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Volume 9 Issue 4

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

Quality by Design in the Development Benefit or Bureaucratic Burden?

Needle-Free Injection

Eradicating Diseases to Improve Global Health

Early Interventions to Reduce the Impact of Immunogenicity On the Development of Biopharmaceuticals

Rethinking the Cold Supply Chain

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Alessia Giangreco alessia@ipimedia.com EDITORIAL MANAGER: Cecilia Stroe cecilia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Virginia Toteva virginia@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Spring 2018. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2017 PHARMA PUBLICATIONS / Volume 9 issue 4 - Winter - 2017

08 The BioRegion of Catalonia: What’s Behind the European Country with More Pharma Companies Per Capita? Last autumn, Barcelona hosted the CPhI Worldwide for the first time, and it was a record-breaking year for the event. In their article, Nuria Pelaez, Anna Rovira and Silvia Labe of Biocat Communication Unit show that although many international investors are not aware of this thriving life sciences cluster, the Bioregion of Catalonia has undergone unprecedented capitalisation of life sciences companies during the last three years, growing at more than 80% annually. 14 The Rise of Cellular Immunotherapy and Global IP Strategies We are at the beginning of a new age in cancer therapy. With a large and growing number of patents and applications in this space, we can expect a large amount of patent litigation in the years to come as companies look to safeguard their market share. Frances Salisbury and Adam Gregory of Mewburn Ellis LLP look into the recent FDA approvals, an important landmark in cellular immunotherapy. 18 Preparing for IDMP: The Latest Advice on How to Ensure a Smooth Transition The forthcoming ISO IDMP standards governing pharmaceutical product information recording have far-reaching implications for the way companies capture, collate, organise and report a very wide range of operational data. Master data management as an approach offers an efficient, definitive way to cope with this. Sonia Monahan of AMPLEXOR International explains in her article how companies can ensure they derive maximum payback from any new system investments. 22 Expanding Markets: Where Next? A Regional Regulatory Roundup Globalisation and the growing efforts to standardise submission requirements and formats internationally continue to open up new markets for life sciences companies. Yet, there are still significant differences in requirements between regions and individual nations. With this in mind, Kimty Bui-Van of ProductLife Group assesses current regulatory climates in four markets with strategic appeal: Benelux, the Baltics, Canada, and South Africa. 26 Got Diversity? Of Course You Do. Now, What Are You Going to Do With It? In her piece, Rosalie Harrison, an International Management Consultant with Borderless, addresses the benefits of inclusion & diversity. She tells us that inclusion is the method in which your organisation will leverage this diversity to achieve real business impact. Apparently, the concept of inclusion is often painfully misconstrued, although it remains the best way to harness diversity for business success. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 30 Quality by Design in the Development: Benefit or Bureaucratic Burden? Petra Botzem and Dr Thomas Hille of LTS Lohmann answer this provoking question in their paper on the

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Contents ICH guideline Q8, with focus on Transdermal Delivery Systems (TDS) development, providing insight on why it is beneficial. Due to its well-structured content, the referenced guideline ICH Q8 describes well-established development strategies, supplying a platform for controlled and organised development, not only for TDS. 36 Accurate Protein Electrostatics add a New Dimension to Structure-based Drug Design The combination of advanced molecular force fields and improved visualisation capabilities has enabled chemists to expand their ligand-only view of the electrostatics of their system to include proteins, water and ligands. Important insights into the causes of ligand binding are now available on desktop computers and laptops, giving chemists unprecedented control over drug design. Dr Tim Cheeseright and Katriona Scoffin of Cresset look into electrostatic interactions, at the heart of drug discovery. 42 Early Interventions to Reduce the Impact of Immunogenicity on the Development of Biopharmaceuticals The development of biological therapeutics has led to remarkable clinical benefits in many indications. But, despite this success, the induction of anti-drug antibodies (ADAs) due to the potential immunogenicity of these therapeutics, remains a significant challenge to the successful development of biotherapeutics. In their paper, Dr Karen Hill and Dr Gary Bembridge of Abzena discuss the impact of immunogenicity and approaches that can be taken in pre-clinical development to reduce the effect on product success and patient experience. 48 Needle-free Injection – Eradicating Diseases to Improve Global Health Needle-free injection technology has evolved significantly over the last 50 years and is now accepted in many routine immunisation settings as a safe and effective vaccine delivery method. Disposable syringe jet injectors are now being used for the delivery of vaccines to eradicate polio, MMR, and influenza, and are showing promising results in vaccine clinical trials for the Zika virus and HPV. In her paper, Dr Erin Spiegel of PharmaJet shows that these devices are fast, safe, and easy to use, with most providers trained in less than 20 minutes. CLINICAL RESEARCH 56 Automated Accountability: Maintaining a Chain of Custody from Release to Destruction New solutions are proliferating to improve the efficiency of the clinical research function within pharmaceutical companies and CROs. In her article, Theodora Sarver of Almac reviews the challenges that sites and sponsors/ CROs face in complying with good practices and explains how accountability can be improved to reduce trial risks and all but eliminate the dreaded reconciliation process. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 60 Rethinking the Cold Supply Chain – Complex Healthcare Logistics Require Innovative Packaging Solutions Healthcare manufacturers should continually look for ways to optimise their cold-chain packaging. In her article, Susan Li of UPS shows that the benefits of doing so can 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

be far-reaching, starting with increased efficiencies and cost savings and extending to safer transportation of pharmaceutical goods and medical devices that improve the quality of lives. 64 What Clinical Teams Should Know about Changing Trial Logistics and how they will Affect Development – PART 2 As we shift to what has been described as “an Amazonlike culture”, sponsors want the same opportunity to track shipments in real time and to obtain real-time data that they can analyse. In her paper, Jennifer Worsfold, of Fisher Clinical Services, explains that this has led to a growing focus on new technology, including downloadable temperature monitors, and the ability to access real-time updates on the location and temperature condition of supply shipments. MANUFACTURING 72 Strategies for Developing A Cost-Efficient, Pharmaceutical Manufacturing Process In their paper, Valdas Jurkauskas and Xiaoyong Fu of STA Pharmaceuticals address the fact that manufacturing process throughput optimisation has become a necessity rather than an option. Only having high product yield, volumetrically efficient process and shortest possible production cycle time will enable the sponsor to withstand future increase in labour and utilities costs and reduce the probability of complex, expensive and risky post-approval changes. 78 Inspecting on the Edge – Understanding Punch Tip Wear Punch tip edge wear can come from a variety of circumstances and may cause significant production quality-related issues. In their article, Bill Turner and Kevin Queensen of Natoli look into the common causes of punch tip wear and how to prevent it. Even though it can be difficult to detect because traditional methods of inspection are ineffective, we learn that fortunately, the use of a horizontal optical comparator makes the inspection job easy – and fast. PACKAGING 84 What does the Falsified Medicines Directive (FMD) Mean for SMEs and CMOs; and More Importantly, Are These Organisations Ready? The implications of the directive are far-reaching and affect all pharmaceutical manufacturers, regardless of size. As time runs out and the deadline grows ever closer, Christian Taylor of Zetes explains in his article how CMOs and SME pharmaceutical manufacturers can ensure they are compliant. If smaller organisations embrace the regulatory changes – using them as an opportunity to optimise their supply chains, they can create true business value, making it pay to be compliant. 88 Designing Smart Integrated Drug Delivery Systems Wearable drug delivery technology is a good example of how drug delivery technology providers continue to stay ahead of the curve. In his piece, Graham Reynolds of Global Biologics, West Pharmaceutical Services, looks into today’s advanced drug delivery systems, complex pieces of technology that can incorporate innovative and intuitive features that can make it easier for patients to self-administer critical medications. Winter 2017 Volume 9 Issue 4


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Contents 94 Why Anti-microbial Protection Remains Crucial in Fight Against Infection Strands of potential superbugs are developing all the time, and everything must be done to ensure they don’t become a topic of hot – and daunting – conversation once more. Here, Stephie Ward of Denny Bros explains the current situation, as the ability to add antimicrobial protection to a range of labels and patient information leaflets (PILs) has given a much broader scope of protection than existing antibacterial properties, with the overlay resistance coupled with important safety advice, dosage details and legal information. 98 Serialisation: The Current Conversation Serialisation remains the hot topic across the pharmaceutical industry, and will continue to be so with the deadlines for compliance fast approaching in both the US and EU. The discussion around serialisation is a juggernaut, continuously gaining momentum with new advice, research, implementation guides and points of consideration added

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to the mix almost daily. In this article, Carlos Machado of SEA Vision US talks through the advice which businesses can use to underpin their move towards an agile, futureproofed solution. TECHNOLOGY 102 From Seller to Navigator: The Changing Role of the Sales Rep While the role of the sales rep is certainly changing, the industry shift towards intelligent engagement means it may prove more valuable than ever. In this article, Jan van den Burg of Veeva Systems discusses the fact that healthcare professionals want pharma to engage with them on a more immediate and in-depth level than ever before. And it’s estimated that by 2020, 67% of HCPs will be “digital natives”; they will have qualified during or after the internet went mainstream, and have relied on digital interactions throughout their professional careers.

Winter 2017 Volume 9 Issue 4


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Editor's Letter It’s the end of 2017, a busy year of networking, building relationships and ensuring that we are all working to the same goal in the life science sector – which ultimately means either helping a patient get better or for them to understand their health better. In this edition of the magazine, we have many interesting articles about technology and the future, which looks exciting. With the past eight years seeing the downscaling of big pharma, now we see the virtual companies start to employ more people and get their projects into clinical trials. Nuria Pelaez, Anna Rovira and Silvia Labe of Biocat Communication Unit show us that although many international investors are not aware of this thriving life sciences cluster, the Bioregion of Catalonia has undergone unprecedented capitalisation of life sciences companies during the last three years, growing at more than 80% annually. In this issue of IPI, we move swiftly from accurate protein electrostatics and structure-based drug design, to designing smart integrated drug delivery systems and the value of needle-free injection or PILs with antimicrobial protection in the grand scheme of eradicating diseases to improve global health. Our experts discuss the trials and tribulations of the forthcoming ISO IDMP standards and the hot topic of serialisation, methods of achieving a sustainable, cost-efficient pharmaceutical manufacturing process, the ICH guideline Q8, and

Kimty Bui-Van of ProductLife Group assesses current regulatory climates in four markets with strategic appeal: Benelux, the Baltics, Canada, and South Africa. Dr Karen Hill and Dr Gary Bembridge of Abzena discuss the impact of immunogenicity and approaches that can be taken in pre-clinical development to reduce the effect on product success and patient experience. Dr Erin Spiegel of PharmaJet shows that needle-free injection devices are fast, safe, and easy to use, with most providers trained in less than 20 minutes. Valdas Jurkauskas and Xiaoyong Fu of STA Pharmaceuticals address the fact that manufacturing process throughput optimisation has become a necessity rather than an option. Only by having high product yield, volumetrically efficient process and the shortest possible production cycle time will the sponsor be able to withstand future increase in labour and utilities costs and reduce the what the Falsified Medicines Directive really means for SMEs and SMOs. The thing is, there is no hiding from the complexity of serialisation, says the Zetes’ expert. Although businesses can no longer put it off, it would seem there is no need for the so-called ‘rip and replace’ approach. There are ways in which serialisation can be ‘retrofitted’ and integrated with the solutions already in place; and it might just prove to be something invaluable for your organisation, now and in the future. A lot is going on in the pharmaceutical industry in these uncertain times. In this era of precision medicine, cancer immunotherapy has focused

probability of complex, expensive and risky post-approval changes. Graham Reynolds of Global Biologics, West Pharmaceutical Services, looks into today’s advanced drug delivery systems, complex pieces of technology that can incorporate innovative and intuitive features that can make it easier for patients to self-administer critical medications. Jan van den Burg of Veeva Systems discusses the fact that healthcare professionals want pharma to engage with them on a more immediate and in-depth level than ever before. And it’s estimated that by 2020, 67% of HCPs will be “digital natives”. We hope you all have a lovely festive period and an exciting 2018 in business, and we hope to see you at a networking event soon.

Lucy Robertshaw Director, Lucy J.Robertshow Consulting on mechanisms able to enhance the development of cell-mediated immunity, and promising therapeutic approaches are currently under clinical investigation. But with developments focused on particular targets, CAR constructs and cancers, the IP experts of Mewburn Ellis have discovered that certain areas of the clinical and patent landscapes are increasingly crowded. They advise companies to consider their freedom to operate at the early stages of CAR design and pre-clinical development. It’s only by identifying patent rights, which could be problematic early on, that taking preventative action would become possible.

Cecilia Stroe

Editorial manager

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

and Executive Vice President, Vienna School of Clinical Research

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters

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

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

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

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Stefan Astrom, Founder and CEO of Astrom Research International HB

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

Steve Heath, Head of EMEA - Medidata Solutions, Inc

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

T S Jaishankar, Managing Director, QUEST Life Sciences

Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2017 Volume 9 Issue 4


It’s a patient, not a package When patient care is on the line, logistics matter. Navigating the future of healthcare takes more than foresight. It takes a supply chain built with collaboration and integration at its core. UPS can help, with solutions built for protecting your product, keeping ahead of compliance demands, and wired to take advantage of emerging opportunities. That’s staying future ready, while delivering today on patient care and profitability.

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Regulatory & Marketplace

The BioRegion of Catalonia: What’s Behind the European Country with More Pharma Companies per Capita?

Last autumn, Barcelona hosted the CPhI Worldwide pharmaceutical fair for the first time. It was a record-breaking year for the event: more than 42,800 attendants from 150 countries, an 18% increase from the previous edition. The city also hosted BIO-Europe Spring 2017, which returned to the city following the success of the editions held in 2010 and 2013 and brought together more than 2500 delegates from 58 countries. These events – and others that are to come – serve as a powerful showcase for Barcelona and the BioRegion of Catalonia, which is internationally recognised as one of the most dynamic healthcare and life sciences ecosystems in Europe. It has more pharmaceutical companies per million inhabitants than any other country in Europe.

Catalonia, located in the north-east part of Spain, with its capital of Barcelona, has a population of more than 7.5 million inhabitants and a territory comparable to countries like Finland, Belgium, the Netherlands and Israel. It is considered by different business rankings as one of the most dynamic and growing regions of Europe. What makes it so attractive for the life sciences sector? The BioRegion of Catalonia brings together more than 870 companies1, from biopharmaceuticals, medical technologies and digital health companies to investing firms. In fact, Catalonia has more pharma companies per million inhabitants than any other country in Europe including Belgium, Switzerland or Sweden. The BioRegion is the origin and headquarters of large corporations in the sector like Almirall, Esteve, Ferrer, Grifols, Bioiberica, Lacer, Reig Jofre and Uriach. Barcelona is also home to the world’s top biopharmaceutical companies, including Amgen, Novartis, Sanofi, Roche, Bayer, B.Braun, Boehringer Ingelheim, Chiesi, Hartmann, Lundbeck and Menarini. 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

On the other hand, Catalonia is ranked third among European countries in terms of biotechnology companies (behind Sweden and Switzerland) and fourth in terms of medical technology companies (behind Sweden, Switzerland and Denmark). It hosts 259 biotech companies and 194 medtech companies, 89 of which research, develop, manufacture and market innovative medical devices and systems. The BioRegion also gathers an increasing number of companies working in digital health (91). More than 300 professional services and suppliers and engineering firms complement the science knowledge with business and technology expertise. Life sciences companies employ more than 42,000 workers and post yearly turnover of nearly €16 billion. The whole sector contributes 7.1% to the gross domestic product (GDP) of Catalonia. A Hub of Excellence Regarding science and research, Catalonia is a hub of excellence. The BioRegion hosts 780 research groups working in 41 research institutes, some of them considered as the best of the world in their field. This is the case for the Centre for Genomic Regulation (CRG, ranked ninth in the top 100 best biomedical centres in the world, according to Scimago Report); the Institute of Photonic Sciences (ICFO) and the Institute of Chemical Research of Catalonia (ICIQ), the first world institution in physics and in chemistry, respectively, according to Max Planck Institute. With 1.2% of the population of the European Research Area, Catalonia has captured 3.3% of the grants awarded by the European Research Council (ERC), 35% of which were to life sciences. This is possible thanks to a pool of local and international talent. One in five researchers in Spain work in Catalonia. More than 5,600 researchers work in Catalan hospitals and research centres, some of them

very well recognised internationally (such as the cardiologist Valenti Fuster or the oncologist Joan Massagué). The BioRegion also accounts for 14 science and technology parks, 12 universities offering biosciences degrees (three of them among the top 200 in the world), two of the 10 best business schools in Europe (IESE, Esade); seven technology centres and three large-scale facilities like the ALBA Synchrotron, the Barcelona Supercomputing Center (BSC) and the Spanish National Genome Analysis Center (CNAG). The research can rely on the support of a modern and accessible healthcare system composed by a leading network of 104 hospitals, 18 of which are developing outstanding research through their research institutes. Quality, safety, fast recruitment of patients and competitive costs make the BioRegion the location of choice for clinical trials. More trials are carried out here than in any other region of Spain, mainly in oncology, and in Phase II (17%) and III (44%). Catalonia has unique capacities i n g e n o m i c s , p h ot o n i c s a n d supercomputing and stands out in oncology research, covering the whole value chain from basic research through highly specialised companies and hospitals that play an important role in clinical and translational research. Also noteworthy are its capacities in medical chemistry, nanomedicine, omic sciences, bioinformatics and big data. The research areas with most growth are regenerative medicine and microbiome, artificial intelligence and robotics, e-health and m-health, graphene and quantum computing. The main therapeutic areas in which biotech and pharma companies work are cancer (often focusing on rare diseases) and neoplasms, dermatology, infectious diseases, and diseases of the nervous system and the respiratory system. Winter 2017 Volume 9 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 9


Regulatory & Marketplace Investment Success Stories The BioRegion of Catalonia has undergone unprecedented capitalisation of life sciences companies during the last three years, growing at more than 80% annually. However, many international investors are not aware of Catalonia and its thriving life sciences cluster. In this sense, local life sciences investment funds are a crucial spur to attract foreign investors. Catalonia counts on 29 local investment bodies in life sciences, including five specialising in the sector, namely Caixa Capital Risc, Ysios Capital, Inveready, HealthEquity, and the last being created, Alta Life Sciences. Between 2015 and the first months of 2017, companies in the BioRegion attracted more than €165 million in investment, 55% higher than the investment attracted between 2013 and 2015. This is because not only has the number of Catalan companies increased, but also R&D projects are more mature and in the phase “ready to invest”.

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One of the most recent success stories is Anaconda Biomed. This pre-clinical stage medical device company, focused on the development of the next generation of neuro-thrombectomy systems for the treatment of acute ischemic stroke (AIS), last May closed a Series A financing of 15 million Euros. The leading investors included new investors Ysios Capital and Banc Sabadell (Barcelona), Omega Funds (Boston) as well as current investor Innogest Capital (Italy). The Catalan company STATDiagnostica, which specialises in diagnostic systems, closed last year its third round of funding with a total of 25 million Euros. The operation was led by Gilde Healthcare, a Dutch private equity investor, and it was completed by other investors of the company: Ysios Capital Partners, Kurma Partners, Caixa Capital Risc, Boehringer Ingelheim Venture Fund, Axis and Indivest Partners. The company also secured last summer a €20 million loan from the European Investment Bank (EIB).

Also in 2016, Aelix Therapeutics, a spin-off of the Catalan private-public consortium HIVACAT to develop treatments for the human immunodeficiency virus (HIV), received €11.5 million in funding through a round led by the Catalan investment entity Ysios Capital, with additional involvement from Catalan Caixa Capital Risc and the venture capital division of pharmaceutical company Johnson & Johnson. In 2015, Minoryx, a company specialising in drug development for rare or minority diseases without treatment, closed a €19.4 capital increase led by Ysios Capital which also included Catalan entities Caixa Capital Risc and Health Equity and international investors Kurma Partners, Roche Venture Fund, Idinvest Partners and Chiesi Ventures. One of the first success stories of the BioRegion was the $21 million global collaboration agreement between Oryzon Genomics and Roche to research, develop and market an experimental drug for the treatment

Winter 2017 Volume 9 Issue 4


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Regulatory & Marketplace

of patients with acute myeloid leukemia (AML) and solid tumours. The contract was signed in 2004 but it was discontinued in 2017 due to a portfolio prioritisation of Roche. One of Europe’s Most Dynamic Startup Ecosystems Since 2010, an average of 50 life sciences companies have been created in the BioRegion each year. Barcelona is one of Europe’s most dynamic startup ecosystems, not only in life sciences but also in new technologies (internet, mobile software & services, e-commerce or big data). Barcelona is the fifth European region in terms of startups according to international rankings such as EU-Startups and Startup Heatmap Europe, among others. EU-Startups places Barcelona behind London, Paris, Berlin and Amsterdam. Today, the capital of Catalonia has over 1,100 startups which employ +10,000 people. What attracted them to the city? Local infrastructures that both feed and benefit from these projects; public and private support programmes and services for entrepreneurship; successful entrepreneurs who have helped to create networks of incubators; accelerators and investment vehicles that safeguard the new companies; and the presence of internationally renowned trade. With startups being one of the strongest employment and income creators in Europe, the CITIE 2015 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

report lists Barcelona as the 4th Best city favouring digital entrepreneurship. Furthermore, the Catalan capital ranks extremely well in terms of cost of living and best location for office space costs. In Barcelona, startups find a competitive environment, local and international talent, access to business angels and venture capital, excellent infrastructures in a strategic location, international incubators and accelerators, leading international trade fairs, a proven success model, first class business schools and great quality of life. Committed to Europe Being a small country competing in a global economy, Catalonia has historically had a clear mindset of the necessity to establish partnerships and alliances with organisations and counterparts around the world, specifically in Europe. This is the reason why Biocat, the organisation that champions and accelerates the life sciences and healthcare ecosystem in the region, has been actively involved in the largest European initiatives in order to positively impact the players of the BioRegion. A noteworthy example of this kind of commitment is the participation in EIT Health, the most relevant European alliance in innovation and entrepreneurship for healthy living and active ageing, which gained approval from the European Institute of Innovation and Technology (EIT) in

2014. Biocat is an associate member of EIT Health and had been working to promote this initiative since 2008, coordinating and driving the organisations participating in the Catalan/Spanish node to make sure the bid reflected the interests of the Catalan/Spanish ecosystem. As a result, one of the nodes was based in Barcelona, together with others in Paris (France), London (United Kingdom), Rotterdam (Benelux), Stockholm (Sweden/Denmark) and Heidelberg (Germany). The alliance is made up of a total of 144 leading companies, universities and research centres from 14 European countries, committed to innovation in health and to improving quality of life in society in general.

Biocat Communications Unit Biocat is a public/private foundation which acts as a strategic agent and catalyst in the construction of the Catalan healthcare and life sciences ecosystem. Its mission is to dynamise all the stakeholders of the BioRegion of Catalonia (companies, research groups and entities, hospitals and innovation support structures) to transform knowledge and technology into economic growth and to create a social impact. More information: www.bioregion.biocat.cat/ Email: info@biocat.cat

Winter 2017 Volume 9 Issue 4


SGD PHARMA unveils its new identity With a global footprint and a strong sales force, SGD Pharma is recognised worldwide as a key player that customers can rely on to support new product development, day-to-day delivery, quality or regulatory support. SGD Pharma benefits from a long know-how and a best-in-class manufacturing footprint. The company has a long-term investment plan to regularly leverage its manufacturing facilities and develop people competencies to be at the cutting edge of the technology. SGD Pharma commits to have the same standard in all its facilities. All plants are certified according to ISO 15378 standard, pharma GMP’s compliant and equipped with ISO 8 clean rooms. SGD Pharma - 14 bis terrasse Bellini - 92800 Puteaux, France www.sgd-pharma.com

INSPIRING CONFIDENCE


Regulatory & Marketplace

The Rise of Cellular Immunotherapy and Global IP Strategies The FDA approval of Kymriah™ was the first in the area of adoptive immunotherapy and chimeric antigen receptor (CAR)-modified T cells. This has been closely followed by approval for Yescarta™. Companies such as Kite Pharma Inc. and Juno Therapeutics are reporting response rates of ~80% for treatment of blood cancers using CAR-T, and with around 300 clinical trials currently in progress, it is clear that we are at the beginning of a new age in cancer therapy.

As these new treatments reach the clinic, we can expect to see an increase in patent litigation in this area. With treatments costing around $500,000 per patient, there is a lot at stake. An effective IP strategy for this technology needs some thought, especially because of the particularities of the therapeutic methods, which may involve different steps being performed in different countries. Patients are not given an “off-theshelf” product, but rather their own immune cells are isolated from their blood, processed, and returned to them. Although the final products are similar in some respects, each patient therefore receives their own bespoke therapeutic agent. Infringement scenarios are different to those that have been traditionally considered for patents for pharmaceutical products, and must be considered at an early stage to ensure that an appropriate patent strategy is pursued. A Crowded Landscape There are currently many patent applications directed to particular CAR constructs, and the use of CARs/ CAR-T cells specific for particular target molecules. Different companies have their own proprietary CARs, with modifications in the transmembrane and endodomain co-stimulatory structures and signal peptides, in 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

addition to the antigen recognition regions. Both treatments so far approved by the FDA modify cells to recognise CD19, and many other groups are also using CD19 as a target. With developments focussed on particular targets, CAR constructs and cancers, certain areas of the clinical and patent landscapes are increasingly crowded. Companies should therefore consider their freedom to operate at the early stages of CAR design and pre-clinical development. By identifying patent rights that could be problematic early on, it is possible to take preventative action. This could be done by making changes to the CAR construct or the treatment to work around a patent right, taking steps to prevent a patent from being granted, or challenging an application/ patent in order to force an applicant/ proprietor to amend the patent claims in such a way that the risk is minimised. For example, many patent offices around the world enable the filing of observations against a patent application during the examination phase, with some among these allowed to be filed anonymously, providing a potential infringer a cost-effective way to take action. Any action taken by a party in respect of a patent/application – both offensive and defensive – should be considered on a global scale, as proceedings in one jurisdiction can have significant implications on proceedings in others. To make sure that action in one country does not compromise future action in another, the strategy must be coordinated, to ensure that the arguments and evidence used in the various jurisdictions are consistent and complementary. The Importance of Method Claims In terms of patent strategy, “composition of matter” patent claims directed to particular actives or formulations have traditionally

been a priority for pharmaceutical companies. However, enforcement of product claims relating to CAR-T cells may be trickier because of the need to demonstrate that each batch of cells falls within the scope of the claim, as each is a bespoke treatment for a particular patient. There can, however, be significant value in method claims relating e.g. to methods for engineering the CAR-T cells, and methods for culturing and expanding the CAR-T cells, provided the claims are not overly complex. Patents covering all or part of a method that becomes a de facto standard required by the FDA for approval could be especially valuable. It’s notable that both current approvals relate to blood cancers, using CAR-T cells that target CD19. The autologous cells are also transformed using lentiviral vectors in both cases. Therefore, although the FDA floodgates may be considered opened to some extent, the FDA is likely to be cautious about significant step-changes, and look more favourably upon treatments that are based substantially on methods and techniques that have been previously approved. Owning patents around these standard techniques could be extremely lucrative, and claims relating to improvements and refinements of the processing steps should not be overlooked. Granted claims around approved methods could also be more commercially useful and enforceable compared to traditional pharma method claims directed to methods for making pharmaceutical products, because the FDA approval process will likely compel any party wishing to bring a CAR-T therapy to market to disclose the methods they use to generate and expand their CAR-T cells. Still, care should be taken to consider infringement and enforcement when drafting such method claims. Winter 2017 Volume 9 Issue 4


Regulatory & Marketplace

The most useful claims will define methods in such a way that all steps will be performed by the same party (i.e. there is a direct infringement). Where the steps would likely be performed by different parties, some jurisdictions such as the USA would require one party to be shown to be controlling the actions of another, in order to consider there to have been an induced infringement.

This is a particular concern in autologous CAR-T cell therapy, where different parts of the therapeutic process may be performed in different jurisdictions. For example, the patient may be in one country while their extracted cells are sent for processing at an approved facility in another country. The extraction, modification and re-administration of the cells to the patient may therefore occur

in different countries, and different infringing acts might fall under the jurisdiction of different patents courts. When drafting and prosecuting claims for CAR-T therapies, attorneys should therefore consider the practicalities of how and where steps of the therapeutic process will be performed. They should think not only of their home jurisdiction, but also

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Regulatory & Marketplace about how courts in other jurisdictions will interpret the claims and consider the infringing acts in those countries, in order to obtain patents that are useful. Future Developments on the Horizon A current limitation to CAR-T technology is the per-patient treatment cost. Key players are working on bringing this down so that the therapy is available to more patients. Kymriah™ and Yescarta™ use autologous T cells, which are taken from the patient to be treated and modified to express CARs. Many companies are now generating “banks” of immune cells, containing cells from donors with a variety of different HLA types that can be matched to a patient, which would provide for the generation of “off-theshelf” allogeneic CAR-T cells. Provided that safety and efficacy of such therapy can be demonstrated, this would be expected to significantly reduce the cost of CAR-T therapy. Another factor limiting the clinical application of CAR-T treatments are the toxic side-effects observed in some patients. In particular, minimising the frequency of cytokine release syndrome and tumour lysis syndrome will be an important goal for future development and refinement of methods for generating/expanding CAR-T cells, and optimisation of dosage regimes. These first FDA approvals relate to CARs with relatively simple structures, and developments in CAR-T technology to date have focused on global changes to the CAR construct, focussed in particular on the target-binding region, and methods for expanding CAR-T cells. In the coming years we are likely to see therapies using CARs having intracellular signalling domains that allow for greater control of the quality and kind of signal induced by target binding, along with systems providing control over the number and location of CAR-T cells within the patient. These improvements will be designed to enhance therapeutic benefit to the patient and reduce side-effects. Until this point, there has also been a focus on blood cancers, but the first clinical trials for solid cancers are now in progress. Obstacles 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

relating to the use of CAR-T to treat solid cancers include tumour penetration issues and the reduced survival/activity of the CAR-T cells in the immunosuppressive tumour microenvironment. The challenges provided by solid tumours may necessitate developments in how the treatment is administered in order to maximise exposure of solid cancers to the CAR-T cells, and modifications of the CAR construct to improve persistence and activity in vivo. There have also been exciting advances in CAR-T cell engineering recently, facilitated by CRISPR/Cas9 targeted genome editing, in which genetic material encoding CARs has been introduced into specific locations of the T cell genome. The resulting CAR-T cells have improved CAR expression, are more potent, and more resistant to inhibition compared to CAR-T cells prepared using lentiviral vectors. Research and development in these different areas is expected to yield patentable subject-matter in the future. Focus on China Around half of all the CAR-T clinical trials in progress around the world today are taking place in China, indicating that the Chinese government is supportive of this treatment approach. However, due to the relatively new patent regime, companies have had varying levels of success in obtaining and enforcing patent rights in China. We can expect that some of these variations will be ironed out as Chinese companies and the government become more patentaware. When the size of the population and economy is also considered, it is important to keep China in mind when drafting applications and obtaining patent rights. For example, the Chinese patent office usually requires claims to closely match the experimental data in the application in order to grant a patent right. Although the patent law was recently changed to allow supporting data to be submitted after the patent has been filed, we can expect examiners to continue to be reluctant to allow claims that they consider to be unduly broad in

relation to the experimental evidence in the application. Including supporting data in the application at the outset is therefore critical to success in obtaining patents in China. An Exciting Time The recent FDA approvals are an important landmark in cellular immunotherapy. Investment and research in this area is growing, and with the numerous technical challenges, there remains huge scope for innovation. With a large and growing number of patents and applications in this space, we can expect a large amount of patent litigation in the years to come as companies look to safeguard their market share. Considering freedom to operate at an early stage and a globally coordinated strategy for obtaining, enforcing, and defending patent rights will be very important for parties looking to bring CAR-T therapies to market.

