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Volume 8 Issue 4

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Uzbekistan A New Spot on the Pharmaceuticals Map Protecting Vaccines With a Sustainable ‘Smart Fibre’ Managing Benefits and Risks of Opioids in Paediatric Populations A Review of FDA Paediatric Advisory Committee on Opioid Studies Understanding the Determinants of Non-adherence A Key to Success in Using Digital Services to Improve Adherence in Inhaler Use

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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 EDITOR: Orsolya Balogh orsolya@pharmapubs.com EDITORIAL ASSISTANT Emoke Karasz emi@pharmapubs.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: John Donalds john@ipimedia.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Heather Bayran heather@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 Februay 2017. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2016 PHARMA PUBLICATIONS Volume 8 issue 4 - Winter - 2016

08 Uzbekistan – A New Spot on the Pharmaceuticals Map Uzbekistan is hosting the TechFarm Exhibition to illustrate the latest advances and the potential hidden in the pharmaceuticals industry of the Republic of Uzbekistan. The pharmaceuticals industry in the country is actively attracting foreign investment and is expanding at a dramatic speed, which is largely due to the convergence of such factors as support from the government, attractive geographical location, free trade agreements with the neighbouring CIS countries and trade agreements with such advanced countries as Korea, China and many others. 10 The Global Impact of Standards As an increasingly globalised industry, healthcare is seeing the rise of legislation and government initiatives to make the use of medicines and medical equipment as safe and cost-effective as possible. With an ageing population and growing economic pressures, healthcare organisations need to make sure they’re at the top of their game when it comes to providing the best deal – whether their customer is a supplier, a hospital, a pharmacy or a patient. Glen Hodgson, Head of Healthcare at GS1 UK, submits a white paper on standardisation. 14 Regulatory Transformation: Cloud Reality Check What role can cloud services such as SaaS play in driving the next generation of regulatory information management, and what are the practical considerations for potentially sensitive data? Siniša Belina, senior life sciences consultant at Amplexor Life Sciences, reports from a recent industry debate. 20 Tipping Point: The Regulatory Year in Review As big an issue as it has become, compliance is the least of life sciences companies’ concerns as 2016 gives way to 2017. But the right approach will equip companies to successfully navigate everything from market consolidation and new market entry to marketing innovation and operational transparency, which will set them in good stead for years to come, says Adam Sherlock, CEO of ProductLife Group. 24 The Devil in the Detail: Five Routine Recall Risks Faced by Modern Pharma With the steely eyes of the regulators firmly trained on everything that life sciences organisations do, the last thing firms want is to incur fines, market delays or worse because of overlooked mistakes in labelling and product information. Growing complexity in life sciences is raising the risk of product mislabelling, potentially putting lives in danger and leaving companies open to hefty fines and delays in product availability, warns Marc Chaillou of Schlafender Hase. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 28 Natural Born Killers Immunotherapy is currently one of the most actively pursued areas of research by biotechnology and pharmaceutical companies. “Control of immune activation can save us,” believes Markku Jalkanen, CEO of Faron Pharmaceuticals. Cecilia Stroe, Staff Editor of IPI, explains that at present, the interest in immunotherapy is largely driven by recent compelling efficacy data in cancers with historically bleak outcomes, and by the potential to achieve a cure or functional cure for some patients. 30 Feasibility is not (anymore) A Plain Search for Investigational Sites Conceptual Evolution of Feasibility Studies in Pharmaceutical Development The sole term ‘feasibility’ has multiple definitions in a clinical environment, leading to certain bias with all stakeholders involved, including pharma companies (sponsors) and all types of contract research organisations (CROs). The most common perception is

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Contents related to a never-ending argument between pharma outsourcing departments and CRO commercial groups, with sponsors expecting CROs to run a (non-defined) feasibility study prior to proposal submission and CROs undertaking a series of schematic actions to create an impression of fulfilled expectation. Anna Baran MD, Chief Medical Officer at KCR, shares her thoughts on feasibility.. 34 How Drug Delivery Systems will Impact the Off-patent Biosimilar Race For generics manufacturers, the race to be the first to file their drug after the original’s patent expires is critical. The FDA stipulates that after a drug comes off patent, generics manufacturers can begin filing an abbreviated new drug application (ANDA) for their version, granting the first company to do so a 180-day period of market exclusivity. This is quite an advantage because the generic offering is less expensive than the original, and for approximately six months their offering is the only generic version available. Kevin Stevens, Director of Product Technology, West Pharmaceutical Services, answers the question of how drug delivery systems will impact the off-patent biosimilar race. 38 Understanding the Determinants of Non-adherence: a Key to Success in Using Digital Services to Improve Adherence in Inhaler Use The prevalence of chronic respiratory conditions, such as asthma and COPD, is increasing. So is the cost of their management. Many inhalation devices and drug products are available on the market to treat these conditions. However, studies have shown that poor adherence to treatment regimens is widespread and severely compromises the effectiveness of the treatment, resulting in poor health outcomes and increased healthcare costs. With 30% to 70% of patients not adhering to their medication regimen it is well recognised that the efficacy of drugs alone is not enough for good outcomes; patient and physician behaviour are vital factors and efforts need to be made to improve them. Suresh Gupta, James Ward, Alex Agis, Katie Cornish, Jaquie Finn and Tim Murdoch at Cambridge Consultants drive us into the usage of digital services, improving adherence in inhaler use. CLINICAL RESEARCH 44 Managing Benefits and Risks of Opioids in Paediatric Populations: A Review of FDA Paediatric Advisory Committee on Opioid Studies This is a follow-up to an earlier Watch article regarding the FDA’s action plan to proactively reduce prescription opioid abuse. This action plan consists of several wide-ranging strategies, the successful implementation of which will greatly impact pharmaceutical companies attempting to gain approval for opioid analgesic medications. Henry Riordan at Worldwide Clinical Trials focuses on opioid studies. 48 Unifying Clinical: Why Systems are Causing Costly Inefficiencies Information-sharing is common practice among many physicists, astronomers, and geneticists, who actively share data from resources such as the Large Hadron Collider, the Hubble Space Telescope, and the Human Genome Project. So why is the experience of clinical researchers so different? Why, at the innovating heart of the sciences industry, where access to high-quality clinical data is key to accelerating trials, are companies and functions within companies still operating in siloes? In this editorial, Rik van Mol at Veeva Systems shares his views on the subject above. LABS & LOGISTICS 52 End-to-end Process Excellence to Ensure Uninterrupted Delivery Orsolya Balogh, Managing Editor of IPI, talks to Alex Guillen, Cold Chain Director at Fisher Clinical Services, about how end-to-end process excellence can ensure uninterrupted delivery, and how it is of particular importance for the cold chain shipment of IMP supplies.

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58 Protecting Vaccines with a Sustainable ‘Smart Fibre’ As far back as 2005, the World Health Organisation (WHO) reported that up to half (50%) of all vaccines transported globally were ruined due to poor distribution procedures, with a resulting significant impact on human life. Today, in 2017, the situation remains largely unchanged. So what credible and sustainable passive packaging solution can help solve this humanitarian issue? Keith Spilsbury, Strategic Director at Woolcool, answers the question. 64 UAE – Dubai: Opening the New SkyPharma Facility of Emirates In mid-September, Emirates SkyCargo has unveiled its new purposebuilt pharma facility – certified under EU good distribution practice guidelines. The airlines operate the first and biggest GDP-certified multi-airport hub in the world. On the 18th September, Emirates SkyCargo’s new purpose-built facility dedicated exclusively to the secure and timely transport of temperature-sensitive pharma shipments at Dubai DXB. Orsolya Balogh, Managing Editor of IPI, was there to report on the proceedings. 66 Flying High The air cargo industry is the preferred logistics partner of the pharmaceutical industry as it relies on air transport for its speed and efficiency in delivering high-value, time-sensitive and temperaturecontrolled cargo. But maintaining the required temperatures from end to end of the supply chain is quite a challenge and the air cargo industry is stepping up its game. Cecilia Stroe, Staff Editor of IPI, looks into the long-term investment IAG Cargo is making at Heathrow Airport and the expansion of their premium freight capabilities. MANUFACTURING 72 Improve Production Efficiency from Tablet Design to Tool Material Specification Efficiency in solid dose manufacturing can be improved at the earliest stages of the tablet design process, by utilising precise tooling specifications. The design and material selection can have a major influence on the final product. With the help of a quality tooling manufacturer to identify specific requirements, elimination of downstream tabletting problems can be achieved. Laurence Mead, I Holland’s Customer Support Group Engineer, explains that if the devil is in the details, don’t leave it to chance to identify it. 76 How New Dosage Forms Prolong the Lifecycle of Mature Products An age-old problem of the pharmaceutical industry is what to do if product sales are dropping or are anticipated to drop. How can you revitalise an ageing product, boost brand loyalty and recapture interest? One approach is to develop existing APIs into one or more alternative dosage forms. This article, written by Dr Thomas Hein, Senior Vice President, Commercial and Regulatory Affairs at Hermes Pharma, looks at the benefits of user-friendly dosage forms, and what they offer to the pharmaceutical industry. 82 Parenteral Preparations, Challenges in Formulations Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants. They are sterile preparations intended to be administrated directly into the systemic circulation in human or animal body. They are required, like any pharmaceutical dosage forms, to meet the pharmaceutical quality standards as described in pharmacopoeias and to be safe for the intended purpose of use. Dr Elham Blouet, Global Market Manager Injectable and Dialysis, Global Business Unit Pharma & Health at Roquette, discovers the challenges of parenteral preparations. 86 The Serialisation Challenge As a result of increasing concerns over falsified medicines, reimbursement fraud and theft throughout the pharmaceutical supply chain, by 2019 over 55 countries will have introduced serialisation and track and trace regulations. The serialisation of licensed drug

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Contents products is essentially the introduction of a 2D barcode which will, when combined with comprehensive track and trace systems, allow the industry to follow products from manufacture to the point of sale. Staffan Widengren, Director Corporate Projects at Recipharm, submits a white paper on the challenges of serialisation. PACKAGING 90 Establishing Interoperability for Product Identification and Authentication Systems In our digitised society, the coding of individual products with unique codes for authentication and tracking is becoming increasingly widespread. To enable these processes, various IT systems are already in place or steadily emerging, and related industries are booming. Correspondingly, both options and obligations for brand owners and producers continue to proliferate. What is currently missing is a strategic approach to reconcile the individual systems with their often diverse and multifaceted functionalities. Dr Marietta Ulrich-Horn at Securikett submits an article on product identification authentication systems. 92 Pharmaceutical Artwork in Safe Hands Historically, artwork for the packaging and labelling of pharmaceutical products has been the final part of a long process to get a product ready for market. All too often, it was treated as a rushed after-thought. Changes in the marketplace have ensured this approach has had to improve due to the increasingly complex nature of many products, many requiring a higher level of control. The key driver has been the introduction of new regulations with a greater focus on the risks to patient safety and prescribing errors. Bob Houghton at Multipack, in cooperation with Gill Wright, Design & Development Director at Cirrus, submits an interesting read on pharmaceutical artwork. 94 On the Right Track How the Packaging of Investigational Medicinal Products Influences Patient Compliance How does the packaging of investigational medicinal products influence patient compliance? The quality of trial results depends largely on patient compliance, which is affected by both predictable and unpredictable factors. One of these predictable factors is packaging. Anthony Morrow Business Development Manager at Faubel & Co. Nachfolger GmbH discusses this point. 96 Ampoules – A Traditional Product with a Future Ampoules were developed at around the same time as injections were invented as a form of medical treatment. This type of primary packaging allows the pharmaceutical drug to come into contact with only the inert and gas/vapour-impermeable material of glass. Ampoules are also completely tamper-proof. Although ampoules have been competing with vials for quite a while now and increasingly also with pre-filled syringes, they are still the global number one choice of primary packaging for injectables. Lothar Haaf, General Manager of Gerresheimer Wertheim GmbH with Dr Volker Rekowski, Quality Director Europe & India, Tubular Glass Converting Chairman of the Gerresheimer Quality Council has written for IPI about ampoules.

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Editor's Letter It should come as no surprise that when looking for new trends in pharmaceutical development and outsourcing, the industry giants often referred to as big pharma are the most popular topic of interest. Big pharma has been a leader in identifying ways to maintain or improve profitability while simultaneously making efforts to speed up the process of bringing new drugs to the market. While these giants receive their share of flak (oftentimes from the media inciting the general population), they are also a source of inspiration and guidance for the biopharmaceutical industry and a signal of what’s to come. The escalating operation cost for every drug company and the vigorous control of the healthcare cost by the government in almost all countries, coupled with the low efficiency in their operation for a number of years, have forced all drug companies to seriously address these issues. Streamlining their internal operation and more diligently seeking external resources have become their core strategies. Besides the operational factors, the fast emerging of new technologies in drug R&D has also forced drug companies to rapidly adapt to the new R&D environment. Today, drug companies are in desperate need of developing better drugs with high success rates and low cost. To achieve these goals, they increasingly resort to the combination of internal effort and external resources. This issue of IPI features various articles which provide unique insights into the new outsourcing

demands and strategies of global drug companies large and small, in both R&D and manufacturing and in both small molecules and biologics. These articles will help professionals in the life science-related industries gain a better view about what is really going on currently in the global pharmaceutical outsourcing industry. Within the Regulatory & Market section, we bring you a country analysis on Uzbekistan. Is Uzbekistan a new spot on the pharmaceuticals map? As big an issue as it has become, compliance is the least of life sciences companies’ concerns as 2016 gives way to 2017. But the right approach will equip companies to successfully navigate everything from market consolidation and new market entry to marketing innovation and operational transparency, which will set them in good stead for years to come, says Adam Sherlock, CEO of ProductLife Group. Within the Drug Discovery, Development & Delivery section, Kevin Stevens, Director of Product Technology, West Pharmaceutical Services, answers the question of how drug delivery systems will impact the off-patent biosimilar race, and Suresh Gupta and team, at Cambridge Consultants drive us into the usage of digital services, improving adherence in inhaler use. In the Clinical Research section, Henry Riordan at Worldwide Clinical Trials writes on managing benefits and risks of opioids in paediatric populations: a review of FDA Paediatric Advisory Committee on Opioid Studies.

This edition of IPI will be attending the Cool Chain Logistics Conference, organised by IQPC. Temperature-controlled logistics is a very important aspect within the pharmaceutical industry. Therefore IPI endeavours to publish regular updates on the movement of this industry. IPI journalists were invited to the opening of the Emirates SkyCargo facility in Dubai and also to the IAG facility at Heathrow (UK). Both the reports are featured in this issue. IPI is one of the official media partners to another major industry event in the pharmaceutical packaging world. Pharmapack is becoming one of the fastest growing packaging exhibitions within the pharmaceutical arena. Dr Marietta Ulrich-Horn at Securikett submits an article on product identification authentication systems, and Lothar Haaf, General Manager of Gerresheimer Wertheim GmbH writes on ampoules – a traditional product with a future. I would like to thank all authors, advertisers and readers who have helped to make IPI into one of the most reputed journals in the industry. We wish each and every one of you a Very Merry Christmas and a Wonderful 2017. I look forward to meeting you all in the New Year Orsolya Balogh Managing Editor – Pharma Publications

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

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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Regulatory & Marketplace

Uzbekistan – A New Spot on the Pharmaceuticals Map Uzbekistan is hosting the TechFarm Exhibition to illustrate the latest advances and the potential hidden in the pharmaceuticals industry of the Republic of Uzbekistan. The pharmaceuticals industry in the country is actively attracting foreign investment and is expanding at a dramatic speed, which is largely due to the convergence of such factors as support from the government, attractive geographical location, free trade agreements with the neighboring CIS countries and trade agreements with such advanced countries as Korea, China and many others. Industry Development Status Currently, more than 130, up from three in the early 1990s, companies in the pharmaceutical sector supply the domestic market, with over a third of demanded medicines, producing nearly 70 pharmacological groups of medicines, which include cardiovascular drugs, vitamins, analgaesics and anaesthetics, antibiotics and antituberculosis drugs, antiseptics, diagnostic products, vaccines, serums, bacterials, and other products. The total number of registered medicaments in the Republic of Uzbekistan is 5914 items of

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medicines and medical purpose and the pharmaceutical market volume is over 650 million US dollars. Furthermore, companies with foreign capital, such as NobelPharmsanoat LLC JV, UltraHealthCare JV, JurabekLaboratories LLC JV, RemedyGroup LLC JV, NovoPharm LLC, HansangPharm LLC JV, Samsun -ToshkentPharm Ltd LLC and others are operating in the Uzbek pharmaceutical market. In the near future, it is planned to attract large companies with a licence to produce original medicals. Target Parameters for Further Industry Development Today, the domestic pharmaceutical industry development strategy includes the following tasks: •

• •

ensuring national drug safety. Its key aspect is guaranteed production of the medical variety from substances to ready medical products; increasing the number of highquality domestic medicines, covering the market for at least 45-50%; innovative domestic products market launch.

Additionally, it is planned to focus efforts

on production of universal generics in all forms, including tablets, capsules, injectable drugs, infusion fluids and others, as well as immunological and psychotropic drugs, insulin, anti-cancer drugs, and medicines from plant material. Advantages The population of Uzbekistan is roughly 32 million, and this makes Uzbekistan the country with the third largest population in the CIS region and the first in the Central Asia Region. The advantages of Uzbekistan in the pharmaceuticals field are as follows: •

• •

necessary legal framework contributing to the creation of an enabling environment for business and providing foreign investors with a package of benefits and privileges; political and macroeconomic stability in the country that guarantees the security of investments; opportunity to enter the markets of the CIS, whose combined population is over 300 million people, and also the existence of an agreement on a free trade zone with Russia, Ukraine, Belarus, Kazakhstan, Georgia, Armenia, Azerbaijan, Moldova and

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Regulatory & Marketplace foreign currency. In October 2003, the government officially announced the possibility of conversion of the national currency for ongoing operations. This process has a temporary status and there are certain cases when businesses may wait for a long time to convert their sums. In addition to that, there are certain restrictions on the conversion of national currency. One of the main reasons that holds back the implementation of the effective conversion is the fact that it would cost significant amounts of money to fix it. In fact, according to the analysis of the European Bank, this procedure will cost at least $200 million for Uzbekistan.

• • • • •

Kyrgyzstan. Moreover, the annual demand of Central Asian countries’ alone is over 15.4 million standard units; convenient geographic location of the country; highly skilled professionals and quality educational institutions; relatively cheap energy; access to unused buildings and structures under zero value on the condition of mandatory investment; growing domestic market. Total annual domestic demand of more than 6.6 million standard units of drugs.

Development of the Pharmaceutical Industry as a Main Objective In order to ensure dynamic and sustainable development of the pharmaceutical industry of the country, saturation of the domestic market with quality and safe medicines, expansion of the local raw material base and producing import-substituting medications, the Resolution of the President of the Republic of Uzbekistan No. PP 2595 “On measures on further development of the pharmaceutical industry of Uzbekistan in 2016-2020”, adopted on September 16, 2016, has provided for production of 130 international non-proprietary names of imported drugs. Also, it provides for implementation of 67 new investment projects to establish export-oriented production of finished pharmaceutical products on the basis of deep processing www.ipimedia.com

of local vegetable, mineral, chemical, and biological materials. Another key priority of the Government of the Republic of Uzbekistan is to implement technological modernisation of the pharmaceutical industry and to establish production of a wide range of generic and innovative medicines. To implement this programme, the local production should be established and launched. In this regard, the state provided a series of measures aimed at simplifying delivery terms (customs preferences) of equipment, importing ingredients and substances, and introduction of modern standards.

However, conversion problems can be solved. It is important to mention that this is because of the fact that there are annual programmes supporting the foreground industries for the development of the economy. From 2007, Uzbekistan aims to localise the production. The programme developed by the Ministries of Economics, Investment and Trade, Finance and others aims for localisation of industrial manufacturing. The industries include agriculture, oil and gas industry, heavy industries, mining, automotive and others. More importantly, this program supports the pharmaceutical industry as well. It is important to mention that enterprises that are involved in realisation of these programmes are granted special tax privileges and preferences. Namely, they are released from customs taxes for importing technological equipment and parts, from income taxes, property taxes and others. This is one of the main arguments that encourages companies to consider doing business in Uzbekistan.

Currently, the country lacks production of pharmaceutical medicines in the areas of tuberculosis, asthma, oncological, cardiovascular, psychological and neurological and other diseases. Economic Distinctive Characteristics The economy of Uzbekistan has certain features that may influence the development of the programme. Most significant of them is possibly the foreign currency conversion problem. There are numerous long debates on why the country is reluctant to convert the national currency to foreign ones, and whether free conversion will be implemented. In the period 1996-2003, there was a system of numerous exchange rates and normalised exchange of

Oyimkhon Babadjanova, Marketing director ITE Uzbekistan. E-mail: oyimkhon_ babadjanova@iteuzbekistan.uz INTERNATIONAL PHARMACEUTICAL INDUSTRY 9


Regulatory & Marketplace

The Global Impact of Standards

As an increasingly globalised industry, healthcare is seeing the rise of legislation and government initiatives to make the use of medicines and medical equipment as safe and cost-effective as possible. With an ageing population and growing economic pressures, healthcare organisations need to make sure they’re at the top of their game when it comes to providing the best deal – whether their customer is a supplier, a hospital, a pharmacy or a patient.

a unique identifier to be placed on all medical products by February 2019. And to keep supplying medical devices to the USA, it’s necessary to comply with the new Food and Drug Administration (FDA) unique device identification (UDI) regulations that are coming into play between now and 2018. And Europe and the USA aren’t the only ones introducing legislation – similar laws are being passed in countries all around the world.

GS1 standards offer a solution for the anti-counterfeiting legislation we’re seeing increasingly introduced around the world, and give the level of brand protection that’s expected in a sector that becomes more international by the day. GS1 standards enable the unique identification of every person, every product and every place. It’s the details that give the whole picture, whether it’s about a batch number for a product recall or expiry dates for stock management – standards support systems that give healthcare professionals the information they need, whenever they need it.

Counterfeiting is a real problem, even here in the UK. In 2015, the UK medicines regulator, the MHRA, shut down more than 2000 online pharmacies and in the first half of this year, they seized 12,000,000 fake or unlicensed products. A survey revealed that one in eight British people, aged between 18-30, said they’re likely to buy diet pills online in the next 12 months – showing where the demand for these products comes from. It’s for reasons like this that companies have a moral duty to support the coordinated initiatives to reduce counterfeiting – there’s a huge reputational risk if they do not.

The Legislation Imperative When McKinsey released their “Strength in unity: The promise of global standards in healthcare” report in October 2012, their statistics were hard to ignore. And since then, it’s been recognised by the number of regulations being introduced to tackle counterfeiting and to standardise the healthcare systems around the world.

What all these new rules and regulations have in common is that they recommend the use of GS1 standards for the unique and automatic identification of goods. GS1 standards are recognised in legislation around the world for the common language they provide all stakeholders to work together seamlessly and efficiently.

As a result of this legislation imperative, we’re seeing manufacturers, suppliers and healthcare providers implementing GS1 standards across the world, including our very own NHS in England. And it’s the whole supply chain that’s getting involved and seeing the benefits. From what we’ve seen so far, they’re saving time, money and getting better, more accurate product data. They’re also making the supply chain traceable and ultimately, safer for patients.

Implementing global standards across the entire healthcare supply chain could save 22,000-43,000 lives and avert 0.7 million to 1.4 million patient disabilities each year Rolling out such standards-based systems globally could prevent tens of billions of dollars’ worth of counterfeit drugs from entering the legitimate supply chain Healthcare cost could be reduced by $40-$100 billion globally due to the implementation of global standards

In particular, in February this year, the European Parliament released Delegated Regulation (EU2016/16), asking for 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What are the Benefits of Standards? The healthcare sector is catching up with the same standards that have been used globally in other sectors for over 40 years

– making for a more efficient, effective and safe supply chain. GS1 standards are used for identifying, capturing and sharing information – about products, assets, services, people, and locations. In healthcare, this enables the whole sector, whether it’s a hospital, pharmacy or drug manufacturer, to speak the same language and gives true and complete visibility in the supply chain. In the example of medicines, this works through a unique number that gives the product type, batch number and expiry date. It can be verified and authenticated at any point in the supply chain by scanning it using a barcode reader. It’s then checked again before the medicine is dispensed – the pharmacy or hospital verifies it by checking it against the data repository. The benefits of this go beyond meeting regulatory compliance; there are also significant benefits in operational efficiencies and patient safety. It’s about being able to automatically validate expiry dates, or even track and locate safety recalls. With global standards, tracing right down to the individual batch number and which patient it has been given to, can now be achieved. The retail sector has been doing this for years; now it’s the healthcare sector’s turn. The Global Language of Healthcare With exports to more than 200 countries, India is the world leader in the production of generic drugs and vaccines. To maintain and also grow this position, the Indian government is enforcing all possible measures to ensure the safety and security of Indian pharmaceuticals – protecting India’s brand image and preventing counterfeit drugs from entering the supply chain. The complete traceability available through the use of GS1 standards not only gives the ability to accurately identify pharmaceuticals at various packaging levels, but it also provides the ability to collect and store product information that helps identify which manufacturing unit it came from. The main goal is to provide realWinter 2016 Volume 8 Issue 4


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Regulatory & Marketplace time information online to authorities and patients of pharmaceuticals manufactured in India. At the moment, more than 2000 pharmaceutical export manufacturers are estimated to be uploading production-level data for millions of drugs to the system, and this number is expected to grow over the next few months. Getting on board with all the recent legislation was a big motivation for the Indian Government – and they’re not the only ones. Stryker, one of the world’s leading medical technology companies, recently began an implementation programme that will see more than 72,000 of their products become GS1 compliant by 2018. Their main drivers were the advent of the FDA’s UDI Final Rule and the NHS eProcurement strategy – which meant that they, along with all other medical suppliers, needed to update their product labelling to comply. They saw this as an opportunity to standardise all their product identifiers and barcodes – making life easier for their customers and increasing efficiencies in the healthcare supply chain. The organisation first needed to identify the product data owners within the company – a vital step to ensure accuracy and consistency. Once done, they developed sustainable business processes to harvest and consolidate different product attributes into a new product master data system. This approach then created one source of truth for their product data. Standards are crucial to anticounterfeiting legislation and the future of healthcare in general. The Department of Health recognised this in their eProcurement strategy and, whilst many Acute Trusts in England are just making a start, some are already reaping the benefits. Cambridge University Hospitals NHS Foundation Trust was the first hospital in the UK to introduce GS1 standards for the identification and tracking of mobile medical devices using RFID (radio frequency identification) technology. They had identified a problem tracking mobile medical devices and were spending unnecessary time manually locating and recording each device – time that should have been spent focusing on their core tasks of maintenance, repair and delivery of medical devices to the wards. And because equipment couldn’t always be found, additional stock was held, or ad 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

hoc equipment purchased at short notice. In fact, new devices were regularly purchased unnecessarily to replace lost, misplaced and unusable equipment. To solve this, they introduced RFID to automate the process of tracking mobile medical devices and, in order to comply with GS1 standards, they decided to relabel and identify all medical assets with a unique GS1 number. The labels contain a GS1 DataMatrix 2D barcode and also a GS1 compliant RFID tag. This means medical engineers can now travel around the hospital using a specially designed trolley fitted with powerful RFID readers to perform equipment searches and audit wards. With a read range of up to 11 metres, these trolleys automatically record the date, time and location of any tagged devices within range. They also have a small mobile handheld reader with a read range of six metres – used when they perform specific equipment searches or to audit wards. This enables the team to capture asset location information quickly and efficiently. A web-based application then allows users such as nurses and engineers to perform a location search to see the last known location of a device. History reports also show where an asset has been over a defined timeframe. Cambridge University Hospitals NHS Foundation Trust are saving time and money but, most importantly, their new system gives them the data they need to make their hospitals as safe as possible for patients. Bringing all devices under the control of a central system highlighted a number of potential patient safety issues. One example is that the A&E department used to have specific settings on syringe drivers and this sometimes caused problems when these devices were moved to a ward with staff who were unfamiliar with these settings. Now that they know this, all 475 syringe drivers are on a generic setting and staff have been trained to use them. Certainty of Truth What all this data gives us is certainty of truth – we know where drugs and medical equipment have come from, we know who has administered them and we know who they’ve come into contact with. In terms of preventing counterfeit drugs entering the supply chain, and recalling faulty products when they do, it doesn’t get any better than that. The consistency

and accuracy of the data available also means greater efficiency and product visibility throughout the supply chain. As we’ve seen, this reduces wastage, lowers the costs of product recall and enables compliance with forthcoming anticounterfeiting and traceability legislation around the world. The power of this knowledge is clear and ultimately, it gives us a safer healthcare system. Drugs can be tracked from manufacturer to patient, counterfeit drugs are prevented from entering the supply chain and patients can know exactly what medicines and medical devices they’ve been treated with. Manufacturers, suppliers and healthcare providers all benefit, and those not complying will soon get left behind.

Glen Hodgson, Head of Healthcare at GS1 UK, is charged with supporting the NHS and the healthcare industry to deliver a more robust approach to patient safety and greater efficiency through the adoption of GS1 standards. He is a highly accomplished senior executive, with over 15 years of national and international experience, and has served at board level in many operational and commercial roles in the pharmaceutical/healthcare arena. Email: glen.hodgson@gs1uk.org Winter 2016 Volume 8 Issue 4


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Regulatory & Marketplace Regulatory Transformation: Cloud Reality Check

What role can cloud services such as SaaS play in driving the next generation of regulatory information management, and what are the practical considerations for potentially sensitive data? Siniša Belina, senior life sciences consultant at AMPLEXOR Life Sciences, reports from a recent industry debate The need for regulatory information management (RIM) transformation is driving new interest in cloud services, particularly access to the latest applications via software-as-a-service (SaaS) delivery models. But there are different approaches to the cloud, and regulatory priorities to consider, so it is rarely a straightforward decision. With this in mind, life sciences digital content specialist AMPLEXOR Life Sciences hosted an independent panel debate session, with audience participation, at its annual life sciences industry conference in Salzburg.

