Common Technical Document (eCTD)). The MedDRA Maintenance and Support Services Organization (MSSO), as well as the Japanese Maintenance Organization (JMO), recently reported the number of subscribing organisations, which is currently over 5000 in 103 countries. This reflects the successful adoption of MedDRA as a worldwide standard in the protection of public health. The future focus is to explore interoperability between MedDRA and other medical terminologies6. Autumn 2017 Volume 9 Issue 3

Clinical Research Open Access to Big Data – Towards Global Knowledge and Transparency There is a common understanding that the value of safety data is strictly dependent on completeness, credibility and transparency. Increased data transparency supports global innovations, improvement of quality and better efficiency of medicine development programmes. The European Medicines Agency is the first regulatory authority worldwide to provide such broad access to clinical and safety data in accordance with transparency commitments. Information on suspected side-effect reports is publicly Area

Medium term

available in the European database of suspected adverse drug reaction reports []. The system demonstrates the total number of individual suspected side-effect reports submitted to the EudraVigilance database for each centrally authorised medicine. Information on registered clinical trials is available in a public register called EU Clinical Trials Register []. In October 2016, EMA additionally implemented an innovative policy and facilitated open access to clinical reports for new medicines for human use authorised in the European Union []. This was a crucial step undertaken Initiative(s)

for greater transparency of clinical and safety data. Innovative initiatives that focus on the use of mobile technologies and social media in pharmacovigilance are currently under evaluation. New technologies have been found to be powerful in adverse reaction reporting and the monitoring of the safety of medicines. Requirements regarding data transparency and data protection, accountability for data processing and some ethical principles still trigger challenges around the legal framework. EMA plans the further strengthening of the regulations on safety data transparency over the coming years.



Performance indicator(s)

objective Continious


- Network approach


Improve application of

Develop (through relevant

of international

equivalent standards

inspector working groups)

to inspections and

standards and

of good manufacturing

and apply an integrated

training collaboration


and clinical practices

and consistent approach to

agreed, with particular

throughout the world

cooperation with key authorities

focus on China and

(such as China and India)

India - agreed procedures for cooperation 2017


Mechanism to ensure


Ensure appropriate

Implement mechanisms to


representation in

ensure representative and

participation and


relevant fora, to

consistent representation of

feedback through

ensure convergence of

the network in international



fora, and to provide feedback

committee and HMA

to the network, including ICH,




Principles of mutual

Efficient use of

Expand work-sharing

Support the Commission with

global resources

and mutual-reliance

the establishment of a Mutual

recognition agreed


Recognition Agreement with

and implemented

the US

for certain group of medicines

Increase information-sharing



- GCP initiative with

between regulators responsible

PMDA established

for the conduct of clinical trials

- Pharmacovigilance

and pharmacovigilance activities

inspection initiative with FDA established Continious


- Number of training

Training and

Support capacity-

Organise regular training


building of non-EU

courses for GXP inspectors,

sessions organised

for non-EU


with participation of non-EU

with non-EU regulator




- Number of non-EU regulators' representatives trained Table 1. EMA contribution to the global regulatory environment – examples (source: EMA Work Programme 2017, EMA/583016/2016, 17 January 2017)


Clinical Research International Collaboration for Global Health The European Medicines Agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines across the European Union (EU) and also cooperates with many of the world’s largest regulatory bodies outside the EU (United States of America, Canada, Japan, Switzerland, Australia, New Zealand, Israel). Main areas of collaboration and information exchange include: inspections, safety of medicines and issues of mutual concern. The process of sharing information on medicinal products safety between the US Food and Drug Administration (FDA) and the Committee for Medicinal Products for Human Use (CHMP) Pharmacovigilance working party started in 2003 (announced formally in 2014)7. The EMA-FDA international pharmacovigilance cluster activities include the exchange of information on: policies, guidance documents and regulations, risk assessment, concerns over marketing authorisation holder’s pharmacovigilance systems and inspection findings, views on impacts, priorities and goals for pharmacovigilance activities. The pharmacovigilance cluster aims also at complementing the activities of the World Health Organization (WHO), the Council of International Organization of Medical Sciences (CIOMS), the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and the Drug Information Association (DIA)8. Further activities to strengthen the collaboration on pharmacovigilance compliance and inspections activities between EMA, FDA and other non-EU regulators is planned for the next years9. Next Step: Optimising Safety Requirements While the protection of patients’ safety is critically important, unnecessary data collection may be burdensome, and a disincentive for patients to participate in clinical research. In June 2017, 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ICH announced the development of a new safety data collection guideline (ICH 19) consistent with risk-based approaches and q u a l i t y- by- d e s i g n p r i n c i p l e s applicable for some late-stage pre-marketing or post-marketing studies. This guidance will deliver recommendations whether selective safety data collection may be considered and how to maintain a balance between eliminating the unnecessary data and maintaining an adequate characterisation of the drug safety profile at the same time. The aim of the new ICH guideline is to provide the first internationally harmonised guidance on targeted safety data collection to further increase clinical research efficiency and global participation in clinical development10. Since the European pharmacovigilance legislation came into effect, we can observe a continuous dynamic improvement of safety data quality, credibility and transparency. Unfortunately, such desired modifications entail a significant increase of regulatory burden and complexity. The need for adequate optimisation of the safety data collection process has recently been widely recognised. Current changes in PV legislation and guidelines are driven mainly by the need to simplify the safety reporting process and improvement of the quality, transparency and usefulness of safety data collected throughout the entire lifecycle of the medicinal product. Nevertheless, further improvements for mutual benefits would be impossible to achieve without strengthened global collaboration and effective exchange of knowledge and experience between the regulators, manufacturers and patients. REFERENCES 1. Work Programme 2017, European Medicines Agency, EMA/583016/2016, 17 January 2017 2. “What’s new in Pharmacovigilance, QPPV Update”,

European Medicines Agency, Issue 1, April 2017 3. Guideline on good pharmacovigilance practices (GVP), Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products, EMA/873138/2011 Rev 2, 28 July 2017 4. European Medicines Agency website, http://www.ema.europa. eu 5. EudraVigilance stakeholder change management plan, European Medicines Agency, EMA/325783/2016 Revision 2 Corr, 23 June 2017 6. ICH Press Release, “MedDRA Expands Its Global Reach”, ICH MedDRA® Management Board Meeting 7. Gerald J. Dal Pan, Peter R. Arlett, The US Food and Drug Administration-European Medicines Agency Collaboration in Pharmacovigilance: Common Objectives and Common Challenges, Drug Saf (2015) 38:13–15 8. Guiding principles for the international pharmacovigilance cluster, European Medicines Agency, 22 May 2015 9. ICH E19: Optimisation of Safety Data Collection, Final Concept Paper, 27 June 2017 10.European Medicines Agency, Annual Report 2016

Magdalena Matusiak Associate Director, Quality Assurance & Compliance, KCR, specialises in clinical development and quality assurance at KCR. She has broad experience in medical writing, scientific consultations and delivery of pharmacovigilance services during clinical trials and post-approval research. Ms Matusiak has extensive knowledge of clinical trial regulations with major focus on drug safety and effective assessment of the risk-benefit balance. Email:

Autumn 2017 Volume 9 Issue 3

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Clinical Research

Globalising Clinical Trials

Pharmaceutical companies are increasingly embracing the need for running trials across multiple sites globally. The rise of personalised medicine, and its promise of improving the drug development process and focused, faster approval of new therapies, places the industry firmly at the centre of the global genomics initiative. But capitalising on it requires a combination of technologies supported and enabled by increased collaboration among the industry, academia and healthcare providers. Pharma needs data and, as the unprecedented opportunities for data collection improve – from technologies including apps, wearables, sensors, telemedicine, electronic patient records and other medical devices – the industry must become increasingly digitised and collaborative.

By 2020, it is predicted that 601 million connected wearable devices will be in use, up from 97 million in 20151. This explosion in the number of people taking charge of their own health is creating an unprecedented opportunity to transform the pharma industry by enabling data sharing that supports the entire R&D value chain. However, this is only achievable through multidisciplinary research collaborations. By definition, global clinical trials are “large-scale trials conducted across populations from multiple countries to enable high-quality, unbiased outcomes”2. Such undertakings inevitably require new approaches to data transparency and collaboration. At the interface between pharma and healthcare systems, as well as in the pre-competitive world of basic science, complex collaborative approaches have already emerged as a robust strategy for exchanging data and knowledge. And while our increasingly data-driven world is broadening opportunities for innovation and disruption, 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

complexities remain in harmonisation, integration, communication and sustainability.

organisations in these innovations, so that local academic and clinical productivity rises.

Looking beyond the R&D pipeline, globalisation also means that drugs can potentially be marketed in many healthcare territories – can the lessons of data-driven collaboration help scale the necessary regulatory approvals and delivery across multiple localities?

Clinical trial managers should therefore design their programmes to work with local regulators and address ethical concerns. Building on ethical principles outlined in the World Medical Association’s Declaration of Helsinki 3 and the Belmont Report4 among others, a 2000 paper by Emmanuel et al. 5 theorised seven key requirements that must be met for clinical research to be considered ethical, including: (1) value; (2) validity; (3) fair subject selection; (4) favourable risk-benefit ratio; (5) independent review; (6) informed consent; and (7) respect for potential and enrolled subjects of multi-regional clinical trials. These requirements are universal and applicable to any population or site. However, their application requires open and transparent discussion to ensure that trials are seen as fair, necessary and beneficial to the local population, and this should be a key concern of any multi-site trial.

1. Understanding Differences in Populations Genomics and research in personalised medicine increasingly make sense of the differences across populations and individuals. Safety and efficacy of a compound may vary significantly, depending on genetic make-up. Clinical trials rightly restrict the inclusion and exclusion criteria to manage the statistical validity of results. In a global market, this may come at the cost of transferability of results between regulatory territories with distinct populations. It may also be the case that a more genetically varied population provides better insight into individual variability early on, providing greater information gain in the long run, or driving earlier (cheaper) failure. 2. Emerging Markets, Emerging Regulators In emerging markets, a local regulator may be more sympathetic to data gathered, at least in part, in their territory. As well as having 'genetic' relevance to their population, local trial data would indicate that local factors have been considered. These might include availability of diagnostic tests, distribution channels, and clinical expertise that accompany modern complex therapeutics. In territories with strongly interventionist governments there may be increasing demands for pharma to involve, and therefore educate, local clinical teams and healthcare

3. Globalisation: A Key Risk Factor It is widely acknowledged 6 that globalisation has also led to rises in westernised diseases, without the necessary healthcare infrastructure to respond to an increasing burden of chronic disease. Diabetes prevalence in Europe stands between 5% (Scotland) and 13% (Turkey), whereas in the Middle East prevalence rates of 20–25% are not unknown. In 2014 the World Health Organisation put China’s prevalence at 9.4%7. Regionally, in Guangdong China, this is currently estimated at 15%. The increased burden of disease in emerging economies provides a ready market for existing drugs. This will drive localisation of previous trials, attempting to replicate results. However, it also highlights the need to build on any Autumn 2017 Volume 9 Issue 3

Clinical Research existing data collection flows to contribute to global requirements for post-market surveillance. Generic infrastructure for data management and analysis can support both needs. 4. Pharma’s R&D Productivity Challenge In July 2017, GSK announced that they are dropping nearly one in seven of their R&D programmes, with new CEO Emma Walmsley slashing 33 preclinical and clinical-stage molecules from the pipeline and refocusing the remainder in areas that provide substantial returns. GSK isn’t alone in struggling with R&D productivity – Lilly also recently announced a restructuring of their pipeline following the unexpected FDA rejection of baricitinib, the company’s new blockbuster medicine for rheumatoid arthritis, while Merck, Roche and AstraZeneca – to name but a few – faced late-stage failures of their own in early 2017. The efficiency of R&D has declined over decades, while costs have increased8. With disappointing growth in existing markets, analysts predict that lower-income countries will drive the next wave of growth, with McKinsey suggesting that emerging countries will see a doubling of pharma revenues in the next decade9. While clinical trials in emerging economies may reduce the costs at a per-participant level, relying on working in cheaper markets seems misguided. The reverse aspect of applying existing trial results in a different population can strike the R&D programme in reverse, as results are applied back in local markets. A blended global approach, where trials are undertaken at multiple sites in different territories, should reduce this risk and improve productivity for a given budget. 5. Meeting Challenges with Technology To offset the cost and complexity of multiple trial delivery centres in different territories, companies should consider how secure, federated networks can be exploited to deliver global clinical trials.

Broadly speaking, the internet has followed globalisation as a means to connect virtual operations with many sites and territories. When considering a global clinical trial, companies and consortia should leverage the internet to assemble the virtual infrastructure for a programme of trials. Single tech platforms enable data collection, knowledge management, progress reporting and standard setting across trial delivery centres and sites in many territories. Each site may have different characteristics and circumstances, but a well-designed approach will control for this and localise differences while ensuring overall harmonisation. This approach does not imply the centralisation of raw data, or falling foul of local privacy regulations. Emerging tech platforms can provide decentralised de-identification and other techniques for federating data management and even analysis. A devolved approach respects local requirements and helps focus what information needs to be pooled in order to make the scientific case. This approach extends to scaling audit, security and validation of activity across the network. A distributed platform approach ensures that audit coverage is comprehensive and consistently applied. Local service providers can compete to participate in the network and share the risk and complexity of security accreditation. Companies should aim for a global baseline standard in information security management accreditation, with clear documentation and assessment of local variations. Investment in tech platforms can be undertaken with a view to re-purposing the basic investment for post-market surveillance collecting evidence of how medicines are performing, both clinically and economically. This leverages the infrastructure but also local connectivity, access and data sharing agreements with local hospitals and the broader healthcare community. The emerging experience of the Precision Medicine Ecosystem in

Scotland is one to watch, as it may provide a repeatable model for service brokers engaging with the local community while providing a platform to channel engagement with pharma internationally. 6. Managing Barriers to Collaboration Setting aside the challenge of bringing people together in collaborative networks, it is easy to underestimate the practical challenge of ensuring the right kind of infrastructure is available to support a global clinical trial. The systems described are technically feasible but present non-trivial deployment and support challenges. Consider that in the development of cloud services, although the technology is relatively straightforward to operate, only a handful of operators have been able to deliver a truly global cloud platform. Pharma should consider how best to engage with mid-tier cloud providers in order to reach into target territories. At the time of writing there are probably only a few fragmentary networks outside the internal operations of global pharma companies and global CROs. Academic and pre-competitive networks (e.g. the Innovative Medicines Initiative networks) indicate some advance in this approach. These early efforts will address some of the operational challenges and develop useful systems that can help scale future projects. 7. Distributed Data and Federated Analysis One of the opportunities for innovation is new approaches to distributed data management. Global clinical trials may soon require a federated approach to data management and analysis. A centralised approach treats local sites as simply sources of trial data, which is then ingested into a central warehouse for analysis. As with other forms of harvesting or mining, this overlooks the benefit of ongoing engagement, local autonomy and aspirations. A trial delivery centre can take on more responsibility. In the cases where personal data cannot travel outside the territory, there exists the possibility of hosting INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Clinical Research parts of a virtual warehouse. From there, at least two approaches are possible: •  de-identification prior to transmission of the analysis (with additional controls on pooling data at analysis time) •  distributing at least part of the analysis to participant-level datasets in local sites, so that only derived measures or aggregates are integrated at the centre.

addressing the issues of cloud implementation or globalisation. However, the opportunity to build in robust protocols for data exchange, federated analysis and supporting operational processes to be globalisation-ready is an opportunity to leapfrog innovation. A better data fabric should improve visibility and adherence to GCP in other aspects of the clinical development pipeline.

8. Cloud-based Analysis and Collaboration Cloud technology can underpin the federated approach to data management, but also provide a platform for collaboration. This can be approached at different levels, from full service collaborative analytics to lower-level building blocks assembled into trial-specific combinations.

10. The Globalisation Innovation Cycle As global trials expand beyond a traditional set of territories in the US, EU or Japan to include participants in emerging economies, innovative strategies designed to overcome the diverse challenges associated with multi-site clinical trials will be required in order to deliver future innovations. An innovation cycle that covers the R&D lifecycle from discovery through to development and commercialisation should be supported by platform technologies that promote data collection, sharing, analysis and collaboration. In a risk-adverse industry facing productivity and financial challenges, approaches which link multiples sites and connect global data owners, multidisciplinary experts and participants, will be key to harnessing the breadth of human diversity into effective therapeutic discovery.

Trial designers or pharma management should familiarise themselves with the wide range of services offered in cloud platforms: •  Infrastructure as a Service (IaaS): core capability to compute or store data securely and consistently in multiple territories. •  Platform as a Service (PaaS): coarse-grained components to build applications and assemble working systems. •  S o ft wa re a s a S e r v i c e (S a a S) : specialised applications such as electronic data collection (EDC) or recruitment reporting.

9. Considerations for Good Clinical Practice Good clinical practice (GCP) has evolved over the years to ensure that laboratory procedures and overall trial management are safe, ethical and repeatable. This is now ingrained in the industry’s culture – unlike informatics and the demands for complex data supply chains. As in other industries, the recognition that informatics is core business is taking time to percolate through the management structure. In any case, more will be needed to develop GCP standards and guidance to encompass informatics, even without 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

24-31;283(20):2701-11. 6. Bloom DE et al. (2011). The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum 7. WHO, China country profile for diabetes, http://www.who. int/diabetes/country-profiles/ chn_en.pdf?ua=1 8. Schuhmacher A et al. (2016). Changing R&D models in research-based pharmaceutical companies. J Transl Med. 2016;14(1):105. 9. McKinsey & Company (2017), industries/pharmaceuticals-andmedical-products/our-insights/ whats-next-for-pharma-inemerging-markets

Pamela Brankin Pamela joined Aridhia in 2011, taking on the role of Head of Marketing and Communications in 2015. With responsibility for the strategic development, implementation and management of an integrated marketing and communications strategy, as well as the commercialisation and dissemination of strategic initiatives and clinical research programmes, she occupies a pivotal role in the organisation’s ongoing development.

REFERENCES 1. Kantar Health (2016). Connecting with the mHealth consumer, docs/reports/2016-04-edge-ofinsight.pdf 2. CliniExperts, https://cliniexperts. com/initiatives-on-global-clinicaltrials/ 3. World Medical Association. (2001). World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bulletin of the World Health Organization, 79(4), 373. 4. UNITED STATES. (1978). The Belmont report: ethical principles and guidelines for the protection of human subjects of research. 5. Emanuel EJ et al. (2000). What makes clinical research ethical? JAMA. 2000 May

Rodrigo Barnes One of Aridhia’s first employees, Rodrigo joined the company in 2007. He is an R&D software engineer with a mathematical background and has designed and developed analytical and data management applications in a number of healthcare, life sciences and knowledge management start-ups. Rodrigo is skilled at developing new approaches to healthcare information problems, and has been instrumental in designing Aridhia’s approach to big data within healthcare and to the development of AnalytiXagility, the company’s data analysis platform. He is now responsible for technical and product strategy and takes a lead in Aridhia’s approach to precision medicine.

Autumn 2017 Volume 9 Issue 3

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

LEADERS IN PHARMACEUTICAL ANALYSIS Telephone: +44 (0) 20 8977 0750 Email: Website:

Labs & Logistics

What Clinical Teams Should Know about Changing Trial Logistics and How they will Affect Development – PART 1 When it comes to clinical supplies, the journey is every bit as important as the destination. And these days, the journey of clinical supplies to investigator sites is becoming costlier and more complex, much like the global trials for which the materials are bound. The price of failure is high. A supply shortfall, or the inability to deliver needed supplies to clinical sites, can delay the start of a trial or cause an ongoing one to grind to a halt. Supply shortages can imperil an entire development programme and prevent study patients from receiving the drugs a sponsor has committed to provide.