Frances Salisbury She is a member of Mewburn Ellis’ life sciences patent team specialising in the biotechnology, pharmaceutical and agricultural sciences sectors. Her clients include government research organisations, universities and multinational companies who value her expertise in areas such as stem cell technology, tissue culture and personalised medicine.

Adam Gregory He is a member of Mewburn Ellis’ life sciences patent team, and works predominantly in the biotechnology sector. He has experience in drafting and prosecuting patent applications, and works with clients based in the UK, Europe, Singapore and the US. His technical expertise includes immunology, molecular and cell biology, and antibody technology.

Winter 2017 Volume 9 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace

Preparing for IDMP: The Latest Advice on How to Ensure a Smooth Transition The forthcoming ISO IDMP standards governing pharmaceutical product information recording have far-reaching implications for the way companies capture, collate, organise and report a very wide range of operational data. Master data management as an approach offers an efficient, definitive way to cope with this. But what does this involve in practice and how can companies ensure they derive maximum payback from any new system investments? AMPLEXOR International’s Sonia Monahan explains.

As has become only too clear to the life sciences industry, complying with the forthcoming ISO IDMP standards requires much more than additional administrative box-ticking. IDMP increases the range and scope of product-describing data that will need to be submitted as part of regulatory submissions, which the regulators will need to review and approve the data as part of the submission cycle. This demands a significant rethink of the data gathering and submissions process – and a step change in the amount and depth of data that is needed. Not only that, but the additional data first needs to be identified and found. Even if it has been formally captured somewhere, this doesn’t automatically mean it is readily accessible in a submissionfriendly format. Or perhaps some of the detail exists, but it is not complete or up to date. Or if it is, there is no easy way to verify this. Even if the quality of the data is assured, companies will need to consider how easy it will be to lift this data and use it in the way that will be needed for IDMP compliance. So if organisations have been delaying action because of shifting IDMP deadlines, or because they were waiting for the final specifications to be published, they are likely to be working against the clock to get to 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

where they need to be. Although we still don’t know exactly when EMA will require data to be submitted for IDMP purposes, we’re probably looking at two years from now – with a firm mandate likely by the end of 2019. Although this might sound a way off, the deadline will come round soon enough – and it really isn’t long considering that companies need to scope and define their projects, allocate funding, and integrate and test finished solutions. Securing Management Buy-in A priority, then, should be commanding management attention for what inevitably will be a very serious and substantial undertaking. A global perspective may help with this. Although IDMP is essentially a European initiative, its reach does not stop at the continent’s boundaries. The motivations behind EMA’s data intentions (better data quality, better patient safety) are reflected around the world. And, of course, any international pharma business selling into Europe will be affected by IDMP requirements under the same timelines. But more than that, agencies such as Health Canada and Swissmedic are already looking at how they too improve their own internal data, and what the rigours of IDMP might offer to help them; markets in the Asia Pacific are also considering their options. Certainly regulators far beyond Europe are developing a keen interest in IDMP. Brexit is not expected to have an impact on IDMP, other than the expectation that EMA will relocate its headquarters to mainland Europe, incurring some upheaval as Londonbased staff reassess their position and operations resettle. Other than that, we can expect the UK to fall in with IDMP so that it is not out of sync with neighbouring markets. The message consultants have been trying to get across to prompt early action from companies is that, as long as there remains time to do so, organisations have a chance to make

their IDMP preparations a means of improving data management for their own benefit – for instance, as a means of facilitating digital transformation and market innovation, perhaps through the adoption of new business models. If they continue to put off IDMP preparations, on the other hand, they are likely to end up doing the minimum – which may mean cutting corners with information preparation and creating more complexity and work for themselves down the line. Taking stock So what should companies be doing at this point, to ensure they deliver for EMA and for their own interests? The first point is that, even where the final detail around IDMP classifications is not yet known, this should not be a barrier to preparation. Just as a housebuilder does not need to know which fixtures and fittings will go where when they’re still laying the foundations. A more pressing concern is identifying where all of the contributing data currently exists in the company, any sources that might be missing, and how the company is going to bring it all together so it can be used for IDMP purposes. Note that a lot of this data will exist across a broad spectrum of sources beyond regulatory affairs. At a minimum, it will span R&D, manufacturing, clinical and pharmacovigilance activities and systems. So firms will need to review the completeness, currency and quality of all of these diverse data sources, if they are to contribute to a definitive record of product reality. The next aim should be to move things on from initial IDMP data analysis to a broader plan for ‘master data management’ (MDM) that will set the company in good stead for wider transformation, not least by strengthening transparency across the different business operations. Winter 2017 Volume 9 Issue 4


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Regulatory & Marketplace

It is helpful that EMA’s own ambition for ISO IDMP is to improve data’s quality and integrity, so that its value increases. This means getting the underlying data (the master data) in order, using agreed standards. The reason ISO IDMP has taken so long to materialise as a set of confirmed definitions is that so much groundwork has gone into this to get the detail right; it’s also why there are five standards in total, rather than just one. This is intended to be a comprehensive, definitive structure for data management. Companies can enhance and add to this source data for their own internal purposes: the idea is that 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

building on the right foundations and using agreed terminology will make the fuller data more meaningful and easier to repurpose confidently – whether for publishing, pharmacovigilance, resource planning or artwork preparation. If the underlying data is trusted, next stages can happen much more quickly. Beyond compliance requirements, then, companies should be striving for a 360-degree view of product data: a global, integrated view of product information that supports business processes throughout the lifecycle of a product; a definitive master data set that serves multiple applications. The data doesn’t have to be confined to product information

either: agreed identifiers can be used to define other core business entities such as customers, patients, partners, suppliers, locations and employees. Ultimately getting master data under control is about changing the foundation for how life sciences firms operate. Identifying Best Practice So what might MDM best practice look like? Speaking at AMPLEXOR’s recent annual customer conference, Jens Olaf Vanggaard, a senior life sciences R&D consultant at HighPoint Solutions and a member of the ISO IDMP SPOR Task Force Referentials sub-group, provided a useful analysis. Winter 2017 Volume 9 Issue 4


Regulatory & Marketplace Looking at MDM from an IDMP perspective, he noted that a single, finished product takes three forms: the pharmaceutical product as administered; the authorised medical product; and the packaged product that ships to market. This is just one indication of the complexity systems need to be able to cope with to keep data correct and in sync. Below these higher-level definitions are the more intricate product details. The set of processes and solutions used to acquire, enhance and share product data across the enterprise are the key tenets of master data management, Vanggaard says. Further parameters include ‘reference data’, the set of permissible values to be used by other (master or transaction) data fields. This data is typically non-volatile (slow to change). But managing the processes and solutions used to acquire, manage and share this reference data across the enterprise will become increasingly important with the introduction of IDMP. Although the scale of the transition could be construed as daunting, Vanggaard believes the journey to master data management should be viewed as an evolutionary one: the important thing being that companies start somewhere and treat developments as a continuum – with people, processes and technology brought on in parallel. Establishing Control The starting point should be data governance, Vanggaard says, warning that “without good data governance, [companies] are likely to fail - no matter what technology [they] implement.” As long as there might be inconsistent quality and definitions, for example between affiliates and head office, then the value of the system and its potential ROI will be eroded because the data isn’t sufficiently dependable. So it is important to set out early on how quality and consistency will be managed, who owns the data and who is accountable for its quality and integrity. Unless all the right people are on board with this, the endeavour won’t www.ipimediaworld.com

deliver all the hoped-for benefits, so it’s important to get complete buy-in. “Establishing clear communication channels will enable stakeholders to have a say in the data management process, increasing stakeholder acceptance and ownership of the data across the different functions,” Vanggaard advises. Another early priority must be to set down a data strategy, which defines how the company will increase the value, timeliness and reliability of data assets, perhaps by including external data sources which can augment and improve data quality and completeness. Data policies and processes should then provide the documented guidelines, procedures and tasks to direct data stewards and other stakeholders so they can ensure the integrity, consistency and sharing of enterprise data resources. Data stewardship will be critical in extracting value from MDM and IDMP investments. This involves proactive management and oversight of an organisation's data assets. Operationally, the remit can be broken down into a number of clear steps, from initial data profiling/discovery/ scoping, and data modelling, to data cleansing, profiling, enriching, matching, consolidating and relating. Data matching and consolidation stages involve comparing overlapping data across the company to arrive at the ‘best version of the truth’, keeping full cross-references to enable un-linking if needed. Data relating allows records to be grouped logically for management and analysis. Mapping the Journey A checklist of stages companies can expect to go through on the transition to master data management, then, will look something like this: 1. Identify stakeholders (roles and responsibilities) 2. Define data dictionary 3. Define data sources 4. Define target data model 5. Define data quality rules 6. Conduct data pilot

7. Document and communicate pilot learnings 8. Update data dictionary, data sources, data model and data quality rules 9. Prepare business case for implementation phase Given that life sciences companies will have to do much of this groundwork anyway to fulfil the needs of ISO IDMP, it is strongly in their interests to invest the time in getting this right and deriving the maximum business benefit, while future-proofing any investment because other, new regulatory demands will be much easier to meet once the core data structure is in place. Irrespective of whether an organisation plans to implement MDM technology to support IDMP or not, IDMP compliance will require solid data governance and use of master data management principles and processes for data stewardship, so much of the above advice will apply anyway. Ultimately, master data is ISO IDMP’s main focus so it makes business sense to harness this for maximum effect. Research by Gens & Associates suggests that companies using a common model for regulatory information management are 3.5 times more likely to realise business benefits, are 18% more efficient and have 2.5 times more confidence in their data quality. Broaden this approach out to fuller product and operational information, and the potential gains grow exponentially.

Sonia Monahan Vice President of Quality, Risk & Compliance for AMPLEXOR International. She is an industry veteran of 25 years, with an extensive background in the life sciences localisation sector, as well as being a Six Sigma blackbelt. She is also a ISO 9001 and 13485 lead auditor. www.amplexor.com Email: sonia.monahan@amplexor.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace

Expanding Markets: Where Next? A Regional Regulatory Roundup

Globalisation and growing pushes to standardise submission requirements and formats internationally continue to open up new markets for life sciences companies, yet for now, there remain significant differences in requirements between regions and individual nations. With that in mind, Kimty Bui-Van of ProductLife Group assesses current regulatory climates in four markets with strategic appeal: Benelux, the Baltics, Canada, and South Africa.

The Benelux Countries: Belgium, the Netherlands, and Luxembourg At the heart of Benelux and as the home of the de facto capital of the European Union, Belgium is an important regulatory hub, an open environment that adheres closely to European legislation. The ease of communication and the professionalism of the Belgian authorities have made Belgium a popular destination for clinical trials. According to pharma.be data, some 35,250 people were employed in the Belgian pharmaceutical sector in 2016. And thanks to a regulatory framework that supports research, 15 companies have headquarters in Belgium, and there are 14 R&D facilities, 32 production sites, 12 universities and research centres, 14 bioincubators, and seven academic hospitals.1 Market Differentiators One of Belgium’s defining features is its language diversity. Along with French, Dutch, and German, English is spoken widely, making it easy to support all European countries from Belgium while maintaining strong communication with HQ. More often than not, Belgian teams manage regulatory filings on behalf of Luxembourg and the Netherlands. Market Complexities The biggest difficulty companies face in Belgium is the need to have a single responsible person for pharmaceutical information about 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

products marketed locally. The role is crucial — and demanding. It involves ensuring that all medicinal product advertising conforms to laws and regulations. For every change in product information, the responsible person must sign a declaration confirming any translations are correct and consistent. The person is also responsible for medical sample management. The responsible person must be a physician or pharmacist approved by the Ministry of Health, must have at least one year of experience in pharmaceutical information, and must fulfil local qualifications even if not based in Belgium. The person has to have official backup because if the person is away, the agency must be notified. Since the requirement was introduced in 1984, just 1100 people have been authorised in the role – typically those nearing retirement and comfortable with the role’s significant responsibility. Global companies sometimes delay consideration of the requirement for a local responsible person until late in the submission process, which can be a significant oversight given the scarcity of qualified people. Why Belgium or Benelux? In general, Belgium is one of the most straightforward markets in which to base European operations. As a multilingual country that is strategically positioned geographically and with its well-established and transparent regulatory environment, Belgium serves as a progressive hub for European submission management. The Baltics: Lithuania, Latvia, and Estonia Since joining the European Union, Lithuania, Latvia, and Estonia have adopted relevant European Union legislation; and companies preparing local submissions must have authorisation from the local authority (each country has its own)

or from the European Medicines Agency (EMA), depending on the type of registration. The respective national authorities cooperate readily, and they liaise closely with EMA, the European Directorate for the Quality of Medicines & HealthCare, and other international organisations. In Latvia, the State Agency of Medicines assesses medicines before issuing market authorisations. Estonia also has a State Agency of Medicines. And Lithuania’s regulatory body is called the State Medicines Control Agency. With a combined population of around 6.3 million — 2.9 million in Lithuania, 2 million in Latvia, and 1.3 million in Estonia — the Baltic region is not known as a significant producer of pharmaceuticals. Latvia has the strongest pharmaceutical industry among them, with production estimated at €120 million, but the region has a long way to go to catch up to other European markets. Market Differentiators EU legislation requires that a marketing authorisation holder reside in the European Union. None of the Baltic countries requires the presence of a regulatory person, nor must there be a native speaker within each country to work with authorities; and authorities tend to communicate in English. It is advisable to have a native speaker for translations of summaries of product characteristics and packaging materials, however, and to provide advice on product implementation. When a company receives approval for a new variation, the product must be implemented within one year, so having someone in country to monitor the environment and provide information about changes can be invaluable. Market Complexities The Baltic region has seen a marked decline in mortality rates in the past 15 years, yet the rates remain high compared with many other Winter 2017 Volume 9 Issue 4


Regulatory & Marketplace European countries. For instance, Latvia’s premature death rate per 100,000 people is 400 compared with Spain’s 142. That presents particular healthcare challenges. But all three countries have recorded pharmaceutical market growth, with promising potential for innovative life sciences companies. In Estonia, improved reference pricing systems have led to a shift in spending — from older medicines to more-expensive innovative medicines2. Why the Baltics Unlike more-complex European markets, the Baltics are relatively easy to manage from a distance. Their regulatory authorities are easy to communicate with and open to discussion. Dossier submission can be managed electronically via the Common European Submission Portal (or Platform) (CESP), though for Latvia, a signed paper application form, a cover letter, and proof of payment are required via courier or post in parallel with the CESP submission. South Africa As the gateway to the African continent, South Africa is an important pharmaceutical market, though its regulatory regime remains in a state of flux. In June 2017, the government introduced the Medicines and Related Substances Amendment Act and is establishing the new South African Health Products Regulatory Authority (SAHPRA) to oversee medical devices and medicinal products. SAHPRA will replace the Medicines Control Council, but its full scope will be implemented over two years. These are the latest in a series of steps to shake up the regulatory environment. Such steps have also included a move away from the old Medicine Registration Form format to the Common Technical document (CTD), which has been mandatory since 2016. South Africa is also an observer of the International Council for Harmonisation’s (ICH’s) guidelines and to a large extent follows European Union guidelines for the submission of marketing applications. Market Differentiators The South African regulatory environwww.ipimediaworld.com

ment is stringent. Regulators carefully assess every submission and expect companies to strictly adhere to CTD guidelines. And firms submitting marketing authorisation applications in South Africa must be locally-based pharmaceutical companies. Each company must also have a responsible person in the form of a pharmacist registered with the South African Pharmacy Council. The person must ensure adherence to laws related to medicine control and is accountable for all technical and regulatory issues involving a company’s products in South Africa. The responsible person has wide-reaching legal and regulatory responsibilities as well by being responsible for quality aspects related to releases of products onto the market, and for ensuring that all standard operating procedures are in place, that the site master files get compiled, that dossiers are compliant, that pharmacovigilance requirements are being met, and that marketing material is compliant with regulations. Despite its 11 official languages, South Africa currently requires labelling in only English and Afrikaans, but there has been discussion as to whether the patient information leaflet should be made available in other languages. South African – based pharmaceutical companies, subsidiaries, and consultants commonly handle submissions for other African countries, including Botswana, Ghana, Kenya, Mauritius, Namibia, Tanzania, and Uganda. Each country has its own regulatory nuances, requiring experts with relevant knowledge and good working relationships with in-country agents to ensure local compliance. Market Complexities Even though old dossiers can remain in their existing Medicine Registration Form format, if a chemistry, manufacturing, and control variation is submitted, the company must convert the entire submission to CTD and submit a fully updated Module 3. Although this involves a lot of work, many old dossiers contain only scant information, so an update is necessary.

Perhaps the most significant challenge for companies, though, is the national agency’s regulatory backlog: the approval process currently takes around five years. One cause of this was a sudden influx of generic applications in response to price control measures. In addition, the government’s focus on certain diseases that affect a large proportion of the population — such as HIV and tuberculosis — resulted in an increase in associated product applications. More recently, it was decided to do away with fast-track evaluation, too, to ensure all products get evaluated equally. In 2015, South Africa initiated an electronic CTD (eCTD) pilot involving 18 products, which provided good insights into the eCTD process for both companies and regulators and helped speed the review process for at least some of those products. Even though eCTD applications are now accepted for both new chemical entities and generic applications, the time frame for compulsory submission in eCTD format has not yet been set. Why South Africa? As a pharmaceutical market, South Africa is the largest in sub-Saharan Africa – valued at €2.52 billion – and is expected to grow at a compound annual rate of 7.4% from 2014 to 2019, according to data from IMS Health (renamed IQVIA in 2017). From a regulatory point of view, the market follows ICH guidelines similar to European Union requirements. The use of South Africa as a base for building regulatory submissions for other African countries is also highly appealing. Canada As a member of the International Council for Harmonisation, Canada takes a regulatory approach familiar to most global companies. The approach is similar to Europe’s, although Health Canada has implemented certain country-specific regulations. Canada requires that a physical entity (directly owned or otherwise) be in the country for a drug establishment licence. Companies that have experience with the European eCTD or even US subINTERNATIONAL PHARMACEUTICAL INDUSTRY 23


Regulatory & Marketplace mission requirements should find preparing an eCTD for Canada relatively straightforward. The United States and Canada have established a Regulatory Cooperation Council Pharmaceutical and Biological Products working group to enhance regulatory harmonisation between the two countries.3 The pharmaceutical industry in Canada employs around 27,000 people directly and more than 100,000 people indirectly and is growing at a compound annual rate of 2.2%, according to government sources. Most pharma companies are clustered in Toronto, Montreal, and Vancouver. Market Differentiators A m o n g t h e C a n a d a- s p e c i f i c regulatory requirements is the product monograph, which is akin to the EMA’s summary of product characteristics and which documents

non-promotional information about a drug, including its properties, claims, indications, and conditions of use. Health Canada introduced plainlanguage labelling requirements in 2014 to ensure that patient materials are easy to understand. Another consideration is a requirement to publish a product monograph and all labelling in both English and Canadian French, which differs slightly from European French. Although it is not a legal requirement to have someone on the ground in Canada to handle submissions, local knowledge, the ability to liaise with the health authorities, and a one-onone relationship with the client are invaluable. Market Complexities As a straightforward and transparent market, Canada poses few specific regulatory complexities for companies.

However, understanding the local environment and developing a rapport with the local authority are important to avoid delays to market given that, unlike in Europe, there is no predefined time limit in Canada for the question-and-answer review period. Why Canada? Canada is the 10th-largest pharmaceutical market in the world. It has also been rated the best in the Group of Seven industrialised nations for cost-effective clinical trials and medical product testing.4 And it is a leader in biotechnology and vaccines. Given its similarities to both the United States and Europe with regard to regulatory requirements, Canada raises few hurdles for companies – and presents many advantages. As global opportunities expand and barriers to market entry diminish, we can expect to see more pharmaceutical organisations broadening their outlooks as they pursue new growth in 2018 and beyond. As long as they approach the new frontiers with their eyes open and key preparations made, the gains could be substantial. REFERENCES 1. Pharma Figures 2016, Belgium, a Growing Pharmaceutical Hub; file:///C:/Users/Kim%20Ribbink/ Downloads/pharmabe-Figures2016-EN. pdf. 2. “Baltic states’ pharma markets continue to emerge from crisis,” IHS Market, 17 December 2013; https://www.ihs. com/country-industry-forecasting. html?id=1065984949. 3. 2016 Top Markets Report Pharmaceuticals Country Case Study, Canada, International Trade Administration; http://www.trade.gov/topmarkets/pdf/ Pharmaceuticals_Canada.pdf. 4. Competitive Alternatives: KPMG’s Guide to International Business Locations Costs, 2016; https://www. competitivealternatives.com/reports/ compalt2016_report_vol1_en.pdf.

Kimty Bui-Van Head of Function, Regulatory Affairs at ProductLife Group. Email: kbuivan@productlife-group.com

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Winter 2017 Volume 9 Issue 4


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Regulatory & Marketplace

Got Diversity? Of Course You Do. Now, What Are You Going to Do With It? As a professional helping pharmaceutical companies define and drive their diversity initiatives, I am always looking for inspiration to make my point. Sometimes, I have to look no further than my own dinner table. Let me give you a powerful example of my latest epiphany.

My husband is the chief operating officer for a global manufacturing company. Several months ago, he was hosting his worldwide team in Mexico to run a number of Japanese style Kaizen improvement events. One morning, I awoke to a text. It was a smiling picture of my husband covered in all sorts of paints, as if someone had used him as a canvas. I turned the picture to my 15-year-old daughter with a scoff; “See how hard your Dad is working?” My daughter rolled her eyes at me. “He is not just goofing off, Mom. Dad is celebrating the Indian festival of Holi with his team. Everybody knows that.” This exchange stopped me in my tracks. It was, of course, already quite extraordinary that my American husband was in Mexico on behalf of his European company utilising a Japanese system of manufacturing to drive efficiencies while taking time to honour the cultural traditions of the Indian members of his team. It was quite another thing for my 15-year old daughter – who has never been to India – to exhibit such a relevant and timely knowledge of the world. Thanks to apps like Instagram and Snapchat, the diversity of the world is at her fingertips – in real time – no matter where she is. I found this entire exchange deeply relevant to my consulting work in the field of diversity & inclusion. Now when I ask clients the simple question, “Got diversity?” I do not have to wait for the answer. The answer is of course you do. Diversity is present in every industry, including 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

pharmaceuticals. Perhaps you haven’t attained the level or mix of diversity you desire, especially within your leadership ranks (and this is the subject of another article entirely), but diversity is present in every area of your business, i.e., your workforce, your suppliers, your consumers, your investors etc., and it is here to stay. Furthermore, this diversity is not the traditional “equal employment opportunity,” compliance and protected class definition of diversity I was raised on. This is so much more. This diversity is vibrant. It is the stuff of innovation, progress, impact and, yes, profitability. It’s diversity of thought and perspective and personality and approach. It’s generational diversity and a mix of cultural perspectives and experiences that defy categorisation. It’s diversity that dances through the hands of your future workers and consumers as a steady stream of pictures, ideas, foods, merchandise, music, and art. It is a diversity that is woven into the very fabric of our global connections as human beings. So, armed with this relevant diversity definition and realisation, I am more motivated than ever to have the relevant and very simple discussions with clients about their D&I efforts. Now, it goes like this. You have diversity. Now, what are you going to do with it? The answer to this question is inclusion. Inclusion is the method by which your organisation will leverage this diversity to achieve real business impact. Inclusion will help you: • •

Improve the quality of your goods and services through improved innovation and perspective; Attract and retain the most relevant talent; and

Create a workplace that is challenging, satisfying and professionally fun.

Although it remains the best way to harness diversity for business success, the concept of inclusion is often painfully misconstrued. Because it is a competitive crime to watch companies squander this advantage, we at Borderless have created a guide to help you best implement inclusion in your organisation. Keep It Simple: Let’s be honest. Inclusion in the workplace as a concept is not too hard to grasp. All organisations have different kinds of people. To drive business performance, organisations need an environment where everyone is engaged and encouraged to contribute to the best of their ability. This is inclusion. Don’t get caught up in some intangible or ultra-complicated definition. Voice, Not Vote: Inclusion in the workplace is about voice, not vote. You are not creating a democracy or celebrating everyone’s uniqueness with a giant hug. You are trying to make sure you are harnessing the innovative and decision-making benefits of your team’s diverse perspectives and abilities to have a positive impact on your bottom line. You Can’t Just Tick-the-Box: Off-site training programmes? Carved out events? Individualised computer modules? Get real. These things cannot possibly work. Inclusion is inherently about how we work together. As such, inclusion must be created, nurtured and embraced in the environment where people are actually working together on real business issues. This is just common sense. Inclusion is not a discrete, off-the-shelf training programme you check off your list. Winter 2017 Volume 9 Issue 4


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It’s a Leadership Competency: If the ability to lead a diverse team in an inclusive way is not one of the competencies required for your leadership hires and promotions, don’t even talk to me about your inclusion initiative. It is nothing but a pipe dream or, at worst, a bunch of hypocrisy. Inclusion is about competitive advantage and business success, and it is a skill set you should be seeking and developing in your leaders. Oh, and in case it is not yet clear, this makes inclusion a C-Suite issue, not a PR or HR exercise. Relevant to Your Business: Your employees may all be different, but they have one easily identifiable thing in common: the business. People will embrace an inclusive way of working when they can experience the power of its impact on business success, e.g., whether it’s developing and producing better brands and products; attracting and retaining the best talent; or creating a work 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

environment that is energising, engaging and professionally fun. Customised and Collaborative: There is no such thing as a one-size-fits-all D&I approach. Individuals, teams and businesses present on a continuum. Approaches need to be customised and capable of leveraging existing tools and methodologies. Organisational Vitality: Habitual behaviour is our fall-back point when we are stressed, short for time, under deadline, or generally drained of energy. This is the biggest danger to inclusive behaviours and processes, and these stressors are ever present in all of our work environments. Even well intentioned, fully D&I value onboard leaders will fall prey to this impact. As a result, addressing organisational vitality (at the individual, team and business levels) is critical to support a sustainably inclusive environment.

Valuing inclusion as a fundamental aspect of your culture and leadership in our inescapably diverse environment is essential to your competitiveness in the industry. Got your attention? Come talk to us about our customised and business integrated approaches to inclusion.

Rosalie Harrison International Management Consultant with Borderless working with global clients to create customized and business relevant approaches to leverage the benefits of inclusion and diversity, with over 25 years of experience. Born and raised in the United States, she’s since lived in Germany and Belgium. Email: rosalie.harrison@borderless.net

Winter 2017 Volume 9 Issue 4


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Drug Discovery, Development & Delivery Quality by Design in the Development: Benefit or Bureaucratic Burden? An Essay about ICH Guideline Q8 with Focus on Transdermal Delivery Systems Development

The industry cannot enforce any legally binding requirements for a systematic approach to pharmaceutical development. Therefore, the referenced guideline ICH Q8 is rather a descriptive guideline on how the chapter pharmaceutical development (e.g. 3.2.P.2 of registration files) should be written. That said, a unified standard for the principles of development is clearly defined and without design space and its documentation registration relevant data for 3.2.P.2 cannot be provided for registration files.

Key words • • • •

Quality by design approaches in the development of TDS General aspects according to ICH guideline Q8 Establishment of the design space Documentation of the design space

For easy identification, the referenced technical terms of the guideline Q8 are highlighted in bold. The aim of pharmaceutical development is to design a quality product and its manufacturing process. With reference to ICH guideline Q6A, quality of a product is characterised by identity, strength, and purity (as defined) and its reproducible manufacturing process. These same quality requirements were already established in the historical monographs of the German pharmacopeia DAB (DAB) and USP monographs using different words that hold similar meanings: Identification, Assay and Impurities. Furthermore, other statements of the guideline are commonly understood. For example, the statements that ‘quality cannot be tested into products’ and ‘quality should be built in by design’ which means by: • •

Understanding of the development Drug substance and excipients

30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in relevant specifications A defined manufacturing process!