14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The aim was to sort the fact from the fiction, the pros from the cons; and to establish the best approaches to cloudbased solution and service provision in this heavily controlled industry. The discussion brought together some of the most experienced regulatory experts and consultants from the sector: Romuald Braun of uanotau; Peter Brandstetter of IBM’s GBS Life Sciences team; Torben Thorhauge of NNIT; and Steve Gens of Gens Associates. Steve Scribner of consultancy The Scribner Group chaired the session. Current Cloud Adoption Steve Scribner (SS): Is cloud now seen as standard on vendors’ requests for proposals and, if so, to what extent is that a serious intent for pharma organisations (as opposed to just curiosity)? Torben Thorhauge (TT): We do see

it being specified or included as an option. Sometimes it’s just to see if there is a price difference, but in other cases there is very serious intent. Often we end up providing hybrid cloud services – dedicated solutions but with a cloud payment and cloud deployment model. And if you broaden out into other areas, such as innovation around the internet of things (IoT), then pharma companies are definitely looking to the cloud. SS: Traditional pharma has always followed the regulatory requirement to protect data and be accountable for this, with companies creating quite a firewall around themselves. I wonder if regulators have changed their minds at all, with regard to what’s expected of organisations? Steve Gens (SG): No, they haven’t! But their issue is whether data is sufficiently secured – irrespective of the deployment

Winter 2016 Volume 8 Issue 4


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Regulatory & Marketplace model. Our findings show a growing acceptance among life sciences companies that cloud service providers can help this cause. I’ve pulled survey data from 53 companies in relation to cloud/SaaS. Between 2014 and 2016 the number using SaaS had risen from 9 to 15, and half said the SaaS environment is proving better for access and security than internal firewalls and systems. That’s a pretty big statement. SS: In fact, the FDA is encouraging the industry to investigate cloud, which shows that the perception of control is changing. When to Choose the Cloud SS: What preparations might companies need to make before they can move to the cloud? How important is it to introduce greater harmonisation in the global business first? Romuald Braun (RB): Some of this depends on the ‘flavour’ of cloud, but in general this is an evolving process so there is no need to standardise everything before you can take advantage. Yes, we need to think about how we’re going to use the cloud, but in five years, harmonisation could look very different. SS: Peter, can you tell us about the drive to use the cloud to support innovation? Peter Brandstetter (PB): The cloud is key to a lot of activity around big data – where this comes from a lot of different sources. This just doesn’t work without the cloud. The key driver is to make all of this data available in an effective way so it can be analysed all together, collaboratively – not only within but across company boundaries. SS: Does this need a lot of preparation, to be able to extract that kind of value from the cloud? Sinisa Belina (SB), Senior Life Sciences Consultant, AMPLEXOR (member of the audience): A lot of people are using the cloud already without even thinking about it, in the form of Google Docs for example. I don’t think it matters to the user. TT: At a recent conference on digitisation and digital disruption, there were some success stories around innovation and IoT. Companies were approaching this by establishing temporary groups, 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

independent of the established lines of business, to enable new thinking around the implementation of new technologies. Compromising Control SS: I’ve been involved in content management in pharma for 24 years and I’ve found that companies like to have control, and the ability to tailor systems based on their own culture or preferences. If they move applications to a multi-tenanted cloud environment [i.e. one used by other companies], won’t that limit the options for custom configuration? RB: There are obviously pros and cons to a multi-tenanted set-up, and one of the challenges is how you manage variety. Multi-tenanted cloud environments are used extensively to get fast, easy access to functionality. But when it comes to creating a submission, or reacting to adverse effects – something which could trigger changes to 5000 products in 50 countries – you can’t address that with simplicity. Although 80% of your process might be the same as another company’s, do you really want to be reduced to a one-size-fits-all scenario? Elvis Pacelat (EP), VP Life Sciences, AMPLEXOR (audience member): What is the definition of a multi-tenanted cloud when you’re talking about an enterprise application? RB: Good question! Ultimately it’s about resource sharing, but in every system there is an element of that – even in a private cloud, where you’re sharing a virtual infrastructure. Pinpointing the Value SG: There is a lot of confusion around all the different cloud and SaaS variations. We’ve seen that in our surveys, so we tend to look beyond the differences to focus on the value being delivered. For example, of the 15 companies which said they are using SaaS (i.e. the cloud) this year, two-thirds saw faster product innovation going down this route versus using internal systems, and close to 60% saw the time to implementation improve by nearly 50%. That’s due to standardisation at the application and process layer – for example of the clinical trial master file, and common practices. The issues of whether it’s a private or a multi-tenanted cloud is just an implementation or cost decision. PB: At the moment, companies might share the same application but they use different data. In the future we’ll

see companies share the data too. With Watson Health we’re already seeing pharma companies providing and sharing data across organisational boundaries. SS: It was GSK that started this a couple of years ago, opening up clinical trials to a large population for access – it’s a different but interesting trend. Regulatory Considerations SS: What is the implication of shared responsibility in a cloud environment and how far can you reach into the service provider to influence this? TT: Ultimately it’s you who remains responsible to the authorities for the data and for compliance, so it’s up to you to choose the right provider and be able to show they are compliant. That means having the right conversations so they understand what’s needed, and auditing them to ensure they follow specific procedures. SS: Other factors will determine what you need in a service – for example if you’re using it for something time-sensitive (e.g. to support a new marketing application), any disruptions caused by upgrades will be an important consideration, probably leading you to choose a private cloud. TT: There will always be a range of cloud variations to meet different conditions and levels of criticality. I don’t think we’ll see the Utopia of one definitive cloud environment. We’ll continue to see a mix, and hybrid environments which even include on-premise solutions. The challenge is to bring everything into that hybrid. There will be lots of complexity to manage in the future. Which Cloud to Choose SS: It might be an idea to map out which applications lend themselves to a multitenanted cloud, now that we have an idea of its potential limitations? Does anyone have any guidance on this? RB: The scenarios where it may not be ideal are for business-critical applications, or where you need to be sure of high performance. A private cloud may be best here. Or perhaps if you’re having trouble convincing staff that SaaS is the best route, or if you need to do a lot of configuration/alterations to the system to adapt it for your specific needs. TT: Another consideration is the country Winter 2016 Volume 8 Issue 4


Regulatory & Marketplace

Data Sovereignty An audience member: What about the issues of different countries’ security requirements, and trans-border data flow? RB: There are some standards to look for, but I would look at which location has the highest priority (the primary region for your data) and the highest security requirement and meet that, setting parameters for where your data can be. TT: And remember that these restrictions won’t apply to all data. But do be thorough in your evaluation of the service provider’s set-up: don’t assume that just because they are located in Europe that the data will necessarily stay there. They may have subsidiaries or partners in other regions which they use to balance demand. PB: The right solution will be out there; it’s just a case of digging deeper. and the regulations, including any limitations on where data can reside and who can access it. Again, I would probably choose a private cloud if personal data is involved. PB: Real-time or near-real-time systems such as manufacturing execution systems probably don’t lend themselves to a multitenanted environment either. I would say it isn’t really possible to put such systems into the cloud. SS: We hear a lot of myths and marketing hype about the cloud – is this a deterrent, slowing down adoption? TT: The perception that something isn’t secure if it’s in the cloud is out of date. Some enterprises may have an internal IT department the size of a service provider, but even so, the economies of scale, the automated processes, and the high security providers these specialists have to have (because they can’t risk downtime or data loss) make for a strong proposition. So we need to try to change the mind-sets of QA departments when it comes to provisioning IT. Migration Considerations SS: Is the scale of the migration a factor in the decision? SG: It doesn’t really matter: it’s about 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

moving it from point A to point B. EP: I would agree, but what about the physical distance between A and B? SG: It could make a bit of difference for content management, but with advances in telecoms it’s less of an issue now. In fact, one of the benefits for affiliates is readier access. Something else to bear in mind is that even if you run something in your own data centre, the chances are that this isn’t actually local, or that it has been outsourced to a third party. So is that really so different from the cloud when it comes to ensuring performance, access, security and so on? It’s still connected over a network. TT: One of the benefits of cloud-enabling applications is that they then become easier to move in the future. An audience member: I’m building business processes for RIM without really factoring in whether this will happen via the cloud or not. Is that a mistake? PB: You probably need to reconsider the processes in that light, just to make sure you’ll get the full benefits of the delivery platform. One of the advantages of a cloud-ready strategy is that it encourages you to move away from more localised thinking towards greater harmonisation, supporting business change on a more global basis.

Continuing the Conversation As the debate drew to a close, the more reticent cloud evaluators in the room appeared to be in the minority, amid a growing acceptance that cloud does seem to be the answer to a lot of the challenges currently facing life sciences regulatory affairs and quality assurance teams, as well as their counterparts in other business functions. It will be interesting to see how far the debate has moved on in a year’s time.

Siniša Belina is senior life sciences consultant at AMPLEXOR Life Sciences. He started his professional career at Pliva (now a member of the TEVA Group), where in addition to his responsibilities in manufacturing, he also engaged in successful EDMS implementation projects. Belina later joined KRKA’s Regulatory Affairs Department, and finally moved to AMPLEXOR. He applies his detailed knowledge of pharmaceutical documentation and processes to areas of business process analysis and EDMS optimisation. Web: www.amplexor.com Email: sinisa.belina@amplexor.com Winter 2016 Volume 8 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


Regulatory & Marketplace

Tipping Point: The Regulatory Year in Review As big an issue as it has become, compliance is the least of life sciences companies’ concerns as 2016 gives way to 2017. But the right approach will equip companies to successfully navigate everything from market consolidation and new market entry to marketing innovation and operational transparency, which will set them in good stead for years to come, says Adam Sherlock, CEO of ProductLife Group. When we look back on 2016 and 2017, we’ll see a defining moment in the life sciences industry’s history. It isn’t only globalisation, market consolidation, and intensified regulatory scrutiny that have forced companies to take stock of their strategies and processes. The entire market is being shaken up, as innovation and digital transformation become all-pervasive by challenging existing business models and urging organisations to become more open, more cooperative, and more attentive to consumers’ changing priorities.

quickly, and safely. Being able to share the information securely and reliably, meanwhile, is the key to innovative new collaborations, effective supply chain management, and the increased transparency that both the public and market regulators demand. So, it has never been more important to get all of this right. It’s no coincidence that life sciences organisations are currently bolstering their regulatory teams and that relevant skills are in growing demand. But rather than focus on individual regulatory requirements, it’s important that companies keep in mind the bigger picture—meaning, the wider advantages of honing their information management strategies.

To be a dominant player for the next decade or more, a company has to be doing a lot more than ticking boxes. It has to be breaking new ground, forming new alliances, and challenging existing assumptions. Developing and selling more products is no longer enough. There are other trends to assimilate: preventive, collaborative healthcare, wellness, and nutrition in the form of nutraceuticals are just a few of them. The fact that the life sciences industry is heavily regulated and traditionally conservative does not make it immune to disruption, so companies must arm themselves for whatever may be coming over the new horizon.

IDMP: An Important Milestone in Data Management For much of 2016, pharmaceutical companies have been keenly focused on developments around the identification of medicinal products (IDMP) set of standards. Although the initial July 2016 deadline gave way to a more gradual, iteration-based approach to implementation, IDMP has remained an industry priority—as indeed it must. IDMP has a broader set of ambitions than previous standards for drug data management had, which encourages companies to become more systematic and comprehensive in their data recording and handling. IDMP also presents a range of new benefits that companies will become able to exploit for their own purposes if they approach this cleverly.

Those, then, are the broader challenges that strategic decision-makers must ponder as the current year draws to a close and the new one dawns. Companies must be bolder and more dynamic; vigilant yet expansive; steadfast but different. It may seem counterintuitive that the administrative detail of regulatory information management (RIM) should hold the key to much of the foregoing, but it does. Being in control of critical operational data is essential to getting products to market—efficiently,

The transition to the new requirements is taking time, but that’s a good thing for those that want to transition properly. The European Medicines Agency’s (EMA’s) initial priority has been to nail down the higher-level aspects of the IDMP data standards such as (1) the standards referring to the organisation itself (e.g., contact details and details about individuals responsible for various aspects of a medicine) and (2) referential data, which provide controlled vocabularies for a medicine’s dosage, pharmaceutical

20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

forms, country codes, package codes, and weight codes. Details regarding the ways that data about products themselves and their constituent substances will have to be described have yet to be set forth. The latest expectation is that associated sets of guidance will be issued during the first or second quarter of 2017, with implementation due to begin a year later and become mandatory 18 months after that. Despite the constraint, companies are advised not to sit back and wait— especially given the amount of work involved in gathering and preparing data to make sure it is tip-top, clean, and accurate and has the greatest potential for strategic reuse. (One of IDMP’s defining principles is to achieve a very high quality of master data, thereby ensuring maximum integrity once the information is live and in use.) The indications are that many of the larger and mid-size companies are indeed taking a more proactive approach to IDMP—perhaps having learned from the problems that arose with taking a last-minute, tactical approach to its predecessor, the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD). A survey of 29 companies by non-profit group Implementation of Regulatory Information Submission Standards (IRISS) (https://www.iriss-forum.org/news/ iriss-publishes-the-results-readinesssurveys-for-idmp) suggests that a sizable majority (79%) now have IDMP projects under way. The survey also indicates that IDMP project support from senior management has grown: 52% of survey respondents confirmed that projects now have that level of commitment and buyin. Going Further: RIM as the Key to Business Agility With XEVMPD, there was never a clear understanding of what the standard was for, so several companies did not fully exploit the standard internally—such as for their own internal purposes. But any groundwork they have done with regard to XEVMPD is going to help them now, because iteration 1 of the new, IDMP standard uses a lot of the same Winter 2016 Volume 8 Issue 4


Regulatory & Marketplace data fields, which can now be built on. And the evidence seems to suggest that companies do want to achieve more than simply meeting compliance requirements with IDMP: in the IRISS survey, 79% of companies claimed to be using IDMP to improve internal processes. That’s reflected in the way companies say they are approaching regulatory information management now. In a 2016 survey called Pursuing World-Class Regulatory Information Management (RIM); Strategy, Measures and Priorities, Gens & Associates found that companies are redoubling their efforts to improve global information management as a means of (1) boosting their own decisionmaking, (2) accurately and rapidly managing health authority submissions, and (3) enhancing communication as well as the quality of data they share with stakeholders. To that end, 70% of the 54 companies Gens surveyed said they’re undertaking transformational or incremental change to a number of RIM capabilities in order to improve their submission management activities, enhance reporting and analytics, and

strengthen change control processes. But many companies clearly still have a long way to go to realise business benefits from their efforts: as few as eight companies in the survey claimed to have achieved a significant number of those benefits at this stage. The way companies approach RIM varies significantly, but what’s now evident is that companies that adopt a common platform for regulatory information management (aligning the whole business around a RIM programme) enjoy greater business benefits than do those with disparate RIM capabilities. In the Gens survey, organisations with common capabilities were on average 18% more efficient than peers with disparate information management capabilities, confirming that a strong, corporate-wide approach to RIM presents greater potential return on investment. (One Aspect Of) The Bigger Picture: Pharmacovigilance Two of the primary reasons that regulatory

requirements are becoming stricter and farther-reaching are the need to provide maximum levels of patient protection and the need to keep raising the standards consumers can expect. Safety inspections have been intensifying in Europe in recent years, with pharmacovigilance processes and the pharmacovigilance quality system under the microscope. For risk management reasons, including brand reputation, life sciences companies now recognise safety as a high priority, and they’re investing more resources in pharmacovigilance departments. But the greater attention paid to safety doesn’t involve only meeting health authority requirements. Discussions at conferences and pharmacovigilance meetings during the past year suggest that companies are increasingly bringing safety leaders into the inner sanctum during product and portfolio discussions and analysis. Differentiation of marketed products has become a challenge for many companies, and safety is increasingly seen as an advantage. Developing a product that has fewer side-

Product News Sartorius Stedim Biotech presents Virosart® Media First risk-mitigating virus-retentive filter for cell culture media Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, has launched Virosart® Media for virus retention in cell culture media. With this new media filter, the company offers a fast and cost-effective solution for manufacturers to reduce the risk of virus contamination resulting from raw materials, such as chemically defined media, during fermentation.

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of the biggest challenges in today’s upstream processing. ”In the past, downstream virus filters have been used in upstream processing as there were no other adequate solutions available. Our new membrane filter Virosart® Media finally closes this gap in the market,” stated Birte Kleindienst, expert for viral clearance at Sartorius Stedim Biotech.

Virosart® Media lab filter with a filtration area of 5.0 cm2. customers’ upstream processes as it is qualified for > 4 log10 reduction of small, non-enveloped viruses (e.g., MVM) and as a mycoplasma and leptospira retentive filter. A major benefit of this new filter is that midscale and process filters of the Virosart® Media product family will also be qualified as a sterile filter based on the current ASTM guideline. The first product of the Virosart® Media family is a lab filter with a filtration area of 5.0 cm2 for down-scale, flow and capacity studies. The mid-scale filter with 0.29 m² and the process filters with 1 m² and 3 m² will follow in the second half of 2016.

By launching Virosart® Media filter, SSB rounds out customers’ individual risk mitigation strategy in upstream processing with an additional option: With the filters Sartopore® 2 XLG (0.2 μm) for sterile filtration, Sartopore® 2 XLM (0.1 μm) for retention of mycoplasma and with its new Virosart® Media filter (20 nm) for virus retention, SSB enables customers to mitigate risk at three different levels. More information: www.sartorius.com/virosart-media Contact: Sartorius Stedim Biotech GmbH August-Spindler-Str.11 37079 Göttingen www.sartorius-stedim.com

Providing superior filter capacity for cell culture media and high patient safety is one INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace effects and can be tolerated more readily has significant marketing potential. The field of oncology has been a leader in developing safety-focused products whose objective is to directly target a tumour rather than blast a patient with chemotherapy treatments. For example, researchers at Immunomedics are investigating an antibody and chemotherapy regimen called sacituzumab govitecan (IMMU132) for the treatment of triple-negative breast cancer. The benefit of the treatment is that without causing serious damage to surrounding tissue, it targets the Trop2 protein expressed in many cancers. Whether during new product development or during appraisals for acquisitions of companies or portfolios, safety is playing an increasingly important role in decision-making and information-sharing far earlier in the process than it used to. Again, information management becomes the lynchpin by facilitating

companies’ best efforts in this field. And the more robust and reliable the original master data, the more of a head start companies can have and the greater the return on their information management investments. This is a situation that can only grow too. In response to a new goodpharmacovigilance-practice requirement to more carefully monitor the internet, including social networks, companies also are placing more emphasis on big data in efforts to gather information about the real-world use of a drug. That trend presents many complications for industry, including the challenge of how to monitor and manage comments made on social media about a drug. Finding ways to navigate the requirement is likely to become a greater priority in 2017.

life cycle and pharmacovigilance activities—in favour of their taking on a more strategic and commercial role. That shift has become more pronounced during 2016. Evidence of it includes increased outsourcing of submission publishing in countries with affiliates, which is a growing trend among midtier and small life sciences companies, according to Gens & Associates. Larger firms, too, are seeking to take more standardised and less-resourceintensive approaches to information handling, even as they seek to expand their footprints in certain key markets by developing strategic insights that will improve local knowledge and expertise and strengthen their relationships with health authorities.

Organisational Changes: The Role of Affiliates Another thing with a bearing on the ways companies manage information is the push to distance affiliates from operational issues—including regulatory

To support the shift, more and more companies have begun to explore a range of outsourcing options so as to supplement their own on-the-ground experts. LEO Pharma and AbbVie are among companies that have talked openly about outsourcing’s potential to clear head space for affiliate teams, so they can focus on higher-level activities and commercial performance. New Product Tactics Information management for its own sake can take companies only so far. Companies must also think outside the box if they’re going to stay ahead in their markets—especially in today’s climate of disruption. Just as generic drugs are gaining ground, there is a growing trend towards biopharmaceutical drugs which are designed to have active properties similar to products licenced previously. Biosimilar products have been in the news during 2016, helped by the US Food and Drug Administration’s approval of Celltrion’s biosimilar version of Remicade (infliximab), the first monoclonal antibody biosimilar to be approved in the United States. Other biosimilars have also been approved since then. (Biosimilars have been on the market in Europe for more than a decade, and they’re now gaining ground in many countries of the European Union as more information about their safety and efficacy becomes known.) Biosimilars’ appeal is that they give patients greater access to life-saving medications while providing significant cost savings compared with the reference biologics. Innovation around biosimilars is expected to result in so-called biobetters—products that are in fact superior to the original products because

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2016 Volume 8 Issue 4


RegulatoryManufacturing & Marketplace method: Method A – Membrane Filtration of improved targeting, efficacy, or safety changes and trendsTestwill intensify in Even if some of the detail is still For aqueous solutions: The method calls for the routine use of positive and negative controls. profiles. 2017—especially as the next sets of sketchy, by having a solid starting point, Aseptically transfer a small quantity of fluid A on to the membrane and guidance around IDMP get issued and companies will have a better chance of filter it. Transfer aseptically the combined quantities of the preparation Apparatus: Although is still early days as weakly companies sharpen focus on getting where be.membrane. undertheir examination prescribed in the two they medianeed ontoto one Cellulose nitrate itfilters arerelatively used for aqueous, oily and alcoholic and more work is needed to educate— how data gets managed across their solutions, and cellulose acetate filters are recommended for strongly and build acceptance and confidence enterprises. Those things will affect If the solution under all examination has antimicrobial properties, wash the alcoholic solutions. among—physicians and patients, of the functions across a life sciences membrane(s) by filtering through it (them) not less than three successive each of 100 ml, of sterile fluid A. Diluting Fluids: (IP, BP): of biosimilars and organisation, as well quantities, the development as far-flung affiliate Fluid A: Dissolve g of peptic digest of animal tissue (such Adam Sherlock is microbiologist biobetters could1 have a major impact operations. Theas abilities to maintain by times degreeor 200 and ml, a even business Doinnovation not exceedand a washing cycle of five if it bacteriological peptone) or its equivalent water to make 1 litre, filter as life sciences companies look forinnew differentiation through to development been that such professional a cycle does by not oropportunities centrifuge to clarify, adjust to pH 7.1 speed ± 0.2, dispense into flasks in to has to increase their have easy access data thatdemonstrated can help during validation career,.Adam is a twenty-sevenfully eliminate the antimicrobial activity. The quantities of fluid used 100ml quantities and sterilize at 121° C for 20 minutes. to market, improve cost efficiency, and substantiate product claims or respond to veteran of the software and should be sufficient to allow growth ofyear a small inoculum of organisms sharpen their competitive edge as past health authority questions are just as vital. lifeantimicrobial sciences industry. In 2012 substance in he the Fluid B: If the test sample contains lecithin or oil, use fluid A to each litre (approximately 50 CFU) sensitive to the was named to the PharmaVOICE becomes guarantee 80,If adjust 2016towas a challenge operationally, presence of the residual inhibitory material on the membrane. of performance which has been added less 1 mlofofapolysorbate pH 7.1± which recognises the 100 most influential of dispense future prosperity. is yet atanother 2017 is 100, After filtration, aseptically remove the membrane(s) from the holder, 0.2, into flasks andIt sterilise 121° C forstrategically, 20 minutes. and commercially, people in the life sciences industry. scenario wherein a solid, supporting likely to be a tougher one. With digital transfer the whole membrane or cut it aseptically into two equal parts. As CEO of ProductLife Group, Adam is regulatory information on the agenda Transfer one half to each of two suitable Incubatedirection the media for Quantities of sample to be used:management transformation solidly responsible formedia. the overall and not less than days. management of the company, partnerships Forstrategy parenteral preparations: could pay dividends by collating across all industries—not least14health Whenever possible, use contentsdata of the container, but in any and coordinating allthe of whole the product and medicine—innovation will continue and M&A strategy. Prior to ProductLife Group, Observe the containers media periodically during of themarketing 14 days &of case not less than the quantities prescribed in Table to 3(E),bediluting held roles as director involved. highwhere on that agenda for life ofAdam incubation. If the test specimen is positive before 14 days of incubation, necessary to about 100 ml with a suitable diluent such as fluid A. strategic business development at CSC Life sciences, challenging companies to push Sciences and Vice President Global Sales & further incubation is not necessary. For products terminally sterilised by Embracing Change—The Only Constant themselves to the next level, not just with Marketing at ISI. a validated moist heat process, incubate the test specimen for not less For ophthalmic and other non-parenteral preparations: The past year has forced life sciences regard to product development but also Adam holds a Bachelor of Science in Applied Take an amount within the range prescribed in column (A) of Table than seven days. companies to confront manythanwith regard toand the ways their businesses Biology from Liverpool University. 3(E), if necessary, using the change contents on of more one container, Email:asherlock@productlife-group.com fronts—from the routine to the more operate, collaborate, and set themselves liquids immiscible with aqueous vehicles, and suspensions: mix thoroughly. For each medium use the amount specified in column For www.productlifegroup.com ambitious. ofsample. those apart from one another. Carry out the test described under for aqueous solutions but add a (B)strategically of Table 3(E), taken from theAll mixed sufficient quantity of fluid A to the pooled sample to achieve rapid filtration. Sterile enzyme preparations such as penicillinase or cellulose

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Regulatory & Marketplace

The Devil in the Detail: Five Routine Recall Risks Faced by Modern Pharma Growing complexity in life sciences is raising the risk of product mislabelling, potentially putting lives in danger and leaving companies open to hefty fines and delays in product availability, warns Marc Chaillou of Schlafender Hase

symbols used, to the agreed wording and accuracy of local translations. Trying to fulfil all of these conditions while containing the risk of error or omission is to navigate a minefield. It has become a full-time job.

With the steely eyes of the regulators firmly trained on everything that life sciences organisations do, the last thing firms want is to incur fines, market delays or worse because of overlooked mistakes in labelling and product information. Yet incidences of labelling issues and associated product recalls are rising sharply, now accounting for over 50% of all recalls, according to the FDA. The conditions are rife for the trend to continue, due to growing complexity in life sciences firms’ operations and external market requirements.

Meanwhile public pressure, enforced by industry regulators, is driving new demand for transparency on everything from clinical trials and manufacturing processes, to more detail about what goes into modern drugs and how sustainable and ethical an organisation’s practices are. All of this has a bearing on what companies need to say about themselves, where and how. Labelling requirements are far from static.

Below are just some of the scenarios that are driving up the risk of labelling errors, with potential for regulatory intervention or danger to human life. 1. Increased Market Volatility The make-up of the life sciences industry is changing1. As a result, traditional firms are looking at a range of strategies to reduce their reliance on blockbuster drugs and staple revenue streams, while maintaining market share and profits. Approaches include expansion into additional and emerging markets, the addition of new product lines, new forms of collaboration, and increased merger and acquisition activity2. Digital transformation is rising up the agenda, as well as the need to adapt to new sweeping trends such as wellness and preventative medicine (including digital health)3. More personalised care is resulting in growing demand for drug personalisation, resulting in smaller batch numbers. All of these scenarios are putting pressure on drug labelling, which is becoming increasingly complex to manage as the numbers of markets, sales channels, product lines and variations continues to multiply. Each new sideline, each new market, has its own special requirements for labelling – from the claims made and 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2. Image Updates (Rebranding) Companies rebrand themselves all the time. This could be the result of a merger, an attempt to refresh the organisation’s image or distance itself from previous associations, or to appeal to new markets abroad if the old name doesn’t work well in other languages or cultures. In some cases, the only significant change to labelling will be the company logo but this still needs to be managed efficiently on products. Actavis, for example, changed its logo after buying Watson Pharmaceuticals in the US, merging with Warner Chilcott and purchasing Forest Laboratories. Some divisions in Europe were sold to Aurobindo and named Aurovitas; others were sold to Teva and the remaining operations changed their name to Allergan. The changes were necessary, but had wide implications for label management. 3. New Regulations The regulatory climate for life sciences is intense and becoming more so. The EMA and FDA in particular are continuously updating and refining requirements to improve patient safety and corporate accountability, while striving to make conditions and output more uniform across markets. Each year there are a raft of new requirements to fulfil or work towards, while Britain’s plans to exit the EU are creating their own complexities for the industry, its regulators and those

manufacturing in or targeting UK and European markets4. Legal specialists report that there has been a marked overall increase in the amount of regulation in a number of areas, particularly in relation to the marketing and promotion of drugs and devices5, and off-label claims which, in the US, are currently the subject of some legal wrangling. All of this has a bearing on labelling and the scope for falling foul of the latest requirements, especially as long as these differ from one market to the next. Each time new requirements are introduced, or existing terms updated, life sciences manufacturers and distributors must change or update the content of their product labelling, increasing the risk of something falling through the cracks. 4. Track & Trace: Serialisation Requirements/Anti-counterfeit Measures As markets have opened and become more global, regulators have had to work harder to stay ahead of would-be counterfeiters, to maintain product quality and authenticity, safeguard consumers and maintain public confidence. The result is that products now need to be more traceable, and carry unique serial codes that adhere to a particular format. Under the Drug Supply Chain Security Act (DSCSA) in the US6, being phased in over the next three or more years, pharmaceutical manufacturers, repackagers and distributors will need to mark all products with a two-dimensional data matrix barcode comprising the product ID, lot number, expiration date and serial number, enabling product tracing down to an item level. In many cases, the need to incorporate the new data matrix means changing the design of folding boxes in addition to the implications for labels themselves. 5. New Distribution Arrangements and Service Partnerships As life sciences firms become more global in their outlook, they must balance their international ambitions with the practicalities of managing resources, Winter 2016 Volume 8 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 25


Regulatory & Marketplace skills and knowledge across new markets. With uncertain new geographical markets, a company may hold off making a local investment in operations, preferring instead to use a local partner. As well as increasing the organisational/ supply chain complexity, this can also dilute a firm’s control over process continuity, and imposing and maintaining standards. Similarly, outsourcing of routine processes (some pharma and medical device companies outsource labelling and proofreading activities to third parties to save money) can reduce companies’ ability to ensure consistent, compliant labelling, despite the bias towards local market knowledge. Introducing additional layers and additional parties can also make it less clear who is ultimately responsible for quality control and regulatory compliance, leaving companies open to risk. Attention to detail is likely to vary according to who is in charge, who they report to, and what their immediate key performance indicators are. This is despite the fact that the risk of exposure to penalty, market delay and reputational damage – if products are mislabelled for a target market – is of central, corporate concern. If an organisation’s name is on the product, the consequences of an error will always come back to the HQ of the brand owner, no matter who is actually at fault. Ultimately, the impact will be on the main company’s brand, reputation and stock price. Standard operating procedures must be extended right across the international organisation, while spanning any commercial or supporting service partners, if life sciences firms are to protect themselves fully against the dangers of product mislabelling. Why Take the Risk? The more complex life sciences operations become, the greater the temptation to allocate more resources to checks and cross-checks. Yet, no matter how many people are involved in the proofreading process, humans will never pick up 100 per cent of errors. And often it is the smallest omission or typo that proves to be a company’s undoing. People make mistakes. Even with two sets of eyes on a document, proofreaders can develop blind spots – either because they’ve looked at the same content for too long, or because the task is so repetitive 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and unstimulating that the brain has become distracted7. Yet even the smallest editing or artwork oversight can have serious consequences: for example, the difference between “store this product at 2-8°C” and “store this product at 28°C”; “take 1-2 a day” and “take 12 a day”; or “do not chew and swallow” and “do not not chew and swallow”. So these are risks companies can’t afford to take. In a brutally competitive market, time is money. If you set two copies of the novel Huckleberry Finn side by side, each 500,000 words long but with several subtle differences, it would typically take a reliable text verification tool just three minutes to pick up all of the anomalies. By contrast, a human proofreader would need about a week to complete the same task, with no guarantee they would identify all of the ‘errors’ the first time. Even if a recall is eventually averted by human intervention, discovering an issue late in the process could knock out production lines. And, for each day that a product is not on the store shelves, sales are lost and competitors have an advantage. A further benefit to life sciences organisations in streamlining their labelling processes is the potential to redeploy labour. A survey we conducted in 2014 found that companies that have implemented reliable automated proofing typically save an hour per label or, in the case of multiple countries and languages, a day per product; correction cycles are also significantly reduced. More usually companies with automated proofing save five hours per week on manual document verification. Extrapolating this against the average salary of a specialist regulatory affairs employee (estimated at $85,000)8, this works out at a yearly saving/productivity increase of $13,500 per user. This is at a time when regulatory professionals are in high demand because of all of the other pressures they are currently dealing with. Life sciences firms have enough on their plates at the moment, without making things unnecessarily difficult for themselves. If the devil is in the details, don’t leave it to chance to identify it. References 1. New report highlights changing business models in life sciences sector, Oxford Intelligence, May 2014:

2.