It’s no wonder that supply chain logistics are estimated to account for as much as 25 per cent of total annual pharmaceutical R&D costs.1 These cost pressures are projected to grow as a result of an evolution that is altering the clinical trial landscape and generating complex supply chain challenges. Some examples of that evolution in progress include: •  The explosion of cold-chain products in development and move toward shipping even ambient products under temperature controls •  The continuing globalisation of trials and impact of supplying trials in remote emerging market locations •  Evolving importation regulations and the potential fallout for imprecise documentation •  The soaring demand for comparator alongside concerns about safeguarding the integrity of the supply chain •  The growing interest in and potential of direct-to-patient studies •  Emergence of what one supply chain manager has dubbed an “Amazon-like culture” •  Th e n e e d fo r f l ex i b i l i t y a n d contingency planning in a crisisdu-jour world

shifting traffic patterns and other obstacles, clinical supply chain logistics are adapting to accommodate these developments. In addition to discussing how supply logistics are changing, this paper contains examples of how Fisher Clinical Services is deploying flexible solutions to ensure secure, efficient and cost-effective passage of clinical supplies. Challenges and Logistical Costs Escalate ‘The more things change, the more they stay the same’ could easily apply to the biopharmaceutical industry today.

Despite the ever-evolving nature of the industry, drug development remains a lengthy, complex and costly process. A growing list of

challenges is constantly exerting new pressures on the industry: An aging population, the growing cost of healthcare, pressure from every quarter about the cost and safety of drugs, barriers to entry in emerging markets, the wider adoption of generic drugs and keen competition among companies, not to mention increasingly difficult therapeutic targets.1 Now, add to this list the burgeoning cost of logistics for clinical trials. Logistics spending has been on the rise and is projected to increase steadily. Spending on global biopharmaceutical logistics was $72.5 billion in 2014, increased to $78.8 billion in 2016 and is expected to reach $85.8 billion in 2018. By 2020, such spending is projected to climb to $93.8 billion, driven in large part by cold-chain logistics.2 Even with escalating logistical costs, the role of supply chain in the pharmaceutical industry remains underappreciated. Only 39 per cent of pharmaceutical respondents viewed the supply chain as an equally important part of business success as R&D, marketing and sales, according to a 2014 survey.1 This leaves the industry warily eyeing escalating logistics costs and

Much in the way that a GPS constantly adjusts to accommodate 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2017 Volume 9 Issue 3

Labs & Logistics

considering how to reduce them safely. As a US-based supply chain manager put it, “Everyone wants to know what that secret sauce is in terms of getting drugs from Point A to Point B with the least amount of risk at the lowest cost.” Eye on Supply Chain: Logistics 2.0 Call them change-makers, transformers, disrupters. Whatever the name, the six developments discussed here were named by supply chain managers as driving the ongoing evolution in the clinical trial arena. Each of these developments is generating or will generate complex supply chain challenges that demand innovative, flexible and sophisticated solutions. Falling Temperatures The explosive growth of biologics is making cold the new normal and cold-chain management one of the biopharmaceutical industry’s major concerns.

Biologics have been nothing short of a resounding success story for the biopharmaceutical industry, heralded for making giant leaps forward possible in the long-term treatment of cancers, diabetes, rheumatoid arthritis, kidney failure and multiple sclerosis, as well as orphan and other diseases. So it should be no surprise that the primary driver of supply chain costs is the explosion of therapies that require cold storage.

In fact, there appears to be no end in sight.2,3 By 2020, greater than half of bestselling drugs will be cold-chain products, most of which are injectable.4 The growth of the global biosimilars market – which could reach $35 billion by 2020 – is a key contributing factor.3 Maintaining a secure cold-chain through storage, handling and transportation of temperaturesensitive drugs – some worth $1500 per vial – ensures product quality and integrity and compliance with various laws, regulations, guidelines and codes. Cold-chain handling is drawing increased regulatory interest, with both governments and industry updating cold-chain rules in the past decade and expanding the scope of temperature monitoring and control.5 Shipping products, whether they must be maintained in the cold INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Labs & Logistics chain or under controlled ambient conditions, is expensive. To pack and transport materials in the cold-chain, and to demonstrate by process qualification or by measurement that shipments remain cold, merely adds an additional level of complexity. In short, preventing temperature excursions comes at a cost – and costs are climbing.

temperature conditions. A reason for this is differences in interpretation about what constitutes ambient conditions, according to one supply chain manager. A number of Asian countries, including China, considers 0–30○C. to be ambient. Meanwhile, ambient is defined as 15–25○C. under Good Manufacturing Practice (GMP) standards.

In 2018 alone, logistics for cold-chain products alone are expected to cost drug-makers $14.4 billion, a price tag projected to reach $16.7 billion in 2020.2 This includes specialised tertiary packaging and instrumentation such as insulated boxes, blankets, phase-change materials, active temperaturecontrol shipping containers and various temperature sensors and recorders. It also includes air, parcel and truck service.4

Sponsors are beginning to ship even ambient drugs, such as capsules and blister packs, under controlled temperatures accompanied by temperature monitors. There is also a move toward shipping temperaturecontrolled products as frozen shipments, making cold – and colder – the new normal.

Even as costs for cold-chain logistics skyrocket, an increasing number of products are likely to be transported under colder conditions. Regulatory authorities have indicated their preference for shipping all drugs under controlled


Fostering Innovation It’s not a surprise that these developments are increasing the demand for cold-chain services and new packaging and temperaturemonitoring technology. At Fisher Clinical Services, half of all 2016 shipments were temperaturecontrolled compared to a quarter of shipments five years ago. The company is addressing these needs with continued investment in cold-chain storage, distribution capability and expertise across its global network, enabling it to handle growing quantities of cold-chain biologics across the globe: •  In Asia Pacific, Fisher Clinical Services more than doubled

cold-chain capacity for the region with the opening of a new 70,000-square-foot cGMP facility in Singapore and the expansion of the Tokyo, Japan facility. •  In Europe, the company doubled cold-chain capacity in Basel, Switzerland. Fisher Clinical Services also became the first supply chain partner in the industry to make fully automated assembly and labelling of pre-filled syringes from 2○C. to 25○C. Introduced in 2017, this service is exclusively available at the Basel facility, where a dedicated cold facility maintains cold-room conditions from truck to dock, through assembly, storage and distribution. •  In Africa, Fisher Clinical Services extended the cold-chain capabilities of its facility in Pretoria, South Africa.

Fisher Clinical Services also continues to explore and adopt new packaging and technology, including the use of robust, reusable shippers that reduce the burden on investigator sites and the

Autumn 2017 Volume 9 Issue 3


Biomap Temperature Monitoring Solutions to the Life Science Industry and Biomap was approached to propose a solution. After qualifying the requirements, we provided a comprehensive protocol documenting our suggested approach.

Based in Park Royal, West London, Biomap works exclusively in the life sciences industry, providing a wide range of products and services specifically designed to fit with industry regulation. We have experience of working with the world’s largest pharmaceutical companies, implementing multi-level route qualification and temperature mapping programmes.

Over the past 16 years, we have worked hard to provide a concentrated portfolio of service-based solutions a n d t e m p e rat u re - m o n i t o r i n g hardware and software packages. Specialising in industry compliance, we have developed all products and services to support clients with regulatory demands, helping you to take the guesswork out of the requirements for temperature monitoring and qualification. With carefully chosen partners and an excellent reputation in product and service quality, Biomap can offer a range of technologies and products to support the most basic information requirement through to detailed audit trails of temperature data, all required to aid in the decision-making process of product acceptance. Temperature Mapping Biomap’s temperature-mapping service is a tailored solution to map a wide range of storage and transport environments. Regulatory guidelines demand that environments such as warehouses, cabinets, cold stores and vehicles are all mapped and driven by a regularly reviewed risk assessment. The mapping service includes full protocol documentation with floor plans and execution of the installation process, and concludes with a full data analysis service produced in a final report with calibration documentation, data summaries, multi-graphs and recommendations.

Packaging Qualification Packaging qualification projects can be for any packaging method and can include temperature and humidity exposure tests, as well as vibration and impact tests to simulate worst-case shipping scenarios. Winter and summer profiles are designed to meet the specific environments a particular shipping lane will be subject to during transit. Shipping Studies A shipping study documents the temperatures a product is exposed to during transit and can help illustrate trends through certain lanes. There may have been a number of excursions that have already been experienced and need further investigation, or there may be plans for a new shipping lane with no data. Projects are tailored to meet individual client objectives and goals. Case Study Pharmafreight, a specialist freight service provider, operate a compact fleet of dedicated temperaturecontrolled vehicles for the sole purpose of transporting pharmaceutical products throughout Europe. A number of newly acquired vehicles required temperature performance qualification to cGxP standards

After recommending the mappings of vehicles in both an empty state and with product, four vehicles were mapped for a period of 72 hours. Biomap collected the data and produced comprehensive reports for each vehicle designed to support Pharmafreight’s internal standard operating procedures (SOPs) and overall regulatory requirements. Reports included performance a n a ly s i s , s u m m a r y r e p o rt s , multi-graphs and detailed diagrams of logger placement.

Client Comments “Biomap was appointed as Pharmafreight’s vendor in this mapping exercise after it was obvious the individuals involved in the company had a real understanding of what we needed to achieve from both an operational and regulatory standpoint. And throughout the whole experience, Biomap continued to exceed our expectations in terms of both communication of the objectives met and the final reports received. Biomap has set the bar very high for other providers of its kind, and Pharmafreight had no hesitation in appointing the company as its critical supplier for all of its existing and future mapping requirements.” – Andy Hughes, Commercial Director, Pharmafreight UK For more details on this case study and further information about Biomap products and services, please visit our website INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Labs & Logistics environment. In 2016, for instance, Fisher Clinical Services partnered with a sponsor on a pilot programme using a high-performance, phase change material (PCM) reusable shipper. The results were encouraging. In addition to resulting in a lower temperature excursion rate and greater contingency for delays than traditional, single-use shippers, the reusable shippers were lighter and cheaper to ship. While more expensive, the reusable shippers compensated for a higher price tag by significantly reducing waste and environmental impact. The sponsor estimated that the use of reusable shippers would divert 300,000 pounds of waste from landfill in year one, with a targeted reduction of 1.2 million pounds diverted from landfill in year two. Investigator sites similarly gave their thumbs-up, citing the reduced burden and expense of shipper storage and disposal. Increasingly Global Studies: Continued globalisation is increasing logistical challenges as more clinical trials migrate to emerging markets. In pursuit of faster, less expensive recruitment for clinical trials, sponsors continue to target emerging markets. It is worth noting that most studies continue to take place in North America and Western Europe. However, most of the growth in clinical research is taking place in Asia, South and Central America, the Middle East, Africa and Eastern Europe.6 While an enlarged clinical trial universe undoubtedly benefits patient recruitment and diversity, it also multiplies the logistical obstacles for supplying studies.

In addition to inexperience in conducting trials and differing quality standards, there are widespread differences from country to country in Customs knowledge, experience and laws. Many developing countries are also evolving regulatory requirements 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

about the conduct of clinical trials and protection of research subjects. Some are implementing stringent new regulations for importation and clinical research. Failure to adhere to these rules, particularly with respect to documentation, could derail timelines and budgets. In countries such as China, Russia and Ukraine, for example, failure to provide an acceptable rationale for product valuation can result in immediate and future headaches. In addition to higher costs due to revaluation and a fine, the sponsor can look forward to having all of its future shipments “examined with a fine-tooth comb,” as a United Kingdom-based supply chain manager explained. There is also the need to manage logistics complicated by countries’ challenging climates and limited infrastructure. As previously discussed, studies of temperaturesensitive biologics present additional logistical challenges across the supply chain. Temperature excursions can exact significant drug and financial loss and missed patient dosing. Missed dosing violates the commitment to serve clinical trial patients and can put their safety and wellbeing at risk. Finally, there are regional idiosyncrasies – differences of language, both spoken and unspoken, working patterns, culture and religion – that add another layer of logistical complexity. Fostering Innovation Fisher Clinical Services has the industry’s largest network

of fully-owned cGMP facilities strategically located around the world to support the conduct of clinical trials. Some 16 purpose-built, GMP/Good Distribution Practices (GDP)-compliant facilities located across five continents provide the global presence, information systems and quality standards to ensure the flexibility, access and assurance needed for clinical trials. The network of Fisher Clinical Services’ facilities continues to grow. In addition to the expansions and new facilities noted earlier, in the last five years Fisher Clinical Services opened its first clinical services facility in Seoul, South Korea, and doubled its presence in China to include a facility in Suzhou, located in a Free Trade Zone near Shanghai. Each facility is staffed with a team of highly-trained professionals who bring a depth of expertise in managing clinical trials, from protocol design to site receipt of clinical materials. Add to this global expertise an understanding of local requirements and regulations, proficiency in the local language and English, and established working relationships with key parties across the supply chain. Altogether, this allows Fisher Clinical Services to support the regulatory-compliant movement, management and delivery of supplies to more than 150 countries across all therapeutic indications. An example follows. Case Study 1 How an Innovative Transportation Solution Yielded Efficiencies and Cost Savings A leading multinational pharmaceutical company with an extensive clinical trial pipeline approached Fisher Clinical Services to develop a comprehensive, fully managed transportation strategy. The sponsor chose Fisher Clinical Services because of its Total Transportation Management Service, a solution that includes complete oversight of the supply chain processes required to move Autumn 2017 Volume 9 Issue 3

From Pack to Patient

We Deliver On Time & In Full.

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.


Labs & Logistics

investigational medicinal product (IMP) shipments internationally and within countries of choice. A cross-functional Fisher Clinical Services team – including specialists from Information Technology (IT), Quality, Project Management, Engineering, Operations and Finance – convened. Their objective: Defining supply chain strategies to achieve a maximum percentage of on-time shipments and to realise cost efficiencies. The team analysed trial protocols, consulted a logistics database, evaluated data on couriers and applied data-driven objectivity to route and courier choice. As a result of these efforts, the sponsor’s original transportation strategy was changed to reflect a new approach to courier selection. This data-driven courier selection approach optimised cost and performance efficiencies for the sponsor, achieving significant cost savings. Previously, the sponsor was sending 32 per cent of its shipments via premium courier. Thanks to the 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

data-driven objectivity applied by Fisher Clinical Services, the proportion of shipments being transported by premium couriers plummeted to 7 per cent, resulting in annual cost savings of $10.2 million. Meanwhile, on-time shipments increased to 97 per cent from 93 per cent. Short Supply Soaring demand for reference drugs is generating innovative sourcing strategies that must also safeguard the integrity of the supply chain. The escalating volume and complexity of global trials have driven the demand for reference or so-called comparator drugs to record levels. This is creating pressure to source sufficient quantities of comparator within tightening timelines and budget constraints.

As a result, the challenges of global sourcing for clinical trials have never been greater, particularly in emerging markets. Aside from the sheer number of countries involved in the typical clinical trial, a series of regulatory, supply and logistical obstacles magnify the challenge of sourcing comparators in emerging markets. Many emerging markets are creating or evolving their regulatory infrastructures. In addition, some suppliers in emerging markets do not adhere to European or North American quality standards and requirements.

In early 2017, for example, more than 236,000 studies were taking place in 195 countries, a number that has been climbing steadily, according to clinicaltrials. gov, the US registry of clinical trials.6 Autumn 2017 Volume 9 Issue 3

THERMOCOVERS Optimal protection of pharmaceutical air-freight Your benefits o Graded solutions for different applications o All covers made to measure o Closed or with flaps for multi-use applications o Easy handling, application and storage

ECOCOOL Gel-Blankets For additional thermal mass inside the packaging

o Short lead times

ECO-SAFE The proven Solution

ECO-SAFE+ The innovation for 2-25°C

ECO-SAFE++ Hybrid shipper for 15-25°C

o Economic single-or multi use cover for 2-40°C shipments

o Additional thermal mass combined with the efficient ECO-SAFE thermocover o Significantly improved temperature control without increasing chargeable gross volume o Unparalleled performance | price ratio

o Optimal protection through the combination of efficient insulation and internal thermal reserve o Optional: PCM-blankets for even higher performance


T. +49 (0)471 30 94 05-0


Labs & Logistics Maintaining the integrity of the supply chain is another issue of concern. Drug counterfeiting is escalating worldwide, affecting both developed and developing countries. China and India, two top-ranked countries for clinical trials, have also been identified as the sources of an increasing number of counterfeit drugs. The World Health Organization (WHO) estimates that up to 30 per cent of the drugs sold in parts of Asia, Africa and Latin America are counterfeit.7 Fostering Innovation Fisher Clinical Services has a dedicated team of individuals whose sole job is sourcing comparator globally. This team takes the strategic approach of managing supply chain from day one through the conclusion of the trial by maximising options and minimising risk. They begin by assessing the specific risks and challenges in individual markets, and then identify ways to mitigate issues. Direct sourcing of comparator from the manufacturer is almost always the best option because it establishes the shortest, most transparent supply chain, minimising cost and the risk of counterfeit product. When sourcing from a manufacturer isn’t feasible or desirable, however, the team turns to wholesalers and distributors that have been vetted in a rigorous qualification process. The qualification process includes risk assessments of both the supplier and the country of sourcing. Supplier criteria include reputation and referrals, licenses, capacity, pricing and benefits, economic status and financial stability. The country of sourcing is key because some markets are safer than others. Country criteria include whether the regulatory authority requires adherence to GMP, GDP and Certificate of Pharmaceutical Product (CPP) standards, legal provisions on marketing authorisation, regulatory inspection of manufacturers and distributors, import control, and licensing and sanctions for violations of codes of conduct. Another element is the frequency 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

with which counterfeit drugs have been documented in the country.

Ultimately, there is no one-size-fitsall sourcing solution. Every sourcing project requires a tailor-made strategy to deliver the best outcome.

REFERENCE 1. Pelzel, Kristina. “What’s Next for the Pharmaceutical Supply Chain?” Inventory and Supply Chain Optimization, 12 January 2017. http://www. inventory-and-supplychain-blog. com/whats-next-for-thepharmaceutical-supply-chain/ Autumn 2017 Volume 9 Issue 3

Labs & Logistics 2. “Pharmaceutical cold chain logistics is a $12.6-billion global industry.” Pharmaceutical Commerce, 4 February 2017. http:// pharmaceutical-cold-chain-logistics-is-a-12-6-billionglobal-industry/ 3. “Biosimilars market to hit $35 billion by 2020, research suggests.” The Pharma Letter. 13 February 2017. 4. Sowinski, Lara. “New packaging helps life sciences meet complex cold chain demands.” JOC. 19 December 2016. http://www. advancements-packaging-help-life-sciences-meetcomplex-cold-chain-demands_20160226.html 5. Chatterjee, Bikash. “Managing Cold Chain Distribution across the Global Supply Chain: Trends and Regulations.” Pharmaceutical Outsourcing. July/August 2016: pp. 22-24. 6. U.S. National Institutes of Health. 13 February 2017. Clinical resources/trends 7. Blackstone, Erwin A, Fuhr, Joseph P. Jr, PhD, and Pociask, Steve. “The Health and Economic Effects of Counterfeit Drugs.” Am Health Drug Benefits. June 2014; 7(4): 216–224. pmc/articles/PMC4105729/

Jennifer Worsfold Senior Director Supply Chain Solutions – Fisher Clinical Services. Jennifer Worsfold joined Fisher Clinical Services in 1996. A key member of the Global Project Management Leadership Team, Jen is passionate about providing the highest standard of customer service to all Sponsors, always delivering on client expectations. Over the years, Jen has never lost sight of her first priority-“to serve the patient.” From 1996 to 2006, Jen was based in Fisher Clinical Services Horsham and was instrumental in instilling a focus on the customer. She finalized her tenure there as Director of Logistics and moved to the Fisher Clinical Services Allschwil office in 2006. There she led the Project Management of the Manufacturing, Packaging and Distribution services. In parallel, she set up a new facility in Weil am Rhein as a Warehouse and Distribution Centre for strategic customers within the European Union. Jen’s success is evident in the increasing capacity of the Allschwil facility and in the development of the Weil am Rhein facility. Jen has recently taken on a role as Senior Director for Distribution Services; encompassing all aspects of Customer Service and Project Management whilst also supervising day-today operations. A consummate professional, she continues to raise the bar for Quality, Service and Pro-active Project Management at Fisher Clinical Services. Email:


Labs & Logistics

Serious About Tarmac Time – Comparison of Different Approaches for Increased Thermal Protection and New Solutions for Low-mass Pallets of Pharmaceutical Goods Temperature excursions during loading and unloading procedures of air-freight shipments (so called ‘tarmac times’) of pharmaceutical products represent a major challenge for a fully controlled cool chain.