This understanding can be gained by prior knowledge or formal experimental design, which seems on the first view in opposition to the W. Edwards Deming statement: “In God we trust, all others bring data!” Deming, W.E. The New Economics For Industry, Government and Education. Cambridge, MA: MIT Press, 1993

However, the US definition of “prior knowledge” is different from the European understanding of this term. The FDA states that prior knowledge can only be gained by experiments and never by education. Taking the costs of development into account makes the statement remarkable that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions. Finally, this article does not describe the design space for a manufacturing process (since such an approach is comparable to the US process qualification (PQ) or validation process outside the US), but deals exclusively with the establishment of the design space, including its documentation, for development of transdermal delivery systems (TDS). The article is subdivided into two parts detailing how a design space approach may be applied to development of finished product TDS with relation to 1) identity and purity and 2) strengh. Identity and Purity So far, there are no guidelines defining criteria to test identity by following the QbD approach; however, such an approach might be of interest to justify changes of manufacturing sites. For example, this is especially true for excipients used in TDS such as pressure-sensitive adhesives or liners.

Furthermore, it is obvious how purity within the specification and also throughout the life cycle of a product can be achieved (e.g. by utilising pure drug substances and excipients (2.1.2 Excipients) in relevant specifications). The relevance of using pure excipients will be demonstrated with an important TDS ingredient, the pressure-sensitive adhesives. Pressure-sensitive adhesives contain monomers and initiators which are critical impurities in polymers (“critical” in the sense of quality-affecting impact on the final product). Residuals of initiators (or radical starters) in a polymer are critical for the purity of the drug product TDS. They can initiate a radical degradation of the drug substance during the manufacturing or storage of the TDS. Furthermore, non-hazardous excipients (e.g. water) can have critical impact due to the risk for microbiological contamination (2.5 Microbiological Attributes) or hydrolysis of the drug substance when applied transdermally. For these reasons, the use of polymers dissolved in organic solvents rather than aqueous polymer dispersions is preferred for the manufacture of TDS, to minimise the potential risk (the growth of germs is unlikely in organic solvents). The use of oxygen- or light-sensitive substances (e.g. nicotine, buprenorphine and nifedipine) or excipients used as tackifiers (e.g. oleic acid or abietic acid derivative) may prove critical for the stability of TDS, but adequate countermeasures can be applied: • •

Inert gas flushing in the production, but additionally: Relevant specifications of excipients (e.g. peroxide value in resins, oleic acid and PVP or residuals of initiators (or radical starters) in a polymer, see above). Use of antioxidants in optimal Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery

• •

concentration, which can be found in experiments in the design space1. Pouch in tight sachets (4. Container Closure System) Avoidance of light exposure during the manufacturing or storage of intermediates

Strength A Parameter and its optimisation Quite Different in TDS in Comparison to All Other Dosage Forms. A more or less high amount of the drug substance in the TDS is not absorbed, but will be retained in the TDS during the application period, which yields assay and delivery rates that are not identical. Therefore, the parameter strength and also its optimisation are quite different for TDS when compared to all other dosage forms. In general, it is justified to state that the drug substance acts like an enhancer, because a certain part of the drug substance is necessary to enable the transdermal absorption, even though not absorbed!

Nevertheless, the demand of health authorities worldwide to specify an assay with a 95–105% label claim is difficult to justify. Optimisation of the utilisation of the drug substance is a major goal for quality by design applied to TDS. This means the TDS drug content should be as low as possible and not higher than necessary. This approach is not only important for economic reasons,but also regarding aspects of safety, sustainability and avoidance of narcotic abuse. In general, drug substances in TDS are very potent substances, which means they are toxic, expensive, and in some cases controlled substances (e.g. fentanyl, buprenorphine, ritaline or testosterone). It is strictly recommended to consider, besides the quality parameters, two requirements of ICH Q8, which are that the type of dosage form selected is suitable both for the intended use and also for patients` needs.

Please note that the term “selected dosage form” does not mean TDS, in general, but rather a TDS selected from the group liquid-filled reservoir system, matrix system with or without rate-controlling membrane or micro reservoir system. Furthermore, the drug substance can be dissolved or dispersed within the polymer, whereas dispersion can mean either in the form of a supersaturated solution (e.g. suspension), or crystals. Besides optimisation of the assay, the clear definition of the type of dosage form helps to recognise the relevance of the physico-chemical properties of the drug substance (2.1.1 Drug Substance … properties that might need to be examined include solubility, water content, particle size crystal properties … ). In the case of liquid-filled reservoir systems or matrix systems, the drug substance will be dissolved during the TDS manufacturing and particle size is only important for the rate of dissolution during production. It affects only the rate of dissolution, but not the solubility.

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Drug Discovery, Development & Delivery According to the European understanding, the Noyes und Whitney equation can be regarded as prior knowledge; however, some health authorities will request supportive experimental data. In addition, the requirements TDS have to fulfill besides quality parameters (mentioned in the guideline Q8, PART II as patients` needs and the intended product performance) are different from those of other dosage forms. The simplicity of the answer to define the main features of a TDS might sometimes be surprising, as requirements are so simple that developers just forget them. Therefore, it is strongly recommended to point out that a TDS has to adhere to the skin and to deliver the drug substance transdermally over an application period of one or even more days. Afterwards, the TDS has to be removed without any adhesive residuals and – even more important – removal must be painless for the user! For completion, it is necessary to define that reversible adhesion is the tendency of two dissimilar surfaces to stick to one another by wetting both surfaces with a liquid or a polymer in its rubbery state. In the field of transdermal application, one surface is human skin, the other the backing layer of the TDS. Both requirements for the TDS are fulfilled by the one essential excipient, including its essential property, which is the pressuresensitive adhesive polymer building the matrix of TDS. One of the most unique physical properties that defines a polymer is its glass transition temperature, t g, which directly correlates with its mechanical property. In case the tg of the polymer is lower than room temperature RT (tg < RT) it acquires rubber-like characteristics, surfaces can be wet, and the polymer acts as an adhesive. Polymers exposed to temperatures below their specific t g become hard and brittle and are no longer adhesives. Due to the decreased motion of the polymer chains, the diffusion of the drug substance in relevant amounts is not sufficient and transdermal absorption is impossible. 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This introduction was required to work out the main items of the approach, how to optimise the assay of the drug substance with systematic and targeted experiments by taking input factors into account. If it is accepted that just a certain amount of the drug substance in TDS can be utilised via transdermal absorption, then it becomes obvious that optimisation of the drug substance assay means an optimisation of the transdermal absorption. This is because the higher the relative amount of drug substance is absorbed transdermally, the lower the absolute drug substance assay in the TDS. When planning experiments within the design space, prior knowledge can be applied, but should not be taken schematically 1:1. According to Hadgraft 2 and Davis ‘vehicles’ containing the drug substances in the form of supersaturated solutions have a clear advantage for transdermal drug application compared to drug solutions at or below its concentration of saturation cs. They emphasise the relevance of drug substances` ‘thermodynamic activities’ over their concentrations, and justify this hypothesis as follows, starting with Higuchi`s modification of Fick`s diffusion law: F = D x Cskin / L where: F: Flux/ area D: Diffusion coefficient of the drug substance in the stratum corneum L: Effective thickness of the stratum corneum cskin: Concentration of the drug substance in the outer layer of the stratum corneum

U n d e r s t a b l e equilibrium conditions, flux will be at a maximum, when the outer layer of the skin is saturated and, by definition, this will occur when the TDS matrix is also saturated with the drug substance. In that stage, the calculation can be written: cs vehicle x Pc = constant. That means that if the partition coefficient of the drug substance vehicle/ stratum corneum is higher, the lower the drug substance concentration of saturation cs in the vehicle (that means in the TDS!) is. Consequently, the amount of drug substance absorbed transdermally depends on its concentration at saturation, but neither on its conc e n t r a t i o n n o r (e v e n m o r e remarkable) on its absolute content! Therefore, Hadgraft and Davis support the utility of supersaturated systems for the development of TDS; that means TDS containing the drug substance above its concentration of saturation c s , which can be described as: cvehicle > cs Without reflection, this explanation allows the conclusion that it only needs the determination of the lowest cs of a drug substance in different polymers, followed by the manufacture of TDS with a high amount of the drug substance in the respective polymer and a high drug loading. As a consequence, this approach results in a TDS with a maximum of thermodynamic activity and the utmost utilisation of the drug substance, however:

where:

So far, the life cycle and patients` needs of a TDS have not been considered, as supersaturated systems have the tendency to crystallise during the shelf life, and adherence to the skin after 24 hours or longer has to be assured.

cvehicle: Concentration of the drug substance in the vehicle (which means in the TDS) and

What does it matter if the highest thermodynamic activity is obtained, if the TDS does not stick?!

P c : Partition coefficient of the drug substance vehicle / stratum corneum

Bridging the gap between an optimised flux and skin adhesion of TDS is exactly the challenge,

Furthermore, they define: cskin = cvehicle x Pc

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Drug Discovery, Development & Delivery

whereas in parallel drug substance, crystallisation in the polymer should be avoided. Based on this information, a systematic development of a TDS essentially consisting of an acrylate copolymer matrix and a drug substance will be outlined, which conforms to ICH guideline Q8. Acrylate copolymers have been chosen because they are still the most important pressuresensitive adhesives today. In general, the following explanations are also relevant for poly isobutylenes and poly siloxanes. First of all, the drug concentration at saturation has to be determined. This parameter depends on the chemical structures of the monomers – the dissolution is allocated in the oscillating polymer side chains – rather than the molecular weight distribution influencing the viscosity and, as a consequence of this, rate of diffusion, the glass transition temperature and lastly the adhesion properties of the pressure-sensitive polymer. After the determination of the cs value, the so-called systematic targeted experiments (design space) in the form of binary blends consisting of drug substance and polymer will be performed. Starting with the defined cs, the test series will be continued by increasing the drug substance content (input parameter) gradually (cs + x % drug substance in the polymer matrix) with a main focus on the flux and adhesion properties (output parameter), because the drug substance can have either positive (by reducing the glass transition temperature) or negative (by reducing the wetting properties of the surface) impact on the adhesion strength. In parallel, it is recommended to monitor the in vitro dissolution, because crystallisation can be the root cause for decreasing of the dissolution. The binary mixtures have to be stored under accelerated 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

conditions (e.g. 40°C) as increasing of the storage conditions will expedite crystallisation, as higher temperature increases the velocity of diffusion and decreases the viscosity of polymers.

is of benefit in describing wellestablished development strategies and providing – due to its wellstructured content – a platform for controlled and organised development, not only for TDS.

After identifying the optimal polymer type, experiments with polymers of different relative viscosity have to be performed. In linear polymers (e.g. in poly acrylates or poly isobutylenes) dynamic and complex viscosities correlate, because both depend on the molecular weight distribution (as long as the polymers will not be further cross-linked after polymerisation). The relative viscosity will be tested in polymer solutions of defined solid content (e.g. 2 %) because content of solids and the molecular weight distribution also have an impact on the viscosity. Therefore, the viscosity allows an indirect determination of the molecular weight distribution.

REFERENCES

The aim of the experiments is to provide knowledge of whether the viscosity of 2 % (w/w) polymer solution impacts the adhesion properties of the binary mixtures and whether the viscosity is sufficient to stabilise the supersaturated solution. A stable supersaturated solution will avoid any drug substance crystallisation or, in case of individual crystals, indicate whether an impact towards the in vitro dissolution can be observed. Finally, due to the similarity of process qualification/validation and the QbD approach, it might be reasonable to adopt the PQ approach towards documentation in the QbD approach. This means to follow a protocol approved prior to any experimental activities, since expectations fixed prior to any experiments followed by a comparison between expectations and results, because that demonstrates that the developers understand what they are doing, even if no specifications can be set in the very early phases of research and development. Conclusion In the headline, the provoking question had been raised as to whether the QbD approach is a further bureaucratic burden in scientific research. In fact, the very opposite is right, because ICH guideline Q8

1. The efficacy of antioxidants is specific for all drug substances and depends on the milieu. Therefore, the most efficient antioxidant has to be found for all dosage forms, experimentally.Voigt, Lehrbuch der pharmazeutischen Technologie Verlag Chemie, Weinheim New York 1979. 2. Davis, A, Hadgraft, J.; Supersaturated Solutions as Topical Drug Delivery Systems 11, Drugs and Pharmaceutical Sciences 59, 243 – 267.

Petra Botzem Senior technician in the LTS R & D department. She has a fund of experience in the development and scale up of TDS and oral thin films. She handles manufacturing site changes of inactive ingredients and tech transfers processes of final dosage forms. Her experiences have been gained in both manufacturing sites of LTS in Europe as well as the USA. Furthermore, Petra is co-inventor of several patents. Email: petra.botzem@ltslohmann.de

Thomas Hille Pharmacist and got his Ph.D. in natural science at the University of Bonn. He is a director at LTS R & D department and has developed TDS from the lab formulation through all steps resulting in international registrations and launches on all five continents. Thomas holds several international patents for TDS formulations and manufacturing processes, especially for TDS containing narcotics. Thomas keeps himself fit by biking and rowing. Email: thomas.hille@ltslohmann.de

Winter 2017 Volume 9 Issue 4


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Drug Discovery, Development & Delivery

Accurate Protein Electrostatics Add a New Dimension to Structure-based Drug Design Electrostatic interactions are at the heart of drug discovery. The combination of advanced molecular force fields and improved visualisation capabilities have enabled chemists to expand their ligand-only view of the electrostatics of their system to include proteins, water and ligands. Important insights into the causes of ligand binding are now available on desktop computers and laptops, giving chemists unprecedented control over drug design.

Protein Fields have Great Potential The most important factors affecting molecular recognition are electrostatics, 3D shape and hydrophobicity. Being able to create accurate computational models for all three of these factors across both ligand and protein active sites holds great potential for successful drug design. Ligand electrostatics have become increasingly accurate over recent years and are now widely used in drug design1. Computational and scientific advances have meant that we have moved from thinking about electrostatics in terms of specific features of the ligand – such as the potential hydrogen bond network – to a detailed view of electron-rich and electron-poor regions around the

ligand. The ability to see this detail has enabled chemists to gain a far better understanding of how activity is affected by chemical changes, leading to great improvements in new molecule design and increased efficiency in lead optimisation. Until recently, the corresponding view of protein electrostatics had remained limited. Protein-ligand contacts tended to be viewed in the context of a limited number of interaction types, focusing primarily on hydrogen bonds and hydrophobic contacts. Now, with new methods and force fields, it is possible to model the electrostatics of proteins in far more detail, leading to practical insights into how and why particular ligands are effective inhibitors. Protein Interaction Potentials Protein fields, or protein interaction potentials (PIPs), work by probing a virtual protein with a charged atom to detect regions of positive and negative within the protein active site. The results are visualised as a surface with contours that reflect the change in potential. These detailed maps of the electrostatic character of the protein active site help researchers to understand more about the fundamental processes that underlie ligand-protein binding.

Figure 1: Ligand electrostatics (contoured at 3.5 Kcal/mole) for a 0.4nM PERK kinase inhibitor showing negative (blue) and positive (red) electrostatic interaction potentials. 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

PIPs can be calculated in seconds, making it possible to compare calculations for different conformations of the same protein. For example, chemists can see how loop movements can change the binding of fragments that are not interacting directly with the moving residues. Different proteins in the same family can also be compared, to fully understand where and how selectivity can be achieved and where this might prove elusive.

Figure 2: Protein fields (contoured at 3.5 Kcal/ mole) on the dry protein structure from PDB 4G31, PERK Kinase showing electron negative (blue) and positive (red) regions of the active site. Ligand (yellow) shown for orientation. The protein electrostatics predict electron-rich aromatics are required in the centre of the pocket (ligand has an indazole) and for the hinge-binding motif (ligand has pyrrolopyrimidine). Protein fields predict trifluoro aromatic and associated benzylic CH2 to be favourable in the DFG out pocket.

However, the accurate calculation of protein electrostatics requires a thorough electrostatic treatment of all amino acids within the protein active site, not just those with a polar side chain. In particular, the treatment of aromatic residues is critical to understanding where pi-stacking would be preferred with an electronrich or an electron-poor ligand. This is achieved in more advanced force fields such as AMOEBA2 or Cresset’s XED3, which have a more complex electrostatic model allowing for the properties of aromatic residues to be more correctly computed. The Need to Understand Water In addition to a more complex description of atoms, the correct handling of water is critical to success in generating accurate electrostatics inside protein active Winter 2017 Volume 9 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery sites. No calculation of electrostatic potentials in the active site can be complete without also considering whether water molecules are tightly bound and contributing to the potentials and ligand binding.

think of them as effectively being part of the protein system rather than part of the solvent.

Here there are two possible solutions: modelling water as explicit molecules, or including a mathematical model to represent the water that is present. Modelling water using a mathematical construct to simulate the electrostatic effect of water molecules on the ligand or protein electrostatics is a popular way to solve many problems within physical chemistry. However, in the consideration of the electrostatics of the protein active site, this approach is limited. The problem is that the protein active site is not bulk solvent, nor is it a vacuum, nor pure protein. In general, it exists at the intersection of solvent and protein phases. As such, many of the assumptions of continuum water models break down. To calculate protein interaction potentials requires an approach that can both simulate the electrostatic shielding effects of bulk water when considering amino acid residues that are distal to the point of interest, while also in the same calculation give full weighting to residues that are only a few Ångstroms away. This is achieved using a dielectric function that has a distance dependence but is also sensitive to the local electrostatic environment. Using this more complex electrostatic modification, close residues have more influence than those further away from the active site and yet cooperation between residues is maintained. This approach works well for many protein-ligand systems with good complementarity observed between the protein electrostatics and those of the ligand. However, in many proteins, localised water molecules are central to the functioning of the protein or critical to maintaining the correct protein fold. These waters cannot sensibly be modelled by a continuum solvation model, and it is better to 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3: Where does bulk water stop and bound water begin? Many computational models deal with water as a solvent continuum which breaks down as water becomes explicitly bound.

Ligand, Protein and Water Molecules Must Be Treated Equally Well The Reference Interaction Site Model (RISM) is a modern approach to solvation based on the integral equation theory of liquids [3D RISM 4]. It has seen increasing use as a method to analyse the structure of water in and around protein active sites. The accuracy of 3D-RISM depends on the closure used and the functions used to compute the intermolecular potential between the protein and water molecules. In practice, the potential function consists of van der Waals interactions and electrostatic interactions. Using 3D-RISM in combination with an electrostatically accurate force field should lead to more accurate 3D-RISM water placements and energies. The calculation of water positions and energetics on empty proteins using 3D-RISM is not new. However, as we understand more about ligand binding and water’s role in mediating interactions with the protein, there is a need to understand how the stability of water changes with ligand binding. To do this requires force fields that treat the ligand, protein and water molecules equally and equally well. Some more advanced protein force fields such as AMOEBA require extensive parameterisation before they can be applied to ligands, while traditional ligand force fields such as MMFF lack the required complexity in their electrostatics. The XED force field bridges this gap: it is a universal ligand and protein

force field that includes more detailed electrostatics, enabling RISM calculations to produce accurate results both for apo proteins and protein-ligand complexes. Combining Protein Fields and Water Informs Molecular Design To demonstrate the effectiveness of calculating protein and ligand electrostatics from the same force field, together with accurate water prediction, several ligand-protein complexes were downloaded from the Protein Data Bank (PDB) into the structure-based design application Flare5. Method The ligand and protein structures were carefully prepared using Build Model6. Residues lining the active site were minimised with the XED force field. Positive and negative protein interaction potentials were calculated and displayed as iso-surfaces, both for the ‘dry’ protein structure and the ‘hydrated’ structure, including crystallographic water molecules predicted to be strongly bound by 3D-RISM analysis as implemented in Flare. The ligand electrostatic potentials were also calculated using the XED force field and compared with the protein interaction potentials of the dry and hydrated protein active site. Application to Bruton's Tyrosine Kinase Bruton’s tyrosine kinase (BTK) is a target important to proliferation of cancers that depend heavily on B-cells such as chronic lymphocytic leukemia and mantle cell lymphoma but autoimmune diseases such as rheumatoid arthritis. Several crystal structures of BTK bound to inhibitors are available in the Protein Data Bank. Examining structures 4ZLZ and 4Z3V7, the ligands interact with the active site by making H-bonds both with the hinge region and P-loop backbone residues. For the ligand from 4ZLZ, the interaction with the P-loop is mediated by a water molecule. The protein interaction potentials of these structures were Winter 2017 Volume 9 Issue 4


Chemistry at Abzena Abzena provides comprehensive chemistry services to pharmaceutical, biotech and agrochemical companies as well as governmental and academic research institutes. Abzena has a strong background in synthetic organic chemistry and extensive experience of custom synthesis. Abzena also provides comprehensive services and technologies to enable better biopharmaceuticals

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 39


Drug Discovery, Development & Delivery calculated and studied for insights into ligand design. Each protein was downloaded, prepared and protein interaction potentials added in the region of the active site. The ligand and all crystallographic water were ignored in the calculation. The electrostatics of the dry active site of 4Z3V match the ligand fields in a very precise manner. As would be expected, the hinge residues give rise to regions of negative (blue below) associated with H-bond acceptor carbonyls of Glu475 and Met477 while the H-bond donor NH of Met477 gives rise to a region of positive in the protein interaction potential. More surprisingly, this positive region stretches away from the hinge to encompass much of the region occupied by the ligand cinnoline ring. This strongly suggests that ligands with electron-rich heterocycles are preferred in this area. The edge of the cinnoline ring also shows favourable interactions, particularly the 5 and 7-position hydrogens which are close to or enter regions of negative potential on the protein.

Figure 4: protein interaction potentials for 4Z3V.

Examining the protein interaction potential in the region of the ligandâ&#x20AC;&#x2122;s pendant indazole ring shows further favourable interactions from the NH to a region of negativity created by the carbonyl of Gly414 and from the 4-H and 5-methyl into a region of negative formed by the residues 525â&#x20AC;&#x201C;527. Interestingly, this negative patch comes from multiple sources â&#x20AC;&#x201C; the carbonyl of Arg525, the side chain carbonyl of Asn526 and the carbonyl of Cys525. Additionally, the NH of Phe413 on the P-loop creates a region of positive that is matched by the nitrogen lone pair on the indazole ring. However, this region of positive mimics that found in the hinge region by stretching into the region of space occupied by the electronrich heterocycle. In contrast, the protein interaction potential of the dry active site of 4ZLZ shows a good, but imperfect, match of the ligand fields (compare Figure 4 and Figure 5). While the match of the protein fields in the region of the cinnoline ring is similar, 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 5: protein interaction potentials for 4ZLZ showing (in ball and stick rendering) a water molecule that fits the protein potentials and mediates an H-bonding interaction between the protein and ligand. Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery the field derived from the P-loop residues does not stretch to the ligand’s pyridyl group. Instead the positive and negative fields encode for a water molecule that mediates an interaction between the protein and ligand. In this case, inclusion of this water molecule in the definition of the protein active site restores the complementarity between protein interaction potential and observed ligand. Interestingly, the complementarity between protein interaction potential and ligand when including the water molecule in the calculation is mimicked when looking at ligand electrostatics. Including the water molecule as a part of the ligand gives an electrostatic pattern that more closely matches the pattern of the 4Z4V indazole ligand than is obtained from the native 4LZL ligand alone.

related proteins to identify selectivity opportunities, and understand SAR trends and ligand binding from the protein’s perspective. REFERENCES

Figure 7: RISM results on 4ZLZ. The top picture shows the oxygen isodensity surface at ρ=5. The bottom shows the localised RISM waters, coloured by ΔG.

Figure 6: electrostatic interaction potentials calculated for ligands from 4Z3V, 4Z3V including a single water molecule and from 4ZLZ showing greater complementarity when the water molecule is included.

In the absence of 4Z3V structure, it would be natural to ask how displaceable is the bridging water from 4ZLZ? The 3D-RISM water analysis method using the XED force field can answer this question.

this water molecule is displaceable (as proven by the 4Z3V ligand and structure), but also indicates that the displacing group needs to have the correct electrostatics and shape to avoid losing affinity.

Figure 7 shows the results of the 3D-RISM calculation on 4ZLZ. The oxygen density surface clearly shows a region of localised water near the nitrogen of the pyridine, and the 3D-RISM localisation algorithm suggests a water molecule should exist in exactly the spot where it is seen in the crystal structure. The 3D-RISM thermodynamic analysis indicates that this water molecule is neither particularly stable nor particularly unstable. This is consistent with the fact that

Protein Electrostatics and Water Prediction Improve Ligand Design Protein interaction potentials and ligand fields are a powerful way of understanding the electrostatics of ligand-protein interactions. The inclusion of stable water molecules following a 3D-RISM analysis dramatically improves the precision of the method for the characterisation of protein active sites. The information gained from protein interaction potentials can be used to inform ligand design, compare

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1. Comprehensive Medicinal Chemistry III, 2017, Vol. 3, Chp. 11, 253-296. See also citations at http://cresset-group.com/ citations/ and https://docs. eyesopen.com/eon/pub.html. 2. J.W. Ponder and C. Wu. “Current Status of the AMOEBA Polarizable Force Field”, J Phys. Chem. B. 2010, 114 (8), 2549-2564. 3. J. G. Vinter. “Extended electron distributions applied to the molecular mechanics of some intermolecular interactions”, J. Comp. Aided. Mol. Des. 1994, 8, 653-668 4. D. Chandler, J.D. McCoy and S.J. Singer. J. Chem. Phys., 1986, 85, 5971. A. Kovalenko and F. Hirata, J. Chem. Phys., 1999, 110, 10095. 5. http://www.cresset-group.com/flare 6. O.V. Stroganov, F.N. Novikov, A.A. Zeifman, V.S. Stroylov and G.G. Chilov. Proteins 2011, 79(9), 2693-2710. 7. C.R. Smith, D.R. Dougan, M. Komandla, T. Kanouni, B. Knight, J.D. Lawson, M. Sabat, E.R. Taylor, P. Vu and C. Wyrick. J. Med. Chem. 2015, 58, 5437-5444

Tim Cheeseright Tim has a DPhil in Chemistry from the University of Oxford. He joined Cresset immediately after its founding in 2002. As Director of Products Tim is responsible for Cresset’s software. He has been instrumental in developing the easy to use scientific software that characterizes Cresset products today.

Katriona Scoffin is a science writer working for Cresset.

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Drug Discovery, Development & Delivery

Early Interventions to Reduce the Impact of Immunogenicity on the Development of Biopharmaceuticals The development of biological therapeutics such as humanised antibodies has led to remarkable clinical benefits in many indications. Despite this success, the induction of anti-drug antibodies (ADAs), due to the potential immunogenicity of these therapeutics, remains a significant challenge to the successful development of biotherapeutics. This article looks at the impact of immunogenicity and approaches that can be taken in pre-clinical development to reduce the impact on product success and patient experience.

The decades that followed the approval of the first biotherapeutic (insulin, 1982), have seen a dramatic increase in both the number of approvals and the rate at which they are being approved. Biologics now account for over 30% of licensed pharmaceutical products and accounted for over 25% of the new drug approved by the CDER in 2015. For monoclonal antibodies alone, since the commercialisation of the first mAb in 1986, this class of product has grown significantly. By 2014, forty-seven mAb products had been approved in the US or Europe. At the current approval rate, it can be anticipated that approximately 70 monoclonal antibody products will be on the market by 2020, with combined worldwide sales of nearly $125 billion1. Despite this success, biologics can elicit immunological responses when administered to patients, which can affect their safety and efficacy. These side-effects fall into two categories; pharmacological (largely predictable adverse reactions resulting from the interaction between the biologic and its target) and non-pharmacological. Non-pharmacological adverse events include immunotoxicity, which includes both immune responsemediated and non-immune responsemediated reactions. 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This article focusses on the impact of immunogenicity, and the resultant anti-drug antibodies (ADAs), that can result in neutralisation and hypersensitivity reactions to a range of biotherapeutics. We will also comment on the clinical consequences of immune responses to biopharmaceuticals, why this should be avoided and approaches that can be taken in the pre-clinical development phase to provide an approach to reduce the immunogenicity risk of biopharmaceuticals. The Whys and Wherefores of Immunogenicity Immune responses to biopharmaceutical agents are wide-ranging, and can be directed against agents that are both human and non-human in origin. The mechanism by which immunogenicity is triggered remains unclear, although the tolerance to self-proteins may be broken by a number of factors linked to both the product and the patient 2,3. Product factors include dose, route and frequency of administration, immunomodulatory capacity of the protein therapeutic, and formulation4. Patient factors that influence immunogenicity include immune competence (e.g. whether the patient is receiving immunosuppressive treatment), patient’s MHC haplotype and intrinsic tolerance to the protein

therapeutic. Other factors influencing immunogenicity are listed in Table 1. Product-related • M o l e c u l a r s t r u c t u re – primary amino acid sequence or variants • Aggregates, degradation products, oxidised or deaminated forms • Host cell DNA/proteins • Duration of treatment • Previous exposure • Cellular or soluble target • Biological properties of the therapeutic product Patient-related • Genetic profile • Immune status • Disease state Other medication Table 1: Examples of factors that influence unwanted immunogenicity of therapeutic proteins

Antigen processing and presentation is central to the development of an immunogenic response. Patient and biologic-specific factors mentioned above, exert their influences on immunogenicity by modulating antigen processing and presentation events such as antigen uptake, epitope presentation and maturation of antigen-presenting cells (Figure 1)5.