3.

4.

5.

6.

7.

8.

http://www.oxint.com/pressdetails. cfm?id=109&title=New%20report%20 highlights%20changing%20 business%20models%20in%20life%20 sciences%20sector Appetite for M&A activity in global life sciences and health care sector set to increase in the next three years, according to Deloitte survey, Deloitte, October 2014: https://www2. deloitte.com/gt/en/pages/aboutdeloitte/articles/lifesciences-mandatrends-survey.html Disruptive Technologies and Emerging Trends Drive Life Science Transformation, Frost & Sullivan, June 2016: http://ww2.frost.com/ news/press-releases/disruptivetechnologies-and-emerging-trendsdrive-life-science-transformation/ Brexit and the Pharma & Life Sciences industry - there will be change, PwC, July 2016: http://pwc.blogs.com/ health_matters/2016/07/brexit-andthe-pharma-life-sciences-industrythere-will-be-change.html The life sciences, drugs and healthcare industry in 2016 and beyond: trends and predictions, Practical Law, 2016: http://uk.practicallaw.com/2-6280625 Drug Supply Chain Security Act (DSCSA) for Pharmaceutical Manufacturers, GS1 US, October 2015: https://www.gs1us.org/ DesktopModules/Bring2mind/DMX/ Download.aspx?command=core_dow nload&entryid=1298&language=enUS&PortalId=0&TabId=785 What’s Up with That: Why It’s So Hard to Catch Your Own Typos, Wired.com, August 2014: http://www.wired. com/2014/08/wuwt-typos/ RAPS.org: Salary Calculator: http:// www.raps.org/jobs-careers/salarycalculator/

Marc Chaillou is International Market Manager at Schlafender Hase, provider of TVT (www.text-verification. com), a respected text verification tool for the life sciences industry. He specialises in helping companies prevent packaging and labelling issues, to achieve cost savings and improve essential but routine processes through the use of technology. Email: marc.chaillou@sh-p.de www.text-verification.com Winter 2016 Volume 8 Issue 4


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Drug Discovery, Development & Delivery

Natural Born Killers Immunotherapy is currently one of the most actively pursued areas of research by biotechnology and pharmaceutical companies. “Control of immune activation can save us”, believes Markku Jalkanen, CEO of Faron Pharmaceuticals. At present, the interest in immunotherapy is largely driven by recent compelling efficacy data in cancers with historically bleak outcomes, and by the potential to achieve a cure or functional cure for some patients.

responsible for TAM transformation into tumour supportive cell types. On 30 November 2015, Faron announced findings that showed the active pharmaceutical ingredient of Clevegen (humanised anti-Clever-1 antibody) increases Th1-lymphocyte mediated immunity (Palani et al., 2016). This may indicate that Clevegen binding initiates a process that results in conversion of pro-tumoural M2 macrophages to proinflammatory M1 macrophages.

Faron's second most advanced drug development project, Clevegen, revolves around Clever-1, an endothelial cell surface molecule involved in cancer growth and spread. The active pharmaceutical ingredient of Clevegen is a humanised anti-Clever-1 antibody.

Recently, the Company has expanded the development strategy for its novel cancer immunotherapy candidate and filed patents which have opened up new application opportunities for Clevegen, in conditions where removal of suppression of local or systemic immunity is desirable, and now aims to extend the range of Clevegen indications through a technology platform called `Tumour Immunity Enabling Technology` (TIET), which can be used alone or in combination with other immune checkpoint molecules.

The innate immune system has a highly complex role in the progression of cancer, as all tumours are infiltrated by immune cells, for example macrophages, neutrophils, T cells, dendritic cells, mast cells, myeloid derived suppressor cells and natural killer cells. Depending on the immune cells stimulated and activated, they can either have a protective effect for the host through suppression of tumour growth or a deleterious effect by promoting tumour growth, invasion, metastasis and angiogenesis. Tumour associated macrophages (TAMs) have emerged as an essential constituent of the tumour environment, with influence over many aspects of cancer such as proliferation and survival, as well as interaction with surrounding elements (angiogenesis, escape from anti-tumour specific immunity). When TAMs populate a tumour, one of the very significant influences they exert over it is a strong increase in immune suppression. And Clever-1-positive TAMs represent one major macrophage population involved in the elimination of host immune activity against the tumour cells. Clevegen is an anti-Clever-1 antibody which targets Clever-1-positive TAMs in cancer patients. This antibody has two significant ways to intervene in the TAM role in tumour growth and spread: prevent TAM infiltration into a tumour and block TAM-to-Tumour cell interaction 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“It all comes down to Clevegen`s ability to convert pro-tumoural M2 macrophages to pro-inflammatory M1 macrophages, helping the immune system to combat cancer. But at the same time, the removal of immune suppression caused by M2 macrophages could provide a significant boost to the efficacy of other immune checkpoint molecules already in use or under development”, explains Dr Jalkanen. The innate immune system has a highly complex role in the progression of cancer and multiple mechanisms have been identified that tumours use to evade the immune system. Professor David Adams, Director of NIHR Birmingham Liver Biomedical Unit, is examining the role of chronic inflammation in promoting liver cancer, and exploring dendritic cell vaccination approaches to target hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is the second leading cause of global cancer deaths and its incidence is rising. Advances in medical treatment have resulted in improved survival for many common malignancies, but not HCC. Since there is good

evidence that HCC stimulates an immune response, immunotherapy represents a potential treatment option. However, despite efficacy in animal models, most clinical trials of tumour immunotherapy have been disappointing in HCC. Professor Adams has a long-standing interest in understanding how leukocyteendothelial interactions regulate the recruitment of effector cells in chronic liver disease. He and his group have defined molecular mechanisms used by the hepatic endothelium to control the entry of leukocytes from the blood into the liver. The researchers have recently begun to use this information to develop new therapies for liver disease by targeting pathways involved in the recruitment of therapeutic cells including dendritic cells, stem cells and regulatory T cells that may be used to manipulate immune responses in patients in vivo. Understanding why the immune response fails to control the tumour is a crucial step if immunotherapy is to become clinically effective. However, emphasises Adams, “one single approach isn`t going to work”. No doubt about it, given the complexity of anti-tumour immunity, to be effective, immunotherapy will need to combine several approaches and target multiple pathways.

Cecelia Stroe - IPI Staff Editor Winter 2016 Volume 8 Issue 4


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Drug Discovery, Development & Delivery Feasibility is not (anymore) A Plain Search for Investigational Sites Conceptual evolution of feasibility studies in pharmaceutical development

The sole term ‘feasibility’ has multiple definitions in a clinical environment, leading to certain bias with all stakeholders involved, including pharma companies (sponsors) and all types of contract research organisations (CROs). The most common perception is related to a never-ending argument between pharma outsourcing departments and CRO commercial groups, with sponsors expecting CROs to run a (non-defined) feasibility study prior to proposal submission and CROs undertaking a series of schematic actions to create an impression of fulfilled expectation. One may expect that the same paradigms are present in every type of project sourcing, starting from the construction business and finishing in niche expert consulting services. The philosophy of the pharmaceutical industry is and will always be designed around the wellbeing of human beings. Unfortunately, the level of competition between pharma providers coupled with an increasing pressure of time- and cost-efficiency poses a risk towards the industry’s core values. Balancing the real subject matter discussion with the need to constantly acquire new business remains a real challenge. CROs, regardless of best will, follow the mainstream by filling in the costing grids and pasting ‘feasibility results’ to their proposals, developed over 5-10 business days, to ensure opportunities remain in their sales tracking systems, hopefully converting into awards. The aim of this article is to systematise industry objectives and measures undertaken to achieve work under the broad term of ‘feasibility’ and to make an attempt to define added value for external stakeholders involved. In addition the author makes an attempt to consider the actual impact of Big Data theme on the clinical trial industry, with potential impact on clinical trial design and site selection strategies. Feasibility Steps Undertaken during Development Lifecycle Step 1 – Business Recognition Following standards of business management, a feasibility study should 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

precede every new development. In the pharma/device industry, first activities typically commence at the level of business development groups. A given candidate is subject to analysis in terms of its market potential, competitive advantage, available benchmarks, and eventually return on investment. For the sake of naming convention these feasibility studies can be called business or commercial ones, and are typically retained within business/commercial groups without involvement of scientists or regulatory teams. In certain cases a business investigation is triggered from a different angle, not by a compound as such, but more by the outcomes of the portfolio analysis. Its conclusions may include missing coverage of a therapeutic area or a signalling pathway. This can even be classified as Step 0, as it will have to lead to target molecule identification and associated mergers, acquisitions or in-licensing processes.

ago. Another opportunity for a feasibility study extension is seeking scientific advice from payers, as a standalone or parallel process with regulatory scientific advice from EMA or national regulatory bodies. There have been examples in the industry, particularly in the area of oncology, where payers required different types of evidence from manufacturers for future evaluation of health technology assessment (HTA) bodies. The standard case is a debate over whether to choose overall survival versus quality of life, as here, regulatory bodies will always consider a different angle than an HTA body. And in the end, the prescribers are the ones to convince as there is still a number of apparent breakthrough therapies which disappeared from the radar following the granting of marketing authorisation. The real-life market never made an effort (consciously or unconsciously) to adopt the drug in day-to-day medical practice.

Step 2 – Therapeutic and Regulatory Science Once the development target is identified and qualified business-wise, some would already consider the big things as having been done, while others are still about to initiate their journey through guidelines, treatment standards and multiple other sources, to work out the best scientific and operational approach for a given product development.

Obviously payers’ advice as a part of feasibility shall be considered only in a selected number of cases. Based on current recognition of its advantages, advice should be sought before finalisation of registrations studies (e.g. Phase III or Phase IIb studies). Apart from standard questions typically stated in briefing documents for regulatory bodies, payers may also advise on economic evaluation (model design, sources of data resource used and utility values).

Therapeutic and regulatory feasibility is irreversibly bound to conceptual work on every protocol outline. Study design and objective selection is no longer a result of accidental decision and pure continuation of the proof of concept stage. Increasing volumes of regulatory guidelines from authorities in ICH regions, and a number of unwritten expectations from leading therapeutic communities, have made study design work more complex than a decade or two

In recent years, regulatory feasibility seems to have included scientific advice as a must. Product candidates like orphan drugs, advanced therapy medicinal products, biosimilars and biobetters seem to be ideal candidates for scientific advice, not only due to lack of benchmarks, but also to seek efficiencies in their development programmes as faster time to market will always remain the guiding principle for the industry. Winter 2016 Volume 8 Issue 4


Drug Discovery, Development & Delivery this class of medicines). While this paper does not aim to analyse the perception of biosimilars, it is just worth mentioning that similar surveys run 5-7 years later were not an operational challenge and the investigator community easily engaged in the dialogues. Contrary to Steps 0-1, when manufacturers typically rely on their own know-how and business intelligence, rarely using market research companies for supportive data collection, Step 2 can be considered for external support. It is very interesting to observe an evolution of the CRO business, which is very aggressively tapping into consulting services, either organically or even more frequently by acquisitions. One could even consider there to be an ethical dilemma when the same organisation is engaged in study design, and then further employed for protocol execution. Wouldn’t the organisation be tempted to encourage a more conservative approach? Every single percentage point in the study lowering the confidence interval may translate to additional dozens in sample size, so the profit will be definite. The other interesting aspect is the question as to whether the actual responsibility for final protocol design lies with the sponsor or the consultant. Within any type of GCP-related activities, the sponsor will never avoid responsibility for its research work, however at the design stage such an assumption is not so obvious. Consulting agreements, on the other hand, rarely include actual liabilities and even if they do, the limits typically set forth are relatively low compared to the overall investment in the ultimate trial. Other common regulatory feasibility opportunities tend to be presented to CROs under the term ‘request for proposal’ (RfP). The product name is disseminated among a number of organisations and as they all strive for either survival or stable growth, there is a good chance the RfP will be properly attacked and the requestor may even receive a ready protocol outline. As stated in the introductory part, opportunities must be advanced to CROs, whatever it takes. There are sponsor companies rejecting discussions with CROs which do not show willingness to perform feasibilities at their own expense, and there are also CROs with business strategies allowing and accepting such a form of business development. Generally speaking, there may be nothing wrong in www.ipimedia.com

such a set-up under the condition that the parties are honest with each other and appreciate that in any business nothing comes for free, defined in economic or relationship perspective. The only practical advice for those approaching multiple CROs for proposals without prior definition of the study design (while expecting a full feasibility assessment for the given product) should be that the quotes collected will never be comparable, and none of the providers will eventually assume responsibility for such a deliverable. In the end it is worth emphasising that regulatory and therapeutic feasibility steps should not only define the study outline per se, but also contribute to an early risk management plan. The party taking over for the next steps should be able to receive a list of perceived issues to be verified or considered when liaising with target investigators and other stakeholders, all to estimate the actual impact of pre-defined risks on study doability and probability of end success. Step 2 alteration – Therapeutic Landscaping: Doability Assessments The term “landscaping” is just like the term “feasibility” used in certain environments with various definitions. Hence the author decided to apply the term “doability”. Following the completion of a scientific exercise, it is advisable to measure its outcomes against the real-life healthcare environment. In the experience of the author, doability studies are run within a representative sample of sites. Biosimilar studies were the first to return very interesting results – although the patient profile and study designs were mirroring originator development, 70 per cent of the sites never returned the results (including the investigators from centres of excellence who directly contributed to setting expectations for

Biosimilar studies are not the only example where the past environment suggested doability prior to going live with global site-level feasibilities. In our recent experience, other candidates are any type of pharmacokinetic trials, particularly those run in paediatric populations. Limited direct treatment advantages from such trials pose a real threat to its successful implementation. Performing a well-designed doability assessment within a carefully selected group of investigators (actually dealing with patients in day-to-day practice) may help to overcome a lot of hurdles and save cost compared to rolling the programme out at full strength upfront. The methodology of a doability assessment should include: • Limited number of investigators / vendors, but of a well-defined profile (practitioners, not absolute scientists) • Proper selection of questions, preferably with pre-defined options of answers • Well-prepared liaisons, preferably with medical background and soft skills enabling feedback acceptance and processing • Avoidance of too high-level considerations; the doability targets should be the ones actually recruiting patients, not those predefining the future position of the drug candidate on the market. In the author’s experience, doability studies performed as extensions to regulatory and scientific feasibilities frequently added value for projects, enabling protocol review, proper shift of geographic focus or even creating evidence for authorities to grant certain waivers in development programmes. The only perceived disadvantage of targeted doability exercises is the impact

INTERNATIONAL PHARMACEUTICAL INDUSTRY 31


Drug Discovery, Development & Delivery on the overall protocol outline. There are cases of feedback clearly challenging the study design and geographical positioning, which is often difficult to accept for regulatory scientists. As an example: rifaximin clinical endpoint bioequivalence studies are imposed by certain authorities to be run in a travellers’ diarrhoea population, despite its limited availability for actual inclusion in a clinical trial. In such cases one could consider reordering the feasibility steps sequence to use the feasibility data for scientific consultations with regulators. Otherwise negative (or at least problematic) outcomes of landscaping activities, if received at later stages, can significantly delay clinical data collection and actual time to manufacturing authorisation application. This is why for less prevalent indications (or diseases which are not typically subject to systematic medical care) it is recommended to conduct regulatory/scientific research in parallel with clinical doability to avoid too much of an idealistic approach, which is quite often the case for regulatory bodies – particularly those less experienced in advice provision. Eventually regulators are representing governmental structures and as such, must care about certain levels of pragmatism in the expectations being set. Otherwise the industry would need to charge payers or even patients for the excess of expenses accrued in the course of an unreasonably exaggerated development programme. Step 3 – Site Selection In the industry, feasibility is quite often considered at the level of massive outreach campaign CROs performing within their database of investigators/ institutions, aiming to find candidates for further selection visits and, ideally, patient enrolment. Whilst the scale of the process justifies its more operational than medical/scientific character, there are still a couple of recommendations to be made based on the preceding steps: Profile of study sites – Certain indications and protocols require real insight into the subject’s medical history to perform a qualitative eligibility check. This is marginally possible in case of patients referred from their long-term

32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

healthcare providers to site management organisations (SMOs). While the SMO concept has its definite benefits (efficiency, level of task distribution between resources, better day-to-day access for clinical research associates [CRAs]), there are still protocols requiring execution within a standard medical setting the patient would receive from his/her long-term treating physician. Profile of investigators – Physicians do not equal one another, despite a theoretically equal level of education and certifications, at least within the EU. Indications with lower prevalence are difficult to deliver without Tier 1 investigators, also called key opinion leaders. It will be a challenge to avoid them for research in advanced stages of cancer, severe inflammatory disorders or rare diseases (patients are concentrated around a few centres of excellence in every country). Such trials will be irreversibly connected with longer startup timelines (high saturation of trials at the site) and increased expectations towards selection of on-site support resources (CRAs) as Tier 1 sites will always tend towards Tier 1 support staff. Study assessments – It is widely known that study protocols got more complicated and the average number of endpoints significantly increased over the last ten years. For example, imaging techniques evolved, driving the parallel increase of protocol expectations, always striving for the most sensitive and specific methodology. Operational staff will not be able to follow all these developments so, prior to launching massive site selection processes, therapeutic and regulatory scientists must ensure appropriate briefing with regard to detailed facilities required for data generation or collection. In the recent experience of the author, polysomnography (PSG)-derived endpoints posed a lot of challenges in view of the increasing role of PSG as a marker and still developing infrastructure of relevant sleep labs (stationary or remotely delivered). Moving towards the conclusion of the article, it is unavoidable to ignore the theme of big data sets collected across

the clinical trial process with the intention to offer improved clinical trial design, site selection, patient enrollment and overall decision making. In the author’s opinion, big data may constitute quite a similar challenge for the industry as did the rapid increase of the number of secondary and exploratory endpoints, consecutively added to clinical study protocols in the last decades. One shall stay aware of the issue of ‘multiple comparisons problem’. As statisticians say, even in completely randomly-generated data, interesting patterns appear. And if the data are big enough and the search exhaustive enough, the pattern can be very compelling. It is definitely early to judge the actual impact of big data analysis on the concerned industry, it would be unfair in view of the scale of ongoing investments in the field. One should just stay conscious reading thru the patterns and treat these rather as one of the signals than a prerequisite driving decision making. Summarising the dissertation, one needs to emphasise the competitive advantage of every step of feasibility studies. Increasing library of information available for analysis and multiple skillsets required to support its stepwise approach converted the surveys into regular projects, requiring proper resource assignment, planning and oversight. Excluding this effort from the overall scheme of action may lead to future losses and discouragement for all stakeholders involved in the research programme, starting from the manufacturer and finishing with the patient. Sponsor companies have a broad selection of supporters motivated commercially or ideologically to support the development of new concepts. Selection of providers and consultants should always be driven by their actual capability and track record. An end-to-end concept, aggressively pursued by large providers (employing the same CRO from the conceptual stage until market access) should always be examined for the actual benefits and risks behind it. Engagement with third parties should be driven by standard principles of the business, including mutual

Winter 2016 Volume 8 Issue 4


Manufacturing Drug Discovery, Development & Delivery Preparation of test solutions: Solution A: Solution of the product under examination at the initial dilution (test solution) Solution B: Test solution spiked with CSE at a concentration at or near the middle of the standard curve (PPC) Solution C: Standard solutions of CSE in water BET covering the linear part of the standard curve Solution D: Water BET (NC) Method: Add solution D, followed by solutions C, A, B. Add lysate and carry out the assay solution in accordance with the instructions of the lysate manufacture.

at the specified wavelength in accordance with the instructions of the References lysate manufacture. 1. Jim Greenwood: Incubator Feasibility Studies. A White Paper Prepared for the

Interpretation of results: National Business Incubation Association; The assay is valid only if 2014 1. The standard curve2. is linear for the range Paul of CSECraddy: concentrations Graham Foxon, Early Scientific Advice from Payers across the used; EU; 2015 2. The coefficient of correlation r is not less than 0.980; 3. 2016 Inclusion, &inLife 3. The mean % recovery of theDiversity, added endotoxin theSciences positive Symposium product control is between 50% andExecutive 150%. Summary 4.

Peter Bruce: Big Data accelerated medical research? Or not? Sourced from Data The concept of total quality controlAnalytics, test refers the process of Mining, Big toData, and Data striving to produce a perfect product Science portal. by a series of measures

requiring an organised effort in order to eliminate errors at every stage in the production. In-process product Dr Anna Baran testing is Chiefis required in order to check the conformance of the product with Medical Officer at KCR. the compendial standards as specifiedShe in the pharmacopoeias. leads the The pharmacopoeias have laid down the specified early limits organisation’s within which the value should fall in order compliant as stagesto be of study per the standards. As the final samples taken for the finished operations and provides product testing is only a representative of a large batch, cross-functional supporta The assay is valid only if significant difference still remains because of minor variation goodwill, lack ofcurve abuse, transparency can beconcentrations called Trial Execution Consulting. to all KCR service areas, 1. The standard is linear for the range of CSE specified limitsensuring in different Since the and used; compliance. The ultimate goal This, if properly placedininthe a development thepharmacopoeias. smooth integration of markets have opened up due to globalisation, it is necessary should set in of a correlation patient-centric 2. Thebe coefficient r is notand, greaterprogram, than 0.980; may significantly increase medical affairs, regulatory and business for a product to comply with the standards the place where 3. The mean % recovery of the added endotoxin in the positive wherever necessary, investigator-centric the execution efficiency and reduce development efforts. ofThroughout her to be marketed. productwith control between 50% and 150%. frustration irreversiblyit isconnected approach, allisavailable technology with career, Dr Baran has worked closely with Calculation: Calculate the endotoxin concentration of solutions A and B from the regression equation obtained with solutions of series C. Calculate the mean percentage recovery of the added endotoxin by subtracting the mean endotoxin concentration in solution A from the mean endotoxin concentration in solution B. Interpretation of results:

not breaching acceptance levels of erroneous operational strategies. competent authorities across Europe, and End point chromogenic As the official pharmacopoeias arein different in national different key contributors. Allmethod the above may has been involved developing Add solution D, followed by solutions C, A, B. The chromogenic parts of the globe, there is a need for the harmonised limit eventually lead to development of new legislation for clinical trials registration. substrate and lysate are added to the solution and incubated for the within which a product should fall to meet the pharmacopoeial business model in the industry which recommended time. Stop the reaction and measure the absorbance

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Drug Discovery, Development & Delivery How Drug Delivery Systems will Impact the Off-patent Biosimilar Race For generics manufacturers, the race to be the first to file their drug after the original’s patent expires is critical. The FDA stipulates that after a drug comes off patent, generics manufacturers can begin filing an abbreviated new drug application (ANDA) for their version, granting the first company to do so a 180-day period of market exclusivity. This is quite an advantage because the generic offering is less expensive than the original, and for approximately six months their offering is the only generic version available. Biosimilars — generic versions of biologic drugs — will soon represent a larger share of the generic market. As is the case with biologics, the generic versions are increasingly being selfadministered via drug delivery systems. Unlike biologic manufacturers that often fold the development of a customised delivery technology into the plan, biosimilar drug makers often rely on “off-the-shelf” systems that are not made specifically for their therapy. However, by choosing the right delivery system partner, biologic manufacturers can more efficiently clear the path to be first to file. The Generic and Biologic Boom The generic drug market in the United States is quickly expanding with no signs of slowing down. According to a 2016 study, the global generics market is expected to experience a 10.53 per cent compounded annual growth rate (CAGR) from 2016-2020, with the value of drugs coming off expired patents equaling $150 billion by 20201. IMS Health found that more than 90 per cent of dispensed medicine will be generic by 20202. Biologics have proven to be some of the more promising drugs in the pharmaceutical industry pipeline. Over the past several years, there has been a steady rise in biologic drugs used to treat chronic conditions because of their potential to offer patients better long-term outcomes and fewer side-effects than traditional, chemical-based therapies. Biosimilar manufacturers are creating generic versions to file once they begin to come off patent. As a result, biosimilars are expected to be a driving force in 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

further expanding the generic drug market in coming years. In Europe, biosimilars have been on the market for more than a decade, but in the United States, the path to market has been slower. In 2010, President Obama signed into law the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which created a pathway to licensure for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. In 2015, the FDA approved Sandoz’s Zarxio, becoming the first biosimilar approved in the US. Since that time, three other biosimilars have been given the FDA’s blessing: Celltrion, Pfizer’s Inflectra, Sandoz’s Erelzi and Amgen's Amjevita. At least 10 more biosimilars are expected to come off patent within the next five years, and according to IMS health, 28 per cent of generics spending will be on biosimilars by 2020, further bolstering the assertion that biosimilars represent a new wave of generic market expansion. With the biosimilar market on the precipice of vast expansion, drug makers are greatly scrutinising the companies they choose to work with to deliver these therapies. Understanding the Delivery System Many biosimilars are designed to be delivered using self-administration technology, which allows the patient to inject the drug wherever they are, as opposed to having to schedule a visit to a doctor’s office. Self-administration represents another swiftly growing trend, which has been driven by the advent of biologic therapies for chronic conditions. Biologic drug makers and delivery system manufacturers have collaborated in recent years to create truly innovative systems that can be safely and easily administered by patients. However, companies developing biosimilars do not have that luxury. Because biologics are very complex, they are more difficult to replicate than small molecule drugs. The time and expense required just to create an

FDA-approved biosimilar leaves little financial resources to develop a delivery system specific to the drug. And even if the capital exists to create a customised delivery system, the time investment required to conduct rounds of gene testing and human factor testing would become a barrier to expedited filing. Given the essence of time for biosimilar drug makers and being the first to gain market exclusivity, designing a custommade delivery system is typically not an option. Instead, biosimilars must be delivered in ready-made delivery systems. The good news for drug makers is that these offerings are being created based on previous designs and data utilised for original biologics drugs. The challenge companies have to face is knowing which delivery system is best for their drug and how quickly their partner can assist them in getting the offering to market. Three critical factors biosimilar manufacturers are looking for in a partner are a track record of patient affinity, an emphasis on quality, and innovation for future applications. Track Record of Patient Affinity A very real shift in delivery devices has occurred, where the design aspects that impact the patient’s affinity for the system are as much of a focus as how it interacts with the drug it’s delivering. Very often, companies that are introducing a biologic therapy to the market work in conjunction with a delivery system manufacturer to customise technology specifically for them. However, as pointed out, that is not the case for biosimilar manufacturers. As a result, it is the responsibility of the drug delivery system manufacturer to have data that demonstrates how patients feel about the technology. Is it easy to use? Is it discreet? Does it limit discomfort? Generic drug manufacturers are looking for more sophisticated devices with data that proves a consistent level of satisfaction with patients. For example, a number of biosimilar therapies that will be coming off patent in the coming years treat conditions that can Winter 2016 Volume 8 Issue 4


Drug Discovery, Development & Delivery greatly compromise a patient’s dexterity and strength, such as rheumatoid arthritis, multiple sclerosis and Parkinson’s disease. If these therapies are to be self-administered, then it is critical that the delivery system manufacturer can, through testing, lend credibility to the claim that patients find it intuitive and easy to use. Not only is it important for delivery system manufacturers to conduct initial tests on their technology, but they should also be able to display a track record of performance related to its use in conjunction with the original biologic therapy. Systems that are not designed with the patient in mind can negatively affect their emotional attitude and motivation to sustain treatment, and ultimately could affect the drug’s impact and success in the marketplace. Emphasis on Quality Biosimilar drug manufacturers — and all self-administered drug makers — place a very significant emphasis on quality measures instituted in development of systems that will deliver their drugs. No longer just an innovative suggestion, Quality by Design has become a nonnegotiable aspect of drug delivery technology development. By applying a data-driven, QbD approach to the design and development of systems like auto injectors, packaging manufacturers can gain a thorough understanding of both the product and the process. This, in turn, enables multiple benefits for end users and manufacturers. For one, the implementation of advanced QbD principles ensures a delivery system that consistently functions as expected. Because a patient will intuitively associate the drug with the delivery system, how the device performs is tied to the patient’s feelings about the drug. As a result, biosimilar drug manufacturers rely on delivery system partners to assist in upholding the drug’s reputation. A self-injection system needs to function consistently and reliably in order for patients to have confidence that it will work. QbD-designed components 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

can enable safe, effective and reliable self-administration. The use of clean, injectable systems with high-quality injectable drug components can also lower the risk of particulates and leachables, helping to reduce patient risk and ensure the drug and its packaging meet strict standards for quality set by regulatory agencies. Additionally, a strong focus on quality and risk mitigation can also drastically reduce the chance of recalls, which can jeopardise patient safety, but also negatively impact the drug manufacturer’s bottom line and reputation. Innovation for Future Applications As with any technology, viability depends on “what’s next.” While patient affinity and quality are prerequisites that will be addressed at all times, injectable drug companies looking to pair their offering with a drug delivery system require features that address emerging challenges and incorporate forwardthinking innovation. •

Connectivity: Smart devices have become a central point of everyday life, whether paying bills, or consuming media or communication. Now this technology is playing a more significant role in medication delivery and may help improve adherence. With many chronic conditions on the rise, there is a need for pharmaceutical companies to tackle the adherence problem in a new way. Smart health-related devices and applications can engage patients in their treatment regimen, encourage them to take a more active role in their self-care, and facilitate communication around adherence to prescribed therapies with their provider. Versatility: In order to meet the needs of a diverse portfolio of pharmaceutical products, system manufacturers are developing selfinjection technology that can be used across all dose volumes for a single drug or across complete portfolios of drugs, regardless of fill volume or viscosity. This versatility may minimise the time to validate and go to market. Adaptability: Biologics often require higher dosages and may need a syringe with greater volume for self-administration — biosimilars are no different. Because biosimilar

manufacturers are potentially not developing their own customised self-injectors, a wider variance of delivery system volumes are critical moving forward. When devices are intuitive and efficient, they reduce the disruption to patients’ daily lives, increasing the potential for optimum adherence, subsequently benefitting the biosimilar manufacturer. Conclusion With so much at stake, biosimilar manufacturers are mindful of how every decision can impact their path to filing first. To that point, it is ever-important for these companies to choose a drug delivery system partner with a proven track record of manufacturing highquality drug delivery technology that patients can use safely and effectively, reduce risk and incorporate innovative design features that address emerging trends. By doing so, drug companies are not only streamlining the race to be first, but maximising the 180-day window of exclusivity they’ve earned by making the best decisions along the way. References 1. "Global Generic Drugs Market 2016-2020." ReportsnReports, May 2016. Web. 07 Oct. 2016. <http://www.reportsnreports.com/ repor ts/586255-global-genericdrugs-market-2016-2020.html>. 2. "IMS Health Study: U.S. Drug Spending Growth Reaches 8.5 Percent in 2015." IMS Health. IMS Health, 14 Apr. 2016. Web. 07 Oct. 2016. <http://www.imshealth.com/en/ about-us/news/ims-health-study-usdrug-spending-growth-reaches-8.5percent-in-2015>.