While pharmaceutical products in the 2-8°C temperature range are usually being transported in more expensive passive or active shipping containers, products in the so-called “controlled room temperature” or “ambient temperature” ranges (mostly 15-25°C but also 2-25°, 2-30°C or 2-40°C) are generally protected by more economical packaging solutions for the direct transport interfaces, i.e. the tarmac times during airport ground handling situations. The standard solution in the industry for this solution is thermal blankets. Currently, a wide range of blanket types coexists on the market, ranging from reflective bubble wrap, over thin reflective covers from nonwoven fabric to thicker, multilayer wrapping solutions. Basically, all of these blanket types aim at providing protection from:

by comparing the amount of energy required to heat one litre of water and one litre of air for an increment of one degree Kelvin.. Whereas the former requires 4183 Joules, the latter only requires 1.036 Joule , i.e. just 0.03% of the energy required to heat the same volume of water for the same increment. Since standard thermal blankets, unlike passive shipper boxes, do not add any thermal mass, palletised goods of low mass are inherently more susceptible to temperature excursion than pallets of higher mass. To illustrate the difference between thermal blankets of different thickness but similar materials (bubble wrap, coated with aluminum foil on both sides), we performed comparative climate chamber tests. Our company’s standard solution, ECO-SAFE (7mm thickness), was compared with two blankets of 16 and 32mm overall thickness. The test was performed on a EUR pallet of 120cm net height. A total of 16 empty corrugated cardboard boxes with dimensions of 600x400x300mm acted as (worst case) dummy load. A

total of 10 dataloggers was distributed symmetrically in the pallets. While the measured temperatures between different logger positions varied slightly, it was irrelevant which logger position is taken to compare different solutions. In the following, the centre logger of each test run is chosen, with the results shown in Figure 1. As can be seen, all thermal blankets significantly slow down the process of temperature equilibration between the ambient temperature and the temperature measured inside the protected pallet with zero mass dummy load. However, the difference in temperature protection between the different covers is only small. Measured by the following thermal

protection metric where TP is a metric which measures the reduced thermal stress in per cent (a value of 1 denotes total protection, i.e. no change in temperature underneath the blankets, whereas a value of 0

•  Heat spikes through solar radiation •  Heat spikes through hot ambient temperatures •  Cold spikes through cold ambient temperatures.

While the use of standard thermal blankets does indeed provide adequate protection for most shipments temperature excursions can occasionally still result from a combination of the following three adverse factors: Very hot or cold ambient temperatures •  Longer than average tarmac times •  Low thermal mass of products. The third factor in particular is often overlooked when determining the performance of a given thermal blanket solution.Why thermal mass is so important is easy to understand 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Results of climate chamber tests.





Thermal protection

Ambient temp










Thermocover 16mm





Thermocover 32mm





Table 1: Numeric summary of climate chamber test Autumn 2017 Volume 9 Issue 3



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Labs & Logistics would denote no protective value at all). Table 1 lists the numeric results from the test. The results imply that doubling the thickness of the thermal blanket yields a five percentage point increase in thermal protection. Even though this difference is measurable, it is questionable if it justifies the associated additional costs (price of thicker blankets, additional required storage space and potentially higher freight costs due to bulkier pallet dimensions) of choosing a thicker thermal blanket. Our answer to the challenge of providing increased thermal protection for low-mass pallets of pharmaceutical goods is the innovative ECO-SAFE+ solution. It consists of five to six so-called Water-Blankets (depending on pallet base format) and a standard ECO-SAFE thermal blanket.

Picture 1: Five Water-Blankets assembled on a EUR-sized pallet

Picture 2: Complete ECO-SAFE+ solution (for clarification, only partly pulled down) 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2: Climate chamber test including ECO-SAFE+

Water-Blankets are sleeves of 38cm width and variable length which are intended to bring additional thermal mass to the low-mass pallets with sensitive goods. They consist of small pockets, filled with water-based gel, and can be produced for any pallet heights. The gel consists of 99.5% water and 0.5% polyacrylate. It is harmless and also used in Coolpacks for the shipment of fresh foods or chilled pharmaceuticals. Unlike traditional cooling elements, Water-Blankets offer the advantage of applying thermal mass to all sides of the pallet and not just to the top. The foil used for the production of Water-Blankets is very pressureresistant, so that pallets wrapped with Water-Blankets remain stackable. For a EUR-pallet with height of 120cm, the Water-Blankets would add around 33kg of thermal mass, without adding additional chargeable volume. This is a main advantage of the ECO-SAFE+ solution, compared to other, more voluminous packaging options, since typically, volumetric weight determines the freight costs.

Since Water-Blankets do not have to be preconditioned in any particular way, the whole operational procedure of assembling a pallet with the ECO-SAFE+ solution does not take more than five minutes on average. In order to assess the thermal p rot e c t i o n a c h i ev e d by t h e ECO-SAFE+ solution, the climate chamber test described in Figure 1 and Table 1 is repeated, this timeincluding the ECO-SAFE+ solution. The advantages of the ECO-SAFE+ solution are directly visible from Figure 2. Compared to the three standard blankets shown before, the temperatures in a pallet protected by five standard Water-Blankets and an ECO-SAFE thermal blanket show significant smaller fluctuations. The minimum temperature during an ambient temperature of -10°C remains above +10°C, whereas the maximum temperature measured during +50°C ambient temperature is just above +30°C. This visual impression is fully confirmed by the summary statistics (see Table 2).





Thermal protection

Ambient temp










Thermocover 16mm





Thermocover 32mm










Table 2: Numeric summary of climate chamber test including ECO-SAFE+ Autumn 2017 Volume 9 Issue 3



Labs & Logistics The thermal protection metric for ECO-SAFE+ reaches 70% compared to values between 41% and 51% for the standard thermal blankets without the additional Water-Blankets. This result confirms the theoretical consideration, that additional thermal mass combined with a standard thermal blanket might outperform very bulky, multilayer blankets in terms of thermal protection. For even better thermal performance, we offer the WaterBlankets in conjunction with a six-piece collapsible pallet shipper, made from EPS side walls, covered with reflective insulation foil (ECO-SAFE++). Even though this solution is suited to fully sustain the important 15-25°C temperature range under most shipping situations, specific customer requirements have led us to produce the ECO-SAFE++ shipper with PCM blankets. By making use of the latent heat stored by specific PCM fluids, even better temperature control can be assured for very specific temperature ranges under most testing ambient conditions.

Picture 4: ECO-SAFE++ shipper (fully assembled)

Dr Florian Siedenburg The general manager of ECOCOOL GmbH, located in Bremerhaven, Germany. Dr Florian Siedenburg graduated in 2006 in Economics and obtained his doctoral degree in Econometrics in 2010. He entered the family-owned business in 2013. ECOCOOL GmbH was founded in 1999. ECOCOOL specialises in the development and distribution of insulating packaging. As of today, thermal blankets and other passive packaging for pharmaceutical air-freight constitute the core business of ECOCOOL. Email:

Picture 3: ECO-SAFE++ shipper (partly assembled) 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2017 Volume 9 Issue 3

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Coding Ensures Safe Food Produce

Making products traceable is a reliable means of increasing the transparency of the supply chain while protecting consumers. In the pharmaceuticals industry, the coding of medicinal products is governed by directives in many countries. However, Track & Trace is also gaining ground in the food industry. Indeed, products are labelled in such a way that they can be traced on their way through the entire supply chain. This makes product recalls much more straightforward, while also making it increasingly difficult for the product to be tampered with. The necessary coding solutions form part of the packaging process and therefore need to be integrated into existing packaging guidelines. In order to make this process as smooth as possible, precise knowledge of processes and expertise in the sector are advantageous.

The complexity of implementing such projects is not to be underestimated! The challenge here lies, on the one hand, with the company implementing the process. This entails analysing processes and potentially standardising them, providing sufficient financial resources and personnel as well as finding a suitable provider. For the provider of serialisation systems and software, the task involves knowing the production and packaging processes of their customer and their product and productionspecific testing requirements inside out. Only then is the provider able to use the perfect solution in the right place and depict the corresponding data flows. Providers not only need to demonstrate extensive software knowledge, but also detailed expertise where sensors and actuators are concerned. Only those who also accurately understand the product flow of the packager and boast plenty of experience in the mechanical integration of machines and modules into the packaging line, will ultimately be able to successfully implement complex serialisation projects. 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Benefits of Pharmaceutical Industry Expertise In the meantime, a large number of projects from the pharmaceutical industry have been successfully implemented. In doing so, the spectrum ranges from the manageable serialisation requirements of small to medium-sized companies to the cross-site, multi-stage aggregation of global pharmaceutical companies. With this in mind, it makes sense to benefit from such experience and refer to tried-and-tested concepts. An example here is the German provider Laetus. The company with headquarters based in the Engineering Region of Darmstadt Rhein Main Neckar, near Frankfurt, offers end-to-end solutions for the pharmaceutical, medical technology, cosmetics and food industry and is armed with more than 40 years of experience in inline quality control. Laetus has been part of the Danaher Group since 2015 and operates with more than 250 employees and branches in the USA, Mexico, Brazil, China, UK, Italy, Spain, Poland and France as an independent company within the product identification platform PID. Furthermore, around 50 agents and distributors represent the company across the globe. As such, the provider is perfectly positioned to offer visual inspection solutions as well as Track & Trace in order to even be able to successfully implement complex, global projects. Flexible Architecture for Needs-oriented Development The core is a GAMP-compliant software architecture with a modular structure, which covers all levels of the ISA 95 standard in its multi-level design. Depending on needs, this covers all requirements placed on reliable traceability from simple serialisation, to multi-stage aggregation, through to commissioning steps in the warehouse and along the supply chain. Of advantage here is the scalability of software, whose range

of functions can be adjusted in line with equipment requirements without a great deal of expenditure. In addition, the company offers an extensive range of machines and modules, which can be used to cover the various requirements placed on coding and verification, on various materials directly on the packaging line or offline. Quality Assured with Vision Inspection Our company has established itself over the decades with its systems for vision inspection in the packaging process. Coding tasks can be extended in the packaging process with vision inspections in order to assure the quality of products in the packaging process. Here the inspection tasks range from code reading and pressure monitoring of additional information in plain text and images, to filling inspection, through to the inspection of a large number of features and properties of the product packaging. Service and Support are the Keys to Success Alongside the much-needed experience, the service and support performances and capacities are ranked as the key criteria behind the success of such a project. We detected this need at an early stage and have developed an extensive global network for individually tailored services. This includes reliable project management. If needed, as prime contractor Laetus assumes responsibility for the entire process from the planning phase through to commissioning. Service level agreements tailored to requirements, reliable repair and spare parts service, around the clock support via the hotline, online or remote meetings and the extensive training offer from the Track & Trace Academy round off the offer, and not only secure your investment, but also the safety of food produce. Autumn 2017 Volume 9 Issue 3


Axel Jung After completing his degree in Electrical Engineering at Siegen University (Germany), Axel Jung has worked for 9 years in the foundry industry. During this time he was engaged in development and project management issues. His primary role was quality inspection, based on image processing functionalities in the production line. In June 2009 he moved to Laetus GmbH, a company supplying to the pharmaceutical packaging industry, a change from heat and dust to a clean room environment. Starting as project engineer he was responsible for packaging security and print & verification applications. Since 2010 Axel Jung is working as Product Manager for Laetus Track & Trace Systems. Within this position he gained valuable experience in Track & Trace requirements globally and steered the Laetus product “Secure Track & Trace” to success. The Track & Trace Academy offers a comprehensive modular training programme tailored to the individual needs.


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How to Combine Serialisation and Late Stage Customisation Time is short: serialisation of prescription medicines will become mandatory in the EU on February 9, 2019, resulting in new labelling requirements as a prerequisite for market access. Other countries and regions are already further ahead. Pharmaceutical manufacturers must therefore invest in suitable solutions now. Simultaneously, late-stage customisation is getting increasingly important due to continuously decreasing batch sizes. If both digital printing processes can be combined in one step, the opportunity to implement compliant and cost-optimised production arises.

The first logical step is to consider where in the production process to most sensibly perform serialisation. During the offset printing of sheets for the later folding cartons? In a contract packaging facility, in special logistics centres, or in the packaging lines of pharmaceutical manufacturers? The solution chosen by the pharmaceutical company will depend on the existing infrastructure as well as several other factors. Therefore, the advantages and disadvantages of any given decision – but also the opportunities associated with them – must be evaluated well in advance. Since every product will soon require a unique serial number, the production of batch sizes of one will soon become compulsory anyway, as it were. What savings in logistics and simplifications can therefore be achieved by coding the carton as late as possible? Decreasing Batch Sizes as an Opportunity Interest in late-stage customisation is increasing for a reason: special products and combined drugs, a growing demand for test batches, and the desire to reduce the costs for the logistics handling of pre-printed packages, as well as the storage costs for ready-to-ship products, reinforce the trend towards smaller production runs. But since the production volume as a whole is not decreasing, 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

this all happens on high-performance packaging lines. Production on order is the most pronounced form of this development. Small batch processing requires many changeovers and thus packaging lines can no longer reach their potential efficiency. In such cases, late-stage customisation can help maintain their economic viability. Late-stage customisation offers various possibilities to increase cost-efficiency: •  Minimising storage space in the delivery warehouse, for instance for 28 country styles in the EU •  Cost saving by replacement of logistic warehouses in many countries with one centralised and more efficient delivery warehouse for several countries is possible •  Dramatic decrease of tied-up capital through stored material value •  Decrease of losses due to damage because of lower stock volume •  Less rework required in case of production errors •  Less re-packing effort in case of changes in regulatory labelling. The most pronounced form of the late-stage customisation approach is production to order based on an almost blank folding carton that becomes large-scale printed. A limiting factor may be its varnish coating that can reduce the adhesion of any ink applied later in the production process. It may therefore be necessary to use an adapted varnish instead. Late-stage customisation can occur at various degrees of technical requirement for different applications. •  Serialisation only with black print •  Monochrome printing of symbols and text, such as dosage •  Colour print of individual markings with or without serialisation •  Large-scale colour print with symbols and serialisation

Linking Marking Processes and Identifying Savings Potentials The opportunity to link serialisation and late-stage customisation suggests itself, allowing manufacturers to design products that are both compliant with regulations and cost-effective. The place in the production process where this can be best implemented depends on several factors, such as existing infrastructure, production volume per product, production speed, frequency and duration of changeovers, the need for expiry date and batch information in the target market, and many others. Additionally, questions must be answered regarding savings potentials through decreased stock values, less storage space, and a reduced number of warehouses as well as the number of folding cartons that can feature a “country-neutral” design, and costs for printing equipment. Taking into consideration the above-mentioned factors, any decision for a solution will be as individual as the requirements and needs of a specific company. Nevertheless, there are typical constellations enabling the complete or partial linking of both marking processes, thereby contributing to a compliant and cost-optimised production with substantial savings potentials regarding warehouses and logistics. Essentially, there are the following options: 1. Integration During the Production of Folding Cartons Until now, the standard practice has been for the country-specific design to be applied to the carton by the producer. If that also includes serialisation, the pharmaceutical manufacturer does not need to invest in printing and checking technology (see also Figure 1, scenario 1a). The number of folding carton styles does not increase through serialisation, since every country version requires its own design anyway. Combined with late-stage customisation in a Autumn 2017 Volume 9 Issue 3

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Manufacturing its efficiency. It must be noted that this approach is only suitable for products with country-neutral primary packaging, such as blisters, and that the package insert may have to be multi-lingual, since the packaging can no longer be opened afterwards.

Figure 1: Late-stage customisation and serialisation can be implemented at various stages during the production process. Depending on the individual situation of a company, it must be determined where the implementation makes economic sense.

single work step, the folding carton manufacturer can achieve logistics savings: they can react quickly and flexibly when pharmaceutical manufacturers order very small quantities. 2. Integration Directly Before the Packaging Line The two above-mentioned steps can also be implemented by the packaging company, which further increases flexibility. If serialisation and late-stage customisation take place directly before packaging, considerable savings can be made regarding storage and logistics, since efforts for procurement, storing, and especially logistics management of country-specific packaging are no longer required (see Figure 1, scenario 1b). Further advantages include a more versatile production without delays caused by ordering and transporting packaging material from external providers, and easy supply of very small and test batches. All current regulations allow for serialisation and late-stage customisation to take place completely offline and before the actual packaging process, which means that all marked packaging material can then be fed into a mostly unchanged line. Thereby, several packaging lines can be fed by one digital printing machine. It is 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

not necessary to invest in printing technology for each individual packaging line and then incur loss of production time for its integration. 3. Integration Directly into the Packaging Line The currently best-known option lends itself well to large-scale production: packaging material already bearing country-specific graphic designs and markings is produced and then serialised for each country on the packaging line (see Figure 1, scenario 2). Depending on the number of export countries, it may be necessary to stock many folding carton styles, which results in increased efforts for storage and logistics. A conscious decision for the scenarios 1a or 1b shown in Figure 1 might be beneficial for every product or product line. 4. Integration in the Logistics Warehouse In order to efficiently operate packaging lines with high-volume production runs, manufacturers can produce “brite stock”, i.e. filled country- and market-neutral packaging. Country-specific design and serialisation are applied in the delivery warehouse by means of late-stage customisation. Thereby, many short production runs can be combined on the packaging line (see Figure 1, scenario 3), improving

If not only the secondary packaging, such as the folding carton, but also the primary packaging, such as the blister, must bear a countryspecific design and marking, this can also be implemented in the logistics warehouse. A country-specific design and serialisation code is printed on the empty, flat folding carton (see Figure 1, scenario 4). In this case, a DataMatrix code containing, for instance, the product code, EXP and LOT, has already been applied to the blister in a blister machine to ensure process safety, preventing mix-ups during later marking processes. This marking and packaging step usually takes place in the delivery warehouse, where packing is often done manually. Therefore, this constellation is most suitable for very small batches or very valuable pharmaceuticals with relatively small quantities that are delivered to many different markets. In general, it must be noted that in all scenarios featuring late-stage customisation, a packaging design where all relevant sides can be easily reached for country-specific marking via a printing system is most favourable. Thereby, expenditures for storage and logistics can be considerably reduced, and whole warehouses can be made redundant. Management of Serialisation Data Irrespective of where exactly serialisation takes place, pharmac e u t i c a l m a n u fa c t u r e rs a r e responsible for their products. As soon as the products enter the market, they must report their serial numbers to a higher authority or governmental agency. A software solution at ISA level 3 or 4, such as Atlantic Zeiser’s MedTracker, is required for the management, and – if required – aggregation of serialisation data. This software must collect data from the packaging lines, Autumn 2017 Volume 9 Issue 3


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Manufacturing This can be achieved by means of contact-free drop-on-demand printing combined with a special UV ink. DoD color printers with a 600 dpi resolution manage transport speeds of up to 50 metres per minute. Since most packaging lines are not prepared for DoD printer integration, offline solutions are an alternative. These can feed several packaging lines, thus implementing late-stage customisation and serialisation in one step while ensuring optimal capacity utilisation.

Image 1: Designing pharmaceutical packaging (i.e. for various country versions, compare picture) as late as possible can help manufacturers to considerably reduce storage efforts.

map aggregation processes, export results, and – depending on the constellation – generate and manage serialisation data. Decision Criteria for Late-stage Customisation Variants Before investing in a late-stage customisation solution, several criteria must be assessed. a) What are the potential savings through the reduction of •  stock value •  management of many packaging and product variants •  storage area •  number of warehouses •  losses due to damage •  expenses due to changes in marking requirements •  increased flexibility b) How many folding cartons can be designed in a country-neutral style •  quantity to be produced per layout c) How much effort results from a possibly necessary change of packaging design and packaging approval d) Handling costs for staff of in-house printing shop or logistics warehouse e) Cost for printing facilities f) Increased cost of inkjet ink compared with offset printing ink Two Processes, One System Solution To manage serialisation data, users need powerful serialisation software 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

which ensures process safety while generating, printing, and storing the codes, as well as checking them with a camera and transmitting them to downstream processes. Further requirements include suitable printing technology that delivers high-quality printing results (regarding contrast, colour brilliance, and lightfastness) for late-stage customisation applications and serialisation at high speeds.