Figure 1: Antigen processing and presentation is central to immunogenic responses to biotherapeutics (Adapted from Sethu et al,20115) Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery Immunogenicity – Why do we Care? So why do we care about immunogenicity? What are the consequences of anti-drug antibodies? The impact of ADAs can have a wide range of consequences, ranging from clinical consequences and reduced efficacy, to safety and cost implications. Clinical Consequences of Immunogenicity Unintended immune responses to biopharmaceutical products (as opposed to desired immunogenicity with vaccine products) can have a severe impact on the safety and efficacy of a biologic. Consequences can range from no discernible or weak effects, to efficacy-limiting effects, or at worst, can include significant morbidity and even mortality in patients. Neutralising ADAs binding to or near the active site of the biologic can prohibit the drug from carrying out its therapeutic function, thus affecting efficacy. Non-neutralising ADAs bind outside the active site of the biotherapeutic, forming immune complexes that can lead to increased clearance of the drug, affecting the pharmaco-kinetics (PK) of the drug. Immune complexes can also lead to increased toxicity and hypersensitivity by accumulating in tissues, causing inflammation and damage. The most serious complications can arise with the production of neutralising antibodies, especially when they target non-redundant recombinant self-proteins and therefore have the potential to cross-react with the patient’s own endogenous protein6. Impact of Immunogenicity Exemplified In 1998, there was an upsurge in the numbers of cases of erythropoietininduced pure red cell aplasia (epo-PRCA) in patients with chronic kidney disease treated with Eprex, an approved erythropoietin (EPO) product. Incidence peaked at approximately 250 newly-reported cases in 2001/2002; surprisingly, many of the cases reported during this period were in patients who had been receiving EPO-α for up to a decade without an issue with PRCA7. www.ipimediaworld.com

Investigations revealed that most of the cases occurred in patients treated with subcutaneous EPO-α (ortho-biotech) following a formulation change requested by the European Medicines Agency (EMEA). EMEA had requested that human serum albumin in the product be replaced by polysorbate 80. Subsequent studies suggested the cause of PRCA was due to either changes in product stability or the formation of micelles caused by high polysorbate 80 concentration. The latter explanation postulated that the EPO molecules were presented on the surface of the micelles at regular intervals exposing them to the immune system8. Later studies identified soluble tungsten in the syringes (from pins used to manufacture the syringes), which may have mediated unfolding and aggregation of the epoetin, causing increased immunogenicity9. This is just one example of how multiple factors can influence the immunogenicity of a therapeutic protein. The Cost of Immunogenicity Companies involved in biological drug development care about the risks of immunogenicity, not only from a desire to deliver safe and efficacious products to the patients, but also from a cost perspective. There are serious development and manufacturing costs associated with managing overt immunogenicity to a product should it occur after launch, to say nothing of the cost of late-stage termination of product development due to overt immunogenicity10. Estimates of the average costs of research and development of a successful new medicine have increased over the last decade from an estimated US$802M at 2000 prices (DiMasi et al. 200311) to US$1,867M at 2000 prices (Paul et al. 201012). In 2012, Novo Nordisk discontinued the development of vatreptacog alfa following analysis of Phase III results. The adeptTM2 trial was one of the largest of its kind for assessing bypassing agents. Vatreptacog alfa, a fast-acting FVIIa analogue with only three amino acid substitutions compared to native FVIIa was found to induce anti-drug antibodies in a few patients. Although not all antibodies were neutralising, some

of them exhibited cross-binding to Novoseven ® (recombinant coagulation FVII, eptacog). ADAs had not previously been reported to Novoseven ® , so this raised concern for the treatment of haemophilia patients with these agents. Subsequent post hoc assessment of the immunogenicity of vatreptacog alfa using multiple pre-clinical immunogenicity assessment approaches, including in silico, MHC-associated peptide proteomics (MAPPs) and ex vivo T cell assays identified an HLA-restricted neoepitope that likely resulted in the observed ADAs 13 . These findings suggest that use of such tools in pre-clinical screening and development of biologics could aid candidate selection and reduce the chances of failure at late-stage development due to immunogenicity. Even manageable immunogenicity can have cost implications for companies, as payers may be less inclined to reimburse a drug which requires costly immunogenicity management, when better alternatives are available. When and How to Tackle Immunogenicity The example of Novo Nordisk’s vatreptacog alfa illustrates how costly it can be to find out about a product’s immunogenicity late in the development process, and why most biopharmaceutical companies are incorporating immunogenicity analysis in general, and T cell epitope analysis specifically into their pre-clinical or even discovery processes. Immunogenicity assessment is also one of the regulatory requirements for biotherapeutic approval, with guidelines advocating the use of immunogenicity testing as early as pre-clinical development14,15. To this end, Abzena has developed a suite of tools to evaluate the immunogenicity of a protein or antibody at the pre-clinical stage. The evidence clearly supports the need for early assessment of immunogenicity, but how do you identify which candidates have issues and what they are? Just as there are multiple elements that contribute to the immunogenic impact of a biotherapeutic, there INTERNATIONAL PHARMACEUTICAL INDUSTRY 43


Drug Discovery, Development & Delivery are also multiple points for the assessment of immunogenicity. Figure 2 details the steps involved in the development of an immunogenic response, and the points which can be evaluated to assess this response. Specific tools and assays exploiting these different parameters of the immune response can be utilised to inform and evaluate the immunogenic potential of biopharmaceutical candidates. Immunogenicity – What Can We Do? Problems associated with immunogenicity to biopharmaceuticals, especially monoclonal antibodies, have been significantly reduced due to advances in molecular biology. There are, however, many recombinant protein biologics that are identical to endogenously expressed human sequences that still elicit potent neutralising immune responses in patients8,16,17. Regardless of how immunogenicity is triggered, one of

the single most important factors in the development of an immune response is the presence of epitopes that stimulate a potent CD4+ T cell response. T Cell Epitopes Drive Immunogenicity CD4+ T cell epitopes are critical in driving T cell dependent immune responses to antigens. During the initiation of a T cell dependent immune response, antigen-presenting cells such as dendritic cells (DCs), capture and process antigens, including therapeutic antibodies as shown in Figure 1a, and present them in the form of short, linear peptides bound in the groove of the MHC class II (b). Binding of the T cell receptor to these MHC class II/peptide/complexes by CD4+ cells (c) triggers an activation cascade in which T cells proliferate, differentiate and provide help to B cells by producing costimulatory cytokines (e.g. IL-2 & IL-4) and by cell-cell contact (d).

Figure 2: Schematic View of T Cell and B Cell Mediated Immune Response to a Therapeutic Antibody 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The immune cascade, from antigen processing and presentation through to secretion of ADAs from plasma cells, provides multiple points to assess the immunogenic response to a biotherapeutic. Whilst in silico tools provide a rapid method for the evaluation of peptide MHC class II interactions and can be used for assessing large numbers of candidates, it is the ex vivo T cell assays that provide a qualitative and quantitative measurement of T cell epitopes. Here we focus on a sub-set of Abena’s EpiScreen™ capabilities to exemplify how immunogenicity to a biopharmaceutical can be understood and mitigated. We will discuss the role of four different assays from Abzena’s EpiScreen™ suite; Figure 3 shows how the tests we will discuss fit into the flow of early biotherapeutic development. The EpiScreen™ suite includes three ex vivo immunogenicity assessment assays that utilise a panel of peripheral blood mononuclear cells (PBMCs) from 50 individuals. The panel is selected to ensure the distribution of HLA-allotypes is representative of the European/ North American population and can be optimised to be representative of the intended population of the candidate drug, consistent with FDA and EMEA recommendations14,15. The three assays are the time course T cell assay, the DC:T cell assay and the T cell epitope mapping assays. EpiScreen™ Time Course and DC:T Cell Assay. The EpiScreen time course and DC:T cell assays are used for immunogenicity risk assessment of whole protein biologics. The time course assay is a PBMC-based assay whilst the DC:T cell assay loads DCs with whole protein for processing and presentation to autologous CD4 T cells. The DC:T cell assay is typically used for biologics that exhibit direct T cell pharmacology. Both assays assess the frequency and magnitude of responses (proliferation and IL-2 secretion) against the whole protein in the study cohort. Assessment of relative risk of clinical stage immunogenicity is achieved by benchmarking against clinically relevant controls included within the assay. Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery

Figure 3: The application of Immonugenicity Testing and Protein Engineering in Early Biotherapeutic Development

Whilst these two assays provide an assessment of the immunogenic potential of the biotherapeutic, it is also important to understand which specific elements of the biotherapeutic elicit this T cell response for the purposes of protein engineering with the aim of reducing immunogenicity. Understanding which individual elements drive the immunogenicity in a biologic can be achieved by carrying out T cell epitope mapping assays, enabling the selection of better lead candidates and facilitating “deimmunisation” of the product to reduce the risk of clinical immunogenicity. EpiScreen™ provides two assays to address this question; the T cell epitope mapping and MHC class II associated peptide proteomics (MAPPs) assays respectively. EpiScreen™ T cell Epitope Mapping If identification and removal of the elements that drive immunogenicity is desired, then T cell epitope mapping studies can pinpoint the exact region of the biotherapeutic to engineer around. EpiScreen™ T cell epitope mapping assays identify CD4+ T cell epitopes within protein sequences by utilising 15mer peptides which span the test sample sequence. These assays provide quantitative (frequency of response to each peptide) and qualitative (magnitude of response to each peptide to compare their relative potency) measurements to map the location of T cell epitopes. From here a core 9mer peptide within the stretch of 15 amino acids can be identified and designated a T cell epitope. Once identified, the epitope itself can be deimmunised by including amino www.ipimediaworld.com

acid substitutions at key residues that reduce or abrogate binding to MHC class II molecules. These assays allow for pre-clinical assessment of the immunogenic potential of whole molecules or by identifying T cell epitopes. Whole protein assays allow for natural processing and presentation of T cell epitopes in the context of MHC class II, however the data generated by these whole protein assays differs from that of assays using synthetic 15mer peptides, which can introduce cryptic epitopes – i.e. presentation of epitopes that are not naturally presented by APCs resulting in false positives and potential for over-engineering of a molecule if taken on their own. The value of these peptide-based MAPPs assays lies in their ability to generate a shortlist of potential T cell epitopes for testing in T cell mapping assays. EpiScreen™ MAPPs Assay The EpiScreen™ T cell epitope mapping assay is a comprehensive means of identifying putative T cell epitopes but relies on extracellular binding of peptides to MHC class II molecules on the surface of DCs. In contrast, MAPPs allow the identification of putative T cell epitopes captured on MHC class II molecules as a result of uptake and intracellular processing of whole protein – more reflective of the natural antigen presentation process. For MAPPs, DCs are loaded with test proteins for processing and presentation of linear peptides in the groove of MHC class II. Following

immunoprecipitation of the MHC class II/peptide complexes from the surface of the DC, the peptides are eluted and analysed by nano-LCMS/MS. The peptides identified are typically different length variants that cluster together and share the same core HLA-DR binding motif. The peptides can then be synthesised and further characterised using T cell assays to determine which of them can elicit T cell proliferation for the purpose of protein re-engineering of the original biotherapeutic by de-immunisation to reduce the risk of clinical immunogenicity, with lower risk of over-engineering due to falsely identified T cell epitopes. Appropriate Assay Format Biopharmaceutical companies continue to develop novel biologics against new targets with new modes of action (MOA). For example, new immuno oncology drugs that target T cells directly and induce T cell proliferation may confound the proliferation observed through immunogenicity in a PBMC-based assay. In these instances, the DC:T cell assay is a more appropriate assay, potentially avoiding direct T cell pharmacology and only presenting linear peptides derived from the biologic to T cells. However, bi-specific antibodies that target T cells on one arm can target or tether to the surface of DC cells depending upon the specificity of the second arm, and this can confound this [DC:T] approach too. Such molecules can be present in the in vitro culture as intact molecules for the duration of the assay and exert pharmacology when the autologous T cells are re-introduced into the assay. In these instances, consideration of testing each arm individually or T cell epitope mapping the variable domains are options to consider. A final alternative strategy for such molecules would be to assess the naturally processed and presented peptides identified by MAPPs in a T cell peptide assay. Immunogenicity risk assessment assay formats will need to adapt and evolve as the biologics they are intended to assess evolve. Only by understanding the MOA of the biologic will it be possible to elect an appropriate assay format from the existing range of assays or INTERNATIONAL PHARMACEUTICAL INDUSTRY 45


Drug Discovery, Development & Delivery indeed develop new assays going forward. Conclusion The increase in the number of biotherapeutics being developed and approved across a range of therapeutic areas, has thrown a spotlight on the importance of understanding the potential immunogenicity profile of these drug types and the risk this might cause to patients. Early immunological testing can provide data about the overarching immunogenicity of a candidate as well as identifying specific immunogenic sequences and epitopes to inform the design and selection of the best clinical candidate. Immunogenicity testing in early candidate selection and lead optimisation is a well-established strategy supported by the FDA and other regulatory bodies. The EpiScreen™ suite of assays provides data that can facilitate lead selection based on the immunogenicity of biotherapeutics, including mAbs and other human and non-human protein therapeutics. It can also confirm reduction in the immunogenicity risk following antibody humanisation and protein deimmunisation. This article demonstrates that early intervention not only helps identify these risks, but opens the opportunity to mitigate those risks through a combination of improved candidate selection and the use of protein engineering techniques to deimmunise the lead candidate. REFERENCES 1. Ecker, D.M., Jones, D.J. and Levine, H.L. The therapeutic monoclonal antibody market. mABs 7(1), 9—14 (2015) 2. Chester, K.A., Baker, M.P. and Mayer A. Overcoming the immunologic response to foreign enzymes in cancer therapy. Expert Rev. Clin. Immunol. 1(4), 549559 (2005) 3. Baker, M.P. and Jones, T.D. Identification and removal of immunogenicity in therapeutic proteins. Curr Opin Drug Discov. Devel. 10, 219-227 (2007) 4. Jaber, A. and Baker, M. Assessment of the immunogenicity of different interferon beta-1a formulations using ex vivo T-cell assays. J Pharm Biomed Anal. 43(4), 1256-1261 (2007) 5. Sethu, S., Govindappa, K., Alhaidari, 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

M., Pirmohamed, M., Park, K. and Sathish, J. Immunogenicity to Biologics: Mechanisms, Prediction and Reduction. Arch. Immunol. Ther. Exp. 60, 331-344 (2012) 6. Ponce, R., Abad, L., Amaravadi, et al. Immunogenicity of biologicallyderived therapeutics: assessment and interpretation of nonclinical safety studies. Regul. Toxicol. Pharacol. 54(2), 164-182 (2009) 7. Casadevall, N., Nataf, J., Viron, B., Kolta, A., Kiladjian, J.J., Martin-Dupont, P. et al. Pure red cell aplasia and antierythropoietin antibodies against human erythropoietin in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469-475 (2002) 8. Schellekens, H. Immunogenicity of therapeutic proteins. Nephrol. Dial. Transplant, 18, 1257-1259 (2003) 9. Seidl, A., Hainzl, O., Richter, M., Fischer, R., Bohm, S., Deutel, B., Hartinger, M., Windisch, J., Casadevall, N., London, G.M. and Macdougal, I. Tungsteninduced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm. Res. 29(6), 1454-1467 (2012) 10. http://www.fiercebiotech.com/ biotech/novo-nordisk-discontinuesdevelopment-of-vatreptacog-alfafollowing-analysis-of-phase-3 11. DiMasi, J.A., Hansen, R.W. and Grabowski, H.G. The price of innovation: new estimates of drug development costs. J Health Econ. 22(2), 151-85 (2003) 12. Paul, M., Mytelka, D.S., Dunwiddie, C.T., Persinger, C.C., Munos, B.H., Lindborg, S.R. and Schacht, A.L. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Reviews Drug Discovery 9, 203-214 (2010) 13. Lamberth, K., Reedtz-Runge, S.L., Simon, J., Klementyeva, K., Pandey, G.S., Padkjaer, S.B., Pascal, V., Leon, IR, Gudme, C.N., Buus, S. and Sauna, Z.E. Post hoc assessment of immunogenicity of bioengineered factor V11a demonstrates the use of preclinical tools. Sci. Transl. Med. 9, eaag1286 (2017) 14. US Department of Health and Human Services, Center for Biologics Evaluation and Research. Assay Development for Immunogenicity Testing of Therapeutic Proteins. US FDA, Rockville, MD, USA (2009) 15. European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins. European Medicines Agency, London, UK (2007) 16. Hochuli, E. Interferon immunogenicity: technical evaluation of interferon-alpha 2a. J Interferon Cytokine Res. 17 (Suppl 1), S15-S21 (1997) 17. Namaka, M., Pollitt-Smith, M., Gupta, A., Klowak, M., Vasconcelos, M., Turcotte, D. et al. The clinical importance of neutralizing antibodies in relapsingremitting multiple sclerosis. Curr. Med. Res. Opin. 22:223–239(2006)

Gary Bembridge Senior Director Scientific Affairs – Immunology. Since joining Abzena in 2013, Gary has managed business development activities associated with immunological responses to biotherapeutics, ensuring that immunogenicity assessment and bespoke immunological studies are tailored to partner’s needs. Prior to this, Gary worked at Huntingdon Life Sciences (Envigo) as a Biopharmaceutical Product Development Manager and shared responsibility for designing safety studies and non-clinical development programmes for all biologics, providing scientific support and advice to the immunology department. Previous roles at GSK’s BioPharm R&D unit included Biology Leader investigating the immunogenicity and efficacy of DNA vaccines, molecular adjuvants and anti-inflammatory antagonist mAbs where he co-authored several patents in these fields. Gary completed his PhD from the University of Bristol, Department of Veterinary Medicine. Email: gary.bembridge@abzena.com

Karen Hills Marketing and Business Development. Karen is a consultant in pharma/ biopharmaceutical business development and marketing, working with Abzena in Cambridge. Since joining Abzena, Karen has focused on marketing across the areas of cell line development, chemistry manufacturing and immunology at Abzena. Karen has a PhD in molecular biology from Cambridge University and an MBA from London Business School. Her background includes sales, marketing and business development for companies ranging from start-up biotech to big pharma. Email: karen.hills@abzena.com

Winter 2017 Volume 9 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 47


Drug Discovery, Development & Delivery

Needle-free Injection – Eradicating Diseases to Improve Global Health Needle-free injection technology has evolved significantly over the last 50 years and is now accepted in many routine immunisation settings as a safe and effective vaccine delivery method. Disposable syringe jet injectors are now being used for the delivery of vaccines to eradicate polio, MMR, and influenza, and are showing promising results in vaccine clinical trials for the Zika virus and HPV. The devices are fast, safe, and easy to use, with most providers trained in less than 20 minutes.

Delivering vaccines without a needle addresses a host of issues surrounding needles. For example, there are about 800,000 needle stick injuries annually in the US1 and this is an even larger issue internationally. Accidental needle sticks have been an ongoing safety issue for providers and patients, accounting for 33,800 new HIV infections, 1.7 million hepatitis B infections and 315,000 hepatitis C infections annually.2 In addition, as many as 500 million used needles are added to trash dumps and landfills every year, with 75 million of those needles potentially infected with blood-borne illnesses.2 No needle means no needle-trash, reduction of needle stick injuries and the potential for improved acceptability, coverage and efficiency of vaccine delivery. How Needle-free Injectors Work The spring-powered injectors use a narrow stream of fluid that goes through the skin in about 1/10 of a second. There is no power or electricity needed. Needle-free injectors are precisely designed for

vaccine delivery into certain tissue depths of the body, whether it be intramuscular (into the muscle, see Figure 1), subcutaneous (below the dermis level), or intradermal injection (directly into the dermis level, see Figure 2). Additionally, the needle-free syringe is auto-disabling, eliminating the possibility of reuse, and calibrated for a specific vaccine volume, either 0.5mL or 0.1mL dose. While needle injection is largely dependent upon the provider’s technique, which can have a wide variation in terms of accuracy and injection speeds, needle-free injection uses a simple point-and-click approach, resulting in consistent delivery every time.

IM and SC Needle-free Injections (0.5mL Disposable Syringe) 1. Prepare the Injector

Figure 3a

2. Fill Syringe

As shown in Figures 3a-3d and 4a–4e, the needle-free injectors are easy to use, employing a simple four-step process, and most users are self or web-based trained in less than 20 minutes. Figure 3b

3. Load Injector

Figure 1: The 0.5mL PharmaJet® Stratis® Injector delivers vaccines to the intramuscular (IM) and subcutaneous (SC) depths.

Figure 3c

4. Give Injection

Figure 2: The 0.1mL PharmaJet® Tropis® Injector delivers vaccines to the intradermal (ID) depth.

Figure 3d

The workflow using the PharmaJet intramuscular/subcutaneous needlefree device (Stratis) is comparable to needle-syringe (See YouTube video: https://www.youtube.com/ watch?v=0ag-v7bv960). 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2017 Volume 9 Issue 4


5 THINGS TO CONSIDER

WHEN MANUFACTURING CONNECTED DRUG DELIVERY DEVICES The estimated number of connected drug delivery devices continues to increase and the impact of this trend could be significant, explains Phillips-Medisize

While digital connectivity or connected health can improve the coordination and delivery of patient care, original equipment managers need to keep these five things in mind when creating connected drug delivery devices: 1 2 3 4 5

Development strategy and design consideration Situation analysis and patient compliance Connectivity ecosystem Wireless subsystem Security of device and information

As the Internet of Things continues to become an integral part of people’s lives, the opportunity to use it within drug delivery device applications remains promising. The manufacturers and device designers must identify, investigate and overcome these challenges so that the implementation of wireless and other related smart technologies can be achieved. When done successfully, connected systems enable the patient and caregivers to have a 360° view of both the patient and the disease – not only to manage adherence, but to improve results by understanding the effect of the regimen.

www.ipimediaworld.com www.phillipsmedisize.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 49


Drug Discovery, Development & Delivery ID Needle-free Injections (0.1mL Disposable Syringe) 1. Prepare the Injector

Figure 4a

2. Fill Syringe

Figure 4b

3. Load Injector

Figure 4c

4. Give Injection

support the global demand, and this shortage is anticipated to continue for years to come.3,4 As part of its Global Polio Eradication Initiative (GPEI), the World Health Organization has been working closely with PATH and the Gates Foundation to clinically evaluate alternate delivery options and technologies, including fractional dose needle-free delivery, to address increases in demand and vaccine supply shortages.5 Multiple clinical studies evaluated the effectiveness of one full dose of polio vaccine (0.5mL) administered intramuscularly vs. two fractional doses (0.1mL) administered intradermally, with either a needle and syringe or a needle-free injection device (PharmaJet ® Tropis ®). As summarised in Figure 5, the studies found that two fractional doses of intradermal IPV (fIPV) (2 doses x 0.1mL) were superior to one full dose (0.5mL) administered intramuscularly 6 , thus using 60% less vaccine.7 This means 2–3x more children can be vaccinated with the same amount of vaccine.

schedule. These countries include Argentina, Bolivia, Brazil, Chile, Colombia, Cuba, Ecuador, El Salvador, Honduras, Nicaragua, Paraguay, Peru, Uruguay and Venezuela.”10 While the clinical studies provided a workable solution for the supply shortage, they also recognised the ongoing difficulty of administering vaccines intradermally with the Mantoux technique using a needle and syringe. Administration can be slow, technically difficult, inconsistent, and painful (see Figures 6a and 6b). Additionally, many healthcare workers are not familiar with the intradermal technique, making it unsuitable for house-to-house campaigns, and the inconsistent delivery is less than ideal for mass immunisations. Conversely, the PharmaJet Needle-free Injector is easy-to-use and requires minimal training (see Figures 6c and 6d). Healthcare workers that have used the device found that they quickly became proficient in providing consistent and rapid injections.11 Comparing Needles to Needle-free for Intradermal Injections Mantoux Technique (Needle)

Figure 4d Deltoid Injection Figure 6a

Figure 6b

Needle-free Technique Figure 5. IPV Fractional dose immunogenicity8

Figure 4e Lateral Thigh Injection

The workflow using the PharmaJet intradermal needle-free device (Tropis) is 25% faster than a needlesyringe (See YouTube video: https://www. youtube.com/watch?v=prwEHS3KN_8). Protecting Every Last Child: Fractional Dose Delivery and Polio Eradication Polio is a crippling and potentially fatal infectious disease, mainly affecting children under five years old, and there is no cure. The move from oral polio vaccine (OPV) to injectable polio vaccine (IPV) to eliminate “wild” types of polio has created a worldwide shortage. It is estimated that less than half the amount of polio vaccine is available to 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Fractional dose polio vaccine delivery has been endorsed by the WHO and the Indian Ministry of Health, as it also provides a more cost-effective option. Specifically, the WHO Strategic Advisory Group of Experts (SAGE) recommends that countries adopt a two fractional dose IPV schedule in the routine immunisation and outbreak response. 9 The Technical Advisory Group on Vaccine-preventable Diseases (TAG) and Pan American Health Organization (PAHO) endorsement states that “countries that administer more than 100,000 doses of IPV each year and have the capability to adequately train health care workers and supervise implementation should immediately begin to prepare to implement a fractional dose IPV

Figure 6c

Figure 6d

Figure 6: Comparison of Mantoux technique with needle (a and b) to Needle-free technique (c and d)

The needle-free injector’s simple point-and-click design ensures consistent and accurate intradermal injection. Additionally, the preparation and administration time is 50–70% less than needle and syringe, making it an ideal choice for vaccination campaigns.12 And, because there is no needle, healthcare workers can work fast and not have to worry about needle sticks. The PharmaJet needle-free device is currently being used as part of the polio eradication effort in Bangladesh, Cuba, Gambia and Pakistan. Winter 2017 Volume 9 Issue 4


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Drug Discovery, Development & Delivery MMR Vaccine Delivered without a Needle Measles is a leading cause of childhood deaths globally, with 3 million cases diagnosed and nearly 1 million deaths each year. The WHO estimates that global immunisation coverage for measles containing vaccine in 2013 was 84%, with many countries still well below the recommended 95% level required to interrupt endemic measles transmission. For example, in India, the coverage averages only 66%, with rates below 50% in many parts of the country.13 A recently completed Phase IV clinical study, supported by the Gates Foundation and PATH, included 300+ children aged 15-18 months over a 12-month period. The objective of the study was to demonstrate the non-inferiority of seropositivity of MMR vaccine administered using the needle-free injector to MMR vaccine administered by needle and syringe for all three components of the vaccine. Secondarily, there was an objective to assess and compare the safety of MMR vaccine administered by needle-free jet injector vs. needle and syringe. The results showed comparable non-inferiority performance and safety to that of the traditional needle and syringe.14 Needle-free injection is being used to administer the MMR vaccine TRESIVAC NF (needlefree) in Cambodia and India. Needle-free Flu Shots Influenza is one of the most common preventable infectious diseases. In the US alone, approximately 10-20% of the population contracts influenza each year, which accounts for about 226,000 hospitalisations and 36,000 deaths annually.15 While morbidity and mortality affect mostly the young and old, all age groups are affected. The US Department of Health and Human Services (HHS) has established a Healthy People 2020 campaign that includes the goal of 70 per cent flu vaccination compliance by the year 2020, versus 43 per cent in 2016.16,17 In 2014, The Lancet published a study that demonstrated that the delivery of an influenza vaccine with the PharmaJet needle-free jet injector compared favourably 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to a traditional needle and syringe delivery. This was the first definitive non-inferiority study to measure the immune responses to all three influenza viruses induced after administration of a seasonal flu vaccine by a jet injection device as compared to a needle and syringe. The study also found that 89 per cent of the people receiving the needlefree injection reported they would choose a needle-free injection over needle and syringe for their next injection.18 Patient and Provider Feedback – using Needle-free to Increase Compliance and Productivity The Centers for Disease Control and Prevention (CDC) recommends annual flu shots for all adults, yet only around 43% of them receive the yearly vaccination; many citing a fear of needles as a reason for non-compliance. Needle-free devices provide an option for the one in four adults who have a fear of needles.17,19 More than half of adults aged 20–64 years who are employed are affected by the flu, resulting in about 111 million lost working days every year. Workplace health influenza immunisation programmes are an important factor to consider for addressing decreased productivity, when a simple flu shot could decrease work absenteeism and significantly reduce the spread of influenza to others. According to the US National Institute for Occupational Safety and Health (NIOSH), the cost associated with sick days and lost productivity is approximately $7 billion in the US annually. Despite the potential benefits of vaccination,

one study showed that only about 20% of healthy working-age adults aged 18–49 years receive an annual flu shot.20,21,22 During the 2016–17 influenza season the PharmaJet Stratis® needle-free injection system was used in multiple workplace health influenza clinics. There were 35 vaccinations events, which included employees from BP Oil, Cargill, Denver International Airport, Ernst & Young, Morgan Stanley, Terumo BCT, TriNet, and Xerox, among others. Surveys were completed by patients and caregivers to collect feedback regarding the acceptability and usability of the device, whether it should be an option for next year, and the potential to increase influenza immunisation coverage at a particular site.23 Patient Surveys Overall, 1018 surveys were completed by working individuals, 18-64 years of age, who received a needle-free flu shot at one of the influenza vaccination events. Figure 7 shows results for each of the three key questions regarding satisfaction, likelihood of choosing a needle-free injection next year, and likelihood of recommending a needlefree injection. In summary (see Figure 7a-c): • • •

The majority of patients (97%) were satisfied with the needlefree shot 95% of patients responded that they would choose needle-free again next year 95% said they were likely to recommend the needle-free option to friends and family

How satisfied were you with today’s needle-free flu shot?

Figure 7a: Satisfaction with needle-free injection

For next year’s flu vaccination, will you choose to receive your flu shot with a needle-free injection?

Figure 7b: Likelihood of choosing a needle-free injection next year Winter 2017 Volume 9 Issue 4


53 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery How likely are you to recommend a needle-free flu shot to your family and friends?

Figure 7c: Likelihood of recommending a needle-free injection to family or friends. Figure 7: Patient survey results regarding: a) satisfaction with the needle-free injection they just received; b) likelihood of choosing a needle-free injection next year; and c) likelihood of recommending a needlefree injection to family or friends.

Healthcare Provider Surveys

Combining surveys from providers at these flu clinics and those from previous seasons, there were a total of 67 healthcare providers that completed the survey, including contract nurses, pharmacists and occupational health nurses. (24) In summary (see Figure 8a-d):

• • •

91% said they were satisfied with ease of use 87% would like the option of needle-free next year 82% said they would be likely to recommend needle-free flu shots to their colleagues 45% thought that offering a needle-free option could increase flu vaccinations by more than 10% at their facility.

How satisfied were you with the ease of use?