Kevin Stevens is a Director in Product Innovation and Technology at West Pharmaceutical Services, Inc., supporting selfadministration. Kevin has worked on the development of various West drug delivery systems including the SmartDose® platform and SelfDose® self injector system. Kevin has been with West for 16 years and has also worked in West’s Contract Manufacturing business. Find West on Twitter and LinkedIn. Email: kevin.stevens@westpharma.com Winter 2016 Volume 8 Issue 4


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Drug Discovery, Development & Delivery Understanding the Determinants of Non-adherence: A Key to Success in Using Digital Services to Improve Adherence in Inhaler Use 1 Introduction The prevalence of chronic respiratory conditions, such as asthma and COPD, is increasing. So is the cost of their management. Many inhalation devices and drug products are available on the market to treat these conditions. However, studies have shown that poor adherence to treatment regimens is widespread and severely compromises the effectiveness of the treatment, resulting in poor health outcomes and increased healthcare costs. With 30% to 70% of patients not adhering to their medication regimen1 it is well recognised that the efficacy of drugs alone is not enough for good outcomes; patient and physician behaviour are vital factors and efforts need to be made to improve them. Adherence is defined as the extent to which a patient’s behaviour in following their treatment regimen corresponds with agreed recommendations or instructions from their healthcare provider2. Adherence is influenced by multiple factors – such as the patient’s socioeconomic situation, the healthcare system they are part of, the characteristics of the disease and the therapies offered, and many of them are patient-related and patient-specific2. Improving adherence needs a multidisciplinary and patientcentred approach: one such approach is to improve adherence through digitallyenabled inhaler systems and services. Digital technology and the services it enables have a huge potential to improve behaviours and adherence, and make up the focus of this paper. The recent rise of digital technologies in healthcare has been substantial, with the global digital heath market in 2015 valued at some $77 billion3. There have been particularly big developments in the respiratory disease sector, with recent partnerships being established between AstraZeneca and Adherium, Novartis and Qualcomm Life, and Boehringer Ingelheim and GSK with Propeller Health4, to name a few. Several examples of digital technology-enabled inhaler devices are currently in development, in clinical trials or on the market, such as Propeller by Propeller Health5; CareTRx by Gecko Health6; the medication inhaler 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sensor by Cohero Health7; Smartinhaler by Adherium8; Inspiromatic by Inspiro Medical9, and Digihaler by Glenmark10. The trend suggests that there is a race amongst manufacturers and pharmaceutical companies to include some form of digital technology within their inhaler devices and be amongst the first to bring a “smart inhaler” on to the market. But will these “smart” devices change behaviours, help improve adherence or result in better patient outcomes? Or will they meet the same fate of a number of health and wellbeing tracker digital products that initially created excitement in the market, but soon faded away11 because they were merely technology-driven, and did not cater for users’ real needs? Time will tell, but it is suggested that, so far, digital technology-enabled devices are “technology-driven, often without the involvement of the people they are aimed at”12. Digital technology and services undoubtedly have the potential to improve behaviour, adherence and outcome. However, a technology-driven inhaler device, designed without the understanding of the problems that they are intended to address, is likely to result in yet another product with expensive electronics that is soon forgotten and the digital features quickly ignored. To address this fully we need a multistage approach. First, we must try and understand the top-level problems that patients, their caregivers and healthcare providers face today and why these are determinants to poor adherence. Second, we must design and implement digitallyenabled, flexible and personalised service offerings to address them as best we can today. Third, and perhaps most importantly, we must use these new digital features to measure, analyse and adapt how all the users of these services behave in order to continuously improve patient outcomes. To address this first step, our organisation conducted a piece of analytical research to understand the potential issues with current inhaler devices throughout every stage of their use-life cycle. This paper highlights

some of those issues and discusses how digital technologies and services may be able to address them. Whilst this paper is not exhaustive in its coverage of potential issues and digital solutions, it highlights the importance of an end-toend understanding of the problems that patients and physicians are facing before formulating any digital solutions. 2 Approach to Understanding Problems To understand the issues that different stakeholders – e.g. patients, caregivers and healthcare providers – face with existing inhaler devices, the method described in Figure 1 was deployed. The method is based on a peer-reviewed, published paper13.

Understand device landscape

Identify search terms

Search internet/databases and tabulate results

Analyse search results

Present findings

Figure 1: Method for identifying determinants to poor adherence The research identified a wide range of inhaler devices – many of which are currently on the market, some are still under development and others that have been on the market previously. These inhaler devices ranged from metered dose inhalers (MDIs) to dry powder inhalers (DPIs), with different types of drugs for various conditions (predominantly asthma and COPD). The researchers then identified search terms, e.g. ‘brand name’, ‘drug generic name’, ‘device name (if any)’, for each of Winter 2016 Volume 8 Issue 4


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Drug Discovery, Development & Delivery the devices identified. These search terms were used to search the internet (e.g. PubMed and Google search) and publicly available device incidents databases, such as the US Manufacturer and User Facility Device Experience (MAUDE), in order to identify issues with the use of these devices. The search was not limited to the use of the devices to take a dose only, but to the whole use-life cycle from prescription to disposal. The focus was to identify issues that may contribute to non-adherence. The search activities took place in August and September 2016. All the findings were tabulated for future analysis. The data were analysed to identify and categorise the issues that may cause poor patient adherence. Some of the findings are presented in this paper to highlight the benefit of understanding the determinants of non-adherence, prior to developing solutions to improve adherence. 3 Examples of Determinants of Nonadherence A number of issues were identified throughout each step of the inhaler use-life cycle. Figure 2 shows a simple schematic of a typical inhaler use-life cycle and highlights some of the issues identified.

not know the correct use of the inhaler15 and therefore provide incorrect training to patients. It is often assumed that HCPs would know the correct use of the inhaler, which may not be true. The research also found that in some instances, the training provided to patients was inadequate, e.g. insufficient time was allowed for training16 the patientsâ&#x20AC;&#x2122; ability to use the inhaler was not assessed, patients did not receive refresher training, etc. According to one report, only 11% of patients receive repeat training17. The research also identified a number of potential use errors at all stages of the process, including failure to remove the mouthpiece cap of the inhaler, inadequate/inappropriate shaking of the inhaler, incorrect orientation19, failing to prime the inhaler19, and inappropriate maintenance and storage of the inhaler18. The research also found a number of issues with inhalation techniques, e.g. exhaling into the inhaler19, inability to achieve correct flow rate19, breathhold after inhalation too short, and inadequate shaking of MDIs. One report indicated that the most frequent use errors with MDIs were press-and-breath incoordination19. The research also found reports of patients and their healthcare providers mistakenly believing that the patients are using their inhaler as intended and adhering to their treatment regimen, when in reality, they were not20. There are also reports of patients knowingly discontinuing the use of their inhaler because of various reasons, e.g. they found the inhaler too difficult to use or they fear the side-effect of the treatment. This may indicate that there is a need for both patients and healthcare providers to track the use of the inhaler. The research also found that it is not always clear to the patient when they need to get a new inhaler or indeed how to identify when the inhaler is empty21.

Figure 2: Schematics of a typical inhaler use-life cycle and example causes of nonadherence One of the commonly reported issues we have seen is the lack of adequate training of patients and their caregivers. Some reports suggest that some patients do not receive any training when they receive their inhaler14. Others suggest that the healthcare professionals (HCPs), such as doctors and nurses, may themselves 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The issues in use described above are only a small subset of difficulties and issues faced by the users and healthcare providers. However, they underline the need for a new approach to understand and address them. Our organisation believes that understanding, designing for and continuously improving behaviours of all users through the intelligent application of digital services and human factors engineering is the key to improving patient outcomes for chronic respiratory conditions.

4 How Digital Service Technologies Can Address Behaviour, Adherence and Outcome The digital technologies behind the internet of things (IoT) are driving a revolution every bit as impactful as the original industrial revolution. The technology behind it â&#x20AC;&#x201C; the low-cost sensors, the connectivity and the data systems â&#x20AC;&#x201C; however, is not the reason this revolution is so dramatic. Rather, it is what this technology can enable; both for users and for providers. In the context of inhalers, connecting the device to be part of a digital service focussed on chronic respiratory conditions allows us to explore and crucially, by closing the loop through reliable data, improve behaviours of patients, caregivers and healthcare professionals alike. Three of the most widely discussed digital initiatives in healthcare are WellDoc, Omada Health and Propeller Health. Welldoc is a mobile applicationbased intervention for type 2 diabetes that focuses on self-management to record current behaviours and encourage better ones. With just the digital service and without any electronic devices, they have shown a 1.7 point reduction in A1c from a baseline of 9.7% of their active participants22. Omada Health take a similar selfmanagement approach, complementing the mobile application with a range of connected electronic devices such as weighing scales, pedometers and fitness devices. Part wellness and part health programme, Omada Health seeks to address chronic conditions such as type 2 diabetes and heart disease through better behaviours alone23. Propeller Health target COPD and asthma. Working through insurers and employers, they provide a smart buttonlike device to add to existing inhalers, thus connecting their use to a mobile application. The data gathered in this way is combined with self-management tools, reports and reminders in order to learn from and then to improve the behaviour and thus the long-term health of the patients. They report up to 50% more doses taken on schedule (adherence) and up to 79% reduction in asthma attacks as a consequence5. What these examples have in common is that the focus is not on the device, but on understanding and engaging with use Winter 2016 Volume 8 Issue 4


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Clinical Research problems and user behaviour. So, how does making an inhaler smart allow us to close the loop on user behavior and adherence? Sensors similar to those found in every smartphone can measure how an inhaler is used: a three-axis accelerometer shows when the device is being used and also how the device is orientated when it is used. More detailed analysis of the motion allows us to know more about how the device was used; was the DPI drug shaken or the MDI not, for example. Or perhaps the patient’s exacerbation is so bad that their hands are simply shaking too much to be able to use the inhaler properly. And let us not forget, simply knowing when or if an inhaler has been used is useful information. How does the patient behave when there is not an exacerbation to trigger their actions? Or simply, how many times has the inhaler been used and will it need replenishing soon? Adding a mems microphone to the inhaler enables us to listen to how the device is used – perhaps how the patient inhales or how bad their exacerbation is at the time. Or perhaps the capsule is empty in the case of a capsule inhaler. Typically all this data is collected via the patient’s own phone – a device which has its own sensors, and crucially, a device which is part of the everyday life of the patient and thus able to provide a wealth of additional “contextual” information. In this case, is the patient walking at the time? If so, how fast? Was this on their normal route to the shops, or was this a new activity? Connect to wider sources of information and it is possible to tell if, for example, they in an area experiencing high levels of smog, heat or dust. Added all together, the use of sensors allows us to gather data reliably and seamlessly. Bringing this together with context allows us to understand the behaviour better, which in turn allows us to improve them, resulting in better adherence and outcome. It is important to note that we are not only watching the patient. We can also gather data on caregivers and HCPs too – and here too we can work to change behaviours, all to improve the lives of those that need it most.

42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

5 Conclusion Digital technology and the services they enable have a huge potential to improve behaviours, adherence and treatment outcome, but only if we apply a truly multidisciplinary and patientcentred approach that goes beyond the technology. References 1. Rand CS and Wise RA. 1994. Measuring adherence to asthma medication regimens. American Journal of Respiratory and Critical Care Medicine. 2. WHO. 2003. Adherence to long-term therapies: Evidence for action [Online] Available from: http://www.who.int/chp/ knowledge/publications/adherence_full_ report.pdf [Accessed 04/10/2016]. 3. P&S Market Research. 2015. Global Digital Health Market Size, Share, Development, Growth and Demand Forecast to 2022 – Industry Insights by Technology [Online] Available from: https:// www.psmarketresearch.com/marketanalysis/digital-health-market [Accessed 01/09/2016]. 4. Kamat V and Finn J. 2016. It’s just an App isn’t it? [Online] Available from: h t t p : / / w w w. o n d r u g d e l i v e r y. c o m / publications/66/Cambridge.pdf [Accessed 01/09/2016]. 5. Propeller Health. 2016. Propeller Health. [Online] Available from: https://www. propellerhealth.com/how-it-works/ [Accessed 15/08/2016]. 6. Gecko Health. 2015 CareTRx by Gecko Health [Online] Available from: https://www.caretrx.com/ [Accessed 15/08/2016]. 7. Cohero Health. 2015. Cohero Health [Online] Available from: http://www. coherohealth.com/our-solution [Accessed 15/08/2016]. 8. Adherium, 2016. Adherium Smartinhaler [Online] Available from: http:// www.smartinhaler.com/ [Accessed 15/08/2016]. 9. Inspiro Medical. 2016. Inspiro Medical [Online] Available from: http://www. inspiromedical.com/default.asp [Accessed 15/08/2016]. 10. Glenmark. 2016. Digihaler [Online] Available from: http://glenmarkrespiratory. com/digihaler/ [Accessed 05/10/2016]. 11. Jonah C. 2016. Microsoft discontinues online Band 2 sales, has no plans for a Band 3 [Online] Available from: http://www. mobihealthnews.com/content/microsoftdiscontinues-online-band-2-sales-has-noplans-band-3 [Accessed 04/10/2016]. 12. Deloitte 2015. Connected health: How digital technology is transforming health and social care [Online] Available from: http://www2.deloitte.com/content/dam/ Deloitte/uk/Documents/life-scienceshealth-care/deloitte-uk-connected-health. pdf [Accessed 04/10/2016]. 13. Gupta SP and Pidgeon A. 2016. An analytical approach to identifying potential use-related issues concerning a medical device under development. J Med Eng Technol. 40(3):61-71.

14. Lavorini F, Mannini C and Chelline E. 2015. Challenges of Inhaler Use in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease. [Online] Available from: http://emjreviews.com/wp-content/ uploads/Challenges-of-Inhaler-Use-inthe-Treatment-of-Asthma-and-ChronicObstructive-Pulmonar y-Disease.pdf [Accessed 09/09/2016]. 15. NHS Cumbria. 2016. Common Mistakes with inhaler Technique. [Online] Available from: http://www.cumbria.nhs.uk/ ProfessionalZone/MedicinesManagement/ EnhancedSer vices/common-mistakesinhaler-technique-Dec-12.pdf [Accessed 09/09/2016]. 16. Murphy A. 2016. How to help patient optimise their inhaler technique. [Online] Available from: http:// w w w. p h a r m a c e u t i c a l - j o u r n a l . c o m / learning/learning-article/how-tohelp-patients-optimise-their-inhalertechnique/20201442.article [Accessed 20/09/2016]. 17. Melani AS, Zanchetta D et al. 2004. Inhalation technique and variables associated with misuse of conventional metered-dose inhalers and newer dry powder inhalers in experienced adults. Annals of Allergy, Asthma & Immunology, 93(5), 439-446. 18. Newman SP. 2005. Inhaler treatment options in COPD. European Respiratory Review, 14(96), 102-108. 19. Fink JB and Rubin BK. 2005. Problems with inhaler use: a call for improved clinician and patient education. Respiratory care, 50(10), 1360-1375. 20. Lareau SC and Yawn BP. 2010. Improving adherence with inhaler therapy in COPD. Int J Chron Obstruct Pulmon Dis, 5, 401406. 21. Westerik JA, Carter V, et al. 2016. Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting. Journal of Asthma, 53(3), 321-329. 22. Patrick YT, Peeples M et al. 2016. eHealthassisted lay health coaching for diabetes self management support. [Online] Available from: http://www.welldoc.com/ images/uploads/ADA_2016_Poster_-_ GIL_Project_Final_6.8.16_%281%29.pdf [Accessed 11/10/2016]. 23. Sepah SC, Jiang L and Peters AL. 2016. Translating the Diabetes Prevention Program into an Online Social Network validation against CDC Standards [Online] Available from: http://tde.sagepub.com/ content/40/4/435.abstract [Accessed 11/10/2016].

Suresh Gupta, James Ward, Alex Agis, Katie Cornish, Jaquie Finn and Tim Murdoch Cambridge Consultants, Cambridge, United Kingdom

Winter 2016 Volume 8 Issue 4


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Clinical Research Managing Benefits and Risks of Opioids in Paediatric Populations: A Review of FDA Paediatric Advisory Committee on Opioid Studies This is a follow-up to an earlier Watch article regarding the FDAâ&#x20AC;&#x2122;s Action Plan to Proactively Reduce Prescription Opioid Abuse1. This action plan consists of several wide-ranging strategies, the successful implementation of which will greatly impact pharmaceutical companies attempting to gain approval for opioid analgesic medications. These strategies include a reexamination of opioid labelling and monitoring; the prioritisation of abuse-deterrent formulations and non-opioids; the expansion of reversal medications; and importantly a more comprehensive assessment of paediatric issues. The recent labelling changes for OxyContin for use in patients aged 11 and older have generated substantial controversy both from lawmakers and patient advocacy groups. For many years, opioids such as this were prescribed off-label to children in severe pain and fears stemming from practice deviations anticipated after this approval have emerged. Of note, this approval came without convening an advisory committee and although arguable, several prominent lawmakers and pain researchers have lamented that had there been an advisory committee meeting there probably would not have been an approval. To help address issues such as this, the FDA assembled a Paediatric Advisory Committee to deliberate on the use of opioids in children and adolescents with the goal of providing further guidance for labelling, the development of high-quality evidence to guide treatment, as well as methods to improve practice patterns in order to reduce opioid abuse and diversion2. The purpose of this CNS Watch article is to review the discourse and conclusions from this meeting and highlight strategies designed to optimise the development and approval of paediatric analgesic medications. The scourge of opioid abuse in the United States has received much publicity in recent years and appropriately so; it is estimated that over 2 million people in the United States suffer from substance use disorders related to prescription opioid use, with another 467,000 suffering heroin use disorders. Of note, many of those addicted to prescription opioids 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

later â&#x20AC;&#x153;transferâ&#x20AC;? their addiction to heroin as this is often less expensive and easier to obtain. As a result of this opioid epidemic, there have been calls for policy-makers to stem the tide of opioid over-prescription through the introduction of regulations regarding the prescribing (particularly for refills) of opioids and increased funding and support of non-addictive analgesics1. In addition, many physician prescribers have begun to self-regulate, and indeed, current data substantiates a recent decline in the number of opioid prescriptions written in the United States since 20133. However, despite this positive development, concerns remain regarding the potential of an overcorrection in the prescription of opioids and what this could mean to the millions of people who suffer from debilitating pain by potentially limiting their access to much needed treatment4. This is especially the case for our most vulnerable populations, such as children and adolescents, where the options for treatment are already restricted and where the regulatory process for making novel treatments available is relatively poorly demarcated. To help remedy this, the FDA recently convened a meeting to discuss opioid use in the paediatric populations with the purpose of ensuring a balance between the exuberance to control the spread of opioid use disorders whilst a guaranteeing that patients continue to have access to the appropriate treatments for their pain and, importantly, to address ways to incorporate paediatric populations into future clinical studies of opioids. This two-day gathering of the Joint Meeting of the Anaesthetic and Analgesic Drug Products Advisory Committee [AADPAC], the Drug Safety and Risk Management Advisory Committee [DSaRM], and the Paediatric Advisory Committee [PAC], was held on 15-16 September 2016 in Silver Spring, MD and included members of the FDA and paediatricians from across the United States, all of whom are charged with managing chronic pain in this vulnerable population, including pain secondary to post-operative treatment, cancer, sickle cell and other critical illnesses.

The session began with a broad overview of the regulatory considerations for drug development in paediatrics, including an appraisal of the current approach for studying opioid analgesics in paediatrics from both pharmacological and clinical perspectives. Passage of the Best Pharmaceuticals for Children Act (BPCA) and the Paediatric Research Equity Act (PREA) in 2002 and 2003, respectively (both made permanent in 2012) were watershed events in the development of paediatric therapeutics. Together, these acts have led to at least 637 paediatric label changes and have ensured that paediatric populations are carefully considered in the development of all drugs. However, these laws have also made clear that many drugs previously thought to be safe in children are not; and that drugs without paediatric labelling represent a clear barrier to access for children, as up to 50% of drugs for children are still used off-label (albeit down from 80% pre-BPCA/PREA). Unfortunately, these acts have not had a real impact in regard to opioids as some of the most commonly used opioids (including oxycodone IR, methadone and morphine ER) still have no paediatric labelling, while many others (including buprenorphine, codeine, hydrocodone, etc.) are pending. Previous FDA guidance acknowledged the difficulty of conducting pain studies in children and permitted an extrapolation of clinical data from adults to children, as long as pharmacokinetic (PK) data was available and sufficient. However, extrapolation proved inadequate for drugs with a novel mechanism of action and this approach was reconsidered with updated guidance provided in 2012. This updated guidance contained requirements for the approval of both immediate-release (IR) and extended-release (ER) opioids in paediatrics with specific guidelines for both children and adolescents in each category. Despite this explication, numerous challenges in study design and enrolment in paediatric pain trials remain for sponsors developing paediatric analgesics. Perhaps the most obvious challenge is overcoming apprehension on the part of parents to enroll their Winter 2016 Volume 8 Issue 4


Clinical Research children into any clinical study (whether can result in insufficient enrolment and opioid or not) due to the uncertainty inadequate statistical power. There is regarding relative benefits and the risk also consternation on the part of study for additional harm. Many institutional investigators and/or their institutions review boards (IRBs) are now requiring that often view these studies adversely, language specific to opioid dependency which creates a general reluctance to that may cause concern for the parents take part in the first place. Finally, as deciding whether to enroll their child in with the investigation of opioids in any a pain study. In this case, supplemental population, there is the potential for informed consent materials such as diversion and abuse. Adolescent patients booklets and flip charts that are easy may be particularly vulnerable to this to read and bright in color may prove risk, but also parents must be carefully beneficial. In addition, the involvement scrutinised for diversion. All of these of the investigator in study-related factors make investigators relatively discussions can help to alleviate parental reluctant to participate in these much concerns when opioids are being tested. needed trials. It is also the case that the representative placebo-controlled studies may not Recommendations for overcoming the have the same practicality or utility aforementioned challenges, all of which as in the adult population both from have implications for future clinical work, an ethical perspective and due to the were also provided by the FDA. The first fact that children, especially younger recommendations involve the robust use of Figure 1 – Universal patient contact card ones, cannot express pain intensity adequate and properly designed clinical An implementation team also ensure outlined are and addressed. nor relief previously in a consistent reliable pharmacology studies in will paediatrics, in that patient contact cards are available This implementation team works in manner adequate for valid measurement order to improve both the extrapolation patientsprocesses and participating collaboration with the purposes. Therefore, theclient use of(sponsor/ an open and provide dose selection for both clinical with all the information CRO – clinical research organisation) label model in paediatrics may need to IR and personnel ER analgesic formulations. For they need the support in to understand study early be fully considered. Boththe of complete these concerns phaseabout investigations, theservices use of PK support requirements – including all a neat, compact and readily-available aspects of patient support, whether package. The patient contact card should clinical, medical, logistical or technical. have a universal design to ensure that the

modelling prior to the actual paediatric PK study through the use of adult data can aid in this process, particularly when physiological parameters such as weight, age and gender are taken into account. This modelling may be of particular benefit when deciding upon the initial dose in a paediatric (single ascending dose) SAD or (multiple ascending dose) MAD trial or when PK data from the IR or ER formulation is already published, as is the case for the majority of opioid medications. Additionally, the number and timing of blood samples collected during a paediatric PK programme should take into account the differences in absorption between adults and paediatric populations. Suggestions for overcoming the challenges in conducting later phase efficacy studies were also discussed. For example, patient/nurse-controlled contact centre can easily direct the analgesia (PNCA) is one recommended patient, or in the case of the tool for use immediate release patient opioid presenting at more a hospital or studies, withthemselves NCA being prevalent clinicPCA other the study centre, the than withthan relatively younger patients. treating healthcare professional, to also the Utilisation of the PNCA method may necessary information to assist with queries about the patient’s participation in the study.

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help to overcome some of the issues regarding overall exposure and placebo in paediatric studies. In these studies, all patients receive standard of care (SOC) PNCA with either study drug or placebo added to this. If the study drug is effective, there should be less SOC drug utilised and the primary efficacy endpoint is represented as the delta in the amount of SOC between the two treatment groups. Finally, in order to guard against the potential for abuse in adolescents, the FDA recommendations are similar to studies of adults; namely look for signs of diversion, minimise the amount of drug distributed at any given time and assess risk on a patient-by-patient basis. In terms of post-approval commitments, the FDA will require sponsors to conduct several studies as well as mandate an annual reporting of adverse events, including accidental exposures and overdoses in children and adolescents. This will be done in an attempt to provide a more comprehensive analysis of side-effects, medication errors and prescribing patterns (including the types of prescribing physicians as well as the various types of treatment indications), and help to identify factors important in creating and maintaining adolescent opioid use disorders so that these can be successfully addressed in future clinical development programmes1.

46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

References 1. Riordan, H. (2016) A Review of FDA’s Action Plan to Proactively Reduce Prescription Opioid Abuse. Journal for Clinical Studies Vol 8 (2) Jan pp 1012. 2. Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee Meeting Announcement, 15-16 September 2016, FDA Center for Drug Evaluation and Research, Silver Springs, MD, materials accessed online at http:// www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848. htm 3. Goodnough, A. and Tavernise, S. (2016) “Opioid Prescriptions Drop for First Time in Decades”, NY Times, 20 May 2016; accessed online, at: http:// www.nytimes.com/2016/05/21/ health/opioid-prescriptions-drop-forfirst-time-in-two-decades.html 4. Kano, T. (2016). “The Problem of Pain”, Thiruvananthapuram, The Economist, 28 May 2016, accessed online at: http://www. economist.com/news/international/21699363-americans-are-increasingly-addicted-opioids-meanwhile-people-poor-countries-die

Barry J. Dussault, Jr., MBA is Senior Director of Project Management, Neuroscience at Worldwide Clinical Trials (WCT). Mr Dussault has worked in all phases of drug development over the course of his 18-year career, with a recent focus upon clinical project management in roles on both the biotech/sponsor and CRO side. Since joining WCT, he has specialised in the design and conduct of analgesia and opioid addiction and dependency clinical trials. Henry J. Riordan, Ph.D. is Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. Dr Riordan specialises in clinical trials methodology and has advanced training in biostatistics, experimental design, neurophysiology, neuroimaging and clinical neuropsychology. He has over 100 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology. Email: henry.riordan@worldwide.com Winter 2016 Volume 8 Issue 4


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Unifying Clinical: Why Systems are Causing Costly Inefficiencies Information-sharing is common practice among many physicists, astronomers, and geneticists, who actively share data from resources such as the Large Hadron Collider, the Hubble Space Telescope, and the Human Genome Project. So why is the experience of clinical researchers so different? Why, at the innovating heart of the sciences industry, where access to high-quality clinical data is key to accelerating trials, are companies and functions within companies still operating in siloes? The answer may, in part, lie in technology. Over the past two decades, as clinical trials have expanded in both scope and complexity, companies have dedicated teams to focus on specialised functions – such as study start-up and safety. Many of these teams then either built systems to support these specific functions, or bought existing solutions piecemeal. Trials expanded globally and functions continued to diversify – as did the systems used to handle those tasks.