The robustness of the line and software design in case of disturbances and malfunctions is a key factor, especially for serialisation. This means that the machine software and the machine architecture must match the requirements based on practical experiences, and the interface between the machine and the serialisation software must operate seamlessly and without any interference in order to ensure stable processes. Atlantic Zeiser combines these features for the first time in one solution: all variable information regarding the market, language, or product is printed on a flat or

Image 2: A flat pharmaceutical folding carton is printed just in time with special UV ink via contact-free drop-on-demand (DoD) printing technology. Autumn 2017 Volume 9 Issue 3


Image 3: Just in time and completely in colour: for the first time, the DIGILINE Versa enables users to combine serialisation and late-stage customisation for folding cartons.

glued carton one step upstream the packaging process in multiple colours, while serialisation takes place during the same work step. Thanks to the new OMEGA Pro generation of drop-on-demand UV inkjet printers, the DIGILINE Versa system is capable of printing graphics, text, and serialisation codes in four or six colours and to verify the complete layout by means of a high-resolution camera system. Due to the use of UV curing inks, the print is especially high-contrast

and resistant to water, light, and wear. The integrated unique code software ensures process reliability during generation, printing, and storing of codes that have been checked by a camera, including reporting for downstream processes. Moreover, the system is very robust regarding disturbances and special situations, which is a key factor for serialisation. A stable process requires machine, printer, and software to be perfectly coordinated and to have a robust connection to the higher-level serialisation software.

Conclusion: New Technology and Individual Design Result in Savings Late-stage customisation and serialisation processes can be combined at several steps during the production process. Moreover, the combination with late-stage customisation opens up savings potentials – through optimised line utilisation and through considerable cost reductions for storage and logistics. The choice of the process stage where it makes most economic sense to link serialisation and late-stage customisation depends on a wide range of individual factors. Each pharmaceutical manufacturer will evaluate these differently regarding their products and production facilities – corresponding decisions are therefore companyspecific. The above-mentioned scenarios show model options with existing technical solutions that can be found in practice. Manufacturers considering the combination of both marking processes should therefore consult a one-stop supplier of both hardware components and the required serialisation software. Thereby, in-house staff are not burdened with the tasks of system integration.

Helmut Schneider Product Manager in Atlantic Zeiser‘s Pharma & Packaging Solutions division, specialises in the development and marketing of system solutions for serialisation, late-stage customisation, and track and trace applications. In addition, his expertise includes the coding and product individualisation of folding cartons, blisters, and labels. Prior to his position as a product manager, Helmut Schneider spent years designing and planning complete plants for product individualisation and headed the projects to implement these solutions. Email: helmut.schneider@ Image 4: The serialisation of pharmaceutical packaging will soon become mandatory in the EU. At the same time, the market demands increasingly small batch sizes. In light of this, pharmaceutical manufacturers require process-reliable and cost-efficient solutions.



Steps to Properly Inspect & Purchase a Tablet Press in the US and Abroad The Inspection We want to help our customers make the best choices when purchasing used equipment. Over time, we realised most of the questions our sales group receives revolve around the basic inquiry, “What do I look for when inspecting a used piece of equipment?” With this article, we will focus on tablet presses — sharing tips from equipment specialists who have seen more than their fair share. So without delay, here’s what your engineers, technicians, and procurement professionals should thoroughly inspect before committing to purchasing a used tablet press.

One of the most common inquiries received when buyers are searching the second-hand equipment market includes “what do I look for when inspecting a used piece of equipment?”. It is important to ensure confidence before making a purchasing decision for your company, and a lot of factors come into play when conducting a proper inspection. With tablet presses, some of the primary components that should be checked before purchasing include the turret, pressure rolls, fill cam, hoppers and chutes, as well as the maintenance records, manuals and types of controls. We gathered all of the essential information from leading engineers, technicians, and procurement professionals to provide prospective buyers with quality tips for inspecting tablet presses.

measurement (specifically the punch bores – both upper and lower and the die pockets). Turret Inspection Part 2 This second inspection tip is slightly more labour-intensive and any damage present cannot be detected with the naked eye. You will need a ‘go/no-go’ tool to measure each bore and pocket to check for slop. A go/ no-go is a tool that is used to test certain parts of a tablet press (turret and tooling). There are different go/ no-gos for measuring the punch bores (upper and lower) in a turret. They are also made for measuring the die pockets and the tooling heads. They are used to determine what parts of the machine are ‘in spec’ and which are ‘out of spec’ – you will need to check every station on a turret. All of the positions could measure out fine, or as a ‘go’, and will not need to be bored and bushed to bring them back to spec.

great condition, you will next want to inspect the press’s pressure rolls – both the pre-compression rolls and the main compression rolls. When performing this visual inspection, you will want to look for any signs of scoring or wear. If there are signs of wear, and the pressure rolls are no longer the same measurements, both sets can be re-ground to a smooth measurement, but only to a certain diameter. If they fall below the minimum diameter, they will need to be replaced. Feed Frame Inspection If the turret and the pressure rollers are in good condition, the next component you will want to inspect is the feed frame. This entails another visual inspection, during which you are checking for: •  Any physical deformation •  Rust •  Materials obstructing the feeders You will want to get as close a look as possible, as one of the most common problems associated with a malfunctioning feed frame is that there are large granules or broken tablets lodged in the feed frame, obstructing the flow of material.

You should be looking for any signs of: •  Damage •  Wear and tear •  Rust •  Physical deformation

Turret Inspection Part 3 Another good way to check the overall condition of the turret, and the tablet press as a whole, is to open the panels on the bottom of the press, revealing a hand crank for manual operation. This crank, or hand-wheel, is connected to the press’s main gearbox and will allow you to rotate the press, and visually confirm that it rotates smoothly and without any odd noises or delay. While performing this inspection, if you notice a delay or hear any scraping or grinding noises, then it is possible that the gearbox in the press will need to be replaced or rebuilt. Generally speaking, a visual inspection of the turret should suffice. If the turret appears to be in good condition, with no signs of wear and tear or damage, it usually indicates that the press as a whole was properly maintained throughout its usage.

Aside from a basic visual inspection, turrets can also be inspected for

Pressure Rolls Inspection After ensuring that the turret is in

Hoppers and Chutes Inspection The last part of your inspection

Turret Inspection Part 1 One of the most critical components of a tablet press is the turret. This crucial component should be the first part of the tablet press that gets your attention.


Fill Cam Inspection The fill cams, both upper and lower, are important components to a functional tablet press. Unfortunately, due to the nature of their task, they wear away quickly. Although it is not crucial that the cams be in pristine condition, it is important to note what condition they are in since that fact is usually an indication of how the press was maintained and whether or not it was properly cleaned during its period of usage. Fortunately, even if the cams are in horrible condition, and the rest of the press seems to be in great condition, the cams can be easily replaced.

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Manufacturing could easily be your first; however, I wanted to list these tips in order of importance. With regard to the used press’s hoppers and chutes, you will want to ensure that both are installed securely and intact, with no signs of cracks or holes. In order to be sure that the hopper and chutes are in good condition and properly installed, you will want to visually check the tablet press for signs of any spillage. The presence of tablet ingredients outside of the hoppers and chutes could indicate a leak somewhere in the system. With these tips in mind, you will be able to gauge the quality of a used tablet press before putting any money on the table, ultimately enabling you to make the right decision, the first time. Maintenance Records, Manuals, and the Type of Controls Part 1 After closely inspecting all of the above, you will want to ask the seller of the press for any documentation they have that details their efforts to provide consistent and regularly scheduled preventative maintenance to the tablet press and all of its individual components. This is crucial, since even the best naked-eye inspection can overlook or simply miss indicators of problems lurking inside the press. Maintenance Records, Manuals, and the Type of Controls Part 2 You will also want to request the OEM’s manual for the press. This is less important than the maintenance records, since even if they do not have the manual, you can, in most cases, visit the OEM’s website to download the manual. But nonetheless, if the seller still has the original manual that came with the

press, it is likely they treated their press with care and used it within the guidelines of the manufacturer. Lastly, you will want to take note of what type of controls accompany the press. This is mostly a matter of preference, as some tablet presses come with slick, digital, touchscreen displays, while others (usually the older models) come with analogue controls, complete with seemingly outdated knobs and buttons. Purchasing a Tablet Press in the United States Once you know what to look for when inspecting your tablet press, you should be ready to make your purchase. But before you move forward, remember there are a lot of different rules and regulations in place by the government when purchasing a tablet press. Some of these regulations may affect a buyer’s transaction, so it is important to know and understand these. In the United States, tablet presses are regulated by the DEA, domestically. The DEA tracks which companies have purchased this instrumentation and where they are being used. When a buyer comes to us to purchase a tablet press, there are a number of proper steps to follow before releasing the equipment to them. Here is a quick overview of the process. Step 1: The Tablet Press is Sold We then report the sale to the DEA, including the sales information, the exact address of the purchaser, and information of the carrier transporting the tablet press.

Step 2: We Wait The typical wait time once a request is submitted to the DEA is about 15 business days. Step 3: Shipment Once the tablet press is verified, we are able to ship the item. Once the tablet press is shipped, we must also provide a copy of the signed Bill of Lading, confirming it was delivered to the registered location. Purchasing a Tablet Press Abroad If you are purchasing a tablet press in a country other than the US, the DEA has no jurisdiction, and thus there is typically no wait time for shipment. Instead, the seller simply notifies the DEA of the sale and informs the DEA that the press will no longer be at the registered location. Tablet presses that originate outside the USA and are entering back into the USA must be registered with the DEA. We have to provide port of entry, date of entry, and copy of signed Bill of Lading confirming delivery to the registered location. Other Regulations Additionally, some of our sellers have their own DEA compliance departments. For example, though it might only take 15 days to get in touch with the DEA, the seller’s policy could state that they have scheduled release times of 30 days. Always ask the sellers which processes they utilise to ensure everyone is on the same page.

Mark Middlemist He is a pharmaceutical equipment expert. He works with many global leaders of the industry. For the past 18 years he has been working with EquipNet revolutionising the way companies manage their surplus assets. Mark will attend CPHi show in Frankfurt; contact him to schedule a meeting during the show. Email:


Autumn 2017 Volume 9 Issue 3


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Innovation Drives Productivity and Efficiency in Tablet Production Innovation drives growth, and ultimately improves productivity and efficiency. This is very much apparent in the pharmaceutical and nutraceutical industries, where increasing demand from the developing world is pushing tablet tooling manufacturers to be cutting-edge. This attitude to forward-thinking development has been particularly prevalent in the last decade, with shorter lead times now essential to remain competitive.

The manufacture of oral solid dosage forms has come a long way since the process of the hand rolled pills used in previous centuries. In the beginning, tablets would be formed by being rolled into a ball, then into a long pipe shape which was divided into lengths to roughly calculate dosage. This then progressed into using tiles with graduations so that the pipe could be rolled to a specific length equal to a more accurate dose. It was then that one of the first innovations was developed – the pill machine, which measured and cut the pipe into accurate pieces. This was still very much a manual process, but with careful manipulation, it could produce rounded portions which were then rolled under a pill rounder to make the cut portions spherical.1

dies – the introduction of ‘hobbed tips’. This is a process which uses a high precision metal master of the desired tablet design to cold form the punch tip detail. This pioneering technique ensures the production process is accurate, quicker, cheaper, and – most importantly – repeatable. This has now become the standard for quality punch manufacturing and is used by other tablet tooling producers across the world. A couple of decades later came perhaps the most significant innovation in terms of productivity; the large-scale manufacture of multi-tips, which is still one of the most important advances (but not wholly adopted) in the industry to date. It is only in recent years that the wider tablet production industry has started to integrate multi-tips into its production process as the demand for solid dosage forms grow. What made multi-tips so unique is their ability to increase production without investment in new machinery or personnel. It is now considered the most productive form of tablet manufacture.

A multi-tipped tool is a punch that can make more than one tablet per station with each rotation of the press. This can range from a two-tip punch to one with over 40 tips per punch face. By successfully implementing multi-tipped tooling, tablet manufacturers can significantly reduce the need to invest in expensive tablet presses, thereby lowering the overall capital spend. The number of tool set-ups required per production batch is also reduced, with product batches completed quicker, thereby decreasing the overall time required to produce the product. Since multi-tipped tooling was introduced, there have been four main designs which include ‘internal’ and ‘external’ cap fixing, ‘pin fixing’ and the ‘monoblock’ design. Each design has its own advantages and disadvantages, and it’s important to take these into account when selecting the right solution. The internal cap fixing design is a composite assembly that has seamless joints, which prevents interference and damage to turret punch guides and damage to oil and dust seals, therefore reducing contamination. The tips are reasonably straightforward to replace

Tablet production has since advanced, and innovations, thanks to the research and development of tablet tooling manufacturers, have revolutionised tablet production into the mainly automated process we know today. However, pharmaceutical manufacturing is an ever-changing environment and to produce tablets cost-effectively, investment in new technologies and processes must constantly be made. Tipped to Change The 1960s brought with them one of the most notable innovations in the development of tablet punches and 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Multi-tip tooling increases productivity without investment in new machinery. Autumn 2017 Volume 9 Issue 3

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Manufacturing if they become damaged and, due to the multi-part nature of this design, different material and coating options can easily be applied. Similar to this design is external cap fixing. While this does have a joint on the punch barrel, it can house more tips per punch due to the cap being fitted to the outside of the punch body, leaving more of the face free for tips. A good option for punch tips that are likely to require replacement is the pin fixing option. It is a simplified assembly with fewer component parts, making the exchange of damaged or worn-out punch tips less complicated. The most recent innovation in multi-tip design is the monoblock. This is manufactured from a single piece of steel, meaning that there are no joints, thereby eliminating any slight risk of damage to the punch guides or seals. It is also the ideal option for use in WIP (wash in place) machines, or for manufacturers who require cleaning techniques with no assembly or disassembly. Further Developments in Tablet Tooling Clearly the modern tabletting process is an exacting one and, wherever possible, tooling materials need to be optimised for the task. To this end, Rotahead punches were developed which allow the head to rotate independently to the punch body, thereby providing a 'bearing' between the punch head and the cams. This can assist with problems like uneven head wear as there are less ‘resisting forces’. It is also possible that the press can be operated at faster speeds, thereby producing a higher tablet output. In addition, the head and body can be manufactured from different optimised materials which can result in an extended tool life and less wear on the compression rollers. It is not just the physical tablet tool itself that has helped to advance tablet production. The accompanying accessories are also making a difference. One product that has made an impact is bellows and drip cups. 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Monoblock multi-tip punches are manufactured from a single piece of steel.

Contamination from lubrication and powder during the tabletting process can cause costly manufacturing problems like black spots on tablets, resulting in high numbers of rejected tablets, increased wear on punch guides, and the tightening of upper punches, which can cause excessive machine downtime and high maintenance costs. Bellows and drip cups help to prevent tablet and punch guide contamination during the tablet compression process. This has most recently advanced with the introduction of a metalized design which ensures any tiny fragments of the material will not reach the end user, as they are identifiable by standard metal detection equipment.

XDF is a novel patented head form which has been designed to increase dwell time on existing presses without the need for expensive modifications. XDF can give users higher press speeds for challenging products and formulations, enhancing tablet compaction and cohesion.

Po s s i b ly t h e m o s t re c e nt introduction in tablet tooling is the newly created elliptical head flat tool XDF (eXtended Dwell Flat), developed by a leading manufacturer of tablet tooling for the pharmaceutical and nutraceutical markets. This is currently the only realistic way to achieve more dwell time without slowing down an existing press or upsizing punches.

Investigation into the cause of formulation sticking to punch tip faces was undertaken and a predictive tool was developed to calculate the punch coating solution required for each individual job.

Forecasting the Future To be innovative, it is not just a matter of designing and producing unique tooling and accessories; you need to be able to understand the properties and characteristics of formulations being compressed in order to solve difficult tabletting problems. One of the most universally confounding is sticking.

TS A R ( Ta b l e tt i n g S c i e n c e Anti-Stick Research) Predict enables the identification of the appropriate anti-stick punch coating solution for Autumn 2017 Volume 9 Issue 3

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Manufacturing forces to each of the coatings within the PharmaCote range. The model then determines the coating with the lowest predicted adhesion force and the best at reducing the sticking issue of that particular formulation.

Rotahead punches can assist with problems like uneven head wear.

formulation-sticking issues without the need to carry out expensive and time-consuming, full-scale, trial-and-error experiments with several anti-stick coatings. Because the physical properties of any sticky formulation are unique, there is no one-size-fitsall anti-stick solution. The model considers the properties of the API, and calculates the Van der Waals

Take Advantage of Contemporary Technology Modern manufacturing requires advancement not just in traditional production methods but also in the monitoring processes used. According to the Food & Drug Ad m i n i s t rat i o n (F DA) , ‘m a ny firms do not take advantage of contemporary technology.’ Because of this, production can be affected. They cite a number of reasons for reductions in manufacture, including ‘deficient […] facilities and processes, old manufacturing platforms (antiquated facilities, inefficient/ unstable processes), unpredictable manufacturing leading to quality problems, defects, and supply, manually intensive operations vs. automation and human error still being very prominent.’3 For this reason, it is also essential to push forward management systems that use innovative software technology. In-depth monitoring of tablet production is an extremely important procedure in pharmaceutical tablet manufacture. Without a system that controls the process effectively, there can

be adverse effects to the bottom line. Manufacturers should have a complete audit trail covering tooling usage and maintenance. This is not only good practice, but an important regulatory requirement in the majority of pharmaceutical environments. The costs of tool replacement are often known; however, there can be unexpected expenses including the replacement of tools due to avoidable damage. Implementing a management system to monitor aspects of the tooling cycle will increase production, and reduce tablet press downtime and lead time to market. Within pharmaceutical manufacturing, the importance of knowing where tools are, and what condition they are in, should be a priority. Without this information, either unnecessary tooling replacements are made, reducing productivity, or punches are deployed when they should be in maintenance or replaced. This can lead to problems with the end tablet when it is found that the tooling being used does not meet the highly demanding process and/or requirements of the tablet manufacture. Rejected tablets, wasted formulation and press downtime are the usual results. In addition to this, not having a clear picture of tooling availability may lead to the loss of opportunities in

Tooling Management Systems can help to monitor tablet production and comply with regulations. 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Manufacturing a fast-moving competitive environment. Implementing a tooling management system from an experienced and respected tooling expert will fulfil the core requirement of enabling tablet manufacturers to manage their tooling in an ordered, traceable way. Modernising pharmaceutical production will lead to processes that can keep up with the requirements expected in today’s highly demanding manufacturing environment. To do this, however, innovation in tablet tooling has to continually develop for optimal tablet production to take place. Through pioneering development, and the progressive research carried out by specialist tablet tooling manufacturers, the production of tablets will continue to advance and grow. REFERENCES XDF allows manufacturers to increase dwell time on existing presses. the-dna-of-the-worldsmost-innovative-companies1020#oTf0zripyvsoRPgS.99 3. downloads/drugs/ developmentapprovalprocess/ manufacturing/ucm324354.pdf

Alex Bunting Marketing Manager. Alex manages the marketing team at I Holland, is a graduate of English and member of the Institute of Digital Marketing. He joined I Holland in April 2008 having spent the previous years working in Environmental Science. Alex was instrumental in the design of the 2010 edition of the widely adopted Eurostandard, educational animations and hosts I Holland’s extensive webinar program.

1. Royal Pharmaceutical Society 2. http://knowledge.

Product News Sartorius Stedim Biotech introduces Sartobind® Cassettes New modular membrane chromatography solution for large-scale applications Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, has expanded its range of single-use membrane chromatography solutions with Sartobind® Cassettes. This convenient, pod-like modular system has been developed for commercial applications in both capture and polishing. New Sartobind® cassettes offer the same flow path, bed heights (4 and 8 mm) and void volume ratios as Sartobind® capsules, and are compatible with Q, S, STIC PA and phenyl ligands. The new design goes beyond the previous 5 L size limitation for capsule formats, expanding the boundaries of membrane chromatography. Multiple cassettes, each with 0.8 L or 1.6 L membrane

volume, can be set up in three different stainless steel holders resulting in maximum membrane volumes of 20, 50 or 100 L, respectively. Data demonstrates direct scalability from the 3 mL Sartobind® nano capsule to 20.8 L (13 cassettes) in the Pilot Filter Holder. Pressure-flow performance and the shape of breakthrough curves are identical to the smaller capsule sizes, independent of the number of cassettes used. Set up can be accomplished within minutes, even at manufacturing scale, whether for capture applications or for flow-through removal of process contaminants. The capture of large proteins such as viruses and virus-like particles (VLPs), protein conjugates and blood factors plays a key role in modern bioprocessing. The unique Sartobind® cassette system now enables large-scale bind-and-elute membrane chromatography for such targets. “For the first time, the high binding capacity of membrane adsorbers can be used at almost any scale in commercial vaccine

The newly developed Sartobind® cassette system is a unique single-use solution enabling large-scale bind and elute membrane chromatography.

manufacture. Now, a 200 L Q anion exchange column for adenovirus capture can be easily replaced by a 20 L Q adsorber cassette system”, says Dr. Stefan Fischer-Frühholz, membrane chroma-tography expert at Sartorius Stedim Biotech. For more information about Sartobind® membrane adsorbers click here: filtration-and-purification/membranechromatography Contact: Sartorius Stedim Biotech GmbH August-Spindler-Str. 11 37079 Goettingen

New Sartobind® cassettes go beyond the previous size limits of membrane adsorbers and can be directly scaled from a 3 mL capsule (Nano) up to 20.8 L.