Figure 8a: Satisfaction with ease of use

For next year’s flu vaccinations, would you like the option of needle-free shots at your facility?

Figure 8b: Wanting the option of needle-free shots in their facility

How likely are you to recommend needle-free flu shot to your colleagues?

Figure 8c: Likelihood of recommending to colleagues

How much could your flu vaccinations increase next year by offering the option of a needle-free flu shot?

Figure 8d: How much vaccination could be increased by offering needle-free Figure 8: Healthcare provider survey results regarding: a) satisfaction with ease of use; b) needle-free option for next year c) likelihood to recommend to colleagues; and d) how much vaccination could be increased by offering needle-free 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Future Vaccines NIH Clinical Trial for Needle-free Zika Vaccine Shows Promise There are now more than 30,000 diagnosed Zika cases in every state but Alaska, with most of those in the US territory of Puerto Rico. Because it is now known that Zika can be transmitted through mosquitoes, blood and sex, that number is expected to rise. The National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) is using the Stratis 0.5mL needle-free device in a DNA vaccine clinical trial for a Zika vaccine, and the results are promising. DNA vaccines are a rapidly developing field. Unlike traditional vaccines, like for flu or measles, that contain whole viruses, DNA vaccines contain just a tiny piece of a virus’s genetic code, making them safe and easy to work with. For these vaccines to work, the DNA vaccine must get directly into the cells. For that purpose, a new delivery method was needed.25 Various pre-clinical and clinical preliminary studies have shown that the performance of nucleic acid-based vaccines (DNA and RNA) when injected with needle-free injectors have been superior to needle-syringe delivery and at least equivalent to other delivery methods.26 The NIH announced the start of the Phase II Zika vaccine trial in March 2017, which consists of two studies in the US, Central and South America. Part A will further evaluate the vaccine’s safety and ability to stimulate an immune response in participants, and assess the optimal dose for administration. Part B will attempt to determine if the vaccine can effectively prevent disease caused by Zika infection. "A safe and effective vaccine is urgently needed to prevent the often-devastating birth defects that can result from Zika virus infection during pregnancy," says NIAID Director, Dr Anthony S. Fauci. "Evidence also is accumulating that Zika can cause a variety of health problems in adults as well."27 Needle-free Providing a More Comfortable Experience – HPV Vaccine Human papillomavirus or HPV is the main cause of cervical cancer affecting 530,000 women annually and an additional 10 million women are impacted by a long pre-invasive Winter 2017 Volume 9 Issue 4


Drug Discovery, Development & Delivery disease called cervical intraepithelial neoplasis (CIN). Current standard therapy for CIN 2/3 varies between countries and regions and often involves surgical removal of the affected tissue. These invasive procedures are associated with bleeding, infection, cervical stenosis, scarring and, most importantly, pre-term deliveries in subsequent pregnancies. As a result, there is a significant need for an effective therapeutic vaccine to treat existing HPV infection and associated pre-malignancies and malignancies of the cervix and thereby prevent the development of cervical cancer caused by human papillomavirus. 28,29 In late 2016, Vaccibody AS announced the results of the Phase I clinical trial of their VB10.16 HPV vaccine delivered with the Stratis needle-free jet injector. Martin Bonde, the CEO of Vaccibody AS noted, “While other DNA vaccines developed for this indication require delivery with in vivo electroporation, which is quite painful for the patients, VB10.16 is delivered by needle-free injection, which we believe improves patient compliance tremendously and will be a significant asset in further development of this product.”29 Given that multiple vaccine doses are required for the HPV vaccine, improved compliance with needlefree is an important advantage over traditional methods. In March 2017, Vaccibody AS announced the start of their Phase IIa clinical study: an exploratory, open-label, multi-centre study with VB10.16 immunotherapy for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2/3) caused by human papillomavirus 16 (HPV 16). The vaccine is also being delivered with the Stratis needle-free injection system.29 1. United States. Centers for Disease Control and Prevention. National Institute for Occupational Safety and Health. Preventing Needlestick Injuries in Health Care Settings. N.p.n.d. Web. http://www.cdc.gov/niosh/ docs/2000-108/pdfs/2000-108.pdf 2. Health-care waste, World Health Organization Fact sheet No 253, November 2015; http://www.who.int/mediacentre/ factsheets/fs253/en/ 3. IPV introduction and RI strengthening, WHO; http://www.who.int/immunization/ diseases/poliomyelitis/endgame_objective2/ inactivated_polio_vaccine/en/ 4. Inactivated Polio Vaccine Supply and www.ipimediaworld.com

Demand Update, September 2016, Unicef Supply Division; https://www.unicef.org/ supply/files/Inactivated_Polio_Vaccine_ (IPV)_-_september_2016.pdf 5. To help end polio, intradermal delivery takes center stage, Vaccine and Pharmaceutical Technologies News and Updates – PATH, May 2016, http://www.path.org/newsletters/ vaccine-technologies-newsletter.php 6. Immunogenicity to poliovirus type 2 following two doses of fractional intradermal inactivated poliovirus vaccine: A novel dose sparing immunization schedule. Anand A., et al. Vaccine, 2017 May 19:35(22):2993-2998; https://www.ncbi.nlm. nih.gov/pubmed/28434691 7. Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial, Anand A., et al., Vaccine. 2017 May 19;35(22):2993-2998. doi: 10.1016/j.vaccine.2017.03.008. Epub 2017 Apr 20. 8. Use of fractional dose IPV in routine immunization programmes: Considerations for decision-making, WHO Polio Global Eradication Initiative, March 2017; http://www.who.int/immunization/ diseases/poliomyelitis/endgame_ objective2/inactivated_polio_vaccine/ fIPV_considerations_for_decision-making_ March2017.pdf?ua=1 9. Weekly epidemiological record, World Health Organization, June 2, 2017, page 309, http:// apps.who.int/iris/bitstream/10665/255611/1/ WER9222.pdf?ua=1 10. Ad hoc Virtual TAG Meeting 20176, 10, March 2017, Washington D.C., USA, p. 7; http://www. who.int/immunization/sage/meetings/2017/ april/6_2017_TAG_Ad-hoc_Meeting_Report_ EN.pdf 11. PharmaJet Inc., Doc. #60-10214-001A Cambodia Healthcare Worker Interview Video 12. Intradermal Administration of Fractional Dose of Inactivated Poliovirus Vaccine (fIPV) Using Tropis® Intradermal Needle Free Injection System, Karachi Pakistan, Community Based Polio Vaccination Campaign, December 2016; Ali Faisal Saleem, Mach Ondrej, Muhammad Tahir Yousafzai, Attaullah Baig, Roland Sutter, Anita KM Zaidi, Aga Khan University, Karachi Pakistan, WHO, Geneva, Switzerland 13. Serum Institute of India website, Health FAQ – Measles, http://www.seruminstitute.com/ content/faq_measles.htm 14. Effect of jet injection on infectivity of measles, mumps, and rubella vaccine in a bench model, Coughlin, MM, et al., Vaccine (2015), http://dx.doi.org/10.1016/j. vaccine.2015.07.013 Norwalk MP, et al, Improving Influenza Vaccination Rates in the Workplace. Am J Preventive Med, 2010, Vol 38 pp 237-246 Healthy People 2020, Office of Disease Prevention and Health promotion (ODPHP), HealthyPeople.gov. Immunization and Infectious Diseases IID-12.12. https://www. healthypeople.gov/2020/topics-objectives/ topic/immunization-and-infectiousdiseases/objectives Updated March 23, 2016v 17. Flu Vaccination Coverage, United States 2316-2017 Influenza Season, CDC, https:// www.cdc.gov/flu/fluvaxview/coverage1617estimates.htm 18. Needle-free jet injection for administration of influenza vaccine: a randomized

non-inferiority trial, McAllister, L et al, Lancet 2014: 384:674-81 19. Survey of the prevalence of immunization non-compliance due to needle fears in children and adults. Taddio A, Ipp M, Thivakaran S, et al. Vaccine 2012: 30: 48074812 Web. 20. Centers for Disease Control and Prevention Website, Frequently Asked Flu Questions 2016-2017 Influenza Season. Accessed October 2016 (http://www.cdc.gov/flu/about/ season/flu-season-2016-2017.htm 21. Lee BY, et al, Economics of Employersponsored workplace vaccination to prevent pandemic and seasonal influenza. Vaccine, 2010, Vol. 28 (37), pp 5952-5959 22. US Centers for Disease Control and Prevention Website, National Institute of Occupational Safety and Health Activities: Surveillance Tracking Influenza Cases and Preventive Measures. Accessed 2017. https:// www.cdc.gov/niosh/topics/flu/surveillance. html 23. Needle-free jet injection in workplace influenza clinics, Miller, T, et al., ONdrugDELIVERY, May 2017, Issue No. 75, pp. 18-21, http://www.ondrugdelivery.com/ publications/75/PharmaJet.pdf 24. Doc. #61-10194, Third Party Review – Stratis PMS Health Care Provider. Internal PharmaJet Document, 2015. 25. The Zika Virus, Nov. 6, 2016, CBS 60 Minutes,( http://www.cbsnbews.com/ news/60-minutes-zika-in-the-unitedstates-mosquito-disease/) 26. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an openlabel, non-randomised, prospective, first-in-human phase 1 clinical trial. Alberer M et al. Lancet. 2017 Jul 25. pii: S0140-6736(17)31665-3. 27. Zika vaccine trial site in Peru led by Fogarty trainee, Global Health Matters, May/June 2017, Volume 16, Issue 3 28. Vaccibody announces positive results from the phase 1 part of the clinical trial, press release, August 25, 2016, www.vaccibody. com/news 29. Vaccibody announces positive results from the 12-month analysis of the Phase 1 part of the clinical trial VB C-01 in patients with high-grade cervical dysplasia, press release, June 21, 2017

Erin Spiegel Dr Erin Spiegel is the Regulatory Affairs Manager at PharmaJet, Inc., a medical device company developing needle-free injection technologies. Erin specialises in regulatory strategy for medical devices, drugs, and biologics. She spent the first half of her career developing vaccines and biologics and has expertise in genetic engineering, virology and molecular biology. Erin received her PhD in biophysics and genetics from the University of Colorado and her BS in animal science from the University of Nebraska-Lincoln. Email: erin.spiegel@pharmajet.com

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Clinical Research

Automated Accountability: Maintaining a Chain of Custody from Release to Destruction New solutions are proliferating to improve the efficiency of the clinical research function within pharmaceutical companies and contract research organisations (CROs). One work stream, in particular, that has been ripe for transformation is the process by which sponsors demonstrate to regulatory authorities that all investigative products (IP) have been handled in accordance with Good Clinical Practices (GCPs) and Good Manufacturing Practices (GMPs).

The accountability and reconciliation process is noted for being time-consuming and error-prone, two characteristics that result in it adding significantly to trial costs and timelines. The onerous task of reconciling discrepancies in supply records that have accumulated over the course of a trial often adds as much as two years to the study closeout phase. In many cases, accountability and reconciliation are still paper-based, and in others they are supported by fragmented solutions that do not completely solve the problem. For example, accountability solutions that do not prevent discrepancies from creeping into data sets do little to improve reconciliation. Solutions that fail to link the drug assignment to the chain of custody records don’t provide a continuous, unbroken lineage of what was assigned, dispensed and returned, so they cannot confirm study compliance with regard to IP consumption. In contrast, chain of custody software that is integrated with the trial’s interactive response technology (IRT) system provides visibility to, and an audit trail of, product conditions and movement throughout the trial. This improves patient safety, reduces trial risks, and strengthens monitoring and compliance, while cutting costs and shortening timelines. In the following pages we review the challenges that sites and 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sponsors/CROs face in complying with good practices and explain how accountability can be improved to reduce trial risks and all but eliminate the dreaded reconciliation process. The Regulatory Requirements: Accountability — and Proof of It As is often the case with regulatory guidance, worldwide regulatory bodies like the FDA, EMEA, etc., document on maintaining an auditable chain of custody for drug products, stipulate what must be achieved, but not how it should be achieved. Nor do regulators specify how requirements can/ should vary with different forms of IP packaging, across therapeutic areas, or by study design (open label, double blind or single blind). The requirements for maintaining a chain of custody are governed by GCPs (which relate to the protocol and the treatment and protection of the study subject) and GMPs (which pertain to the manufacture, distribution, and quality of the investigational product). Essentially, the sponsor must be able to prove that the IP administered to patients was in a safe condition and that it was used only by subjects and according to the prescribed dose. All unused IP must be accounted for at the end of the trial, and any discrepancies in records must be documented and explained. A Necessary Evil Capturing accountability data and reconciling any discrepancies in it has been called a “necessary evil.” It is important, but it is also painful, time-consuming, and costly. Site staff are required to record the movement and dispensation of IP at every step of the way through a trial, whether it is in accepting a shipment, administering a drug to a patient, or accepting an unused drug kit back from a patient. But, this seemingly simple requirement is difficult to meet because site staff are busy with their first priority: patient care. Maintaining

records is made cumbersome with a variety of fragmented solutions, variations among vendor products and standard operating procedures (SOPs) that complicate the site’s work. Different aspects of the chain of custody are recorded in different systems, and often accountability work needs to be duplicated on paper records to adhere to site SOPs. Complying with expectations – both those of the sponsor and of their own internal processes – is commonly a struggle for patient-facing site staff. Consequently, their records are often incomplete and contain errors (many caused by having to transcribe information from multiple fragmented systems into one). Some sponsors have sites record accountability information in the electronic data capture (EDC) system. However, because the EDC is not used for randomisation and trial supply management (this is performed in the IRT), this method creates a gap in the chain of custody record. It cannot automatically be used to help ensure – or validate – that the drug assigned is the same one that was administered, returned, and destroyed. This problem is exacerbated by the fact that sites update EDC records retroactively, causing further delays in detecting errors early, let alone correcting them. It then falls to CROs and sponsors to correct these errors, complete missing data, and resolve discrepancies in the records. The work is so laborious that it is typically not addressed until the end of the trial. This reconciliation process can add months and even years to the trial timeline, delaying the approval of a new therapy. Despite there being a number of solutions on the market, the problem persists. One sign that accountability issues have not been adequately addressed is the number of warning (483) letters that the FDA issues to site investigators concerning the chain of custody and specific processes around accountability and protocol compliance at sites. In fact, inadequate record-keeping and Winter 2017 Volume 9 Issue 4


Clinical Research inadequate accountability for IP are two of the most common issues cited in FDA warning letters.1 The Current State, by the Numbers An informal poll of Almac Clinical Technologies’ clients shows that: •

About HALF rely on a combination of paper and electronic solutions for tracking supplies returned for destruction. 52% had chain of custody issues that caused data problems, short supplies, or delayed timelines. 65% had dispensing errors that impacted patient treatment, safety, and/or data validity. 30% use EDC systems to collect accountability data from sites. 65% use an IRT system to collect accountability data from sites. 85% still use some form of paper records for accountability and reconciliation.

Envisioning the Ideal Solution Currently, there is no standardisation or best practice that will guide sponsors on how to collect, present, and maintain accountability data. This disparity of approaches has led to the problems just described. In order to overcome these persistent challenges, the industry needs a solution that: •

Provides end-to-end traceability. For the chain of custody to be complete, the IRT and accountability functions must be handled in the same system (see Figure 1.) This then can satisfy both internal and external auditors. Is configurable. Any solution must work with all protocols and supply designs without adding to start-up time. In other words, the size, complexity, and design of the IP should not affect the ability of the system to function. The system should also be flexible enough to work with multiple IP destruction strategies with different site, country, or study-level parameters.

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Figure 1: An End-to-End Chain of Custody

Ideally, the solution should be configurable even if certain study details (such as whether IP must be accounted for at the unit or kit level) have not yet been determined at the time of the system build. Prevents errors and omissions. Problems should be prevented to the extent possible and if they do occur, the system should make it easy to catch them quickly before they multiply. Delivers real-time visibility to all IP-related events. Users should be able to analyse and crossreference patient records with supply records, all on a single screen. They should be able to assess and report on the progress of the entire chain of custody, again in real time. And, they should be able to perform root-cause analysis of issues relating to any IP event so they can address them as soon as possible Is easy and intuitive for users. For site staff to use a system when and how intended, it must make their jobs easier and guide them through the steps they’re asked to perform instead of being an obstacle in their daily work.

Recommendations Companies wishing to maintain a complete, electronic chain of custody will need to: • Capture accountability and reconciliation data in the IRT system. This is the only way to

leverage both clinical and supply events in the process. Companies that attempt to track chain of custody from within their EDC system cannot realise the benefits discussed here unless they transfer the chain of custody functions into the IRT (this is because it is the IRT that stores the randomisation and dispensing information).Continued use of the EDC system for accountability will only perpetuate the problem of data fragmentation and transcription errors. At the same time, continuous feeds from IRT systems to EDC can keep the two systems in sync so that sites can continue realising the patientcentric information and benefits that EDC systems offer. Engage supply and distribution vendors early. To avoid having the supply strategy, packaging design and accountability procedures developed as an afterthought, be sure to involve your vendors when you are still discussing the protocol. All of these considerations should be addressed in parallel, not sequentially so that the best protocol and supply cost-saving strategies are taken into account up front for maximum trial benefits. Train and motivate site staff to use the chain of custody tool throughout the trial. An electronic chain of custody solution is designed to be used as the trial progresses, not sparingly or at the end. A well-designed INTERNATIONAL PHARMACEUTICAL INDUSTRY 57


Clinical Research system will guide users through steps to ensure complete collection of data and will provide error-correction workflows – benefits that can only be realised when the system is used routinely. Supporting Clinical Operation’s Compliance and Operational Efficiency A chain of custody tool that functions within an IRT would be more than a “housekeeping” tool for managing and monitoring supplies. It would support the clinical operation’s dual goals of compliance and operational efficiency. Almac Clinical Technologies’ Accountability & Reconciliation Tracking (ART™) within IXRS® 3 (our IRT system) is native, extended functionality that: •

Supports compliance with GCP. Because the software captures both the drug assignment (within the IRT) and details on the IP that was dispensed and returned, it serves as an extra step to ensure that the protocol was followed. Non-compliance is both reduced and highlighted for remediation. Makes it easy for monitors to do their job. The toolkit provides one consolidated view of clinical and supply information that enables clinical research associates (CRAs) to plan their work up front and immediately assess compliance and identify problems. Then they can correct them equally and easily. Produces correct and complete records. Intuitive workflows guide site users through all required steps so that they produce correct records. Validations stop users from committing wrong data, ensuring accurate capturing of information. Increases patient safety. Realtime validation checks at the time of dispensing and system back-end checks on the eligibility and condition of drug supplies throughout the supply chain reduce the opportunity for patients to be given the wrong treatment or a treatment that has expired or experienced a temperature excursion. Speeds study closeout. Due to the electronic accountability function, the system catches most discrepancies before they’re

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

recorded, and those that do occur can be addressed at once. User errors are eliminated due to system validation checks. So, discrepancies don’t accumulate, and reconciliation at the end of the study should be just a formality that doesn’t extend the study timeline. It is well known in the industry that every day that a study is extended a sponsor can lose anywhere from $600,000 to $8 million in sales opportunity costs.2 Slashing study closeout times will significantly impact a sponsor’s/CRO’s margins and profitability.3 End-to-End Visibility/Accountability for Supply Management Almac’s paperless chain of custody user interface provides real-time traceability of clinical supplies as the study progresses, making compliance with GMP routine and reconciliation and at study close a mere formality. For supply managers, the tool provides: •

Full Traceability, On-Demand Assessment. Supply managers have 100 per cent visibility to supplies throughout the supply chain, at any point in time. A barcode-enabled platform provides reliable traceability of supplies as they move through the trial, recording their whereabouts and condition. Immediate Reconciliation Capabilities at the Depot. The system guides site users through the process of managing and documenting returned IP (unused, damaged, or expired drugs and empty containers), forcing them to complete all of the required fields. Logic checks prevent basic data entry errors. Thus, the information that is passed on to depots is cleaner and more complete than what is delivered via paper-based systems, so depots can close their records at once. When depots receive returned shipments from sites, they can easily compare the kit contents to the full accountability details provided in the shipment manifest. An audit trail. At any time, users can access a complete and auditable trail of the physical chain of custody for all clinical supplies.

These records can be produced for auditors, indicating that 100 per cent of lots and returned shipments were successfully destroyed. Conclusion An electronic chain of custody solution that incorporates all IP events — from IP release all the way through to product destruction — in a single system is the only way to comply thoroughly with GCPs and GMPs. When this solution is armed with validations and flexible, configurable workflows, then one will gain maximum efficiencies and streamlining in the accountability and reconciliation processes. The right system will help sponsors and CROs realise time savings that come from easy setup, streamlined site ops, error reduction, and discrepancy resolution. Additionally, real-time validation checks at the time of dispensing and ongoing visibility to the condition of drug supplies throughout the supply chain improve compliance, reduce risk to patient safety, and safeguard against trial delays. REFERENCES 1. “Top 3 Reasons an FDA Warning

Letter is Issued to a Study Investigator,” imarc, accessed at http://www.imarcresearch.com/3reasons-fda-warning-letter-issued 2. http://blog.covance.com/2013/02/ clinical-trial-challenges/ 3. https://social.eyeforpharma.com/ clinical/slashing-cost-clinical-trials

Theodora Sarver Manager, Product Management at Almac. She oversees a group of product managers and is responsible for executing the full product roadmap and strategy from inception to commercialization and maintenance. She has successfully delivered a number of SaaS, custom and B2B products used in clinical trial supply management and operations. Email: theodora.sarver@almacgroup.com

Winter 2017 Volume 9 Issue 4


OFFERING DEEP INSIGHTS INTO KEY AREAS OF CLINICAL DEVELOPMENT » Patient Recruitment » Research Network » Risk-Based Monitoring » Randomization & Trial Supply Management » Electronic Data Capture » Medical Imaging » Cardiac Safety Learn more at BIOCLINICA.COM

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59


Logistics & Supply Chain Management

Rethinking the Cold Supply Chain Complex Healthcare Logistics Require Innovative Packaging Solutions

When unplanned events such as weather delays cause product spoilage, it’s easy for healthcare executives to react by instituting an acrossthe-board increase in insulation material. But a thorough evaluation of the supply chain may reveal a better solution to manage cold-chain packaging costs – one that could deliver savings, improve efficiency and possibly create better outcomes for patients. By considering the wide range of variables that make up the supply chain – including packaging, delivery speed, environmental data about shipping lanes and pack-out requirements – healthcare companies can make adjustments that enhance logistics, reduce spoilage and damage, improve space utilisation and optimise transportation assets.

Over time, it’s natural for inefficiencies to inadvertently creep into the supply chains at even the best-run healthcare companies. Many shipping operations have developed organically over many years, with modifications and adjustments made in response to unique events or imperfect audits. Eventually, these “inherited” shipping practices – and their costs – may spiral beyond all reason, the result of well-intended decisions made by business professionals whose service to the company may have ended years before. Decision-makers at these companies may have turned their focus to core issues like research and development – and may not be aware of the advanced methods for delivering their products. Without a proper assessment, it is impossible to know whether packaging is optimised to best perform its function at lowest possible cost. And sometimes the outcome of an assessment is the opposite of what conventional wisdom might dictate. Indeed, inherited supply chains often have inherent inefficiencies and are ripe for analysis. There are frequently 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

gains to be made, and lessons to be learned along the way. Finding the right solutions begins by establishing a group of experts with a strong understanding of your business. Typically, this group should include product managers, operations and warehouse personnel, logistics planners and packaging engineers. Each expert should be able to express the present parameters of control within their respective areas of expertise, and to be able to project the implications of adjusting those parameters. For example, a shipping manager should not only fully understand the terms of the shipping services presently utilised, but also to be able to speak to the cost and service implications of moving to a faster, or less urgent, service. Product managers must be able to express the conditions which will cause products to decrease in efficiency and, perhaps along with regulatory compliance managers, determine the deviations in conditions which will cause products to fail regulatory standards. Individually and as a team, this group can perform a thorough evaluation of your supply chain and identify areas that could be improved. This group should start by documenting the flow of packages and their contents. As the process map is built, it will become clear that product, packaging and transportation are part of a symbiotic relationship. Close attention should be paid to the following: •

Dimensional weight of packages, which determines the cost of shipping large – but light – packages.

Product ordering, storage and handling. It’s important to assess product ordering patterns to determine the location of the majority of units shipped and

also to determine any seasonality in ordering patterns. •

Outer shipping containers and packaging failure information. By improving the ratio of product payload-to-shipping case size, it’s possible to reduce the transportation cost of total units shipped. If payload and shipping cases show a higherthan-anticipated rate of failure in transit, laboratory testing may be needed to dig deeper into the root cause in order to find solutions.

Specific cold-chain considerations. Start by examining the typical failures found most often at the end of the supply chain, such as temperature excursion or physical damage. As in most areas, the Pareto 80/20 rule is a good place to start an analysis. Begin assessing where the majority of failures are occurring and determine the patterns of failure types. Identify the 20 per cent of issues that generate 80 per cent of deviations. Then prioritise them and address them by order of importance. Analysis may find, for example, that 80 per cent of potency problems are associated with 20 per cent of customers. It is then possible to work backwards and identify the problem.

Packaging types, testing and sustainability. All packaging should be assessed against shipment, product and transit needs. Any custom solution also needs to consider temperature criteria, anticipated time in transit, size, weight and other design constraints. Ambient temperature, shipping lane profile and payload space also factor into this evaluation.

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Logistics & Supply Chain Management the opposite of its intended goal. Every hour the package remains in transit is an hour that it is exposed to risk, and it is often the case that a package shipped by a faster service with less packaging, insulation and refrigerant is the better option to help prevent product spoilage – as well as a less costly option when taking into account the cost of product loss.

of refrigerants to be used in pack-out can be determined with a high degree of accuracy. In fact, shippers may choose to design seasonal pack-outs where, for example, a lower-cost, lighterweight pack-out for spring and fall may be selected on some routes during warmer weather, instead of a heavy-duty, universal pack-out that protects products throughout the year.

create models that will predict how the packaging will perform under adverse conditions. The lab analysis should include component, vibration, drop, shock and environmental tests. Finally, assess package performance against real-life conditions. These include: •

Ambient temperature along the package delivery route can directly affect the temperature stability of contents inside the package. Desert heat or arctic blasts can spoil a controlled room temperature product shipment if the proper packing patterns and transit times have not been followed. Hence the importance of route and seasonal shipping frequency information. Many shippers worked with their carriers to develop temperature profiles for various products and supplemented this data with additional research from individual logistics companies. Consideration of pack-out and refrigerants. Information about the transit route, handoffs and the amount and condition

62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Shipping service level and time in transit. The longer a cold-chain package is in transit, the more refrigerant or phase-change material is needed, which in turn lowers its possible payload size. Longer transit times increase the per-unit cost of shipping a cold-chain product and may increase the complexity of the pack-out. In such cases, a faster shipping option with less packaging, insulation and refrigerant may be a better option. Conversely, decreasing transit time may preserve payload size, but incrementally increases the transit cost. However, the universal default to a lower service level and longer transit times may in fact achieve

Healthcare manufacturers should continually look for ways to optimise their cold-chain packaging. The benefits can be far-reaching, starting with increased efficiencies and cost savings and extending to safer transportation of pharmaceutical goods and medical devices that improve the quality of lives. And while improving the transportation of pharmaceutical products and medical devices can have a profoundly positive impact on business costs and efficiency, “getting it right” helps fulfil the most important purpose of healthcare: making people well.

Susan Li She joined UPS in 2011 as a marketing manager in the healthcare strategy group. She specialises in temperature-sensitive packaging logistics and manages the UPS Temperature True ® Packaging programme, providing cold-chain package consulting services to healthcare customers. She is also a member of the ISTA Thermal Council. Susan has extensive marketing and product development experience in the healthcare industry, developing her understanding of global cold-chain management in the pharmaceutical and biotechnology industries. She has an undergraduate degree in biochemical engineering from East China University of Chemical Technology, a Master of Arts degree in biological science from Smith College and an MBA from Kellogg School of Management, Northwestern University.

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Logistics & Supply Chain Management

What Clinical Teams Should Know about Changing Trial Logistics and How they will Affect Development – PART 2 An Amazon-like Culture: The emergence of what has been dubbed an “Amazon-like culture” in the biopharma industry is driving the demand for 24/7 tracking of clinical supply shipments and the technology making it possible.

Purchasing goods from Amazon, the world’s largest internet-based retailer, comes with knowing exactly where that order is at all times – from the time it departs the warehouse to when it can be expected to reach a customer’s hands.

want 24/7 access through a portal to all their shipments in transit across the globe. It is worth noting, however, that the desire to know the location and estimated arrival time of clinical supply shipments is not limited to sponsors. Investigator sites also want to know when to expect shipments, as the following case study relates.

documentation review and the payment of taxes and duties for inbound shipments •

Collaborating with courier partners to define routes and agree on proposed delivery schedules as a means of minimising risks and potential shipment delays

Fisher Clinical Services works closely with sponsors and investigator sites to preschedule supply shipments and minimise shipment delays, as we did so successfully during the 2016 Summer Olympic Games in Rio de Janeiro, Brazil.

Scheduling shipments with investigator sites, and encouraging them to confirm that patients would be able to keep their clinic appointments during the Games

Fostering Innovation Fisher Clinical Services is investing heavily in information systems that can track shipments from warehouse to investigator, putting the company at the forefront of efforts to provide the comprehensive information sponsors require.

While anticipation for the Games was high in Brazil, so were anxieties about the potential impact of distribution of clinical supplies in the country. Fisher Clinical Services Brazil took proactive actions to minimise the impact of the Games on supply deliveries. Those steps included:

Pre-approving holiday requests from Fisher Clinical Services’ employees so staff could attend the Games without affecting supply deliveries or other colleagues’ workloads

As Daniel Fernandes, General Manager of Fisher Clinical Services Brazil, said: “A patient is waiting no matter what sporting event is taking place.”