Today, most clinical teams work with many different applications that do not enable collaboration externally or easily allow for sharing of documents and data internally. In fact, clinical operations teams now use as many as 20 different non-integrated systems to manage global trials – from electronic data capture (EDC) systems and study start-up applications to clinical trial management solutions (CTMSs) and electronic trial master files (eTMFs). The life sciences industry invested large amounts of money in on-premise enterprise systems during the 1990s, and now these ageing technologies are a hindrance because the systems cannot “talk” to each other and therefore don’t enable crucial sharing. With fragmented teams supported by disparate systems, it’s hardly surprising that information-sharing is not an intuitive part of the clinical research process. In our 2016 industry-wide survey, nearly half (49%) of all respondents cited integration between their eTMF and CTMS

applications as a key need1. But today, clinical and operational data reside in multiple separate systems, including EDC, eTMF, and CTMS applications. Study teams also obtain data from various third-party providers, which adds complexity to the clinical trial process. For example, information regarding investigational products can come from interactive response technology, a contract research organisation (CRO), or an inventory management system. Endpoint data may also come from various labs or imaging providers – and few of the systems interoperate. And with systems that are not designed to work together, process inefficiencies are rife. Most study managers rely heavily on manually compiled spreadsheets to get a view of issues across a single study or portfolio of studies. According to another recent study, more than 90% of study managers export data directly from their CTMS and EDC systems, only to manually roll them into central spreadsheets with data from other systems2. Spreadsheets are even still used for oversight of CROs. “The clinical development process is highly inefficient due to a number of factors, including the inconsistent use of a large number of incompatible technologies,” said Ken Getz, associate professor at Tufts University School of Medicine and chairman of the Center for Information and Study on Clinical Research Participation. “Transparency, compatibility, and integration are critical factors driving technology adoption among clinical research professionals, patients, and the broader healthcare environment.” Time is Money – and Inefficiencies are Costly Clinical trials represent nearly 70% of all R&D costs, with much of the cost due to the sheer amount of time spent on supporting as a result of manual and inefficient processes. Gartner estimates that just one day of drug development costs a sponsor $37,000 – and this is low compared with the high costs of speciality drug development, such as oncology therapies.

48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2016 Volume 8 Issue 4


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Clinical Research Accelerating clinical trials is an industry imperative, but achieving it relies on the ability of research teams to manage vast amounts of trial data. And therein lies the challenge. Since 2000, the volume of data in a Phase III study has risen by more than 50% and the cost per patient for a clinical trial has almost doubled3. Traditional EDC systems add to this complexity and cost by requiring site staff to spend significant amounts of time managing clinical data. System set-up, maintenance, inflexibility, and lack of integration have slowed down the pharmaceutical industry’s ability to get clean data and quickly make informed, confident decisions during trials. Lack of transparency is another big problem. Gaps in the various handoffs during their key processes and lack of interoperability in their systems prevent executives from knowing if clinical studies are performing to plan. They have little visibility of impending challenges, such as lagging patient enrolment – where sites may require additional support – and what risks exist regarding study compliance. Without real-time data, it’s difficult to identify issues, let alone investigate and mitigate them. Unifying the Clinical Technology Landscape In an ever more complex clinical landscape that increasingly involves external partners and other stakeholders, there is a clear need to streamline clinical operations and data management – and ultimately eliminate manual processes. Unifying the clinical suite and bringing documents, people, and workflows together on one platform may provide the solution. “The integration of clinical practice and clinical research data, nextgeneration e-clinical technology solutions that unify end-to-end clinical processes, and improvements in protocol design execution feasibility will all be critical success factors in driving higher levels of efficiency, performance, and data quality,” said Getz. By uniting even just three crucial clinical systems, a company can reduce the number of steps in the end-to-end processes of creating a protocol, collecting essential documents, supporting the submission, and finalising the clinical study report from an average of 26 to just eight – a 60% reduction. 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

All stakeholders working on the same platform dramatically reduces the tedious back-and-forth between team members, logging in and out of different systems, and downloading and uploading of the same documents multiple times in multiple places. When systems are interconnected, information automatically flows between them seamlessly – driving faster time to market. “The industry has been forced to settle for clinical data management systems that have been short on innovation and high on complexity,” said Henry Levy, chief strategy officer at Veeva Systems. “Vault EDC and Vault eSource will offer an innovative, integrated approach that will deliver the data quality and realtime access that is needed to make faster, informed decisions and cut the cost and complexity of trials,” said Levy. Unifying clinical operations on a modern platform optimises resources, ensures greater accuracy, reduces risk, and speeds time to market. However, the biggest hurdle to this end state is unplugging legacy systems without impacting the way business gets done today. In our recent executive symposium, clinical executives agreed that business continuity in the face of a technology upgrade was their biggest concern. According to participants, often an ageing, on-premise CTMS application serves as a major clinical artery for the enterprise. Custom integrations are built between their CTMS and eTMF systems to funnel final investigational site-trip reports and follow-up letters to ensure they have an inspection-ready eTMF for auditors at any time. As a result, the thought of replacing legacy systems can make management nervous: if one system is replaced, it can be difficult to ensure their custom integrations will still work. But what if the CTMS, eTMF, and all other clinical systems were on one common platform, easily accessible in the cloud? Then the need to manually move operational data and documents from one system to the other is negated. The most up-to-date documents and operational data automatically would appear in the various clinical applications with the right metadata in real time, as it happened, increasing visibility, accuracy, and accessibility.

When the clinical landscape is unified on a single platform, there is one source of truth that is always correct and up to date in real time. Providing access to all stakeholders, including CROs, investigator sites, and other external partners is simplified. This unified technology landscape will provide one view within and across clinical trials from end to end. And with that, the industry will be emboldened to bring innovative new therapies and drugs to market faster and at less cost. Sharing certain pieces of data will allow researchers and clinicians to quickly build upon already-proven theories – and fruitful, efficient collaboration will finally become commonplace. References 1. Veeva 2016 Paperless TMF Survey – Annual Report, by Veeva Systems, June 2016. The report is also available online. 2. Clinical Leader, “Survey – Do Spreadsheets Still Hamper Clinical Trial Speed & Quality?” by Ed Miseta, August 8, 2016. Click here for more. 3. Ken Getz, Clinical Trial Complexity (Tufts: November 2012) and Penelope K. Manasco, M.D., 10 Things to Speed Development, Lower Costs, and Enhance Quality with Existing Clinical Budgets (MANA RBM: 2016)

Rik van Mol is Veeva’s vice president responsible for the Veeva Vault R&D suite of applications with a focus on the European market. He has nearly 20 years’ experience in business/IT consulting and regulated content management in the life sciences pharmaceutical sector. His experience has been built in assisting clients through complex transformational programmes across the life sciences value chain, including clinical, regulatory, and manufacturing/supply chain areas, for some of the world’s largest companies. Email: rik.vanmol@veeva.com. Winter 2016 Volume 8 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Labs & Logistics

End-to-end Process Excellence to Ensure Uninterrupted Delivery IPI’s Orsolya Balogh talks to Alex Guillen, cold chain director at Fisher Clinical Services, about how end-to-end process excellence can ensure uninterrupted delivery, and how it is of particular importance for the cold chain shipment of IMP supplies

So I often recommend, without losing sight of the “strong areas”, to start with questioning the efficiency of the areas in the supply chain where you are not fully in control. Put a team of people together to evaluate your process excellence in these weaker areas.

Why is the end-to-end process so important? The best way to answer your question is with the phrase - “a chain is only as strong as its weakest link”. Let me illustrate this further for you - imagine a metal chain where all of the links look exactly the same on the outside, but in truth there is a weak link. This is particularly dangerous because the weakest link, due to a crack or oxidation, is not visible to the naked eye. Analogically, sometimes we look at all phases of our supply chain the same way without realising that one of them might just be our weakest link. Then, no matter how much excellence you instil in your processes across all phases of the supply chain, your supply chain will only be as good as your weakest phase.

That’s interesting, Alex, particularly as a high percentage of IMP shipments are temperature-sensitive. Can you delve a little deeper into the “weak areas” you just mentioned. Sure. Firstly, the packaging of clinical supplies - not all companies can handle primary and secondary packaging within temperatures of 2-8°C or even 15-25°C. In today’s world, with a high percentage of biologics requiring primary packaging in specified temperatures of -10°C, companies are outsourcing this to specialist providers. Why? In my experience, infrastructures that allow packaging at these low temperatures require significant investment, not only in bricks and mortar and temperature control systems, but also in terms of personnel training so as to ensure that operational guidelines are strictly adhered to.

This is particularly relevant when shipping cold chain IMP, where it is imperative to maintain product integrity and an uninterrupted supply chain from end to end. In your experience, where are the weakest links? That’s a good question. Many companies invest a lot of time and effort in defining process excellence in areas of the supply chain that are “easier” to manage, e.g. control during movement of product within the facility and/or the temperature monitoring of shipments. But companies often neglect, or put less effort into, the areas of the supply chain that are deemed to be “weak”. For example, lowtemperature packaging areas, shipments going through extreme conditions, transit through problematic customs checks, storage in remote areas, remote clinical sites and, last and not least, what happens to the drug before administering it to the patient.

52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Depending on what statistics you look at, somewhere between 50% and 60% of all molecules in development are now biological. Biologics are inherently less stable than small molecules and invariably require a much colder supply chain from end to end. Is there an alternative solution? Yes, an alternative solution is to pack the IMP under some form of controlled ambient temperature and monitor the Time Out of Refrigeration (TOR) of the product while it is being packed. This will allow the manufacturer to calculate, based on stability data, the overall remaining life of the product after leaving the packaging facilities. Monitoring TOR, however, can prove quite challenging particularly when there is aggregation during the process. This requires traceability of temperature control from bulk product to the final

single use vial. Traceability is not easy and requires sophisticated automated control systems. You mentioned delivery through extreme temperature conditions and/or remote locations? The globalisation of clinical trials has led to the shipment of IMP across borders, across continents and hence across climates. Where the shipment is to experience extreme temperature conditions across the supply chain, the biggest mistake is to choose an inappropriate shipper. Best to choose a shipper, at the outset, that will withstand extreme temperature conditions. In addition, it is recommended that companies collect data on the shipments journey - temperature exposure, time delays, time at tarmac and heat exposure. Having that data allows the company to make the right decisions in terms of the type of shipper to use, how to protect it along the supply chain and in its choice of courier. Word of caution - controlled temperature packaging today is mainly tested against standard profiles such as ISTA 7D or the vendor’s own standards. These will most probably not give you the right information in terms of performance of shippers in extreme conditions. Therefore, it is better to rely on data that is collected objectively. Then you can develop profiles that reflect reality. My advice is for you to challenge your shipper supplier to provide you with packaging solutions that are based on actual, objective data and that suit your clinical trial needs. Delays in customs must be an issue, particularly in less developed countries? In the past this used to be the case mainly in developing or “unstable” countries but customs delays can happen anywhere these days. Prolonged checks or delays in customs clearance can result in an interrupted supply chain, loss of control and a potential impact on product integrity, which can have disastrous consequences when related to IMP shipments. Although customs authorities claim to handle IMP Winter 2016 Volume 8 Issue 4


Labs & Logistics correctly, how can you know for sure? Furthermore, customs’ routines may change without warning due to other factors. Terrorist attacks and high alerts in parts of the world has already had an impact on stricter controls being enforced by customs. Other worldly events, such as the Olympic Games in RIO, can also impact on customs clearance timelines. What can companies do to prevent problems at customs? Smarter packaging, temperature monitoring and “over- communication.” In terms of packaging, one solution is to use packaging with extra protection, one that is capable of withstanding thermal shocks, for example sudden very low or very high temperatures. Often customs officials assume that cold chain can be maintained by placing the shipper inside freezers. However, many types of shippers that maintain temperature ranges of 2-8°C will do so under ambient

54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

conditions, but will send the product to freeze if the ambient temperature goes below 0°C. Many custom officials do not know this and put shippers into freezing temperatures believing that this will protect the product. However, this is not the case. To avoid this happening, it is wise to use higher performance packaging that will withstand freezing conditions. In terms of communication, good labelling is imperative. Clear instructions on how to handle IMP shipments are likely to inform and even educate customs authorities on how to handle clinical trial supplies. In some parts of the world clinical research is new to customs officials, so education is of paramount importance. Companies such as Fisher Clinical Services are committed to inform and educate customs to help them understand the consequences of customs delays on IMP shipments. After

all, reduced customs delays streamlines the supply chain, helps maintain IMP integrity and often accommodate tight patient dosing schedules. You mentioned monitors? The industry is continually evaluating new and evolving technologies in terms of temperature monitoring devices. Standard technology such as data loggers capture the temperature of the shipment as it goes around the world, giving you an added level of reassurance that temperature specifications are being maintained. There are also smart mechanisms that provide data to clinicians using QR codes. It is all very well having this data. However, more importantly, it should be put to use to improve end-to-end process excellence. And what about storage requirements? Significant investment is needed to accommodate storage at 2-8°C, -20°C, -80°C and all the special ranges that are

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Labs & Logistics sometimes required for IMP. Not every biotech/pharma and distribution centres has the capacity to store, handle & distribute high volumes of biologics and ancillary supplies. Capacity constraints impede on distribution centres especially where Sponsors pool supplies for distribution to investigator sites at later dates.

information or instructions from the courier and when there is a general lack of understanding by the sponsor as to the layout and working environment of the investigator site. For example, reusable shipper programmes have been embraced by investigator sites recently as they reduce waste and storage constraints at the investigator site.

In fact, revised EU GDP Guidelines have put more pressure on distribution centres handling and storing IMP. For those cGMP facilities that are already compliant with these guidelines and that can uphold responsibility and liability for supplies, it is business as usual, but for others it can be a challenge. To complicate matters, many depots and distribution centres expect you to believe that these temperatures are being maintained based on contract and quality agreements already signed with them. Whilst the reputation of the depot is important, in order to ensure end-toend process excellence you should be in a position to demonstrate to regulators that you have full visibility of temperature conditions for your IMP storage & handling.

Technology is particularly important in the end-to-end process, particularly when IMP is delivered to the investigator site. Having visibility, control and the ability to react to anomalies helps maintain product integrity up until patient dosing occurs. To this end, Fisher Clinical Services works closely with investigator sites, even sponsoring a global investigator site panel forum that addresses issues faced by the investigator sites, and together with sponsors, solutions are sought.

Ensure to review quality agreements yearly to verify that conditions stated in the quality agreements are being maintained. To mitigate risk, all Fisher Clinical Services facilities are whollyowned with global processes and systems in place to correctly control and monitor temperature conditions, ensuring cold chain product integrity at all times. At the outset you mentioned investigator sites. How can you ensure that there is no “weak link” once IMP is delivered to the investigator site? One of the weakest links in the supply chain is, undoubtedly, the clinical site. This is by no means due to negligence at the sites as most sites do their best to maintain the integrity of the IMP. It is a weak link simply because it is at the end of the supply chain. The Sponsor must rely on Good Clinical Practices (GCP) at the site, and all sites are different. The level of knowledge to comply to GCP can vary between sites, regions and countries. Site personnel understand the importance of handling cold chain supplies with additional care. However, this can prove challenging, especially when they receive incorrect or unclear instructions; limited or no information in terms of temperature tolerances; little 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What about direct-to-patient? Surely process excellence is paramount to ensure integrity of supplies? Whilst most clinical trials are conducted at investigator sites, there are times when patients choose to partake in a trial when the IMP is delivered direct-topatient. Even in these instances, it is usual that a qualified practitioner will visit the patient’s home to deliver and administer the IMP. This does not raise any concerns in relation to safety and compliance as the IMP is administered by a trained nurse or physician. However, the cost can be high. However, when IMP is delivered directly to patients, without the presence of a qualified practitioner, cost is high and risk is also high. How is it possible to correctly monitor IMP intake at the right times and how do you ensure proper handling and storage of IMP at the patients’ homes? Here again, technology is making this possible thanks to special sensors in blisters, packaging and clothing monitoring drug intake. Advanced RFID/GSM/GPRS technology for cold-chain traceability is also key to collating data to assure sponsors of product integrity; perhaps a topic for a subsequent dialogue Orsolya? This has been an interesting discussion, Alex. What are the key takeaways? In summary, we can say that, although we have made great progress in managing the supply chain and applying end-toend process excellence, the speed of technology advancements is accelerating

us into potential new levels of cold chain visibility, management and control. We are working in a conservative industry, by nature. 20 years ago we were happy when we were able to monitor temperature in shipments; 10 years ago we were happy to see that we could make sense of the data collated to improve our processes; 5 years ago we were astonished that we could view our shipments on our mobile devices and in real time. Whatever happens next will continue to help us to ensure security of supplies across the supply chain and will allow us to react quickly so as to ensure uninterrupted deliveries. It will be up to the innovation teams of every organisation in the clinical trials world to take advantage of the speed of technology advancement, a quest that is certainly embraced by Fisher Clinical Services as we continue to supply hope to patients all over the world.

Alex Guillen has established a notable career in the pharmaceutical and chemical industry Over the course of more than 15 years, . He has held a variety of management roles, including Chief Executive Officer for Escort Cold Chain Solutions SA (ECCS) in Switzerland; General Manager for Sinorgchem Europe in The Netherlands; and Director of Commercial Operations, European public markets for Novartis Vaccines in Oxford, UK. Alex joined Fisher Clinical Services in December 2013 and is responsible for the overall global clinical strategy for cold chain. He holds a bachelor degree in business administration from George Washington University in Washington, DC, and speaks fluent English, French, Italian and Spanish with basic knowledge of German. Winter 2016 Volume 8 Issue 4


Labs & Logistics Protecting Vaccines with a Sustainable ‘Smart Fibre’ As far back as 2005, the World Health Organisation (WHO) reported that up to half (50%) of all vaccines transported globally were ruined due to poor distribution procedures, with a resulting significant impact on human life1. Today, in 2017 the situation remains largely unchanged. So what credible and sustainable passive packaging solution can help solve this humanitarian issue? Vaccine damage is caused mostly by failings in cold chain logistics and current man-made insulated packaging materials. Polymer-based insulated packaging materials, such as polystyrene (EPS), are not sufficiently effective at maintaining temperature control when exposed to uncontrollable ambient extremes, and are neither sustainable nor environmentally-friendly. It is now widely recognised by the pharmaceutical industry - reinforced by EU good distribution practice (GDP)2 legislation in 2013 - that there is a growing and urgent need for an effective, genuinely sustainable and environmentally-responsible passive insulated packaging solution for the global distribution of temperaturesensitive healthcare products under varying climatic temperature conditions. Cold-chain temperature control is necessary to prevent damage to life-saving vaccines caused by heat exposure. However, keeping vaccines too cold is just as harmful as keeping them too warm, since freezing damages many vaccines. Protecting vaccines from freeze damage remains one of the most poorly addressed problems in vaccine management3. The maintenance of accurate and uniform temperatures is, therefore, of significant importance in improvements to global human healthcare. Studies conducted in several countries, in hot and cold climates, developed and lessdeveloped economies, show frequent occurrences of sub-zero temperatures in the cold chain. Yet health workers and cold-chain managers are often unaware of how vaccine freezing occurs and the significance of its consequences4. 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

More children than ever before are being reached with immunisation – over 100 million children a year. Yet despite extraordinary progress over the past decade, 24 million children, almost 20% of the children born each year, did not get the complete routine immunisations. Reaching these vulnerable children, typically in poorly-served remote rural areas, deprived urban settings, fragile states, and strife-torn regions, is essential if the Millennium Development Goals are to be equitably met. Maintaining potency and viability during storage and distribution is therefore an essential process to ensure that all vaccines administered are as effective as possible. It is absolutely critical that many medicines and vaccines are maintained within a tight temperature range e.g. 2° to 8°C, during global transit under extremes of climatic conditions. ‘Getting cost-effective vaccines to the people who need them is complicated. Successfully delivering high-quality vaccines requires a comprehensive temperature-controlled delivery system called the "cold chain." Vaccines need to be transported at the correct temperature to prevent them from either freezing or being exposed to too much heat. In many countries, it's difficult to ensure this type of transport from the airport to the children in the village who need the vaccines. We believe that a coordinated effort to develop and distribute underused and new vaccines can save millions of lives’5. As a result, important changes to EU GDP in 20136 now require pharmaceutical companies, wholesalers and distributors to prove through real-time validation, summer and winter, that coldchain delivery systems and packaging employed are capable of maintaining strict temperature control for the duration of the journey to patient, this being typically 72 hours. Without such proof, bodies such as FDA (USA) and MHRA (UK) will not issue the necessary licences required for wholesale distribution of pharmaceutical products. The development of passive insulated packaging materials and containers

with natural thermal buffering properties represents a powerful solution to address the problems arising from an uncontrollable temperature interruption during cold-chain distribution – the ‘weak links’ in the chain. The most widely-used passive insulated packaging for the delivery of vaccines on a global level is EPS. Expanded polystyrene is a man-made material deriving from oil. Every year, 20 billion cubic feet of EPS is produced for use across a variety of industry sectors. Imagine these 20 billion cubic feet were blocks laid end to end; they would circle the earth 152 times. A significant amount of vaccines are delivered to countries that have poor waste management recycling and waste disposal infrastructures for polystyrene, creating an enormous environmental impact. Roadsides are lined with waste polystyrene that will not biodegrade for hundreds of years7. The inefficient temperature control and the environmental issues that are created when using EPS are compounded by the potential growth in demand for time-temperature sensitive vaccines and medicines required by emerging markets such as China, South America and Australasia. These regions are vast in size and have extremes of climate, poor transport and distribution infrastructures. All these factors demand greater temperature-control performance from passive insulated packaging. The insulative inefficiencies of EPS are compensated by the extensive use of phase change materials (PCMs). In an attempt to achieve specific time and temperature challenges, current packaging usually consists of large lined or moulded EPS boxes with as many as 30 PCM units per package, each PCM unit typically weighing 500g. This produces enormous and heavy packages relative to the small product to be transported, thus making delivery to more remote geographical areas almost impossible. As regards the global issue of temperature damage to vaccines, ‘the Winter 2016 Volume 8 Issue 4


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Labs & Logistics most common cause of exposure to freezing temperatures is the failure to correctly condition ice packs prior to transport. The practice of immediately placing deep-frozen ice packs, which can reach temperatures as low as -20°C, in well-insulated cold boxes, places freeze-sensitive vaccines at the greatest risk to thermal shock’8

temperature logged by one of the data loggers used in the trial or standard ambient temperatures used by the industry to represent that period of time), that takes the internal temperature of the pharmaceutical package below the minimum safe level, such as 2°C in the case of live vaccines, adversely affecting its efficacy.

With and without icepack barriers    

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economically viable and environmentally and socially responsible. Employing coarse waste wool, a byproduct of the meat industry, for which the farmer has no commercial use, makes for a very effective economic argument to use as a replacement for EPS. In effect, this creates a high value-added product from a waste material stream. At present, the EPS manufacturers are making modest improvements in product development with existing materials. The properties of the material they produce allow only small incremental advances toward becoming more sustainable and effective. Radical thinking is required to create an innovative, disruptive solution.

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Figure 1: Graph showing the 'Spike' and elimination using barriers

Figure 1: Graph showing the ‘Spike’ and elimination using barriers Woolcool Standard v EPS / FoiledBubbleWrap / FoilBox 713219 Temperature 27.10.14 ambient 635933 Temperature 27.10.14WCsufacemeat

635932 Temperature 27.10.14PBsurfacemeat 635930 Temperature 27.10.14foilbxoutmeat

713222 Temperature 27.10.14chillboxoutmea

In 2002, the founder of Woolcool, Angela Morris, worked as a packaging consultant for the UK National Trust, and was briefed to consider options for keeping fresh food and perishable products chilled below 5°C for at least 24 hours to ensure safe delivery direct to the consumer. Using polymer-based, unsustainable and environmentallyunfriendly packaging materials was not an acceptable option, as this did not fit with National Trust environmental policy and ethics. Alternative natural materials were considered, such as bio-plastics and starch-based products, these were tested and found to be unsuitable for this type of packaging application.

26

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AMBIENT

22

20

Temperature (°C)

18

16

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12

FOILBOX Under 5degC for 4hrs 20mins

10

8

EPS Under 5 degC for 16hrs 40mins

FOILED BUBBLEWRAP Under 5degC for 10hrs 50mins

6

WOOLCOOL Under 5degC for 25hrs 10mins

4

2

36 hrs

33 hrs

30 hrs

27 hrs

24 hrs

21 hrs

18 hrs

15 hrs

12 hrs

9 hrs

6 hrs

3 hrs

0 hrs

0

Figure 2: Temperature performance Comparison Graph between current packaging materials

Figure 2: Temperature performance comparison graph between current packaging materials Thermal shock can be identified on a trial graph as a significant, sharp downward temperature ‘spike’, as shown by the green line in Figure 1 (data was obtained by the authors following standard internal laboratory procedures that are compliant with the GDP 2013 guidance. Ambient temperature refers to 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

How can this huge global cold-chain problem be solved? There are two distinct issues, firstly, to find a solution that is not only effective at maintaining the 2-8°C temperature range across extremes of climatic conditions and over long periods of time and eliminates the ‘spike’, but also meets the criteria of sustainability, being

Wool was considered as a possible solution. There is archaeological evidence that wool technology has been used for at least 6000 years by our forebears, not only for garments but also as an insulative building material and for the storage of fresh foodstuffs. Today the National Trust uses sheep wool to insulate their properties as this maintains the original form of insulation used in the past. It must be stressed that the insulative properties of wool enable protection from both heat and cold. Because of their crimped nature, when wool fibres are packed together, they form millions of tiny air pockets which trap air, which in turn serve to keep warmth in during winter and out in the summer. Wool's unique advantage is its breathability. That is its ability to absorb and release moisture from the surrounding air, without compromising its thermal efficiency. Sheared dirty wool was washed and scoured to a prescribed process that falls Winter 2016 Volume 8 Issue 4


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 61


Labs & Logistics under Pollution, Prevention and Control (PPC) regulations 2000. Clean 800gsm wool was felted to a thickness of 35mm, using a mechanical needling process, where no heat is used. The resulting felt was covered with a recyclable medium density polyethylene (MDPE) sleeve to produce liners that were used to line the inside of a corrugated cardboard box. Using a strictly controlled protocol, a timed temperature trial was undertaken, which included an EPS moulded box, a corrugated cardboard box lined with polyethylene foam and the wool-lined corrugated cardboard box. All had the same product volume, same type and weight of phase change material and the same weight and type of food product. The ambient temperature was recorded and temperature data loggers were used within the boxes. The wool-lined box outperformed the man-made materials and demonstrated superior insulation capability. Product development continued and millions of wool liners have since been manufactured and used to transport fresh and frozen food and, more recently, temperature-sensitive pharmaceutical products. In 2016 this equated to the fleece from approximately 3 million sheep – more than 10% of the UK sheep population. All commercial insulation material is tested for its Lambda or K value, which is the rate at which heat is transmitted through a material, measured in watts per square metre of surface area for a temperature gradient of one Kelvin per metre thickness, simplified to W/mK. The lower the1. value, the better the thermal Table Lambda - W/mK efficiency of the material.

Depending on the weight of wool per square metre and the felting process, when wool was tested independently, values were recorded as low as .029 W/ mK, bearing in mind that still air, which is the most effective natural insulator has a value of 0.02 W/mK. See Table 1 for insulative values of various packaging and other materials. The lower the λ value, the better the insulation property of the material. The inherent properties of the complex wool fibre structure (see Figure 3) have evolved over millions of years, protecting sheep from extreme seasonal weather conditions, extreme temperatures and dry, wet or humid conditions. This has created a ‘smart’ fibre that as yet has not been replicated by modern textile technology.

Cuticle On the outside of the wool fibre is a protective layer of scales called cuticle cells. They overlap like tiles on a roof. This stops water penetrating the fibre but allows absorption of water vapour. This makes wool water-repellent and resistant to water-based stains. Cortex The cortex – the internal cells – make up 90% of the fibre. There are two main types of cortical cells – ortho-cortical and para-cortical. These provide fibre crimp, which makes wool feel springy and provides insulation by trapping air, thereby improving its thermal insulation properties. Cortical cell The cortical cells are surrounded and held together by a cell membrane complex, acting similarly to mortar holding bricks together in a wall. The cell membrane complex allows easy uptake of dye molecules. Macrofibril Inside the cortical cells are long filaments called macrofibrils. These are made up of bundles of even finer filaments called microfibrils, which are surrounded by a matrix region.