Continuous API Manufacturing – It’s Time to Go with the Flow There has been a recent surge in interest in using more continuous processes in the pharma industry as the benefits have become more widely known. This is due to the availability of more expertise in the area of flow chemistry over the last decade, in combination with the need for the industry to develop safer, faster and more sustainable processes, with higher quality and less expensive products. But the first thing we need to do is define what we mean by continuous processing and flow chemistry. The industry is running two broad types of continuous processing, in finished formulations and API manufacturing – often commentary in the media has made little effort to separate these, and they invariably get confused. Whilst continuous processing in finished formulations with the potential of on-demand dosing is extremely exciting, for the purpose of this article we are instead going to specifically look at the improvements flow chemistry can bring to process development and manufacturing for APIs.

It is time the wider pharma community set aside the decade-old views of continuous manufacturing as a ‘luxury but impractical tool’ and looked at the technology as a practical and valuable approach that can resolve our everyday chemical processing issues. Flow chemistry offers a more streamlined and continuous synthesis process as well as a variety of advantages compared to a batch operation. Incorporating a flow operation results in increased production with decreased capital. In terms of safety, flow reactors for pharmaceutical reactions are normally run in much smaller volumes than those of batch reactions. Dealing with toxic chemicals is also safer – cytotoxic APIs can be produced in inexpensive, dedicated, and disposable equipment sets for production of low volumes of these compounds in the laboratory fumehood. Not only is flow chemistry safer than batch, it is also more efficient – 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

better heat and mass transfer alongside less back mixing contribute to enhancing the purity profile and product recovery. The small size of the microreactors, either PFR or CSTR, allows for much higher reaction temperatures and pressures as compared to batch reactors, enabling us to safely perform reactions that were previously unstable in batch. Reactions can also undergo superheating, enabling them to be heated above their boiling point, further resulting in faster reaction rates. The flow operation reduces the break time between consecutive steps and can significantly reduce the manufacturing time. An important advantage of flow chemistry is the ability to fully control many of the parameters, such as mixing, temperature, and reaction time. By having the capability to add or remove heat almost instantaneously, one could remove the heat generated from a reaction; for exothermic reactions or a reaction requiring hazardous materials, this is an especially important benefit. Flow reactors also allow control over residence time, which is the time that the reaction is exposed to a set temperature, allowing for far more precise reaction times. This is immensely beneficial, particularly if a reaction creates more than one product. There is also continuous monitoring of the quality – such as purity – by online or offline sensors, so parameters can still be fine-tuned during the operation in order to obtain the best product quality. During a batch process, you would need to wait until reaction is completed, and by then it may be too late to make any adjustment. The intense mixing in flow chemistry is provided by microreactors, which enables scientists to use multiple phase systems and fewer solvents, and produce purer material – reducing unit operation and work-up steps. The high temperature-high

pressure flow reactors reduce reaction time and provide better conversion whilst using starting material more efficiently. This requires tightly controlled process analytical technologies (PAT), and resolution of any quality assurance issues related to acceptability of the intermediates. Microreactors can be designed to fit the requirements needed for the reaction, therefore providing customisation opportunities. In addition, microreactors have low maintenance and operational costs without abandoning productivity and efficiency, which provides an economic incentive. These technological advancements are valuable and vital assets in flow chemistry and have expanded the versatility in its use. Although the advantages are clear, before a flow process can be developed, a working small-scale batch process should still exist since, in general, developing a flow step may take much longer than its batch equivalent. However, once a flow step has been developed, its scale-up is far easier and encounters fewer issues than in batch. The reason for this is that the sizes of the reactors in the scale-up version are normally less than 20 times the lab version. For example, the diameter of lab-scale PFR tubing is normally around 1/16” - 1/4”, and its pilot plant version is around 3/8” - 1/2” – these are not very different in size. The scale-up in the batch process could be 100 to 1000 times bigger than the original lab-scale process – this is impractical as mixing and other engineering aspects can complicate such large scale-up operations. The flexibility and versatility that continuous flow allows cannot be disregarded – minimal adjustments are needed in a flow operation to increase the capacity of the reactor. For example, scaling up, numbering up, or scaling out, which is increasing the capacity of microreactors, increasing Autumn 2017 Volume 9 Issue 3

Manufacturing the amount of micoreactors, and running the reaction for longer, respectively. There are four types of flow systems which have distinct features, specialised for different reactions. Type 1 and 2 are for catalyst-free reactions, where type 1 has reagents flow directly through the microreactor and type 2 has a reagent in solid state. Type 3 and 4 require a catalyst, whereas type 3 has a homogeneous catalyst flowing through the system, and type 4 has the catalyst confined to the reactor as the reagents flow through, making it useful for multistep synthesis. The total cost of producing a final product depends on the cost of the process R&D, starting materials, and the operational costs – of these, the latter two have the greatest impact on the overall cost. Using the flow operation, cost incentives include the reduction of energy costs and reduction of impurities and waste products. Awareness by chemists of the capabilities of flow chemistry as an enabling technology gives them the power to design shorter synthetic routes, and therefore also reduce the cost once operational. Of course, reducing waste promotes efficiency, enhances purity, and is beneficial to the environment. Companies may realise too late that their drug has an excessive, multi-step process that could have been shortened and since their cost would be unnecessarily high due to a longer synthetic route, this could result in losing substantial amounts of profit. If we assume that flow facilities provide major benefits at larger scales, we could see that later-phase and commercial products are more

amenable to continuous processing. Big pharma such as Lilly, GSK, and Novartis are already preparing for launch of their pilot or commercial plant facilities and, at this time, these plants are built within their own companies. However over time these companies may decide to outsource such operations to CMOs or CDMOs – we have one such flow chemistry partnership with big pharma, but we’re very much in the minority. Our belief is that it’s only a matter of time until much more flow work is outsourced, and we have kept part of our capacity free in anticipation of this. During development, flow steps seem to be more appropriate for early steps of the synthetic route where less expensive raw materials are available for process development and the volume of the material to be processed is more. Perhaps the majority of the APIs currently produced at a commercial stage have the required volume to be turned into flow. However, due to regulatory issues, limited changes can be applied to the existing commercial processes but it can still potentially be achieved with some investment and time. The transition from batch to flow operation is generally thought of as both costly and inconvenient, but implementing this change in early development is simple and beneficial. Comparing Phase I and Phase III, it is much easier to manage changes in development and regulation if switched at Phase I, but to switch at Phase III would result in a delay in market release and a loss in both time and money.

Yet, the number of flow steps during development remains stubbornly below 5%. The message here is clear: for flow chemistry to deliver on its huge promise, pharma and CDMOs need to build the platform into the Phase I process R&D of innovative API programmes. This requires commitment from the beginning of a project, and a wider commitment to running in flow whenever possible. Flow chemistry has suffered slow implementation into the industry – especially as compared to some other industries such as oil and gas – even though more are beginning to recognise its benefits. This is largely due to the increase in demand for flow chemists while there remains a lack of experience and education in the field. With an entirely new manufacturing process, people may be reluctant to adopt it as they think it may slow down the manufacturing process, something which the FDA may be able to combat through deregulation. The safety, efficiency, and flexibility of flow chemistry are what drives its high interest, and are why it’s becoming an essential component in research, development, and for the future of the industry. This article has been abridged from STA Pharmaceutical’s contribution to the CPhI Annual Report. http://www.

Dr. Sam Tadayon is a Chemical Engineer, PhD, with research focusing on Process Engineering in Pharmaceutical Industry. He worked in Wyeth Pharmaceutics for around 8 years before joining STA Pharmaceuticals in Shanghai/China in 2011. Since then he is leading the Process Engineering team of around 40 scientists including the flow chemistry team. Dr. Tadayon has been involved with around 400 projects mainly involved with process development of crystallization, flow chemistry, and other chemical engineering aspects of the pharmaceutical processes. Email:



Analytical Lab Services are the Cornerstone of Successful Product and Process Development; Biopharma can Offer you the Full Package Biopharma Group’s USA division, Biopharma Technology LLC (BTLCC), is dedicated to offering services to our US customer base. In utilising our consultancy and training expertise, BTLLC provides impartial contract research, analysis, process reviews, product and cycle development services, training courses and analytical instrumentation (FDM, DTA and impedance, DVS) to the global biopharmaceutical and related industries. Our aim is to provide a world-class service to our customers and to meet the precise needs of your projects. To this end, we work together to agree a work programme and budget that is appropriate to the size and stage of the project, whether this be a single cycle run, individual analysis or a complete formulation development programme.

Together with our knowledge of pilot-scale and industrial freeze-dryers, Biopharma offers a uniquely comprehensive service  and  training courses (scheduled, customised on-site or webinar options)  covering all aspects of freeze-drying technology from pre-formulation through to full-scale production and dried product analysis. Biopharma Group’s expertise also extends into analytical instrumentation and is at the forefront of technological developments having, in 2016, launched the most advanced freeze-drying microscope (FDM), the Lyostat5, with its unique tilt-back imaging station and the Lyotherm3 frozen state solution analyser, which combines traditional DTA with electrical impedance to provide the most accurate data relating to critical event stages to optimise freeze-drying process development.

step in many industries such as pharmaceuticals, biotech and freezedrying. Understanding the critical temperatures for each solution can improve the longevity and efficacy of the processes that use this phase. Often, cycles may be operating at lower temperatures than is required, which leads to longer processing times and therefore inefficiency. Having detailed and clear analysis data will allow for determination of clear parameters, which in turn will result in increased efficiency and productivity. In addition to understanding critical temperatures, distinguishing the phase transitions that occur during lyophilization also promotes efficiency and stability. The most effective method of determining these phase transitions is impedance analysis (Zsinφ). The Lyotherm3 is an analytical instrument for frozen state solutions that combines both electrical impedance (Zsinφ) and traditional thermal (DTA) analysis techniques, adding a new dimension allowing for greater detail and more informed decision-making.

When used in conjunction with Biopharma’s Lyostat5 (FDM), a complete picture of the behaviour of the frozen material can be obtained. Measuring the eutectic point (Teu) and collapse temperature (Tc), the Lyostat5 establishes accurate knowledge about the product’s collapse behaviour. This is vital when developing a new cycle, scaling up or developing a formulation for freezedrying, as freezing a solution at the right temperature will save time and money. Both the Lyotherm3 and Lyostat5 are supplied fully validated with full installation and training offered as standard and, when combined with our impartial analytical lab services consultancy services, Biopharma is able to offer you a one-stop shop to maximise your project’s success.

Lyostat5 and Lyotherm3, the Most Advanced Analytical Instrumentation Designed Specifically to Meet the Needs of End Users Establishing the behaviour of frozen state solutions is an essential 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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•  Collaborative Research Biopharma has significant experience in collaboration with academia and industry and is keen to establish new relationships. •  Process Review Lyophilization process reviews are a key service that will check whether your process is suitable for your product.

Trust in Our Experience: Expert Analytical Lab Services The unique characteristics of each product type, formulation and application mean that every project presents a different and new set of challenges. Here’s the core analytical services available:

•  Process Optimization & Scale-Up Minor changes in formulation, container or equipment can affect the efficiency of a lyophilization cycle. This service ensures your processes are optimized for your requirements at laboratory or production scale.

•  Product Characterization In-depth characterization of your product to determine its key thermal event temperatures and behavior is the first step in product and process development.

•  Freeze Drying Production We offer a small-scale lyophilization service to provide process testing, production flexibility, or fall-back capabilities.

•  Training Courses We provide a range of options for training in lyophilization technology, including regularly scheduled, customized and webinar courses.

If you would like to find out more about how Biopharma Technologies LLC can assist you, or to discuss your requirements in greater detail, please contact Chuck Hauswald via: or +1 (484) 477-2136

•  Formulation Development Fo r m u l a t i o n d e v e l o p m e n t combines product characterization with our extensive knowledge of excipients. A well-designed formulation provides protection from the stresses of lyophilization, whilst ensuring a favorable thermal profile. •  Cycle Development A successful lyophilization cycle provides reliable, safe processing. Biopharma’s cycle development services tailor the lyophilization process to the requirements of your product and the capabilities of your equipment. •  Specialist Analysis Dynamic Vapour Sorption (DVS) is a gravimetric technique that measures how quickly a sample absorbs a solvent vapour, and how much solvent in total is absorbed.



Do Sterility Test Isolators Need to be So Complicated?

In an article called Paradise Lost written by Jim Agalloco, president of Agalloco & Associates, Jim talks about the intent of early simple isolators for use in the pharmaceutical industry and how that expected “paradise” was never fully realised as isolator designs became more complex. He sums up his article by saying, “No regulator has mandated that isolators be designed to cleanroom standards, and the more we devoid ourselves of that misdirection the easier it will be to implement what should be the globally acknowledged superior technology of isolator”.

A good example of how simple isolators have been made complicated can be found in sterility test isolators. Isolators have been around the pharmaceutical industry since the early 1980s and in the nuclear industry (glovebox technology) since the 1950s. Isolators are used to create an airtight barrier or enclosure around a piece of equipment or process to provide absolute separation between the operator and product. The operator can perform tasks through half-suits or glove ports. Isolators provide a specific environment inside the isolator using HEPA filters. The environment can be positive pressure or negative, can have humidity control or oxygen control, use unidirectional airflow, and can either protect the product from the operator (as with aseptic processes) or protect the operator from the product (as with potent product handling).

and outlet HEPA filter and operates under turbulent airflow. This unit also utilises a PLC, which very early isolators did not have. However, since the introduction of hydrogen peroxide decontamination generators, automated communication between the isolator and generator are needed. The US Pharmacopeia 1208 discusses the design of sterility test isolators. It states that the isolator must meet Class 100 conditions at rest but does not need to meet this classification during operations. Nor does the isolator need to meet an air velocity or air exchange rate criterion. Therefore, turbulent airflow is acceptable in a sterility test isolator; laminar airflow (unidirectional) is not required. EU GMP Annex 1 focuses on the manufacture of sterile medicinal products where a Grade D background environment, at minimum, is required. Laminar airflow is needed inside the isolator for manufacturing. No mention is made of sterility test isolators.

Figure A: Simple sterility test isolator

The earliest uses of aseptic isolators were for sterility testing. Sterility test isolators make up most of the aseptic isolators in use and are available in many different sizes and configurations. Sterility test isolators do not need to be installed in a classified area. No formal requirement exists for a Grade D environment, but the area should be controlled to allow only trained personnel. The room should also have temperature and humidity control. The simple sterility test isolator shown in Figure A has a positive pressure blower, an inlet 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Unidirectional airflow in sterility test isolators is not needed. It may help with distribution of decontamination vapours but this can be achieved with the proper number and placement of distribution fans inside the isolator. In some instances, half-suit isolators (see Figure B) are needed due to the size of product being tested. Unidirectional airflow would be disrupted by the half-suit. Is particulate control needed in a destructive test? Should the

test environment duplicate the filling environment? Certainly viable monitoring should be conducted in a sterility test isolator so that it can be shown there is no contamination inside the isolator during testing. This was particularly of interest in the past when a work station isolator, often equipped with a single or double half-suit due to its size, was meant to maintain “sterility” over weeks and sometimes months at a time. A transfer isolator full of product and test supplies would be decontaminated daily and then connected to the work station isolator via a rapid transfer port (RTP) as shown in Figure B. Materials would pass securely from the transfer isolator into the work station isolator without breaking the “containment” of either isolator. The work station isolator would be monitored daily for viable organisms using simple settle plates. The more sophisticated viable monitoring systems of today were not available. Yet the simple method was effective. Non-viable monitoring wasn’t done in a sterility test isolator until a few years ago. Is it really necessary to know how many non-viable particles are in an isolator when the product is to be discarded? If passing sterility test results without knowing the non-viable counts in the sterility test isolator of 20 years ago was acceptable then, it certainly could be acceptable now. Another “nice to have” on an isolator is an airlock. Airlocks are used to enter additional items or exit waste and finished media for incubation out of the isolator. Things to consider with airlocks are the size, number of glove ports needed and the environment. The environment of an airlock can be that of a neutral chamber with no pressure control and no airflow. It can also be positive pressure with turbulent airflow Autumn 2017 Volume 9 Issue 3

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Technology through HEPA filters or unidirectional airflow. Finally, the environment might need to be decontaminated with hydrogen peroxide or another agent. If many tests are being conducted in a day/week where the objective is to keep the main testing chamber “sterile”, the airlock(s) can enter and exit materials by first adding the materials into the airlock, then decontaminating the airlock. Once the airlock decontamination cycle is complete (usually in much less time than a larger chamber) and the airlock reaches the appropriate positive pressure and airflow, the door to the main chamber is opened and materials transfer is performed. However, if testing is done once per day or a few times per week, the airlock can be replaced with a good checklist and SOP. Here the main chamber hatchback window is opened and all test materials, product media, etc., are stored on the wire rack shelves in the isolator. Shelving size can easily be determined by simply placing all items needed for sterility testing on a lab bench and “taping” off the footprint of the shelves. This will help determine if a four-glove isolator is sufficient or if a longer six-glove isolator (Figure C) is needed.

The hatchback window is closed and the decontamination cycle is initiated. Once the cycle is complete and the isolator is in run mode under positive pressure HEPA-filtered air, testing can begin. At conclusion of testing, the hatchback window is opened and test samples are taken to the incubator and waste removed. The isolator is cleaned and is ready for the next sterility test.

Once all items are in the isolator, the checklist is reviewed to ensure nothing has been forgotten.

An isolator with no airlocks saves equipment cost and validation expenses.

Figure C: Six Glove sterility test isolator

In conclusion, an effective sterility test isolator for low-volume testing can be a four-glove isolator with a main chamber in 316L stainless steel with a safety glass hatchback window. The isolator will operate under positive pressure, with turbulent airflow through inlet and outlet HEPA filters. A PLC will control the isolator and also communicate with decontamination generators for an automatic decontamination. It can also include stainless steel wire rack shelving for supplies. For high-volume testing a similarly operated isolator with six gloves or even halfsuits can be used. A transfer isolator can be employed as in the past to bring test materials to the work station isolator. The transfer isolator will also operate as a positive pressure, turbulent flow isolator. These simpler systems achieve the goal of eliminating false positives during testing and a lower cost.

Gary Partington Extract Technology, Sales/Marketing Manager. 30 Yrs experience in aseptic isolator design, containment isolators, gloveboxes,downflow booths, RABs & mobile cleanroom. Figure B: Half-Suit Sterility Test Isolator 110 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Autumn 2017 Volume 9 Issue 3


Sizing up the Benefits of Sterile Drug Manufacturing Techniques Sizing up the Benefits of Sterile Drug Manufacturing Techniques Sterile manufacturing environments are open to many sources of potential contamination if not managed correctly. Air filtration systems, materials transfer and not to mention operators – a fully-gowned operator may create as many as 150,000 particles per minute, many of which are viable and are potential hazards during the manufacture of sterile drugs. The need to ensure the safe and sterile transfer of active pharmaceutical ingredients (APIs) and formulation ingredients during aseptic processing has driven the development of multiple techniques that can be employed in cleanroom environments to minimise the risks from contaminants. Christian Dunne, global product manager at ChargePoint Technology, explores approaches to sterile processing and compares several techniques, including aseptic isolators, restricted access barrier systems (RABS) and aseptic split butterfly valve (SBV) technology.