Cold-chain temperatures are monitored across the supply chain, giving sponsors the reassurance that product integrity is maintained at all times. Because Fisher Clinical Services handles a high volume of shipments via various carriers, we pride ourselves on basing supply chain decisions on objective data.

Communicating the Games’ schedule to global project managers so they could advise sponsors to plan for continuity of supplies

Preparing for large pre-Games shipments of supplies by having our logistics and warehouse teams on hand to work additional hours Saving time by expediting

Now, as we shift to what the US-based supply chain manager described as “an Amazon-like culture,” sponsors want the same opportunity to track shipments in real time and to obtain real-time data that they can analyse. Of course, clinical supplies are more precious than a book or DVD shipping from Amazon, which raises the stakes considerably. This has led to a growing focus on new technology, including downloadable temperature monitors, and the ability to access real-time updates on the location and temperature condition of supply shipments.

Our Voice of the Customer research indicates that sponsors 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Case Study 2 How Planning Prevented Supply Shortages During the 2016 Summer Olympic Games

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Logistics & Supply Chain Management Patient-centricity Direct-to-patient trials are gaining the interest of sponsors and stand to become a bigger part of the clinical trial landscape.

a long-term outcomes study, non-ambulatory situations, rare diseases, and therapeutic areas that demand data collection from various stakeholders.

There could be no better example of patient-centricity than direct-topatient (DTP) studies. Although only a small percentage of clinical trials today are following the DTP model, DTP studies have the potential to become a trial of choice for certain therapeutic areas or studies.

DTP studies are convenient and time-saving for patients, particularly those who lack transportation or live in remote locations. There are shortcomings as well, however; chief among them reluctance on the part of some patients to self-administer drug.

DTP trials are a natural outgrowth of the growing trend toward self-administration of drugs, particularly for chronic diseases. Whereas traditional clinical trials are conducted at investigator sites, whose staffers provide trial medication to subjects during scheduled appointments, DTP trials eliminate the investigator site altogether.

There are a great many advantages for sponsors. DTP studies improve the patient experience, leading to higher engagement and retention rates with better outcomes.

Instead, trial medication is delivered directly to the patient’s home. Due to the nature of the medication, however, in many instances a healthcare professional assists with drug administration in the home.

However, significant obstacles remain. Sponsors must still contend with greater transportation costs, thanks to a high volume of small shipments and the reverse logistics of shippers and biological specimens. Cold-chain supplies must be shipped to remote and often difficult-to-find locations in temperature-controlled containers. Studies still need to be managed centrally by a remote study coordination centre. Finally, there is little regulatory guidance on designing and executing DTP studies, with rules varying from country to country.8

Fostering Innovation Fisher Clinical Services discusses DTP studies with sponsors on a case-by-case basis. Discussions

“Everyone is talking risk management,” said the US-based supply chain manager of his day-to-day interactions with sponsors.

In traditional clinical trials, the investigator site is responsible for collating data outcomes during the trial. Sponsors usually appoint centralised data centres to collate study data for DTP trials. Not every study is appropriate for the DTP model. The ideal profile includes a non-interventional study that does not require diagnostic testing prior to taking the study drug, a remote-study approach,

From a logistics point of view, DTP studies drive efficiencies across the supply chain by reducing the number of handoffs and investigator site costs.

begin with a careful review of sponsor responsibilities for DTP studies. For example, sponsors first must ensure that dispensing DTP is legal in the countries named in the protocol. Details of DTP distribution must be included in the clinical trial application (CTA) submission. For countries that present import challenges or delays in clearing shipments through customs, Fisher Clinical Services recommends that the sponsor consider using local depots. The next step in the discussion is addressing the following questions: •

Does a licensed healthcare provider need to be present to receive and administer the medication? How can the sponsor ensure that temperature specifications are maintained once the medication is delivered to a patient’s home? What is the process for collating data? What simulates a prescription?

In light of the absence of regulatory guidance with respect to DTP studies and the inconsistencies from country to country, Fisher Clinical Services recommends that sponsors take time to evaluate the feasibility of this approach with their particular trials. A Crisis-du-jour World Flexibility and contingency planning have become the price of admission in clinical development.

It’s no wonder. From supply shortages and natural disasters to terrorist incidents and acts of war, the news is a constant reminder of the need to be flexible and factor “what ifs” into logistical plans. Although clinical supplies were historically considered part of the execution phase of trials, they have become a key component of the planning process. With increasingly complex global studies taking place 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Logistics & Supply Chain Management in challenging therapeutic areas, never has the need for flexibility in the supply chain been greater. In an industry where circumstances change on a dime – countries are added or dropped mid-trial, an urgent need arises for new translations or additional regulatory reviews, or missing documentation puts supply shipments and trials at risk – flexibility means accommodating changes rapidly. It is essential to be predictive, responsive and agile, according to a study by the Tufts Center for the Study of Drug Development, which described an ideal supply chain strategy as one that can provide study materials to any site within 24 hours.

chain. Effective supply planning requires striking a balance between what’s known and unknown, risk and budget, the needs of the trial and those of patients. Planning effectively requires taking a multitude of variables from a variety of sources into consideration to create a supply plan that is flexible enough to withstand life’s unexpected events and constant evaluation to make necessary adjustments. Fisher Clinical Services factors in variables that include enrolment speed, milestone attainment, dating and extensions, material availability, blinding, distribution systems and numerous dosages, forms, sizes and shapes.

As an individual at an investigator site put it: “I can work with a difficult or complex protocol even if I haven't been given any detailed training. If a study is slow to enroll, I can figure out ways to increase our enrolment, but the one thing I can’t work without is the drug itself. If there is no IMP, the study cannot go forward.”

The team stresses that overage is not an indication of wasteful planning. Simulation can help to identify risks and potential areas for savings. Running out of materials can be more expensive than investing in some overage at the start of a trial. In other words, it’s best to avoid being penny wise and pound foolish. Overage is necessary.

Fostering Innovation Flexibility and contingency planning are about ensuring that the right investigator sites and patients receive the right clinical supplies at the right time. Accomplishing this demands sound supply forecasting and the ability to maximise research efficiency through supply optimisation.

Supply Optimisation That’s a key principle of clinical supply chain optimisation, a comprehensive supply strategy at Fisher Clinical Services. The strategy is based upon ensuring that study drugs reach patients when and where they are needed, while minimising overall drug wastage and reducing risk.

Supply Forecasting In a survey of clinical trial professionals by the Tufts Center for Drug Development, better supply forecasting was listed as a top concern. Although seemingly simple, supply forecasting is highly complex. Armed with a calculator and a protocol, it’s logical to assume that determining the required quantities of IMP and comparator would be a matter of multiplication. It isn’t. Relying exclusively on a mathematical formula for forecasting supply needs fails to factor in all that can go wrong to disrupt a supply 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

supply stock-out. Stock-outs are costly because they jeopardise patient safety, the success of a study, and the sponsor’s reputation and relationship with influential clinical investigators. Proactive and comprehensive from strategic planning through execution, supply optimisation encompasses all elements of clinical supply chain management, including: • •

• •

How much drug should be manufactured and when How much comparator is needed and the most appropriate sourcing strategy How to optimise supplies of study drug and comparator How to package, label and transport study drugs for maximum efficiency at minimal cost How to ensure that clinical trial supplies reach clinical sites when they are needed How to monitor drug supplies and patient enrolment to avoid stock-out

While stock-out is the worst thing that can happen in the course of a clinical trial, missing a crucial document necessary to import study drug constitutes another type of crisis, as the following case study demonstrates. Case Study 3 How a Logistics Team Overcame the Challenge of a Crucial Missing Document A crucial missing document can generate a crisis that threatens a clinical trial, as one resourceful Fisher Clinical Services’ logistics team can attest.

Supply optimisation increases value while appropriately addressing risk – striking a balance between the quantity of drug that should be produced for a study and the risk of running out of drug during the course of the study, a situation known as

A global pharmaceutical client of Fisher Clinical Services purchased comparator for use by a clinical site in Russia. Unfortunately, the Certificate Of Analysis (COA) for the product was missing, creating a problem of monumental proportions: An umbrella license from the Ministry of Health is necessary in order to ship patient kits into Russia, and a COA is required to grant the umbrella license. Winter 2017 Volume 9 Issue 4


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Logistics & Supply Chain Management The team contacted the supplier and the manufacturer, but neither could provide the COA. Since Russia played a major role in the recruitment strategy for the trial, this put the study in jeopardy. The Fisher Clinical Services team and client joined forces by teleconference to consider other options. After examining the documentation used to obtain approval for the clinical trial, they assembled a packet containing those supporting documents in place of the COA. The packet of documents, together with a cover letter explaining the absence of the COA, were then submitted to the Ministry of Health by Fisher Clinical Services. The strategy succeeded. The Ministry of Health agreed to accept the supporting documents in lieu of the COA and granted the umbrella license. The Russian site received the supplies on time, the trial took place with no additional complications, and patients were not left waiting.

were identified – call them the “what ifs” – into logistical plans. If you aren’t convinced that that’s necessary, ask yourself this question: How often has anything ever gone exactly as planned? Weigh options. Choose a supply chain partner with the knowledge, experience, breadth of services and global footprint necessary to address vulnerabilities with flexible solutions. Forecast with care. Bear in mind that running out of materials can be more expensive than investing in some overage at the start of a trial. While no one advocates wasting drugs, experience has established that some overage is necessary. Remember the patients. Clinical trial logistics are aimed at ensuring that the right drug reaches the right patient at the right time. Conducting a trial comes with a commitment to serve trial patients – imagine your parent, grandparent, child or friend – by putting their safety and wellbeing first.

REFERENCES (Full reference list Part 1 and 2)

Looking Forward: How to Manage Changing Trial Logistics •

Start early. The time to begin discussing supply logistics is while the protocol is under development. Although that might appear premature, early planning translates into maximum options. Identify vulnerabilities. Ask questions and brainstorm potential logistical problems with the clinical team and a trusted supply chain partner. Identify the areas that may require special attention. Opt for maximum flexibility. Build the vulnerabilities that

70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

1. Pelzel, Kristina. “What’s Next for the Pharmaceutical Supply Chain?” inventory-andsupplychain-blog.com. Inventory and Supply Chain Optimization, 12 January 2017. http://www. inventory-and-supplychain-blog. com/whats-next-for-thepharmaceutical-supply-chain/ 2. “Pharmaceutical cold chain logistics is a $12.6-billion global industry.” Pharmaceuticalcommerce.com. Pharmaceutical Commerce, 4 February 2017. http:// pharmaceuticalcommerce. com/supply-chain-logistics/ pharmaceutical-cold-chainlogistics-is-a-12-6-billion-globalindustry/ 3. “Biosimilars market to hit $35 billion by 2020, research suggests.” thepharmaletter. com. The Pharma Letter. 13 February 2017. http://www. thepharmaletter.com/article/ biosimilars-market-to-hit35-billion-by-2020-research-

suggests 4. Sowinski, Lara. “New packaging helps life sciences meet complex cold chain demands.” JOC.com. JOC. 19 December 2016. http:// www.joc.com/internationallogistics/cool-cargoes/ advancements-packaging-helplife-sciences-meet-complexcold-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. ClinicalTrials.gov. U.S. National Institutes of Health. 13 February 2017. Clinical Trials.gov. https:// clinicaltrials.gov/ct2/resources/ trends https://clinicaltrials.gov/ ct2/search/map 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. https://www. ncbi.nlm.nih.gov/pmc/articles/ PMC4105729/ 8. Covington, Deborah and Veley, Kristin. “The Remote PatientCentered Approach in Clinical Research.” AppliedClinicalTrials. com. 12 January 2017. file:///C:/ Users/Janet/Downloads/ Appliedpercent20Clinicalpercent20 Trialspercent202015percent 20Febpercent20(1).pdf

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.” Email: jennifer.worsfold@ thermofisher.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 71


Manufacturing

Strategies for Developing a Cost-Efficient Pharmaceutical Manufacturing Process The last two decades of the twentieth century gave us medicines that were products of our innovation and technological advancement. Devastating epidemics such as HIV infections could be treated as well as widespread illnesses like high cholesterol, hypertension and diabetes. Cancer survival rates were improved and life expectancy increased by nearly five years worldwide between 1980 and 2000.1

Plavix, Prevacid and Seroquel, just to name a few therapeutics that were approved for marketing between 1990 and 1999, affected lives of millions and earned the highly-sought blockbuster status. Notably, Pfizer’s Lipitor, approved for marketing in 1997, was on TIME magazine’s “Top 10 best-selling product list” in 2014, second only to Sony’s PlayStation and followed by Toyota’s Corolla, America’s sweetheart and the best-selling car ever.2 We continued to witness a steady number of marketing approvals in the first decade of the twenty-first century. While blockbuster drugs from previous decades continued to account for more than half of the total pharmaceuticals sales in the mid-2000s,3 the newly-marketed medicines ranged from blockbusterpotential to ones more focused on narrow indications and not expected to offset the sales generated by blockbusters as their brand name patent protections expired. The 2005 New York Times article “Blockbuster drugs are so last century” forecasted that the pharmaceutical industry will focus on the development of medicines that are aimed at smaller patient populations and could be rapidly advanced through clinical development, incurring lesser costs and possibly having fewer side-effects.4 While this is certainly true to some extent, the first decade of the twenty-first century gave us a number of blockbuster medicines that continued to have a significant 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

impact on our lives, for instance, Nexium®, Advair®, Abilify®, Crestor® and Neulasta ®, all approved for marketing between 2000 and 2009. Today’s pharmaceutical business is far more complex than in the past when fewer marketed products, stable drug demand, and high profit margins were the norm. Pharmaceutical business is rapidly becoming global with about half of the industry growth in emerging markets.5 Thus, a pharmaceutical company's objective is to build a sustainable and cost-efficient supply chain that meets global regulatory requirements. There are three key factors in pharmaceutical development: (1) quality of clinical trial material administered to patients, (2) time to develop processes and controls, produce and distribute clinical trial material, and conduct trials, and (3) money to fund ongoing development programmes. Time controls quality: given enough time we will develop robust processes with adequate controls to reproducibly deliver high-quality clinical trial material. In turn, quality controls the cost – in other words, the ease of achieving quality will dictate cost. The industry remains committed to patient safety, thus no supply chain cost reduction could be derived from reducing quality oversight. As an increasing number of drug candidates enjoy accelerated clinical development timelines, the traditional development of phase-appropriate manufacturing process and controls may not be an optimal approach to chemistry, manufacturing and controls (CMC). There simply may not be enough time to redevelop process and controls as clinical studies rapidly advance through phases. The pharmaceutical company, who is a programme sponsor, should assess early on whether the focus should be on

development of commercialisationready CMC, regardless of the clinical development phase. The supply of clinical trial materials for both high-volume therapeutics, such as high-dose and large clinical trial patients’ population anti-microbials, and low-volume and small patient population orphan-designated drugs, which typically are on an accelerated clinical development timeline, present challenges to sponsors. This article discusses the three factors of the manufacturing process throughput: (1) materials yield, (2) volumetric efficiency and uniformity, and (3) production cycle time, and provides examples of how the manufacturing process can be optimised utilising process throughput concept. As successful clinical programmes rapidly advance through the development phases and near the marketing application submission, the related CMC programmes should not fall far behind but rather be ready to transition from clinical to commercial supply chain. There are numerous examples of accelerated development programmes. For instance, marketed Imbruvica (ibrutinib), the Bruton’s tyrosine kinase inhibitor, administered as an oral dose capsule for treatment of mantle cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma, was developed within four and a half years by Pharmacyclics LLC, an AbbVie Company, in collaboration with Janssen Biotech, Inc., a Johnson & Johnson Company. Notably, the first human was treated with ibrutinib in 2009, followed by Phase II studies and convincing efficacy and safety data in 2012. Three Breakthrough Therapy Designations by the US FDA were granted in 2013. Following the submission of the new drug application (NDA), the drug received approval in November 2013. Large-volume pharmaceuticals present challenges, requiring drug Winter 2017 Volume 9 Issue 4


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Manufacturing supply for thousands of patients in late-phase clinical trials. Furthermore, in the same timeframe, the sponsor needs to fulfill regulatory requirements to position for a successful process validation as part of the transition from clinical to commercial supply chain. An example of a steep increase in clinical trial material demand to supply another successful and rapidly advancing clinical development programme is captured in Figure 1. Startlingly, within three years, clinical trial

direct impact on critical quality attributes of API or formulated drug. The companies that fully or partially outsource process development and manufacturing activities should identify and engage contract development and manufacturing organisations (CDMOs) that have sufficient critical mass, i.e. expertise, resources and capacity, to respond to ever-changing manufacturing trends and achieve these four objectives within a limited time. The labour and utilities (natural gas

Figure 1. Example of evolution of clinical trial material demand over three-year period

material demand increased from 10 kg to more than 6 metric tons. The combination of high daily dose, large clinical trials and rapid advancement from the start of a Phase II study to marketing application submission present challenges to manufacturing process development teams which have two major objectives: supply clinical trial material and meet regulatory milestones to enable successful commercial launch and supply chain. There are four components to achieve readiness to transition from clinical to commercial supply chain: (1) lock of the manufacturing processes for drug substance and product, and evidence of adequate stability for each segment of supply chain; twelve months’ stability data is expected, according to guidelines ICH Q11, (2) determination of critical quality attributes for API and formulated drug, (3) agreements with regulatory agencies worldwide about regulatory starting materials (RSMs) designation, and (4) assessment of manufacturing process parameters, establishment of their acceptable operating ranges and determination of whether any process parameters are critical, i.e. variability in parameter’s range would have a 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and electricity) costs are the major contributors to production cost and should be considered when identifying opportunities for optimisation of manufacturing process. Traditionally, pharmaceutical process development teams tend to focus on materials yield, and while it is an important indicator of process efficiency, other contributors to process throughput, such as production cycle time and volumetric efficiency, should

There are three key factors that affect process throughput: (1) materials yield, (2) volumetric efficiency and uniformity, and (3) production cycle time. The yields are increased by optimising the efficiency of chemical reactions and minimising losses in isolation operations. This is typically achieved by studying reaction mechanism and influencing reaction course by choosing the right reagents’ stoichiometry, solvents, temperatures, addition rates, etc. The benefit of increasing materials yields is obvious: larger quantities of intermediates and final products are produced per batch, thus fewer batches are required to achieve inventory objectives. The volumetric efficiency is achieved by identifying the highest possible batch concentration, allowing for the largest quantities of starting materials and products in each production train. The volumetric uniformity across all operations further simplifies processing by employing the same size equipment for multiple manufacturing steps. The optimal production cycle time is achieved by assessing the purpose and efficiency of each operation, eliminating all unnecessary ones and shortening the duration of remaining operations. A case study is presented below to illustrate the manufacturing process throughput optimisation. A schematic presentation of process consisting of three distinct manufacturing steps is shown in Figure 2.

Figure 2. Schematic presentation of the three-step manufacturing process

be assessed and optimised to achieve full manufacturing process potential. The following is an analysis of how process throughput controls manufacturing efficiency.

Below are the results of process throughput optimisation for each of the three manufacturing steps. All volumes, expressed as L/kg, are related to 1 kg of API.

Table 1. Manufacturing step 1: process throughput optimisation results Winter 2017 Volume 9 Issue 4


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12


Manufacturing As the yield of manufacturing step 1 was high (92%) for the first intermediate (Table 1), the process optimisation efforts were focused on improving the poor volumetric efficiency by decreasing maximum batch volume allowing for larger batch size. This objective was achieved primarily by identifying an optimal solvent for the isolation of the first intermediate. By design, the step 1 product had a low solubility in the new solvent, thus requiring much lower volume (12 L/kg) to obtain the same high yield, without any loss of the productâ&#x20AC;&#x2122;s quality. The nearly threefold net increase in volumetric efficiency translated into a significantly increased input and output scales, affording 133 kg of first intermediate in the same size production train. Furthermore, careful assessment of purpose and duration of each operation provided an opportunity to shorten production cycle from five to three days.

and output scales, affording 115 kg of second intermediate in the same size production train. Optimisation of process parameters and assessment of purpose and duration of each operation allowed for reduction of the production cycle from eight to five days.

Table 3. Manufacturing step 3: process throughput optimisation results

The long production time, poor volumetric efficiency and modest product yield were at the centre of the manufacturing step 3 optimisation efforts (Table 3). As the main purpose of this step was the ultimate purification to yield the product which met acceptance criteria for all critical

Table 2. Manufacturing step 2: process throughput optimisation results

Th e l ow y i e l d of s e c o n d intermediate and poor volumetric efficiency were the focus of manufacturing step 2 optimisation (Table 2). The emphasis was on studying the chemical reaction mechanism and optimisation of related process parameters to positively influence the course of reaction and to suppress or eliminate unproductive pathways, which led to loss of second intermediate yield and demanded elaborate purification methods. The optimisation efforts resulted in nearly doubling the product yield (75%). Moreover, as the significant increase in yield was achieved by enhancing the desired reaction pathway, this simplified the purification, as it demanded lower quantities of solvents, fewer operations and shorter cycle time to achieve the required product quality. The more than two-fold net increase in volumetric efficiency translated into significantly increased input 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The optimisation of volumetric efficiency, material yield and production cycle time resulted in a significantly increased product output (84 kg) in addition to nearly four-fold reduction in cycle time from fifteen to four days.

quality attributes, naturally this step employed large quantities of solvents and generated significant amount of waste. A study was conducted to assess the product stability in all media used in step 3 and optimise process parameters, such as acidity or alkalinity, temperature, rates of materials addition, residence time in each media, accordingly. The production equipment was also assessed with a particular focus on filtration and drying of the product. An in-situ, real time monitoring of the drying process was introduced which provided an opportunity to determine the earliest time point at which acceptance criterion was met and the product was ready for packaging.

The impact of overall process throughput improvements is summarised in Table 4. The increase in materials yield, decrease in solvent demand and reduction of waste, and shortening of the production time created a sustainable, more environmental-friendly and cost-efficient manufacturing process and had a direct impact on labour and utilities cost reduction. As many drug candidates rapidly advance through clinical studies and as producers of generics are in the rearview mirror of every marketed brand name therapeutic, pharmaceutical manufacturing plays a very important role in building a sustainable commercial supply chain. Manufacturing process throughput optimisation has become a necessity rather than an option. Having high product yield, volumetrically efficient process and shortest possible production cycle time will enable the sponsor to withstand future increase in labour and utilities costs and reduce the probability of complex, expensive and risky post-approval changes driven by the need to address the unacceptable cost of goods. As shown in the example above, the optimal process throughput will also minimise environmental impact through reduction of input materials, waste, natural resources and energy consumption.

Table 4. Overall process throughout improvements Winter 2017 Volume 9 Issue 4


Manufacturing REFERENCES 1. World Bank Open Data; data.

2.

3.

4. 5.

worldbank.org. Calio, V., Frohlich, T. C., Hess, A. E. M. “These Are the 10 BestSelling Products of All Time” Time Magazine, May 15, 2014. Jacquet, P., Schwarzbach, E., Oren, I. “The new face of blockbuster drugs” In Vivo: The Business & Medicine Report, May 2011. Berenson, A. “Blockbuster drugs are so last century” The New York Times, July 13, 2005. Berk, P., Gilbert, M., Herlant, M, Walter, G. “Rethinking the Pharma Supply Chain: New Models for a New Era”, Boston Consulting Group publication

Xiaoyong Fu Ph.D. Dr Fu is the SVP, API Development & Commercialization at STA Pharmaceutical, responsible for API process R&D and manufacturing from phase I through commercial launch. Formerly Xiaoyong was a Senior Fellow, process chemistry at Merck Research Lab and Schering-Plough Research Institute. Dr. Fu earned his Ph.D. in Organic Chemistry from University of Wisconsin-Milwaukee.

Valdas Jurkauskas Ph.D. Dr Jurkauskas is the Vice President, Head of Chemistry, Manufacturing and Controls (CMC) and Technical Operations At Akebia Therapeutics in Cambridge MA. Prior, he has held positions at Corbus, STA Pharmaceutical, Cubist and Vertex. Dr. Jurkauskas earned his PhD in Organic Chemistry at the Massachusetts Institute of Technology and his B.S. degree in Chemistry at the University of Toronto.

Product News Sartorius Stedim Biotech launches new versions of data analytics software solutions SIMCA® and SIMCA®-online software updates in the UmetricsTM Suite help manufacturing industries make better business decisions and optimize process control Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, has introduced a new version of its SIMCA® and SIMCA®-online data analytical solutions, which are offered by its subsidiary Sartorius Stedim Data Analytics, formerly known as Umetrics. Every day, businesses generate a vast array of data derived from a variety of different sources. This data holds the key to better performance. The challenge is to interpret this information in a meaningful way. However, with so many parameters and such vast system complexity to consider, it is hard to find a solution that is both powerful and smart enough. SIMCA®, an established advanced data analytics and visualization program as part of the company’s proven Umetrics™ Suite, makes it possible to combine and analyze data from all sources to isolate, understand and act on the hidden gems that hold the secret to better decision-making and greater business success. SIMCA®’s multivariate data analysis engine enables companies to swiftly detect and analyze deviations from normal operating conditions by modeling an idealized process. Once this model is transferred into SIMCA®-online, it serves as a valuable reference for your current production. The newly enhanced software offers an intuitive graphical interface and the flexibility to handle complex data, such as reworking, splitting and www.ipimediaworld.com

merging, and more. SIMCA® projects can be uploaded directly to an available SIMCA®-online server for real-time visualization of the process from a data point of view.

process understanding and more consistent product quality, users will be able to reduce risk, speed up time to market and accelerate business growth.

The real-time monitoring and prediction system, SIMCA®-online, constantly monitors processes to provide a continuous snapshot of the users’ operations. It not only helps to identify when set parameters change, but also enables remedial action to be taken before production is affected, ensuring that product quality remains consistent. With this level of control, it is possible to maximize resource efficiency, minimize operational costs and benefit from increased confidence in end-product quality. Among the new features in SIMCA®-online is the self-service analytics capability, which allows anyone to create fundamental process models, regardless of their background. The new notification system, along with the new web client, gives the user peace of mind about the quality of production anywhere and anytime as this system provides an overview of the production processes on devices such as tablets or mobile phones. SIMCA® and SIMCA®online have been developed according to GAMP5 and have been extensively tested and validated. These programs are also used by the EMA and FDA for Real-Time Release testing.

A complete solution encompasses software, training, support and project management. Also, as part of the Sartorius Group, a global company with approximately 7,500 employees, Sartorius Stedim Data Analytics provides the backup of an international network.

As leading experts for analyzing data, Sartorius Stedim Data Analytics helps companies in any industry, which include the pharma, chemical and food sectors, find the growth opportunities they need using the comprehensive Umetrics™ Suite. These solutions enable them to harness the wealth of data within an organization, identifying vital elements to improve the results of research, product development and manufacturing processes. With improved

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The real-time monitoring and prediction system, SIMCA®online, constantly monitors processes to provide a continuous snapshot of the users’ operations.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 77


Manufacturing

Inspecting on the Edge – Understanding Punch Tip Wear Wear to the edges of punch tips is a commonly overlooked aspect of many tooling inspection procedures. Tip wear is typical and can be influenced by many different sources, including poor tablet and tool design, granulation characteristics, improper steel selection for the application, and improper press setup. It is quite typical for inspection technicians to pay attention to the punch cup face. Wear to the cup face is generally not responsible for typical tablet defects such as capping, lamination, and flashing. These tablet defects are more related to punch tip land and outer edge wear.

While proper inspection can help prevent many commonly encountered tabletting defects, the practice of punch tip inspection often only includes checking the size of the tip by measuring them with a micrometer or calipers. Since the measuring anvils (contact surfaces) of these instruments are 3-6mm (0.120-0.250”) wide, they only check for the largest dimension. Often wear to the very edge of the punch tip (Illustration A) is relatively small, undetectable using traditional measuring equipment and techniques, and may not be easily observed by unassisted visual inspection. Some form of magnification is necessary to properly and thoroughly inspect punch tips for edge wear. The good news is that tip wear can be easily inspected using a horizontal optical comparator!

A. Severe outer tip edge wear

Punch tip edge wear can result from a number of conditions and may cause a myriad of problems including raised edges on the final compressed tablet, commonly referred to as “flashing” (Illustration B). Tablet flashing, in turn, can cause many other issues after the 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

compression event. When tablets are subjected to de-dusting, the flashed edges may break off and cause rough, poorly defined edges. Tablets with flashing and rough edges can be difficult to film coat and can lead to loose particles adhering to the coated tablet surface. To minimise defects and downtime it is important to understand the most frequent causes of punch tip edge wear.

Particle size can also affect tip wear. When small particles known as fines are present, they can sift into the gap between the punch tip and die bore (Illustration C). These small particles, combined with the cyclic motion of the punches can cause wear on the outer edges of punch tips. While often there is little or no choice as to the components of a formulation, controlling particle size and tip-to-die bore clearance can work together to reduce unnecessary tip wear and extend tool life.

B. Excessive flashing on tablet

Common Causes of Punch Tip Wear Formulation/Granulation Characteristics – Abrasion due to granulation is a common cause of tip wear and is generally a larger issue in the nutraceutical industry. Nutraceutical products are usually composed of different vitamins and minerals, most of which are quite abrasive, including magnesium, calcium, iron and zinc. Pharma products with a higher percentage of API typically require higher compression forces which may accelerate tip wear. Besides degrading the finish of the punch cup and wearing of any embossing or score lines, abrasive ingredients also wear away the land and the outer edge of the punch tip. Once any wear occurs to the edge of the punch tip, particles will become trapped in the increased gap between the tip edge and die wall. Then as the punch moves vertically, the abrasive particles are ground in-between the tip and die wall, accelerating the wear to both tool components. Once this occurs there is no turning back… the “snowball effect” takes over and the wear process is accelerated.