Figure 3: Wool Fibre Structure Each element of the fibre structure is responsible for imparting special properties to the fibre, for example:

Matrix The matrix consists of high sulphur proteins. This makes wool absorbent because sulphur atoms attract water molecules. Wool can absorb up to 30% of its weight in water and can also

Mediterranean Temperatures Trial 627261 Temperature 3.9.14 Woolcool trpl 713232 Temperature 9.9.14 ambient

(K values) of materials

35

62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

25

20

15

10

5

114 hrs

108 hrs

96 hrs

90 hrs

84 hrs

78 hrs

72 hrs

66 hrs

60 hrs

54 hrs

48 hrs

42 hrs

36 hrs

30 hrs

24 hrs

18 hrs

12 hrs

6 hrs

0

102 hrs

Table 1: lambda - w/mk (k values) of materials

30

Temperature (°C)

K Values 50 W/mK 1.6 W/mK 1.1 W/mK 0.12 W/mK 0.037 W/mK 0.029 W/mK 0.020 W/mK

0 hrs

Material Steel Concrete Glass Wood EPS Wool Still Air

Wool Trial at Mediterranean Temperatures - 95 hours between 2° and 8°C Figure 5: Wool Trial Fig at5:Mediterranean Temperatures – 95 hours between 2° and 8°C

Winter 2016 Volume 8 Issue 4


Labs & Logistics

Table 2: Known and researched properties of wool Thermal

A natural thermostat. Stable climate control, warm and cold

WPC Research

Hygroscopic

Absorbs and releases moisture up to 35% of its own weight

(Cassie 19581)

Elasticity

Naturally returns to its original size and shape

(Harris 19422)

Carbon Sink

Wool absorbs carbon from the atmosphere whilst sheep graze

Natural material

Absorbs Toxins

Proven to absorb and lock in toxins such as Formaldehyde

(Curling et al 20113)

Absorbs Bacteria

Wool has natural antimicrobial properties

(Ammayappan et al 20095)

Eco-friendly

Wool is compostable, releasing nitrates back into the soil

Natural material

(Wortmann et al 20094)

1

Cassie, A. B. D. 1958. The physics of fibres with special reference to wool. Wool Industries

2

Harris, M., L. R. Mizell and L Fourt. 1942. Elasticity of Wool as Related to its Chemical Structure. Journal of Research of the National Bureau of Standards, Vol 29, Washington. 3

Curling, S. F., C. Loxton and G. A. Ormondroyd. 2011. A rapid method for investigating the absorption of formaldehyde from air by wool. Springer Science and Business Media, LLC. 4

Wortmann, G., S. Thome, A. Sweredjuk, G. Zwiener and F. J. Wortmann. 2009. Chemisorption of protein reactive indoor air pollutants by wool. University of Manchester, UK 5

Ammayappan, L. and J. Jeyakodi Moses. 2009. Study of Antimicrobial Activity of Aloevera, Chitosan and Curcumin on Cotton, Wool and Rabbit Hair. Central Sheep and Wool Research Institute, Jaipur, India. Fibers and Polymers 2009 Vol 10., No.2, 161-166. Research Association, Headingley, Leeds.

absorb and retain large amounts of dye. This region is also responsible for wool’s fire-resistance and anti-static properties. Microfibril Within the matrix area, there are embedded smaller units called microfibrils. The microfibrils in the matrix are rather like the steel rods embedded in reinforced concrete to give strength and flexibility. The microfibrils contain pairs of twisted molecular chains. Twisted molecular chain and helical coil Within the twisted molecular chains are protein chains that are coiled in a helical shape, much like a spring. They link each coil of the helix, helping to prevent it stretching. The helical coil – the smallest part of the fibre – gives wool its flexibility, elasticity and resilience. The optimisation of wool fibre properties, as listed in Table 2, would enable vaccines and medicines to be delivered safely according to time and temperature industry requirements, thus providing a viable and superior alternative to existing oil-based packaging. Independent trials have proven beyond doubt that due to its superior insulation properties, significantly less PCM material is required to maintain temperatures within the packaging between 2° and 8°C for 72 hours and up to 150 hours, whilst also eliminating the damaging downward temperature ‘spike’ (see Figure 5). www.ipimedia.com

This can also mean a 50% reduction in overall pack footprint, combined with a 60% weight reduction and an increase of 25% in product capacity – a ‘win-win’ for cost savings and improved logistics efficiency. The IP resulting from this research has resulted in four new UK Patents Pending and the creation of a new, groundbreaking insulated packaging product, “LifeGuardian’, which was successfully launched at IQPC Cool Chain Europe in January, 2016. Whilst there are approximately 1 billion shearable sheep globally, this renewable resource is insufficient to totally replace EPS and other man-made insulated packaging materials. However, there is sufficient wool of the grades required to fulfill the global demand for the packaging of high-risk, temperaturesensitive vaccines, a US$ 30Bn market that is expected to grow at approximately 12% CAGR to 202010. Replacing oil-based packaging with a superior, natural ‘smart fibre’, which is available globally, will not only save lives by ensuring the safe and effective delivery of medicines, vaccines and blood products but also protect environments and help communities on a global level11. The real challenge however, is not proving the performance of wool, but rather convincing the pharmaceutical industry to open its eyes and accept the huge credibility that wool, this amazing

natural and sustainable ‘Smart Fibre’, possesses. References 1. WHO Department of Immunisation, Vaccines and Biologicals 2005. Monitoring Vaccine Wastage at Country Level. WHO/V&B/03.18. Rev1 2. 2013 EU Good Distribution Practice (GDP) Guidelines for the wholesale distribution of medicines for human use. (2013/C 343/01) 3. Matthias D. M., Robertson, J., Garrison, M. M., Newland, S. and Nelson, C. 2007. Freezing temperatures in the vaccine cold chain: A systematic literature review. Vaccine 2007: 25; 3980 – 3986. 4. WHO 2007. Aide-memoire for prevention of freeze damage to vaccines. WHO/IVB/07.09. 5. Bill & Melinda Gates Foundation. 2012. Vaccine-Preventable Diseases Overview. www.gatesfoundation.org/vaccines/ pages/overview.aspx 6. EUROPEAN COMMISSION Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (Text with EEA relevance)(2013/C 343/01) 7. Bandyopadhyay, A. and Basak, G. C. 2007. "Studies on photocatalytic degradation of polystyrene". Materials Science and Technology 23 (3): 307– 314(8). Maney Publishing. 8. WHO 2007. Aide-memoire for prevention of freeze damage to vaccines. WHO/IVB/07.09. 9. Source: wwwchem.uwimona.edu. jm 10. Research & Markets Inc. 20 May 2014 (“Global Vaccine Market Outlook to 2020”) 11. Source: Sustainable, Insulated Packaging, Sheep Wool http://www. icevirtuallibrary.com

Keith Spilsbury, Strategic Director, Woolcool Keith Spilsbury has over 30 years’ experience in sales and marketing, having held senior European management positions with several blue-chip international companies. His business skills have enabled The Wool Packaging Company to establish its product Woolcool® as an international brand leader within the sustainable insulated packaging sector for mail order food and temperature-sensitive pharmaceuticals. Email: keith@woolcool.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 63


Labs & Logistics UAE – Dubai: Opening the New SkyPharma Facility of Emirates In mid-September, Emirates SkyCargo unveiled its new purpose-built pharma facility – certified under EU Good Distribution Practice guidelines. The carrier operates the first and biggest GDP certified multi-airport hub in the world. On the 18th September, Emirates SkyCargo opened their new purpose-built facility dedicated exclusively to the secure and timely transport of temperature-sensitive pharma shipments at Dubai DXB. His Highness Sheikh Ahmed bin Saeed Al Maktoum, Chairman and Chief Executive of Emirates Airline and Group, along with His Excellency Abdul Rahman Al Owais, Minister of Health, and His Excellency Humaid Mohammaed Obaid Al Qatami, Chairman of the Board and Director General of Dubai Health Authority, were present at the inauguration. “Pharmaceuticals are one of the most important products we transport because of the impact on people’s lives and communities across the world. As a leader in the global air cargo industry, we decided that it was not only important for us to build state-of-the-art cool chain facilities for the transport of pharma products, but also go the extra mile and ensure the compliance of our operations against the highest international standards. Our customers can continue

to rest easy, knowing that shipping their high-value and temperature-sensitive goods with Emirates SkyCargo is a safe and efficient choice for their business and end customers,” said Nabil Sultan, Emirates Divisional Senior Vice President, Cargo.

The Facts The first and largest GDP-certified multiair hub in the world offers 4000 square metres of space, dedicated to pharma cargo. It also features temperaturecontrolled individual positions in the automated aircraft pallet handling system and five temperature-controlled acceptance and delivery truck docks. The Cargo has been awarded the certification of compliance under the EU GDP guidelines by Bureau Veritas, following an audit conducted by the certification agency’s team from Germany. The certification validates the carrier’s adherence to the strict guidelines on the transport and handling of pharmaceutical products and covers all Emirates SkyCargo handling activities for pharma products in Dubai.

The Numbers • 11,000 square metre extension of Emirates SkyCentral terminal • 4000 square metres of space dedicated to pharmaceutical cargo

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88 temperature-controlled individual positions in the automated ULD handling system Five temperature-controlled acceptance and delivery truck docks 8600 square metres of combined handling space dedicated for pharma products 11,000 tonnes of pharmaceutical products shipped in 2015 150 cities across 82 countries in six continents More than 250 aircraft, including 15 freighters, 13 Boeing 777-Fs and two B747-400ERFs

The New Facility The new Emirates SkyPharma facility at DXB works in conjunction with Emirates Sky Central DWC, the carrier’s freighter hub in Dubai World Central. Both facilities complement the range of innovative cool chain products and solutions offered by Emirates SkyCargo, including the Cool Dolly, the White Container, and White Cover Advanced – which are designed to prevent temperature fluctuations or spikes from occurring during any part of the transportation process. “Throughout the audit process we found strong evidence of Emirates SkyCargo’s commitment across all levels to deliver high quality and secure transport for pharma products,” said Mr Ahmad Chauk, Vice President, Sales and Marketing, Middle East, India, Caspian Sea & Africa Operating Group, Bureau Veritas. The financial year 2015-16 was really strong for Emirates SkyCargo, with a 6% increase in airfreight, to 2.5 million tonnes. Contributing 14% of the airline’s total transport revenue, Emirates SkyCargo continues to play an integral role in the company’s expanding operations.

Orsolya Balogh Managing Editor IPI 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2016 Volume 8 Issue 4


Are your pharmaceuticals on time, in the right condition, and in the right location?

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Labs & Logistics

Flying High at IAG Cargo The air cargo industry is the preferred logistics partner of the pharmaceutical industry as it relies on air transport for its speed and efficiency in delivering highvalue, time-sensitive and temperaturecontrolled cargo. But maintaining the required temperatures from end to end of the supply chain is quite a challenge and the air cargo industry is stepping up its game. Cecilia Stroe, staff editor of IPI, looks into the long-term investment IAG Cargo is making at Heathrow Airport and the expansion of their premium freight capabilities. There is no doubt that, as the cool chain sector is growing, fuelled by the rising movement of pharmaceuticals, investing in infrastructure has become a high priority across the supply chain. IAG Cargo, the business created following the merger of British Airways World Cargo and Iberia Cargo in 2011, is set to build a new premium facility at its London Heathrow Hub, with a larger dedicated Climate quality centre for pharmaceuticals, new delivery and collection doors and an advanced warehouse management system that will prioritise freight. Twice the size of IAG`s existing Premia facility, the building has been designed around the modern demands of premium airfreight and will become operational in 2018, managing the flow-through of all express prioritise shipments and passive constant climate shipments. “IAG Cargo’s four airlines now carry more premium freight than at any point in their combined history. With the continued growth of high speed e-commerce and cool chain logistics in particular, as well as the ongoing expansion of the IAG family and network, we need facilities that are ready for the next generation of premium freight,” said Drew Crawley, CEO of IAG Cargo. “We believe that the blend of our next generation aircraft, new freight facilities such as this one and our expanding network mean that IAG Cargo is extremely well positioned in the market to meet the current and future premium 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

freight demands of all our customers. Our new premium warehouse will be built away from existing Premia, leaving our current operation and customer service unaffected,” pointed out Crawley. It`s been an exciting year for the new CEO, Drew Crawley. “We think premium is where we can really differentiate. I believe in getting to understand the needs of the customer, by which I mean the shipper. We need to get ahead of the game, to constantly meet the needs of the market and we have the tools in our kit.” Don`t Get Left Out in the Cold Ten years into carrying pharmaceuticals on a dedicated temperature-controlled service, the carrier has seen strong growth in their segment. If in the first year, its Constant Climate service moved 400-500 shipments, now it carries over 35,000 shipments annually. The volume growth has followed the increase of global pharmaceutical sales, which passed the $1 trillion mark for the first time at the end of 2014 and is anticipated to reach $1.3 trillion by 2018.

carrier, we offer the safest and smoothest way to ship time- and temperaturesensitive cargo,” explains Dorling. The biggest challenges the industry is facing are cost management, regulatory compliance, product security and mitigating product damage and spoilage, avoiding temperature excursions in shipments on unprotected airport tarmac areas, that is. Experts believe the new frontier for the cold chain is truly opening up with the rise of personalised medicine, cell therapy and gene-editing and a number of developments are generating growing demand for active temperature-controlled solutions. The emphasis on prevention at national health authority level, for example, has fuelled a constant flow of vaccine shipments around the world and the rise of biologics, highly sensitive to temperature excursions, is boosting the demand for temperature-controlled transport.

Alan Dorling, Global Head of Pharmaceuticals and Life Sciences of IAG Cargo, expects this momentum to grow, despite efforts in the industry to rein in expenditure. Faced with cost pressure and slimming margins, pharma shippers have experimented with ocean transport, but Dorling thinks ocean freight is an alternative – not a competitor to airfreight: “speed-to-market remains a strong factor in favour of air freight.”

There is a move from single, multi-site manufacturing to global manufacturing and other key developments include the rising instances of diabetes, particularly in central Latin America and the Middle East, which is fuelling the major rise in insulin sales, expected to reach $48 billion by 2020. “Obesity is a worldwide epidemic problem for the major developed countries and incidences of diabetes are growing at a rate of more than 12 per cent a year. Insulin has become a vital biological product that needs temperature control, so it is very much an airfreight product. Insulin is one of our most shipped products,” Dorling said.

If complete control is what you`re looking for, Constant Climate delivers all the care and precision whether transporting vaccines, biotech products, diagnostic samples or any other temperature-sensitive pharmaceutical material. “We make sure it stays in perfect condition every step of the way. It is all about speed and efficiency. With priority access to capacity, the latest cut-off time and the earliest cargo available of any

Constant Climate, the precision temperature-controlled product designed for the transportation of temperaturesensitive pharmaceutical material, offers a choice of two flexible cold chain management systems. The active and passive variants of Constant Climate have the capacity to support temperaturespecific shipment requirements ranging from as low as minus 20˚C to as high as 25˚C. Winter 2016 Volume 8 Issue 4


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www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67


Labs & Logistics

The active solution, using sophisticated active heating and cooling containers, maintains a stable internal temperature regardless of changes in the ambient temperature. This solution supports temperatures from -20°C to +25°C and has features such as a shipment prealert process, which means no shipment will be arriving unannounced, reducing aircraft side out; at the same time, the latest possible delivery to aircraft and immediate transportation to warehouse upon aircraft unloading is meant to minimise tarmac exposure time, “the biggest risk in an airport,” according to Dorling. The passive solution is designed for the transportation of pre-packaged shipments to maintain the desired product temperatures, ensuring product integrity without any human intervention. Best Practice is “Thinking Inside the Box” Globalised production requires airfreight to link pharmaceutical manufacturing with packaging and an array of other elements, pointed out Dorling. This time around, he says, it`s a case of “having to think inside the box” because the main concerns of the shippers in temperaturecontrolled supply chains are human error, temperature monitoring capabilities, and transparency. This business is all about expertise, 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

training and up-to-date facilities. There is no way around it, stresses the manager: “There is a quality manager at every station to ensure outstanding performance, temperature control every step of the way. Customers want total reassurance during transit, storage, loading and throughout the flight.” He points out that IAG Cargo was the first European airline to achieve QEP accreditation across multiple countries and to have been awarded Wholesale Distribution Authorisation and Good Distribution Practice Certificate for medicines by a national authority, the UK Medicines and Healthcare Regulatory Agency (MHRA). Since 2014 the carrier also offers specialist GDP and IATA Chapter 17 regulation training, through the so-called “GDP academy”, a joint venture with Exelsius, providing over 1000 hours annually of training for its supply chain partners. According to David Shepperd, Commercial Director of IAG Cargo, “it`s easy to look at the industry and to say there`s not much room for investment,” but investing “is a vote of confidence in the business.” A business that took a while to take off, he remembers. “It was a slow burn, but now I believe in our current place in the premium market, one that

has changed in the last five years. IAG is in the midst of a major fleet renewal programme, which is opening up new route opportunities and providing greater capacity on key trade lanes.” IAG`s setup now comprises 110 constant climate centres, which cover the main traffic lanes for this industry. The company has a combined workforce of more than 2500 people, covering a global network of over 350 destinations. “Over the past few years we have continued to see year on year growth in premium freight. Our commitment to consistently deliver a high level of service to our customers has undoubtedly influenced our strong performance in this market. We want to continue our growth and performance in this sector and our new facility will help to deliver this,” added Sarah Coulson, Head of Strategy and Business Development.

Cecilia Stroe IPI Staff Writer

Winter 2016 Volume 8 Issue 4


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

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Advertorial Just What the Doctor Ordered: Yusen Logistics, the Best Medicine for your Supply Chain Whether modelling and executing complex global solutions or providing regional operations, Yusen Logistics has the network and the industry expertise to support the highly complex healthcare supply chain across air, ocean, road and rail.

to improve and optimise supply chains drives innovation and holds the key to competitive advantage.

Headquartered in Tokyo, the company has built a solid foundation over the last 25 years, investing heavily in specialised services, facilities, personnel and knowledge, says Carsten Reuter, Head of Healthcare Industry Vertical, General Manager Europe Region.

When it comes to optimising freight models, explains the manager, it all comes down to meeting challenging timescales, temperature demands and security requirements and operating within GDP compliance. “The demands are getting stricter and it is all about getting from theory to practice and focusing on doing things smarter; and having a greater flexibility to consolidate, whether it is by road, air or ocean.”

Demand-driven, Yusen has become a truly global operating logistics service provider, offering supply chain management, planning and consulting, global freight forwarding services and domestic transportation services in all major markets for all industries.

“Yusen`s capabilities have increased and developed in a dedicated service. It is a clean operation and is more about doing things the right way, adapting international processes to suit local situations. This is what really differentiates us from the pack,” Reuter points out.

We are talking about a global network spanning nearly 300 cities in 40 countries, with almost 2.16 million square metres of strategically located warehouse space; a network that in Europe alone has 77 operational sites, over 670,000 square metres of warehouse space and more than 4300 employees.

What Happens at ‘Ground Level’? According to Yusen`s philosophy, in order to arrive at any strategic solution, it is essential to fully appreciate what happens at ‘ground level’.

There is a lot going on in this industry and it will definitely not get easier going forward, thinks Carsten Reuter. As big pharma faces cost pressures, the need

Yusen Logistics’ Healthcare Control Tower, located in Milton Keynes, manages global air and sea freight movements complete with a full range of Customs and fiscal services, linking into the company`s offices around the world.

“The Control Tower enables us to offer efficient solutions for deliveries into and collection from our pharmaceutical road transportation network,” explains James Colson, General Manager Yusen Logistics (UK). “What we offer is added value, smart road freight in the most costeffective manner.” With the right team in place and a strong collaborative approach embedded, Yusen is now focusing on continuous improvement, by examining trends and identifying opportunities. “We continuously look at ways to improve things and implementing procedural changes”, adds the UK manager. The pharmaceutical supply chain specialists at Yusen apply the Japanese principle of Gemba, working closely, onsite with their customers to design more agile, lean global supply chains. We are definitely agile enough to meet customer, market and legislative requirements, reveals Carsten Reuter. The Control Tower provides aerial views across Europe, whatever the origin or destination, as well as managing inbound/outbound global flows. This enables centralised planning of panEuropean transport movements in order to maximise vehicle utilisation, minimise empty running, reduce pallet costs and achieve environmental benefits, whilst ensuring product integrity. “Over the years, we have focused on building core competencies and capabilities and at the moment we are well equipped and able to support international operations and provide visibility to the customers at all times,” adds James Colson. Yusen Logistics has in-depth experience in re-engineering complex global flows and optimising freight models. “We pride ourselves on improving quality, eradicating risk and achieving ongoing cost-down, faced with challenging timescales, temperature demands and security requirements.”

70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2016 Volume 8 Issue 4


Advertorial enhance performance, reducing lead times and costs can all be achieved, whilst reaching performance targets.

A Lean, Mean Machine Yusen Logistics` European Pharmaceutical Superhighway carries nearly 2 million pallets per annum, providing both shared and single-use solutions to highly complex supply chains for customers ranging from global manufacturers to small biotech companies. Managed by the Control Tower, the Superhighway relies on a strategic network of specialist pharmaceutical hubs that consolidate and cross-dock product for onward delivery throughout Western and Eastern Europe and worldwide. It is a high-security service, which provides high-quality, cross-border, temperature-controlled coverage on a true pan-European basis, with flexible GDP solutions ensuring complete product integrity and legislative compliance, Colson explains. Solutions range from the delivery of raw materials, including API, into the manufacturing process to delivery of finished drugs and equipment to inmarket distributors, hospitals, pharmacies and surgeries. “We have to work with strict parameters. However, pharma is a very dynamic operation and to meet peaks and demands, we need extreme flexibility.” Yusen`s Pharmaceutical Superhighway is serviced by a GDP-approved fleet of 5500 trailers and 210 express vehicles, a mix of own resources and those of fully audited and approved haulier partners (45 core carriers, long-term partnerships, many of whom are family businesses and are audited every two years). The www.ipimedia.com

hauliers are managed by a dedicated team, who ensure they meet current GDP regulations, as well as providing the highest level of reliability and security to Yusen Logistics’ customers. All vehicles are temperaturecontrolled for both ambient and cold chain products, GPS tracked with remote temperature monitoring and operating to GDP guidelines, ensuring safe transit and delivery. For controlled drugs and narcotics, additional controls are in place, including dedicated solutions for a single pallet upwards where required. The Superhighway operates on the inhouse strategically developed transport management system, Vision, which has been tailored to the exacting demands of pharmaceutical tracking requirements. Dedicated healthcare experts manage all transactions from receipt through final delivery, ensuring GDP compliance and full shipment transparency throughout the supply chain. Using Vision, the planning team can build milk-runs, co-loads and road trips, and decide whether to cross-dock product or deliver direct. Vision also manages payment of the haulier partners and generates customer invoices. The system ensures receipt of PODs and temperature reports, providing reports to support operations and KPI data so that freight can be optimised, delivering continuous improvement. With maximised co-loading opportunities for onward movement to

More Connected, with Vision “A Rolls-Royce type of service” as Carsten Reuter sees it, the Control Tower represents for James Colson very much “the ultimate connecting element”: relying upon total quality management, total product maintenance and visual management to deliver maximum quality. In the past 18 months, there`s been a massive investment in the development of Vision, a third-party vehicle tracking system meant to give customers access to data. “For the customers, it is a proactive tool. The industry demanded this and we were willing to make the investment. This is what we do; we listen to what the customer needs are and we develop in that precise direction. With security being an ever increasing issue, adding an extra layer of visibility was extremely important.” According to Colson, it is simply about providing maximum visibility, tracking and planning across the supply chain, from origin to destination. As a proprietary online solution, Yusen Logistics’ systems are customisable and integrate seamlessly with each customer’s current systems and processes. The flexibility afforded by this approach allows for quick implementation times and minimal business disruption, while providing maximum business control. “We can bring our customers so much extra value, by allowing their supply chain to deliver strategic competitive advantage rather than simply being an unavoidable operational cost. It is definitely a win-win situation; that`s why we are integral to their business.”

Carsten Reuter Head of Healthcare Industry Vertical, General Manager Europe Region Yusen Logistics (Europe) Tel. +49 (0)40 468957 551 (direct) James Colson General Manager Healthcare, Yusen Logistics (UK) Ltd Tel: +44 (0)1525 287321

INTERNATIONAL PHARMACEUTICAL INDUSTRY 71


Manufacturing

Improve Production Efficiency from Tablet Design to Tool Material Specification Efficiency in solid dose manufacturing can be improved at the earliest stages of the tablet design process, by utilising precise tooling specifications. The design and material selection can have a major influence on the final product. With the help of a quality tooling manufacturer to identify specific requirements, elimination of downstream tabletting problems can be achieved. It is important to implement an effective tooling specification for a number of reasons, including reducing the time to market, by addressing specific product challenges and preventing nonconforming product which will ultimately reduce costs through quality by design (QbD), and result in a faultless end product. To introduce effective tooling specification, it is key to open up discussions with your tablet tooling supplier. By providing detailed information, the most productive solutions can be found for specific tabletting requirements. Details including tablet product and press and tooling information will all help in specifying the most appropriate requirements for the job.

Figure 1 – Effective Tooling Specification Tablet tooling manufacturers can optimise the design and material selection to allow the best possible productivity for the tablet tooling in the press. This is done by obtaining clear basic information on the product. It is important to firstly look at the formulation being used as this can have a significant influence on tablet design, 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tool material selection and coating. Some formulations can cause adverse effects on the punch tips when under compression, causing abrasion, pitting or corrosion. Although tools are manufactured from hardened and tempered tool steel, the demanding processes involved can lead to deterioration if the tool material is not optimised to suit the formulation being compressed. Some granules are extremely hard and abrasive and can scratch, wear and impregnate the steel surface. Other granules can contain corrosive elements which react with the steel.

Figure 2 - Issues you might encounter (sticking, pitting, corrosion, wear) These effects can be reduced by understanding the nature of the formulation to be compressed and carefully selecting a tool steel and/or tool coating to resist this at the earliest stage of the tool specification process. A competent tooling supplier will have a range of steels and coatings in order to fulfil a mix of properties, the optimum being those that combine the very best combination of properties to suit your specific product. Dwell Time Dwell time is the time that the punch head remains in contact with the compression roller and is another important factor to be considered when initiating good tooling set-up. Many tablet formulations are dwellsensitive and require more time under compression to guarantee they come

off the press without any faults. Some granules are extremely difficult to compress effectively and require extended time under peak compression to obtain the required tablet hardness and prevent any problems. Slowing the tablet press down to achieve an increase in dwell can eradicate these issues, but this leads to a reduction in tablet production. With the help of a tablet tooling expert who has innovative tooling solutions, it is possible to increase the dwell time without slowing the press speed. Tablet Shape & Profile The correct tablet shape and profile is key in finding a successful tooling specification. When specifying tablet tooling, a very important element to start with is the design of the tablet. The choice of shape and profile is critical, as different tablet shapes and profiles can present different challenges. There are two basic tablet shapes – round and non-round; however, the complexity of non-round shapes is extremely varied and many complex designs may require specialised tool manufacturing capability. Once the shape has been decided, next to consider is the tablet profile. The type of profile required is influenced by several factors: the granule, embossing requirements, coating process, packaging and the company’s branding.

Figure 3 – Tablet Profile If the design is to be heavily embossed with a lot of characters, it is important to avoid tablet profiles with a deep cup, Winter 2016 Volume 8 Issue 4


Manufacturing such as the ball or pill. Deep cup profiles can cause a softer core in the tablet which can in turn lead to sticking. It will also reduce the available space for the embossing itself; the use of a profile that is shallower with a reduced cup depth will allow for a larger embossing area. These are all details that any quality tooling provider will have knowledge on and can be incorporated easily in the design. Branding When considering the visual appearance of the tablet, it is crucial to think about the type of font and logo. Typefaces and designs must take into account practicality of tablet manufacture. Tablet designers need to consider how the identification will scale up and down according to the size of the tablets being produced.

Figure 4 – Logos and embossing Focus on the correct font style is also important to avoid tabletting problems such as ‘sticking’ and ‘picking’. Sticking occurs when particles of the tablet formulation adhere to the punch face. It has a negative effect on appearance of the tablet and can become so serious that production can be interrupted, and in extreme cases the punches may have to be removed to be cleaned. This is disruptive and labour-intensive, reduces yields and increases production costs. Picking is another problem directly linked to tablet design. Picking is compressed granule that has adhered to the detail on the punch face, resulting in ‘picking out’ of parts from the tablet face. To reduce picking, the best practice is to design font styles that have large open counters and no sharp corners, which could act as a trap for granule. Selection of the right font style can also help to avoid coating problems, tooling failures and lack of distinction. Failure to consult with an expert tablet design team could result in a product that looks good on paper but is not practical to produce. www.ipimedia.com

Figure 5 – Sticking v Picking Coating Consideration should be given as to whether the tablet is to be coated. Successful coating is dependent on tablet profile and its ability to roll to ensure even coverage. Coated tablets present challenges for the tablet designer. Many of the variables are within the manufacturer’s control but expert tablet design can help eliminate potential problems. Coating can also be a major factor in the choice of the cup profile being used. Applying a double radius profile would help if the product is to be coated as it allows the tablet to roll better in the coating pan to ensure even coverage. If a flat bevel profile, for example, was applied, the tablet would just skid in the pan and not roll over, leading to a number of problems including twinning, when tablets stick together. This is normally caused by the flat surfaces of the tablets coming into contact and adhering to each other. To avoid this, a slightly curved surface can be applied, which reduces the contact area and eliminates the problem. The process of defining the best shape and profile for the coating process can be addressed easily if an effective tooling specification is implemented. Problems like twinning will have a major effect on tablet waste, however they can be avoided with the expert knowledge of the tooling supplier

Anti-counterfeiting Techniques With counterfeiters becoming more technologically advanced, basic tablet designs are easily reproduced. The purpose of an anti-counterfeiting feature is usually to enable the authentication of an item, and also to act as a deterrent to anyone considering counterfeiting a product. An expert tablet designer can employ techniques to make this more difficult. If counterfeiting is a threat to your product and brand, it is important that your marketing or R&D departments work in partnership with a specialist tablet design team so that any counterfeit measures will be incorporated into the design from the outset. If left unchecked, counterfeiters my take a share of your market and indeed your profits. Complex Designs and the Effect on Tooling Tablets are becoming more complex and unusual in both shape and profile. As the tablets become more intricate, so does the tooling, which increases the demand for tooling strength, durability and overall performance. This has to be a major consideration when designing a tablet and brings us to the next important factor that needs to be discussed with the tooling manufacturer - the press and tooling equipment. Tablet tooling has to combine intricate design and functional requirements to ensure productivity and durability are at their maximum in manufacture. To follow this important process, tool coatings are commonly used to offer a solution to tablet punch and die wear, and solve sticking issues. It is important to remember that punches and dies are the most critical interface with your end product, the tablet, so using the correct material and coating is imperative.

Figure 7 – Complex Designer Shapes Figure 6 - Twinning INTERNATIONAL PHARMACEUTICAL INDUSTRY 73


Manufacturing Tooling Performance When looking at tooling performance, consideration should be given to the tools’ ability to manufacture tablets that are representative of a manufacturer’s requirements and product yield. There is little point in selecting a design that will not stand up to the demands of tablet production. The following should be considered when designing the product: • • •

Are the fitting processes controlled for designs that require delicate handling and setting up? Is the choice of tooling material and coating appropriate for the formulation being compressed? Once a cycle is completed, are the tool maintenance procedures optimised for ensuring prolonged tooling life? Can the design withstand prolonged cyclic loading and fatigue to produce a well compacted tablet? This is particularly important when specifying a requirement for multitip tooling.

These questions are important to ask and also lead to examining any tooling management that may have been implemented. In pharmaceutical manufacture, the importance of efficiency and accuracy in managing and monitoring tooling is paramount. Without a system that controls the procedure effectively, there can be adverse effects to the bottom line. Installing a system that allows tablet manufacturers to keep a record of the tablets being produced from the quantity to batch information, production can run efficiently. There are innovative systems out there that can incorporate this whilst including indepth guides to tooling specification and troubleshooting, so any problems are flagged up and rectified quickly, resulting in increased productivity, saving both time and money.