Approaches to Aseptic Manufacturing Barrier technologies such as isolators and RABs are designed to provide micro-environments which have been seen to provide better levels of microbiological protection for a process than that of traditional open cleanroom environments. The aim is to separate the operator from the product and prevent harmful contamination spreading to critical operations in the drug production process. Isolators Isolators are an arrangement of physical barriers that provide an enclosed working space that is detached from the surrounding environment. This enables manipulation to be undertaken within the space from outside the enclosure, without compromising integrity. These enclosures use a combination of techniques to provide and maintain the clean environment such as 112 INTERNATIONAL PHARMACEUTICAL INDUSTRY

positively pressurised chambers maintained through closed loop control of the chamber pressure. HEPA filtered air, supplied to the chamber in a laminar flow to ensure particulate generation is suppressed and removed efficiently and integrated bio decontamination systems, to provide a six-log reduction to the chamber surfaces. Due to the high-performance requirements for these enclosures, integrated pressure decay tests have become the norm during start-up and prior to any bio decontamination phase, with the leak of the chamber being a key factor in the classification of the device. See ISO14644 on leak rates for separative devices. RABS The RABS approach puts a physical barrier between operators and production areas, while still offering the flexibility to interact with the process outside a sealed enclosure. To allow a more limited barrier to be permissible, RABS must be set-up in high-class, generally ISO 7 cleanrooms.

There are two different types of RABS which are commonly used. The first are active RABs, which actively pull the air from outside the cleanroom environment, filtering and extracting it so it is completely isolated. The second type are standard passive RABS that utilise the cleanrooms (HVAC) system. Within these two formats, there are sub-categories which can be defined as follows. Comparisons Between Isolators and RABS In comparison to isolators, RABS can ensure faster start-up times and improve the ease of changeover. They can also bring increased operational flexibility and reduced validation expenditure. Although isolators do offer the advantage of higher integrity chambers for a more robust closed solution. Many pharmaceutical companies are finding that the use of aseptic SBV technology, integrated to either the isolator or RABS for the transfer of material in or out of the enclosure, complements the sterility assurance required for the encloses.




Traditional open










ISO 7 with ISO 5

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critical zones

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using simple

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(curtains) and





generally open

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gloved access



for access.

to the need to

and aseptic

gloved access

gloved access

combine RABS

rapid transfer

and aseptic

and aseptic

and isolator


rapid transfer

rapid transfer


devices sited in

devices (as


grade B – ISO

required) sited

together with

7 cleanroom.

in grade B – ISO

integration into

Possible ‘open

7 cleanroom.

different zone

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Typically, no


operator access

operator ‘open


in process.

door’ access in process.

RABS contribute distinct advantages by enabling operators to maintain a distance from the process, while allowing the enclosure to be opened if significant intervention is required. Autumn 2017 Volume 9 Issue 3

Technology SBV Technology The aseptic split butterfly valve (SBV) provides a safe method of transferring product from one container, process vessel, isolator or RABS to another, while ensuring the sterility of the transfer is not compromised.

Fundamentally, the SBV consists of two halves: the active (alpha) unit and the passive (beta) unit. Each half consists of half of the ‘butterfly’ disc. The active unit is attached to the stationary process equipment such as a mixing vessel, while the passive unit is attached to the mobile container, such as an intermediate bulk container (IBC) or flexible bag. When the two parts are brought together, the disc halves join to form a single disc, sealing any surfaces which may have been exposed to a compound during transfer. The two discs then operate as one disc and can be opened to allow transfer of product from one location to another. The unique design of the aseptic SBV enables decontamination to take place in a closed environment. Once sealed, a gap is created between the discs and hydrogen peroxide gas is flushed through this enclosure to decontaminate the space. The process of validation is done in the same manner as that of an isolator or RABS with the use of chemical indicators to ensure full coverage of the enclosure is obtained and biological indicators to ensure a six-log reduction has been achieved. Adoption of aseptic SBV technology allows manufacturers to benefit from

a closed handling method that not only achieves the required sterility assurance level (SAL) and reduces the requirement for manual intervention, but also offers the opportunity to reduce the resource associated with cleaning and validating large areas. The method minimises cleaning requirements and, consequently, downtime, while also increasing flow and yield from product transfers. Processing time varies between four and 30 minutes, depending on the gassing system utilised. This is extremely fast when compared to a conventional airlock or Isolator which could be in the region of four to six hours. SBV can also contribute considerable cost savings in comparison to traditional approaches, being as much as three to five times cheaper than alternative methods. The aseptic SBV also makes it possible to downgrade the surrounding cleanroom environment because of the integrity of the approach. Conclusion The selection of an appropriate aseptic transfer technology will come down to a variety of factors, including the unique requirements and possibilities within a manufacturing facility, as well as the type of products being processed. Isolators are easier to decontaminate, monitor and offer a high degree of sterility assurance, while RABS provide both increased operational flexibility and speed of changeover which appeals to many manufacturers, particularly contract manufacturers that need to be

able to adapt to different customer products and manufacturing processes. Aseptic SBV technology not only complements and works in harmony with these solutions, but in some applications can replace them; reducing the reliance on cleanroom environments while offering increased sterility assurance and improved ergonomics. Barrier systems are vital to ensure product quality and operator protection, and each of these technologies has its place. It is vital that a full evaluation of products and processes against the various systems takes place in an early-project phase to ensure the right technology is selected.

Christian Dunne Global Product Manager for ChargePoint AseptiSafe Christian is the Global Product Manager for ChargePoint Technology for the aseptic range of products. Over the past 15 years, Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries in the form of high containment and aseptic process solutions. For the past four years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly range of solutions in the aseptic and containment fields, handling high potent/sterile powders and small-scale components, where both product and operator protection are paramount. While working on many aseptic applications, Christian has integrated a number of different bio decontamination systems and consequently has an in-depth understanding of their performance and application. This knowledge was key to the development of the now established AseptiSafe Bio valve, used for the transfer of sterile powders in the industry. Christian is an active member of ISPE and PHSS.



Smart Thinking Drug Delivery Connectivity Beyond the Smartphone

Phillips-Medisize highlights the challenges and opportunities in drug delivery connectivity from incorporating modern technologies with patient requirements.

As drug delivery devices, such as inhalers, have become smaller and more portable over recent decades, they have simultaneously become more complex and smarter in their functions, most recently featuring the ability to provide and communicate information through appropriate modern connectivity methods. According to Bill Welch, chief technology officer, PhillipsMedisize Corporation, drug delivery device producers need to respond to this trend by a ‘systems engineering’ approach. This aims at reducing financial and other risks in efficient device development meeting more advanced technical requirements, as well as ensuring required devices reach the market within agreed schedules. These risks go right through the value chain, from the biopharmaceutical customer, to the developer and producer of drug delivery devices through to users, patients and health system payers. T h e sy s t e m s e n g i n e e r i n g approach, as applied by PhillipsMedisize, requires the company to pay attention to each individual component contained within drug delivery systems, as well as to the components, sub-systems and overall system. Welch says this approach is more robust than a conventional linear product development route in that it requires some engineers dedicated to systems and others to sub-systems development, as ‘this is what makes the whole system work together’. System engineering needs to be performed on components, sub-systems and overall systems at an early ‘proof-of-concept’ stage. This involves on one hand, higher up-front early development stage costs than with linear product development, while on the other hand it saves 114 INTERNATIONAL PHARMACEUTICAL INDUSTRY

other expenses later on (e.g. if a need arises to trace back the cause for a device not properly functioning at a later stage in development or marketing). Up-front development costs mentioned by Welch can be minimised by integrating design for manufacture (DFM) and design for assembly (DFA), as ‘80% of product cost and quality is often determined during the first 20% of the product development timeline’. Morten Nielsen, president of the company’s Medicom Innovation Partner subsidiary, said: “If DFM and DFA are abruptly introduced at the end of the design phase, manufacturing strategy is not aligned with the device strategy, likely introducing late-stage changes that threaten stakeholder requirements or programme feasibility.” Smart Connectivity Solutions While drug delivery device development has tended to be more involved with mechanical functions, incorporating today’s compact electronic technologies into devices requires additional attention. Not only is it important to note how electronic data can be collected by the device, but also how the collected data can best be used to benefit patients, carers, nurses, doctors, payers, insurance companies and so on. So, there is development emphasis on how sensors can be embedded in drug delivery devices, to communicate by wireless or Bluetooth technology to a smartphone or tablet app, rather than having to plug the device into some other equipment or storage device. Once data has been captured, it can be presented to all those

with a justification in receiving and analysing data to optimise treatment solutions. This can include treatment correction communicated back to the patient via a smart device app, potentially reducing exacerbations or the need for hospital treatment. It is the patient who does the monitoring and applies treatment correction. This an important factor with pulmonary diseases such as asthma, where patients can self-administer today with established dry powder inhalers (DPIs) and metered dose inhalers (MDIs), as well as more recent soft mist inhalers (SMIs). It also means more attention has to be paid to patients’ data security and privacy rights, as there will be an increasing amount of data to be handled and protected. For example, a vast increase in the production of large molecule biologics drugs is expected to increase the market value for self-administration of such drugs, which will overtake the value of the self-administered insulin market – the largest and fastest-growing self-administration area so far. However, before drug delivery device producers start looking at connectivity requirements to provide effective outcome-based healthcare in this new market, they need to have solved how drug delivery devices can be designed to provide primarily self-administered injection of the viscous solutions involved. Autumn 2017 Volume 9 Issue 3

Advertorial This is quite a different challenge compared with that of powder inhalation devices. Patients need to have devices they can easily use for self-administration, as otherwise the ‘big data’ connectivity reports a poor outcome for the patient due to lower dosing adherence. Additionally, less understanding of the disease is acquired by health system stakeholders. The problem of poor adherence has been brought to light by the University of Texas Medical Branch (UTMB) in the results of a study revealed in December 2014. UTMB found that only 16% of patients surveyed used an epinephrine auto-injector properly. It pointed out: “More than half missed three or more steps, the most common error being not holding the unit in place for at least 10 seconds after triggering epinephrine release.” Other common errors included failure to place the device’s needle on the thigh and not depressing the device forcefully enough to activate injection. It was further established by UTMB that ‘only 7% of users demonstrated perfect technique and 63% missed three or more steps’. The most common ‘misstep’ here was not completely exhaling before inhaler use, while failure to shake the inhaler before the second medication ‘puff’ was also a common error. These are the types of problems that can be addressed by incorporating real-time error detection, notification and correction in smart drug delivery devices, with audio, visual and tactile feedback. It has also been suggested that problems of device clogging and patients forgetting device advisory information received from healthcare professionals (HCPs), and/ or instructions accompanying the device, should be addressed in this way. Furthermore, it is suggested that patient error may also be prevented through the use of electromechanical inhalation devices with breath sensing and other advanced technology. Smart devices and connectivity were addressed in a joint workshop in spring this year by Welch and his colleague Kevin Deane, executive VP, Front End Innovation at Medicom Innovation Partner at the RDD Europe Respiratory Drug Delivery conference in Antibes, France.

The workshop participants gravitated around patient-centric benefits as the primary source of value drivers and opportunities for connected health. Themes around improved treatment, better patient education, patient empowerment and social support were discussed by a majority of the groups. In the interactive workshop presentation, titled ‘Realizing benefits of connected health in respiratory drug delivery’, the authors referred to healthcare costs taking increasingly high shares of gross domestic product, while ‘dosage forms evolve and connected devices proliferate’. They maintained that increasingly complex, targeted and personalised drugs mean devices are becoming ever more critical to patient acceptance and drug performance. Connectivity was seen as an enabler for reducing waste, saving costs, personalising treatments, improving clinical trials and even evolving device designs. Furthermore, the challenges to implementing connected health seemed to align around technical issues, poor business cases, concerns around data ownership/security/ privacy, regulatory risks and general reservations about ‘change’. That there are already more connected devices than people, with the average person soon to have as many as six devices online, should be seen in the context of the uptake rate of digital infrastructure occurring five times faster than the adoption rate of electricity and telephones, the authors stressed. They advocated that a ‘connected health approach’ should cover the entire ‘patient care journey’, saying that the new ‘patient-centric’ approach means the delivery method becomes the key connection point between the drug, its producer and the patient for many therapies entering the market today. Welch and Deane said that secure cloud storage is a key central element in a fully connected respiratory health service setup, in which two-way interaction takes place via the cloud between the delivery device and the patient, as well as between the patient’s app and a ‘dashboard’ for nurses and other HCPs. Data in the cloud can be a source of information for trend analysis by health system

payers and the pharmaceutical industry on a ‘no cure, no pay’ basis, Welch and Deane suggested. Within individualised treatment scenarios in a fully connected health system, they said automated patient adherence monitoring and symptom/event logging benefit, above all, respiratory drug delivery. Patients can benefit here from individual disease-related information and alerts, such as data on local pollen and pollution levels, and HCPs can remotely monitor their patients. Pharmaceutical companies also have benefits such as automated supply chain logistics for medicine re-ordering. However, Welch and Deane questioned whether longerterm costs of running and maintaining a well-functioning connected health setup are known. Whether there is clarity on the return of investment (ROI) achievable from upfront investments, or on reimbursement to HCPs for provision of added value services, the authors emphasised that a successful delivery device design must be useful in meeting a specific need, user-friendly, desirable through its appeal to the user and capable of efficient and reliable manufacture in commercial volumes. The device strategy to address an outcomebased solution should be combined with a manufacturing strategy to get to market at target quality, cost, time and risk, Welch and Deane maintained.

Bill Welch CTO, Phillips-Medisize Corporation. Over 25 years of contract design, development and manufacturing experience, primarily serving customers in the drug delivery, health technology and diagnostics markets.



So, You Think You Have an Invention?

You’ve worked hard, inspiration has struck and you think you have an invention. Congratulations! However, the success of an invention can depend not just on the advantages that the invention provides, but also on the strength of the patent that protects it. By considering the following seven points, you can put yourself in a better position to obtain strong protection and so improve your chances of making a success of your invention.

A patent is essentially an agreement between society and an inventor. It encourages inventors to tell the public about their inventions, in return for a twenty-year monopoly for commercialising their invention before any competition. So, society benefits from knowledge of technological advancements and innovators are insulated for a time from would-be competitors. This agreement requires fully disclosing your invention to the public; it is important to consider whether keeping the information confidential might be preferable. This may be appropriate, for instance, if the costs of obtaining a patent are not commercially justified, or if you know your product cannot be reverseengineered to uncover the ingredients or method of manufacture. On the other hand, patents can provide commercially useful protection, and often represent good value when research investment and likely product revenue are considered. Since a patent allows a proprietor to stop other people’s activities for a long period of time, these rights are granted judiciously to ensure that both sides of the agreement are upheld and that inventors do not obtain protection for more than they are due. A patent application will be carefully scrutinised with this in mind. A patent will only be granted to the first to file for a novel and non-obvious invention. It can be important to file 116 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the application quickly, otherwise you risk losing the ability to obtain a patent at all if someone files an application for the same invention before you, or publicly discloses information that either teaches your invention or means it is obvious. Balancing a timely filing with a well-prepared patent application can be difficult, and we would recommend that you seek advice from a patent attorney to assist you, but consideration of the following seven points will help you give them the information they need to help you get strong protection. 1. Is it useful? An invention must be useful. It could involve making a new useful product, a new use of a known product, and/ or a new method of doing or making something. In UK patent law, we sum this up by stating that the invention must have industrial applicability. Therefore, a scientific discovery is not patentable as such, instead you need to find a useful application of that scientific discovery. For example, you might have discovered the mechanism by which a drug exerts an effect. If the drug is already known, and all the discovery provides is an explanation of why and how it is effective, then that does not teach anyone to do anything new. However, if knowing the mechanism means that now you can identify a particular patient group for whom the treatment will or will not be particularly effective, a new treatment regimen that will be more effective, or a new complementary drug combination, then the new knowledge can be used to support a new patent application directed at the drug for use in the treatment of the new patient subgroup, the new treatment regimen, or the new drug combination. 2. What’s been done in the past? It is not necessary to know absolutely all the information that has been made public and is relevant to your invention (so-called ‘prior art’). It is normal for

additional prior art to be found by the patent office during the examination process. However, it is useful to have an idea of what has been done previously, especially what has been done to solve the same problem as the invention, or what has been done or used instead of it. You may need to explain during examination why your invention is new and not obvious in view of the prior art, and your patent attorney will want to provide at least pointers to this explanation in the patent application. Therefore, it is useful for them to know about any academic articles, presentations, earlier patent applications, etc., when they prepare your application. As an expert in your field, you are probably best placed to draw such publications to their attention and to explain the differences between those publications and your invention. 3. Have you told anyone? A patent application is assessed against essentially everything made public, in any form, before it is submitted to the patent office. If you have told anyone about your invention, and it wasn’t under an obligation of confidentiality, then that disclosure could stop you getting your patent. It is safest to keep the invention secret until after the patent application has been submitted. Additionally, if you are planning to develop your invention further then it might be best to keep it secret for 12 to 18 months even after the application has been filed, so that you will be able to protect those developments. If you must speak with someone about your invention, for example to seek funding to develop it, then there are steps you can take to preserve confidentiality, for example using non-disclosure agreements (NDAs). Even if you have told someone about your invention without such an agreement in place, or made public details of it before your application has been filed, if you act quickly there are steps that a patent attorney might be Autumn 2017 Volume 9 Issue 3

Technology able to take to help you obtain at least some protection for your invention. Therefore, if you have disclosed or intend to disclose information about your invention before the application is submitted, you should talk to a patent attorney as soon as possible so that they can best advise you on how to preserve your ability to seek patent protection. 4. Are you the only inventor? Often, the development of an invention is a collaborative effort rather that a solo one. Agreeing exactly who made a significant contribution can be complicated, but it is also important. Inventors have a right to be named as such on the patent, and ostensibly the invention and patent application or patent will belong to the inventors. Often the inventors’ ownership will transfer to one or more companies or institutions due to their employment or an alternative agreement, but the correct ownership of the invention, and so the patent, will always depend on who the inventors were. Ideally, if collaborators from different companies or institutions will be working together and that work may result in an invention, then a collaboration agreement should be put in place before the work begins, so that it will be clear how any resultant patent applications will be owned and controlled. However, if such agreements have not been pre-established then it will be important to agree inventorship, ownership and who will have control of any patent application, as soon as possible. With delay comes the possibility that the people or organisations involved will develop competing interests and that relationships will sour, leading to potentially expensive disagreements over the invention and patent. Indeed, such disagreements could weaken the patent itself, and possibly the value of the invention. For example, the much-publicised patent battles over the initial CRISPR patents are superficially described as being led by the University of California (UC) on one side and the Broad Institute in Cambridge, Massachusetts on the other. However,

the earliest Broad patent applications suggest that up to ten inventors were actually involved in developing the described inventions, and those inventors have been associated with up to four institutions; disagreements regarding which inventors were, and which should have been, listed on those applications, and consequently which institutions owned the rights in those applications, have led to disputes in the US courts as well as arguments with which opponents have sought to attack the European patents. Earlier discussion and agreement about inventorship and ownership, before or soon after the inventions were made, might have avoided these disputes and attacks. 5. What are the essential components of your invention? The claims of a patent will clearly and specifically describe what it covers, i.e. define exactly what the owner of the patent can stop other people from doing. To give a fair reward for your inventive contribution, they should be broad enough to cover all possible ways of carrying out your invention, but they should not be so broad that they cover products or methods that do not work. The claim strategy will depend on your commercial requirements. In order to craft useful claims, and to provide some defensive scope in the form of narrower, fall-back claims that might be used to overcome objections during examination, your patent attorney will need to know how much flexibility there is in the specific components of your invention. Does a particular chemical have to be used as a reagent or catalyst in your inventive reaction, or can any member of a group of chemicals be used? Does a particular amino acid sequence have to be present in your biological product, or is it sufficient if particular motifs or residues are in certain positions? For each component or step of your invention, you should consider whether it is essential and if so, how specific you need to be about it. If the definition provided in the patent is too specific, competitors may be able to take the substance of your invention but avoid infringement by using minor modifications not covered by the claims.