C. Tip wear on O.D. edge and small particle sifting inside die bore

Tablet Design – The design of the tablet plays an integral role in the functionality and longevity of the tooling. Once the innovator travels down the path of tablet design, approval, R&D and scale-up, it must then move to production. When tooling is made for production, it is subjected to increased cyclic stresses compared to the R&D phase. If the cup is excessively deep or if the concavity of the cup is steep near the edge (as with some compound cups) and creates near vertical surfaces they will be more susceptible to abrasion. This type of cup design is not as robust as a standard cup and will require more land than its counterpart. Steps to strengthen the edge of the punch cup include reducing the slope of the cup and more importantly, introducing an appropriate amount of land into the tablet design. Land unfortunately gets a bad reputation, as many believe additional land will cause soft edges and more difficulty with film coating. Most tool vendors know the value of land and may incorporate it into the design. However, many are Winter 2017 Volume 9 Issue 4


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Manufacturing forced to use “minimal” land width which is usually only approximately 5% of cup depth. Knowledgeable tablet designers consider that land width should be closer to 10% of cup depth, and occasionally up to 20-25% of cup depth, especially for difficultto-compress tablets that require high forces. Any punch tip with no land (razor sharp edge) is considered unwise. Having sufficient land in your tablet design adds strength and wear resistance, both on the inside of the cup and on the outside of the tip, while creating a more robust tablet and enhancing tablet stability. Turret Condition – Even though your tooling may be in optimum condition and configuration, problems may quickly arise if they are used in a tablet press with a worn turret. The most common and unrecognised wear points of a turret are the die pockets. Dies are made from harder wear-resistant steel compared to the typical die table and are often installed without the proper installation tools and technique. If the dies are not installed with accurate vertical guidance, keeping them perfectly straight and aligned with the pocket, they will damage the top section of die pocket. Hence this will eventually result in oversized die pockets and loose-fitting dies. On a turret with worn die pockets it is quite common for dies to fall in halfway, and then have to be driven in to be fully seated. This is an obvious indicator that the top half of the pocket is worn oversize. Dies that just “drop in” are easier to install, but consider what happens when the die lock is tightened. The die, and more importantly the die bore, will be pushed out of centre to the punch tips. It is vital that the die bore be accurately centred to the punch tips. If not centred, the upper punch tip edge may strike the lead-in chamfer at the top of the die upon entry (Illustration D). Repetitive striking will quickly cause wear to the edge of the upper tip (Illustration E). With continued use, this edge wear can cause flashing on the tablets as previously described. The striking can be so severe that it may curl metal of the tip inwards into the cup. This condition is called J-hook (Illustration F), and may cause capping and lamination 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of the tablets. Also, if the die bore is not well-centred, the lower punch tip will have contact with the bore on one side with all the clearance on the opposite side. This increased clearance will allow product to sift into the gap, also potentially causing excessive wear previously described. It may also create a defect to the tablet on the lower edge where the tablet band and the cup face meet (Illustration G).

D. “Drop in” die pushed out of centre by die lock screw causing tip edge contact with the lead-in chamfer of the die.

E. Resulting damage to punch tips

F. Typical J-hook

G. Off centre lower face and resulting tablet defect

Also, wear in the key slot of the upper punch guides on the turret can allow angular misalignment between the upper tip and the shape of the die bore. This may allow for opposite corner edge wear to the upper tip. This key slot wear can be addressed through the proper set-up procedure called pre-loading, discussed later in the article. Reducing and Preventing Tip Wear To prevent potential tip wear, good communication with your tooling supplier is vital. By having some forethought and seeking consultation regarding tooling material selection, periodic inspections of critical turret parts and adhering to proper press set-up procedures can all work together to mitigate tip wear and extend tool life.

Tool Design (Configuration) – The rotary “B” tool was designed more than 120 years ago, during the early stages of the industrial revolution, with the “D” tool design quickly following. Refinements, often called tool options, are commonly made to the basic tool design for better performance and to extend tool life. One of the most commonly used options is tapered dies. This option is typically used to resolve capping and laminating issues, and to make it easier to eject the tablet from the die. Aside from resolving these tabletting issues, tapered dies can help offset mild turret misalignment by guiding the upper tip into the bore, bypassing the potential contact with the lead-in chamfer. The amount and depth of taper can be customised and machined to meet individual tabletting needs and press set-up requirements. Steel Type and Hardness –Selecting the proper steel type can help to reduce tip wear for abrasive granulates. Reputable tool vendors offer a variety of different steel types for challenging formulations. Abrasive wear-resistant tool steel grades include AISI (DIN) D2 (1.2379), M2 (1.3343), DC-53 and K-340. For very abrasive products, punches can be produced from premium wear-resistant PM grade steels (PM=Particle Metallurgy), such as, PM-3V, PM-9V and PM-10V. As the hardness increases on premium tool steels, so does the abrasive wear-resistance, but it must be noted that the impact toughness decreases somewhat (Illustration H). Some steels are required to be cryogenic tempered (-184°C, -300°F) to increase wear-resistance and receive full return on investment. If your vendor does not offer this tempering process, the steel type or your tooling vendor should be reconsidered. It is the combination of each steel’s unique chemistry and the related heat treatment process that allows the different steel types to attain their advantageous unique mechanical properties. This makes them ideal for the wear-resistance needed for abrasive formulations, yet still allows them to support the compression forces needed for the high-stress, high-cycle loading conditions of tablet compression. Tolerance Stacking – Tolerance stacking refers to the condition where the dimensional and geometric Winter 2017 Volume 9 Issue 4


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Manufacturing used often in the industry but is a valuable piece of equipment. For a reasonable investment, it is the only efficient method to check punch tip wear.

H. Toughness vs. wear-resistance of various tool steels

tolerances on assembled parts (punches, tips, die O.D., die I.D., die pocket, punch guide, key and key slot) combine to create the worst possible fit condition. In addition to alignment of critical components on the turret, tolerance stacking on the turret and tools combined, can also affect tip-to-die alignment. When all these tolerances are at their extremes, it creates a situation where punch-todie contact is possible, even when all components are comfortably within tolerance. Turret – Most turrets are manufactured in three sections. When a press experiences a sudden stoppage event or accident, this can shift a section out of alignment. If any section of the turret is out of alignment, this can lead to unnecessary contact between the punches and dies, resulting in wear to the punch tips. Periodic turret inspections can mitigate this by identifying that a turret is no longer properly aligned. Press Set-up – Press set-up can be critical in reducing and preventing accelerated tip wear. Pre-loading is the process of twisting the keyed upper punch in the direction of turret rotation while using the upper punch to set the angular alignment of the die bore shape. Pre-loading simulates the rotational forces that the upper punch experiences when the press is in operation. When using shaped/ keyed tooling, pre-loading is often not practised. All presses have clearance in the key slot of the turret, which may increase further as the turret wears. If the punches are not pre-loaded when setting the die alignment, the upper punch will shift angularly as the turret rotates (Illustration I). This creates angular misalignment between punch tip and die bore, resulting in accelerated wear to the outer edge of the upper punch tip due to 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

contact with the die bore as it enters. Following simple set-up procedures such as pre-loading, combined with periodic turret inspections, can greatly reduce unnecessary tip wear.

I – Part 1. Punch key not pre-loaded

I – Part 2. Punch key flush with the left side of slot after pre-load applied (Note: these photos depict CW rotating turret)

I – Part 1. Punch key not pre-loaded

Inspecting for Tip Edge Wear Visual inspection for tip edge wear is quite challenging, especially without magnification. The quickest and most efficient method is to use a horizontal optical comparator (Illustration J). An optical comparator (often called a comparator) is an apparatus that applies the principles of optics to the inspection of manufactured parts. In a comparator, the magnified silhouette of a punch tip is projected upon a screen, usually at 10x, but can also be at 20x or even greater magnification. The wear of the part can be easily inspected, and even measured against prescribed limits. Unfortunately, a comparator is not

J – part 1. Horizontal optical comparator

J – part 2. Inspection of punch tip with worn edge on optical comparator

Conclusion Punch tip edge wear can come from a variety of circumstances and may cause significant production qualityrelated issues. It is important to understand and know how to identify the most common causes of this type of wear. Punch tip edge wear can be difficult to detect because traditional methods of inspection are ineffective. Fortunately, the use of a horizontal optical comparator makes the inspection job easy – and fast. The most versatile piece of inspection equipment, a comparator provides a bright, crisp image for error-free inspection of the punch tips. Avoiding punch tip edge wear when possible, and quickly identifying when it does occur, will provide great benefits to the quality of your tablets and to your production operation.

Bill Turner Bill Turner is the Technical Service Manager of Tooling and Tablets at Natoli Engineering Company. He educates and trains Natoli sales and service staff and conducts industry training seminars regarding tablet design, tool design, and troubleshooting. Email: eng@natoli.com

Kevin Queensen Kevin Queensen is a Mechanical Engineering and Technical Service Support at Natoli Engineering Company. His focus is primarily on specialty tablet/tooling designs along with determining new max compression force calculation methods and performing Finite Element Analysis (FEA). Email: eng14@natoli.com

Winter 2017 Volume 9 Issue 4


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AN EXPERT IN MEDICAL DEVICES Plastibell (headquarters in Izernore, France), is an expert when it comes to injection molding and assembly, producing a broad range of complex plastic products for different industries. The company is internationally active with seven industrial sites in four countries. The Healthcare Division accompanies its customers in the development of Medical and In Vitro Diagnostics Devices (MD/IVD), from the earliest design stage, right through production.

PHARMAPACK EXHIBITION Visit us at Pharmapack Exhibition at booth D40 ! This event takes place in Paris Expo, Porte de Versailles on 7 & 8 February 2018. Discover our innovations and new developments! Follow Plastibell on LinkedIn! www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 83

Pharmapack 2017


Packaging What Does the Falsified Medicines Directive (FMD) Mean for SMEs and CMOs; and More Importantly, Are These Organisations Ready?

The Falsified Medicines Directive (FMD) 2011/62/EU will come into full force on 9th February 2019. The legislation, which was passed by the European Union Parliament, aims to increase the security of the manufacturing process and delivery of medicines throughout Europe, providing greater protection for patients.

Larger pharmaceutical companies have long been implementing changes to their processes, but some smaller SMEs have been slow on the uptake, many holding back from making any changes, awaiting clarification around confusion which stemmed from other countries receiving extensions, as well as waiting to see what effect Brexit may or may not have on the legislation. However, it has now become clear that the UK will not be granted an extension and Brexit will have little to no effect on the implications of FMD. With less than 200 working days before it comes into effect, CMOs and small to medium-sized pharmaceutical manufacturers can no longer delay when it comes to becoming compliant with the regulation. The implications of the directive are far-reaching and affect all pharmaceutical manufacturers,

regardless of size. As time runs out and the deadline grows ever closer, how can CMOs and SME pharmaceutical manufacturers ensure they are compliant, in time? What Are the Requirements of FMD? Firstly, it is important that manufacturers know and understand what the requirements of the Directive (FMD 2011/62/EU) are. If we look at the directive in a broader sense, the requirements fall into five separate categories, broken down below: 1. An obligatory feature on the outer packaging of prescription medicines that demonstrate identification and enable product verification. 2. An obligatory feature on the outer packaging of prescription medicines to demonstrate that they haven’t been tampered with – an anti-tamper device (ATD). 3. Strengthened requirements for the inspection of the m a n u fa c t u re rs o f a c t i v e pharmaceutical ingredients. 4. Manufacturers are obligated to report any suspicions of falsified medicines. 5. An obligatory logo must be applied to websites of legally operating online pharmacies, with a link to official national registers. From February 2019 onwards, if a manufacturer fails to comply with any aspect of the directive it will have to withdraw its products from circulation within the European market. With the consequences of non-compliance so high, pharmaceutical manufacturers and distributors alike must now take steps to ensure their supply chains are ready for the regulation. How Will the FMD Regulations Work in Practice? Counterfeit medication costs the pharmaceutical industry billions of pounds every year and, more

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importantly, it puts patients at risk. As such, serialisation is the key to ensuring that businesses become and remain compliant, keeping patient safety at the fore. The directive requires that at the point of manufacture, all packaging must carry a GS1 compliant, 2D barcode that contains specific information, including a serial number so that the location of production can be ascertained and uploaded to the European Medicines Verification Organisation. The introduction of the barcode will also allow the product to be checked at any point in the supply chain. Wherever the product is, the barcode can be scanned and the product can be checked to ensure it is where it’s supposed to be, and that it hasn’t been sold before – ensuring its validity. At the point of distribution to patients, the product will then be verified and de-serialised, so that serial number cannot be used again. If a unique serial number does come up somewhere else in the future, the product can easily be identified as counterfeit. There’s no denying that for those without robust serialisation processes currently in place, these implementations will be complex, but the benefits of being compliant far outweigh any initial concerns. The Key Challenges Faced by CMOs and SMEs With a high level of outsourced pharmaceutical production, CMOs Winter 2017 Volume 9 Issue 4


Packaging and replace’ approach has to be taken. This doesn’t always have to be the case. If smaller organisations take the time to review their entire supply chain and all of its processes, there are ways that serialisation can be retrofitted and integrated with the solutions already in place. This high level of integration is something that will prove to be invaluable to organisations now and in the future. and smaller pharmaceutical manufacturers are a key part of the global supply process. Yet, many are still delaying the initiation of their serialisation projects. One of the main reasons is a perceived high cost and the sheer magnitude and complexity of the projects can also be seen as a deterrent. However, businesses can no longer stall; time is of the essence and organisations will have to comply. The equipment will have to be serialised, that serial number will have to be electronically checked for content, and it will have to be sent to the European Medicines Verification Organisation. It is increasingly important for CMOs and SMEs to have the capability to meet international requirements, but it’s also crucial that they remain flexible enough to meet the differing requirements of their customers. Ultimately the implications are significantly more complex than just making modifications to their physical labelling machines and infrastructure. There is a preconceived idea that in order to introduce compliance and a higher level of serialisation into the supply chain, a costly ‘rip

What Are the Key Considerations CMOs and SMEs Should Take When Choosing a Vendor? One of the key challenges that comes with serialisation is the complex mix of data including master data and transactional data – tracking a

serialised item through the packaging execution process and the physical product. Compliance requires all of these elements to be continuously and dynamically associated. As such, when smaller organisations are looking at a vendor to implement their serialisation processes, they should look for one that is capable of delivering overall equipment efficiency as well as compliance. They should be able to demonstrate the capability to integrate the serialisation solution within a business’s existing IT and packaging infrastructure, maintaining speed on the packaging line and adding true business value.

For example, small batch repackaging organisations could implement a handheld device that not only scans a product, but also takes a low-res image of the seal over the packet at the time of scanning. The image wouldn’t need to be sent to the legislation hub, but the manufacturer could store the image so that if they were to be audited they could prove that the boxes were securely sealed. Innovative and scalable solutions like these will keep smaller businesses compliant, but don’t require a complete overhaul of existing systems. A major challenge faced by many serialisation projects is between the software and the hardware already in place. More often than not, the two will work in silo and businesses can no longer allow this to continue. Quite often, for example, you will see machine vendors providing equipment and devices with very little expertise or consideration for the software and vice versa. So, it is important for smaller organisations to ensure they look for vendors that can bring together both of the necessary skills and capabilities to reduce project complexity, risk and delivery timeframes. It is important for manufacturers to evaluate any potential providers on their ability to help the business stay agile. If an organisation chooses a serialisation system that is heavily

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 85


Packaging reliant on specific hardware or software, for example, it will not be able to take advantage of any new processes or technology without having to re-implement a whole new project further down the line. It is vital that businesses have scalable, agile solutions that are not embedded so that they don’t encounter issues in four or five years’ time because technology has progressed and left them behind. This should also be seen as an opportunity for organisations to automate the process that manages the packaging line and work order process, which in turn reduces the risk of human error at input, further decreasing the risk of non-compliance and process failure. There’s no hiding from the complexity of serialisation. In the majority of cases for larger pharmaceutical companies, they can afford a multi-vendor approach, but this isn’t something that smaller manufacturers necessarily have the means to implement on a large scale. Instead, they need to look for innovative vendors that can assess the entire business and bring all the software, data and hardware together harmoniously in a cost-efficient way. CMOs and SMEs should start with a broader perspective of how they

can extend the value of compliance and then refine their plans with a phased, modular approach that puts steps together in accordance with regulatory timescales. Once they have mapped out their approach to meet minimum standards, they can then also look at taking advantage of enhanced efficiencies that they were previously unable to achieve. Serialisation is only the beginning; the next business driver that will come into play is track-and-trace, so taking steps now to have a serial number in place is one thing, but there are much broader business benefits. Implementing a serialisation process that is completely scalable also ensures that further capability can be unlocked throughout the supply chain as and when it is required. Beyond Compliance; Future-proofing Supply Chains Ultimately, serialisation can be seen as the entry level, enabling manufacturers to capture all of their supply chain events from manufacture right the way through to wholesale and distribution. The ability to capture and store data this way – creating complete real-time visibility and greater traceability – will unlock efficiencies throughout the entire supply chain. Allowing CMOs and SMEs to be poised to

react to future regulation changes and making it easier for them to keep up with the larger pharmaceutical organisations. It is very likely that legislation will progress in the coming years. It can already be seen in other industries that have undergone serialisation and have now moved on to track-andtrace. Behind this legislation, there are distinct efficiency and quality advantages to be found. For example, through defining each serialised item, recalls can subsequently be simplified. The complexity of the pharmaceutical supply chain cannot be disputed, but if smaller organisations embrace these regulatory changes – using them as an opportunity to optimise their supply chains, update data flows and break down silos – they can create true business value, making it pay to be compliant. Despite the deadline looming, there is still time for CMOs and SMEs to build comprehensive and agile serialisation infrastructures in time for 9th February 2019.

Christian Taylor Business Consultant, Zetes. Christian is a GS1 accredited Business Consultant specialising in serialisation and the FMD and UDI legislations. With over 10 years’ experience delivering infrastructure and software solutions within industries including; pharmaceutical, military and government, Christian is one of the leading authorities in the ZetesAtlas solution in the UK and Europe.

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Winter 2017 Volume 9 Issue 4


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Packaging

Designing Smart Integrated Drug Delivery Systems

Being diagnosed with a chronic condition is not easy. Whether it is diabetes, haemophilia, rheumatoid arthritis or multiple sclerosis, a patient is sure to begin a lifelong journey of care. After the initial shock of diagnosis has worn off, patients may experience a sense of relief that the cause of their health issues has been found. But many will respond with deep-seated emotions, such as anger or depression. The need to adhere to a regimen of treatment may be met with denial, fear or anxiety.

While adjusting to their new normal, patients around the world with chronic diseases are also seeking freedom from frequent doctors’ visits, opting instead to self-administer their critical medications at home. This trend is emerging alongside another: an increase in new biologic and biosimilar medicines for the treatment of many autoimmune diseases. In fact, the QuintilesIMS Institute predicts that biologic treatments for autoimmune diseases will continue to see increasing usage across geographies, and spending on these therapies will reach $75–90 billion by 2021. In addition, biosimilars will be available for several leading autoimmune products by 2021, potentially allowing wider use of these medicines.1 As the industry shifts to be more sensitive to patient needs, and to activities to improve overall outcomes, the notion of in-home self-administration presents an opportunity to improve the overall patient experience, but creates the challenge of complying with described treatment regimens. This is where an injectable medicine’s delivery system can help patients achieve their self-administration goal by making it a less painful, more streamlined and simplified process. For most patients, an easy-touse, integrated drug containment 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and delivery system can be key to enabling the consistent routines that bring about compliance with care plans. When delivery systems are intuitive and efficient, they stand a better chance of helping patients stick with their treatment protocol because the impact on their daily routines lessens. Conversely, injectable drug delivery systems deemed inconvenient, intimidating or complicated can negatively affect a patient’s emotional attitude and motivation to sustain adherent behaviour. And in many cases, looks count, too: discreetness of the drug delivery system can be very important to certain patients. Some new integrated delivery systems can make it easy and convenient for patients to self-administer injectable medications without calling undue attention to the administration process, creating distractions to others or prompting feelings of stigmatisation. Such a shift from a product-centric focus to a patient-centric focus can help biopharmaceutical and drug delivery system manufacturers design a product that helps encourage compliant behaviour. Putting Patients First in Drug Containment System Design No matter what type of delivery system is selected for a particular injectable drug product, there are several elements that must be carefully considered when designing a drug delivery system. The primary goal of any drug delivery system is to ensure that a patient safely receives the proper dose of a prescribed medication. In years past, if a delivery system failed or was used incorrectly, patient error was most often the culprit. While providing detailed instructions is important for any pharmaceutical manufacturer, failure to follow directions should be minimised by providing proper training to the patient and/or caregivers.

Now, the industry is rethinking that stance, and the priority is engineering improved usability into the drug delivery system to help enable patients to achieve better outcomes. In order to design a drug delivery system that meets the needs of both the drug and the patient, the pharmaceutical manufacturer and its packaging and delivery system partner must consider the interface between the drug, container, delivery system and patient. Understanding Patients Informs Usability Effective drug therapy requires more than simply having an effective molecule. Rather, it is the combination of a safe drug within a suitable container and/or delivery system, as well as an understanding of patient needs as they relate to administration. Drug manufacturers should take into account four main facets of this integrated drug delivery approach that, when planned early in the development process with a packaging and delivery system partner, can lead to better outcomes: Primary Container Format – The selection of a drug’s primary container is an important consideration for drug efficacy and stability. Vials may be necessary for initial use during the drug development stages, but a syringe or cartridge system may provide a desirable solution for the patient when the medicine reaches the market. Custom containment systems may also help to differentiate the product, and should be considered early in the development process. Drug/Container Compatibility – Hand-in-hand with the type of primary container is making sure the container material can be safely and effectively paired with the injectable drug product. Is the elastomeric material compatible with the drug? What are the levels of extractables and leachables? Will a barrier film Winter 2017 Volume 9 Issue 4


Our Commitment,

The Industry-leading Experience

Our Pledge,

The Industry Leading Experience

At PCI, we provide our clients an industry-leading experience by helping turn difficult applications into successful health outcomes. We launch over 50 products per year by supporting leading pharmaceutical and biotech companies with insights gleaned from our extensive experience to ensure product success in the market, coupled with a patient-focused approach. Our customers enjoy a broad range of solutions for a variety of delivery forms, including oral solid dose, powders, liquids and semi-solids, as well as parenteral and injectable delivery. In addition, we support a secure supply chain with industry-leading experience in anti-counterfeiting and Serialization technologies, supported by an integrated global supply network encompassing more than 80 Serialization-ready lines.

We invite you to learn more about what our commitment can do for the success of your product.

Please Join Us at:

pciservices.com 7-8 Feb. | Paris, France

Stand J24 Š Copyright 2017 PCI Pharma Services. All Rights Reserved


Packaging or coating be required for the elastomer? Choosing the proper drug container material can help prevent chemical incompatibility issues that could impact a drug’s purity, stability or efficacy. It is also important to explore all of the available options for containment materials. While glass is suitable for many pharmaceutical products, high pH drugs or otherwise sensitive drug products may be incompatible with glass vials or syringes; therefore, it may be beneficial to consider containers made from alternative materials such as cyclic olefin polymers. The filling, handling and secondary assembly processes must also be considered as an integral part of providing the overall delivery system. Container/Delivery System Interface – Once the primary container system has been selected, efforts must be made to ensure that it works with the delivery system. Dimensional tolerances and functionality should be tested to ensure proper activation and gliding forces. If the interface between the primary container and

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the delivery system is not effectively understood, the performance of the combined system may suffer. For example, when considering the use of a glass prefillable syringe in an auto-injector, manufacturers must ensure that the stress placed on the glass does not cause breakage or that the force in the auto-injector is enough to overcome variability in dimensions, functional performance and siliconisation effectiveness to ensure complete dosing. Patient Interaction – Perhaps the most essential consideration is how the patient will use the drug delivery system. Even the most innovative drug can only provide the appropriate therapeutic benefit if it can be delivered effectively and the patient adheres to the necessary treatment regimen. Simply designing a drug delivery system that patients/users “can” use is no longer sufficient. Delivery systems should be designed in a way that encourages patients to want to use them. This starts from a thorough understanding of patient needs, including the fact that these

needs may change during their treatment journey. Human factors analysis may be helpful here and can yield significant insight into patient behaviours, motivations and needs. In addition, there is increasingly a fifth element to be considered that involves the potential for drugs to be effectively prescribed and reimbursed. With increasing costs for many modern biologic drugs, patient access may be determined by whether their insurance plan will cover the costs of the medicine. Developing Smart Delivery Systems Technology is a ubiquitous part of our culture, and drug delivery systems are following this trend. This is especially true for self-administration systems that can incorporate electronics to deliver doses at specific intervals and connectivity that allows patients and providers to track adherence via smartphone apps. Far removed from a vial and syringe in a doctor’s office, today’s advanced drug delivery systems are complex pieces of technology that can incorporate

Winter 2017 Volume 9 Issue 4


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Packaging innovative and intuitive features that can make it easier for patients to self-administer critical medications.

to create a new delivery system or adapting existing systems to address new technological advances.

However, this shift has created an interesting challenge: while self-administration technology grows more complex, it must easily integrate into a patient’s life. Irrespective of delivery features, drug delivery system manufacturers must ensure a number of qualities are present to bring value to their pharmaceutical partners. Key to this mission is creating technology that patients want to use by providing drug delivery systems that are:

Wearable drug delivery technology is a good example of how drug delivery technology providers continue to stay ahead of the curve. When originally introduced, wearable injectors combined the drug with the delivery system to automatically deliver the therapy. They dramatically reduced mistakes by ensuring patients received an accurate dosage at the time they needed it. But how could they be improved? By making wearable drug delivery systems compatible with smartphone applications, the technology became even more powerful. Now, patients can easily track dosage history, which can be analysed and shared with physicians, who can better understand where patients are in their journey to offer the most complete care.

Less painful : Ma ny d r u g delivery partners are developing self-administration systems that minimise discomfort. For example, using a large-volume injector can help to address the issue of discomfort during self-administration, as they can mitigate perceived pain with lower flow rates (higher flow rates are often associated with pain). Easy to use: Regardless of how innovative a delivery system is, it must be simple enough for anyone to use successfully. Arthritis patients, for example, may have limited dexterity, which inhibits their ability to use the delivery system. Through rounds of patient testing, manufacturers can ensure the platform is user-friendly.

When delivery systems are intuitive and efficient, they reduce the impact on patients’ daily lives, increasing the potential for optimum adherence, which, in turn, delivers the kind of platform pharmaceutical partners need to market their drug. Driving Innovation and ROI As we have seen across all industries, new technology can become obsolete quickly. Pharmaceutical companies are relying on their drug packaging and delivery partners to remain continuously innovative and design integrated drug delivery systems that address the swift adoption of new technology. This can be achieved by working with pharmaceutical partners 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To that end, drug delivery system manufacturing rosters now include scientists, software developers and engineers to make sure the self-administration systems are in sync with the latest technological advances. Many drug delivery systems will be connected to the Internet of Things (IoT), and companies and their packaging partners are leading the way to bring meaningful features to the patients they serve. It is critical that these innovative efforts result in demonstrable return on investment (ROI) for biopharmaceutical companies, as they have to show patients, insurance companies, healthcare professionals and sometimes regulatory agencies that their drug is not only effective, but provides value. More and more, biopharmaceutical companies – which have less time resources to take contract manufacturing in-house – are relying on delivery technology partners to help them become market differentiators. By developing integrated drug delivery systems that promote accurate dosage and encourage greater compliance, greater potential exists for reduction in long-term healthcare spending for everyone involved.

Partnering for Patients Patients start their journey with an initial diagnosis, but they travel a long road with a chronic condition. Pharmaceutical and delivery systems manufacturers must begin product development with that in mind, and create systems and options that will not only help patients learn to care for their condition, but also comply with their prescribed treatment regimens throughout their course of care. To best create patient-centric sy s t e m s , b i o p h a r m a c e u t i c a l manufacturers should seek packaging and delivery system partners that can apply proprietary technologies, manufacturing excellence and patient understanding to their drug products and the products’ delivery and administration systems. Such partnerships will help drug marketers offer successful, integrated solutions, benefitting manufacturers, clinicians and patients alike, while helping to ensure optimum adherence and improving patient outcomes. Because after all, isn’t that the shared goal of everyone involved? REFERENCES 1. QuintilesIMS Institute. Outlook for Global Medicines through 2021: Balancing Cost and Value. December 2016.

Graham Reynolds Vice President & General Manager, Global Biologics, West Pharmaceutical Services, Inc. Mr. Reynolds joined West in 1980, and throughout his long career with West has held a range of positions with increasing responsibility. He was recently appointed to lead the Biologics market unit, one of three primary areas of focus for growth for the company’s proprietary products and services. Email: graham.reynolds@ westpharma.com

Winter 2017 Volume 9 Issue 4


ma meditec medical expertise ma meditec supplies the medical technology industry with production assembly and testing systems for medical devices (e.g. contact lenses, stents, inhalers, insulin pens, auto-injectors, tips and cups) as well as providing services for compliance with quality guidelines and validation in medical production. Our service portfolio also includes robust support of our clients during the DQ/IQ/ OQ phase and the preparation of GMP-compliant documentation.

automated assembly solutions for medical devices

MA micro automation develops and builds assembly, adjustment and testing systems for its clients in industrial manufacturing in the medical technology and optoelectronic sectors. Wherever possible, we rely on widely established standard modules and supplement them where necessary with specially developed individual components and modules. Anywhere where assembly with high precision, rapid cycle times and often with low weight, is carried out, MA micro automation GmbH is the go-to company in the market place. Excellent customer proximity, high quality and a strong mutual basis of trust are the most important principles of our work. A philosophy that our clients appreciate.

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Packaging

Why Anti-microbial Protection Remains Crucial in Fight Against Infection You can’t always believe what you read in the media. One week, a newspaper might be telling us we are winning the fight against MRSA – an infection that still brings chills to anyone with experience of a hospital in recent times. But any such story is quickly followed up by warnings of another ‘superbug’ taking over as the dreaded one to watch.