Figure 8 – Stress and Fatigue Analysis

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Finite Element Analysis Stress and fatigue analysis of a punch tip should be considered by using finite element analysis, or FEA. Quality tablet tooling suppliers will use this method in the design process. When assessing the results of the FEA, it is essential to identify areas of high stress concentration which can lead to breakage. A good tablet design should ensure that the stresses are equally dispersed across the shape. An expert tooling designer will be able to add appropriate strengthening features such as blended lands and profile changes. They should also ensure that any embossing detail is not in direct proximity to the high stress areas. Optimising the embossing position on the tablet face can be of benefit to the strength of the design, rather than detrimental. One of the most important features of any tablet design is the blended land. Often, tablet manufacturers elect not to apply a land as it may not be visually acceptable on the finished tablet. Lands that are applied incorrectly, either unevenly or made too large, can present a range of issues, including flashing or lamination during compression, chipping of the land during take‐off, or build‐up of coating on the edge of the tablet, which will eventually chip.

and produce a detailed drawing of the tablet to be produced. This will consist of information that will be required to make a successful tablet. Tool drawings should include specifications, tolerances, clearance and instructions that the manufacturing team use to create the finished precision engineered product. All the information on the drawing is critical to ensuring high manufacturing standards. Once the initial drawing is made, further detail – for example, critical parts of the tooling like headforms and key positions – should be investigated. Providing your tooling supplier with the correct information early on will help in identifying the right specification without delay. Multi-tip Tooling With productivity and volume becoming an increasingly key requirement, investigating ways to improve output is essential. This is something that can be considered once the desired design and tooling information is decided.

Tablet Drawing

The most effective way to fulfil this requirement is through multi-tip tooling which offers a number of benefits, including greater productivity, owing to the increased number of tablets per turret rotation, and a reduction in runtime per output of tablets, leading to less maintenance per batch and reduced press set-up time. Multi-tip tooling also reduces the press set-up time for the quantity of tablets produced. There should be no requirement to purchase a new tablet press to increase production when a multi-tip solution is adopted, therefore there is no capital outlay on new tablet presses and fewer presses are required to satisfy production levels.

Figure 9 - Tablet Drawing Example

Figure 10 – Multi-tip Tooling

Quality tooling suppliers will take all the information and elements given to them

With the combination of correctly designed tablets and multi-tip tooling

When a blended land is applied correctly, it will optimise tablet and tooling strength and performance. A correctly selected and applied blended land provides benefits to handling, loading, setting, tooling strength, the visual appearance of the tablet and ultimately, your brand.

Winter 2016 Volume 8 Issue 4


manufactured using the correct raw material and coatings, the use of multi-tips is the obvious answer to greater productivity. Conclusion We have seen that to improve tablet production efficiency, it is imperative to implement an effective tooling specification. In order to find the correct design for the product being produced, consultation with an expert tablet designer should take place in the early stages of the process. The design should not only be unique and visually appealing, but also robust and producible in a rigorous tablet manufacturing environment. Making just a few simple changes to a design can stop future problems, from picking and sticking to counterfeit issues. Working closely with a tablet tooling expert will help in addressing specific product challenges and protects against nonconforming products. By divulging information on the company and the product being produced, the tooling manufacturer can put all the pieces of the puzzle together by introducing a QbD concept, and offer the expertise and knowledge to eliminate downstream problems, which will result in a reduced time to market and improved costings.

Are your plants ready

to swiftly respond to changing markets and production needs, reliably provide top quality drugs while meeting regulatory compliance?

As this year marks I Hollandâ&#x20AC;&#x2122;s 70th Anniversary in providing the highest quality tooling and technical support service to customers, the tabletting science experts will be sharing their tooling excellence with tablet manufacturers through a new series of webinars. These will discuss tablet design and tool material selection, tool features and configuration, and tooling maintenance and lifecycle management.

We can help you to have them.

Laurence Mead has been with I Holland for 10 years. He joined as an apprentice mechanical engineer and trained in every area of the punch and die manufacturing process, before settling on tablet and tool design as his specialism. Laurence now works as part of I Hollandâ&#x20AC;&#x2122;s customer support group, delivering expert advice and quality designs to I Holland customers around the world. Email: laurence.mead@iholland.co.uk

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Powder Handling Excellence


Chapter Title Manufacturing

How New Dosage Forms Prolong the Lifecycle of Mature Products An age-old problem of the pharmaceutical industry is what to do if product sales are dropping or are anticipated to drop. How can you revitalise an ageing product, boost brand loyalty and recapture interest? One approach is to develop existing APIs into one or more alternative dosage forms. This article looks at the benefits of user-friendly dosage forms and what they offer to the pharmaceutical industry. There are a number of reasons why an ageing product or brand may need a boost. Perhaps a product will soon come off patent and generic versions are anticipated to appear on the market. Alternatively, perhaps your OTC product is facing increased competition and is losing market share. Could reformulating your API into alternative dosage forms be the way to make your product more popular? Through adding further dosage forms, you could potentially build a product range that leverages existing brand loyalty, whilst better meeting the needs of end-users. Alternatively, it could be that reformulation offers the opportunity to combine one or more APIs or enable once-daily dosing, boosting the efficacy or convenience of a product. Reformulation as a user-friendly dosage form could be the way forward… What are User-friendly Dosage Forms? User-friendly dosage forms are orally administered alternatives to conventional solid tablets and capsules. They include effervescent tablets, instant drinks, orally disintegrating granules, chewable tablets and lozenges. Whilst each form has its own distinct advantages, they share three common benefits for end-users: they are easy to swallow, convenient to take and are specially formulated to have a pleasant taste. The Trouble with Tablets Tablets and capsules have for many years been the standard method for patients to take medication. Yet solid tablets may be considered uncomfortable and even painful to swallow, depending on size, shape and surface texture. This can present a problem – even for people who do not ordinarily find 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

swallowing difficult. A recent survey conducted by HERMES PHARMA and the Spiegel Institut Mannheim found that, out of approximately 2000 people surveyed in the US and Germany, over half experienced difficulties swallowing tablets and capsule1. What’s more, these findings were not unique to a specific demographic, such as the elderly or infirm. Indeed, 70% of people under the age of 34 found swallowing solid tablets difficult – the highest of all the age groups studied. Frequently cited reasons include tablets being too large, getting stuck in the throat, or having an unpleasant taste or odour. And it is not just swallowing that people dislike about tablets. With modern consumers and patients increasingly used to having choice and convenience in their lives, there exists a clear demand for dosage forms that come in a variety of flavours and are convenient to use ‘on the go’. Amongst older users, difficulties associated with opening blister packaging are also a common complaint. The survey also discovered that, in an effort to get around the difficulties associated with swallowing their medicine, many people modified their tablets by chewing them, breaking them up before swallowing or by dissolving them in water. Such actions change the way the formulation works, altering the API release profile and impacting on bioavailability and efficacy. Perhaps most worryingly, around one in ten surveyed resorted to not taking their medication at all. Non-compliance not only presents risks to an individual’s health, but the healthcare system as a whole. In the US, for instance, non-compliance is believed to cost the healthcare system as much as $289 billion a year2. It’s clear, therefore, that the solution to this problem will undoubtedly win favour with healthcare experts and end-users alike. How do User-friendly Dosage Forms Help Combat these Issues? User-friendly dosage forms offer smart solutions to these challenges, whilst creating a convenient and enjoyable

user experience that can differentiate a product from its competitors. Chewable tablets, for instance, are a convenient alternative to conventional tablets. In order to survive, human beings learn to chew nutriment from an early age, making chewing a natural process for us. Hence most people find chewable tablets are very easy to take. As they do not need to be taken with liquids, they can be incorporated into daily routines. From a formulation perspective, they are well-suited for converting poorly soluble APIs into a user-friendly form, and various packaging options allow lightsensitive APIs to be stored reliably. Lozenges that dissolve slowly in the mouth also offer many of the benefits associated with chewable tablets, with the added advantage that they are capable of providing an extended localised effect, in addition to a systemic effect. For this reason, they are ideally suited for treating ailments such as sore throats. The patient experience can be enhanced by adding flavour and a fizzy effect, which can stimulate saliva production and ease dissolution in the mouth. Orally disintegrating granules (ODGs) are another liquid-free alternative to traditional tablets. They consist of small grains of one or more API that can be poured into the mouth directly from the stick pack (which is a small sachet) and immediately swallowed. As the dosage form is dissolved while swallowing they can offer rapid release of API and excellent bioavailability. With packaging options that include light-protection for photosensitive APIs, and both easyto-tear and child-resistant packaging, ODGs can be used for a diverse range of products. Drinkable medicines, prepared by adding effervescent tablets or instant powders (“instant drinks”) to water, offer an easy way for consumers and patients to take their medicine, adding benefits associated with increased hydration. As the API is dissolved prior to consumption, they result in excellent bioavailability and rapid absorption, ensuring reliable efficacy. Effervescent drinks form a Winter 2016 Volume 8 Issue 4


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Chapter Title Manufacturing buffered solution that increases the pH of the stomach and allows APIs to pass quickly into the small intestine, minimizing gastric irritation. Both instant drinks and effervescent tablets offer significant potential in terms of flavoring, and are designed to dissolve completely in the glass without leaving residues or foam. As there is almost no size limitation to either dosage form, they allow large amounts of API, or even a combination of APIs to be taken in a single dose. Taste A challenge and an opportunity of developing user-friendly dosage forms is that they are tasted more thoroughly than conventional tablets â&#x20AC;&#x201C; and palatability of the oral dosage form plays a considerable role in patient compliance. Flavouring and/or taste masking are often required to overcome the typical bitterness or sourness inherent with many APIs. For user-friendly dosage forms, this opens the door to a wide range of flavouring opportunities for the pharmaceutical industry. Innovative combinations of flavour and application are possible. For example, during the recent development of an orally disintegrating granule painkiller containing caffeine and acetaminophen (paracetamol), HERMES PHARMA chose a cappuccino flavouring in part for its association with caffeine. Careful consideration of the product and its therapeutic application can ensure flavours work in harmony and enhance the user experience. As taste assessments on new medicine products involve lengthy and costly clinical trials and require approval by an ethics committee, it is therefore important to have a clear strategy based on an understanding of what flavours work well with APIs in order to shorten the formulation development process. Partnering with third-party companies is one way in which pharma can tap into this expertise. It can be difficult to achieve taste masking using sweeteners and flavourings alone, so other techniques may be used in combination. For ODGs, a coating is applied that prevents API release in the mouth but yet permits release during the window period of the API. At HERMES PHARMA, one method we have found to be 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1. User-friendly dosage forms at a glance â&#x20AC;&#x201C; Overview of some of the benefits of user-friendly dosage forms Winter 2016 Volume 8 Issue 4


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Manufacturing

particularly successful for ODGs is hot melt coating. Originally developed for the food industry, hot melt coating involves spraying a molten lipid-based mixture onto a solid API particle at carefully controlled temperatures, which then solidifies to form a homogeneous coating. Not only does this method remove the need for organic solvents, but it also provides shorter processing times and lower production costs. How can Pharma Use User-friendly Dosage Forms to their Advantage? Rising R&D costs and patent protection issues pose significant challenges to the pharmaceutical industry. Reformulation of existing medicines into new dosage forms can therefore be a particularly useful approach to extending patent protection. Such product lifecycle management strategies make it more difficult for rivals to create similar products, particularly if specialist technologies for taste masking or control of API release are required. User-friendly dosage forms present not only an opportunity for pharmaceutical companies to extend product lifecycles – they can also build brand equity and increase market share. Alternative oral dosage forms can outperform tablets and capsules when it comes to user experience. In the survey mentioned above, it was clear that people who have had experience with these dosage forms, such as instant drinks and chewable tablets, scored them more favourably than conventional tablets and capsules across all criteria, including taste and ease of preparation. This indicates that they better meet consumer needs, making them more likely to be successful in the market than traditional solid forms. By extending a product range 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to meet customer preferences, either through flavour differentiation or by creating more user-friendly formulations, pharmaceutical companies can leverage existing brand equity.

can also be used to ensure products maintain their efficacy whilst in storage. Such approaches reduce demands in terms of storage conditions, ensuring products remain user-friendly.

A d d i t i o n a l l y, i n n o v a t i v e pharmaceutical companies can increase their market share and reputation by creating products that are viewed as new and exciting. Alternative dosage forms create opportunities for pharma to develop new products optimised for specialised patient groups, such as children or the elderly, and target new audiences, such as the ‘on the go’ and sports product market. Some user-friendly dosage forms, such as effervescents or instant drinks, are less restricted in size than conventional tablets, allowing two or more APIs to be combined in a single dose. This creates opportunities for pharma to develop products that offer multiple health benefits or enhanced efficacy due to coadministration. Single products such as these can remove the need for additional medicines, increasing existing brand loyalty and attracting new users.

Conclusion It is clear that while people want convenience and easy-to-swallow medicines and that these improve compliance, many are not happy with the conventional tablets on offer to them. For the pharmaceutical industry, this provides a significant opportunity to differentiate themselves in the market and to revitalise old products by reformulating into new dosage forms and building product ranges.

With customers demanding convenience, packaging provides another opportunity for pharmaceutical companies to set themselves apart from the competition. User-friendly oral medicines come in a wide range of packaging forms, from easy-to-open sachets to tubes of effervescent tablets. With effervescent tablets, for instance, patented technology such as TOPO granulation can be used to produce stable and humidity-resistant products that still dissolve rapidly when added to water. For products containing lightsensitive APIs, aluminum-coated sachets

Dr Thomas Hein is Senior Vice President Commercial and Regulatory Affairs at HERMES PHARMA. Having earned his PhD in pharmaceutical technology at the University of Regensburg in Germany, Dr Hein has made significant entrepreneurial contributions to HERMES PHARMA. Since 2001 he has been responsible for the division’s commercial operations, worldwide portfolio management and marketing.

References 1. www.swallowingtablets.com 2. Viswanathan, M. et al. (2012) ‘Interventions to improve adherence to self-administered medications for chronic diseases in the United States: A systematic review’. Annals of Internal Medicine, 157(11): 785– 795.

Winter 2016 Volume 8 Issue 4


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Manufacturing

Parenteral Preparations; Challenges in Formulations 1) Introduction Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants1. They are sterile preparations intended to be administered directly into the systemic circulation in the human or animal body. They are required, like any pharmaceutical dosage forms, to meet the pharmaceutical quality standards as described in pharmacopeias and to be safe for the intended purpose of use1, 2, 3. In addition to be sterile parenteral preparations must be pyrogen-free. Sterility can be achieved by different processes of sterilisation that should be appropriate to the formulations4, while the pyrogen-free aspect will require, if no depyrogenation process is used during the preparation of the sterile drug products, the use of pyrogenfree pharmaceutical ingredients, drug substances or API (active pharmaceutical ingredient) and excipients. They are usually supplied in singledose glass or plastic containers (PVC – less recommended nowadays, or polyolefin) or more and more in pre-filled syringes or pens to facilitate the ease of use1. This article will describe the main challenges encountered during the formulation of parenteral preparations, as well as Roquette’s solutions meeting the formulator’s needs. 2) Properties of Parenteral Preparations The parenteral preparations are intended to be administered through the human or animal body, either by direct injections (for example, bolus intravenous (IV), intramuscular (IM) or subcutaneous (SC)) or by infusion with a controlled infusion rate or by direct implantation through IM or SC. They must meet the following minimum compendia criteria1, 2, 3: • •

To be sterile and pyrogen-free To be clear or practically exempt

82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of visible particle and to be free from sub-visible particles as required by pharmacopeias EP, USP and JP No evidence of phase separation for the emulsions, or aggregates formation for aqueous dispersion such as injectable Mab (monoclonal antibody) preparations In case of suspensions, the use of appropriate particle size and any sediment should be readily dispersed upon shaking to give stable formulations and ensure the correct dose to be withdrawn and injected.

Parenteral preparations may require the use of excipients that should be biocompatible, be selected for the appropriate use and to be included at the minimum efficient concentration3. The functionality of these excipients is as follows: •

• • • •

To make the preparations isotonic with respect to blood (glucose/ dextrose, mannitol, sodium chloride…) To adjust the pH to the physiological one (mineral or organic acids or salts) To prevent the degradation of the drug substances (stabiliser…) To ensure or increase the drug substance’s solubility To provide adequate antimicrobial preservative property (only applicable to multidose preparations)

It should be stressed that excipients should not adversely affect the intended medicinal action of the drug products, nor, at the concentration used, cause toxicity or undue local irritation. 3) Challenges in Formulations The main challenge of all the different parenteral dosage forms is to achieve a good compatibility of the drug substances with the excipients (no formation of new impurities either by degradation of the drug substance or formation of new chemical entity between the drug substance and the excipients) as well as

the compatibility of the preparations with the primary container (no leachability or adsorption to container)3. With regard to solutions and emulsions, the drug substances should be soluble and remain soluble during the entire shelf-life of the drug products. When drug substances are not soluble, dissolution can be achieved by the use of, for instance, either co-solvents, or surfactants, or a soluble pro-drug, or eventually the use of solubility enhancers such as the cyclodextrins, thanks to the formation of inclusion complex. The pH is one of the critical aspects of parenteral preparations, which should have a pH close to the physiological one. However in certain cases, a compromise should be found between the pH, ensuring stability of the drug substance (such as for peptides requiring alkaline pH or proteins at pH close to the isoelectric point) and the physiological one. In all cases, large volumes preparations (LVP, i.e. more than 100 ml as defined in pharmacopeia) should not contain a pH buffer as the blood has already a buffer effect property that could enter into competition with the injected drug product. The stability of the drug substance is another critical point that a formulator can face during the development of the formulation. Unstable drug substances will lead to the formation of new impurities jeopardising the safety of use of the preparations. When the use of a stabiliser is justified (for instance the use of mannitol as free-radical scavenger or cysteine in paracetamol solution for injection), it should be included at the minimum concentration demonstrated to be efficient at release and during the entire shelf-life3. In the cases of powders for injection or infusion obtained through a freeze-drying process, the use of a bulking agent (such as mannitol) and /or a cryoprotector will be needed when the dose of drug substance(s) cannot solely ensure the formation of acceptable “cake”. Finally the process of sterilisation Winter 2016 Volume 8 Issue 4


Manufacturing should be selected according to the characteristics of the parenteral preparations (for instance, heat steam sterilisation for aqueous solutions and dry heat for non-aqueous solutions), but in any case it can be justified by the nature of the primary containers4. Figures 1 & 2 below display the decision trees for the selection of the sterilisation process for aqueous products or non-aqueous solutions including semi-solid and dry powder products. The efficiency of the selected sterilisation process should be demonstrated through validation studies, using the appropriate biological indicators, to ensure an ASL (assurance sterility level) of 10-61.

Figure 1: Decision tree for sterilisation choices for aqueous products (CPMP/ QWP/054/98).

4) Roquette’s Solutions5 A pyrogen-free range of products with high pharmaceutical standards and being biocompatible for the manufacture of parenteral preparations has been developed. LYCADEX® PF (dextrose/ glucose monohydrate pyrogen-free) is used as a source of carbohydrates in large volume and small volume preparations (LVP and SVP) and in parenteral nutrition (TPN) as well as osmotic agent for dialysis solutions. PEARLITOL® PF (mannitol pyrogen-free) is used in LVP and SVP as APIs and isotonic agent, as well as bulking agent for freeze-dried injectable powders. NEOSORB® PF (sorbitol pyrogen-free) is also used as a source of carbohydrates in LVP and SVP as well as osmotic agents in sterile irrigating fluids. KLEPTOSE® HPB & HP parenteral grade (hydroxypropyl betacyclodextrin pyrogen-free) are widely used as solubility and stability enhancers of APIs, as well as enhancers of clinical tolerance. SODIUM GLUCONATE PHARMA is usually used as a source of biological organic salts and as a pH regulator. All these pyrogen-free range of products are obtained from natural and renewable raw materials. Besides their compliance to pharmacopeias and other ICH quality requirements (for instance ICHQ3D for elemental impurities), all these pyrogen-free products, even when used as excipients, are manufactured in compliance to GMP and ICHQ7, and certified by competent authorities (ANSM, the French Competent Authority, and US FDA). 5) Conclusion Parenteral preparations are sterile and pyrogen-free preparations intended to be administered directly into the systemic circulation in the human or animal body. They should meet the pharmaceutical quality standards as described in pharmacopeias and ICH guidelines, and also ensure the clinical tolerance as well as to be safe for the intended purpose of use.

Figure 2: Decision tree for sterilisation choices for non-aqueous liquid, semisolid or dry powder products (CPMP/ QWP/054/98). 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

References 1. EP, USP and JP Pharmacopeias 2. ICH Q6, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products 3. ICH Q8, Pharmaceutical development 4. Decision trees for the selection of sterilization methods (CPMP/ QWP/054/98) 5. www.roquette.com

Roquette, thanks to its know-how and experience gained by serving, for decades, the big players in the injectable and dialysis markets, has developed a range of pyrogen-free products that meet all the required pharmaceutical standards and which are GMP/ICH Q7 certified whether they are used as APIs or excipients.

©Roquette-2016 Dr Elham Blouet, Global market manager Injectable and Dialysis, Global Business Unit Pharma & Health, ROQUETTE. Elham Blouet, Pharmacist with several years of experience in industrial pharma companies and health authorities agency. She joined Roquette in 2007 with a current position as Global Market Manager (Injectable & Dialysis) in the Global Business Unit , Pharma & Health.

Winter 2016 Volume 8 Issue 4


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Manufacturing

Strategies to Prepare for Serialisation The Serialisation Challenge As a result of increasing concerns over falsified medicines, reimbursement fraud and theft throughout the pharmaceutical supply chain, by 2019 over 55 countries will have introduced serialisation and track and trace regulations. The serialisation of licensed drug products is essentially the introduction of a 2D barcode which will, when combined with comprehensive track and trace systems, allow the industry to follow products from manufacture to the point of sale. The EU requirements for serialisation come into force in 2019, which may seem a long way off, however, the process of incorporating serialisation into a production line is complex and time-consuming, particularly if you are supplying to multiple markets with varying regulations. So, how can you work with your contract development and manufacturing organisation (CDMO) to ensure you’re ready for serialisation? Staffan Widengren, director corporate projects at Recipharm, discusses the various complexities you should consider when developing your serialisation strategy. The Geographic Complexities In a global environment such as the pharmaceutical industry, drug developers and their CDMOs can be responsible for the manufacture and distribution of licensed drug products in multiple geographic locations, which means adhering to the regulations of many different markets. No two countries have passed the exact same legislation when it comes to serialisation and track and trace systems, so it is imperative that you work with your CDMO to understand the unique requirements of each country you operate within. Although the EU Falsified Medicines Directive (FMD) and the US Drug Supply Chain Security Act (DSCSA) are not legal requirements until 2019 and 2017 respectively, there are numerous countries which already have comprehensive regulations in place. For example, in 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Turkey, the Ministry of Health introduced legislation in 2010 making serialising and tracking medicines via a 2D data matrix barcode compulsory. Prescription drugs in this country can no longer be reimbursed without a valid barcode. Many factors can vary from country to country. Although many markets require GS1 standard barcodes, there are exceptions. Companies supplying to China must serialise their products with a linear barcode, while the Brazilian market requires a 2D data matrix with human readable information, including a unique identifier, a batch number, a registration number and expiry information. And it’s not only the barcode format that varies, the origins of the serial numbers and barcodes will also differ depending on the market. The EU’s FMD requires the production of randomised serial numbers to eliminate the likelihood of predictable unique device identifiers (UDIs), whereas in China, pharmaceutical companies must request them from the government and supply the allocated serial numbers to their CDMO prior to production. In this case, it is vital that you discuss with your CDMO whether it can integrate pre-supplied serial numbers into its serialisation solution. Other factors which can vary based on geographic location include product scope. Most countries’ track and trace laws cover all prescription medicines, however there are certain countries which only require serialisation for selected drug classifications. There can also be additional requirements, for example, in South Korea, legislation demands monthly reporting on over-the-counter medication, as well all prescription drugs. Serialisation at a packaging level also differs from country to country. In Europe, a product only needs to be serialised at unit level, whereas in South Korea and India, serialisation is mandatory on primary, secondary and tertiary levels of packaging, making aggregation a vital part of the production line when serialising products for these locations. Although aggregation is not a legal

requirement in every country, many drug developers and CDMOs have recognised that it can help to speed up the product’s journey through the supply chain by allowing recipients to scan one barcode on the outer packaging, instead of scanning each individual box inside. As such, a number have decided to introduce aggregation to improve business efficiency. With this in mind, your CDMO should be able to integrate aggregation into their serialisation solution where necessary. However, aggregation can also increase the cost and complexity of serialisation, so you need to consider the pros and cons with your CDMO at an early stage. With these considerations in mind, it is easy to see how implementing serialisation can become a bigger task than originally anticipated. As such, it is critical that you work closely with your CDMO to ensure stringent pre-planning takes place and that your preparations are on schedule. By identifying all of the markets you currently operate in, or that you intend to move into in the near future, and familiarising yourself with their individual legislation, you can ensure you have a robust serialisation solution which is fit for purpose. The complex nature of serialisation makes previous experience of approaches, particularly in Asian markets, a plus when it comes to selecting a CDMO. If your CDMO has been involved in the process before, they are more likely to have a comprehensive understanding of the challenges, which will make seamless implementation more likely. The Technical Considerations There are also a number of technical requirements to take into consideration. Your CDMO should have established relationships with hardware and software providers that can comprehensively cater for your serialisation requirements now and into the future. It is important to decide how you will generate and manage the serial numbers and barcodes. Does your CDMO offer this service and if not, will you look to outsource the responsibility to an external company or develop a system to manage Winter 2016 Volume 8 Issue 4


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Manufacturing the track and trace system in-house? And, once you’ve stored the information, how will you share it with the relevant authorities? If your CDMO will be responsible for storing the information on your serialised products, then they should have systems to ensure the security of the data. Factors to consider include their data flow, management and storage and whether they have an IS architecture designed specifically to support the transfer of sensitive data between relevant parties. It’s also important to consider your packaging requirements. Is there space on your existing design to cater for the new barcodes and if not, how long will it take to redesign? Do you need to introduce tamper-evidence? And how will this work with your product? For example, there is no sense having a serialised sleeve around a blister pack if the original drug can easily be replaced with counterfeit medication. You will also need to consider the printing techniques to be used. For example, depending on where the product will be supplied and what kind of data matrix is required in that location, you may need to use a high-quality printer, such as a laser printer or thermal inkjet printer to ensure the barcode can be scanned successfully throughout the supply chain. The potential obstacles and hurdles to implementing a company-wide serialisation process are vast; however, by outlining your requirements at an early stage you will be able to address them before they have an impact on your supply chain. The Financial Considerations Serialisation is a huge task, so it’s no surprise that many pharmaceutical companies are concerned about the financial impact of the new regulations. Your CDMO should have a pricing model in place that can help to reduce or eliminate any upfront investment required to implement new processes and systems for serialisation. A standard solution that complies with multiple geographic regulations can also help to reduce complexity and therefore cost. The Time Constraints The European Stakeholder Model (ESM) suggests that four to five years is a realistic timeframe to successfully 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

implement serialisation processes. A Guide To Best Practice 3 Years To Serialisation Deadline • Customer consultations with CDMOs – your requirements for serialisation and aggregation, your locations and the relevant legislation • Financial planning – will serialisation and aggregation be a separate fee or incorporated into your supply agreement? • Create a user requirements specification (URS) for each type of machine • Select and sign a master services agreement (MSA) with vendors for equipment and software (Level 1 to Level 4) • Perform factory acceptance test (FAT) and site acceptance test (SAT) on serialisation and aggregation equipment – staff training should form part of this process • Create a deployment plan and establish a project organisation with central and local teams • Review each stock keeping unit (SKU) and determine need for artwork changes (e.g. space for printing of the barcode and tamper-evidence label/ human readable text size etc.) 2 Years To Serialisation Deadline • FAT and SAT continue • Continue to update and refine deployment plan • Customer and CDMO agreements should be signed • A CDMO should start connecting customers to the Level 4 serialisation system 1 Year To Serialisation Deadline • FAT and SAT continue • Start to serialise products and perform performance qualification (PQ) runs for customers 6 Months To Serialisation Deadline • Serialisation processes should be operational and ready to start in line with the EU 2019 deadline • Continue to serialise products and perform PQ runs 3 Months To Serialisation Deadline • Final preparations for serialisation take place and processes should be operational The Impact of Poor Preparations Failing to prepare adequately

for

serialisation could affect your supply chain in more ways than one. Of course, the biggest concern is missing the EU and US deadlines, bringing your production line to a halt. This could not only mean costly downtime, but a loss of business in key markets due to a perceived noncompliance. There is also the potential for product shortages and wastage due to errors. All of these outcomes could result in an impact on the end consumer – the patient. There’s also the risk of damaging your reputation if you struggle to implement serialisation effectively. Summary Introducing serialisation across multiple production lines is no small task, and the best strategy to ensure success is to methodically plan your preparations and identify potential problems before they arise. The key is to give yourself plenty of time and work closely with your CDMO to map out what you need from them and how they can support you throughout your serialisation journey. Underpreparing for the looming EU and US deadlines has the potential to significantly impact your supply chain, leading to production downtime and product wastage and shortages. You need to have serialisation firmly on your agenda for the coming years to ensure you remain competitive in an increasingly demanding market.