The importance of this was recently highlighted in a case brought against Actavis in the UK courts. Eli Lilly have a patent with claims covering the use of the disodium salt of pemetrexed in combination with vitamin B12 for treating cancer. Actavis supplied a different salt of pemetrexed with vitamin B12. Eli Lilly accused Actavis of infringing their patent. Fortunately for Eli Lilly, the UK Supreme Court decided that the reference to a disodium salt of pemetrexed in the claims should be understood broadly, so that the use of a different salt by Actavis does in fact infringe. However, this was a surprising result for many, and indeed overturned the decision of the lower court. The uncertainty for both Actavis and Eli Lilly, as well as the expense of the complex court case, could perhaps have been avoided if the claims had been written to more broadly cover many salts of pemetrexed. 6. What would someone need to carry out your invention? A key part of the agreement with society is that a patent application must provide sufficiently detailed instructions to carry out and obtain the benefit of your invention across the breadth of the claims. If it is deemed deficient in this respect, this cannot be rectified through amendment and so can be fatal to the application or patent. The instructions may be provided, for instance, through a description of the required steps and reagents or a worked example. You must describe any reagents and conditions that are necessary, and, for example, there are systems you can use to provide controlled access to biological organisms or materials if their supply is restricted but they are vital to working the invention. Similarly, you must describe any tests that need to be carried out for the invention, for example to record measurements or check activity of components, and a description of a test must be particularly specific and defined if the test is not a standardised one. For example, your invention may be based on your discovery of a new antibody that binds a specific receptor and has a particular desirable effect. In order to make sure that a patent covering that antibody and similar acting ones INTERNATIONAL PHARMACEUTICAL INDUSTRY 117

Technology has sufficient information, you may need to: allow controlled access to a hybridoma expressing that antibody and/or provide the sequence of the antibody or key parts of it; describe the specific antigen and/or epitope to which the antibody binds; and describe what tests must be carried out to determine whether another antibody has similar desirable activity or not. Also, if there are any conditions or reagents that a reader might expect to be able to include as part of the invention, for example a routinely used preservative, but that cannot be included because it would prevent the invention working, for example due to inhibitory interactions, then that should also be mentioned in the patent application. What you actually need to provide will depend on the specific details of your invention and the breadth of the claims, but generally the more information provided about the capabilities of the invention and how to carry it out, the better the position you will be in to obtain broad patent protection. 7. Can you show that your invention actually works? To get your patent, the patent office will check that your invention is not obvious over the earlier prior art. In Europe, for example, that means the invention must provide a technical solution to a problem, compared to the closest earlier publication, and that an unimaginative person in your field would not have arrived at your invention by routine work when trying to solve the same problem. You don’t need to have had a “eureka” moment, and indeed the problem might be a significant one, such as providing an improved method or product, or it might simply be to provide an alternative method or product.

However, in order to convincingly argue that you provide a solution to a problem, you must make it at least plausible from your application that your invention actually works, i.e., that it actually solves the problem. The safest approach is to include experimental evidence of the effect that your solution relies on, for example in vitro or in vivo evidence of the effectiveness of a drug. If that is not possible, then providing a plausible explanation for the effectiveness of your invention may be convincing, for example by explaining how the mechanism of action of the drug corresponds to the aetiology of the condition you claim it treats. A recent decision of the European Patent Office to revoke a patent belonging to Bristol-Myers Squib emphasises the importance of this. The patent was for dasatinib (Sprycel), a tyrosine kinase (TK) inhibitor for treating leukemia. Even though dasatinib is now known to be effective and valuable, it was decided that the teaching of the patent application did not make it plausible that dasatinib had the TK inhibitor activity required by the invention. In particular, although dasatinib was disclosed in the application as one of hundreds of compounds of interest, and although those compounds were said to have TK inhibitor activity which could be used to treat diseases including cancer, no data was provided showing that any of the compounds, let alone dasatinib, actually inhibited TKs relevant in cancer. Once plausibility was denied, it was not possible to rescue the patent. So, Are You Ready to File? Considering the above points should help you work with your patent attorney to prepare a strong patent

application. It may be that you have realised that you need to conduct further experiments, or undertake further research, to provide more complete information. Delaying filing to do so may be worthwhile, but it may also be risky, considering the importance of filing the application in a timely manner. In that case, talking with your patent attorney may help you decide the best way to proceed.

Dr Ben Tolley Ben is a qualified European Patent Attorney. Ben's professional interests include drafting and prosecuting UK, European and International patent applications for a wide range of life sciences technologies. He has worked with a range of clients from multinational corporations and SMEs to universities. Ben has particular experience in the field of gene editing technologies, genetic testing, antibodies and diagnostic biomarkers. Email:

Dr Emma Longland Emma is a Senior Patent Attorney with experience in all aspects of patent work, including drafting and prosecution of patent applications, defending and attacking patents during EPO oppositions and appeals, and providing freedom to operate and due diligence advice. Emma has always had a wide-ranging practice, working for clients in many different fields, although with an emphasis on the medical and biotechnology fields. This has included cases concerning, for example, vaccines, humanised antibodies, anti-cancer pharmaceuticals, treatments for autism-spectrum disorders, personalised medicine, diagnostic markers, and medical devices. Email:


Autumn 2017 Volume 9 Issue 3


DSCSA Enforcement Delay – What Now?

The Other Shoe Drops With the recent FDA announcement regarding a one-year delay in enforcement of the Compliance Policy for ‘Product Identified Requirements Under the Drug Supply Chain Security Act' (DSCSA), many are left asking what this actually means for the wider pharmaceutical industry or for their own company’s initiatives. While the FDA communication specifically indicates a delay in enforcement, it is clear there is no delay of the law itself; a telling signal to the industry that this serialisation challenge is real.

Within the industry there had already been much speculation and scepticism regarding what would happen in November 2017. Given the history of deadlines coming and going in California for most of a decade, followed by a national mandate passed by the US congress (albeit watered down), many in the industry were left dubious that the government could realistically enforce the deadline. Furthermore, regulations and administration in Europe, Brazil and China have been walked back, morphed, or changed over the past 12-18 months, adding to the industry’s scepticism. Over the past three to six months, the drumbeat of industry representatives appealing to the FDA for delayed enforcement has steadily increased. Despite best efforts, the industry as a whole is not, and will not be, prepared for November of this year. While many leading pharmaceutical companies have actively progressed their serialisation initiatives, a large proportion dragged their heels in a wait-andsee approach to enforcement. Equipment suppliers, third party EPCIS providers, consultants and CMOs raised concern over the anticipated skyrocketing demand on resources as we approached the deadline. Since the beginning of 2017, those concerns have been fully 120 INTERNATIONAL PHARMACEUTICAL INDUSTRY

realised. The industry simply does not have the collective resources to enable every pharmaceutical company to comply. Fortunately, the FDA listened to their concerns and acted accordingly. So What Now? The industry has been given a reprieve, some breathing room, to help it manage through the collective implementation. In the scope of work required for serialisation implementation, an additional 12 months is not a lot of time, frankly. It would be a very poor decision for any company to delay their current activity with the thought that the goal line has moved significantly. PCI Pharma Services has publicly stated that we have no intention to slow down any activity currently underway as we support our clients’ serialisation implementation. In February of this year, we announced a dramatic capital equipment investment that will have us triple our existing serialisation capacity. We have grown our in-house dedicated serialisation team to over 30 associates. To give perspective on our own scope of work, we fully expect to install and enable over 80 individual packaging lines to be serialisation-ready in support of drug products destined to reach over 100 countries around the world. We have

been actively serialising commercial drug product for global markets for over five years; in doing so, building the considerable experience and expertise needed to execute a well prepared and thoughtful implementation strategy. In engaging the wide spectrum of clients, it is apparent that we seem to be the exception rather than the rule. Opportunity Knocks The recent delay in enforcement does create a number of opportunities to regroup on serialisation strategy. The wide majority of the industry has been solely focused on meeting the minimum requirements, namely having a serialised code on their packages as of November 2017 and doing their best to manage supplies pre-/post-serialisation to minimise their liability of legacy unserialised drug in the downstream supply chain. Even some traditional blue-chip multinational pharmaceutical companies have communicated that their strategy is to quite simply meet the law in its most basic requirements. With the enforcement delay, aggregation is one area for opportunity in ensuring the industry gets it right this time around. The DSCSA regulations call for a unique identifier, a serialised code, to be placed on every saleable prescription Autumn 2017 Volume 9 Issue 3


Ompi EZ-fill® ISS: An Integrated Safety System for Prefilled Syringes Ompi expands its Ompi EZ-fill® Syringes offer by adding an Integrated Safety System (ISS) for staked needle syringes. Ompi EZ-fill® ISS is an innovative, fully passive safety system designed to guarantee end users’ safety and reduce total cost of ownership for the pharmaceutical companies.

Ompi EZ-fill® ISS is the first development within the platform licensed by Tip-Top, a primary designer of proprietary safety needlestick protection devices and technologies. Based on their mini-Max design, Ompi EZ-fill® ISS avoids piercing after rubber needle shield removal, providing an end-user experience similar to a standard syringe. “Ompi EZ-fill® Integrated Safety Systems (ISS) is a breakthrough in the safety systems technologies,” says Andrea Zambon, Marketing Director Pharmaceutical Systems division at Stevanato Group. “In addition to end users’ safety and intuitive use, it enables the pharmaceutical company to maintain the glass primary container of choice. Ompi EZ-fill® ISS is designed to fit the existing fill-finish formats. It is supplied in a standard Nest & Tub configuration for easy processing on current fill-finish lines, with a significant reduction in terms of total cost of ownership.” The Integrated Safety System is the result of a rubber needle shield inserted in a plastic shield with flexible wings, combined with a ring and a hub, pre-assembled on the Ompi EZ-fill® Syringe. Its functional performances allow the needle to be locked inside the safety device with no possibility of exposing it again, after usage. “After Ompi EZ-fill Integrated Tip Cap (ITC), the Ompi EZ-fill Integrated Safety System (ISS) is another successful result of the synergies within the Stevanato Group companies,” says Mauro Stocchi, General Manager Pharmaceutical Systems division at Stevanato Group.

“Balda, a provider of plastic solutions and delivery devices recently acquired by the Group, designed and produced all the plastic parts of the Ompi EZ-fill ISS, in order to perfectly fit Ompi EZ-fill Staked Needle Syringes.” Ompi EZ-fill® Integrated Safety System (ISS) has been developed for all formats of staked needle syringes and it is customisable in terms of needle gauge and length, barrel volume, ISO standard rubber components and siliconisation. It meets the needs of different drug products applications, such as biotech, heparin and vaccines.

to high-value ones such as syringes and cartridges for auto-injectors and pen-injectors. Vials, cartridges and syringes are also available sterile and ready to fill (Ompi EZ-fill®). Ompi boasts a global footprint with high-quality production plants in Europe (Piombino Dese and Latina in Italy, Bratislava in Slovakia), Mexico (Monterrey), Cina (Zhangjiagang, near Shanghai) and a plant under construction in Brazil (Sete Lagoas, Minas Gerais).

About Stevanato Group: Founded in 1949, Stevanato Group is committed to creating systems, processes and services that guarantee the integrity of parenteral medicines. It comprises two operational divisions dedicated to serving the pharmaceutical industry: Pharmaceutical Systems with Ompi which specialises in glass primary packaging and Balda, which focuses on speciality plastics and delivery devices; Engineering Systems with Spami, Optrel, InnoScan and SVM, specialising in glass processing, inspection systems, assembly and packaging solutions.

Thanks to the safety systems platform, Ompi will be pleased to offer a wider range of safety systems in the future.

These two divisions enjoy a close, synchronous relationship, featuring daily exchanges which ensure that Stevanato Group has complete control over the entire production process.

About Ompi – A Stevanato Group Brand: Ompi is part of the Pharmaceutical Systems division of Stevanato Group. It offers the widest range of glass primary packaging, from traditional ones such as vials and ampoules,

The Group also benefits from the SGLab activity that provides technical and analytical services on the potential interaction between drug and container. INTERNATIONAL PHARMACEUTICAL INDUSTRY 121

Packaging drug product package. Technically, the DCSCA for 2017 does not require aggregation until closer to the year 2025. The process of aggregation marries up serialised codes on individual saleable packages with their mates in secondary and tertiary packaging for the purposes of traceability. For example, 24 cartons may be placed in a corrugated shipping container. Each of the 24 cartons will have a distinct serialised code, as well as the shipper itself. In turn, each shipper placed on a pallet will be subsequently married to the serial number of that pallet itself. Utilising the principles of aggregation, various partners within the supply chain – such as the pharmaceutical company and distributor, wholesaler, and the pharmacy customer – can affirm the contents of each pallet or case by the data configuration. Without the use of aggregation, one is left to ‘infer’ what is contained, or be left to physically open and investigate the contents to verify what is contained within. While the DCSCA for 2017 does not require aggregation, there are many benefits to using it right out of the gate. PCI has taken a stance that inference would not be used and aggregation is the only trusted and reliable method to ensure 100 per cent verification of all codes. This is borne out of practical experience, having supported client projects where a non-aggregation approach was desired by the client, and real-world operational challenges arose. Aggregation creates a methodology whereby codes are captured and catalogued, in sequence, as packages


data aggregation and reserve the right to charge back pharmaceutical companies in the event they have to unpack supplies to artificially create this information. Aggregation does add additional complexity to implementation planning, but the benefits far outweigh the incremental investment. The DSCSA legislation makes clear that it is also something the FDA supports in a robust supply chain.

travel through the line. A genealogy is created in real-time within a batch. In a non-aggregation environment, situations such as missing code verifications or line stoppages can lead to a literal needle-in-a-haystack approach to product reinspection to provide the assurances required. Alternatively, reinspection with aggregation is precise, down to the case or tray, because of the data catalogue. Furthermore, effective use of aggregation can actually streamline packaging processes and improve both OEE and line efficiencies by integrating more robust processes and advanced line inspection technologies. Other benefits to aggregation are realised by downstream supply chain partners. In the US, each of the ‘big three’ drug distribution companies have made it plainly clear that they will not accept inference in the supply chain. Their position is that despite the basic requirements of the law, they demand drug product with

The Key Principle – Safe Medicines In the rush to meet the requirements of the DSCSA November 2017 requirement, the industry has somewhat lost sight of the spirit of the original legislation. The discovery of counterfeit and non-regulated foreign versions of Avastin in several US states (across a multitude of hospitals and oncology clinics as recently as 2013) is a stark reminder. The DSCSA legislation is only a first step in addressing the introduction of counterfeit, adulterated or grey-market drug product into the legitimate healthcare supply chain. While the legislation is intended to mobilise the industry, in and of itself the legislation does little to curb the threat posed to patients by these illicit activities. In keeping patients safe, the onus is on the drug company to develop, execute and maintain a comprehensive anticounterfeiting strategy, including serialisation. Serialisation is a good first step and the industry will have advanced it as an executed national standard over the next 12 months. The use of serialised codes provides a verification opportunity for individual points in the supply chain, as well as the pharmacist and patient. One glaring hole in the regulations currently is the methodology for a patient to actually verify their medicines. There simply is no central database or online resource patients can use, even if they opted to verify the authenticity of their serialised medicine at the moment. This is a critical issue yet to be resolved in the initiative and little information would suggest it is being established in this calendar year, despite the original November deadline for the presence of serialised codes. Autumn 2017 Volume 9 Issue 3

US requirement for TE-ring on ophthalmic dropper bottles | Dropper bottle System A now with a blocked TE-ring on the bottle | All dimensions, properties and material are kept the same | Design of TE-ring modified October 24 – 26, 2017 | Frankfurt

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Packaging Similarly, there is no infrastructure currently to affirm medicines have been consumed and that a serialised code should then be taken out of the ‘good list’, if and when that list is even accessible to patients. This creates a scenario where two packages could bear the same legitimate code, yet one may not be from the legitimate supply chain, thereby defeating the purpose of the serialisation initiative. One can reasonably deduce that with the sophistication of global counterfeiters and the money to be made, it is only a matter of time before these gaps are exploited by the criminal element. Comprehensive Anticounterfeiting Strategy There are tools and methodologies to help thwart bad actors, including readily available features and technologies to employ. It is worth noting that there are basic philosophical differences in the US DSCSA approach as compared to the EU’s Falsified Medicines Directive (FMD). A key feature of the FMD is the need for tamper-evident solutions in an effort to ensure the integrity of the package, coupled with the serialised codes. Legislation does not require specific anticounterfeiting technologies to be integrated, but many leading firms do opt to employ these features in their tamperevident solution. While both pieces of legislation have their benefits and drawbacks, this requirement is noteworthy and helps advance the cause, as well as helping to propel a global standard for pharmaceutical companies as part of their strategy. All of this speaks to the need for individual drug companies to develop and maintain truly comprehensive anticounterfeiting initiatives to protect their medicines and their patients. Laws to protect patients are notably weak in their penalties and there is no industry watchdog to actively detect out counterfeit medicines. The FDA has largely been reactive to events of large-scale counterfeit medicines and is not resourced appropriately to proactively pursue illegal activity. Major pharmaceutical companies may employ investigative teams which partner with law 124 INTERNATIONAL PHARMACEUTICAL INDUSTRY

enforcement, but unfortunately are left to a daunting task in policing the integrated global supply chain and its bad actors. Unfortunately, smaller pharmaceutical companies simply do not have the wherewithal to police in this manner. With the significant rise in the market value of specialised medicines, this is a problem for drug companies big and small. The question is where to concentrate resources to achieve the desired results. Where to Focus Efforts It is clear that the best and most focused strategy is utilisation of tools and technologies in the drug product and its associated packaging. This involves use of cutting-edge overt and covert technologies to discourage counterfeiting. These technologies have to be rotational and multi-layered in nature, using a focused strategy to stay one step ahead of very sophisticated counterfeiters. Patients, pharmacists and hospitals have to have a way of positively verifying their medicines are authentic, from a legitimate pedigree, and continually kept in appropriate conditions – particularly pertinent for biologics demanding an end-to-end cold chain. A failure of any of these factors can put vulnerable patients at risk. A Good First Step The US DSCSA legislation was intended to jumpstart the industry and it has done so. With a storied history of delays, the pharmaceutical industry has not moved out of first gear, but needs to quickly upshift. Leadership from organisations such as GS1, HDA, and GTT, among others, has at least provided the opportunity to coalesce around a common cause and advance the collective. The implementation of serialisation seems herculean today, but serialisation will quickly be as commonplace as retail barcoding and electronic payment. The key will be to capitalise on the momentum of the serialisation initiative to translate this experience and knowledge to subsequent activities in securing the supply chain and the continued advancement of anticounterfeiting technologies to keep patients safe.

PCI is in the business of providing life-saving medicines to patients around the world. Drug product should never put a vulnerable patient in harm’s way, particularly those with compromised health. We have to advance industry practices to ensure safe and effective medicines around the world. Our patients deserve nothing less than our best.

Justin Schroeder Senior Executive Director, Global Marketing & Design at PCI Pharma Services Justin Schroeder is the Senior Executive Director, Global Marketing & Design at PCI Pharma Services, responsible for global marketing, creative package design and new account development with a focus on the development and commercialisation of new products. Mr. Schroeder has over 20 years of experience in outsourced pharmaceutical services in various roles including Engineering, Project Management, Marketing & Development. He holds a Bachelor of Science from the School of Packaging at Michigan State University and an MBA in Marketing from Northern Illinois University. Mr. Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email:

Autumn 2017 Volume 9 Issue 3



EFFICIENCY MATTERS Thanks to our knowledge, we optimize processes by developing products and services that meet the needs of our customers and support patient compliance.



Tungsten in the Production of Prefillable Syringes – Also Possible Without Tungsten Approximately 3 billion pre-filled syringes were sold worldwide in 2016, and the prospects for growth remain good. Drugs based on technologically manufactured active ingredients (biotechnology medications) filled into syringes currently thereby have a share of approximately 15% of the total market value for pre-filled syringes. These high-growth biotech drugs, such as monoclonal antibodies, are, due to their complexity, sensitive with regard to possible interactions with individual syringe components. Undesirable protein aggregations can thus arise in the filled syringes during storage, which impair the effectiveness of the medication. Syringe system manufacturers therefore strive for a reduction or avoidance of syringe components like silicone oil (in the final syringe) or tungsten(from the forming process). This article concerns itself with the reduction and avoidance of tungsten in prefillable glass syringes.

Use of the Tungsten Pin Tungsten is a contact material ideally suited to and often used for the production of glass syringes. When the glass tubes are heated to approx. 800-1200°C, form rollers shape these into a cone shape at the later front end of the syringe. In order to keep the bore open and define its interior diameter, a tungsten pin is inserted into every syringe to this purpose.