Here, Stephie Ward, Senior Marketing Executive at world-leading labelling and print company, Denny Bros, talks us through the current situation and why anti-microbial protection is a valuable piece in the armoury against healthcare infections. The Current Situation Recently, Clostridium difficile (C-diff) appears to have taken over as the most dangerous of hospital-acquired infections. It is true that the number of healthcare-associated infections (HCAI) in UK hospitals remain relatively low – and a lot of credit must go to NHS Trusts remaining vigilant and guarding against complacency. But these ever-changing headlines also show the climate of infection is also always changing. Strands of potential superbugs are developing all the

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time and everything must be done to ensure they don’t become a topic of hot – and daunting – conversation once more. Cost and the Global Threat An obvious knock-on effect is the cost of tackling such infections. In the UK, these costs are estimated to be in the region of £1 billion a year, at a time when healthcare budgets appear to be permanently squeezed. The issues remain a big threat globally. The 20th Annual Superbugs & Superdrugs Conference in London on 19th–20th March 2018 has been designed to raise awareness and highlight various strategies to ensure a global commitment to tackle the ever-increasing problem of multidrug-resistant bacteria. Such a conference is to be welcomed, as every relevant party must work together to tackle problems in the pharmaceutical industry. This year’s event will gather leaders from pharmaceutical companies, academia and the wider scientific community together with regulatory agencies and publicprivate partnerships, to discuss the growing threat of antibiotic resistance. On the agenda will be discussions around the various strategies in place to support antimicrobial resistance research and development, evaluate

the latest scientific advancements for tackling antimicrobial resistance, and consider potential novel candidates and alternatives to antimicrobials. According to the event website, it will also focus on the strategies pharmaceutical companies use to assist the development of new therapeutics and drugs, how to obtain funding for new projects and address why there is a current lack of incentives for researchers working in antimicrobial resistance research and development. But the measures to tackle such threats are increasingly becoming more resolute. How does Antimicrobial Protection Work? One such recent advance has been the ability to add antimicrobial protection to a range of labels and patient information leaflets (PILs). This has given a much broader scope of protection than existing

Winter 2017 Volume 9 Issue 4


How can taking something away make it more? Introducing the new UniSafe™ springless, passive safety device No spring means it’s safe, reliable and cost effective.

Come and visit us in Pharmapack in Paris at Stand B14 to find out more about UniSafe™

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 95


Packaging

antibacterial properties with the overlay resistance coupled with important safety advice, dosage details and legal information. The fact that the instructions can be in multiple languages is another distinct advantage. This antimicrobial protection adds another layer and pushes hygiene standards up even further for pharmaceutical manufacturers and even food producers. The introduction of antimicrobial properties into the varnish of labels and leaflets will give even greater levels of protection from unwanted bacteria. This feature helps limit the emergence and spread of superbugs such as MRSA, E-coli, Salmonella, Listeria and Legionella and severely reduces the growth of any microorganisms, fungi or mould. Antimicrobial properties work continuously and effectively to restrict growth before it appears. It eradicates the bacteria which cause contamination and infection. As bacteria can be carried on both personnel and equipment, it is in the healthcare providersâ&#x20AC;&#x2122; interest to limit the possible transfer of any

bacteria from containers to medical staff or directly to patients. The antimicrobial properties contain silver to create additives for use in almost any material where hygiene, performance or aesthetics are important, while it is even unaffected by cleaning chemicals such as chlorine beach, disinfectants and alcohol. How Effective Is It? Products containing anti-microbial properties are routinely tested at an independent laboratory and are typically proven to be at least 99.9% effective against MRSA and E-coli. Once an anti-microbial floodcoat has been applied, it is essentially there to stay. Ionic silver-based additives will not lose efficacy due to leaching or migration, and since they are evenly dispersed throughout the material, even scratches and abrasion do not affect the antimicrobial performance. I m p o r t a n t l y, a n t i - m i c r o b i a l additives are unaffected by cleaning chemicals such as chlorine bleach, disinfectants and alcohol. Even harsh industrial products like MEK (methyl ethyl ketone) do not diminish the antimicrobial properties of products containing this property.

Why Choose Anti-microbial Protection? Independent testing has proven anti-microbial additives to be effective against a huge range of bacteria including MRSA, E-coli, Salmonella and Legionella. But the purpose of this property is not to create a sterile environment as we all know that being exposed to certain types of bacteria builds a healthy immune system. But bacterial infections such as MRSA and Listeria can be very serious and anti-microbial properties act as a complimentary measure. The main function of an antimicrobial protection is to offer continuous and permanent protection against microbes which can cause contamination, odours and degradation.

Stephie Ward Stephie Ward is the Senior Marketing Executive at Denny Bros Ltd and has been with the company for three years. She has a business studies degree from the University of Liverpool and is a Chartered Marketer, with broad marketing experience gained from having worked in financial services, waste management, professional services (chartered surveying) and now specialist printing. Her role covers all aspects of marketing for Denny Bros Ltd. Email: stephanie.ward@dennybros.com

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Winter 2017 Volume 9 Issue 4


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Packaging

Serialisation: The Current Conversation

Serialisation remains the hot topic across the pharmaceutical industry, and will continue to be so with the deadlines for compliance fast approaching in both the US and EU. The discussion around serialisation is a juggernaut, continuously gaining momentum with new advice, research, implementation guides and points of consideration added to the mix almost daily. The cumulative effect is the creation of a ‘serialisation echo-chamber’ brimming with information that is increasingly hard to navigate and digest. There are, however, a handful of threads that are a constant throughout the dialogue. In this article, Carlos Machado, serialisation director at SEA Vision US, talks through the advice which businesses can use to underpin their move towards an agile, future-proofed solution.

Serialisation is an Investment, Not an Expense Serialisation still holds a stigma within the industry, particularly because of its cost. Recent research has revealed that the biggest barrier to serialisation compliance is the cost of implementation – with 54% of industry professionals citing it as their biggest concern. This hurdle is compounded by the 33% of the industry which feels that the implementation process is also a drain on internal resources¹. Whilst it cannot be denied that complete compliance will involve plenty of dedicated resource, serialisation will revolutionise ways of working and the industry for the better. The importance of seeing serialisation as an investment rather than an expense, cannot be stressed enough. When planning and implementing a serialisation solution, additional benefits can be added along the way. Before taking to compliance strategies, businesses can look at their key performance indicators and identify any system changes that can be made alongside the serialisation up98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

heaval. Companies must remember the goal; regulations exist for good reason and the long-term aim of serialisation – to establish the authenticity of each product and ultimately improve patient safety – will always outweigh any temporary burden. Serialisation will boost the industry’s reputation and protect people, meaning that a company’s brand and stakeholder value can also be protected and enriched. Do Not Underestimate the Task at Hand The FDA’s decision to delay the active enforcement of the Drug Supply Chain Security Act (DSCSA) to November 2018 serves to highlight another stumbling block in the way of tight timescales. This recognition of the need for more time not only brought welcome attention to the timescale issues being faced, but is further evidence of the need to acknowledge the scale of the task at hand. With some companies yet to start developing a serialisation solution, the postponement in the US came as a welcome reprieve. It is vital that the delay is not perceived as an opportunity to relax, but as a warning shot that highlights the need to start early to ensure a robust solution is in place. Serialisation is a vastly complex process that requires comprehensive plans and a clear roadmap. Ineffective planning can lead to bottlenecks within the supply chain, faulty lines leading to low-quality service, and additional costs.

The kind of change required is fundamental to each business and impacts every department in some way. Serialisation needs to be overseen at a corporate level and should also be perceived as an opportunity to introduce standardised and modernised approaches across the organisation. This could include reviewing standard operating procedures (SOPs) and ways of working, training materials and resources, responses to faults, maintenance and support and best practice generally. Effective planning can also help you ensure all costs are covered in advance, as many may see the need to renew or purchase new machinery, as their current equipment was not built with serialisation in mind. Think Third Party: A Serialisation Partner The enormity of the task at hand can be tricky for many, and as deadlines fast approach, the need to find support and outsource serialisation implementation has become more common and encouraged, particularly across smaller and mid-sized companies that do not have the in-house resources for a full-time, dedicated project team. The DSCSA delay also reinforces the need to use the additional time to find a reputable partner to guide you through the serialisation journey. Strategic partnerships make sense due to the time-sensitive nature of the task, particularly when research shows that 36% believe they have a Winter 2017 Volume 9 Issue 4


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Packaging

knowledge gap in their existing teams when it comes to serialisationš. Still today, many corporations have no idea what serialisation means for their operations, and think it is as simple as adding a code to their packaging. There are key factors to consider when selecting a serialisation partner as they need to be technical experts who are well-versed in testing serialisation lines and offering scalable solutions using both proposed and incumbent resources. Scaling up means having the ability to adapt the solution in the future, allowing companies to stay on top of the latest requirements on local and global levels. These all rest alongside other vital factors such as how they communicate, manage and understand businesses, as they will guide and support them through all stages pre- and post-implementation, and even across facilities and countries. Look and Learn More than 40 countries across the world have serialisation guidelines, yet no two countries have the same requirements. Whilst the specifics might vary, lessons can be learned from global compliance, and between the US and EU as they work towards compliance. For example, as Turkey implemented its regulations, companies found the need to build in as much flexibility as possible into their systems to help reduce 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the amount of downtime in their packaging lines. This future-proofs serialisation solutions as they can adjust to any further regulatory changes. They also found that effective communication practices between business operations and third parties are vital to overall success, and that complacency is counterproductive when it comes to understanding international requirements. Track, Trace and Train A comprehensive and phased plan with regular benchmarks is a must, as evaluating progress is the only means of hitting a deadline. The project must also consider post-delivery implications which can only be managed with training and testing. Employees should be trained early and often as adjusting to new equipment, software, and ways of working is a lengthy process. Running pilot lines or test lines with newly-trained employees will allow them to practise first-hand before unveiling official production. Summary The number of voices contributing to the discussion around serialisation grows daily, with more advice, guidance and tips adding to the hubbub. This isnâ&#x20AC;&#x2122;t too much of a surprise; serialisation is the biggest regulatory change to impact the pharmaceutical supply chain in many years and offers the industry

an opportunity to revolutionise its practices as we head towards compliance. Whilst the road ahead may appear daunting, there are many guides to help along the way, especially from third parties. It is important that businesses establish a realistic timeframe, recruit the best resources and get to work. The serialisation challenge is one to be met with blue-sky thinking. REFERENCES 1. http://www.zenithtechnologies. com/zen-blog/ cost-serialization-compliance/

Carlos Machado A serialisation director at SEA Vision US and is responsible for sales, operations, implementation and post-project support services in the US and Canada. As part of the serialisation initiatives, Carlos is leading the partnership between SEA Vision and Zenith Technologies, implementing its serialisation product suite, focusing on speed to deliver, engineering excellence and a superior customer experience. In his previous role as director of operations at a leading anti-counterfeiting technology provider, Carlos helped to pioneer the serialisation concept and define the future of authentication. He has a wealth of experience in assisting pharmaceutical manufacturers with track and trace technologies and has worked on more than 75 serialisation projects, from both an operations and delivery perspective.

Winter 2017 Volume 9 Issue 4


Advertorial Securikett has Opened its New Premises in November 2017 – More Space for Tamper-verification Label Production SECURIKETT®, a global leader in tamper-evident labels and product security solutions, has moved all its production facilities and administration to new headquarters. In good time for the implementation of the EU Falsified Medicines Directive (2011/62/EU), the new premises offer more room for production and R&D to cope with the increased demand for tamper-evident labels in the pharmaceutical market.

SECURIKETT® has recently launched a new series of highlytransparent VOID-seals. They are particularly designed for compliance with the FMD, the European Falsified Medicines Directive (2011/62/EU) and other new global regulatory requirements to secure pharmaceutical boxes against product fraud, such as counterfeiting, refill or unauthorised relabelling. These new labels are available in different transparent shades, and can include UV-luminescent ink. SECURIKETT®'s adhesive VOID technology prevents the label from being tampered with or transferred to other products without a clear indication. A previously invisible symbol or text appears irreversibly, when the label is removed. The novelty: highly transparent shades leave any text or codes readable even when fully covered, and they do not interfere with the overall packaging looks and design. The SECURIKETT® suite of tamper-verification labels also comprises other highly efficient and

The new headquarters of SECURIKETT®, including the production building, was officially opened on 9th of November 2017.

proven solutions such as fibre tear labels or labels with easy-open tab. For high-risk profile markets, the company offers specialties such as three-colour-VOID, soakingdetection-VOID or dry-peel-VOID. Highlights of the opening event included a multi-stage workshop which took place in different parts of the premises. A quiz helped visitors, in a playful manner, to learn about the security system and environmental characteristics of the new building. With its top modern, well-secured building and processes, SECURIKETT® could already reach compliance with International Standard ISO 14298:2014 “Management of security printing processes”, for which the company is certified.

The highly-transparent VOID labels for tamper-verification may be placed on top of a data matrix code, and typically do not require packaging re-registration. www.ipimediaworld.com

Around 280 persons participated in the evening opening ceremonies. With an export share of more than 80%, SECURIKETT® is one of the world's leading suppliers of physical and digital product security solutions for detecting counterfeits and preventing illicit trade.

Mike Isles, executive director of EAASM, the European Alliance for Access to Safe Medicines, highlighted the importance of security in the field of pharmaceutical products, in particular the challenges of online sales, also subject to the FMD.

In their welcome address, co-founders and CEOs, Werner Horn and Dr Marietta Ulrich-Horn, expressed their trust that the new building would “provide an appropriate setting for the company’s status and future development opportunities”. INTERNATIONAL PHARMACEUTICAL INDUSTRY 101


Technology

From Seller to Navigator: The Changing Role of the Sales Rep Much has been written about the supposed "death of the sales rep." Digital disruption, declining rep access to physicians1, and the increasing appetite of healthcare providers for readily available digital information have led some industry observers to suggest that the traditional field-sales role might one day become obsolete. But while the role of the sales rep is certainly changing, the industry shift towards intelligent engagement means it may prove more valuable than ever.

Healthcare professionals want pharma to engage with them on a more immediate and in-depth level than ever before. It is estimated that by 2020, 67% of HCPs will be “digital natives.” This means they will have qualified during or after the internet went mainstream, and have relied on digital interactions throughout their professional careers2. According to a recent study, nearly three-quarters of doctors use search engines weekly or more often3, and more than half use digital life sciences resources regularly, with product-related information as the most accessed website resource4. HCP expectations, coupled with a shift across the industry towards customer-centricity, are compelling communications teams to tailor engagement to each customer’s needs and anticipate how – and when – they will want to consume information. “Gone are the days when we could just sit down with somebody for 45 minutes and detail them with a paper sales aid,” says Dan Gandor, head of digital accelerator at Takeda. “It’s about reaching them online, offline, face to face, when they want it, how they want it.” For field reps, this presents an opportunity to deepen the relationship with their customers and broaden points of engagement with the HCP. Historically, if an HCP asked for a piece of information to be sent by email, a rep’s only option would have been to push for another face-to-face meeting 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to deliver that information. Leveraging other channels, such as approved email or remote detail, means the rep can deliver on the request from the HCP, which, in turn, drives a better customer experience. Kara Zubey, senior director of HCP engagement at GlaxoSmithKline, explains, “The customer is expecting more of them, and they also want to be more for their customer. They want to be able to answer their questions. They want to have information at their fingertips.” But responding to the needs of customers with relevant, timely information is just the start. The true value of multichannel is in the insight gleaned from HCP interaction with the various touch points – and that is where reps can really enhance their value. In a well-orchestrated, multichannel interaction, the frequency of engagement can increase by thinking carefully about when face-to-face interaction would make sense versus a digital interaction. This approach to intelligent engagement is the most dramatic shift in the role of the rep, as Zubey explains: “To be able to carry through a conversation not only between calls, but also between interactions that are happening on the digital level, sales representatives need to understand how their conversation is intertwined with all the other touch points. That’s a very different model than historically, where it’s really been face-to-face selling as the primary channel.” Alex Azar, former president of Lilly USA and former deputy secretary of the US Department of Health and Human Services, notes that rather than sidelining reps, this new digital model puts them firmly at the centre. “I really think that the sales rep becomes – or remains – a critical part,” he says. “That doesn’t mean that there aren’t a lot of changes that can and should happen as we think about technology in building a suite of services around that rep – or where a rep doesn't have access, building that as a substitute.”

Glen Tate, senior director of IT at Medac Pharma, agrees. “What digital disruption allows us to do is enhance what the rep is doing,” he says. “We can use the digital technology to integrate marketing. We can take items that sales operations have created and push that back to marketing, and then integrate sales reps into all three of those things.” But if today’s reps are key to joining the dots between digital tools and platforms, they must also learn to read between the lines. Their role is becoming increasingly subtle, requiring them to understand the finer nuances of influencing the HCP. This understanding needs to leverage the information and insight available to them, as well as their personal understanding of that HCP – their attitude, behaviour and values. These various information sources need to be applied in the right way. And that’s where the human factor comes into play. Consider an online-only digital transaction, such as a travel-booking site. If you are dissatisfied with any aspect of the service, you more than likely leave that site and find an alternative. You feel no loyalty to that initial provider – predominantly because there’s no human involved in the interaction. Ultimately, it’s about understanding the customer and building trust, says Rick Priem, global CRM manager of Nestlé Health Sciences. “I don’t believe personally that today, physicians necessarily look to a rep to be the sole source of their information,” he explains. “But, rather, the sole source of their access to information. The rep who can provide that access is the rep who’s going to be successful – and the company that’s going to be successful. So the more tools that we provide them that can do that, that is how we believe we are going to become that trusted advisor.” It’s a valid point. The amount of information available to HCPs is growing at an incredible pace, and the difficulty of accessing information Winter 2017 Volume 9 Issue 4


Advertorial

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. www.ipimediaworld.com

“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). www.ompipharma.com www.ez-fill.com

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. www.stevanatogroup.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 103


Technology is increasing at the same pace. In an ever-more complex digital landscape, the field rep will continue to play a key role in navigating all that information to find what the HCP needs in a quick and convenient manner. “The sales professional is, to these multi-billion-dollar, many-thousandpeople pharmaceutical companies, that broker of capabilities,” says Azar. “They're the face of this massive global company to that physician’s office, for the massive amount of services and capabilities and information available from that company, if done well.” So, while the function of today’s rep may be evolving from seller to navigator of information, it’s clear that the role will continue to be critical to the relationship between healthcare and pharma. In short, it seems, the death of the pharma sales rep has been greatly exaggerated.

REFERENCES 1. ZS Associates Access Monitor 2016 Executive Summary 2. LBiHealth – The Year of the Digital Native HCP 2014 3. DRG Digital (formerly Manhattan Group), Taking the Pulse 2017 4. DRG Digital, ePharma Physician Study

Jan van den Burg The vice president of commercial strategy at Veeva Systems, shaping advances in cloud-based software to enable modern multichannel communications between life sciences companies and healthcare providers. He has over 20 years’ experience in software and services, mostly dedicated to pharmaceuticals. Prior to joining Veeva, Jan led the life sciences sales & marketing group at IBM Global Business Services, and set up and ran the European business for Proscape Technologies.

104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2017 Volume 9 Issue 4


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Exhibitions & Conferences

The Future Is Now – Pharmapack Europe 2018 to Showcase Evolution and Revolution in Packaging and Drug Delivery Pharmapack Europe 2018 (#pharmapackeu) has announced the comprehensive event programme for Europe’s dedicated pharmaceutical packaging and drug delivery conference and exhibition taking place on 7–8 February at Paris Expo Porte de Versailles, Paris. The packed event programme includes keynote speeches from leading industry figures, a symposium, educational workshops, and a learning lab that will explore regulatory changes and impacts, challenges in packaging & devices development, biologics, materials, sustainability and quality consistency, and how new patientcentric innovations in drug delivery will revolutionise lives and improve treatment adherence. Furthermore, new for Pharmapack Europe 2018 is the Start-up Pitch, a unique opportunity for companies at an early stage or pre-commercialisation phase to present their idea in front of industry experts.

Pharmapack Europe is an essential event for industry insights and the latest industry innovations that are reimagining the capabilities of pharmaceutical packaging and drug delivery. One area that provides opportunities and challenges is biologics, a growth area for the pharmaceutical industry both now and in the future, with biologics representing 70% of drugs currently in development. Pharmapack Europe 2018 will include keynote presentations on the key factors for successful collaboration on pharmaceutical packaging development for biologics, speeches on integrated approaches towards the

106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

design of drug delivery platforms for biologics, and case studies assessing delivery options for injectable biologics. In addition, patientcentric considerations provide new avenues of innovation in drug delivery solutions. Sessions will be dedicated to innovations in packaging that improve patients’ lives, identifying new areas of opportunity in designing the future of drug delivery packaging, and practical solutions to help stakeholders innovate in this area. “The pharmaceutical packaging and drug delivery industry is at the crest of a new wave of innovation and opportunity. We have developed an extensive programme for Pharmapack Europe 2018 to provide the industry with insights from leading industry experts, practical guidance and workshops on challenges and opportunities, and networking and collaboration opportunities through our International Meetings Programme to enable visitors to share knowledge and experience to drive business forward,” said Anne Schumacher, Brand Director, Pharmapack Europe. “Following on from the success in 2017 we are

also continuing to provide focussed support for new companies through our Start-up Hub and Start-up Pitch programme. This unique programme provides the leading opportunity in Europe to directly meet and discuss business opportunities with international pharmaceutical and biopharmaceutical companies. A limited number of spaces are still available.” The 2018 Start-up Hub will showcase young companies as being amongst the most innovative in the industry. Companies in the Start-up Hub will benefit from increased access to potential customers, partners and investors at Pharmapack Europe 2018 from which to forge new and lasting relationships. New for 2018 is the Start-up Pitch, offering non-commercialised companies the opportunity to present in front of a start-up panel of experts and an audience of industry professionals. The Start-up Hub and Start-up Pitch are organised in collaboration with Early Metrics, the pan-European rating agency for start-ups and innovative SMEs, assessing the potential growth of early stage ventures by analysing a company’s non-financial metrics. If you are interested in participating in the Start-up Hub or Start-up Pitch please visit https://www.pharmapackeurope. com/innovation/start-up-focus. Pharmapack Europe 2018 will take place on 7–8 February at Paris Expo Porte de Versailles, Paris. Register now for free: http://bit.ly/2Ccjr15

Winter 2017 Volume 9 Issue 4


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Exhibitions & ConferencesExhibitions & Conferences

Anglonordic Life Science Investment Conference

On the 15th May 2018, the Annual Anglonordic Life Science Investment Conference will take place in Central London at County Hall, right across the Thames River from the Houses of Parliament. Over its long history, Anglonordic’s now-familiar format makes for an informative and interactive day of pitches, panel discussions and reports. We expect over 200 attendees at the highest levels of seniority from R&D and investment firms based in the UK and Scandinavia, and beyond.

The 2018 edition of Anglonordic moves a new venue. Perched above the Thames River, the airy, open format of County Hall’s conference rooms, arranged on a single floor, will make a refreshing change. Introduced in 2017, the Technology Room stream will include keynote talks, a panel discussion on medical and biomedical technologies enabling current and future innovation and up to 12 growth companies will provide pitch presentations. Last year’s Technology Room feature presentations on collaborative growth in the Swedish life science industry, burgeoning clinical trials based in the UK National Health Service, the investment scene in bio/ medical technology, and big pharma’s strategy in adoption technologies across healthcare, biotech and materials. 2017 Keynote speakers included: •  Edward Kliphuis, Investment Director, Merck Ventures

- Investment Status in the Innovative Technologies •  Dr Birgit Reitmaier MBA, Head of Technologies & Biomarkers Merck KGaA - Enablers and Technologies from the Pharma Perspective •  Anders Lönnberg, National Life Sciences Coordinator, Government of Sweden - Swedish Industry Strength through Collaboration •  Divya Chadha Manek, Head of Business Development, NIHR Clinical Research Network - Delivering Clinical Research to Make Patients, and the NHS, Better The traditional Biotech Investment Room will feature pitch presentations from companies developing novel medicines and some long-term favourites including ‘The Interview’: last year Hakan Goker, Investment Director at Merck Ventures, quizzed cancer drug discovery entrepreneur Tony Kouzarides, Professor of Molecular Cancer Biology at The Gurdon Institute, University of Cambridge. In the long-established panel discussion ‘If I knew then what I know today’, experienced company builders will reflect on their own successes and failures, prompted by well-known industry commentator and Tweet-master Mike Ward, Global Director of Content, Informa Pharma Intelligence. The Biotech Program will include a report on the status of European funding, a panel discussion on opportunities and challenges and keynote presentations reflecting the legal, regulatory and therapeutic landscape in the UK and Scandinavia.

•  Ravi Srinivasan, Partner, J A Kemp - Building an IP Portfolio to Enhance Value •  Hakan Goker, Investment Director, Merck Ventures - Latest News on European Funding

Anglonordic is notable for its high representation of R&D CEOs and investors, but a number of handpicked exhibitors will be present. These are core industry players and supporters, providing high-value representation of service companies to maintain the exclusivity of the conference. 1:1 partnering will, as always, be available, with the new ‘unlimited’ format enabling a much greater level of interaction. Last year, over 250 meetings were booked throughout the day. Media partners PharmaVentures Insights will offer TV interviews on site, to be broadcast free on their website and available for free licence on other sites. Anglonordic remains one of the few life science conferences in the UK that is exclusively for European investors and R&D companies to connect with each other. For an invitation, please save the date – 24th May, 2018.

2017 Keynote presentations included: •  Baroness Prof Susan Greenfield, CEO, NeuroBio - New Therapies: Precision Medicine & Neurodegenerative Disease 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2017 Volume 9 Issue 4


The Parenteral Drug Association presents the...

2018 PDA Annual Meeting March 19-21, 2018 | Orlando, Florida

Exhibition: March 19-20 | 2018 PDA Manufacturing Intelligence Workshop: March 21-22 | Courses: March 22-23

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Take advantage of numerous networking opportunities and see the latest technology in action in the Exhibit Hall. Be a part of this exciting meeting filled with novel approaches and strategies for bringing products to market! Learn more and register at pda.org/2018Annual From March 21-22, learn how the industry is developing its capacity to better employ and advance the use of big data in manufacturing and supply chain management at the 2018 PDA Manufacturing Intelligence Workshop. Learn more and register at pda.org/2018MI

Following the meeting, PDA Education will host a choice of seven courses as part of the 2018 PDA Annual Meeting Course Series to help you further advance your knowledge. Learn more and register at pda.org/2018AnnualCourses www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 109


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PLUS TWO INTERACTIVE HALF-DAY PRE-CONFERENCE WORKSHOPS TUESDAY 16TH JANUARY 2018 A: Combining ‘traditional’ human factors with smart drug delivery devices for hybrid parenteral development Workshop Leader: Jacquie Finn, Head of Digital Health, Cambridge Consultants, and Colleague 08.30 - 12.30 B: Navigating the Silicone Layer Workshop Leader: Oliver Valet, Co-Founder, rap.ID and Lisa Krapf, Application Scientist, rap.ID 13.30 - 17.00 SPONSORED BY

www.pre-filled-syringes.com/ipi Register online or fax your registration to +44 (0) 870 9090 712 or call +44 (0) 870 9090 711

@SMIPHARM #PFSSMI


Advertisers Index Page 111 10th Annual Pre-Filled Syringes Europe (SMI Group) Page 111 15th annual conference on Controlled Release Delivery (SMI Group) Page 79 AbbVie Inc Page 39 Abzena Page 17 Adents International Page 61 AirbridgeCargo Page 73 AMRI Page 37 Aptar Pharma Page 47 Beneo GmbH Page 59 Bioclinica Page 27 Butterworth Laboratories Limited Page 75 Capsugel Page 29 Cresset Group Page 99 Denny Bros Ltd Page 67 EcoCool GmbH Page 97 Emphasys Innovatec Page 35 ExpreS2ion Biotechnologies IBC Gaplast GmbH Page 91 Gerresheimer Page 11 HGF Ltd Page 9 Kahle Automation BC Lindal Group Page 87 LTS Lohmann Therapie-Systeme AG Page 93 MA micro automation GmbH Page 5 Mikron Group Page 33 Nemera Page 103 OMPI Page 95 Owen Mumford Ltd Page 89 Packaging Coordinators, Inc Page 110 Pharmaworld.TV Page 49 Phillips-Medisize Page 83 Plastibell Page 71 Powder Systems Ltd Page 81 Presspart Page 69 QuickSTAT Page 77 Sartorius Stedim Biotech Page 3 Schott Page 101 Securikett Page 13 SGD Pharma Page 51 Stolzle Glass Group IFC Sulzer Mixpac Ltd Page 19 TeamTechnik Maschinen und Anlagen GmbH Page 105 Terumo Pharmaceutical Solutions Page 63 TP3 Global Page 7 UPS Page 15 & 31 Valsteam ADCA Page 53 WestRock Page 25 Wickham Laboratories Ltd Page 65 Woolcool Ltd

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

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112 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Winter 2017 Volume 9 Issue 4


novel solutions in plastics

Visit us in Paris 7 â&#x20AC;&#x201C; 8 February hall 7.1 booth E10

Headquarters GAPLAST GmbH 82442 Altenau www.ipimediaworld.com Germany

Contact us: Tel. +49 (0) 8845 7413-0 www.gaplast.de info@gaplast.de

We develop innovative packaging and applications for pharmaceuticals, INTERNATIONAL PHARMACEUTICAL cosmetics INDUSTRY 113 and medical devices.


Aerosol technology for pharmaceutical excellence. Expert in manufacturing metering valves, bag on valves, and actuators for a wide range of pharma applications. Pulmonary, nasal, topical & rectal delivery, pain relief, skin treatments, hand sanitizing, nutraceutical & food supplements

The Lindal KHFA metering valve:

Open chamber or capillary retention design

Suitable for suspension, solution and hybrid formulations

Offers performance meeting international specications

More info: Visit: www.lindalgroup.com Email: info@lindalgroup.com Search Google: Lindal pharma

Lindal Group is driven by innovation.

© Lindal Group Ltd. All Rights Reserved.

IPI - Winter 2017  
IPI - Winter 2017  
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