Staffan Widengren, Director Corporate Projects at Recipharm, is Programme Manager for the Recipharm global serialisation project and part of a global steering committee that is working closely with clients in Europe to ensure they plan and implement changes that comply with pending regulatory requirements for drug serialisation. Staffan has been working as Quality Director/ Qualified Person and General Manager within Recipharm since 2002, and in June 2015 assumed the role of Programme Manager for Recipharm’s global programme for serialisation. Recipharm has worked with clients in Asia on track and traceability, already providing serialised products in markets including Turkey, Korea and China. The company is investing €40m over the next three years to enhance its serialisation capabilities. Recipharm is preparing a range of educational papers aimed at training staff internally across its global network and supporting customers with the challenges of serialisation, verification and complying with new regulatory requirements. Winter 2016 Volume 8 Issue 4


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Packaging Establishing Interoperability for Product Identification and Authentication Systems In our digitised society, the coding of individual products with unique codes for authentication and tracking is becoming increasingly widespread. To enable these processes, various IT systems are already in place or steadily emerging, and related industries are booming. Correspondingly, both options and obligations for brand owners and producers continue to proliferate. What is currently missing is a strategic approach to reconcile the individual systems with their often diverse and multifaceted functionalities. To tackle this issue, a particular working group has been tasked by the ISO TC 292 on security and resilience to develop a new standard for establishing interoperability. Today, the internet has become pervasive throughout our lives. This development certainly entails many benefits, as it interlinks the whole world and enables us thus to profit from an ever greater choice of products and offers. The downside of this trend is that regulations and control increasingly get blurred. While the issues of counterfeit medicines and illicit trade in drugs have formerly been limited to emerging markets, they are meanwhile also invading the Western world – online. In the face of this threat, digital product security is of growing importance. As a prerequisite for implementing effective track and trace systems, serialisation and coding constitute a major trend. As such, coding represents a bridge between an individual product and its pertinent information, which can be updated daily and made available online. There are various reasons why this link is increasingly important. First of all, by giving each of them a unique ID, products and objects can be identified, verified, and traced piece by piece, consequently allowing the possibility of establishing or improving certainty about their genuineness. With each identification process, valuable data may be created. Finally, coding systems also provide new means for communication, in particular with end users. Various IT systems are in place to make such unique item identification work. In addition to that, different means for marking are available today at 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

comparatively low cost, such as printed QR or GS1 DataMatrix-Codes linking to the internet. Beyond that, the deployment of electronic IDs like RFID chips is reflecting the current trend for the internet of things. Needs and requirements of brand owners and producers to proactively protect their products against counterfeiting and illicit trade, as well as respective legal obligations, are steadily expediting the coding of individual products, and will continue to do so in the future. As the complexity in this area will certainly not decrease, it is therefore crucial that individual solutions are capable of interoperating with different other systems, be they private or publicly governed.

One code may serve several purposes. The MILLEPEDIA® app extracts codified information from the serial embedded into this GS1 DataMatrix Code.) Interoperability is the key word – pharmaceutical companies thereby may • • • •

Implement the systems of their choice Retain their data privacy Draw on the developing progress and features of UID systems Implement one solution for global application

A prerequisite for interoperability is the recognition and vetting of a UID (unique identification) service. There may be different options for achieving this, such as combining the URL with the UID-code e.g.: h t t p s : / / v . c o d i k e t t . com/?GKZSGSV7C3M13ZBR using a prefix or postfix with the UID code [e.g.: (97)123(21) GKZSGSV7C3M13ZBR , or integrating the UID into the GS1 DataMatrix format [e.g.: (01)9120049640010(17)151231

(10)20231(21) GKZSGSV7C3M13ZBR]. The latter will be of major importance for the pharmaceutical industry, as today the GS1 DataMatrix is the preferred format to depict the UID on a pharmaceutical product. Against this backdrop, standards may be understood as a common language to help establish communication and exchange between different systems. While the previous research of the working group has highlighted the fact that virtually all stakeholders in product security have a strong interest in enabling interoperability among the various existing and emerging systems for digital product identification, effective interoperability is today still in an early stage. Without a common standard, it will certainly evolve only slowly. However, the challenge is to not narrow down new ways and technologies by creating the one and only IT architecture for interoperability, but rather to describe the underlying agreements and secure arrangements. Through the establishment of trusted third parties, enhanced interoperability will involve a higher level of security. This will help to increase the dismantling of fake product identification services. Dr Marietta UlrichHorn holds a PhD in philosophy from the University of Vienna, and has graduated as Master of Business Administration from the Vienna University for Economics and Business and the Carlson School of Management, Minnesota. She is cofounder and CEO of SECURIKETT®, a company providing both complex security labels for physical protection of products and the CODIKETT® digital solution. MILLEPEDIA®, providing for interoperability, is the latest IT product coming out of the pipeline. At the ISO she is particularly assigned to the TC 292 on security and resilience, where she is project leader of ISO WD 16678 part 2, set up to shape the interoperability of track and trace systems. Email:marietta.ulrich-horn@securikett. com Winter 2016 Volume 8 Issue 4


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Packaging Pharmaceutical Artwork in Safe Hands Historically, artwork for the packaging and labelling of pharmaceutical products has been the final part of a long process to get a product ready for market. All too often, it was treated as a rushed afterthought. Changes in the marketplace have ensured this approach has had to improve due to the increasingly complex nature of many products, many requiring a higher level of control. The key driver has been the introduction of new regulations with a greater focus on the risks to patient safety and prescribing errors. However, despite a clear recognition of the importance of artwork, the World Health Organization estimates that around 50% of product recalls are still attributed to artwork errors and mislabelling. The industry’s ‘speed to market’ requirements have put more pressure on artwork teams across all aspects of the supply chain to deliver ‘right first time’ and ‘on-time’ for critical product launches. This has inevitably meant the risk from errors is much higher. A Changing Supply Landscape It was previously commonplace for unaudited ‘local’ suppliers to produce market-specific artwork, with no asset control of artwork files and even less control if the process was global. The associated risks for error and for noncompliance were high in this scenario. A typical ‘big pharma’ organisation, even today, would have multiple vendors, some compliant and some not. The market is seeing a significant shift to control artwork lifecycle changes and new product launches via a truly complaint artwork partner. Why Do Things Still Go Wrong? The pressure to get products quickly into the marketplace can impact on the quality of the artwork brief. This inevitably results in more artwork cycles due to errors and omissions and further extends lead-times and escalates costs. The reasons are all too often obvious… poor input equals poor output. The issues can be numerous but the majority of cases largely fall into just a few categories: typographical errors on supplied copy, technical drawings are not correct or 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

mistakes on standard elements such as barcodes, expiry dates and even the use of incorrect pack profiles. Amazingly, poor or ambiguous annotations on artwork are frequent and often result in questions and further delays. One of the common misunderstandings within the artwork supply chain resonates from a lack of understanding of the print process. Customer/vendor agreements often mean the printer cannot change the files and need to seek client permission, which leads to further delays. One of the common errors is a lack of understanding regarding the technical attributes required to print and the incorporation of the correct file build and pre-press requirements from the artwork vendor. Many printers will modify artwork files, for colour correction, file build and layering, adding bleed and correcting image resolution, to suit pre-press requirements, and it is unlikely that this is reported. Many printers will interpret the quality agreement to simply not modify content and deem artwork changes as part of the pre-press process. In the worst case scenario, the print vendor will change the files, adding inherent risk as the file will not be checked again for approval, so the likelihood of the product going to market with an error is very high. These issues largely stem from a lack of understanding of what’s required. In order to develop the right artwork briefs, it’s essential to build a partnership that is set up for success with both parties working to get the best output. Leading artwork providers will be dealing with many different customers, with 1000s of artwork requests, all with differing needs and requirements. All customers are different and an agency will need to be sure it is delivering exactly what’s required. Getting it Right… It is important to clearly define the brief prior to any outsourcing, and that both parties agree source documents and rooting. The introduction of a brief acceptance step to approve the content of the brief prior to commencement of the order is simple, yet effective. This flight-check should take place before any artwork is created. This prevents

any delays in lead times and ensures any ambiguous information or missing detail is clarified. The use of the source data (the brief) as the lead document will also ensure compliance at every stage. Policing the process throughout and reviewing every stage will reduce the artwork cycles as well as other benefits such as improved consistency and supplier relationships. Artwork creation is often complex to meet new product launch campaigns, multiple markets and formats and exacting legal requirements. Effective brand management prevents damaging hard-earned reputations, product recall…or even putting patients’ lives at risk. When products are introduced into new markets, often termed ‘localisation’, dedicated brand knowledge and technical expertise will ensure a brand is globally consistent and protected. For the artwork agency, without a clear brief, extended lead times also unfairly impact on service ratings such as OTIF and KPI measures. These are all too often incorrectly measured from the submission of the incomplete brief, heaping frustrations and undue pressure on the teams involved. Selecting the Right Artwork Partner Pharmaceutical artwork is a specialist market and any supplier’s workflow should be compliant with PS9000 / ISO9001, audited and dedicated to providing an artwork service. A supplier’s artwork systems should fit in with your own ways of working. There should also be a clear understanding that the approved artwork file should not require any further manipulation by the print vendor so there are no touch-points in the process. The use of an automated workflow will significantly reduce the potential for any errors. In short, it is essential to be set up for success; good input equals good output. Gill Wright, Design & Development Director, Cirrus Based at Leicester, A graphic design graduate Gill has responsibility for artwork management services and structural design. Gill regularly presents to the world’s leading healthcare companies and has an in-depth knowledge of the changing packaging requirements of this highly regulated sector.

Winter 2016 Volume 8 Issue 4


EXCELLENCE IN CLINICAL TRIAL LABELING. Contact us and find out the latest updates concerning patient centricity, e. g. an index for a direct access to country pages.

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Packaging On the Right Track How the Packaging of Investigational Medicinal Products Influences Patient Compliance The quality of trial results depends largely on patient compliance. Patient compliance is affected by predictable and unpredictable factors. One of these predictable factors is packaging. ISPE Survey In a survey conducted by ISPE (International Society for Pharmaceutical Engineering) in 2013, subjects of clinical trials were questioned about their experiences when using IMPs (investigational medicinal products). 77% found their medication easy to use. Since the survey was almost exclusively based on responses by US patients, ISPE decided to expand it to the UK, the European Union and Asia. Study findings were published a few months ago. Consistently with the US survey, patients' opinions about the overall ease of use were positive both in the EU (85%) and in China (88%). Besides having the opportunity to ask clinical site staff how to use the medicine, packaging, such as package inserts or labels, was found to be helpful. Patients' increasing preference for having IMPs delivered directly to their homes (75% in the EU; 78% in China; 78% in the US in 2013) clearly shows how significant secondary packaging is. For site personnel, briefing patients on the phone means an effort as opposed to dosing instructions that can be read on the packaging. In addition, all the relevant information is directly and durably attached to the medication and subjects do not necessarily require any technical equipment such as mobile phones or computers to access it. Comprehensive Support To reproduce all the necessary information in a reader-friendly font size (ISPE recommends 6 to 7 points while the European Commission even considers 9 pt font size as adequate) booklet labels are often used for the purpose of multilingual IMP identification. This being said, only 23% of the European patients surveyed actually saw the booklet label, 45% opened it, 54% were able to view their language, and font size was deemed adequate by 71%. 41% of the Chinese subjects saw the booklet label, 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

more than 80% opened it, and 75% were able to find their way through it easily. "The need for comprehensive information is growing. Booklet labels take care of this but ease of use would still appear to need improving", Anthony Morrow, Business Development Manager Northern Europe at Faubel explains. This is why Anthony Morrow is in favour of adding clearly visible opening arrows as well as partly rough or rubberized surfaces to booklet labels. Such visual and tactile features draw attention. Moreover, these special surfaces give users a good grip especially with IMP bottles. Besides blisters, the second most common form of primary packaging used are bottles, according to the ISPE study. "The specific design of the easy-peel opening section helps when separating the layers of the label. That's what makes it very easy to open", says Morrow. Once the label is open, there is a thumb index to facilitate navigation through the booklet. Patients can get to their national

language in just one move. Pictograms or QR codes linked to instructions for use videos are to be regarded as text supplements. Within the clinical trial supply chain, booklet labels do not only allow efficient distribution and safe identification worldwide, but they can also be combined with any measure designed to maximise ease of use in a single product. Patient centricity Thanks to these technological advancements, patient's needs are taking centre stage for Anthony Morrow. "We are on the right track, because patient compliance is continuously improving and the quality of clinical trial results is secured."

Anthony Morrow Business Development Manager, Northern Europe at Faubel & Co. Nachfolger GmbH Winter 2016 Volume 8 Issue 4


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Packaging Ampoules – A Traditional Product with a Future A Zero-defect Production Strategy for a Demanding Market Ampoules were developed at around the same time as injections were invented as a form of medical treatment. This type of primary packaging allows the pharmaceutical drug to come into contact with only the inert and gas/vapourimpermeable material of glass. Ampoules are also completely tamperproof. Although ampoules have been competing with vials for quite a while now, and increasingly also with pre-filled syringes, they are still the global number one choice of primary packaging for injectables. Although demand has declined slightly for ampoules in developed nations, this negative trend is offset by clear growth in demand in the cost-sensitive growth markets of emerging nations.

Type of amopules: straight-stem, funneltype and sealed ampoules Wertheim – Center of Excellence for Ampoules Increasingly stringent quality requirements for ampoules, reflecting developments across the entire medical technology product market, have resulted in quality being a central factor of competition. Innovative and highly sensitive active ingredients, faster filling machine speeds and an increasingly strict regulatory framework mean that ampoules today tend to be developed for specific applications – and precise compliance with specifications is a must. 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The international centre of excellence for ampoules at Gerresheimer AG in Wertheim meets these requirements with a consistent “product by process” strategy. The plant has over 60 years of experience in ampoule manufacturing and makes regular investments in plant technology and process development so that it can supply highest-quality products to its customers. Around 700 million ampoules are manufactured in Wertheim every year. The plant was established in 1957 as Fritz GmbH. The former familyowned company has been part of the Gerresheimer Group since 1989 and was renamed as Gerresheimer Wertheim GmbH in 2007. The plant’s growth and global development has been supported by the establishment of a comprehensive quality management system. In 1994 it gained ISO 9001 certification, followed by FDA approval for supplies to the USA in 1997. In 2006 it received ISO 15378 certification for compliance with GMP principles in the production of primary packaging materials, and in 2015 it obtained DIN 50001 (EnMS) certification. The Wertheim plant also plays a key role in the Gerresheimer organisation’s international standardisation and process optimisation efforts. Gerresheimer manufactures more than two billion ampoules worldwide every year at five production plants. Ampoules – Designs and Opening Systems Most ampoules are manufactured in accordance with the DIN ISO EN 91871/2 standard in straight-stem, funneltype, and sealed designs. Straight-stem and funnel-type ampoules are supplied open, so the customer has to wash and sterilise them before filling. Sealed ampoules, as the name indicates, are supplied sealed. They are sterile on the inside as a result of the high temperatures in the manufacturing process, which means the customer can open them with a sharp flame, fill them and then reseal them. All the ampoule types can have various opening systems that make it easier to break off their tips. Each opening system is associated with specific ergonomic and particulate contamination characteristics. Some ampoules have score rings applied between the body and

neck. Others have a colour break ring (CBR) burned on that weakens the glass structure at the designated break point. The most popular opening system today is the OPC (one point cut) system, which involves an approximately 2mm long section of the surface between body and neck being carefully scored. A coloured dot on the bulbous part of the ampoule indicates where to apply pressure. When pressure is applied to the dot, the top of the ampoule snaps off. It is very easy to control the break on OPC ampoules, and glass particle contamination is very low. Coloured coding rings or customerspecific printing can also be applied.

Opening systems: Score ring, colour break ring, one point cut Customised packaging solutions are available for pharmaceutical drugs with challenging requirements. Dimensions and glass quality can be tailored to the specific requirements of the drug itself and to the filling process. For example, the hydrolytic resistance of the glass can be increased by controlling the temperatures when the ampoules are being formed. An additional ammonium sulfate treatment inhibits alkali ion leaching, which is important when the ampoules are being used as a primary packaging for sensitive pharmaceutical formulations. A silicone coating is often applied to the inside surface of the ampoule to make it hydrophobic. This prevents high viscosity products from sticking to the surface and allows the entire contents to be emptied out. Manufacturing Process Ampoules are manufactured from thinwalled type I borosilicate glass. Highquality, precise-dimensioned glass tubing with a low incidence of cosmetic defects is essential to the manufacturing of defect-free ampoules. In the first stage Winter 2016 Volume 8 Issue 4


Packaging

of ampoule production, the carousels are filled with glass tubes. In the shaping process, the ampoule is then heated up by gas torches and drawn to shape it from the base to the tip. Then it is separated from the glass tube and the base of the next ampoule is shaped. The next stage of the production process is the application of code rings, break rings, or the OPC dot and the scoring of the ampoule surface between the body and neck. Sealed-type ampoules have their head shaped by a special tool. The ampoules are then annealed in a furnace at 600° Celsius and their colour codes, break rings, or surface printing are burned on. Total Quality Control Medical technology products quite rightly have to meet exacting quality requirements. An uncompromising quality management system ensures that defective products never reach the pharmaceutical companies or, ultimately, the consumers. One of the most important prerequisites for high product quality is highly automated production and inspection processes. The elimination of human intervention in production processes, other than in exceptional circumstances, also eliminates a key source of defects. Laboratory tests involving the destruction of the products are regularly performed on random samples taken from the production lines. They serve to check ampoule break force in the opening process, for instance. The hydrolytic resistance of the ampoule’s inside surface is also tested in the lab. An optimised process control enables it to manufacture ampoules with hydrolytic resistance values that are between 30 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and 50% lower than the values stipulated in the ISO standard. The necessary measurements are taken in the laboratory using the traditional titration method, and also by way of flame atomic absorption spectrometry (FAAS). FAAS is the method that customers generally request today.

Hydrolytic resistance laboratory

testing

in

the

The majority of quality inspections, including dimensional quality inspections, are one hundred per cent inline. Every ampoule that is manufactured is inspected in detail by automated camera systems before the packaging process takes place. They are rotated in front of the camera to ensure that nonconformities and defects can be detected on the ampoules’ entire surface area. Advanced image processing technology not only ensures uncompromising quality, it also improves the production process efficiency by substantially reducing the number of false rejects. The inspections cover up to 28 different parameters, including the compliance to specification of all exterior dimensions, the correct positioning of the code rings, the OPC dot, and the break ring. To exclude the risk of the wrong products being filled into the ampoules, an increasing number of customers are insisting on having their own inspection equipment on the production lines to check code ring colour combinations. Customer-specific

camera systems are used to ensure that colour saturation and intensity are in line with customer requirements. The length of the score on OPC ampoules is also checked, because this information can be used to calculate its depth and whether the break force conforms to specification. If the ampoules are printed, the texts have to be checked for legibility, absence of errors, and compliance with customer specifications. Special inline optical character recognition systems are used for this purpose. Automatic cosmetic defect recognition equipment can be found on every single production line. The Japanese market is particularly stringent about defect-free ampoules without any colour splashes or scratches. Also, customer quality inspection systems often reject products with cosmetic defects. For example, if particles or colour splashes are created when the ampoule is melted, they can be interpreted as burn marks by customer inspection systems. So the early identification of cosmetic defects in the ampoule production process makes the customer filling process more stable with fewer rejects. Product by Process Although one hundred per cent product quality inspections provide assurance, they aren’t the only important element of the Gerresheimer quality strategy. It aims to control the production process with such a degree of precision that defective products are never even manufactured. This is achieved by shifting the focus from quality control to product and process development. Proof of process capability and therefore supply reliability is becoming Winter 2016 Volume 8 Issue 4


www.plastibell.com

AN EXPERT IN INJECTION MOULDING Plastibell (headquarters in Izernore, France), is an expert when it comes to injection molding, producing a broad range of complex plastic products for different industries. The company is internationally active with eight industrial sites in four countries. Healthcare Business Unit of plastibell serves customers in the medical, diagnostic, pharmaceutical, otc, animal health and hygiene areas, medical devices,primary and secondary packaging or consumer products, among others, in medium to large series.

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Packaging

Cosmetic defects on the ampoule body and printing errors all the individual break forces. The control chart, Gaussian distribution and capability analysis with Cp and Cpk statistical measurements allow prompt responses to negative trends. The objective is a process that is so stable that hardly any adjustments are necessary. In this kind of process, the products donâ&#x20AC;&#x2122;t just look identical on the outside, they are consistently identical in every respect. Camera inspection and high-precision recalibration of the ampoule shaping process an increasingly important supplier selection criterion for pharmaceutical customers, in addition to product quality. A defined product quality can only be delivered reliably and sustainably if both the product itself and the effects of material characteristics and process parameters on the productâ&#x20AC;&#x2122;s quality are understood. Design of experiment (DoE) is an indispensable tool for systematic statistics-based analysis. Obviously, it is impossible to gain any useful information about the production process if the key process parameters are established by trial and error. In DoE, several factors are investigated concurrently and their effects are established in a multivariate analysis. The DoE results can be used to develop a strategy for production process control. The goal is a process window in which the process capability index (Cpk) is higher than 1.33. To reduce variability to the minimum, the ampoule production machine has been optimised and controls are beyond the manufacturerâ&#x20AC;&#x2122;s standard. In this context, product quality monitoring not only involves rejecting defective products, it also performs the

second and equally important function of providing statistical data for process control that can be used for the realtime optimisation of the production process. Ampoules are manufactured on a tool-free basis, so this approach works very well because the final product is completely transparent and therefore optically measurable. Even before the pre-heated glass tube is shaped into ampoules, cameras check its dimensions and precisely adjust the gas torches. Any minute dimensional non-conformities in the glass tube, even if they are just one hundredth of a millimetre in size, are corrected on the basis of the evaluated image data so that they do not affect the dimensional accuracy of the ampoule. This facilitates homogenous ampoule processing and fast, interruption-free customer filling processes. The scoring of the OPC ampoules is acoustically monitored to ensure that any defects are discovered then and there, rather than later on in the dimensional inspection. The regular laboratory testing of production line samples also provides input for statistical process control. The system records and statistically evaluates

High precision calibration of the ampoule shaping process A stable production process remains almost entirely within the defined process limits. 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Supporting the Pharmaceutical Industry The ampoule manufacturer has to supply the pharmaceutical industry with products that optimally satisfy their requirements for primary packaging for a specific pharmaceutical drug or a specific application. The supplier and the customer select or modify products, sometimes even developing brand new ones, that meet all customer specifications regarding shape, dimensional precision, and primary packaging properties. The product also has to be suitable for reliable filling on fast lines. The quality assurance and process control know-how operating in Wertheim has proven to be so valuable that many customers are now taking advantage of it to optimise their own production processes. In particular, they are reducing rejects by systematically avoiding burnt material when filling sensitive pharmaceutical drug batches, meaning that the ampoule manufacturer not only delivers customerspecific, reliably manufactured products to the customer, but also supports customer filling plant optimisation.

Lothar Haaf General Manager of Gerresheimer Wertheim GmbH Senior Product Manager for Ampoules in Europe Tubular Glass Converting Dr Volker Rekowski Quality Director Europe & India Tubular Glass Converting Chairman of the Gerresheimer Quality Council Winter 2016 Volume 8 Issue 4


Chapter Title

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 101


Exhibition - Reviews and Previews Pharmapack Europe: 2017 Marks 20 Years of the Pharma Packaging and Drug Delivery Event! Meet with leading suppliers and discover the latest innovations in the industry Pharmapack Europe (#PharmapackEU), organised by UBM EMEA, is a two-day exhibition and conference dedicated to pharmaceutical packaging, drug delivery and affiliated industries. Next year’s event is on 1 & 2 February 2017 at Paris Expo Porte de Versailles (Hall 4), Paris. 2017 marks the event’s 20 years, and over its lifetime it has grown in size, profile and popularity from a bi-annual event to a major annual show that attracts 5100+ visitors and over 380 exhibitors from more than 70 countries around the world. Attendees and delegates range from CEOs and CMCs to pharmacists and business executives, working in every area from R&D and drug development to purchasing, engineering, marketing, logistics and business development. Pharmapack concentrates around innovation, networking and education Innovation Innovation is at the very heart of Pharmapack. An Innovation Gallery showcases selected industry innovations from exhibitors. This platform offers a unique opportunity to discover all the new packaging and drug delivery solutions launched on the market in the last 12 months. All participating products automatically enter the Pharmapack Awards for Exhibitor Innovations. The Pharmapack Awards have been a central aspect of Pharmapack since its inception in 1997, and bestow recognition on the most exciting innovations and breakthrough developments. In 2017, the Pharmapack Awards are focused on two categories: ‘Exhibitor Innovations’ and ‘Health Products’. The latter category recognises health products (human/ veterinary medicine and medical devices) that have been launched to market since March 2016 and before January 2017. This award acknowledges the successful collaboration of pharmaceutical companies and their packaging suppliers. Both categories recognise veterinary, pharma, biopharma companies and packaging suppliers

who have developed products that have significantly contributed to the proper use of medication, increased patient/ user safety and compliance, or represent a significant step towards sustainable packaging. Vincent Tempelaere, CEO, Eveon – 2016 Exhibitors Innovations Winner for Intuity® Lyo – says : “Pharmapack is the ideal place, whether you are a visitor or an exhibitor. As a visitor you have a snapshot of the innovations on the market. As an exhibitor you have a lot of visitors coming to your stand. We are certain that the Pharmapack award we received this year helped generate a high number of visitors on our booth, curious to know more about our innovation. The Award is a strong acknowledgement of our innovative solution, and it is very important to us.” The winners of both categories will be revealed live during the awards ceremony, hosted on the first day of the show, during the exhibitor and visitor cocktail party. The Pharmapack Start-up Hub is an all-new addition for 2017, designed to let innovative young pharma firms benefit from valuable networking and learning opportunities at a price that suits their budget. Exhibitors in the Pharmapack Start-up Hub will be highlighted as the most innovative firms at the show, giving them a unique platform to showcase their ideas, meet potential customers, partners and investors and forge new relationships that will help them develop for years to come. Are you wondering what the future holds? This is the place where you can discuss with the companies that are set to shape the future! Education Pharmapack is a unique place to sharpen up technical and industry knowledge. The extensive content programme comprises: A two-day conference focused on industry trends (note: simultaneous translation French/English will be available): • •

102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Innovation & compliance Patient adherence

Impact of patient-centricity and biologics on packaging and device development

Hear from industry experts from Biocorp, DCA Design International, Novartis, Pfizer and West Pharmaceutical. A one-day symposium concentrated on the hot topic of “Serialisation, Track & Trace”, featuring key speakers from Atlantic Zeiser, Montesino, Optel Vision and Sanofi. Learning-Lab are free-to-attend 30-minute presentations where exhibitors share their latest news, products and research on a dedicated area on the show floor. Networking Pharmapack allows for fruitful exchanges and meetings. The show floor has dedicated networking areas and an international meetings lounge where meetings arranged pre-show through the dedicated matchmaking programme can be held in a quiet and business-oriented environment. 20 years calls for a celebration: the exhibitor & visitor cocktail party will be the opportunity to celebrate 20 years of success at Pharmapack and 20 years of innovation and product launches, and to recognise today’s innovative companies. Pharmapack is a unique opportunity for companies to boost their networks and kick-start their growth – there’s never a shortage of new faces to meet. Anne Schumacher, Event Director Pharmapack, commented: “2017 is another extremely exciting year for Pharmapack as we celebrate 20 years with our biggest show to date. Pharmapack Europe is an integral platform to develop new ideas and explore patient changing solutions of tomorrow. As the industry globalises, we are seeing new innovators presented from the US and the rest of the world, alongside our core European audience.” For more information visit http://bit.ly/2bsKfNq and get registered for Pharmapack Europe 2017!

Winter 2016 Volume 8 Issue 4


EXHIBITION & CONFERENCE 1 & 2 FEBRUARY 2017 PARIS EXPO, PORTE DE VERSAILLES, HALL 4

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Chapter Title

SMi proudly present their 13th annual conference on…

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PLUS TWO INTERACTIVE HALF-DAY PRE-CONFERENCE WORKSHOPS Tuesday 17th January 2017, Copthorne Tara Hotel London Kensington, London WORKSHOP A | 08.30 – 12.30 The future of parenteral drug delivery - moving from drug delivery devices to therapy management ecosystems Workshop leader: Vaishali Kamat, Head of Digital Health, Cambridge Consultants WORKSHOP B | 13.30 – 18.15 Regulatory challenges at the interface of medicines and medical devices Workshop leader: Janine Jamieson, Regulatory Consultant, ex-MHRA assessor

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@SMIPHARM #PFSSMI INTERNATIONAL PHARMACEUTICAL INDUSTRY 105


Preview RDD Europe 2017 Scientific Conference equipment designers, component and service providers, and consultants. Exhibitors display innovative technologies and services throughout the conference in our signature tabletop format. In order to participate in the Technology Exhibition, your company must be a conference sponsor. Further information about RDD Europe 2017, including the detailed program and registration details, is available now at http://www.rddonline.com/ rddeurope2017 About RDD Online RDD Online manages the organization of Respiratory Drug Delivery meetings in the US, and partners with Aptar Pharma to run RDD meetings in Europe and Asia.

Register now to attend the RDD Europe 2017 Scientific Conference to be held April 25-28, 2017, in Antibes, France. The Respiratory Drug Delivery (RDD®) Europe 2017 scientific conference will welcome pulmonary and nasal drug delivery experts from around the world to Antibes, France, April 25-28, 2017. The joint organizers of this prestigious event, RDD Online® and Aptar Pharma announce the opening of registration at www.rddonline.com/rddeurope2017. Bringing the Respiratory World Together Respiratory Drug Delivery Europe is a major conference bringing together experts from around the world to exchange emerging scientific knowledge and providing a dynamic forum for business networking. RDD Europe attracts high level academic, industrial and regulatory scientists and clinicians. It is a must attend conference for companies involved in the research, development, testing or marketing of medicines, devices and services associated with pulmonary or

nasal products. In addition to expert speakers, RDD Europe 2017 features: Scientific Poster Session Scientific Posters highlighting recent nasal and pulmonary pharmaceutical research. Five of the best posters will be showcased during ‘Posters on the Podium,’ a fast-paced interactive session in the main auditorium. All accepted graduate student poster abstracts are automatically eligible for the VCU RDD Peter R. Byron Graduate Student Award. The Poster abstract submission deadline is January 6, 2017. Abstracts may be submitted via the conference website. Workshop Session Participants can self-select and attend interactive technical Workshops highlighting innovative technologies, products and services. Technology Exhibition The Technology Exhibition offers extensive networking opportunities with a range of specialists including device and

106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Other RDD Online services available at www.rddonline.com include the provision of scientific and technical publications, aerosol testing equipment including dose collection tubes and mixing inlets, webbased training, textbook publishing, service directories and recruiting services of interest to companies active in pulmonary and nasal drug delivery. For more information, please visit www.rddonline.com About Aptar Pharma Aptar Pharma is a part of the AptarGroup family of companies, along with Aptar Beauty + Home and Aptar Food + Beverage. AptarGroup, Inc. is a leading global supplier of a broad range of innovative dispensing solutions for the beauty, personal care, home care, prescription drug, consumer health care, injectables, food, and beverage markets. AptarGroup is headquartered in Crystal Lake, Illinois, with manufacturing facilities in North America, Europe, Asia and South America. To learn more, visit www.aptar.com/pharma.

Winter 2016 Volume 8 Issue 4


ATTEND • PRESENT • EXHIBIT • SPONSOR

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Winter 2016 Volume 8 Issue 4


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