The Advantages of Tungsten Are: •  Heat-resistance; expansion coefficient similar to that of borosilicate glass •  Self-lubricating •  Flexible, easy to handle Disadvantages can occur when traces of tungsten remain following the forming process in the cone area: •  Abrasion •  Tungsten oxide •  Possible later interaction with proteins after filling of liquid drugs Influence of Tungsten on Biotech Medications Tungsten is, in fact, a heavy metal, but the potentially remaining tungsten quantities are extremely minor and have no toxic effect on patients. Problematic on the other hand is the fact that some biotechnology medications react sensitively to traces of tungsten or their oxides and can induce protein aggregations. This takes place as the result of electrostatic molecular interactions or the formation of chelate complexes with oxygen, nitrogen, or sulfur atoms, which are a component of the protein molecules. As a consequence of the cone-shaping process, invisible or visible deposits can form in the cone area, which are no longer acceptable to the pharmaceuticals customer. Tungsten oxides are initially not detected during the production

Use of the tungsten pin in glass syringe production 126 INTERNATIONAL PHARMACEUTICAL INDUSTRY

o f (e m p t y) g l a s s sy r i n g e s . Potential incompatibility only becomes conspicuous during the stability studies carried out by the pharmaceuticals companies. Pharmaceuticals companies are called upon to test the compatibility of their medications with the primary packaging material. The use of tungsten-reduced or ideally metal-free produced syringes thereby reduces the risk of protein-packaging material interactions. Regulatory positions can be found in, for example: •  the FDA Guidance for Industry – Immunogenicity Assessment for Therapeutic Protein Products and •  the PDA Technical Report No. 73 - Pre-filled Syringe User Requirements for Biotechnology Applications

These documents recommend special leachables and extractables analyses, including reference to tungsten. Exposition studies (“spiking studies”) are recommended for the tungsten analysis in order to evaluate the risk of interactions. Particularly the chemical milieu (pH value) is decisive for the occurrence of tungsten-induced protein aggregations: •  Tungsten polyanions are primarily created in the acidic milieu •  Proteins can form complexes with polytungstates; depending upon the pH value, these are partially reversible •  Sodium tungstate (Na2WO4) is the most potent molecule

Only a few protein formulations are to date demonstrably known to form visible deposits in pre-filled syringes, meaning that tungsten compounds only generate protein aggregations in a few cases. Examples include Epoetin Alfa (Seidl et al. 2012) and several monoclonal antibodies at low pH values (Bee et al. 2009). Autumn 2017 Volume 9 Issue 3

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Packaging Influence of the Filling Technology The filling process of the prefillable syringe can also have an influence on the formation of protein aggregations due to tungsten. In the case of the vacuum stoppering process, the liquid comes into direct contact with the inner cone, as, in contrast with the stoppering tube process, no small air bubbles remain between the liquid and inner cone. This direct contact can bring tungsten traces into contact with the sensitive proteins during the storage period. Tungsten Values in the Production Process There have been a number of studies on the measurement of tungsten in the syringe cone. The cone diameter has a strong influence on these measuring values, meaning that values of 50-500 ppb/syringe can be observed with RTF syringes (RTF needle syringes, washed, siliconised, nested, and sterilised). Individual outliers caused by fluctuations in the process temperature or abrasion of the tungsten pins are also possible.

step of RTF production. On average, the tungsten load can in this way be reduced by approximately 90%. Visible particles are also significantly reduced in this process step. Effect of the washing process on


of tungsten impurities

>90% on average

Particles >0.3 mm


Particles >0.1 mm


Reduction of the tungsten and particle load through the washing process in glass shaping.

This washing process can be carried out with all syringe formats (0.5 ml, 1 ml, 1-3 ml) and all cone shapes (Luer cone, Luer lock, stakedneedle). Another “final rinse” with WFI later takes place in the RTF process. The washing process takes place directly following the shaping of the syringe body. The measurements were carried out in accordance with the specifications in the USP (NF

Prefillable syringe, tungsten oxides remain in the bore following syringe forming.

<730> Plasma Spectrochemistry) and the Ph. Eur. (2.2.58 Inductively Plasma Coupled-Mass Spectroscopy). Tungsten-free and Metal-free Glass Syringes With a few decisive technical adaptations to a glass shaping line, production of syringes with other metal pins or with ceramic pins can also be carried out. When replacing other metals, one speaks of tungsten-free syringe production; with ceramic pins of metal-free production. Metal-free Luer cone and Luer lock syringes in all syringe sizes (0.5 ml, 1 ml long, 1-3 ml standard) are available. Metal-free in this case does not refer to components of the glass or impurities (elemental impurities), but instead to the material of the pin used. Metal-free Syringe – Choice of the Ceramic Pin The material selection for the pin is an important element in process development. Besides the stability of the process, product quality is also decisive. The ceramic material may thus not generate any particles (abrasion) and the pin material should fulfil biocompatibility requirements in accordance with ISO 10993. Experiments with scanning electron microscopy (SEM) in combination with X-ray microanalysis (EDX) were also carried out for the ceramic material used. They show no traces of the ceramic material in the bore. The pin material is hard, durable, and abrasion-resistant. The biocompatibility tests also

Another effect is of relevance for needle syringes: Because the needles are glued in, the glue seals the inner bore, which contains tungsten, to a great extent, meaning that fewer tungsten oxides are later found on the surface. Washing Process for Tungsten Reduction Defined, very low tungsten values can already be achieved by a special washing process directly following syringe body production. This washing step is integrated into the glass forming line and should not be confused with the WFI washing 128 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Washing process for glass syringes for the significant reduction of tungsten or tungsten oxides. Autumn 2017 Volume 9 Issue 3

Carefully Crafted

Sensitive biopharmaceuticals? We take the challenge • Drug delivery solutions & technologies for injection and infusion • Expert platforms in pharmaceuticals, polymers, coatings, precision and miniaturization technologies

• Abided passion to Quality and Regulatory Affairs support • Committed to improved drug delivery and patient comfort Please note that some products may not be available in all regions, check with your local TERUMO Pharmaceuticals Solutions contact for details.


• Silicone oil-free configuration


• PLAJEX™ available in staked-needle and integrated luer lock format

Packaging show no conspicuous features in contact with living cells. The material is not cytotoxic, is suitable for syringe production and fulfils the requirements of the ISO 10993-5 and the USP <87> (Elution test).

Measurements with EDX showed no peaks caused by ceramics.

broadly and is even better suited for sensitive biotech drugs. In past years, Gerresheimer has already made a decisive contribution to the improvement of sterile, prefillable syringe systems with other innovations.

4. Parenteral Drug Association 2015: Pre-filled Syringe User Requirements for Biotechnology Applications Technical Report No. 73; ISBN: 978-0-939459-82-7

•  The baked-on RTF® syringe reduces the load with silicone oil to less than 10% in comparison with spray siliconisation •  Optimised siliconisation processes for spray siliconisation improve the product properties like breakaway and slide forces •  Compatibility with automatic injection systems has been ensured. The company’s own G3 camera system hereby makes a great contribution to product quality and increases customer benefits •  Extensive functionality studies help find the best syringe system in connection with dedicated plunger stoppers •  Own closure systems like the TELC® Luer lock seal add additional security with the integrated tamper-evident feature •  Reduction of glass to glass contact and particle reduction in the production process thanks to the most modern RTF technology.


Light and electron microscopic experiments showed no impurities in the cone.

COP Syringes As an alternative to glass syringes, plastic syringes (COP) can also be used as a primary packaging material when sensitivity of the liquid formulation exists with regard to tungsten. In the case of ClearJect® and Gx RTF® ClearJect® COP syringes, no tungsten pin is used in production. The production process in injection moulding takes place with an in any case tungsten-free mould. Conclusion The reduction of tungsten and the metal-free production make a big contribution to making pre-filled syringes safer. The prefillable syringe can thus be used even more 130 INTERNATIONAL PHARMACEUTICAL INDUSTRY

1. Bee JS et al. 2009: Precipitation of a monoclonal antibody by soluble tungsten; J Pharm Sci. 2009; Sep.2009; 98(9):3290-301. doi: 10.1002/jps.21707. 2. Seidl et al. 2012: TungstenInduced Denaturation and Aggregation of Epoetin Alfa during Primary Packaging as a Cause of Immunogenicity; Pharm Res. 2012 Jun; 29(6): 1454–1467. Published online 2011 Nov 18. doi: 10.1007/s11095-011-0621-4;PMCID: PMC3349029 3. FDA Guidance for Industry 2014: Immunogenicity Assessment for Therapeutic Protein Products; U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER)

Bernd Zeiss Manager Technical Support Medical Systems Business Development. Gerresheimer Bünde GmbH Dipl.-Biol. Bernd Zeiss studied biology, microbiology and chemistry at Goettingen University, Germany. Today Bernd Zeiss is part of the Center of Excellence for Prefillable Syringes in Buende. As Manager Technical Support Medical Systems he concentrates on drug-container interactions, new developments in the field of prefillable syringes (e.g. materials like COP), on technical studies related to PFS and on technical documentation. Email:

Autumn 2017 Volume 9 Issue 3

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

Co-located with:

24 - 26 October 2017 Messe Frankfurt, Germany





ICSE, co-located with CPhI Worldwide, connects the world of Contract Services in Pharma. Attendees can network with industry professionals from across the globe to establish the best outsourcing partners, the latest manufacturing capabilities and the best opportunities to streamline product portfolios.

“Big pharma, small pharma, specialty pharma and packaging... everyone is here!”

“You have to be here to be a big player in the industry!”

Cedric Roesler CEO, Diffway

Cosmas Mukaratirwa Managing Director, Cospharm


WHY ATTEND ICSE?  Cost Effective: 42,000 pharma professionals from 150+ countries in one location


rate CPhI Worldwide as the leading global gathering of the pharmaceutical industry

 Entire pharma supply chain: 2,500+ exhibitors covering ingredients, APIs, excipients, finished dosage, contract services, packaging, machinery and more


agree that CPhI Worldwide is the most important show in the pharmaceutical industry’s calendar

 Industry developments: stay up-to-date on market news and trends during the Pre-Connect Congress, CPhI Pharma Innovation Awards and Pharma Insight Briefings


believe that CPhI Worldwide is a great show to find new business opportunities

 Free access: 1 ticket, 5 shows, 150 free seminars, innovation tours, innovation gallery and matchmaking

* post show survey 2016 Organised by:



Events, Conference, Reviews

The World of Pharma Returns to Frankfurt

Welcome to the 28th CPhI Worldwide! “The event returns in a year when many developments and potential changes are sweeping across the global pharma landscape, with Britain’s exit from the EU and the new administration in Washington being amongst the most notable. This year we return to one of the most important global growth markets in the pharma industry and Europe’s largest pharmaceutical market, Germany. The country is perfectly placed in the centre of Europe, making it an ideal location for the development, production and sale of world-class pharmaceuticals, with the market predicted to be worth $86 billion by 2021. It’s a truly dynamic time for the global pharma industry, and CPhI Worldwide provides an opportunity to come together and focus on the latest trends, technologies and insights. Above all else, it is a platform for the industry to drive forward new partnerships, do business and grow.” Orhan Caglayan, Brand Director Europe, UBM

Running concurrently with the pharmaceutical ingredients halls are four other nearby brands, helping visitors quickly identify the right event for their business’s needs: •  ICSE is an outsourcing focused event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs, bringing the contract community together under one roof. •  InnoPack connects buyers and specifiers from the packaging and pharmaceutical industries, showcasing all the newest innovations in pharma packaging. •  P-MEC Europe features exhibitors from traditional large-scale capital equipment to companies focused on instrumental analysis, measuring and testing technologies, materials testing, laboratory and quality control. •  Finished Dosage Formulation for every aspect of the finished dosage supply chain, from big pharma and CMO to in/out-licensing and dossier specialists.

Event Overview CPhI Worldwide will take place on 24–26 October 2017 at the Messe Frankfurt, Germany. After last year’s record-breaking event, the world’s most prominent pharma executives are ready to gather again for three days of collaboration, information dissemination, and discussions that will define the future of the industry.

Beyond the exhibition, the CPhI Pharma Insight Briefings will offer participants the chance to access a diverse range of content through succinct 45-minute sessions. These in-depth seminars on specialist topics and regional updates will take place throughout the course of CPhI Worldwide.

The 2016 CPhI Worldwide event in Barcelona saw an all-time record attendance of over 42,000 people, with 2550+ exhibitors from 156 countries. Building on this success, CPhI Worldwide 2017 will host over 20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma, machinery, and many more.

As well as the many free-to-attend industry seminars, the Innovation Gallery will provide a showcase for some of CPhI's most exciting new products. Moreover, a team of pharma  experts will  also present visitors with the opportunity for guided Innovation Tours, which run across each of the three days at CPhI Worldwide.


This year’s CPhI Pre-Connect Congress will take place on 23rd October, the day prior to CPhI Worldwide, and offers its most exciting and comprehensive agenda to date. This platform gathers experts and thought leaders from the entire pharmaceutical supply chain to provide insights into the latest developments. This year’s conference will also examine engaging and forwardthinking topics, such as analysis of biosimilar uptake in the US and Europe, the future of continuous processing and discussions on innovative therapies such as CRISPR, immunotherapy and personalised medicines. The CPhI Annual Report also launches its 5th edition. This eagerly anticipated collection of essays will provide thought leadership on the industry’s hottest topics and issues, with contributions by Ajaz Hussain, Emil Ciurczak, and Alan Sheppard, amongst others, and a contract services overview from Gil Roth of the PBOA. Finally, in recognition of pharma excellence, the vastly expanded CPhI Pharma Awards returns to the show for its 14th year, with eight new categories – awarding an impressive 20 commendations in celebration of the most successful and innovative pharma achievements. Held in the heart of Europe’s largest pharma market, this year’s event is an unmissable opportunity to network with existing contacts, learn, and engage vital new customers that will be invaluable in moving your business to the next level.

Register now for CPhI Worldwide 2017 at:

Autumn 2017 Volume 9 Issue 3

The Parenteral Drug Association presents:

2017 PDA Europe Conference, Exhibition

The Universe of Pre-filled Syringes & Injection Devices Improving Patient Outcomes with Innovative Drug Delivery

Register by 7 Oct 2017 and SAVE!

7-8 November 2017 Austria Center Vienna | Austria


genesis 2017

London’s premier Life Science & Healthcare networking conference QEII Centre, Westminster, London | 14 December 2017 Genesis 2017 is brought to you by One Nucleus. This year’s focus is From Bio-Innovation to Health and Wealth Delivery in Tomorrow’s World and will build on our previous 16 years of experience in assembling a forum where industry executives, investors, academic researchers, policy makers and expert advisers can exchange ideas. Genesis 2017 will feature: Plenary Presentations and Panel Debates Parallel Leadership Streams covering Building Tomorrow’s Deals, Combining Strengths to Create Tomorrow’s Medicines, A Digital Tomorrow and Developing Tomorrow’s Medicines 800+ delegates from across the international Life Science and Healthcare industry 50+ exhibitors from across the globe Prescheduled face to face meetings Genesis Fringe: focused events pre and post Genesis 2017 BioNewsRound Award The MedTech Boardroom

Join in the conversation #ongc17


Autumn 2017 Volume 9 Issue 3


SMi presents the 12th annual conference on...

Cold Chain Distribution DEC

13th - 14th


Copthorne Tara Hotel, London, UK The race for the last mile - Maintaining GDP compliance in an ever changing climate CHAIRS FOR 2017: • Tony Wright, CEO, Exelsius


Sponsored by: • Bob Hayes, Director, SeerPharma (UK)

INDUSTRY EXPERTS INCLUDE: • Umit Kartoglu, Scientist, World Health Organization • Glyn Stacey, UK Stem Cell Bank Director, NIBSC (MHRA) • Chris Wallace, Senior Director - International Supply Chain, Sanofi Genzyme • Gianpiero Lorusso, Director, Supply Operations & General Services Global Manufacturing & Supply, Merck Serono S.p.A.

• Stephen Mitchell, Quality Lead, Logistics Partnership, GSK • David Spillett, Key Account Director, World Courier • Stephanie Fitt, Sales Manager UK & Scandinavia, Emball’iso • Mark Edwards, Managing Director, Modalis Ltd.

Register online or contact the team on tel: +44 (0) 870 9090 711 or email: ACADEMIC & GROUP DISCOUNTS AVAILABLE



SMi presents the 3rd Annual Conference on...

Lyophilization USA

Sponsored by

CONFERENCE: 16TH - 17TH | WORKSHOPS: 15TH | NOVEMBER 2017 Renaissance Woodbridge Hotel, Iselin, New Jersey, USA Optimizing lyophilization cycles through innovations in formulation and process analytical technology CHAIR FOR 2017:

• Andrea Weiland-Waibel, Managing Director, Explicat Pharma GmbH


• Lokesh Kumar, Associate Scientist, Genentech • Charlie Tang, Associate Director, Formulation Development, Regeneron Pharmaceuticals • Guido Schmitz, Global Head of Packaging & Technology Innovation, Bayer Consumer Care • Perceval Sondag, Principal Statistician, Arlenda • Eric Munson, Professor, Pharmaceutical Sciences, University of Kentucky • Kelly Forney Stevens, Drug Product Development, GSK Vaccines • Melissa Lash, Scientist, Large Molecule Drug Development, Johnson & Johnson


Wednesday 15th November 2017, Renaissance Woodbridge Hotel, Iselin, New Jersey, USA

Implementation of Quality by Design principles into lyophilization processes 08.30 - 12.30 Workshop Leader: Andrea Weiland-Waibel, Managing Director, Explicat Pharma GmbH Introduction to Design of Experiments 13.30 - 17.30 Workshop Leader: Perceval Sondag, Principal Statistician, Arlenda

Register online or fax your registration to +44 (0) 870 9090 712 or call +44 (0) 870 9090 711 @SMIPHARM #lyousa ACADEMIC & GROUP DISCOUNTS AVAILABLE INTERNATIONAL PHARMACEUTICAL INDUSTRY 135

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5 7 9 13 15 19 23 25 27 29 31 & 41 37 45 47 51 55 57 59 61 65 69 73 75 77 79

3rd Annual Conference on... Lyophilization USA 12th annual conference on... Cold Chain Distribution Sulzer Mixpac Ltd Vetter Pharma International GmbH Mikron Group Gaplast GmbH Wickham Laboratories Ltd Capsugel Eppendorf AG. Amplexor International Taconic Biosciences, Inc MA micro automation GmbH Eurofins Scientific Owen Mumford Ltd. Valsteam ADCA ENG Hermes Arzneimittel GmbH Valsynthese SA Abzena Nemera Bioclinica LISA – Life Science Austria Cobra Biologics Matcon Beneo GmbH Butterworth Laboratories Biomap Limited Fisher Clinical Services EcoCool GmbH Wool Packaging Company Limited

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81 83 85 87 89 91 95 97 99 101 103

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106 &107 109 111 114 & 115 119 121 123 125 127

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Quick International Courier Powder Systems Limited Therapure BioPharma Inc. Constantia Flexibles Novo Nordisk Pharmatech A/S Emphasys Industrial AbbVie Inc. Albany Molecular Research Inc. AptarGroup, Inc. Huber Kältemaschinenbau AG Sartorius Stedim Biotech GmbH Biopharma Group Adents International BMG Labtech Phillips Medisize Alfasigma S.p.A. Stevanato Group Gerresheimer AG Faubel & Co. Nachf. GmbH ExpreS2ion Biotechnologies ApS Terumo Medical Corporation ICSE – International Contract Services Expo The Parenteral Drug Association: 2017 PDA Europe Conference, Exhibition Genesis 2017 Pfizer CentreOne Kahle Automation

I hope this journal guides you progressively, through the maze of activities and changes taking place in the pharmaceutical industry

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Autumn 2017 Volume 9 Issue 3

With Pfizer CentreOne contract manufacturing, you have our dedicated team by your side and a world of Pfizer resources at your back.




PC1-17-0011-210mmx297mm-July, 2017 © 2017 Pfizer Inc. All rights reserved. INTERNATIONAL PHARMACEUTICAL INDUSTRY 137

IPI - Autumn 2017  
IPI - Autumn 2017